Pharmacological Management of Sickle Cell Disease by djh75337



Pharmacological Management
of Sickle Cell Disease
Uche Anadu Ndefo, PharmD, BCPS; Angie Eaton Maxwell, PharmD; Huong Nguyen, PharmD
Candidate; and Tochukwu L. Chiobi, PharmD

 Educational Objectives                                            Pathogenesis
                                                                      Sickle cell disease is characterized by a structural abnormal-
 After reviewing this article, readers should be able to:          ity in the beta-globin chain of the hemoglobin molecule within
 I Define the basic hematological defect in sickle cell disease.   the red blood cells (RBCs). The sickle mutation is a single base
                                                                   change (GAT → GTT) in the sixth codon of exon-1 of the beta-
 I Identify the mechanisms of action and adverse events
                                                                   globin gene on chromosome 11. This change leads to the
   associated with standard treatment options.                     synthesis of the beta-globin polypeptide of the hemoglobin
 I Review the protocol for preventing stroke and infection in      molecule. This mutation causes the replacement of the normal
   patients with sickle cell disease.                              glutamic acid with valine acid, thus resulting in the formation
                                                                   of the sickle cell hemoglobin (HbS). This hydrophobic amino-
 I Identify treatment options currently under investigation.
                                                                   acid substitution causes the hemoglobin to take on a “sickle”
                                                                   shape when in a deoxygenated state.
                                                                      The ability of these sickled cells to adapt to their surround-
Introduction                                                       ings is impaired, especially in the microvasculature. These
   Sickle cell disease (SCD) is the most common inherited          cells hemolyze prematurely, accounting for the chronic anemia
blood disorder in the U.S., affecting about 72,000 Americans.      frequently encountered by patients with SCD.5 The paucity of
It is also the most common inherited disease among African-        sickled cells in newborns with SCD led to the discovery that
Americans and affects approximately one                                                   fetal hemoglobin (HgF) reduces the
out of every 500 newborns. People of other                                                severity of SCD by preventing the forma-
races are also affected by SCD, with a rate                                               tion of the hemoglobin S polymer.6
of one of every 1,000 to 1,400 Hispanic-                                                     Fever, dehydration, hypoxia, acidosis,
American births.1 A significant prevalence                                                stress, and a cold environment may pre-
of the mutation responsible for sickle cell                                               cipitate sickling, although a precursor
has been reported among other ethnic groups such as those          event is not always identified.7,8 The pathophysiology of SCD
native to Italy, Greece, Turkey, Saudi Arabia, India, Pakistan,    is considerably complex, involving abnormalities of hemo-
Bangladesh, China, and Cyprus.2                                    globin, the RBC’s membrane, er ythrocyte hydration, the
   In 2004, 83,149 hospitalizations were attributable to SCD in    endothelium, vascular tone, inflammatory responses, leuko-
the U.S., at a cost of almost $488 million.3 Episodes of pain,     cytes, and coagulation. This forceful combination of factors
chronic hemolytic anemia, and severe infections are some of        results in cell interactions, generating hemolysis and micro-
the common characteristics of this disease that begin in early     vascular obstruction, ultimately leading to damage of nearly all
childhood.4 Management of SCD is geared toward preventing          organ systems.9
complications and reducing the number of sickle cell crises.

                                                                   Risk Factors
Dr. Ndefo and Dr. Maxwell are Assistant Professors of Pharmacy        Two million people worldwide are carriers of or have the
Practice in the College of Pharmacy and Health Sciences at Texas   sickle cell trait. Carriers are usually asymptomatic and have a
Southern University in Houston, Texas. They are also Drug          low percentage of sickle hemoglobin (HbS). Two parents who
Information Specialists at Harris County Hospital District in      are carriers can both pass on the sickle cell trait to their off-
Houston. Huong Nguyen is a pharmacy student at Texas Southern      spring, resulting in SCD. There is a 50% chance with each
University. Dr. Chiobi is a recent graduate of Texas Southern      pregnancy for the child of two sickle cell carriers to be born
University.                                                        with the sickle cell trait, and there is a 25% chance for the child
                                                                   to be born with SCD (Figure 1).
Accepted for Continuing Education Credit March 4, 2008.

