JOURNAL OF THE INDIAN MEDICAL ASSOCIATION

D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (1) JOURNAL OF THE INDIAN MEDICAL ASSOCIATION ISSN 0019-5847 Volume 106 • Number 09 • Kolkata • September 2008 D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (2) Originals and Papers Variations of Adolescent Blood Pressure by Multifactorial Analysis in an Urban Slum of Kolkata INDRANIL SAHA*, BOBBY PAUL**, APARAJITA DASGUPTA***, PRAMIT GHOSH**** To find out the factors responsible for variations of adolescent blood pressure, a community-based cross-sectional study was undertaken among 1081 adolescents, aged 10-19 years, selected by simple random sampling in an urban slum of Kolkata, Chetla in 2003-04. Age, educational status, additional ghee / butter intake with diet, family history of hypertension, weight, height and body mass index were found to be associated with blood pressure in unifactorial analysis, hence these variables were considered for multifactorial analysis. All these independent variables were correlated with both systolic and diastolic blood pressure except additional ghee/butter intake with food. In stepwise multiple regression analysis, age, education, family history of hypertension, weight, height and body mass index contributed 64.6% of the total variation of systolic blood pressure, where weight alone contributed to 62.6% while 35.4% of variations remained unexplained. In case of diastolic blood pressure, 56.8% of the total variations were due to age, education, family history of hypertension, weight, height and body mass index, out of which weight alone contributed 56% while remaining 43.2% of total variations remained unexplained. Since singlemost important predictor of blood pressure was weight, regular aerobic physical activity, dietary modification, behavioral changes and health education are recommended for weight reduction and prevention of obesity. [J Indian Med Assoc 2008; 106: 571-4 & 578] Key words : Adolescent blood pressure, independent variables, correlation, stepwise multiple regression, weight, height, body mass index, age, education. B lood pressure distribution in a population has been a subject of considerable discussion. Varying results have been obtained under different conditions. Various personal, social and environmental factors like age, sex, social status, diet have been cited as possible correlates. Identification of determinants of blood pressure levels and the mechanisms by which they act early in life may provide the foundations for the primary prevention of hypertension in the general population. Some attempts have been made in India to explain influence of some of these factors, particularly in adult population but data relating to adolescent population seem to be scarce. The present study was undertaken to find out the factors responsible for *MD (Commun Med), Assistant Professor of Community Medicine, RG Kar Medical College and Hospital, Kolkata 700004 **MD (Commun Med), DCH, Assistant Professor of Community Medicine, Institute of Postgraduate Medical Education and Research, Kolkata 700020 ***MD (Commun Med), Professor of Community Medicine, All India Institute of Hygiene and Public Health, Kolkata 700073 ****MD (Commun Med), Demonstrator of Community Medicine, Calcutta Medical College and Hospital, Kolkata 700073 Accepted January 16, 2008 variations of adolescent blood pressure in Chetla, an urban slum of Kolkata. MATERIAL AND METHOD A community-based cross-sectional study was carried out in Chetla, the urban field practice area of All India Institute of Hygiene and Public Health, Kolkata, India, from June 2003 to May 2004. Out of the four sectors of Chetla, one sector was selected by simple random sampling method to carry out the study, keeping the logistics of fieldwork in view. Total adolescent population of that sector was calculated to be 1428. Considering 2.93% prevalence of hypertension among adolescents in urban area1, 95% confidence limit and allowable error 15%, the sample size was calculated to be 1140, using the formula : N.pqZ2 n= N . L2 + pq Z2 Ten per cent allowance was also taken for non-response and thus final sample size was 1254. But finally 1081 subjects could be interviewed, with a response rate of 94.8%. Initially a list of families having adolescents was prepared from family folders of the selected sector available 571 D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (3) 572 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 at urban health centre, Chetla and a sampling frame of intake (Add-g/b) with diet, F-Htn, Wt, Ht, BMI. Hence only adolescent population was constructed out of it. From the these factors were considered for multifactorial analysis frame, the required number of sample study subjects was of blood pressure. Correlation matrix was obtained between selected by simple random sampling technique. 7 independent variables described above and 2 dependent The different variables were taken as follows: Age, sex, variables ie, SBP and/or DBP. All the independent variables education (Edu), occupation, socio-economic status, had significant correlation with both systolic as well as religion, marital status, salt intake, frequencies of egg, fish, diastolic blood pressure, except F-Htn. But no correlation meat, and butter/ghee intake, addiction – tobacco and was found between SBP and DBP and Add-g/b intake with alcohol, family history of hypertension (F-Htn), physical food. Significant correlations were also observed between activity, oral contraceptive pill (OCP) use, body weight, many of the independent variables themselves. This height, body mass index (BMI) and blood pressure. suggests, that interaction between the independent variables Data recording was done by house-to-house visits. themselves may have an influence in the prediction of SBP Informed verbal consent and co-operation was sought from and DBP of an individual (Table 2). each study subject before initiation of the interview In stepwise multiple regression analysis, age, Edu, Faccording to the predesigned, pretested schedule. Study Htn, Wt, Ht and BMI contributed 64.6% of the total variation subjects were interviewed and measurements of blood of SBP while 35.4% of variations remained unexplained. pressure, weight (Wt) and height Table 2 — The 9 Variable Correlation Matrix (Ht) were taken using standard Variable Age Edu Add-g/b F-Htn Wt Ht BMI SBP DBP 2-5 techniques and tools . Age 1.000 0.315** 0.079** -0.017 0.794** 0.705** 0.689** 0.587** 0.610** Three measurements of blood Edu 1.000 0.062* 0.045 0.522** 0.401* 0.449** 0.408** 0.329** pressure were taken at the Add-g/b 1.000 0.052 0.069* 0.057 0.063* 0.042 0.056 interval of five minutes each and F-Htn 1.000 0.102** 0.064* 0.102** 0.074* 0.078* 1.000 0.841** 0.891** 0.791** 0.748** mean of these three readings W t 1.000 0.527** 0.600** 0.613** were taken as systolic blood H t BMI 1.000 0.753** 0.689** pressure (SBP) and diastolic SBP 1.000 0.811** blood pressure (DBP) DBP 1.000 respectively and same blood **Correlation is significant at the 0.01 level (2-tailed) pressure instrument was used *Correlation is significant at the 0.05 level (2-tailed) throughout the study and was checked periodically for any loss of mercury height or any Out of the total variation, significant statistical contribution leak in the tubing or the control valves3. The measurements was noted in case of Wt (62.6%), Ht (1.5%) and age (0.3%), were taken at home ie, the natural setting of living and are while remaining 0.2% of the variation were due to combined likely to be more close to the actual3. Individuals who were effects of Edu, F-Htn and BMI, which was statistically not available due to hospitalisation, migration or any other insignificant. In stepwise multiple regression analysis, the causes were excluded from the study. A maximum of three equation was as follows: visits were given for each individual to minimise non- YSBP = 67.128 + 1.134 X1 (Model 1) response. YSBP = 102.852 + 1.407 X1 – 0.313 X2 (Model 2) Correlation coefficient, stepwise multiple regression YSBP = 102.509 + 1.498 X1 – 0.297 X2 – 0.362 X3 (Model 3) analysis was performed Where X1, X2 and X3 are the respective using SPSS software Table 1 — Score Assigned to Different Categorical scores for Wt, Ht and age of an individual and Variables for Multifactorial Analysis (version 10.0). To perform YS is the predicted SBP of that individual in Variables Scores assigned this analysis discrete original unit (mm Hg) (Table 3). 0 1 2 variables were assigned Most ie, 56.8%of the total variation of DBP Educational Illiterate Up to >Standard X scores 6 and continuous status (Edu) was due to age, Edu, F-Htn, Wt, Ht and BMI Standard X variables were taken as Additional among the study subjects and remaining 43.2% No Yes absolute value ie, the ghee/butter of variations remained unexplained. Out of the actual observed value intake (Add-g/b) total variation, statistical significant Family history No Yes (Table 1). contribution was noticed in case of Wt (56%), of hypertension Edu (0.5%), and BMI (0.2%), while remaining (F-Htn) OBSERVATIONS 0.1% were due to age, F-Htn and Ht combined After unifactorial analysis of blood pressure with all signifying an insignificant role in the variation of DBP. the variables, following were observed to have association The equation came out as follows: with it viz, age, educational status, additional ghee/butter YDBP = 47.961 + 0.676 X1 (Model 1) D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (4) 574 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 Table 3 — Regression Co-efficients and Their Significance in Multiple Regressions for SBP among the Study Subjects (n=1081) Model summary/coefficients Variables Model summary : R R square F Significance 0.804 a 0.646 326.172 0.000 0.791 b 0.626 1806.425 0.000 0.641 962.451 0.000 0.801 c 0.803 d 0.644 649.586 0.000 a Predictors : Constant, age, Edu, F-Htn, Wt, Ht, BMI b Predictors : Constant, Wt c Predictors : Constant, Wt, Ht d Predictors : Constant, Wt, Ht, age Coefficients : Unstandardised Stan- Standardised t Signicoefficients dard coefficients ficance Model B error beta 1 (Constant) 67.128 Wt 1.134 2 (Constant) 102.852 Wt 1.407 Ht -0.313 3 (Constant) 102.509 Wt 1.498 Ht -0.297 Age -0.362 *p<0.001 **p<0.05 1.017 0.027 5.422 0.048 0.047 5.403 0.057 0.047 0.119 0.791 0.982 -0.226 1.045 -0.215 -0.091 65.978 42.502 18.969 29.079 -6.703 18.974 26.425 -6.353 -3.034 0.000* 0.000* 0.000* 0.000* 0.000* 0.000* 0.000* 0.000* 0.002** YDBP = 47.989 + 0.716 X1 – 1.409 X2 (Model 2) YDBP = 45.781 + 0.633 X1 – 1.371 X2 + 0.307 X3 (Model 3) Where X1, X2 and X3 are the respective scores for Wt, Edu and BMI of an individual and YD is the predicted DBP of that individual in original unit (mm Hg) (Table 4). Table 4 — Regression Coefficients and Their Significance in Multiple Regressions for DBP among the Study Subjects (n=1081) Model summary/coefficients Variables Model summary : R R square F Significance 0.754 a 0.568 235.127 0.000 0.560 1372.926 0.000 0.748b 0.752 c 0.565 700.791 0.000 0.753d 0.567 470.815 0.000 a Predictors : Constant, Age, Edu, F-Htn, Wt, Ht, BMI b Predictors : Constant, Wt c Predictors : Constant, Wt, Edu d Predictors : Constant, Wt, Edu, BMI Coefficients : Unstandardised Stan- Standardised t SigniCoefficients dard coefficients ficance Model B error beta 1 (Constant) : 47.961 Wt 0.676 2 (Constant) : 47.989 Wt 0.716 Edu -1.409 3 (Constant) : 45.781 Wt 0.633 Edu -1.371 BMI 0.307 *p<0.001 **p<0.05 0.695 0.018 0.691 0.021 0.388 1.182 0.042 0.388 0.134 0.748 0.793 -0.085 0.701 -0.083 0.102 68.996 37.053 69.421 33.672 -3.629 38.721 15.126 -3.533 2.299 0.000* 0.000* 0.000* 0.000* 0.000* 0.000* 0.000* 0.000* 0.022** DISCUSSION Age, Edu, Wt, Ht and BMI had significant correlation with both systolic as well as DBP, except Add g/b intake with food, where no such correlation was found and the correlation was found to be much less for F-Htn. The interaction between independent variables as observed in the correlation matrix may have an influence in the ultimate prediction of SBP and DBP of an individual. Similar results have been reported by Gupta and Ahmad3 and Rosenthal et al5. Initially multiple linear regression analysis (enter method) was attempted, but the model was a poor fit for this set of data, because of the interaction between the independent variables themselves (Table 2), which can be only explained by the “best linear unbiased estimator” (BLUE) property. Then stepwise regression was done to predict the SBP and DBP. Literature review seems to be scarce in this relation with adolescent population. This observation merits further exploration with adequate sample size. Indrayan et al7 in their study in Allahabad among 1559 years age group reported 21.6% and 15.3% of variation of SBP and DBP respectively were due to age, sex, build, social class and diet. The smaller explained component of SBP and DBP in Allahabad study as compared to present study (21.6% versus 64.6% for SBP) and (15.3% versus 56.8% for DBP) probably reflects the facts that the Allahabad study did not measure Wt and Ht directly and instead categorised the subjects on visual inspection of type of body habitus and thus ignored a most important determinant of blood pressure level, namely body weight. Chadha et al8 in their study among 5-14 years children in Delhi, showed that age and Ht were the principle determinants of SBP and Ht was the principle determinant of DBP and once Ht entered the regression model, sex no longer remained a significant determinant of SBP or DBP. Rosenthal et al5 found 21% of variation of SBP were due to BMI, arm length and arm circumference and 15% of variation of DBP was due to Wt. These values as reported in different studies are not strictly comparable with each other because of the different methodology (cut-off points and age groups). Since the major contribution of the variations of blood pressure (SBP and DBP) was Wt, hence maintenance of normal Wt is very much essential for prevention of high blood pressure in future. Regular aerobic physical activity, avoidance of junk food, behavioural changes and health Edu are recommended for prevention of overweight and obesity. REFERENCES 1 Laroia D, Sharma M, Diwedi V, Belapurkar KM, Mathur PS — Profile of blood pressure in normal school children. Indian (Continued on page 578) D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (5) Originals and Papers Acute Pancreatitis in Goa — A Hospitalbased Study S G BARRETO*, J RODRIGUES** A prospective analysis of the epidemiology and outcome of patients admitted with acute pancreatitis to a tertiary health care centre in Goa was carried out during the time period of 1st June, 2003 to 31st January, 2005. The patients studied were those who were admitted to the Goa Medical College with a diagnosis of acute pancreatitis based on a serum amylase of greater than 180 Somogyii units with appropriate clinical and radiographic evidence.The selection criteria were fulfilled by 282 patients. Acute pancreatitis accounted for 2.29% of all admissions and 4.9% of all deaths in the department of surgery. The disease was seen to affect males more commonly (96.1%), alcohol, being the predominant (92.2%) aetiological factor.The median age for occurrence of the disease was 40 years. Severe acute pancreatitis was encountered in 32.9% cases with a mortality rate of 12.05%. Mortality was higher in patients older than 50 years. Complications included pseudocysts (n=34), abscess (n=2), necrosis (n=6), ascites (n=13), acute respiratory distress syndrome (n=13), acute renal failure (n=14), shock (n=14), coagulopathy (n=1) and pleural effusion (n=26). The widespread availability and use of locally made cheaper varieties of alcohol in our geographical location explains the trend towards alcoholic pancreatitis and younger age groups being affected by the disease. [J Indian Med Assoc 2008; 106: 575-8] Key words : Acute pancreatitis, Goa, epidemiology. A cute pancreatitis is a protean disease capable of wide clinical variation, ranging from mild, self-limiting discomfort to apocalyptic prostration even resulting in death within days of onset. The incidence of acute pancreatitis is increasing1,2 and is associated with a high mortality especially in its severe form. The present study highlights the significant contribution of this disease to admissions and deaths in a hospital setting. However, acute pancreatitis continues to remain a disease that needs to be evaluated in a population-based study in India. Department of Surgery, Goa Medical College, Goa 403202 *MBBS, Junior Resident **MS, DNB, FICS, Associate Professor Accepted August 11, 2008 MATERIAL AND METHOD During the 11/2 years period between 1st June, 2003 and 31st January, 2005, patients admitted to the Goa Medical College and Hospital (tertiary health care centre) with a diagnosis of acute pancreatitis were included in the study. The diagnosis of acute pancreatitis was based on appropriate clinical and radiographic evidence accompanied by a serum amylase concentration greater than 180 Somogyii units (by the Somogyii method). At admission, each patient underwent a detailed history taking into the type and frequency of alcohol (if any), or history of gallstones, trauma to the abdomen, cardiac surgery, any drug intake, passage of worms in stools, etc. 575 D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (6) 576 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 A history was also obtained about the patient’s present complaints as well as a trigger event. Patients or their relatives were asked about their preadmission health status, with an enquiry into the previous similar episodes. All patients were subjected to a clinical assessment. Pancreatitis was classified as severe if the patient : (1) Died. (2) Developed complications – (a) Local – As per the Atlanta classification viz, pancreatic necrosis, acute fluid collections, pancreatic pseudocysts, pancreatic abscess, and pancreatic fistula. (b) Systemic – Cardiovascular, gastro-intestinal, renal, respiratory and neurological. (3) Underwent emergency surgery or therapeutic procedure including peritoneal dialysis, intercostal tube insertion or tapping of pleural effusion, intensive care. Patients undergoing elective surgery for gallstones were not included in the severe category. All other episodes of acute pancreatitis were classified as mild. Gallstone-related disease was based on the identification of gallstones by radiology/ultrasonography/ CT scan. Alcohol-related disease was assumed if there was a clear history of alcohol consumption before the attack of pancreatitis in the absence of other identifiable causes. Demonstration of a linear echogenic structure in the pancreatic duct associated with a prior history of passage of worms in stool was considered proof of ascariasis as the cause of pancreatitis. CT demonstration of a transected/oedematous pancreas following trauma to the abdomen associated with raised amylase and clinical features were considered proof of trauma as the aetiologic agent. In the absence of any cause by clinical, biochemical or radiological evidence of associated cause, the pancreatitis was labelled idiopathic. In the study, patients referred to this institute from the neighbouring states were excluded. OBSERVATIONS AND DISCUSSION The study comprised 282 patients who fulfilled the selection criteria. There were 271 males (96.1%) and 11 females (3.9%) patients. The patients were divided into the following age groups, <44years, 45-54years, 55-64years, 65-74years, and >74years. The incidence in each of these age groups was 68%, 22%, 7.4%, 2.1% and 0.35% respectively. The median age for occurrence of the disease was 40 years. Alcoholic pancreatitis accounted for 92.6% cases while biliary disease was implicated in 6% of cases. Isolated pancreatic duct ascariasis was found to be the aetiology in one patient. One case each of traumatic and idiopathic pancreatitis was seen. While analysing geographical break up a constant distribution of cases over the various ‘talukas’ of Goa was noted. Severe diseae was noted in 32.9% patients. The complications encountered in these patients were: Pseudocysts (n=34; 12.1%), abscess (n=2; 0.7%), necrosis (n=6; 2.1%), ascites (n=13; 4.6%), ARDS (n=13; 4.6%), acute renal failure (n=14; 5%), shock (n=14; 5%), coagulopathy (n=1; 0.4%) and pleural effusion (n=26; 9.2%). The complications can be well compared with those of other studies (Table 1)3,4. The incidence of HIV infection in the patients of this series with acute pancreatitis was 3.5%. The mortality rate was 12.05% in all age groups. However, the age specific mortality rates showed an increasing trend with advancing age as : <44years (9.3%), 45-54years (12.9%), 55-64 years (23.8%) and >65years (33.3%). IT is found that alcohol was the leading cause for acute pancreatitis. The easy availability of alcohol, especially the locally prepared variety, which is sold at a very low cost could be the reason for this. Although alcohol is widely consumed all over the world, it does not seem to play such a major aetiological role in acute pancreatitis as much as it does in the present study. Further studies could thus be conducted to determine the ingredient in these locally prepared spirits, which cause such a high incidence of acute pancreatitis. The male sex was involved in 96.1% cases. The reason for this is probably the fact that alcohol is a major cause for acute pancreatitis in this geographical location and the use of alcohol is not so common amongst women. It is interesting to note that in the studies 5,6 highlighting the aetiology of the disease in North India and Europe, gallstones play the most significant role (Table 2). Table 1 — Complication of Acute Pancreatitis and Its Comparison with Other Studies Complication Necrosis with/without haemorrhage/phlegmon Pseudocyst Abscess Pseudoaneurysm Pancreatic ascites ARDS/pneumonia Renal failure Coagulopathy Pleural effusion Shock Others Fan et al3 Larvin and McMahon 4 5.2% 2.7% 1.03% Present study 2.1% 12.1% 0.7% 4.6% 4.6% 5% 0.4% 9.2% 5% - 6.8% 1.7% 3.4% 1.1% 3.4% 4.5% 2.2% 2.2% 6.25% 4.5% Table 2 — Comparison of Aetiology of Acute Pancreatitis with Other Studies5,6 New York Gallstones Alcohol Idiopathic Miscellaneous 32% 20% 18% 29% Sweden 38.4% 38.1% 23.2% 6.6% New Delhi 49% 23.6% 16.5% 10% Goa (present study) 6.75% 92.2% 0.35% 0.7% D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (7) 578 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 Ascariasis is reported as Table 3 — Comparison of Median an important aetiologic Age of Patients with Other Studies Study Median age (years) factor in Kashmir. 