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Table 1 Prophylaxis of Complications from Sickle Cell Disease

Complication                                                                        Prophylactic Therapy
Streptococcus pneumoniae sepsis                            Newborns to 3 years:
                                                              • Penicillin VK, 125 mg orally twice daily
                                                           3 to 5 years:
                                                              • Penicillin VK, 250 mg orally twice daily
                                                           2 years:
                                                              • 23-valent Streptococcus pneumoniae polysaccharide vaccine (PPV23)
Bone marrow aplasia and megaloblastic erythropoiesis 1 mg folic acid daily
Stroke                                                     Exchange transfusions
Pain episodes                                              Hydroxyurea
                                                           Initiation of treatment:
                                                              • 10–15 mg/kg/day single daily dose for six to eight weeks
                                                              • complete blood count every two weeks
                                                              • percent fetal hemoglobin every six to eight weeks
                                                              • serum chemistries every two to four weeks

Diagnosis                                                              Treatment Options
   Screenings for SCD at birth are now performed in most                  The only cure for SCD is bone marrow transplantation,
states in the U.S. The presence of hemoglobin S (HbS) with             which usually necessitates a human lymphocyte antigen
elevated fetal hemoglobin (HbF) and the absence of hemoglo-            (HLA)- identical family member donor. There is an 85% disease-
bin A indicate either sickle cell anemia or beta thalassemia. It       free survival rate, with a 7% transplant-related mortality rate
is imperative that sickle cell anemia be detected early, be-           and a 9% graft failure rate.10 Barriers to the widespread use of
cause preventive care must begin by the time a child is two            bone marrow transplantation in patients with SCD include a
months of age to improve survival.                                     lack of suitable bone marrow donors and the need to identify
   The diagnosis of SCD is usually confirmed by electro-               patients with an adequate risk-to-benefit ratio. For these rea-
phoresis. The sickle cell trait is also identified in screenings of    sons, drug therapy for SCD continues to be the primary mode
newborns, who have a much lower percentage of hemoglobin               of disease management, focusing on decreasing the complica-
S than other patients with SCD.                                        tions of this disease (Table 1).

                                                                          Hydroxyurea, the only agent that the Food and Drug Admin-
                                                                       istration (FDA) has approved for the management of SCD, is
                                                                       indicated for sickle cell patients who have had at least three
                                                                       painful crises in the previous 12 months. Hydroxyurea prevents
                                                                       the complications of SCD by increasing HbF and total hemo-
                                                                       globin concentrations, by decreasing the adhesion of sickled
                        AS          AS                                 cells to the endothelium in vitro, and by increasing polymer-
                                                                       ization time.11
                                                                          The Multicenter Study of Hydroxyurea in Sickle Cell
                                                                       Anemia (MSH) was a randomized, double-blind, placebo-
                                                                       controlled clinical trial in which adult patients were assigned
                                                                       to receive hydroxyurea and placebo. Treatment with hydroxy-
                                                                       urea resulted in a 44% difference in the median annual rate of
                                                                       painful crises: 2.5 crises per year in the hydroxyurea arm vs.
                                                                       4.5 crises per year in the placebo arm. Because hydroxyurea
                AA        AS        AS        SS
                                                                       reduced the frequency of episodes of pain, acute chest syn-
 Figure 1 Risk factors. Two parents with the sickle cell trait         drome, and the need for blood transfusion, the study was
 (AS) have a 25% chance of having a child without the sickle           stopped four months early.12
 cell trait (AA), a 50% chance of having a child with the sickle          A nine-year follow-up of the participants in this trial showed
 cell trait (AS), and a 25% chance of having sickle cell disease       a 40% reduction in mortality rates for patients taking hydroxy-
 (SS). In this inherited condition, both hemoglobin A and S are        urea.13 In small clinical trials of hydroxyurea in children with
 produced in the red blood cells (more A than S).                      SCD, the agent was found to be safe and efficacious, and these
                                                                       effects were sustained in long-term trials.14–16

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Table 2 Treatment Options for Complications from Acute Sickle Cell Disease

Complication                                                                Therapy
Pain                         Mild to moderate                               Codeine with acetaminophen or aspirin
                                                                              • orally every three to four hours
                                                                            Hydrocodone with acetaminophen
                                                                              • orally every three to four hours
                             Moderate to severe                             Morphine sulfate immediate-release (MSIR)
                                                                              • IV every two to four hours
                                                                              • orally every three to four hours
                                                                              • IV or orally every three to four hours
Infection                    Fever without a source                         Empirical therapy coverage for:
                             (rule out sepsis)                              Streptococcus pneumoniae, Salmonella, Haemophilus influenzae,
                                                                            gram-negative enterics
                             Meningitis                                     Streptococcus pneumoniae, Neisseria meningitides, H. influenzae
                             Chest syndrome                                 S. pneumoniae, Legionella, Mycoplasma pneumoniae, respiratory
                                                                            syncytial virus, Chlamydia pneumoniae
                             Osteomyelitis/septic arthritis                 Salmonella, Staphylococcus aureus, S. pneumoniae
                             Urinary tract infection                        Escherichia coli, other gram-negative enterics
   IV = intravenously.
   From National Institutes of Health. The Management of Sickle Cell Disease, 4th ed. revised, June 2002.22

  Hydroxyurea’s potential benefits should be weighed against                   After the pain has diminished and has tapered off, an oral
the risks of bone marrow suppression, which is reversible                      analgesic can be given.
when the drug is discontinued. Complete blood counts are                          The opiate drugs that have been studied to treat SCD include
recommended every four to eight weeks after the hydroxyurea                    morphine, hydromorphone, fentanyl (Duragesic, PriCara),
dose is stabilized.                                                            and codeine-related agents.20 Morphine is considered the drug
                                                                               of choice for the treatment of acute sickle cell pain (Table 2),
Pain Medications                                                               whereas meperidine (Demerol, Sanofi-Synthelabo) should be
   Pain, which is usually attributed to ischemia from the ob-                  avoided because of the increased risk of seizures in patients
struction of blood vessels by sickled cells, is the most common                with renal dysfunction, which can occur in patients with SCD.
symptom of SCD. It can be acute or chronic, and it varies
among individuals in its frequency and intensity. Pain is the                  Infection Prophylaxis
primary cause of hospitalization in patients with SCD, which                      Patients with SCD are at an increased susceptibility to pneu-
is why proper management of pain in this population is essen-                  mococcal infection primarily because of the development of
tial.17                                                                        functional asplenia, which can occur at as early as six months
   The general approach to the treatment of pain is to identify                of age.21 In the absence of a functional spleen, the organ can
the causes, which include infection, extreme temperature, and                  no longer serve its immunological functions of clearing bac-
emotional stress. Usually, however, there is not an identifiable               teria from the blood and synthesizing antibodies, circum-
cause, and the pain crisis occurs without warning. Milder pain                 stances that can lead to an increased frequency of infection.22
is treated with general nonsteroidal anti-inflammatory drugs                      In the PRophylaxis with Oral Penicillin in children with
(NSAIDs) such as ibuprofen and ketorolac tromethamine                          Sickle Cell Anemia (PROPS) study, when infants received pro-
(Toradol, Roche) or analgesics like acetaminophen and tram-                    phylactic penicillin between three months and three years of
adol (Ultram, PriCara).                                                        age, pneumococcal infection rates decreased by 84%.23 PROPS
   Severe painful episodes should be treated with parenteral                   II evaluated the consequences of discontinuing penicillin pro-
opiates at frequent intervals, not on an as-needed basis. In a                 phylaxis at five years of age, and there was no difference in the
study comparing intermittent intravenous (IV) injections and                   rates of infection in the penicillin arm, compared with the
patient-controlled analgesia (PCA), PCA reduced the length of                  placebo arm (relative risk = 0.5).21
stay and was as efficacious as the injections.18                                  On the basis of the PROPS and PROPS II results, children
   Acute episodes of pain may also be treated with IV hydration,               younger than three years of age should receive 125 mg of
and milder episodes may be treated with oral hydration—                        penicillin orally twice daily, and children between three and five
regardless of the patient’s state of hydration—to slow or stop                 years of age should receive 250 mg of penicillin orally twice a
the sickling process, which can be promoted by dehydration.19                  day. For patients who are allergic to penicillin, erythromycin