65 Fan et al3 The median age of Blamey et al7 52.3±18.6 patients diagnosed with Larvin and McMahon4 6 2 acute pancreatitis Vessentini et al8 55 according to other Neoptolemos et al9 52 58 studies3,4,7-11 is shown in Talamini et al10 Funnell et al11 31.2 Table 3. Present study 40 The median age of patients in this study was comparable to the study conducted by Funnell et al11 but much lower than other studies. Interestingly the main aetiological factor in both the studies was alcohol. HIV associated pancreatitis in this series was 3.5% whereas in Goanese population it is 0.5%. This is most probably due to the direct virus infection of the pancreas or due to associated alcohol intake, as these patients were neither on antiretroviral treatment nor were they suffering from clinical evidence of opportunistic infection or AIDS related neoplasms. While all these patients had severe acute pancreatitis, the mortality was not seen to be increased. In the studies by Blamey et al 7 and Larvin and McMahon 4 , severe Table 4 — Comparison of Mortality disease was seen in Rates for Acute Pancreatitis with Other Studies 15.8% and 20% Mortality rate respectively. We report a Study 6% higher incidence of Fan et al3 7 10.6% severe disease (32.9%) Blamey et al 4 probably because ours is Larvin and McMahon 7.6% 15% Thomson et al1 a tertiary care institute, Neoptolemos et al9 3.7% 11% which is a referral centre, Funnell et al11 Present study 12.05% as well. (Continued from page 574) The mortality rate were in this study is also comparable to those of most other studies (Table 4)1,3,4,7,9,11 although a higher mortality can be expected at a referral centre. REFERENCES 1 Thomson SR, Hendry WS, McFarlane GA, Davidson AI — Epidemiology and outcome of acute pancreatitis. Br J Surg 1987; 74: 398-401. 2 Wilson C, Imrie CW — Changing patterns of incidence and mortality from acute pancreatitis in Scotland, 1961-1985. Br J Surg 1990; 77: 731-4. 3 Fan ST, Lai EC, Mok FP, Lo CM, Zheng SS, Wong J — Prediction of the severity of acute pancreatitis. Am J Surg 1993; 166: 262-8. 4 Larvin M. McMahon MJ — APACHE-II score for assessment and monitoring of acute pancreatitis. Lancet 1989; ii: 201-5. 5 Toouli J, Brooke-Smith M, Bassi C, Carr-Locke D, Telford J, Freeny P, et al — Guidelines for the management of acute pancreatitis: Working Party Report. J Gastroenterol Hepatol 2002; 17: S15–S39. 6 Khuroo MS, Zargar SA, Yattoo GN, Koul P, Khan BA, Dar MY, et al — Ascaris-induced acute pancreatitis. Br J Surg 1992; 79: 1335-8. 7 Blamey SL, Imrie CW, O’Neill J, Gilmour WH, Carter DC — Prognostic factors in acute pancreatitis. Gut 1984; 25: 13406. 8 Vesentini S, Bassi C, Talamini G, Cavallini G, Campedelli A, Pederzoli P — Prospective comparison of C-reactive protein level, Ranson score and contrast-enhanced computed tomography in the prediction of septic complications of acute pancreatitis. Br J Surg 1993; 80: 755-7. 9 Neoptolemos JP, Kemppainen EA, Mayer JM, Fitzpatrick JM, Raraty MG, Slavin J, et al — Early prediction of severity in acute pancreatitis by urinary trypsinogene activation peptide: a multicentre study. Lancet 2000; 355: 1955-60. 10 Talamini G, Uomo G, Pezzilli R, Rabitti PG, Billi P, Bassi C, et al — Serum creatinine and chest radiographs in the early assessment of acute pancreatitis. Am J Surg 1999; 177: 714. 11 Funnell IC, Bornman PC, Weakley SP, Terblanche J, Marks IN — Obesity: an important prognostic factor in acute pancreatitis. Br J Surg 1993; 80: 484-6. Pediatr 1989; 26: 531-6. 2 WHO — Hypertension control: report of a WHO Expert Committee. WHO Tech Rep Ser 1996; 862: 1-83. 3 Gupta AK, Ahmad AJ — Normal blood pressures and the evaluation of sustained blood pressure elevation in childhood. Indian Pediatr 1990; 27: 33-42. 4 Anand NK, Tandon L — Prevalence of hypertension in school going children. Indian Pediatr 1996; 33: 377-81. 5 Rosenthal J, Labarthe DR, Selwyn BJ, Soberon G — The Blood Pressure Study in Mexican Children (BPSMC): I. Distribution and correlates of blood pressure in adolescent Mexican girls. Int J of Epidemiol 1992; 21: 40-7. 6 Friedman GD — Primer of Epidemiology. 4th ed. New York: Mc Graw Hill, 1994; 224-47. 7 Indrayan A, Kumar A, Srivastava RN — Multifactorial analysis of blood pressure level in Allahabad urban community. Indian J Public Health 1974; 18: 3-7. 8 Chadha SL, Vasan RS, Sharma PS, Shekhawat S, Tandon R, Gopinath N — Age-and height-specific reference limits of blood pressure for Indian children. Natl Med J India 1999; 12: 150-6. The appearance of advertisement in JIMA publication is not a guarantee or endorsement of the product or the claims made for the product by the manufacturer. — Hony Editor Are you getting JIMA regularly ? Are all your branch members getting JIMA regularly ? If not, please contact us with current postal address and name of the branch. — Hony Secretary D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (8) Practitioners' Series Prevalence of Microvascular Complications in Metabolic Syndrome in Comparison to Type 2 Diabetes Mellitus ANISH AHAMED*, GHANSHYAM PALAMANER SUBASH SHANTHA*, GAURAV AGARWAL*, N SENTHIL**, NEETA PAUNIKAR**, M K SUDHAKAR*** To identify the prevalence of microvascular complications in patients with metabolic syndrome and compare them with patients with only diabetes mellitus, a retrospective study was carried out at a tertiary health care centre in South India with 150 patients, in two groups of 75 with almost identical age distributions. The test group (n=75) fulfilled the NCEP AT III guidelines for metabolic syndrome. The control group (n=75) had only diabetes mellitus and no other components of metabolic syndrome.They were assessed for the microvascular complications of diabetes mellitus, namely retinopathy (by direct ophthalmoscopy and zeiss f450 plus fundus camera), nephropathy (using overnight spot albumin/ creatinine ratio) and neuropathy (using clinical features, abnormal results on Achilles tendon reflex and sensory perception by 10 g Semmes Weinstein monofilament). In the test group, 33.3% were found to have retinopathy, while in control group 13.3% had retinopathy; 38.7% in the test group and 22.7 % in the control group had nephropathy; 50.7% in the test group and 26.7% in control group had neuropathy. On comparison the test group had statistically significant (retinopathy p<0.05, nephropathy p<0.001and neuropathy p<0.05) increase in the prevalence of microvascular complications as compared to the control group. Patients with metabolic syndrome have more prevalence of microvascular complications as compared to patients with only diabetes mellitus. [J Indian Med Assoc 2008; 106: 583-8] Key words : Microvascular complication, metabolic syndrome, diabetes mellitus. R isk factors for type 2 diabetes mellitus and cardiovascular disease are usually present together– a condition known today as ‘metabolic syndrome’. Insulin resistance seems to be the underlying mechanism linking the different components of the syndrome together1. Historically, Department of General Medicine, Sri Ramachandra Medical College, Chennai 600116 *MBBS, MD Postgraduate Student **MD, Assistant Professor ***MD, Professor clustering together of hypertension, central obesity, dyslipidaemia, with and without hyperglycaemia is recognised for many decades and has been prospectively demonstrated in the Framingham study2, and the Scandinavian Study3. Later, Reaven, in 1988, immortalised these features in his Banting memorial lecture — “The Role of Insulin Resistance in Human Disease”, in which he referred to it as ‘syndrome X’. After being known as insulin resistance syndrome for a few years, it was renamed metabolic syndrome in 1999 by the WHO, as 583 D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (9) 584 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 they were not convinced that insulin resistance accounted for all its features. Insulin resistance has been shown to have a strong association with central obesity, the tendency for which is quite significant among Asian Indians, so much so that India has the dubious distinction of being the diabetes capital of the world. Unfortunately, there are not enough studies thus far, that have brought to light the effect of metabolic syndrome on the Indian population. In our endeavour, we aim to find the clinical profile and prevalence of microvascular complications in metabolic syndrome, and whether it has a bearing on microvascular complications in diabetics. By studying a population representative of the people of the subcontinent, we hope to make a valuable addition to the limited data available on the people of this region with regard to this syndrome thereby drawing attention to this nemesis that threatens to reach epidemic proportions soon. The Study : An observational, cross-sectional study was carried out among 150 patients enrolled in the free diabetic and hypertensive clinic at a tertiary health care centre in Chennai (South India) between October, 2004 and August, 2005. All the patients were diabetics for less than 5 years. They were divided into two groups of 75 patients each. The study patients (n=75) qualified the criteria for metabolic syndrome (NCEP III criteria)4,5. The control patients (n=75) had type 2 diabetes mellitus and no other features of metabolic syndrome. Waist circumference was measured at the level of mid-point between lowest costal margin and iliac crest by using the inch tape and the measurement was expressed in cm. Early morning fasting blood sample (minimum 8hours fasting) was obtained and analysed for fasting blood sugar (FBS) and fasting lipid profile (FLP). HbA1c was measured in all patients. Overnight spot urine sample was taken for measuring urine albumin / creatinine ratio (ACR) using DCA 2000, Bayer Diagnostics Europe, Dublin, Ireland with a coefficient of variation of 2.8%6,7. The average of 3 blood pressure readings taken in the right arm in supine position was taken as the final value8. In the test group, 2 or more components in the presence of IFG or type 2 diabetes were considered metabolic syndrome. Retinopathy was assessed using direct ophthalmoscopy and fundus colour photographs (zeiss f450 plus fundus camera) after complete pupillary dilatation. The diabetic retinopathy disease severity scale was used as per Wilkinson et al9. For assessing nephropathy, ACR>30mg/g was taken as abnormal. Distal sensory neuropathy (DSN) was assessed by clinical features and abnormal results on Achilles tendon reflex and sensory perception by 10 g Semmes Weinstein monofilament. The monofilament was applied perpendicularly to skin surface. The approach, skin contact and departure time of the monofilament is approximately 1.5 seconds, with sufficient force for the filament to bend. The patient was asked to say ‘yes’ when the filament was felt. The monofilament was not applied to ulcer sites, callous scar or necrotic tissue. Patients with serum creatinine >1.2 mg/dl, on oral contraceptive pills or any secondary causes of dyslipidaemia eg, nephrotic syndrome, having neuropathy due to causes other than diabetes eg, HIV, chronic illness, alcoholics, those having congestive cardiac failure, active infection, or on statins, angiotensin receptor blocker and angiotensin converting enzyme inhibitors were excluded from the study. Student ‘t’ test and Chi-square analysis were applied as applicable. Statistical analyses were performed using SPSS windows version 10.0 software (SPSS Inc., Chicago, Illinois). P-value <0.05 was considered significant for all the analyses. Analysis and Comments : There were 40 males and 35 females in both metabolic syndrome as well as type 2 diabetes mellitus groups. Fig 1 shows agewise distribution of cases. More patients in the age group 46-60 years were suffering for the metabolic syndrome/diabetes mellitus (p<0.001). Fig 1 — Distribution of Age in Both Groups Mean waist circumference of males in the test group was 94.9cm and mean among females of the test group was 94.6cm. In the control group the mean waist circumference was 86.43cm in males and 85.54cm in females. Statistically significant difference in waist circumference was present in between 2 groups (p<0.001). There were no statistically significant difference between HbA1c and duration of diabetes between the test and the control group. In fact, the test group females had a value much higher than the NCEP III cut off of 88cm. According to Kumar et al10, the waist circumference in metabolic syndrome group was 97.2 cm compared to 85.6 cm in type 2 DM group almost matching the present observation and a similar D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (10) 586 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 study by Costa et al11 using WHO criteria for metabolic syndrome which was BMI and waist hip ratio. Waist circumference is an independent risk factor for insulin resistance11, and it replaces BMI and waist hip ratio as a predictor of the same. As there was no statistically significant difference in HbA1c levels and duration of diabetes between the test and the control groups, the difference in prevalence of microvascular changes between these two groups cannot be attributed to the difference in glycaemic control, thereby adding more validity to the present study. In the test group 33.3% had retinopathy, of which 28% had mild non-proliferature diabetic retinopathy (NPDR), 4% had moderate NPDR and 1.3% had severe NPDR (Fig 2). In control group 13.3% had retinopathy of which, 9.3% had mild NPDR, 4% had moderate NPDR and 0% had severe NPDR. In order to avoid observation bias we used direct ophthalmoscopy followed by fundus colour photographs. None of them in both groups had PDR. Retinopathy was more prevalent in patients with metabolic syndrome and increased linearity according to number of features of the same, as found by multiple logistic regression analysis in one study11 who used WHO criteria to diagnose metabolic syndrome. They had a retinopathy prevalence of 44% in metabolic syndrome to 20% in type 2 DM. A study by Isomaa et al12 observed that a high HbA1c was related to retinopathy. Though our study didn’t use multiple logistic regression analysis for retinopathy, patients with metabolic syndrome had a significant increase (p<0.05) in the prevalence of retinopathy as compared to diabetic patients. Lower prevalence rate of diabetic retinopathy is seen among the study patients as compared to studies done on western population .The probable explanation for this discrepancy could be that in this study the duration of diabetes was much less as compared to the other western studies10. Nephropathy had a prevalence of 38.7% in the test group as compared to 22.7 % in the control group which had a high statistical significance (p<0.001). This observation matched those with of Costa et al11, where prevalence rate of nephropathy in both groups were 38% (metabolic syndrome group) versus 28% (type 2 diabetes mellitus group). According to Isomaa et al12 the patients with metabolic syndrome had a higher prevalence of microor macroalbuminuria (23% versus 7%; p=0.003). Spangler and Konen 13 study adds that the addition of one component of deadly quartet eg, hypertension, hyperlipidaemia and abdominal obesity to pure diabetes doubled or tripled the odds of an elevated urinary albumin excretion. In this study the prevalence of DSN in test group was 50.70% against 26.70% in control group on addition of monofilament test and absent Table 1 — Distal Sensory Neuropathy in Both Groups ankle reflex Distal sensory Metabolic Type 2 DM (Table 1).This neuropathy syndrome had a statistical 49.30% 73.30% s i g n i f i c a n c e Nil Monofilament test 48.00% 26.70% (p<0.05). Costa Ankle reflex absent 2.70% 0% et al10 observed Total 50.70% 26.70% DSN of 44% in p<0.05 metabolic syndrome compared to 24% in type 2 diabetes mellitus group and that peripheral neuropathy increased progressively with the clustering of metabolic syndrome features. This study proves the hypothesis that there is a significant increase in the prevalence of microvascular complications in patients with metabolic syndrome as compared with patients to diabetes alone. The limitations of this study were that this was a hospital based study with fewer patients which could have overlooked the high prevalence rate of microvascular complications in metabolic syndrome patients. The high prevalence of distal sensory neuropathy may be due to bare foot walking which has not been taken into account. In the last few years there has been a lot of research and publications on microalbuminuria. Micro-albuminuria is not only considered as an indicator of early renal dysfunction but also as a marker of subclinical atherosclerosis, low grade systemic inflammation, systemic endothelial dysfunction and increased cardiovascular risk14-16. Hence all patients with microalbuminuria with metabolic syndrome should Fig 2 — Retinopathy Changes in Both Groups Fig 3 — Nephropathy (Proteinuria mg/g creatinine) in Both Groups D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (11) 588 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 13 Spangler JG, Konen JC — Hypertension, hyperlipidemia and abdominal obesity and the development of microalbuminuria in patients with non-insulin dependent diabetes mellitus: J Am Board Fam Pract 1996; 9: 1-6. 14 Tsioufis C, Dimitriadis K, Antoniadis D, Stefanadis C, Kallikazorus I — Interrelationship of microalbuminuria with the other surrogates of atherosclerotic cardiovascular disease in hypertensive subjects. Am J Hypertens 2004; 17: 470-6. 15 Stehouwer CD,Nauta JJ, Zeldenrust GC, Hackeng WH, Donker AJ, den Ottolander GJ — Urinary albumin excretion, cardiovascular disease, endothelial dysfunction in noninsulin dependent diabetes mellitus. Lancet 1992; 340: 319-23. 16 Hans I, Michael HO, Kristian W, Knut BJ, Lars HL, Carl Erik M, et al — Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: Losartan Intervention for Endpoint Reduction in Hypertension Study. Hypertension 2005; 45: 198-202. undergo rigorous diet and exercise schedule to decrease their comorbidities and consequently decrease their cardiovascular risk. REFERENCES 1 Resnick HE, Jones K, Ruotolo G, Jain AK, Henderson J, Lu W, et al — Insulin resistance, the metabolic syndrome, and risk of incident cardiovascular disease in nondiabetic American Indians: the Strong Heart Study. Diabetes Care 2003; 26: 861-7. 2 Ho KK, Anderson KM, Kannel WB, Grossman W, Levy D — Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation 1993; 88: 10715. 3 Pedersen TR, Wilhelmsen L, Faergeman O — Follow-up study of patients randomized in the Scandinavian Simvastatin Survival Study (4S) of cholesterol lowering. Am J Cardiol 2000; 86: 257-62. 4 Hans W — Use of waist circumference to predict insulin resistance. BMJ 2005; 330: 1363-4. 5 Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) — Expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001; 285: 248697. 6 Poulsen PL, Mogensen C — Clinical evaluation of a test for immediate and quantitative determination of urinary albumin to creatinine ratio. Diabetes Care1998; 21: 97-8. 7 Hoy W, McDonald SP — Albuminuria: marker or target in indigenous populations. Kidney Int 2004; 92: S25-S31. 8 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA,Izzo JL, et al — The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-7). JAMA 2003; 289: 2560-71. 9 Wilkinson CP, Fiederick CF, Klein RE, Kevis TR, John R, Sten VJ — Diabetic retinopathy disease grading. Ophthalmology 2003; 110: 1677-82. 10 Kumar R, Adhikari P, Dutta P, Mathew JC — Clinical study on metabolic syndrome. J Assoc Physicians India 2003; 51: 225-9. 11 Costa A, Canani LH, Lisboa HRK, Stress GJ — Aggregation of features of the metabolic syndrome is associated with increased prevalence of chronic complication in type 2 diabetes. G Diabet Med 2004; 21: 252-5. 