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ethyl succinate (e.g., EryPed, Abbott) 20 mg/kg, divided into          it is proposed that folate in anemia raises hemoglobin levels
two daily doses, can provide adequate prophylaxis.24 Prob-             and helps provide a healthy reticulocyte response,32 the use of
lems with penicillin prophylaxis include compliance, drug              folic acid in patients with SCD is not well supported by the
cost, patient tolerance, and resistant strains of micro -              primary literature. One prospective, randomized study, pub-
organisms.25                                                           lished in 1983, found no “striking effects” of folic acid supple-
   Immunizations in children with SCD should include all reg-          mentation in sickle cell anemia on the hematological profile or
ular vaccines, with the addition of the flu vaccine yearly after       on growth in children with SCD who received this nutrient.33
six months of age; pneumococcal vaccine at two and five years              In another study that measured folate stores in children
of age; and, possibly, meningococcal vaccine.26                        with SCD who were not receiving folic acid, folate levels were
                                                                       found to be adequate.34 The National Heart, Lung, and Blood
Stroke Prevention                                                      Institute guideline for SCD does recommend folic acid sup-
   The prevalence of stroke in patients with SCD was reported          plementation for patients with sickle cell anemia at the dose of
to be 11% before routine screening with transcranial Doppler           1 mg/day.21
ultrasonography (TCD) and monthly transfusions for primary
stroke prevention in children at risk. Not all children with           Pulmonary Hypertension
SCD are at equal risk for stroke; Doppler ultrasound should               Some studies have suggested that pulmonary hypertension
be performed to assess the patient’s blood flow velocity, be-          (PHTN) is common in patients with sickle cell anemia. A
cause high blood flow velocity has been correlated with a sub-         prospective study of sickle cell anemia reported a 31% preva-
sequent stroke in children with SCD.27                                 lence of PHTN in children 10 years of age and older.35 There
   In a randomized study of children with SCD, patients who            is emerging evidence on the treatment of traditional PHTN
had abnormal results (time-averaged mean blood flow exceed-            with prostanoids such as epoprostenol (Flolan, GlaxoSmith-
ing 200 cm/second) received standard-of-care or transfusions           Kline) and phosphodiesterase-5 inhibitors such as sildenafil
with a target hemoglobin S concentration of less than 30%. The         citrate (Revatio, Pfizer). The FDA approved sildenafil for the
study was terminated early, because there was a 92% difference         treatment of PHTN in 2005.
in cerebrovascular accidents (CVAs) between the standard-of-              A study conducted at the Howard University Center for
care group and the transfusion group.27                                Sickle Cell Disease tested PHTN reversibility by giving prosta-
   It is still not known when, if ever, it is optimal to discontinue   cyclin infusions to eight patients with PHTN during cardiac
prophylactic transfusions in patients with abnormal TCD re-            catheterization.36 Pulmonar y pressures were significantly
sults. The Optimal Primary Stroke Prevention in Sickle Cell            reduced in six of the eight patients who received the in-
Anemia (STOP 2) Trial Investigators randomly assigned chil-            fusions. An open-label, uncontrolled pilot trial of 12 patients
dren who were receiving prophylactic transfusions to either            with SCD and PHTN found that sildenafil improved exercise
stop receiving them after 30 months or to continue with them.          capacity and PHTN.37
The endpoints evaluated were abnormal TCD findings or
stroke; neither event occurred in the arm that continued trans-        Priapism
fusion therapy. The arm that discontinued therapy had 14                  Priapism, possibly resulting from decreased blood flow to
abnormal TCD results and two strokes within 4.5 ± 2.6 months           the corpus cavernosum, is a known problem in men with
of stopping transfusions.28 Children with abnormal TCD out-            SCD.38 Usually precipitated by sexual activity, priapism has a
comes had a hydroxyurea-related decrease in TCD flow velocity          prevalence of between 6% and 38% in SCD patients.39 There are
from 216 ± 14 to 173 ± 31 cm/second, suggesting the possible           two kinds of priapism: (1) “stuttering,” defined as repeated
benefit of switching to hydroxyurea for stroke prevention.29           short episodes, with each episode lasting for between 30 min-
   With regular transfusions comes the burden of iron over-            utes and three hours, and (2) “prolonged,” defined as episodes
load; until recently in the U.S., this condition was treated only      lasting for more than three hours.
with deferoxamine (Desferal, Novartis), which was admin-                  Acute episodes of priapism lasting for more than two hours
istered by subcutaneous or IV infusion. A new once-daily oral          should be treated in the emergency department. Penile aspi-
chelator, deferasirox (Exjade, Novartis), when compared with           ration, followed by irrigation of the corpus cavernosum with
deferoxamine in patients with SCD and iron overload, was               a sympathomimetic agent, should be initiated if detumescence
found to be safe and effective in these patients.30                    does not occur an hour after the patient’s arrival. Oral terbu-
   At the time of this writing, a study evaluating the role of         taline (Brethine, aaiPharma) and pseudoephedrine (e.g.,
aspirin in the stroke prophylaxis in children was recruiting           Sudafed, Pfizer) have demonstrated efficacy in the treatment
participants.31                                                        of priapism.40