12 Isomaa B, Henricsson M, Almgren P — The metabolic syndrome influences the risk of chronic complications in patients with type 2 diabetes. Diabetologia 2001; 44: 114851. D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (12) Practitioners' Series A Study of Comparison of Efficacy and Safety of Talc and Povidone Iodine for Pleurodesis of Malignant Pleural Effusions SIBES KUMAR DAS*, SAMIRENDRA KUMAR SAHA**, ANIRBAN DAS***, ARUP KUMAR HALDER****, SOURINDRA NATH BANERJEE*****, MUKUL CHAKRABORTY****** Pleurodesis is considered as the best palliative therapy for the treatment of symptomatic malignant pleural effusion. Several chemical agents are used for this purpose with variable efficacy and safety. The present study is to compare the effectiveness and safety of talc and povidone iodine as chemical agents for pleurodesis in patients of malignant pleural effusion. Fifty-two patients with malignant pleural effusion admitted in the department of chest of Calcutta National Medical College , Kolkata were selected for the study. Pleurodesis with povidone iodine and talc in slurry was done in 28 and 24 patients respectively. Efficacy and safety of these agents were assessed during a follow-up period of six months. Among the 52 patients , 42 were males and 10 females. Age ranged from 40 to 64 years with mean age of 56.4 years. In 41 patients effusion was secondary to bronchogemic carcinoma, 8 had effusion secondary to breast carcinoma, 1 had effusion due to non-Hodgkin’s lymphoma, while primary malignancy was unknown in 2 patients. Among the 24 patients treated with talc pleurodesis, 20 had bronchogenic carcinoma, 3 had breast carcinoma and 1 had unknown primary malignancy. Out of the 28 patients treated with povidone iodine pleurodesis, bronchogenic carcinoma was present in 21 patients, breast carcinoma in 5 patients, non-Hodgkin’s lymphoma and unknown primary malignancy was present in 1 patient each. Pleurodesis with talc showed complete success in 19 patients, partial success in 3 patients and failure in 2 patients. Pleurodesis with povidone iodine showed complete response in 24 patients, partial response in 1 patient and failure in 3 patients. Chest pain occurred in 4 patients of talc pleurodesis and 5 patients of povidone iodine pleurodesis, 3 patients of each group had fever. There was no death in the peripleurodesis period. During the 6 months follow-up, 12 patients of talc pleurodesis and 18 patients of povidone iodine pleurodesis died. Talc is slurry and povidone iodine is equally effective and safe pleurodesing agent for symptomatic malignant pleural effusion. However povidone iodine can be preferred option because of easy availability and low cost. [J Indian Med Assoc 2008; 106: 589-92] Key words : Maligant pleural effusion, pleumodesis, povidone iodine, talc. hemical pleurodesis should be considered in patients with malignant pleural effusion who are not candidates for systemic chemotherapy, and who do not have chylothorax1. A large number of chemical agents are useful for this purpose. Recent guidelines2,3 for the management Department of Respiratory Medicine, Calcutta National Medical College and Hospital, Kolkata 700014 *DTCD, MD (TB & Respir Dis), Assistant Professor; At present: Associate Professor **MD (TB & Respir Dis), Professor ***MBBS, MD (TB & Respir Dis) Postgraduate Trainee ****MBBS, DCH, MD (TB & Respir Dis) Postgraduate Trainee; At present: Senior Resident *****DTCD, Senior Resident ******DTCD, MD (TB & Respir Dis), RMO cum Clinical Tutor 589 C of malignant pleural effusions have described talc as the best sclerosant due to maximal rate of success. Povidone iodine, a good local antiseptic has also been used successfully as a chemical agent for pleurodesis in several studies4-6. The purpose of the study was to compare the efficacy and the safety between povidone iodine and talc as chemical agents for pleurodesis in malignant pleural effusions. The Study : A total of 52 patients of malignant pleural effusion admitted in the chest department of Calcutta National Medical College, Kolkata between January 2005 and D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (13) 590 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 January 2007 were selected for the study. Informed consent was taken from each patient before pleurodesis. Inclusion criteria for selecting the patients were : (1) Confirmed malignant pleural effusion (positive pleural fluid cytology and / or pleural biopsy). (2) Symptomatic with dyspnoea. (3) Life expectancy of more than 4 weeks. (4) Clinical and radiological evidence of mediastinal shift to the opposite side of pleural effusion. (5) Relief of dyspnoea with therapeutic thoracentesis. Exclusion criteria were as follows : (1) Asymptomatic pleural effusion. (2) Mediastinum central or shifted to the same side of pleural effusion. (3) Life expectancy less than 4 weeks. (4) Chylothorax. (5) Pleural effusion secondary to chemosensitive malignancy (however pleurodesis was offered if the effusion persisted after chemotherapy). (6) Known hypersensitivity to talc or povidone iodine. Patients of malignant pleural effusion satisfying the inclusion criteria were selected for pleurodesis. An intercostal chest tube (24 F) was introduced under local anaesthesia through the 5th intercostal space in the midaxillary line and was connected to the waterseal drainage system. The drainage was continued till radiological confirmation of fluid evacuation and lung re-expansion. Injection lignocaine (2 mg / kg) mixed with 50 ml of normal saline was infused through the tube. Injection midazolam 5 mg was given intravenously simultaneously for conscious sedation. After 20 minutes, pleurodesis with talc in slurry was performed by injecting 5g sterile asbestosfree talc dissolved in 250 ml of normal saline via chest tube. Povidone iodine pleurodesis was performed by injecting 20 ml of 10 % of povidone iodine solution was injected through the chest tube along with 80 ml of normal saline. The tube was clamped for 2 hours and the patient was rotated in all directions. The tube was then unclamped and the drain was removed when the drainage was less than 150 ml per day. All patients were observed in the ward for immediate postoperative complications and managed accordingly. Following discharge at stable condition, they were followed up in the chest outdoor for next 6 months to look for any adverse reaction, successfulness of pleurodesis or death of the patients. Success was assessed as : Complete success — Absence of evidence of fluid reaccumulation on chest x-ray till end of follow-up or death. Partial success — Reaccumulation of fluid but not requiring therapeutic thoracentesis till end of follow-up or death. Failure — Lack of success as defined before. were included in the study; 24 of them got pleurodesis with talc in slurry and 28 with povidone iodine. Forty-two patients (81%) were males and 10 females (19 %). They were between 40 - 64 years of age with mean age of 56.4 years. The complete list of underlying malignancy is shown in Table 1. Table 1 — Distribution of Cases according to Distribution Malignancies Causing Pleural Effusion (n=52) of patients for Type of malignancy No of cases (%) pleurodesis Bronchogenic carcinoma : 41 (79%) with talc and Squamous cell carcinoma 12 povidone Adenocarcinoma 27 Small cell carcinoma 2 iodine is Breast carcinoma 8 (15%) depicted in Non-Hodgkin’s lymphoma 1 (2%) Table 2. Unknown primary 2 (4%) Table 2 — Distribution of Cases for Pleurodesis with Talc and Povidone Iodine (n=52) Type of malignancy Tale pleurodesis (n=24) 7 (29%) 12 (50%) 1 (4%) 3 (12%) 0 1 (4%) Povidone iodine pleurodesis (n=20) 5 (17%) 15 (54%) 1 (4%) 5 (17%) 1 (4%) 1(4%) Squamous cell carcinoma Adenocarcinoma Small cell carcinoma Breast carcinoma Non-Hodgkin’s lymphoma Unknown primary Complete success was seen in 19 patients (79 %) of the talc group and 24 patients (86%) of povidone iodine group (p > 0.5). Three patients (12%) of talc group had partial success and 1 (4 %) had partial success in povidone iodine group (p > 0.5). Two patients (8%) in talc group and 3 patients (11%) in povidone iodine group had failed pleurodesis (p > 0.5). Most patients tolerated pleurodesis well. Four patients (16 %) had chest pain and 3 patients (12%) had fever with talc pleurodesis whereas 5 patients (17%) had chest pain and 3 (11%) had fever in povidone iodine group. All responded to non-narcotic analgesics and antipyretics. There was no serious adverse effect or no immediate death. However 12 patients (50 %) in talc group and 18 (64 %) patients in the povidone iodine group died during 6 months follow up (p > 0.1). Comments : Talc [Mg3Si4010(OH)2], a naturally occurring magnesium sheet silicate was first used as an agent to produce adhesions as a preliminary to lobectomy in 19357 but its use in treatment of malignant pleural effusion dates back to 19588. It is used for pleurodesis in two forms – talc in slurry and talc poudrage. Talc in slurry is used via intercostal tube and talc poudrage via thoracoscopy or by video-assisted thoracic surgery (VATS). Talc used for pleurodesis is asbestos-free and sterilised by dry heat, gamma irradiation, or ethylene oxide. Povidone iodine is a Analysis : Total 52 patients, who satisfied the inclusion criteria D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (14) 592 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 soluble complex of iodine with polyvinyl pyrrolidone. It slowly releases free iodine which is responsible for its topical antiseptic property8. Low pH (2.97) of povidone iodine solution has been proposed to be responsible for its sclerosing activity9. Success rate of talc in slurry varies from 81 % to 100 % in different series10-12. Success rate of povidone iodine pleurodesis varies from 64 % to 100 %4-6. The present study has similar success rates of these two agents. Acute respiratory distress syndrome (ARDS) is reported to be occurring after talc pleurodesis, both as slurry12,13 or as poudrage14 with some reports of death13,14. This may be due to high doses used because using lower doses (2-5g) has lower incidence of ARDS11,15. However, there was no incidence of ARDS in this study. The only side-effects noted in this study were chest pain and fever occurring in both the groups with almost similar frequencies. In a recent review16, talc pleurodesis produced chest pain in 7% patients and fever in 16% patients. Povidone iodine produced chest pain in 0-5.8% cases in different studies4,6. In conclusion, both talc in slurry and povidone iodine are safe and effective agents for pleurodesis in symptomatic malignant pleural effusions. Povidone iodine has added benefits of easy availability, negligible sideeffects and low cost. On the other hand talc is less easily available and recently reported to be related to serious side-effects like ARDS. So despite comparable efficacy, povidone iodine seems to be safer option for pleurodesis. REFERENCES 1 Light RW — Pleural Diseases. 4th ed. Baltimore : Lippincott, Williams and Wilkins, 2001: 108-34. 2 Antony VB, Loddenkemper R, Astoul P Boutin C, Goldstraw , P, Hott J, et al — Management of malignant pleural effusions. Am J Respir Crit Care Med 2000; 162: 1987-2001. 3 Antunes G, Neville E, Duffy J, Ali N — BTS guidelines for the management of malignant pleural effusions. Thorax 2003; 58: 29-38. 4 Echavarria A, Pinzon V, Bares JP, Fernandez E — Intracavitary treatment of malignant pleural effusion with iodine – povidone [Engl Abstr]. Rev Med Panama 1991; 16: 69-74. 5 Kelly-Garcia J, Roman-Berumen JF, Ibarra Perez C— Preliminary report : iodopovidone and bleomycin pleurodesis for effusions due to malignant epithelial neoplasms. Arch Med Res 1997; 28: 583-5. 6 Olivares Torres CA, Laniado-Laborin R, Chavez-Garcia C, Leon-Gastelum C, Reyes-Escamilla A, Light RW — Iodopovidone pleurodosis for recurrent pleural effusions. Chest 2002; 122: 581-3. 7 Bethune N — Pleural poudrage : a new technique for the deliberate production of pleural adhesions as a preliminary to lobectomy. J Thorac Cardiovase Surg 1935; 4: 251-61. 8 Chambers JS — Palliative treatment of neoplastic pleural effusion with intercostal intubation and talc instillation. West J Surg Obstet Gynecol 1958; 66: 26-8. 9 Tripathi KD — Essentials of Medical Pharmacology. 5th ed. New Delhi : Jaypee Brothers, 2003: 804-11. 10 Adler RH, Sayek I — Treatment of malignant pleural effusion: a method using tube thoracostomy and talc. Ann Thorac Surg 1976; 22: 8-15. 11 Webb WR, Ozmen V, Moulder PV, Shabahang B, Breaux J — Iodized talc pleurodesis for the treatment of pleural effusions. J Thorac Cardiovasc Surg 1992; 103: 881-6. 12 Kennedy L, Rusch VW, Strange C, Ginsberg RJ, Sahn SA — Pleurodesis using talc slurry. Chest 1994; 106: 342-6. 13 Rinaldo JE, Owens GR, Rogers RM — Adult respiratory distress syndrome following intrapleural instillation of talc. J Thorac Cardiovasc Surg 1983; 85: 523-6. 14 Rehse DH, Aye RW, Florence MG — Respiratory failure following talc pleurodesis. Am J Surg 1999; 177: 437-40. 15 Weissberg D, Ben-Zeev I — Talc pleurodesis: experience with 360 patients. J Thorac Cardiovasc Surg 1993; 106: 68995. 16 Walker-Renard PB, Vaughan LM, Sahn SA — Chemical pleurodesis for malignant pleural effusions. Ann Intern Med 1994; 120: 56-64. Are you changing your residence ? Please send your new postal address with pincode to enable us to supply JIMA regularly. — Hony Secretary D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (15) Preliminary Report Rheumatological Manifestations in Diabetes Mellitus P SARKAR*, SHANTASIL PAIN**, R N SARKAR***, R GHOSAL****, S K MANDAL**, R BANERJEE** A study was undertaken in the department of medicine from November 2003 to July 2005 with a view to find out the prevalence of different rheumatological problem in Indian diabetic population. Although several such studies have been conducted in western population very limited data are available from our country. A total of 80 patients were studied out of which 43 had some form of rheumatological manifestations. Dupuytren’s contracture was found in highest number of cases (n=23) followed by limited joint mobility in 16 patients; adhesive capsulitis in 19 patients; trigger finger in 4 patients; aglodystrophy, carpal tunnel syndrome and hyperostosis were found in 2, 3 and 2 cases respectively.Symptomatic osteo-arthritis was found in 19 cases. [J Indian Med Assoc 2008; 106: 593-4] Key words : Diabetes, rheumatological complication. D iabetes mellitus (DM) comprises a group of common metabolic disorders characterised by hyperglycaemia. The major complications of diabetes are vascular,both microvascular and macrovascular like retinopathy, neuropathy, nephropathy or coronary artery disease. In contrast, rheumatological manifestations affecting the musculoskeletal system though less life threatening, sometimes lead to considerable debility. Of the various types of complications some are uniquely or commonly associated with DM. These are adhesive capsulitis (AC), shoulder hand syndrome, diabetic hand syndrome, Dupuytren’s contracture (DC) and Charcot’s neuroarthropathy. Several studies have been conducted in western countries to see the prevalence of these rheumatological conditions in diabetic population. However,only limited studies have been done in our country. The present study was carried out to find out the frequency and distribution of different rheumatological problems in Indian diabetic population. MATERIAL AND METHOD The study was undertaken in the department of medicine, Medical College Kolkata. A total of 80 patients (both type I and type II) were selected randomly from the diabetic clinic,during the period of November 2003 to July 2005. A detailed clinical examination was undertaken in Department of Medicine, Medical College and Hospital, Kolkata 700073 *MD (Med), Associate Professor **MD (Med), Assistant Professor ***MD (Med), Professor ****MBBS, Postgraduate Trainee each patient with particular emphasis on the examination of musculoskeletal system. The following patients were excluded from the study: (1) Patients with secondary diabetes (eg,Cushing’s syndrome). (2) Patients with diabetic nephropathy and end stage renal disease. (3) Patients with primary rheumatological diseases. (4) Patients with nonrheumatological causes having rheumatological manifestations in association with diabetes mellitus (eg, cerebrovascular accident with frozen shoulder, alcoholism with Dupuytren's contracture). After examination, the clinical diagnosis of the rheumatological problem was made and recorded. Cases with diagnostic dilemma were investigated for correct diagnoses. These included haemogram, ESR, fasting and postprandial blood glucose, glycosylated haemoglobin, serum urea and creatinine, uric acid and lipid profile, urine for routine and microscopic examination and to see for micro-albuminuria, x-rays of relevant joints as required. Ultimately 2 groups of diabetic patients were formed,one group having rheumatological problems and the other group having no rheumatological manifestations. Frequency of patients with rheumatological manifestations was compared with those without them by c2 (Chi-square) test. OBSERVATIONS Total number of male and female patients in the study were 41 and 39 respectively. The age ranged from 20-76 years with a mean age of 51.8±11.8 years. The duration of diabetes ranged from less than 1 year (lowest 1 month) to 37 years with a mean of 6.46±6.32 years. 593 D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (16) 594 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 Table 1 — Sexwise Distribution of Cases with Rheumatological Manifestations Rheumatological manifestations Limited joint mobility Adhesive capsulitis Dupuytren’s contracture Trigger finger Aglodystrophy Carpal tunnel syndrome Hyperostosis Osteo-arthritis Male 9 7 13 3 1 1 2 6 No of cases Female 7 12 10 1 1 2 0 13 Total 16 (20%) 19 (23.8%) 23 (28.8%) 4 (5%) 2 (2.5%) 3 (3.8%) 2 (2.5%) 19 (23.8%) In this series of 80 patients, 43 (20 males and 23 females) had some form of rheumatological manifestations. Mean age of those affected and those not affected was 55.7±9.9 years and 47.35±12.4 years respectively. This difference in mean age is statistically significant (p<0.001). The male to female ratio of the two groups is not statistically significant (p >0.01). The mean duration of diabetes in patients with rheumatological problems was 8.12±7.75 years and those without any such problems was 4.54±4.07 years. All patients (n=6) with a duration of diabetes more than 16 years had rheumatological manifestation. The difference of mean duration between these two groups is statistically significant (p<0.021). Out of these 80 patients, DC was found in highest number of cases (n=23; 28.8%); limited joint mobility (LJM) in 16 patients (20%); AC in 19 patients (23.8%); trigger finger (TF) in 4 patients (5%); aglodystrophy (AD), carpal tunnel syndrome (CTS) and hyperostosis were found in 2, 3, 2 cases respectively. Symptomatic osteo-arthritis was found in 19 cases (23.8%) (Table 1). There was also significant overlapping in the different rheumatological manifestations.Out of 16 LJM cases 6 had frozen shoulder (AC), 9 had associated DC, 1 had reflex sympathetic dystrophy (AD), 1had TF, 1 had CTS and 4 had osteo-arthritis. Among the 19 patients with AC, 9 had associated DC, 1 had reflex sympathetic dystrophy, 2 had TF and 9 had osteo-arthritis. Among the patients with DC 3had TF, 2had reflex sympathetic dystrophy and 11 had osteo-arthritis. DISCUSSION Of the 80 diabetic patients selected for the study 43 had some form of rheumatological problem. The prevalence of LJM was 20% and it increased significantly with the age of the patient but there was no statistically significant correlation with duration of diabetes. Referring to previous studies,the prevalence of LJM varied enormously in different series. Rosenbloom and Frias1 detected LJM in 30% of diabetics under 30 years of age. Among patients with duration of diabetes more than 4.5 years the prevalence was even higher (48.5%)1. Arkkila et al2 had shown prevalence of LJM as 52.9%. The prevalence of DC was 28.8%. Different studies have reported the prevalence of DC in the range of 20 to 63%. Noble et al3 reported the prevalence of DC in the diabetic population as 42% and a relationship with advanced age and duration. Prevalence of DC increased significantly with age (p<0.001) and duration of diabetes(p<0.01) in this study. The prevalence of AC or frozen shoulder was 23.8%. There was no association with age or duration of diabetes. Bridgman 4 reported an incidence of AC in diabetic population as 11% compared to 2.5% in non-diabetics. Arkkila et al5 reported the prevalence of AC 10.3% in type I and 22.4% in type II patients. There were 19 cases of osteo-arthritis involving mainly the knee and ankle joints with a prevalence of 23.8%. However it is a common problem in general population with old age and obesity. The prevalence of primary generalised osteo-arthritis in Indian population is around 24.8%6. As such the association of osteo-arthritis and diabetes has not proved convincing. However small joint osteo-arthritis is more frequently seen in diabetic people. From the above observations it is clear that more than 50% of diabetics suffer from rheumatological problems and the rheumatological manifestations are similar in pattern to the earlier documentation in western literature. There are variations in certain respect in this study, some of which are due to small sample size,some are due to geographical or population variation. It appears that whatever be the population chosen, clinically detectable soft tissue rheumatism occurs more frequently than clinically detectable bone and joint problems. Explanation to this is clearly not known, but altred microvasculature or altered collagen due to glycosylation are the possible aetiologies, which are in fact the basic machnisms of diabetic complications. REFERENCES 1 Rosenbloom AL, Frias JL — Diabetes mellitus,short stature and joint stiffness–a new syndrome. Clin Res 1974; 22: 92A. 2 Arkkila PE, Kantola I M, Viikari JS — Limited joint mobility in type I diabetic patients: correlation to other diabetic complications. J Intern Med 1994; 236: 215-23. 3 Noble J, Heathcote JG, Cohen H — Diabetes mellitus in the aetiology of Dupuytren’s disease. J Bone Joint Surg Br 1984; 66: 322-5. 4 Bridgman JF — Periarthritis of the shoulder and diabetes mellitus. Ann Rheum Dis 1972; 31: 69-71. 5 Arkkila PE, Kantola IM, Viikari JS — Shoulder capsulitis in type I and II diabetic patients: association with diabetic complications and related diseases. Ann Rheum Dis 1996; 55: 907-14. 6 Bhatt AD, Sane SP, Vaidya AB, Bolar HV — Patterns of rheumatic diseases and antirheumatic drug usage in 11931 Indian patients. J Assoc Physicians India 1994; 42: 346-8. D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (17) GP Forum IMA GFATM RNTCP PPM : Gearing up to Face Ground Realities SATISH CHUGH* To fight the menace of tuberculosis public-private mix model as being nurtured by Central TB Division and IMA may become an appropriate model for the developing and even for developed countries. IMA had sensitised 12147 private practitioners in five target states in India. Also 592 private practitioners have been trained in District Training Programmes. Frequently asked questions in these sensitisation and District Training Programmes are narrated in this article. The whole of India has been covered under DOTS strategy. Case detection rate of 70% is the key factor for the programme to succeed. CTD is able to reach case detection of new sputum positive (NSP) cases up to 55-60%. IMA is expected to fill the gap to reach magical figures of 70% NSP case detection rate. The risk of active tuberculosis with latent infection is increased 100-fold by HIV infection. Treating HIV and tuberculosis together and initiative of HIV treatment as been elaborated. Immune reconstitution inflammatory syndrome (IRIS) is characterised by a clinical worsening of a known condition or the appearance of a new condition after initiating antiretroviral therapy (ART). Details about IRIS have been narrated in this article. [J Indian Med Assoc 2008; 106: 596-9] Key words: Tuberculosis, District Training Programme, sensitisation, new sputum positive cases, HIV/AIDS, antiretroviral therapy, immune reconstitution inflammatory syndrome (IRIS). I ndian Medical Association (IMA) has successfully achieved the indicators laid down under Project Implementation Plan (PIP) for first eighteen months. The buoyant mood in first review workshop at picturesque place in God’s own land at Kovlam in Kerala, on August 8th and 9th was proof enough to prove that. IMA Kerala State Branch needed a special compliment. It was a warm hospitality mixed with real business by participants. Central TB Division (CTD) is going all out to support public-private mix (PPM). A new era is beginning in healthcare delivery system in India where private *NWG Member, IMA GFATM RNTCP PPM Project healthcare providers and public health facilities are building trust, mutual respect and felt-need for each other. Though IMA is junior partner and has minimum of national responsibility to contain tuberculosis but nowhere is being treated as such by CTD. The message is crystal clear, strong enough to percolate to district and sub-district levels to have mutual co-operation between district TB officers, medical officers, TB and members of IMA to fight the menace of tuberculosis together, for years to come. PPM model as being nurtured by CTD and IMA may become an appropriate model for the developing world and even for developed countries to follow. It may become handy to fight other health-related issues of public health 596 D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (18) GP FORUM 597 importance. IMA has sensitised 12147 private practitioners (PPs) and 592 PPs have been trained in District Training Programmes (DTPs) in five target states of Andhra Pradesh, Haryana, Maharashtra, Punjab, Uttar Pradesh and Union territory of Chandigarh as per data provided by IMA GFATM RNTCP PPM Project till March 2008.The figures