Folic Acid and Anemia                                                  Investigational Treatment Options
   In patients with SCD, the RBC count is lower than normal              Niprisan
because sickled cells usually die after 10 to 20 days, in contrast       As a phytopharmaceutical derived from a plant in its origi-
to 120 days for normal RBCs. Because of high cell turnover,            nal state, Niprisan was developed by the Nigerian National
folate stores are often depleted.                                      Institute for Pharmaceutical Research and Development. This
   Folic acid replenishes the depleted folate stores necessary         anti-sickling agent was granted orphan drug status by the
for erythropoiesis. Folic acid supplementation is well estab-          FDA in 2003 under the name Hemoxin, made by Xechem
lished in the treatment of chronic hemolytic anemia. Although          International. Its anti-sickling properties are attributed to its

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ability to prolong or delay the time to polymerization of deoxy-     in daily narcotic usage. Overall, the oral administration of
Hb S.41                                                              L-glutamine has shown a consistent and significant increase in
  A phase 2, double-blind, placebo-controlled, six-month ran-        red blood cell NADH and was well tolerated by the patients
domized crossover trial revealed that the frequency of sickle        with no adverse effects.50
cell pain crisis in the Niprisan arm was significantly reduced.42
A phase 3 clinical trial is under way, and an investigational New      Magnesium
Drug Application (NDA) is being prepared by Xechem for                  De Franceschi et al. suggested that a possible therapeutic
submission to the FDA.                                               strategy for SCD was based on reducing the cellular concentra-
                                                                     tion of sickle cell hemoglobin (HbS) by preventing erythrocyte
  Nitric Oxide                                                       dehydration.51 The major determinant of sickle cell dehydration
   Nitric oxide (NO), a potent vasodilator thought to be de-         is the potassium chloride transporter, which is inhibited by
ficient in patients with SCD, has been suggested as a thera-         increasing the erythrocyte magnesium content. Oral admin-
peutic option.43 Its proposed mechanism of action is its ability     istration of magnesium showed considerable increases in sickle
to limit the sickling of RBCs by preventing them from sticking       erythrocyte magnesium and potassium content and reductions
to vessel walls or by dilating peripheral blood vessels.44           in the number of dense sickle erythrocytes. In addition, the
   Studies by Head et al. suggested that NO increases the            erythrocyte potassium chloride co-transport was reduced
hemoglobin oxygen affinity in homozygous HbS (SS) erythro-           significantly, and the absolute reticulocyte count and the num-
cytes either when RBCs are exposed to NO in vitro or during          ber of immature reticulocytes were greatly reduced.
NO inhalation in low concentrations in vivo.45 It is not clear how      The authors concluded that oral magnesium reduced the
low concentrations of NO enhance oxygen affinity of erythro-         number of dense erythrocytes and improved the erythrocyte
cytes in SCD, compared with normal erythrocytes, but re-             membrane transport abnormalities of patients with SCD, thus
search suggests that NO modifies HbS, thereby reducing poly-         reducing erythrocyte dehydration. Transient diarrhea was
merization and increasing oxygen affinity in sickled RBCs.           the only significant side effect and was noted in one of 10
                                                                     patients in the study.
   The amino acid L-arginine is a required substrate for nitric
acid synthesis by endothelial cells, platelets, and other cells.     Conclusion
In addition to having a deficiency of NO, adults with SCD               Although bone marrow transplantation can cure SCD, it is
sometimes have significantly diminished arginine levels. This        an impractical solution for most Third World countries, which
arginine deficiency may be the cause of PHTN in sickle cell          have a high disease burden. Even in the U.S., bone marrow