have risen by the end August 2008, as lot more DTPs have been held in various target states. In fact CTD and GFATM are satisfied by the progress of PIP and are preparing for PPM in some more states. Frequently asked questions (FAQs) at these sensitisation and DTPs meetings which are being answered through these articles are being taken one by one. Participant’s most often asked question is: what the programme expects from IMA? This question needs to be discussed in some detail. Health delivery system in India is unique. It is unparallel. Private healthcare providers play a crucial role in curative services. In one study it has been revealed that 75% of patients first seek private health facility. Even 49% of TB patients first consult private healthcare providers. Health is a state subject. Health related acts, rules and regulations vary from one state to another. There are many health delivery systems called ‘pathies’ which are in vogue. All are treating TB as per their whims and fancies along with subject teaching. Laws to streamline these anomalies alone do not bear the desired results. Social mobilisation supported by information, education, communication (IEC) and political will yield better results. Once TB was declared global emergency by WHO, Government of India took the initiative to empower CTD to act fast and unhindered. There is a mathematical model which predicts that once a system is able to diagnose (case detection rate) 70% of new sputum positive (NSP) cases and is able to maintain a cure rate of 85%, by 2050, tuberculosis will no more remain a public health problem. By consistent efforts of RNTCP supported by all, IMA in particular, India will achieve the desired result of one NSP case per one million persons by the year 2050. IMA with its enormous numerical strength and its organisational network spread in every nook and corner of this vast country has become a willing partner to accept the challenge to contain this consumptive disease. IMA is a body of professionals who are trained in modern system of medicine. Medical Council of India (MCI), a statutory body which is looking after the medical education in India wields sufficient constitutional powers to ask for maintaining good academic standards and it is doing so. Hence medical graduates coming out of all the medical colleges are having sufficient knowledge about diseases. Once these young graduates become members of IMA they are regularly imparted continuing medical education (CME). Regular interaction in these CMEs sharpens their clinical skills. Through branch sensitisation meetings IMA members have been exposed to CME on IMA GFATM RNTCP PPM. Many of them expressed their willingness to know more about directly observed treatment, short course (DOTS) and then joining the collective efforts of IMA to treat tuberculosis the way laid down by Government of India through CTD and WHO. These members are imparted six hours of exclusive training known as DTP at district headquarters or at TB Units under the direct supervision of DTBO or MO, TB unit. All such doctors as complete this training are given a certificate and are authorised to treat tuberculosis as per norms of RNTCP and are at par with government health facility in providing DOTS for a particular period. In case standard of tuberculosis care is maintained as per guidelines of RNTCP this authorisation continues. IMA has ensured that this partnership will be at equal footing. I am the boss kind of attitude will be nonexistent. The whole of India has been covered under the DOTS strategy. Case detection rate of 70% is the key factor for the programme to succeed. With all sincerity and commitment CTD is able to reach in case detection of NSP D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (19) 598 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 up to 55%-60%. Global Fund to fight AIDS/Tuberculosis/ Malaria (GFATM) has taken the responsibility of funding PPM. All that the system expects from IMA is to fill the gap to reach the magical figure of 70% NSP case detection rate. Once almost all IMA members are sensitised and many of them are trained to treat tuberculosis as per DOTS, filling of this marginal gap will not be a very big task. As 49% of tuberculosis patients first report to private healthcare providers (PPs); an astute clinician who is sensitised, and is empowered to treat tuberculosis as per programme needs; containing tuberculosis will not be a difficult proposition. Every member of the association is expected to contribute. System wants to generate a feeling where every doctor is first a generalist and a specialist later on. A cardiologist or a psychiatrist cannot absolve himself/herself of his/her primary duty towards society. They may think that they can make positive impact in this programme. But every single specialist has a role to play. There are various options available for a PP to join the programme. Message needs to be spread by every doctor irrespective of his/her field of medical practice that anybody having cough/ expectoration of more than three weeks needs to get his/ her sputum examined at any of the DOT/DMC centres. Once the medical fraternity starts spreading this message, stigma attached to TB will start vanishing. First option available to PPs who have been sensitised in these CMEs is to send all tuberculosis suspects to designated microscopy centres (DMCs) public or private. Second option is that they may become DOT providers. These doctors are to be imparted six hours of DTP as already explained. Staff at their facility will be trained to practise DOTS. Third option is to start IMA RNTCP approved DOT centres and DMCs. There are certain conditions and specifications laid down. These are very easy to fulfil. There is least of hassels. IMA in turn will earn respect and honour from Government of India, CTD, international funding agencies, WHO and public at large. There is lot of discussion, debate and FAQs on tuberculosis and HIV/AIDS. Developed nations almost contained tuberculosis before it resurfaced with a bang with the arrival of human immune deficiency virus in 1981. Underdeveloped, developing and third world countries were almost left alone to defend themselves from the scourge of tuberculosis which is in abundance in poor and developing countries. World’s pioneer pharmaceutical laboratories had least interest in developing any new molecule to challenge tuberculosis before 1981. Research lagged behind to an extent that even after 27 years of reemergence of tuberculosis there is no new drug in the shelf of clinicians to reassure their patients to contain the disease if the existing drugs fail. TB is a threat to the peaceful existence of mankind. It has taken the form of pandemic which is being fuelled by HIV/AIDS. The risk of active tuberculosis with latent infection is increased 100fold by HIV infection; primary tuberculosis is also common and accounts for one-third of cases. Certain Unique Issues Associated with HIV Coinfection: * With low CD4+ count there is atypical presentation of tuberculosis. Non-cavitary lesions, involvement of middle and lower lobes and extrapulmonary tuberculosis predominate in presentation. With CD4+ count < 50/cmm extrapulmonary tuberculosis is far more common with pleuritis, pericarditis, meningitis and disseminated disease; chest x-rays typically show lower and middle lobe and miliary infiltrates, usually without cavitation. With CD4+ count>350/cmm lung lesions are typical with upper lobe infiltrates and cavitation. Tuberculosis is associated with increased viral load and more rapid progression of HIV infection. * TB incidence is increased 100-fold with HIV; HIV viral loads are higher and HIV disease progresses more rapidly with active tuberculosis. The increased risk of tuberculosis begins within 1 year of HIV transmission. * One report shows a high rate of morbidity and mortality in the first month of tuberculosis treatment in patients with a CD4+ count < 100/cmm at baseline. Treating TB and HIV Together : Clinicians treating tuberculosis patients need to be familiar with the principles and practice of antiretroviral therapy (ART)1. A patient with HIV-related tuberculosis , the priority is to treat tuberculosis, especially smearpositive pulmonary tuberculosis (on account of the need to stop tuberculosis transmission). Careful evaluation is necessary in judging when to start ART. For a Patient with smear positive pulmonary tuberculosis as the first manifestation of HIV infection, who does not appear to be at high risk of dying, it may be safer to defer ART until the initial phase of tuberculosis treatment has been completed. HIV promotes tuberculosis at all CD4+ strata, but clinical features vary according to CD4+ count. Initiation of HIV Treatment — Do not initiate treatment of both tuberculosis and HIV simultaneously due to overlapping drug toxicities, drug interactions, adherence requirements and the risk of immune reconstitution. Center for Disease control (CDC) and American Thoracic Society (ATS) recommendation is: D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (20) GP FORUM 599 * Continue antiretroviral therapy that was previously started. * Avoid initiating treatment of both and always treat tuberculosis first with HAART introduced at 4-8 weeks.. This decreases the risk of immune reconstitution syndrome (IRIS) and avoids the risk of drug interaction1. Table 1 — Showing Manifestations and Characteristics in IRIS Caused by Myco tuberculosis Manifestations Clinical – High fever, dysnoea, lymphadenopathy, cough, appearance of new effusion, hepatosplenomegaly, ascites, oedema, epidydmo-orchitis,abscess, inflammatory bowel perforation, psoas abscess, etc Radiological – Worsening pulmonary infiltrate or consolidation, intrathoracic and intra -abdominal lymphadenopathy, development or enlargement of cerebral space occupying lesions Characteristic Common during first 8 weeks; caseating granuloma, reactive changes; AFB smear and culture usually negative; often associated with CD4 rise and PPD conversion What is Immune Reconstitution Inflammatory Syndrome (IRIS)? A paradoxical clinical worsening of a known condition or the appearance of a new condition after initiating ART characterises this syndrome2. Occasionally, patients with HIV-related tuberculosis may experience a temporary exacerbation of symptoms, signs or radiographic manifestations of tuberculosis after beginning antituberculosis treatment. Symptoms and signs may include high fever, lymphadenopathy, expanding central nervous system lesions and worsening of chest xray findings1. A work-up for a patient with possible IRIS will depend on the specific clinical presentation. Perform laboratory tests, blood cultures and other diagnostic tests as appropriate to the individual patient. These may include the following: • Complete blood count (CBC) with differential, electrolytes and creatinine, liver function test. • CD4 count and HIV viral load. • Blood cultures for bacteria, acid-fast bacteria (MAC), fungi. • Chest x-ray, other radiographic studies. • Sputum stain and culture. • Biopsy or culture of skin or other lesions. • Lumbar puncture and cerebrospinal fluid studies. • Ophthalmological examination. Table 1 depicts immune reconstitution inflammatory syndrome (IRIS) caused by Mycobacterium tuberculosis along with its reactive manifestations and characteristics. Comments : Once a patient reports to DOT/DMC centre for diagnosis and treatment of tuberculosis, HIV testing and counselling is not a priority. In case the patient wants his/ her HIV testing only then should it be offered. Physicians treating tuberculosis need to be sensitised for HIV. It should be emphasised in unambiguous words that treating tuberculosis is a priority. Operational research is necessary to improve the delivery of integrated tuberculosis and HIV/AIDS prevention and care. Systems need to be developed to greatly increase the accessibility of preventive therapy to people living with HIV in settings of high tuberculosis prevalence. At the same time it is crucial to avoid compromising RNTCP quality. The subsequent FAQs about MDR, XDR, XXDR; empowering people and communities living with tuberculosis; why research lagged behind in pinning down tuberculosis; and impact of tuberculosis on global economy and corporate world will be taken up in subsequent issues of the Journal of IMA. REFERENCES 1 WHO — TB /HIV: A Clinical Manual. 2nd ed. Geneva: WHO, 2004: 138-55. 2 French MA, Price P Stone SF — Immune restoration disease , after antiretroviral therapy. AIDS 2004; 18: 1615-27. D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (21) Case Note A Case of Rhino-orbital Cerebral Mucormycosis with Diabetic Keto-acidosis H SIVARAMAKRISHNAN*, S M KANNAN**, C RAVIKUMAR***, S HARISHANKAR****, SANTHI CHELLAMUTHU***** A 60-year-old lady was admitted in the hospital with the complaints of burning sensation during micturition and abdominal pain. She was diagnosed to have moderate hydronephrosis with left lower 1/ 3rd ureteric calculus for which ureteroscopy and lithotripsy were done. Her pre-operative random blood sugar was normal. On the 7th postoperative day the patient developed diabetic keto-acidosis which was followed by an acute onset of right sided peri-orbital oedema, proptosis and facial pain. Subsequently she developed diminished vision and lower motor neurone type of III, IV and VI cranial nerves paralysis on right side, disorientation and minimal left sided hemiparesis. ENT examination revealed black eschar nasal turbinates, nasal septum and palate and a provisional diagnosis of rhinoorbital cerebral mucormycosis was made. Extensive debridement was done for the patient and the specimen culture showed growth of mucor species. Patient was started on intravenous amphotericin – B and she started improving dramatically. This case of rhino-orbital cerebral mucormycosis with diabetic keto-acidois is presented here for its rarity. [J Indian Med Assoc 2008; 106: 600-1 & 603] Key words : Rhino-orbital cerebral mucormycosis, diabetic keto-acidosis. ucormycosis is generally an acute and rapidly developing fungal infection caused by fungi of the class zygomycetes1. Rhino-orbital cerebral mucormycosis (ROCM) most commonly manifests itself in cases of poorly controlled diabetes especially diabetes with keto-acidosis. Early diagnosis is important and is based on the clinical features (diabetes, black eschar in nose, palate or face) and demonstration of the characteristic hyphae in the biopsy of the nasal mucosa or oral lesions2. Once infection has spread beyond the original site, invasive phycomycosis is almost invariably fatal with or without treatment3. This case is presented here to stress the importance of early diagnosis of a rare but rapidly fatal condition. Department of Internal Medicine, Shree Sudharson Hospitals, Tirunelveli 627003 *MD, Consultant Physician **MS, MCh, Consultant Urologist, Department of Urology ***MS, DLO, Consultant ENT Surgeon, Department of ENT ****MD, GDIPDC, Consultant Physician *****MBBS, DMRD, Senior Resident M CASE REPORT A 60-year-old lady was admitted in this hospital with complaints of abdominal pain and burning sensation during micturition. She was found to have moderate hydronephrosis on the left side due to a large left lower third ureteric calculus. Ureteroscopy and lithotripsy were done for her and a stent was placed in the left ureter for drainaige. Patient was not a known diabetic or hypertensive and her preoperative random blood sugar was 120 mg/dl. Postoperatively the patient developed hypotension and tachycardia and she was treated with dopamine drip, antibiotics (ceftriaxone and amikacin) and intravenous fluids. On the 7th postoperative day (POD), the patient had fever and vomiting. She subsequently developed right orbital and facial pain, right sided facial swelling, headache and diminished vision in the right eye and nasal discharge over 2 to 3 days. Examination — Patient was severely dehydrated and dyspnoeic. She had a temperature of 38.8°C respiratory rate of 33/minute, pulse rate of 110/minute and blood pressure 90/60 mm Hg. There were right orbital and facial swelling, peri-orbital oedema, proptosis on 600 D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (22) A CASE OF RHINO-ORBITAL CEREBRAL MUCORMYCOSIS — SIVARAMAKRISHNAN ET AL 601 right side. Ocular examination on right side revealed diminished vision, decreased ocular motility, conjunctival chemosis, dilated and fixed pupil and central retinal artery occlusion. Central nervous system examination revealed changes in mental status, disorientation, right III, IV and VI cranial nerves paralysis and minimal left sided hemiparesis. ENT examination showed black eschar in the nasal turbinates, nasal septum and the palate on right side. Investigations — On the 7th POD her WBC count was 25,000/ cmm with neutrophils 95 %, lymphocytes 3 % and eosinophils 2%, ESR 55mm in ½ hour and 120 mm in 1 hour, random blood sugar 754 mg/dl, blood urea 105 mg/dl, serum creatinine 1.9 mg/dl. Serum electrolytes showed sodium 131 mEq/l, potassium 3.8 mEq/l, chloride 92 mEq/l, bicarbonate 22 mEq/l. Urine sugar ++++ and urinary ketones were positive. Her random blood sugar levels and presence /absence of urinary sugar and ketones are depicted in Table 1. Chest x-ray AP view showed cardiomegaly. ECG was normal. CT scan brain and paranasal sinuses showed soft tissue mass lesion in the right maxillary and right ethmoidal sinuses and right side of the nasal cavity. There was bony erosion in the medial wall of the right maxillary sinus. There were soft tissue swelling in the periorbital and retro-orbital region with proptosis on right side. Also, there was hypo-echoic area (infarct) in the right frontal lobe. Management — A provisional diagnosis of ROCM was made and extensive debridement was done on right side of the face and the specimen was sent for pathological and microbiological examination. Microscopy of sections showed tangled masses of fungal hyphae with necrotic cell debris. Hyphae were broad, aseptate, irregular showing right angle branching with diagnosis being mucormycosis. Fungal culture showed mucor species grown in culture after 48 hours. Rapid glycaemic control was achieved by intravenous short acting human insulin and the patient was started on intravenous amphotericin B (1.2 mg/kg/day) as soon as the diagnosis was made. The patient started improving dramatically. The patient was discharged at request (in a stable condition) on 21st POD. She was advised to continue intravenous amphotericin B in a hospital very proximal to her residence. DISCUSSION Mucormycosis is an acute, often fatal fungal infection caused by members of the class zygomycetes and the order mucorales. Species of rhizopus, rhizomucor and cunninghamella are the most common causes4 of which the genus rhizopus accounts for most cases of rhino-orbital cerebral mucormycosis5. There are five types of mucormycosis–rhinocerebral, cutaneous, gastro-intestinal, pulmonary and disseminated. Although mucormycosis of any form is still a rarity, it should be suspected in patients who are diabetic or immunocompromised6. Prolonged treatment with antibiotics, corticosteroids and cytotoxic drugs, severe malnutrition, haematologic malignancies and extensive burns have also been associated. Although very rare, cases of ROCM Table 1 — Random Blood Sugar Levels and Presence or Absence of Urinary Sugar and Ketones on Various Postoperative Days Day 3rd POD 7th POD 9th POD 11th POD 15th POD 18th POD 21st POD Random blood sugar 130 mg/dl 754 mg /dl 182 mg/dl 52 mg/dl 94 mg/dl 111 mg/dl 125 mg/dl Urine sugar Nil ++++ ++ Nil Nil Nil Nil Urinary ketones Not done Positive Positive Positive Negative Negative Negative have been reported in healthy individuals7,8. The rhizopus are ubiquitious saprophytic fungi and are present normally in the nasal cavity. The site of onset generally is the nasal mucosa and the disease spreads rapidly to the paranasal sinuses1. From the sinuses the infection spreads to the retroorbital region, the central nervous system and the palate2. Invasion, thrombosis and necrosis are the characteristic findings of this disease. Cerebral infarction occurs when arterial invasion induce thrombosis. Clinical findings include fever, headache, diminished vision, proptosis, peri-orbital oedema, complete ophtahlmoplegia, conjuctival chemosis , fixed and dilated pupil, III, IV and VI cranial nerves paralysis, nasal discharge, nasal stiffness, change in mental status, hemiparesis and black necrotic nasal turbinates, nasal septum and palate. The diagnosis depends on recognition of the fungus in specimens of tissue or of body fluids9. Fungal culture are occasionally positive. CT scan is used to evaluate soft tissue extent, mucosal thickening, bone erosion, intracranial/ cavernous sinus involvement and sinus disease10. Treatment includes immediate correction of underlying disease, aggressive surgical debridement and early rapid institution of intravenous amphotericin B. The combination of amphotericin B and surgical debridement has dramatically improved the outcome over the years11. The highest possible tissue level of amphotericin B should be established. Once the patient is stable, the dose of amphotericin can be reduced depending on the renal status since the drug is nephrotoxic. To achieve higher doses of the drug at the site of infection, intraconal amphotericin B12 is being suggested as an adjunct to the IV (Continued on page 603) D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (23) Case Note Pelvic Tuberculosis in a Postmenopausal Woman Mimicking Ovarian Malignancy — A Clinical Dilemma NALINI ARORA*, POONAM GUPTA**, CHITRA RAGHUNANDAN***, VARSHA JHUNJHUNWALA** A 72-year-old postmenopausal woman presented with dyspepsia, weight loss, abdominal pain, and ascites. Ultrasonography revealed a pelvic mass and evidence of pyometra. Serum CA-125 was raised. Paracentesis revealed lymphocytic exudate but no malignant cells or acid-fast bacilli. However, after drainage of pyometra endometrial curettings revealed epithelioid granuloma with acid-fast bacilli. She had complete recovery with full course of antituberculosis treatment. Thus, pelvic tuberculosis should be considered in the differential diagnosis of ovarian malignancy, which can prevent many unnecessary laparotomies. [J Indian Med Assoc 2008; 106: 602-3] Key words : Ovarian carcinoma, pelvic tuberculosis, serum CA-125. revalence of tuberculosis is increasing worldwide. Extrapulmonary tuberculosis in the form of female genital tuberculosis is typically understood as a disease of young women and its occurrence in postmenopausal women is rare1. The disease can raise a serious diagnostic dilemma due to its protean manifestations and sometimes mimic ovarian malignancy2-4. An unusual case of genital tuberculosis in a postmenopausal woman is reported which