patients; therefore, the infusion of L-arginine has been shown       transplantation is limited by the availability of donors. Pharma-
to reduce vascular resistance and improve blood oxygenation          cological therapies are effective at reducing complications of
in infants with PHTN.46                                              SCD and are safe and easily administered, and they continue
   In one study, L-arginine supplementation improved pul-            to prolong the life expectancy of patients.
monary artery pressures and hemodynamics in primary and
secondary hypertension within one week of therapy. Overall,
arginine was well tolerated with minimal adverse effects.47          References
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    Institute, Division of Blood Diseases and Resources, NIH Pub No.       46. Waugh WH, Daeschner CW, Files BA, et al. Evidence that L-argi-
    02-2117.                                                                   nine is a key amino acid in sickle cell anemia: A preliminary
23. Gatson MH, Verter JI, Woods G, et al. Prophylaxis with oral peni-          report. Nutr Res 1999;19(4):501–518.
    cillin in children with sickle cell anemia: A randomized trial.        47. Morris CR, Morris SM, Hagar W, et al. Arginine therapy: A new
    N Engl J Med 1986;314:1593–1599.                                           treatment for pulmonary hypertension in sickle cell disease? Am
24. What is sickle cell anemia? National Heart, Lung, and Blood In-            J Respir Crit Care Med 2003;168:63–69.
    stitute (NHLBI). Available at:           48. Williams R, Olivi S, Li CS, et al. Oral glutamine supplementation
    Diseases/Sca/SCA_WhatIs.html. Accessed August 10, 2007.                    decreases resting energy expenditure in children and adoles-
25. Pai VB, Nahata MC. Duration of penicillin prophylaxis in sickle            cents with sickle cell anemia. J Pediatr Hematol Oncol 2004;26(10):
    cell anemia: Issues and controversies. Pharmacotherapy 2000;               619–625.
    20(1):110–117.                                                         49. Niihara Y, Zerez CR, Akiyama DS, et al. Increased red cell gluta-
26. Centers for Disease Control and Prevention (DCDC). Sickle cell             mine availability in sickle cell anemia: Demonstration of increased
    disease: Five tips to help prevent infection. Available at: www.           active transport, affinity, and increased glutamate level in intact Accessed October               red cells. J Lab Clin Med 1997;130(1):83–90.
    16, 2007.                                                              50. Niihara Y, Zerez CR, Akiyama DS, et al. Oral L-glutamine therapy
27. Adams RJ, McKie VC, Hsu L et al. Prevention of a first stroke by           for sickle cell anemia: I. Subjective clinical improvement and
    transfusions in children with sickle cell anemia and abnormal              favorable change in red cell NAD redox potential. Am J Hematol
    results on transcranial Doppler ultrasonography. N Engl J Med              1998;58:117–121.
    1998;339:5–11.                                                         51. De Franceschi L, Bachir D, Galacteros F, et al. Oral magnesium
28. The Optimizing Primary Stroke Prevention in Sickle Cell Anemia             supplements reduce erythrocyte dehydration in patients with
    (STOP 2) Trial Investigators. Discontinuing prophylactic trans-            sickle cell disease. J Clin Invest 1997;100(7):1847–1852. I
    fusions used to prevent stroke in sickle cell disease. N Engl J Med
29. Zimmerman SA, Schultz WH, Burgett S, et al. Hydroxyurea ther-
    apy lowers transcranial Doppler flow velocities in children with
    sickle cell anemia. Blood 2007;110:1043–1047.
30. Vichinsky E, Onyekwere O, Porter J, et al. A randomised compar-
                                                                                      Conflict of Interest (COI) Statement
    ison of deferasirox versus deferoxamine for the treatment of
    transfusional iron overload in sickle cell disease. Br J Haematol
                                                                                The authors have no relationships to disclose. The article
    2007;136(3):501–508.                                                    contains a discussion of off-label use. The content of this
31. Lerner NB. Aspirin prophylaxis in sickle cell disease. Trial No.        article has been reviewed under Jefferson’s COI policy.
    NCT00178464. Available at:

                                                                                                          Vol. 33 No. 4 • April 2008 •   P&T® 243

Continuing Education Questions for Physicians and Pharmacists
P&T ® 2008;33(4):238–243
ACPE Program # 079-000-08-016-H01-P
Expiration Date: April 30, 2009
TOPIC: Pharmacological Management of Sickle Cell Disease

CME Accreditation
This activity has been planned and implemented in accordance with the Essential Areas
and Policies of the Accreditation Council for Continuing Medical Education (ACCME)
through the joint sponsorship of Jefferson Medical College and MediMedia USA, Inc.

Jefferson Medical College of Thomas Jefferson University, as a member of the Consortium for Academic Continuing Medical
Education, is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical educa-
tion for physicians. All faculty/authors participating in continuing medical education activities sponsored by Jefferson Med-
ical College are expected to disclose to the activity audience any real or apparent conflict(s) of interest related to the content
of their article(s). Full disclosure of these relationships appears on the last page of the article.

Continuing Medical Education Credit
This CME activity is designed to assist physicians and other health care professionals who are P&T committee members in
making formulary decisions. Its goal is to increase participants’ ability to recognize and treat important medical problems.

Jefferson Medical College designates this continuing medical education activity for a maximum of one Category 1 credit
toward the Physician’s Recognition Award (PRA) of the American Medical Association. Each physician should claim only
those credits that he/she actually spent in the educational activity.

This credit is available for the period of one year from the date of publication.

Although forms will be processed when received, certificates for CME credits will be issued every six months, in February
and August. Interim requests for certificates can be made by contacting the Jefferson Office of Continuing Medical Education
at (215) 955-6992 or by going online to

           Continuing Pharmacy Education Credit
          The Department of Health Policy, Thomas Jefferson University Hospital, is approved by the Accreditation Council
          for Pharmacy Education (ACPE) as a provider of continuing pharmacy education and complies with the
          Criteria for Quality for continuing pharmacy education programming. This program (079-000-08-016-H01-P) is
acceptable for 1.0 hour of continuing education credit (0.1 CEUs) in states that recognize ACPE-approved providers. State-
ments of Credit indicating hours/CEUs will be mailed within six to eight weeks to participants who completed this activity
and submitted a completed evaluation with payment.

How to Apply for CE Credit
1. Each CE article is prefaced by learning objectives for participants to use to determine whether the article relates to their
   individual learning needs.
2. Read the article carefully, paying particular attention to the tables and other illustrative materials.
3. Complete the questions and fill in the answers on the evaluation form on the next page.
4. Complete the CE Registration and Evaluation Form. Type or print your full name and address in the space provided, and
   evaluate the activity as requested. In order for the form to be processed, all information must be complete and legible.
5. Payment of $10 per exam is required for processing and maintenance of records. Make checks payable to P&T®. This
   processing fee is non-refundable.
6. Send the completed form, answer sheet, and $10 payment to:
        Department of Health Policy
        Thomas Jefferson University
        Attn: Continuing Education Credit
        1015 Walnut Street, Suite 115
        Philadelphia, PA 19107
7. Be sure to mail the Registration, Evaluation Form, and $10 payment within one year of the date of publication. After that
   date, this article will no longer be designated for credit and forms cannot be processed.

244 P&T®   • April 2008 • Vol. 33 No. 4
                                                                                CONTINUING EDUCATION CREDIT

Continuing Education Questions for Physicians and Pharmacists
TOPIC: Pharmacological Management of Sickle Cell Disease
ACPE Program # 079-000-08-016-H01-P

     CE Evaluation: Select the one best answer to each of the following questions, and record your response on the
     examination answer sheet. Complete the additional requested information. Forward the answer sheet, with appro-
     priate payment, to the Department of Health Policy, Thomas Jefferson University Hospital, at the address indicated.
     A certificate of completion will be mailed within six to eight weeks of receipt of your exam/payment. (A minimum
     test score of 70% is required.)

                      Multiple Choice                                 6.   According to authors, the following statements
                 Select the one correct answer.                            about infection in patients with sickle cell disease
                                                                           are true except:
                                                                           a. Prophylaxis of infection may be discontinued after five
1.     Sickle cell disease is an inherited blood disorder                     years of age.
       that:                                                               b. Prophylaxis with penicillin is a problem.
       a. affects one of every 1,000 to 1,400 African-American             c. Erythromycin ethyl succinate is not adequate for
           births.                                                            prophylaxis.
       b. involves episodes of pain, chronic hemolytic anemia, and         d. Functional asplenia can occur as early as six months of
           severe infections.                                                 age.
       c. is not a commonly inherited blood disorder in the U.S.
       d. causes complications only in adulthood.                     7.   Iron overload is a complication of the regularly
                                                                           needed transfusions for the treatment of anemia in
2.     The pathogenesis of sickle cell disease does not                    patients with sickle cell disease. Which of the
       include:                                                            following medications was found to be safe and
       a. sickling of red blood cells when deoxygenated.                   effective compared with deferoxamine in the
       b. premature hemolysis of red blood cells.                          treatment of iron overload?
       c. obstruction of microvasculature resulting from sickling.         a. folic acid
       d. a change in the alpha-globin polypeptide of the hemo-            b. vitamin B12
          globin molecule.                                                 c. deferasirox
                                                                           d. none of the above
3.     Bone marrow transplantation is the only cure for
       sickle cell disease, but it is not a common                    8.   A deficiency of glutamine, a consequence of sickle
       procedure because of:                                               cell anemia, may result in the possibility of:
       a. mortality rates exceeding 30%.                                   a. skeletal muscle wasting.
       b. a lack of suitable donors.                                       b. immunosuppression.
       c. graft failure rates below 50%.                                   c. improved wound healing.
       d. disease-free survival rates below 30%.                           d. all of the above

4.     Management of sickle cell disease with                         9.   Folic acid is well supported in the primary
       hydroxyurea:                                                        literature for use in sickle cell disease.
       a. may result in reversible bone marrow suppression.                a. True
       b. may be indicated for patients who have had at least three        b. False
          pain crises in the previous three months.
       c. may prevent complications of sickle cell disease by         10. In the treatment of dehydration in sickle cell
          decreasing polymerization time.                                 disease, oral magnesium showed considerable:
       d. does not require monitoring complete blood counts.              a. decreases in sickle erythrocyte magnesium.
                                                                          b. increases in sickle erythrocyte potassium content.
5.     According to the authors, which of the following                   c. increases in the number of dense sickle erythrocytes.
       should be avoided in patients with pain and                        d. none of the above
       impaired renal function?
       a. morphine
       b. codeine
       c. hydromorphone
       d. meperidine

                                                                                                   Vol. 33 No. 4 • April 2008 •   P&T® 245
                                                                                                                     Pharmacy and Therapeutics
CE Registration and Evaluation Form
Date of publication: April 2008
Title: Pharmacological Management of Sickle Cell Disease
Authors: Uche Anadu Ndefo, PharmD, BCPS; Angie Eaton Maxwell, PharmD;
  Huong Nguyen, PharmD Candidate; and Tochukwu L. Chiobi, PharmD                                                 A Peer-Reviewed Journal for Managed Care
                                                                                                                    and Hospital Formulary Management
Submission deadline: April 30, 2009
ACPE Program # 079-000-08-016-H01-P

Name: ____________________________________________________________ Degree: ____________________________________
Street address: ______________________________________________ Last 4 Digits of Social Security No. (Web ID): __________
City: ___________________________________ State: _________ Zip:__________ Telephone: _____________________________
E-mail Address: _______________________________________ Check one: I Physician I Pharmacist I Other
Time needed to complete this CE activity in hours: I 0.5 hr I 1 hr I 1.5 hr           I 2 hr    I Other _________________________

Certification: I attest to having completed this CE activity. ___________________________________________________________
                                                                     Signature (required)            Date _______________

Answer Sheet
Please fill in the box next to the letter corresponding to the correct answer
 1. a I        b I        c I         d I          6. a I         b I       c I      d I
 2. a I        b I        c I         d I          7. a I         b I       c I      d I
 3. a I        b I         c I        d I          8. a I         b I       c I      d I
 4. a I        b I         c I        d I          9. a I         b I       c I      d I
 5. a I        b I         c I        d I         10. a I         b I       c I      d I

Rate the extent to which:                                         Very High         High       Moderate        Low              Very Low
1. Objectives of this activity were met                                 I            I             I             I                    I
2. You were satisfied with the overall quality of this activity         I            I             I             I                    I
3. Content was relevant to your practice needs                          I            I             I             I                    I
4. Participation in this activity changed your                          I            I             I             I                    I
    knowledge/attitudes                                                 I            I             I             I                    I
5. You will make a change in your practice as a result                  I            I             I             I                    I
    of participation in this activity
6. This activity presented scientifically rigorous,                     I            I             I             I                    I
    unbiased, and balanced information
7. Individual presentations were free of commercial bias                I            I             I             I                    I
8. Adequate time was available for Q&A                                  I            I             I             I                    I
9. Which ONE of the following best describes the impact of this activity on your performance:
          I This program will not change my behavior because my current practice is consistent with what was taught.
          I This activity will not change my behavior because I do not agree with the information presented.
          I I need more information before I can change my practice behavior.
          I I will immediately implement the information into my practice.
10. Will you take any of the following actions as a result of participating in this educational activity (check all that apply)
          I Discuss new information with other professionals                      I Consult the literature
          I Discuss with industry representative(s)                               I Participate in another educational activity
          I Other ____________________________________                            I None
Send the completed form and $10 payment (make checks payable to P&T) to: Department of Health Policy, Thomas Jefferson
University, Attn: Continuing Education Credit, 1015 Walnut Street, Suite 115, Philadelphia, PA 19107.

246 P&T®   • April 2008 • Vol. 33 No. 4

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