posed a diagnostic confusion with malignant ovarian tumour. The awareness of this atypical presentation can avoid unnecessary operative intervention. CASE REPORT A 72-year-old multiparous woman, postmenpausal for the last 20 years was hospitalised because of intermittent lower abdominal pain, dyspepsia with weight loss, and progressive abdominal distension of 6-month duration. She had no history of fever, chronic cough or postmenopausal bleeding. Her husband had suffered from pulmonary tuberculosis about 15 years ago for which he completed a course of antituberculosis treatment. Examination — She was emaciated weighing 32 kg and 146 cm tall. She had no signs of anaemia, jaundice or cyanosis. Cervical and inguinal lymph nodes were not palpable. The abdomen was distended, and there was considerable ascites but no palpable mass. Pelvic examination revealed pale atrophic vagina and normal cervix, neither uterine size nor any pelvic mass could be appreciated due to tense ascites. Investigations — Ultrasound examination revealed marked ascites with a solid heteroechoeic mass of 4x3.6x3.4 cm in the pouch Department of Obstetrics and Gynaecology, Lady Hardinge Medical College, New Delhi 110001 *MD, DNB, MNAMS, Associate Professor; At present : Associate Professor, Department of Obstetrics and Gynaecology, IPGME&R, Kolkata 700020 **MD, Senior Resident ***MD, Professor 602 P of Douglas, and the left ovary was not separately identified from the mass. The right ovary was normal. Endometrial cavity contained fluid with debris suggestive of pyometra. The other abdominal organs were unremarkable. Computed tomography showed similar findings; in addition left sided pleural effusion was noted. No retroperitoneal lymph nodes were observed. X-ray chest revealed left sided pleural effusion. Serum CA-125 was 294 U/ml (normal range 0-35 U/ml). Routine blood biochemistry including renal and liver function tests were within normal limits. Abdominal paracentesis revealed nonspecific inflammatory exudates comprising predominantly of lymphocytes and a few macrophages, but no bacteria, acid-fast bacilli or malignant cells. Ascitic fluid protein and glucose levels were 4.2 g/dl and 54 mg/dl, respectively. Pleural fluid analysis was similar to the peritoneal fluid. Sputum was negative for acid-fast bacilli. Cervical smear showed atrophic changes with no malignant cell. Pyometra was drained twice under antibiotic cover, and then a fractional curettage was done. Endometrial histology revealed inflammatory infiltrates and focal epithelioid cell granulomas with presence of acid-fast bacilli. Endocervical curettings showed a few endocervical glands with underlying normal stroma. HIV serology was negative. Treatment — Antituberculosis treatment was started (isoniazid, rifampicin, ethambutol and pyrazinamide). At 4-week of treatment she had marked clinical improvement, serum CA-125 level decreased to 184 U/ml, ultrasonography showed complete resolution of ascites and pyometra, both adnexas were also normal. Follow-up — At 9-month follow-up, she was found asymptomatic and healthy. DISCUSSION This case presented with adnexal mass, ascites and raised CA125. In a postmenopausal woman these clinical features typically point to a diagnosis of ovarian malignancy. CA-125, a non-specific marker of ovarian cancer can be raised in several conditions including pelvic infections, endometriosis, fibroids, hepatitis, pancreatitis and D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (24) PELVIC TUBERCULOSIS IN A POSTMENOPAUSAL WOMAN MIMICKING OVARIAN MALIGNANCY — ARORA ET AL 603 peritonitis. It has been recommended that postmenopausal women with pelvic mass and raised CA-125 level of 65-95 U/ml should undergo surgery5. However, an increasing number of cases with advanced tuberculosis has been reported with significantly high level of CA-1252-4. It is therefore worth to consider pelvic tuberculosis in the differential diagnosis of ovarian mass with raised CA-125 and ascites especially in the women of developing countries, and in the immigrants in developed nations6. The diagnosis of genital tuberculosis is difficult clinically but a high index of suspicion can help to establish a correct diagnosis. History of tuberculosis in immediate family member as seen in the present case, can be positive in 20% of women with genital tuberculosis7. A definite pre-operative diagnosis is usually difficult with physical examination alone, and ultrasonographic features are often non-specific4,6. Isolation of acid-fast bacilli in smear or culture, and tissue biopsy are two most specific diagnostic tests. Laparoscopic biopsy with frozen section evaluation has been tried with 87% success in diagnosing peritoneal/pelvic tuberculosis8,9. Image guided percutaneous biopsy has a limited benefit10. However, in this woman, sonographic evidence of pyometra, which is extremely rare especially in postmenopausal women with genital tuberculosis1, necessitated its drainage and subsequent fractional curettage, and was an important clue to the diagnosis. There are several case reports where a definitive diagnosis could not be made even after laparotomy, and radical surgery was carried out only to reach a surprise diagnosis of tuberculosis by histopathology2-4. Knowledge about protean and atypical presentations of pelvic tuberculosis would not only prevent unnecessary radical surgery in postmenopausal women but can help in preserving menstrual and ovarian function in premenopausal women. Exploratory laparotomy should be considered when the diagnosis remains in doubt or there is no improvement in spite of antiuberculosis therapy6. (Continued from page 601) REFERENCES 1 Patacchiola F, Di Stefano L, Palermo P, Di Berardino C, Coppola G, Mascaretti G — Genital tuberculosis in a menopausal woman: a case report. Minerva Ginecol 2002; 54: 287-91. 2 Manidakis LG, Angelakis E, Sifakis S, Stefanaki P, Kalogeraki A, Manidaki A, et al — Genital tuberculosis can present as disseminated ovarian carcinoma with ascites and raised Ca –125: a case report. Gynecol Obstet Invest 2001; 51: 277-9. 3 Miranda P Jacobs AJ, Roseff L — Pelvic tuberculosis presenting , as an asymptomatic pelvic mass with rising serum CA-125 levels: a case report. J Reprod Med 1996; 41: 273-5. 4 Penna L, Manyonda I, Amias A — Intra-abdominal miliary tuberculosis presenting as disseminated ovarian carcinoma with ascites and raised CA125. Br J Obstet Gynaecol 1993; 100: 1051-3. 5 Malkasian GD Jr, Knapp RC, Lavin PT, Zurawaski VR Jr, Podratz KC, Stanhope CR et al — Preoperative evaluation of serum CA 125 levels in premenopausal and postmenopausal patients with pelvic masses: discrimination of benign from malignant disease. Am J Obstet Gynecol 1988; 159: 341-6. 6 Jana N, Mukhopadhyay S, Dhali GK — Pelvic tuberculosis with elevated serum CA-125: a diagnostic dilemma. J Obstet Gynaecol 2007; 27: 226-7. 7 Sinha P, Johnson AN, Chidamberan-Pillai S — Pelvic tuberculosis: an uncommon gynaecological problem presenting as ovarian mass. Br J Obstet Gynaecol 2000; 107: 139-40. 8 Koc S, Beydilli G, Tulunay G, Ocalan R, Boran N, Ozgul N, et al — Peritoneal tuberculosis mimicking advanced ovarian cancer: a retrospective review of 22 cases. Gynecol Oncol 2006; 103: 565-9. 9 Ibrarullah M, Mohan A, Sarkari A, Srinivas M, Mishra A, Sundar TS — Abdominal tuberculosis: diagnosis by laparoscopy and colonoscopy. Trop Gastroenterol 2002; 23: 150-3. 10 Vardareli E, Kebapci M, Saricam T, Pasaoglu O, Acikahn M — Tuberculous peritonitis of the wet ascitic type: clinical features and diagnostic value of image-guided peritoneal biopsy. Dig Liver Dis 2004; 36: 199-204. amphotericin. In addition it is said that hyperbaric oxygen therapy may be beneficial13. Therapy may need to be continued for months. Since its first description by Paultauf in Germany in 1885, zygomycosis remains a disease with guarded prognosis. ROCM, diabetic keto-acidosis is thought to have an mortality rate of 50 %1,4. Factors related to a lower survival rate include14 : (1) Delayed diagnosis and treatment; (2) hemiparesis or hemiplegia; (3) bilateral sinus involvement; (4) leukaemia; (5) renal disease; and (6) treatment with deferoxamine. Patients require long-term monitoring to detect recurrence or signs of indolent residual infection. REFERENCES 1 Chun SFS, Stevens DA — Infectious diseases. In: Wyngaarden JB, Smith LH, Bennett JC, editors. Cecile Textbook of Medicine. Vol 2. 19th ed. Philadelphia: WB Saunders, 1992: 1903-5. 2 Morais Perez D, Guerra Gonzalez A, Alonso Benito J, Miyar Villar V, Perez Gonzalez R, Martin Siguenza G — Rhinoorbital-cerebral mucormycosis: review, update and report of a new case (Eng Abstr). Acta Otorrinolaringol Esp 1997; 48: 309-13. 3 Hay RJ, Mackenzie DWR — Fungal infections. In: Weatherall DJ, Ledingham JGG, Warell DA, editors. Oxford Textbook of Medicine. Vol 1. 3rd ed. Oxford: Oxford University Press, 1996: 810-3. 4 Bennett JE — Mucormycosis. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, editors. 5 6 7 8 9 10 11 12 13 14 Harrison’s Principles of Internal Medicine. Vol 1. 15th ed. New York: McGraw-Hill, 2001: 1179-80. Warwar RE, Bullock JD. Rhino-orbital-cerebral mucormycosis: a review. Orbit 1998; 17: 237-45. Bell S, Mahoney L — Mucormycosis: a case study. Crit Care Nurse 2000; 20: 18-23. Fairley C, Sullivan TJ, Bartley P, Allworth T, Lewandowski R — Survival after rhino-orbital-cerebral mucormycosis in an immunocompetent patient. Ophthalmology 2000; 107: 555-8. Castelli JB, Pallin JL — Lethal rhinocerebral phycomycosis in a healthy adult: a case report and review of the literature. Otolaryngology 1978; 86: 696-703. Kamat SR, Shah SP, Mahashur AA, Shah DC, Mehta AP — Disseminated systemic mucormycosis: (a case report). J Postgrad Med 1982; 28: 229-32 Earhart KC, Baugh WP — Rhinocerebral mucormycosis. Emed [serial online]. 2003 January. http://www.emedicine.com/ med/topic2026.htm (accessed Aug 4, 2004). Blitzer A, Lawson W, Meyers BR, Biller HF — Patient survival factors in paranasal sinus mucormycosis. Laryngoscope 1980; 90: 635-48. Luna JD, Ponssa XS, Rodriguez SD, Luna NC, Juarez CP — Intraconal amphotericin B for the treatment of rhino-orbital mucormycosis. Ophthalmic Surg Lasers 1996; 27: 706-8. Price JC, Stevens DL — Hyperbaric oxygen in the treatment of rhinocerbral mucormycosis. Laryngoscope 1980; 90: 526-30. Yohai RA, Bullock JD, Aziz AA, Markert RJ — Survival factors in rhino-orbital-cerebral mucormycosis. Surv Ophthalmol 1994; 39: 3-22. D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (25) Pictorial CME J INDIAN MED ASSOC VOL 106, NO 9, SEPTEMBER, 2008 PRIMARY MEDIASTINAL YOLK SAC TUMOUR IN A YOUNG FEMALE A 14-year-old female student presented in August 2006 with the complaint of left sided chest pain and cough for last six months. She had menarche at the age of 12 years and had history of tuberculosis at the age of 11/2 years which was treated adequately. On examination whole of the left hemithorax had a generalised fullness, breath sounds were absent on left side, and general condition was average. Gynaecological examination was within normal limits. X ray chest (PA view), showed a mediastinal opacity, lateral view suggested a mass in anterior mediastinum. USG and contrast enhanced CT scan (CECT) of abdomen and pelvis showed no detectable mass. CECT of Fig 2 — Microphotograph Showing Large Cells with Mitotic Division and Hyperchromatic Nuclei Suggesting thorax showed a solitary Undifferentiated Carcinoma large heterogeneous mass (12 x 8 cm 2 ) with thick alpha-foetoprotein (AFP) was more than 400ng/ml and serum betaseptum (Fig 1). There was also mild contrast enhancement in anterior HCG was less than 2mIU/ml. Chemotherapy with BEP regime mediastinum with mild pressure effect over left main bronchus. (bleomycin – 30 IU IV weekly, cisplatin – 20mg/m2 daily from day 1 Radiological differential diagnosis was between lymphoma and germ to day 5, etoposide – 100mg /m2 daily x 5 days) was started and the cell tumour. FNAC report suggested undifferentiated carcinoma (Fig patient was improving gradually. Excision of postchemotherapy residual 2, Leishman & Giemsa, X400) and germ cell tumour cannot be mass was planned after four cycles of combination chemotherapy. excluded. All the blood parameters were within normal limits. Serum Patient responded well after first cycle of chemotherapy. But unfortunately brain metastasis was detected after second cycle of chemotherapy. Brain metastasis was treated with palliative radiation therapy and patient died one month after radiation therapy. So planned treatment could not be completed. Department of Radiotherapy, ASIT RANJAN DEB* NRS Medical College and Hospital, SUPRIYO SARKAR** Kolkata 700014 SUDIPTO CHAKRABORTY*** *MD, DNB (Radiother), RANEN KANTI AICH**** Associate Professor DIPTIMOY DAS***** **MD (Chest Med), Associate Professor DEBABRATA MITRA****** of Chest Medicine SUBIR GANGOPADHYAY******* ***MD (Pathol), Assistant Professor ABHIJIT D E******** of Pathology ****MD (Radiother), Assistant) Professor of Radiotherapy, Bankura Sammilani Medical College and Hospital, Bankura 722102 *****MD (Radiother), RMO cum Clinical Tutor ******MD (Radiother), Assistant Professor of Radiotherapy, North Bengal Medical College, Darjeeling 734432 *******MD (Radiother), Professor and Head of the Department ********BSc (Hons), MBBS, RMO cum Clinical Tutor 604 Fig 1 — Contrast Enhanced CT Scan of Thorax Showing a Large Solitary Mass in the Chest Cavity D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (26) Research Analysis Report Evaluation of Sensitivity of Different Organisms to Cefepime and Tazobactum (Megapime XP) in Comparison to Cefepime and Ceftazidime R B PAL*, (MRS) PARAMITA PAL**, VEENA VENKATESH***, K P KULKARNI**** The present study was carried out to evaluate the sensitivity of different organisms to cefepime and tazobactum (megapime XP) in comparison to cefepime and ceftazidime. Samples were collected from clinical specimens and micro-organisms were isolated from clinical specimens. Strains of micro-organisms isolated from clinical specimens were identified using standard methods like morphology, colony characteristics and biochemical reactions. Sensitivity was carried out using Kirby Bauer disc diffusion method. Minimum inhibitory concentrations (MICs) for all the antibiotics were carried out as per guideline of Clinical and Laboratory Standard Institute (CLSI).The results of the study demonstrated that cefepime and tazobactum exhibits good activity against Gram +ve and Gram-ve organisms. [J Indian Med Assoc 2008; 106: 605-11] Key words : Kirby Bauer disc diffusion method, Clinical and Laboratory Standard Institute (CLSI), cefepime, tazobactum, ceftazidime. ATCC 25923 and Pseudomonas aeruginosa ATCC 27853 strains were used for quality control. OBSERVATIONS The percentage of sensitivity of various micro-organisms to 3 antibiotics– cefepime, cefepime and tazobactum and ceftazidime were studied. Out of 30 samples, 73.3% of staphylococcus coagulase positive strains were sensitive to cefepime and tazobactum combination, almost similar to cefepime and ceftazidime. Out of 21 samples, 52.3% of staphylococcus coagulase negative strains were sensitive to cefepime and tazobactum combination, better than either to cefepime or ceftazidime. Out of 25 samples, 96% of E coli strains were sensitive to cefepime and tazobactum combination, better than either to cefepime or ceftazidime. All strains of Klebsiella pneumoniae were sensitive to cefepime and tazobactum combination, whereas Pseudomonas aeruginosa strains were more sensitive to ceftazidime. Out of 11 samples of proteus, 86.3% strains were sensitive to the combination, whereas acinetobacter species shows better response to ceftazidime. Salmonella and enterobacter strains show equal response to all 3 antibiotics (Table 1 & Fig 1-7). Majority of the Gram +ve and Gram -ve bacteria develop resistance to beta-lactam antibiotics by producing enzymes known as betalactamases, which hydrolyse betalactam antibiotics such as penicillins, cephalosporins and carbapenems. These enzymes catalyse the hydrolysis of the beta-lactam ring to effectively destroy the antibiotic’s activity. Although the higher generation cephalosporins exhibits greater stability to hydrolysis by beta-lactamases, extended-spectrum beta-lactamases (ESBLs) do pose a major threat to almost to all the cephalosporins, including cefepime1. The frequency of resistance to beta-lactams among nosocomial isolates has been increasing due to ESBL-producing enteric bacilli. Enzyme inhibitors such as tazobactum have been proved to be extremely useful in overcoming the bacterial resistance by inhibiting the beta-lactamase enzyme. Cefepime has an excellent activity against a wide range of Gram +ve and Gram -ve organisms. However, E faecalis and bacteroides are resistant to cefepime. Cefepime has minimal activity against methicillin-resistant Staph aureus (MRSA)2. The addition of tazobactum provides inhibitory action against a wide ranging beta-lactamases that includes group I cephalosporinases, group 2br TEM beta-lactamases and group 3 metallobeta-lactamases MATERIAL AND METHOD Samples collected from clinical specimens such as urine, sputum, pus, throat swab, wound swab, blood and body fluids. Micro-organisms were isolated from clinical specimens. A total of 186 strains of different micro-organisms were studied which comprised staphylococcus coagulase positive (n=30), staphylococcus coagulase negative (n=21), E coli (n=25), Klebsiella pneumoniae (n=27), Pseudomonas aeruginosa (n=26), proteus species (n=22), acinetobacter species (n=15), salmonella species (n=11) and enterobacter species (n=9). Strains of micro-organisms isolated from clinical specimens were identified using standard methods like morphology, colony characteristics and biochemical reactions. Sensitivity was carried out using Kirby Bauer disc diffusion method. Inoculum was prepared by inoculating the culture in nutrient broth. It was inoculated at 370C. Overnight and turbidity was adjusted to 0.5. McFarland standard suspension was swabbed on Mueller Hinton Agar and antibiotic discs were put on the inoculated Mueller Hinton agar. Plates were incubated at 370C and zone of inhibition was measured. MICs for all the antibiotics were carried out as per guideline of CLSI. Quality control: E coli ATCC25922, Staphylococcus aureus resistant Cefepime Cefepime Ceftazidime and tazobactum intermediate sensitive Fig 1 — Sensitivity Pattern of Cefepime XP, Cefepime and Ceftazidime (in percentage) at Staphylococcus Coagulase Positive Species resistant intermediate sensitive Alkem Laboratories Ltd, Mumbai 400013 *PhD, Proprietor, EOS Laboratories, Thane 401210 **MSc, Proprietor, EOS Laboratories, Thane 401210 ***MD, Medical Advisor ****MD, Medical Director 605 Cefepime Ceftazidime and tazobactum Fig 2 — Sensitivity Pattern of Staphylococcus Coagulase Negative Species in 3 Antibiotics (%) Cefepime D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (27) 606 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 Table 1 — Comparison of Cefepime and Tazobactum (Megapime XP) with Cefepime and Ceftazidime compared to the broad-spectrum betalactamases, such as TEM-1, TEM-2, SHV-1, and others. ESBLs have extended substrate profiles which permit hydrolysis of expandedspectrum cephalosporins such as cefotaxime, ceftriaxone, ceftazidime, cefepime, and others. To date, ESBLs are most commonly produced by isolates of Klebsiella pneumoniae and, to a lesser extent, Escherichia coli ,but infections, colonisation, and nosocomial spread involving other ESBL-producing organisms (such as Morganella morganii; Serratia marcescens; Shigella dysenteriae; several species of enterobacter, salmonella, proteus, and citrobacter; Pseudomonas aeruginosa; Burkholderia cepacia; and Capnocytophaga ochracea) have been reported . A major problem with ESBLs is their capacity to cause therapeutic failures with cephalosporins when the host organism appears to be susceptible to these agents in laboratory tests. The megapime XP (combination of cefepime and tazobactum) is highly sensitive to E coli (96%), K pneumoniae (100%), proteus (86.3%), and salmonella (100%) strains in comparison to cefepime and ceftazidime antibiotics. It is equally effective in enterobacter and acinetobacter species in comparison to cefepime and ceftazidime antibiotics. The drug shows a good activity against staphylococcus coagulase positive (73.3%) and coagulase negative strains (52.3%). MIC values < 1 in clinical isolates for various organisms have been studied with cefepime and tazobactum combination (Table 2 & Figs 8-9). Cefepime and tazobactum exhibits good activity against Gram +ve and Gramve organisms. MIC <1 can inhibit the Organisms Antibiotics Resistance strains (%) Intermediate Sensitive strains (%) strains (%) Zone diameter (in mm of size) with maximum number of inhibition of strains (%) 52.7 (18-20) 36.3 (21-23) 48 (18-20) 21.3 (21-23) 45.4 (18-20) 37.5 (18-20 & 21-23) 41.7 (18-20 & 24-26) 25 (21-23) & above 26) 46.7 (21-23) 50 (21-23) 70.3 (21-23) 70.3 (21-23) 37.5 (21-23) & 24-26) 53.9 (18-20) 46.2 (24-26) 63.2 (above 26) Staphylococcus Cefepime coagulase positive Cefepime and (n=30) tazobactum ceftazidime Staphylococcus Cefepime coagulase negative Cefepime and (n=21) tazobactum Ceftazidime E coli (n=25) Cefepime Cefepime and tazobactum Ceftazidime Cefepime Cefepime and tazobactum Ceftazidime Cefepime Cefepime and tazobactum Ceftazidime Cefepime Cefepime and tazobactum Ceftazidime Cefepime Cefepime and tazobactum Ceftazidime Cefepime Cefepime and tazobactum Ceftazidime Cefepime Cefepime and tazobactum Ceftazidime 16.7 13.3 13.3 42.9 33.3 52.3 40 28 51.9 51.9 42.3 42.3 31.8 13.6 20 13.3 10 14.2 14.3 9.5 12 4.0 12 11.1 7.4 27.0 8.0 9.1 - 63.3 73.3 76.7 42.9 52.3 38.1 48 96 60 37.0 100 40.7 30.8 50.0 59.1 86.3 Klebsiella pneumoniae (n=27) Pseudomonas aeruginosa (n=26) Proteus (n=11) Acinetobacter (n=22) 31.8 86.7 66.7 40.0 33.3 33.3 66.7 9.1 6.7 33.3 33.3 - 60.0 13.3 33.3 53.3 100 100 100 33.3 33.3 33.3 38.5 (above 26) 50.0 (above 24) 60 (above 26) 12.5 (above 24) 36 (18-20) 27.2 (18-26) 723 (21-23) 33.3 (18-26) 33.3 (18-26) 66.6 (18-20) Salmonella (n=15) Enterobacter (n=9) resistant intermediate sensitive Cefepime Cefepime Ceftazidime and tazobactum Cefepime Cefepime Ceftazidime + TZ resistant intermediate sensitive Fig 3 — Sensitivity Pattern of Acinetobacter Species DISCUSSION ESBLs are novel beta-lactamases produced by a variety of Gramnegative bacilli. The distinguishing feature of these enzymes is that Fig 4 — Sensitivity Pattern of E coli Species D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (28) RESEARCH ANALYSIS REPROT Table 2 — Evaluation of MIC Values of Clinical Isolates with Megapime XP versus Cefepime and Ceftazidime Organisms resistant intermediate sensitive Staphylococcus Cefepime coagulase positive Cefepime and (n=30) tazobactum Ceftazidime Staphylococcus Cefepime coagulase negative Cefepime and (n=21) tazobactum Ceftazidime E coli Cefepime (n=25) Cefepime and tazobactum Ceftazidime Klebsiella Cefepime pneumoniae Cefepime and (n=27) tazobactum Ceftazidime Pseudomonas Cefepime aeruginosa Cefepime and (n=26) tazobactum Ceftazidime Proteus Cefepime (n=11) Cefepime and tazobactum Ceftazidime Acinetobacter Cefepime (n=22) Cefepime and tazobactum Ceftazidime Salmonella Cefepime (n=15) Cefepime and tazobactum Ceftazidime Enterobacter Cefepime (n=9) Cefepime and tazobactum Ceftazidime Antibiotics <8(4-8) 8 6 9 4 5 3 5 8 7 4 9 3 1 4 4 1 2 2 0 1 4 5 3 6 1 1 2 611 MIC values <4(1-4) <1(1-0.13) 3 6 6 3 3 2 3 7 4 1 9 6 2 3 3 4 5 5 1 1 1 3 3 3 1 0 1 3 5 5 1 3 1 1 7 1 1 5 1 1 1 1 5 11 4 1 3 2 3 5 2 1 2 0 Cefepime Cefepime Ceftazidime and tazobactum Fig 5 — Sensitivity Pattern of Klebsiella pneumoniae resistant intermediate sensitive Cefepime Cefepime Ceftazidime and tazobactum Fig 6 — Sensitivity Pattern of Pseudomonas aeruginosa resistant intermediate sensitive Cefepime Cefepime Ceftazidime and tazobactum Fig 7 — Sensitivity Pattern of Enterobacter Species Cefepime Cefepime Cefepime and tazobactum co ag ul St as ap e +v h co e ag ul as e -v e E li co K eu Ceftazidime ac te Sa r lm on el la En te ro co cc i ot e ia on m eu pn Cefepime and tazobactum St ap h Fig 8 — MIC Values <1 in Clinical Isolates growth of 80% of enterobacterobacter, 60% of acinetobacter and proteus strains. In clinical situations in which there is increased development of beta-lactamase producing organisms, cefepime- tazobactam combination may be the first choice for the treatment of pneumonia, empiric therapy for febrile neutropenic patients, uncomplicated and complicated urinary tract infections, uncomplicated and complicated skin structure infections and complicated intra-abdominal infections. Fig 9 — MIC Values <1 in Clinical Isolates 1 REFERENCES Amyes SGB, Miles RS — Extended-spectrum b-lactamases– the role of inhibitors in therapy. J Antimicrobial Chemother 1998; 42: 415-7. Burgess DS, Hastings RW, Hardin TC — Pharmacokinetics and pharmacodynamics of cefepime administered by intermittent and continuous infusion. Clin Ther 2000; 22: 66-75. 2 Ac P en sa no gi ru ae s Ceftazidime Pr et ob D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (29) Research Analysis Report Evaluation of Safety and Efficacy of Telmisartan-amlodipine Combination in Treating Hypertension ARIF A FARUQUI* The objective of this open, non-comparative, prospective postmarketing surveillance (PMS) study was to identify, validate and quantify the safety and efficacy associated with the use of fixed dose combination (FDC) of telmisartan 40 mg + amlodipine 5 mg (T40+A5) in hypertensive patients with or without concomitant diabetes. The data was collected from 72 centres from all over India during the period of June 2007 to February 2008. A total of 251 patients of either sex and those who were newly diagnosed stage II hypertension, or those who were uncontrolled on monotherapy with or without diabetes mellitus were included in this study. Patients were prescribed with T40+A5 combination orally. Systolic BP (SBP), diastolic BP (DBP) and heart rate (HR) were measured at the start and at the end of 2, 4 and 8 weeks of treatment. Primary efficacy end points were reduction in clinical SBP/ DBP from baseline to study end and number of patients achieving JNC VII goals. Tolerability was assessed by treatment-emergent adverse events. Out of 251 patients, 208 patients had completed the study (120 males and 88 females), 42 were lost to follow-up the study and one patient was withdrawn due to adverse effects. The mean age of the patients was 54.5 ± 0.98 years for males and 52.94 ± 1.078 years for females. Diabetes mellitus was seen in 64.9% of cases, dyslipidaemia in 2.88%, previous IHD in 7.2% cases and chronic obstructive pulmonary disease (COPD) in 0.50% of cases. Reduction in the mean SBP was found to be 12.08%, 18.92% and 22.90% at the end of 2, 4 and 8 weeks respectively (p<0.001). Reduction in the mean DBP was found to be 10.09%, 14.55% and 17.19% at the end of 2, 4 and 8 weeks respectively (p<0.001). At the end of the study it was found that 86.3% of the hypertensive patients and 70% diabetic hypertensive patients achieved the JNC VII recommended goals. The overall incidence of ADRs was 7.69% with headache (1.92%) and vertigo (1.44%), as the commonest side-effect. According to physician’s assessment of efficacy and tolerability 99.5% of total cases showed good to excellent response. In the treatment of stage II hypertensive patient the FDC of T40+A5 (Telar-AM) was found to be significantly effective in the reduction of SBP as well as DBP. Overall incidence of ADRs was lower and FDC of T40+A5 is well tolerated. [J Indian Med Assoc 2008; 106: 612-4 & 624] Key words : Hypertension, telmisartan, amlodipine, postmarketing surveillance, safety. Hypertension is a cardiovascular risk factor commonly associated with insulin resistance, the metabolic syndrome, and type II diabetes mellitus. Amongst the Indian studies one NIH study1 had reported prevalence of hypertension in diabetics as 51.9% in urban and 29.4% in rural as compared to non diabetics who had 21.9% in urban and 16.9% in rural population. This disease is the most important modifiable risk factor for coronary heart disease, congestive heart failure, endstage renal disease, and peripheral vascular disease. Reducing blood pressure in people with hypertension and diabetes decreases both macrovascular and microvascular complications. Clinical trials using a variety of antihypertensive agents have demonstrated that modest reduction in blood pressure of just 9-11 mmHg systolic and 2-9 mmHg diastolic decreases cardiovascular events by 34-69% and microvascular complications (retinopathy and nephropathy) by 26-46% within just 2-5 years2. Moreover the goal set by JNC VII in diabetic hypertensives is 130/80 mm Hg that is very difficult to achieve with monotherapy. Moreover, combinations with older antihypertensive agents such as thiazide diuretics and beta-blockers have potential adverse effects on glucose and lipid metabolism and may even exacerbate the metabolic syndrome and increase the risk of type II diabetes. Thus, there is a need for an antihypertensive drug combination that can achieve the JNC VII recommended goal without compromising the lipid profile and glycaemic control. The safety of new antihypertensive agents or combination is of special importance as they are likely to be used long term in considerable number of patients in general medical practice. The number of subjects forming the safety database for successful product licenses for fixed drug combinations is only limited and small compared with the number of patients likely to receive a new combination for a common condition such as hypertension. The objective of this postmarketing surveillance (PMS) study is to identify, validate and quantify the safety and efficacy associated with the use of telmisartan-amlodipine combination in hypertensive patients with or without concomitant diabetes. MATERIAL AND METHOD This was an open, non-comparative, prospective study of the *MBBS, MD, General Manager-Medical Services, Medley Pharmaceuticals Limited, Mumbai 400093 612 fixed dose combination of telmisartan 40mg and amlodipine 5mg. The data was collected from 72 centres from all over India during the period June 2007 to February 2008. Full prescribing information was made available to the physicians. A total of 251 patients of either sex were included in the study. Only those patients who were newly diagnosed stage II (JNC VII) hypertension, or those who were uncontrolled on monotherapy with or without diabetes mellitus were prescribed telmisartan-amlodipine combination. Blood pressure was measured at the end of 2 weeks, 4 weeks and 8 weeks of therapy. Patients were monitored for any adverse events reported. Overall global assessment of safety and efficacy was recorded at the end of the treatment. Pregnant and lactating women, women of child bearing potential not following adequate contraceptive measures, those having history of hypersensitivity to either telmisartan or amlodipine, those with evidence of cardiac, renal or hepatic insufficiency, drug or alcohol abuse were excluded. Current medical history with clinical symptoms and physical examination findings were noted. Clinical symptoms and signs were recorded on predesigned case report forms (CRF). Clinical assessment was done at the start of the treatment and at the end of 2 weeks, 4 weeks and 8 weeks of treatment. Concomitant medications administered were also recorded. Primary efficacy end points were reduction in clinical systolic BP (SBP)/ diastolic BP (DBP) from baseline to study end and number of responders (ie, patients who achieved target SBP/ DBP <130/<80 mm Hg in diabetic hypertensive and 140/90 mm Hg in hypertensive) at the end of study. Tolerability was assessed by treatment-emergent adverse events. Details of any adverse event whether considered treatment related or not, reported or noted during the treatment with telmisartan-amlodipine combination were recorded in the appropriate section of the CRF. Data was analysed with the help of graph pad instat version 3.06 statistical package. All the tests were two tailed. Results were considered statistically significant if p<0.05. OBSERVATIONS A total of 251 patients were enrolled. At the end of 8 weeks, 208 patients had completed the study, 42 were lost to follow-up and medication has to be stopped in 1 patient due to dizziness and severe vertigo. The trial population included 57.7% males and 42.3% females D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (30) RESEARCH ANALYSIS REPORT Table 1 — Distribution of Cases (Table 1). The mean age of the patients in the study according to Sex and Age (n=208) group was 54.5 ± 0.98 years Sex No of Age in years for males and 52.94 ± 1.078 cases (%) (mean±SD) years for females. Diabetes Male 120 (57.7%) 54.5±0.98 mellitus was seen in 64.9% Female 88 (42.3%) 52.94±1.078 of cases, dyslipidaemia in 2.88%, previous IHD in 7.2% cases and chronic obstructive pulmonary disease (COPD) in 0.50% of cases (Table 2). Concomitant medications (aspirin, atorvastatin, clopidogrel, glimepiride, metformin and pioglitazone) given to the patients were recorded and about 53.36% patients received some medications while the rest 46.64% received no concomitant medications. Table 3 shows systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate at baseline and after 2,4 and 8 weeks of treatment. Table 4 and Table 2 — Distribution of Cases according to Figs 1-4 show Disease Profile (n=208) the changes in Disease No of cases (%) SBP and DBP after the Hypertension 57 (27%) It Hypertension with diabetes 135 (64.9%) treatment. shows that mean Hypertension with IHD 9 (4.32%) SBP was reduced Hypertension-dyslipidaemia-IHD 6 (2.88%) by 20.9 mm Hg, Hypertension with COPD 1 (0.50%) 613 32.8 mm Hg and 39.7mm Hg at the end of 2,4 and 8 weeks of treatment, respectively. Similarly mean DBP was reduced by 10.08 mm Hg,14.53 mm Hg and 17.16 mm Hg at the end of 2,4 and 8 weeks of treatment, respectively. At the end of study the reduction in mean SBP was by 39.7mm Hg ie, 22.92% and DBP reduced by 17.16 mm Hg ie, 17.19% from baseline which was statistically significant (p<0.001). Table 5 shows the changes in fasting blood sugar (FBS) and postmeal blood sugar (PMBS) levels in 135 patients who were suffering from concomitant diabetes mellitus. In this subset of patients mean baseline FBS was 143.54±3.4 mg/dl which was reduced to 111.059±1.518 mg/ dl at the end of 8 weeks. Similarly mean baseline PMBS was 214.237±5.325 mg/dl which was reduced to 151.918±2.322 mg/dl at the end of 8 weeks, both values being statistically significant from baseline (p<0.001). All the diabetic patients were on antidiabetic medications. Table 6 and Fig 5 mention the adverse drug reactions (ADRs) reported by patients receiving telmisartan-amlodipine fixed dose combination during the study. The most common side-effects reported were headache (1.92%), vertigo (1.44%), and pharyngitis (1.44%), dizziness, nausea, gastritis, dry cough, syncope and pedal oedema together (2.88%). The overall incidence of ADRs was 7.69% in the total number of patients. ADR was observed in only 16 patients (7.69%) and these were not serious. Table 7 and Fig 6 mention the overall assessment of efficacy of treatment by investigators. According to physicians' assessment, 62.5% of the cases had excellent response, 37.01% of the Table 3 — Effect of Telmisartan-amlodipine (Telar-AM) on Heart Rate, Systolic and cases had good response and 0.48% had poor response. Thus 99.51% of total cases showed good to excellent Diastolic Blood Pressure response. Parameters Baseline 2nd week 4th week 8th week Table 8 and Fig 7 mention the overall assessment (mean±SD) (mean±SD) (mean±SD) (mean±SD) of tolerability of treatment by the patients. It is observed Heart rate 86.259±0.6722 81.70±0.5474 80±0.49 80±0.4219 that 60.57% of total cases had excellent tolerability Systolic BP 173.31±1.13 152.47±1.13* 140.548±1.042* 133.67±0.8448* followed by 38.94% of cases showing good tolerability; Diastolic BP 99.82±0.634 89.74±0.5741* 85.293±0.5181* 82.66±0.4524* only 1 patient ie, 0.48% of cases had unsatisfactory tolerance. *P<0.001 versus baseline At the end of the study it was found that 86.3% of the hypertensive patients and 70.37% diabetic hypertensive patients Table 4 — Effect of Telmisartan-amlodipine Combination on achieved the JNC VII recommended goals (Table 9 and Fig 8). Reduction in Systolic and Diastolic Blood Pressure DISCUSSION Week Systolic BP reduction (%) Diastolic BP reduction (%) Compared to the general population, people with diabetes face a 2 20.9 mm Hg (12.08%) 10.08 mm Hg (10.09%) two- to fourfold increased risk of cardiovascular disease (CVD)3. 4 32.8 mm Hg (18.92%) 14.53 mm Hg (14.55%) Concomitant hypertension triples the already high risk of coronary 8 39.7 mm Hg (22.92%) 17.16 mm Hg (17.19%) Fig 1 — Change in Systolic BP Fig 3 — Change in Diastolic BP Fig 2 — Percentage Reduction in Systolic BP Fig 4 — Percentage Reduction in Diastolic BP D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (31) 614 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 Fig 5 — Cases according to Adverse Effect Fig 7 — Global Assessment of Safety Fig 6 — Global Assessment of Efficacy Table 5 — Effect of Telmisartan-amlodipine combination on Fasting and Postmeal Blood Sugar Levels in Diabetic Hypertensives (n=135) Blood sugar Fasting Postmeal Baseline 143.54±3.4 mg/dl 214.237±5.325 mg/dl 8 weeks 111.059±1.518 mg/dl* 151.918±2.322 mg/dl* Fig 8 — Percentage of Patients Achieving JNC VII Goals In the present study the baseline mean SBP was Table 7 — Global Assessment of 173.31±1.13mm Hg which Efficacy of Telmisartan-amlodipine Combination as Assessed by dropped to 133.67 ± 0.8448 mm Hg at the end of the study. Investigator on 3-Point Ranking Scale (n=208) At the end of 8 weeks treatment the change in mean Outcome of result No of cases (%) SBP was 39.7 mm Hg ie, Excellent 130 (62.5%) 22.92% from baseline which Good 77 (37.01%) was statistically significant. Poor 01 (0.48%) Also the baseline mean DBP was 99.82 ± 0.634 mm Hg Table 8 — Global Assessment of which dropped to 82.66 ± Safety of Telmisartan-amlodipine 0.4524 mm Hg at the end of Combination as Assessed by the study. At the end of 8 weeks Investigator on 3-Point Ranking treatment the change in mean Scale (n=208) DBP was 17.16 mm Hg ie, Outcome of result No of cases (%) 17.19% from baseline which Excellent 126 (60.57%) was statistically significant. 81 (38.94%) A similar study of 203 Good 1 (0.48%) hypertensive patients treated Poor with telmisartana m l o d i p i n e Table 9 — Distribution of Cases according to JNC VII Achieved Goals (n=208) combination over a period of 12 weeks Category Achieved goals (%) done by Sharma et al7 Diabetic reported a reduction of hypertensive (n=135) 95 (70.37%) systolic BP by 27.4% Hypertension (n=73) 63 (86.3%) and diastolic BP by 20.1%16. Response rates were 87.3%. In this study overall assessment of efficacy and safety by the investigators was done on three-point scale of excellent, good and poor. It was observed that at the end of 8 weeks therapy, majority of the patients ie, 99.5% of total cases showed good to excellent response and tolerability to study drug, and only 0.48% of cases showed unsatisfactory response. The present study showed that telmisartan-amlodipine is very safe and only 7.69% of cases ie, 16 patients reported ADRs, the commonest being headache (1.92%) vertigo (1.44%), and pharyngitis (1.44%). Less than 1% patients reported dizziness, nausea, gastritis, (Continued on page 624) *P<0.0001 versus baseline artery disease (CAD), doubles Table 6 — Distribution of Cases according to Adverse Drug total mortality and stroke risk, Reactions (n=208) and may be responsible for up to 75% of all CVD events in people Adverse effect No of cases (%) with diabetes 4. Similarly, Dizziness 1 (0.48%) hypertension significantly Vertigo 3 (1.44%) accelerates the progression of Gastritis 1 (0.48%) diabetic nephropathy, Nausea 1 (0.48%) retinopathy, and neuropathy. Headache 4 (1.92%) Tight BP control is cost- Pharyngitis 3 (1.44%) effective and is more rewarding Pedal oedema 1 (0.48%) than hyperglycaemic control in Syncope 1 (0.48%) diabetic, hypertensive patients5. Dry cough 1 (0.48%) Telmisartan and amlodipine are two efficacious antihypertensives with less side effects that would be able to achieve the desired goal of maintaining greater reduction in BP. Telmisartan, in addition to blocking the angiotensin II type 1 receptor, activates the peroxisome proliferator-activated receptor (PPAR)-gamma a well-known target for treatment of the metabolic syndrome and diabetes. By contrast, other angiotensin-receptor blockers do not have activity on PPAR-gamma. Telmisartan is a partial agonist of PPAR-gamma and has a superior tolerability profile without causing the fluid retention and oedema associated with full agonists of PPAR-gamma such as pioglitazone and rosiglitazone. In addition to antidiabetic properties, PPAR-gamma activators may also provide protection against atherosclerosis and coronary events. Calcium antagonists are recommended as a therapeutic medicine for diabetic hypertensive patients, because they have no adverse influence on lipid metabolism or glucose metabolism6. The combination thus helps in treatment of hypertension especially beneficial with those who have concomitant diabetes or metabolic syndrome and thus prevents atherosclerotic cardiovascular disease. D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (32) Current Report Chiral Non-steroidal Anti-inflammatory Drugs — A Review MADAN S HARDIKAR* A chiral centre is noted in majority of the NSAIDs. For NSAIDs the enantiomer with S configuration almost exclusively possesses the ability to inhibit prostaglandin activity. R-enantiomers of NSAIDs have poor COX inhibitory activity. Some Renantiomers are not inert, and many have different actions. The R- to S- chiral inversion varies with biological factors and property of NSAID. The S- to R- chiral inversion is rare for all the NSAIDs. Various preclinical and clinical studies have demonstrated that chirally pure NSAIDs like dexketoprofen, dexibuprofen and S-etodolac are more potent than their respective R enantiomers. Favourable pharmacokinetic and pharmacodynamic profile of dexketoprofen, dexibuprofen and S-etodolac make them effective and well tolerated drug for the treatment of painful inflammatory conditions at half doses of recemate. Thus chiral switch of NSAIDs is a rational approach for the treatment of painful inflammatory conditions. [J Indian Med Assoc 2008; 106: 615-24] Key words : Chirally pure NSAIDs, dexketoprofen, dexibuprofen, S-etodolac. NSAIDs have been prominent analgesic and anti-inflammatory medications since 1898 when aspirin was first marketed. NSAIDs, by inhibiting the enzyme COX and reducing prostaglandin production, diminish inflammation and pain. COX-2-selective drugs were introduced in 1999. Important differences in the actions of individual NSAIDs with the COX active site are complex. Generally, the NSAIDs inhibit both COX-1 and COX-2. Most NSAIDs are mainly COX-1 selective (eg, aspirin, ketoprofen, indomethacin, piroxicam, sulindac). Others are considered slightly selective for COX-1 (eg, ibuprofen, naproxen, diclofenac) and others may be considered slightly selective for COX-2 (eg, etodolac, nabumetone, and meloxicam). The mechanism of action of celecoxib and rofecoxib is primarily selective inhibition of COX-2. There is a growing interest in the role of the induction or prevention of polymorphonuclear neutrophils (PMNs) apoptosis in the control of inflammation. PMNs are short-lived leucocytes that die by apoptosis. Although PMNs are crucial in the defence against infection, they have been implicated in the pathogenesis of tissue injury observed in inflammatory diseases. NSAIDs have been found to modulate human PMN apoptosis in a dose- and time-dependent manner1. NSAIDs and Chirality : Chirality is defined as the geometric property of a rigid object (like a molecule or drug) of not being superimposable with its mirror image. Molecules that can be superimposed on their mirror images are achiral (not chiral). Chirality is a property of matter found throughout biological systems, from the basic building blocks of life such as amino acids, carbohydrates, and lipids to the layout of the human body. The 2 mirror images of a chiral molecule are termed enantiomers. Both molecules of an enantiomer pair have the same chemical composition and structure, but in chiral environments such as the receptors and enzymes in the body, they can behave differently. In case of a drug, the two molecules may have different pharmacokinetic and pharmacodynamic properties. A racemate (often called a racemic mixture) is a mixture of equal amounts of both enantiomers of a chiral drug. Although not all of the NSAIDs are chiral, most of them possess a chiral centre. The chiral NSAIDs are one of the most studied classes for chirality. This class includes the ibuprofen, ketoprofen, fenoprofen, flurbiprofen, tiaprofenic acid, carprofen, pirprofen, benoxaprofen, naproxen, etodolac and ketorolac. For NSAIDs, it is the enantiomer possessing the S configuration that almost exclusively possesses the ability to inhibit prostaglandin activity. Of the chiral NSAIDs, all are traditionally administered in racemic form except naproxen, which is available as the single S enantiomer. The NSAIDs have been intensively studied from the perspective of stereoselectivity in pharmacokinetics. Chiral NSAIDs and their enantiomers viz, ketoprofen, flurbiprofen, *MS (Orthop), D Orthop, Orthopaedic Surgeon, Hardikar Hospital, Pune 411005 and S-naproxen have been found to modulate human PMN apoptosis in a dose- and time-dependent manner1. R-enantiomers of NSAIDs : R-enantiomers of NSAIDs have poor COX inhibitory activity. When potential antinociceptive effects of the S- and R-enantiomers of flurbiprofen were investigated in an animal model of arthritic pain, it was found that S-flurbiprofen was 100-fold more potent than Rflurbiprofen in producing the antinociceptive effect2. Although, the COX inhibition is the property of S-enantiomers, the R-enantiomers of the NSAIDs are not inert. R-flurbiprofen and Retodolac are undergoing development for the potential treatment of Alzheimer’s disease and cancer, respectively. R-flurbiprofen appears to modulate gamma-secretase, the enzyme that cleaves the C-terminal portion of the malignant Abeta (1-42) peptide out of amyloid precursor protein. R-flurbiprofen lowers brain levels of Abeta (1-42), and chronic dosing reduces brain amyloid pathology and prevents defects in learning and memory. As a result, R-flurbiprofen improves the cognitive and behavioural performance, reduces the incidence of psychiatric problems and the average time to a first psychiatric incidence in patients with AD. Currently, Rflurbiprofen is undergoing phase III trials in Alzheimer patients3. R-etodolac has shown promising results in cancer therapy. Retodolac inhibits transcription of a b-catenin–dependent T-cell– and lymphoid-enhancing transcription factor (TCF/LEF) receptor gene in HEK293 cells and to diminish the in vitro survival of chronic lymphocytic leukaemia (CLL) cells4. R-etodolac also has in vivo prostate cancer antitumour activity via its direct effect on the peroxisome proliferator activated receptor-g (PPAR-g) and retinoid X receptor-a (RXR-a) pathways5. R-etodolac induces cytotoxicity in multiple myeloma cells and cell lines6. Chiral Inversion : Chiral inversion is a process in which, one enantiomer of a drug is converted in to its antipode, in vivo. The R-enantiomers of some of the NSAIDs are known to undergo metabolic chiral inversion to their more pharmacologically active antipodes. This process is drug and species dependent and usually unidirectional. For example, the R to S inversion of ibuprofen in humans occurs in the range of 35-85% 7,8 while for ketoprofen it is only between 10 and 13%9-11. For ibuprofen, this might seem to be favouring the use of racemate. However, the bioavailability of dexibuprofen is higher (92%) following administration of the pure S-enantiomer compared to racemic ibuprofen which produces dexibuprofen bioavailability of 71%12 . In addition, the conversion of racemic ibuprofen to S-ibuprofen results in variability of clinical response, including delayed onset of activity, and difficulty in achieving an optimal dose. Also the formation of coenzyme A (CoA) thio-ester during bioinversion of R- to S-ibuprofen may result in toxic effects (eg, interference of lipid anabolism/catabolism). Further, R-ibuprofen bioactivation is susceptible to biological factors 615 D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (33) 616 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 25 mg thrice daily versus ketoprofen 50 mg thrice daily in the treatment of pain due to dental surgery shows that the dexketoprofen trometamol 25 mg is equally effective as compared to ketoprofen 50 mg in decreasing pain due to dental extraction in the first 8 hours of therapy. Dexketoprofen has a better analgesic effect at 24 hours and on the second and third day of therapy as compared to ketoprofen. In this study, dexketoprofen provided significant analgesia within 1 hour of dosing whereas though ketoprofen decreased the pain intensity at 1 hour, statistically significant analgesia was observed only after 8 hours of therapy with ketoprofen25. Dexketoprofen has been studied in acute and chronic management of osteo-arthritis and related symptoms. In osteo-arthritis patients, 3-week treatment with dexketoprofen trometamol 25 mg thrice daily was found to be more efficacious than ketoprofen 50 mg thrice daily. In addition, 75% of the dexketoprofen group had improved compared with 50% of the ketoprofen patients. There were fewer adverse events in the dexketoprofen treatment group22. Morning stiffness in osteoarthritis of the hands is a troublesome symptom that deserves attention in many patients. In such patients, dexketoprofen-trometamol (50 mg) administered early in the morning rapidly reduced the degree of morning stiffness in thirty-five patients compared with nineteen controls27. Dexketoprofen 50 mg IV has also been found to have the equivalent analgesic activity and better tolerability compared to ketoprofen 100 mg IV in the management of postoperative pain after orthopaedic surgery28. In patients with a history of primary dysmenorrhoea dexketoprofen 12.5 and 25 mg and racemic ketoprofen 50 mg significantly reduced pain intensity compared with placebo from 1 hour after dose to 4-6 hours after dose. There were no significant effects of any treatment on activities of daily living, menstrual flow, or associated symptoms. Dexketoprofen was shown to be effective, well tolerated, and did not show any difference in the incidence of adverse events compared to ketoprofen or placebo29. The results of a multicentric, randomised, comparative clinical trial to evaluate the efficacy and safety of dexketoprofen trometamol 25 mg thrice daily versus ketoprofen 50 mg thrice daily in the treatment dysmenorrhoea shows that the dexketoprofen trometamol 25 mg is equally effective as compared to ketoprofen 50 mg in decreasing pain of dysmenorrhoea. Both the drugs have similar onset of action and are safe and well-tolerated in this indication30. Dexketoprofen trometamol is an effective and rapidly acting analgesic for the treatment of acute musculoskeletal injuries. In patients with acute lower limb injury 25 mg oral dexketoprofen trometamol was found to be more effective in reducing pain score at 15, 30, 45, and 60 minutes as compared to diclofenac sodium 50 mg31. Animal studies have demonstrated that addition of subtherapeutic doses of dexketoprofen improves the activity of opioid analgesics like fentanyl 32 . In patients undergoing elective hip arthroplasties, dexketoprofen 25 mg thrice daily, peri-operative and postoperative, markedly improved analgesia and reduced opioid requirement and sideeffects such as nausea, vomiting and sedation33. Thus, synergistic drug combinations should be helpful in improving efficacy of pharmacological treatment of pain while simultaneously minimising drug specific adverse effects34. Dexketoprofen trometamol (25 mg and 50 mg) is a good analgesic for the treatment of moderate to severe pain due to renal colic, comparable to dipyrone (2g) but with significantly greater analgesic efficacy soon after administration, suggesting a faster onset of action of dexketoprofen trometamol35 . Salient features of dexketoprofen — • Most or all COX inhibitory activity of ketoprofen is attributed to the S(+)-enantiomer (dexketoprofen). • R-enantiomer is 30 to 5000 times less potent as an inhibitor of COX-1 and about 100 times less potent as an inhibitor of COX-2. • Dexketoprofen is less ulcerogenic than the racemic ketoprofen and R-ketoprofen. and certain drugs7. The clinical studies13-15 have shown that dexibuprofen, in fact, is equally effective as Ibuprofen at half the dose. For ketoprofen, it requires a substantially high dose of R-ketoprofen, to produce some degree of analgesic activity 9,16,17. The S to R chiral inversion or bidirectional chiral inversion on the other hand, is rare for all the NSAIDs14. The epithelial cells have been found to be the major site of R to S inversion in the intestinal wall with the muscular layer and intestinal contents contributing only to a small extent to the process. Both enantiomers are acyl-glucuconjugated in the epithelial and muscular layers, and the intestinal content18. In the following sections, some clinically important unichiral NSAIDs- dexketoprofen, dexibuprofen and S-etodolac are discussed. Dexketoprofen [S(+)Ketoprofen] Trometamol : Racemic ketoprofen is a 50:50 mixture of S(+)- and R(-)enantiomers16. Most or all COX inhibitory activity of ketoprofen is attributed to the S(+)-enantiomer (dexketoprofen)17. Dexketoprofen has been demonstrated to be an inhibitor of COX-1 and COX-2 activities in experimental animals and humans17. The R-enantiomer is 30 to 5000 times less potent as an inhibitor of COX-1 and about 100 times less potent as an inhibitor of COX-29. Although R-ketoprofen has produced some degree of analgesic activity in animal models and in patients with dental pain (after high doses), this appears related to bioinversion to the S-enantiomer 9,16,17 . Between 10 and 13% bioinversion of R to S occurs in humans9-11. In contrast, there is no inversion of S-ketoprofen to R-ketoprofen 11,17. In addition, Sketoprofen has been found to be significantly less ulcerogenic in the rat gastro-intestinal tract as compared to the racemic ketoprofen and that the R-enantiomer may contribute to the pathogenesis of intestinal ulcers19. This effect was also dose-dependant20. The pharmacokinetic profile of ketoprofen and its enantiomers has been assessed in several animal species and in human volunteers21. The absorption of S-enantiomer from racemic ketoprofen and dexketoprofen trometamol has been found to be equivalent. Dexketoprofen trometamol, given as a tablet, is rapidly absorbed, with a time to maximum plasma concentration (tmax) between 0.25 and 0.75 hours after administration of dexketoprofen trometamol 12.5 and 25 mg respectively. This fast absorption could account for the suitability of dexketoprofen in the management of acute pain. No R-ketoprofen has been isolated in the urine of volunteers indicating that inversion from R- to S-enantiomer is unidirectional21. Clinical studies performed on several pain models have demonstrated that dexketoprofen has analgesic, anti-inflammatory and antipyretic activities while R-ketoprofen weakly demonstrates these effects after conversion to the S-enantiomer. Dexketoprofen is effective at half the dose of racemate9,11. Several clinical trials conducted with orally administered dexketoprofen trometamol in patients affected by acute and chronic pain have confirmed its high analgesic potency and good tolerability profile22-35. The trials have also investigated the analgesic efficacy of oral dexketoprofen trometamol in comparison with enantiomerically equivalent doses of the racemic compound ketoprofen 22,25,26-30. In patients with dental pain dexketoprofen showed comparable analgesic efficacy and tolerability but a faster onset of action than ketoprofen22,25. In patients with extraction of impacted third molar, the level of analgesia produced by dexketoprofen 25 mg was similar to that produced by ketoprofen 50 mg with more rapid onset of action22. Dexketoprofen trometamol 25 mg has efficacy and tolerability comparable to rofecoxib 50 mg in patients after third molar extraction23. Similarly, dexketoprofen trometamol 5 to 20 mg offered pain relief comparable to ibuprofen 400 mg following third-molar extraction. The onset of analgesia was more rapid with dexketoprofen trometamol (50% pain reduction in 0.9 versus 2.1 hours)24. The results of a multicentric, randomised, comparative clinical trial to evaluate the efficacy and safety of dexketoprofen trometamol D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (34) CURRENT • Dexketoprofen has faster absorption than racemate. • Dexketoprofen has established efficacy and tolerability in the treatment of acute and chronic painful conditions. • Dexketoprofen has comparable analgesic efficacy and tolerability but a faster onset of action than ketoprofen. Dexibuprofen [S(+)ibuprofen] : Racemic ibuprofen, which contains equal quantities of R(-)ibuprofen and S(+)ibuprofen, has been used as an anti-inflammatory and analgesic agent for over 30 years. R-ibuprofen and dexibuprofen differ in their physicochemical, pharmacological and metabolic properties. Sibuprofen or dexibuprofen is the pharmacologically active enantiomer of racemic ibuprofen. Dexibuprofen inhibits both COX-1 and COX-2 enzymes36. Dexibuprofen is the S(+)(dextrorotatory)-enantiomer of ibuprofen and accounts for virtually all pharmacodynamic (analgesic, anti-inflammatory, antipyretic) activities of the racemic compound36. In vitro, dexibuprofen is over 100 times as potent as the R-enantiomer as an inhibitor of prostaglandin biosynthesis36. In therapy, potential advantages of dexibuprofen over racemic ibuprofen include lesser toxicity, greater clinical efficacy and/or less variability in therapeutic effects achieved, and easier dose optimisation, all at half the dose of ibuprofen. Several clinical trials and postmarketing surveillance studies have been performed to elucidate the efficacy and safety of dexibuprofen. More than 12,000 patients were studied in 31 clinical trials till 200337. In vivo, the R-enantiomer of racemic ibuprofen undergoes unidirectional enzymatic chiral inversion to S-enantiomer. This occurs in the range of 35%-85%, whereas there is no bioinversion of S- to Ribuprofen7,8 . Although this would favour use of racemic ibuprofen, since most of its inactive enantiomer is converted to active form, conversion of racemic ibuprofen to S-ibuprofen results in variability of clinical response, including delayed onset of activity, and difficulty in achieving an optimal dose; also the formation of coenzyme A (CoA) thio-ester during bioinversion of R- to S-ibuprofen may result in toxic effects (eg, interference of lipid anabolism/catabolism). In addition, R-ibuprofen bioactivation is susceptible to biological factors and certain drugs7,36. The clinical studies have shown that dexibuprofen is equally effective as the ibuprofen at half the dose13-15. Many clinical studies 13-15,38,39 have evaluated the efficacy and tolerability of dexibuprofen. The findings from these studies demonstrate that dexibuprofen is effective and very well tolerated in patients with osteo-arthritis and dental pain. These effects are comparable to diclofenac, celecoxib and double dose of racemic ibuprofen. Dexibuprofen 200 or 400 mg as a single dose was effective in the treatment of acute pain following third-molar extraction in a doubleblind, placebo-controlled study. Effective pain relief compared to placebo was evident for up to 6 hours following the 400 mg dose13. When given for acute pain following third-molar extraction, single doses of dexibuprofen 200 and 400 mg provided pain relief statistically superior to that of racemic ibuprofen 400 mg and placebo during the first hour postingestion; dexibuprofen 400 mg (but not 200 mg) remained statistically superior to ibuprofen 400 mg at 2 and 3 hours, whereas all regimens provided similar analgesia during hours 4 to 6. The incidence of adverse effects did not differ between groups13. An efficacy study was performed to prove the equivalent efficacy of dexibuprofen compared to the double dose of racemic ibuprofen and to show a clinical dose-response relationship of dexibuprofen. The 1 year tolerability study was carried out to investigate the tolerability of dexibuprofen14. In the efficacy study 178 inpatients with osteo-arthritis of the hip were assigned to 600 or 1200 mg of dexibuprofen or 2400 mg of racemic ibuprofen daily. The primary end-point was the improvement of the Western Ontario and McMaster Universities (WOMAC) osteo-arthritis index. A 1 year open tolerability study included 223 outpatients pooled from six studies. The main parameter was the incidence of clinical adverse events. In REPORT 617 the efficacy study the evaluation of the improvement of the WOMAC osteo-arthritis index showed equivalence of dexibuprofen 400 mg thrice daily compared to racemic ibuprofen 800 mg thrice daily, with dexibuprofen being borderline superior (p=0.055). The comparison between the 400 mg thrice daily and 200 mg thrice daily doses confirmed a significant superior efficacy of dexibuprofen 400 mg (p=0.023). In the tolerability study the overall incidence of clinical adverse events was 15.2% (GI tract 11.7%, CNS 1.3%, skin 1.3%, others 0.9%). The active enantiomer dexibuprofen proved to be an effective NSAID with a significant dose-response relationship. Compared to the double dose of racemic ibuprofen, dexibuprofen was at least equally efficient, with borderline superiority over ibuprofen (p=0.055). The tolerability study in 223 patients on dexibuprofen showed an incidence of clinical adverse events of 15.2% after 12 months. The results of the studies suggest that dexibuprofen is an effective NSAID with good tolerability. A double-blind randomised trial15 was conducted to compare the isolated active enantiomer dexibuprofen with the double dose of racemic ibuprofen and to show a dose-response relationship of dexibuprofen in painful osteo-arthritis of the hip. One hundred and seventy-eight patients were randomly assigned to dexibuprofen 600/1,200 mg or racemic ibuprofen 2,400 mg daily. The evaluation of the WOMAC osteo-arthritis index showed statistically significant equivalence of dexibuprofen 400 mg thrice daily compared with racemic ibuprofen 800 mg thrice daily by a Mann-Whitney statistic of 0.578 and the corresponding lower bound of the 95% confidence interval of 0.498. The test for superiority of dexibuprofen was borderline significant with p=0.055. Dexibuprofen 400 mg thrice daily and dexibuprofen 200 mg thrice daily showed a statistically significant dose-response relationship in improving the WOMAC OA index (p=0.023). Patients suffered from adverse drug reactions, mainly gastro-intestinal disorders, 13.34% on dexibuprofen 200 mg, 15.25% on dexibuprofen 400 mg and 16.94% on racemic ibuprofen 800 mg. Thus, the active enantiomer dexibuprofen proved to be an effective non-steroidal anti-inflammatory drug. Compared with racemic ibuprofen half of the daily dose of dexibuprofen shows at least equivalent efficacy. The additional administration of R-ibuprofen in form of racemate does not contribute to the clinical efficacy of racemic ibuprofen. Dexibuprofen, 300 mg orally three times daily for 15 days was as effective as diclofenac sodium 50 mg orally three times daily in a randomised, double-blind, parallel-group trial of 110 patients with osteo-arthritis of the knee. All patients had a baseline Lequesne index score of at least 8. Improvement in the Lequesne index score averaged 5.9 and 7.4 points after 8 and 15 days, respectively, for the dexibuprofen group compared with 5.5 and 7.3 points for the diclofenac group. In physician assessment at study end, dexibuprofen treatment was judged to be ‘very good’ or ‘good’ in 90.9% of patients versus 86.5% of diclofenac patients; in patient self-assessment, dexibuprofen was judged to be ‘very good’ or ‘good’ in 89.1% of the cases versus 82.7% for diclofenac. Dexibuprofen was better tolerated, with 4 patients (7.3%) discontinuing treatment due to adverse effects compared with 8 patients (14.5%) for diclofenac. Further studies of longer duration and placebocontrolled, cross-over design are needed 38. A randomised, parallel-group, double-blind, active controlled clinical trial aimed to assess the relative therapeutic efficacy and tolerability/safety of dexibuprofen and the selective COX-2 inhibitor celecoxib in adults with osteo-arthritis of the hip39. One hundred and forty-eight inpatients were randomly assigned to dexibuprofen 800 mg or celecoxib 200 mg daily. Evaluation of the WOMAC osteoarthritis index proved that dexibuprofen 400 mg twice daily is not inferior to celecoxib 100 mg twice daily with the Mann-Whitney estimator equal to 0.5129 and the corresponding lower boundary of the 95% confidence interval equal to 0.4409. The overall incidence of adverse drug reactions was 12.16% in the dexibuprofen group and 13.51% in the celecoxib group. 8.1% of patients on dexibuprofen and 9.5% on celecoxib suffered from gastro-intestinal disorders. This shows D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (35) 618 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 aggregated into three subscales: Pain (five items), stiffness (two items) and overall physical function (17 items). The three WOMAC subscales can be analysed separately and aggregated into a total score. The WOMAC is valid, reliable and sufficiently sensitive to detect clinically important changes following interventions. Previous studies have suggested that a change of =10% on a WOMAC subscale indicates a minimal clinically important difference (MCID)52. All patients were evaluated after every two weeks for four weeks for efficacy and safety variables. A total of 49 patients in the test group and 52 patients in the reference group completed the study. There was significant improvement (p<0.0001) in VAS pain score, all WOMAC subscales (pain, stiffness and physical function) and WOMAC total score in both the groups. All patients in both groups showed improvement in WOMAC and VAS pain score by >20% (responder criterion). Patient’s and physician’s global assessment of the arthritic condition also improved significantly (p<0.0001). There was no significant difference between the groups for the efficacy parameters. The upper gastro-intestinal symptoms (heartburn, dyspepsia and vomiting) were seen in two patients in S-etodolac group and in four patients in the racemate group. There was no significant difference between the groups for the incidence of side-effects. A total of five patients in S-etodolac group and two patients in Etodolac group dropped out of the study. Only one patient dropped out because of the sideeffects of burning sensation, palpitations and anxiety in the test group. In conclusion, the extended release S-etodolac tablet, at the single dose of 300 mg/day is as effective as extended release Etodolac tablet at the single dose of 600 mg/day thereby further confirming that the S-enantiomer of etodolac is the active NSAID. Both S-etodolac and etodolac were well tolerated with few side effects. This study has established the efficacy, tolerability and safety of S-etodolac extended release tablets in the treatment of osteo-arthritis in Indian patients. Salient features of S-etodolac — • S-enantiomer of etodolac possesses almost all of the antiinflammatory activity while R-etodolac is almost inactive. • S-etodolac is 2.6 times more potent than the racemate and 100 times more potent than R-enantiomer. • S-etodolac achieves greater concentrations in synovial fluid than plasma. • S-etodolac has a favorable pharmacokinetic profile compared to R-etodolac. • Efficacy and tolerability of S-etodolac is comparable to the racemate. Conclusion : In the light of the facts mentioned above it is now clear that the S and R enantiomers of all NSAIDs that are currently used in clinical practice have different pharmacological properties. It is the Senantiomer of chiral NSAIDs that possesses the anti-inflammatory and analgesic activity. R-enantiomer lacks such activity and has a completely different activity. The needless administration of the Renantiomers that make up 50% of racemic NSAID contributes to an increase in dose, pharmacokinetic variability, metabolic load and enantiomer interactions. Thus, it is a rationale approach to perform the chiral switch ie, to replace the currently used racemic NSAIDs by the optically pure S-enantiomers in order to avoid potential harm to patients. The development of dexketoprofen, dexibuprofen and Setodolac are the positive steps in this direction. REFERENCES 1 Zieliñska-Przyjemska M, G³ówka FK, Klaczyñska J— Modulatory effect of chiral nonsteroidal anti-inflammatory drugs on apoptosis of human neutrophils. Chirality 2008; 20: 159-65. López-Muñoz FJ, Ventura R, Díaz MI, Hernández GP, Domínguez AM, García ML, et al — Analysis of antinociceptive effects of flurbiprofen enantiomers in a rat model of arthritic pain. Methods Find Exp Clin Pharmacol 2000; 22: 641-5. that dexibuprofen has at least equal efficacy and a comparable safety/ tolerability profile as celecoxib in adult patients suffering from osteoarthritis of the hip. Salient features of dexibuprofen — • Dexibuprofen is the pharmacologically active enantiomer of racemic ibuprofen. • Dexibuprofen is over 100 times as potent as the R-enantiomer. • Dexibuprofen has lesser toxicity, greater clinical efficacy, less variability in therapeutic effects achieved and easier dose optimization, all at half the dose of ibuprofen. • Dexibuprofen is effective and very well tolerated in patients with osteo-arthritis and dental pain. • Efficacy comparable to diclofenac, celecoxib and double dose of racemic ibuprofen. S(+)Etodolac : S-etodolac is a chirally pure, pharmacologically active form of etodolac containing only S(+)enantiomer. The racemate etodolac has analgesic, antipyretic, and anti-inflammatory properties40. The drug has been shown to inhibit formation of prostaglandin endoperoxides from arachidonic acid41. Etodolac is more selective for induced COX2 (associated with inflammation) over COX-1 (cytoprotective)42. In experimental models of inflammation, etodolac was demonstrated more potent than phenylbutazone, sulindac and naproxen but less potent than indomethacin40. However, in clinical trials, etodolac has shown comparable efficacy and better gastro-intestinal tolerability when compared with non-selective NSAIDs43. Etodolac possesses a more favourable therapeutic index between anti-inflammatory effects and gastric irritation as compared to other NSAIDs44. It is the S-enantiomer of etodolac that possesses almost all of the anti-inflammatory activity while R-etodolac is almost inactive. Setodolac is 2.6 times more potent than the racemate and 100 times more potent than R-enantiomer 45. S-etodolac achieves greater concentrations in synovial fluid than plasma (SF: plasma ratio=1.98 ± 0.8) compared to R-etodolac (SF: plasma=0.91 ± 0.3)46. S-etodolac has a favourable pharmacokinetic profile compared to R-etodolac. S-etodolac rapidly attains the peak plasma concentration and is rapidly cleared from plasma compared to R-etodolac. The pharmacologically inactive R-etodolac has higher plasma concentration compared to S-etodolac. The pharmacokinetic differences are attributed to the greater extent of plasma protein binding of R-etodolac, and to preferential conjugation and biliary excretion of S-etodolac47. In addition, findings from human serum albumin (HSA) study suggest that R- and S-etodolac interact mainly with site II of HSA and are displaced by each other48. Using both the isomers simultaneously (ie, racemate etodolac) thus leads to significant interactions between the isomers for competitive binding to HSA. Thus, it is justified to use a single active, potent enantiomer with the anti-inflammatory activity ie, S-etodolac. Numerous studies40,49,50 have established the efficacy and tolerability of racemic etodolac compared to other NSAIDs in the treatment of osteo-arthritis, rheumatoid arthritis and postoperative pain. Efficacy and safety of S-etodolac and etodolac in the treatment of osteo-arthritis was compared in an open label, multicentric, comparative clinical trial in Indian patients51. A total of 108 Indian patients, diagnosed with osteo-arthritis were enrolled in the study. All patients received either S-etodolac ER 300 mg (test) or Etodolac ER 600 mg (reference) tablets once daily. Assessment was done on the basis of WOMAC score and visual analogue scale (VAS) pain score, patient’s and physician’s global assessment of the arthritic condition. WOMAC is a three-dimensional, disease-specific and selfadministered health status questionnaire, which is commonly used in osteo-arthritis outcomes research. For this study, the Likert scale version 3.1 was used, which contains 24 items for rating symptoms and functional impairments with five response categories (0=none, 1=mild, 2=moderate, 3=severe, 4=extreme). The WOMAC items are 2 D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (36) 622 3 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 Geerts H — Drug evaluation: (R)-flurbiprofen—an enantiomer of flurbiprofen for the treatment of Alzheimer’s disease. I Drugs 2007; 10: 121-33. Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM, et al — Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 2004; 101: 3118-23. Kolluri SK, Corr M, James SY, Bernasconi M, Lu D, Liu W, et al — The R-enantiomer of the nonsteroidal antiinflammatory drug etodolac binds retinoid X receptor and induces tumor-selective apoptosis. Proc Natl Acad Sci USA 2005; 102: 2525-30. Yasui H, Hideshima T, Hamasaki M, Roccaro AM, Shiraishi N, Kumar S, et al — SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma. Blood 2005; 106: 70612. Gabard B, Nirnberger G, Schiel H, Mascher H, Kikuta C, Mayer JM — Comparison of the bioavailability of dexibuprofen administered alone or as part of racemic ibuprofen. Eur J Clin Pharmacol 1995; 48: 505-11. Rudy AC, Bradley JD, Ryan SI, Kalasinski LA, Xiaotao Q, Hall SD — Variability in the disposition of ibuprofen enantiomers in osteoarthritis patients. Ther Drug Monit 1992; 14: 464-70. Cooper SA, Reynolds DC, Reynolds B, Hersh EV — Analgesic efficacy and safety of (R)-ketoprofen in postoperative dental pain. J Clin Pharmacol 1998; 38: 11S-18S. Jerussi TP, Caubet JF, McCray JE, Handley DA — Clinical endoscopic evaluation of the gastroduodenal tolerance to (R)ketoprofen, (R)-flurbiprofen, racemic ketoprofen, and paracetamol: a randomized, single-blind, placebo-controlled trial. J Clin Pharmacol 1998; 38: 19S-24S. Rudy AC, Liu Y, Brater C, Hall SD — Stereoselective pharmacokinetics and inversion of (R)-ketoprofen in healthy volunteers. J Clin Pharmacol 1998; 38: 3S-10S. Cheng H, Rogers JD, Demetriades JL, Holland SD, Seibold JR, Depuy E — Pharmacokinetics and bioinversion of ibuprofen enantiomers in humans. Pharm Res 1994; 11: 824-30. Dionne RA, McCullagh L — Enhanced analgesia and suppression of plasma beta-endorphin by the S(+)-isomer of ibuprofen. Clin Pharmacol Ther 1998; 63: 694-701. Mayrhofer F — Efficacy and long-term safety of dexibuprofen [S(+)-ibuprofen]: a short-term efficacy study in patients with osteoarthritis of the hip and a 1-year tolerability study in patients with rheumatic disorders. Clin Rheumatol 2001; 20: S22-9. Singer F, Mayrhofer F, Klein G, Hawel R, Kollenz CJ — Evaluation of the efficacy and dose-response relationship of dexibuprofen (S(+)-ibuprofen) in patients with osteoarthritis of the hip and comparison with racemic ibuprofen using the WOMAC osteoarthritis index. Int J Clin Pharmacol Ther 2000; 38: 15-24. Barbanoj MJ, Gich I, Artigas R, Tost D, Moros C, Antonijoan RM, et al — Pharmacokinetics of dexketoprofen trometamol in healthy volunteers after single and repeated oral doses. J Clin Pharmacol 1998; 38: 33S-40S. Mauleon D, Artigas R, Garcia L, Carganico G — Preclinical and clinical development of dexketoprofen. Drugs 1996; 52: 24-46. Sattari S, Jamali F- Involvement of the rat gut epithelial and muscular layer, and microflora in chiral inversion and acylglucuronidation of R-fenoprofen. Eur J Drug Metab Pharmacokinet 1997; 22: 97-101. Cabré F, Fernández F, Zapatero MI, Araño A, García ML, Mauleón D — Intestinal ulcerogenic effect of S(+)-ketoprofen in the rat. J Clin Pharmacol 1998; 38: 27S-32S. Nieto AI, Cabré F, Moreno FJ, de la Lastra CA — Mechanisms Involved in the attenuation of intestinal toxicity induced by (S)(+)-ketoprofen in Re-Fed Rats. Dig Dis and Sci 2002; 47: 90513. 2 1 Barbanoj MJ — Clinical pharmacokinetics of dexketoprofen trometamol: recent studies. Methods Find Exp Clin Pharmacol 2006; 28: 3-5. 2 2 McGurk M, Robinson P, Rajayogeswaran V, De Luca M, Casini A, Artigas R, et al — Clinical comparison of dexketoprofen trometamol, ketoprofen, and placebo in postoperative dental pain. J Clin Pharmacol 1998; 38: 46S-54S. 2 3 Jackson ID, Heidemann BH, Wilson J, Power I, Brown RD- Doubleblind, randomized, placebo-controlled trial comparing rofecoxib with dexketoprofen trometamol in surgical dentistry. Br J Anaesth 2004; 92: 675-80. 2 4 Gay C, Planas E, Donado M, Martínez JM, Artigas R, Torres F, et al — Analgesic efficacy of low doses of Dexketoprofen in the dental pain model. Clin Drug Invest 1996; 11: 320-30. 2 5 Data on File 1 — A Multicentric, Comparative, Randomized, Parallel Group Clinical Trial to Evaluate the Efficacy and Safety of Dexketoprofen trometamol in the Treatment of Dental Pain. 2 6 Beltrán J, Martín-Mola E, Figueroa M, Granados J, Sanmartí R, Artigas R, et al — Comparison of dexketoprofen trometamol and Ketoprofen in the treatment of osteoarthritis of the knee. J Clin Pharmacol 1998; 38: 74S-80S. 2 7 Rovetta G, Monteforte P, Brignone A, Molfetta L, Buffrini L— Early-morning administration of dexketoprofen-trometamol in morning stiffness induced by nodal osteoarthritis of the hands. Int J Tissue React 2001; 23: 63-6. 2 8 Zippel H, Wagenitz A — Comparison of the efficacy and safety of intravenously administered dexketoprofen trometamol and ketoprofen in the management of pain after orthopaedic surgery: A multicentre, double-blind, randomised, parallel-group clinical trial. Clin Drug Invest 2006; 26: 517-28. 2 9 Ezcurdia M, Cortejoso FJ, Lanzón R, Ugalde FJ, Herruzo A, Artigas R, et al — Comparison of the efficacy and tolerability of Dexketoprofen and Ketoprofen in the treatment of primary dysmenorrhea. J Clin Pharmacol 1998; 38: 65S-73S. 3 0 Data on File 2- A Multicentric, Comparative, Randomized, Parallel Group Clinical Trial to Evaluate the Efficacy and Safety of Dexketoprofen trometamol in the Treatment of Dysmenorrhea. 3 1 Leman P, Kapadia Y, Herington J — Randomised controlled trial of the onset of analgesic efficacy of dexketoprofen and Diclofenac in lower limb injury. Emerg Med J 2003; 20: 511-3. 3 2 Gaitán G, Herrero JF- Subeffective doses of dexketoprofen trometamol enhance the potency and duration of fentanyl antinociception. Br J Pharmacol 2002; 135: 393-8. 3 3 Iohom G, Walsh M, Higgins G, Shorten G- Effect of perioperative administration of dexketoprofen on opioid requirements and inflammatory response following elective hip arthroplasty. Br J Anaesth 2002; 88: 520-6. 3 4 Miranda HF, Puig MM, Dursteler C, Prieto JC, Pinardi GDexketoprofen-induced antinociception in animal models of acute pain: synergy with morphine and paracetamol. Neuropharmacology 2007; 52: 291-6. 3 5 Sánchez-Carpena J, Domínguez-Hervella F, García I, Gene E, Bugarín R, Martín A, et al — Dexketoprofen Renal Colic Study Group.Comparison of intravenous dexketoprofen and dipyrone in acute renal colic. Eur J Clin Pharmacol 2007; 63: 751-60. 3 6 Mayer JM, Testa B — Pharmacodynamics, pharmacokinetics and toxicity of ibuprofen enantiomers. Drugs Fut 1997; 22: 1347-66. 3 7 Kaehler ST, Phleps W, Hesse E — Dexibuprofen: pharmacology, therapeutic uses and safety. Inflammopharmacology 2003; 11: 371-83. 3 8 Hawel R, Klein G, Mitterhuber J, Brugger A — Double-blind comparative study of the effectiveness and tolerance of 900 mg dexibuprofen and 150 mg diclofenac sodium in patients with painful gonarthrosis. Wien Klin Wochenschr 1997; 109: 53-9. 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (37) 624 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 properties of the enantiomers. J Med Chem 1983; 26: 1778-80. 4 6 Brocks DR, Jamali F — Enantioselective pharmacokinetics of etodolac in the rat: tissue distribution, tissue binding, and in vitro metabolism. J Pharm Sci 1991; 80: 1058-61. 4 7 Brocks DR, Jamali F — The pharmacokinetics of Etodolac enantiomers in the rat. Lack of pharmacokinetic interaction between enantiomers. Drug Metab Dispos 1990; 18: 471-5. 4 8 Mignot I, Presle N, Lapicque F, Monot C, Dropsy R, Netter P — Albumin binding sites for Etodolac enantiomers. Chirality 1996; 8: 271-80. 4 9 Andelman SY — Etodolac, aspirin, and placebo in patients with degenerative joint disease: a twelve-week study. Clin Ther 1983; 5: 651-61. 5 0 Ciompi ML, Puccetti L, Bazzichi L, Remorini E, Marotta G — Etodolac versus Diclofenac: double-blind cross-over study in rheumatoid arthritis. Int J Clin Pharm Res 1989; 9: 217-22. 5 1 Data on File 3 — A Multicentric, Randomized, Comparative Clinical Trial to Evaluate the Efficacy and Safety of S-Etodolac in the Treatment of Osteoarthritis. 5 2 Kapstad H, Rustoen T, Hanestad BR, Moum T, Langeland N, Stavem K — Changes in pain, stiffness and physical function in patients with osteoarthritis waiting for hip or knee joint replacement surgery. Osteoarthritis Cartilage 2007; 15: 837-43. 3 9 Hawel R, Klein G, Singer F, Mayrhofer F, Kahler ST — Comparison of the efficacy and tolerability of dexibuprofen and celecoxib in the treatment of osteoarthritis of the hip. Int J Clin Pharmacol Ther 2003; 41: 153-64. 4 0 Joubert L, Mullane JF, Merlo M — Clinical pharmacological profile of Ultradol(R), a new nonsteroidal anti-inflammatory drug. Curr Ther Res 1982; 32: 74-88. 4 1 Ferdinandi ES, Cayen MN, Pace-Asciak C- Disposition of Etodolac, other anti-inflammatory pyranoindole-1-acetic acids and furobufen in normal and adjuvant arthritic rats. J Pharmacol Exp Ther 1982; 220: 417. 4 2 Glaser K, Sung ML, O’Neill K, Belfast M, Hartman D, Carlson R, et al — Etodolac selectively inhibits human prostaglandin G/H synthase 2 (PGHS-2) versus human PGHS-1. Eur J Pharmacol 1995; 281: 107-111. 4 3 Liang TH, Hsu PN — Double-blind, randomised, comparative trial of Etodolac SR versus Diclofenac in the treatment of osteoarthritis of the knee. Curr Med Res Opin 2003; 19: 336-41. 4 4 Martel R, Klicius J — Comparison of the anti-inflammatory and ulcerogenic effects of Etodolac with several clinically effective anti-inflammatory drugs. Agents Actions 1982; 12: 1. 4 5 Demerson CA, Humber LG, Abraham NA, Schilling G, Martel RR, Pace-Asciak C — Resolution of Etodolac and antiinflammatory and prostaglandin synthetase inhibiting (Continued from page 614) dry cough, syncope or pedal oedema. Vertigo was severe enough in one patient, which required discontinuation of therapy. Otherwise the drug did not produce any life threatening adverse effect requiring hospitalisation. At the end of the study it was found that 86.3% of the hypertensive patients and 70.37% diabetic hypertensive patients achieved the JNC VII recommended goals. Hypertension and diabetes together considerably accelerate the development of macrovascular and microvascular complications. Combined antihypertensive therapy plays a crucial role in achieving targeted BP reductions. The drug was well tolerated by the trial population and no ADR was reported in most cases and only mild ADR was observed in 7.69% of the cases. ACKNOWLEDGMENT We acknowledge the physicians of The Indian TelmisartanAmlodipine Study Group which consist of following doctors all over India. Dr Rajendra Dhore – Amrawati, Dr Shirish Ardhapurkar – Nanded, Dr G B Gupta – Raipur, Dr Rohit Shah – Nasik, Dr K G Pargaonkar – Aurangabad, Dr I B Mishra – Rewa, Dr M A Sami – Palna, Dr S R Gatagat – Latur, Dr Mukund Ganeriwal – Nagpur, Dr Sanjay Jain – Nagpur, Dr J Subhedar – Ratlam, Dr Prashant Pophalkar - Akola, Dr Ravi Bhatia – Indore, Dr O P Jugtawat – Khandwa, Dr N S Morya Sagar, Dr Satish Ghosh – Kolkata, Dr S M Rohtagi – Patna, Dr S N Mishra – Patna, Dr Durga Sankar – Muzaffarpur, Dr Yogesh KadamPune, Dr Gopal Chatterjee – Dhanbad, Dr Dilip Kumar – Motihari, Dr Syamal Kundu – Bankura, Dr Subrata Kundu – Burdwan, Dr Anjan Ghosh – Kolkata, Dr Ashis Chatterjee – Kolkata, Dr P K Ghosh – Kolkata, Dr Ashfaque Ahmad - Midnapore, Dr A K Jha – Purnia, Dr D Mitra – Kolkata, Dr H Aktar – Kolkata, Dr N Chatterjee – Kolkata, Dr Anupam Das – Kolkata, Dr Debasis De – Kolkata, Dr Indranil Maitra – Kolkata, Dr S K Tandon - Allahabad, Dr Shantanu Ghosh – Bhagalpur, Dr A K Tandon - Varanasi, Dr Ashok Kumar – Lucknow, Dr Brijesh Singh - Raibareilly, Dr S P Shrivastava – Lucknow, Dr R K C Mishra - Gorakhpur, Dr Vinod Paramshetti – Sangli, Dr Vinod Chajed - Dhule, Dr Deepak Jawale – Bhusawal (Jalgaon ), Dr T S Jagtap Satara, Dr K Rajesh – Kolhapur, Dr Sanjay Godbole - Mumbai, Dr Pravin Shingi – Manmad (Nasik ), Dr Mangesh Tiwaskar- Mumbai, Dr Rajesh Ghagare – Mumbai, Dr Santosh Nagare – Mumbai, Dr Shivaraj C Pataria – Mumbai, Dr B M Karwa – Mumbai, Dr C Velani – Mumbai, Dr Kaldane T G - Mumbai, Dr Abhay Salve – Ahmednagar, Dr Anil Adya - Delhi, Dr Anil Kumar Bhatt – Dehradun, Dr Ajit SawhneyBareilly, Dr Pradeep Kawatra – Delhi, Dr Ravinder Kumar – Delhi, Dr Sandeep Jain – Meerut, Dr Anil Gomber – Delhi, Dr J S Kochar – Delhi, Dr S K Arora – Delhi, Dr Gunasekaran – Chennai, Dr R S Jawahar – Kakinada, Dr Praveen M – Vijayawada, Dr G Ravikanth – Hyderabad, Dr R Gopinath – Madurai, Dr Sundar – Chennai, Dr S Selvamoorthy – Thanjavur, Dr V Rajkumar – Salem. REFERENCES 1 The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Institutes of Health, National Heart, Lung, and Blood Institute, November 1997; New Delhi: NIH Publication No 98-4080. 2 Barry S, Jones RE — Management of hypertension in diabetes. Diabetes Spectrum 2006; 19: 25-31. 3 Backman JA, Creager MA, Libby P — Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002; 287: 2570-81. 4 James RS, Murray E, Edward DF — Diabetes, hypertension, and cardiovascular disease: an update. Hypertension 2001; 37: 1053-9. 5 Deedwania P — Diabetes and hypertension, the deadly duet: importance, therapeutic strategy, and selection of drug therapy. Cardiol Clin 2005; 23: 139-52. 6 Tuomilehto J, Rastenyte D, Willem H — Effect of calciumchannel blockade in older patients with diabetes and systolic hypertension. N Engl J Med 1999, 340: 677-84. 7 Sharma A, Bagchi A, Kinagi SB, Sharma YK, Baliga VP Bollmall , C — Results of a comparative, phase III, 12-week, multicenter, prospective, randomized, double-blind assessment of the efficacy and tolerability of a fixed-dose combination of telmisartan and amlodipine versus amlodipine monotherapy in Indian adults with stage II hypertension. Clin Ther 2007; 29: 2667-76. D:\SEPTEMBER-2008\SEPTEMBER-2008.PM65 (38) 626 J INDIAN MED ASSOC, VOL 106, NO 9, SEPTEMBER 2008 "JIMA" Committee (Elected Member) Hony Associate Editors Dr Chandan Banerjee 9433013407 Dr Tamonas Choudhari 9830067567 Hony Assistant Secretary Dr Iskandar Hossain 9830435487 Members Dr Malay Kumar Maitra 9433072008 Dr. Sudarsan Ghosh Dastidar 9830031950 Dr Tapas Chakraborty 9434036741 Dr Rahul Dutta 9331031516 Dr Manabbrata Majumdar 9433010974 Thiruchirappalli Branch (Tamilnadu) — The Branch held CME on 26-07-2008 on the topic ‘Recent Developments in the Understanding and Management of Diabetic Retinopathy’ by Prof Dr P Namperumalsamy. The Branch conducted free medical camp along with Sri Palaniyandavar Medical Trust at Puthanampatti village on 13-07-2008. One hundred three patients are benefited in the camp. Branch conducted free medical camp at Chinnappanaiyur village (adopted under the aegis of Aao Gaon Chalen project) on 26-07-2008. Virudhunagar District Branch (Tamilnadu) — The Branch organise CME on 30-08-2008, the topic ‘Oral Hypo Glycemic Agents’ talk was given by Dr Dharama Raja. Announcements 15th Annual Conference of API West Bengal Branch to be held on 1st and 2nd November, 2008 at The Park Hotel, Kolkata. For further details, please contact : Prof Alok Kumar Ghosh, Chairman and Prof R N Sarkar, Hony Secretary, Association of Physicians of India, West Bengal Branch, Secretariat: ‘Moon Plaza’, 62, Lenin Sarani, 2nd Floor, Flat No. 2D, Kolkata 700013, Phone : (033) 22276024, 2227-6048, E-mail : NEOCON 2008 XXVIII Annual Convention of National Neonatology Forum will be held on 11-14th December, 2008, Kolkata. For further details, please contact : Dr Bikash Bhattacharya, Organising Secretary, NEOCON 2008, 53, Creek Row, Kolkata 700014, Website : www.neocon2008kolkata.org Corrigenda (1) In the Branch Notes column vide pp 476, JIMA July issue 2008, the name of the Secretary of the Branch would be Chandan Banerjee instead of Cnandan Banerjee published under subheading, Calcutta Branch (Bengal). (2) The word ‘enormous’ has been published inadvertently as ‘enromous’ in the Book Review in the August, 2008 issue of JIMA, pp 544. — Hony Editor ALL INDIA ADVISORY BOARD Dr A Murugganathan Dr Ajay Kumar Singh Dr Arun Kumar Thakur Dr Arvind Jain Dr Dipak Dhar Choudhury Dr E Vijayendra Reddy Dr G K Ramachandrappa Dr G K Thakur Dr Gulab Aggarwal Dr Hozie Dara Kapadia Dr Jitendra B Patel Dr K C Raju Reddy Dr Lalbhai M Patel Dr M Balasubramanian Dr M V Vijaya Sekhar Dr Manabandra Goswami Dr Miland Naik Dr Mohan Gupta Dr (Mrs) V Janaki Dr N L Aggarwal Dr Om Prakash Singh Kande Dr Om Prakash Tewari Dr R K Aggarwal Dr R Ramesh Dr S P Sexena Dr Sahajanand Prasad Singh Dr Samar Banerjee Dr Santosh Kumar Mondal Dr Satish Chugh Dr Srijoy Patnaik Dr V C Velayudhan Pillai Dr Vijay C Panjabi Dr Vinay Aggarwal Availability of IMA Guest House at Kolkata A Super Deluxe Air Conditioned Guest House close to Sealdah Railway Station and Esplanade having 8 rooms at IMA House, 3rd floor, 53, Creek Row, Kolkata 700 014. The Guest House is available to the members/officers with authenticated forwarding letters and/or introduction. Deluxe Single Bedded Room (AC) ----------- Rs.600.00 per day Deluxe Double Bedded Room (AC)----------- Rs.500.00 per bed per day Double Bedded Room (AC) --------------------- Rs.400.00 per bed per day Triple Bedded Room (AC) ----------------------- Rs.400.00 per bed per day Dormitary (5 bedded, Non-AC) ----------------- Rs.200.00 per bed per day Facilities : • Lift • Colour TV with Cable connection • Security • Telephone • Cold & Hot Water • Pantry • Car Hire facility • Luxury Rooms with Granite flooring Complimentary : Bed Tea, Biscuits with Breakfast (Veg / Non-veg) For further details please contact : Dr. Sibadatta Chaudhury, Hony Joint Secretary, Indian Medical Association (Hq), Kolkata, IMA House, 53, Creek Row, Kolkata - 700 014, Phone : (033) 22360573, 2237-8092, Fax : (033) 2236-6437, E-mail : j_ima@vsnl.net