CHEMOTHERAPY OF PROTOZOAN PARASTIC INFECTION

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CHEMOTHERAPY OF PROTOZOAN PARASTIC INFECTION Powered By Docstoc
					       CHEMOTHERAPY OF PROTOZOAN PARASTIC INFECTIONS
       (Antiamoebics, drugs used in the treatment of trichomoniasis, gardiasis,
       trypanosomasis. leishmaniasis and anthelminthics)
                      J C Nwanze (STRICTLY NOT FOR SALE)
Etiological Factors (Causes) of Parasitic infections
   (1) Population crowding
   (2) Poor sanitation and health education
   (3) Inadequate control of parasitic vectors and reservoir
   (4) Introduction of agricultural water control and supply system
   (5) Increased world travel, population migration and military operations
   (6) Development of resistance to agents used for chemotherapy or control of vectors.

   Aim and Principles
   Chemotherapy remains the most effective, efficient and inexpensive method to
   control most parasitic infections. For optimal results, such therapies must be
   combined with other public health measures appropriate for the particular infection,
   environment, and host population.

    Criteria
    To be used for mass chemotherapy, and ideal anti parasitic agent should be:
    a) Easily given preferably by oral route in a single dose or divided doses on the same
        day.
    b) Chemically stable for long periods under climatic conditions of use
    c) Ineffective as an inducer of drug resistance
    d) Inexpensive.
  Population-based chemotherapy would ideally be instituted only after appropriate
parasitological and epidemiological studies have been conducted to determine patterns of
transmission and both the age specific prevalence and intensity of infection as these
variables relate to disease.
Drugs Used in the Chemotherapy of Helminthiasis.
 Anthelminthics are used to rid the body of worm known as helminthes. The term
anthelminthics applies to agents that act either locally to expel worms from the
gastrointestinal or systematically to eradicate species and developmental forms of
helminthes that invade organs and tissues. Simultaneous with more than one type of
parasitic helminthe is common in many tropical regions. Moreover, due to human travel
and migration, worms can spread to geographical locations that previously had been free
of these organisms.

DIETHYLCARBAMAZINE (BANOCIDE)
It is a piperazine derivative.
Anthelminthic Action.
Diethylcarbamazine causes disappearance of microfilariae of wuchereria bancrofti,
w.malayi and Loa loa from the blood of man. The drug causes microfilariae of
Onchocerca volvulus to disappear from the skin but does not kill microfilariae in the
nodules that contain the adult (female) worms.


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The drug has two mechanisms of action against susceptible microfilariae:
         1) Decreases the muscular activity and eventually immobilizes the organism,
             this may result from a hyperpolarizing effect on the piperazine moiety, and it
             causes the dislocation of the parasites from their normal habitats in the host.
         2) The second action is to produce alterations in the micro filarial surface
         membranes, thereby rendering them susceptible to destruction by host defense
         mechanism.
    Studies with mammalian cells suggest that diethylcarbamazine may compromise
intracellular processing and transport of certain macromolecules to the plasma
membrane.

Pharmacokinetics
Diethylcarbamazine is rapidly absorbed from the gastrointestinal tract. Metabolism of
diethylcarbamazine is both rapid and extensive. After a single oral dose, the
concentration in plasma peaks in 1 to 2 hours, the plasma half-life is about 10 to 12
hours.
Toxicity and Side Effects
Untoward direct reactions to diethylcarbamazine include: (a) anorexia (b) nausea (c)
headache (d) at high doses-vomiting.
Clinical Uses
Diethylcarbamazine can be used effectively to treat infections caused by W. bancrofti, W,
malayi, Loa loa and O. volvulus.

IVERMECTIN
This semi synthetic agent is used extensively in veterinary medicine to treat and control a
wide variety of infections caused by parasitic nematodes (roundworms) and arthropods
(insects, ticks and mites) that plague livestock and domestic animals.
In humans, ivermectin is now the drug of choice in the treatment and control of
onchcerciasis, the filarial infection responsible for river blindness.

Antiparasitic Activity
The drug causes immobilization of affected organisms by producing a tonic paralysis of
the peripheral musculature. The mechanism of this action is not well understood,
although potentiation of the release and binding of gama-aminobutyric acids (GABA) is
thought to be involved. Lack of GABA-mediated neural control of peripheral muscles in
cestodes and trematodes may explain why ivermectin is ineffective against these
organisms.
The drug causes little discernable harm to adult parasites but seems to affect developing
larvae and to block egress of microfilariae from the uterus of adult female worm.

Pharmacokinetics.
The half-life of the drug is about 10 hours. The highest tissue concentration occur in the
liver and fat.




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Clinical Uses
Single doses of ivermectin (0.15 to 0.20 mg/ kg ) given every 6 to 12 months are
considered effective, safe and practical for the control of onchcerciasis in man.


MEBENDAZOLE
Mebindazole is a member of a number of benzimidazole derivatives, including
albendazole and flubendazole, which were developed as broad spectrum anthelmintic for
animal and human use.

Anthelmintic Action.
 Mebendazole is a versatile anthelmintic agent, particularly against gastrointestinal
nematodes where its action is independent of its systemic concentration. It is highly
effective in ascariasis, intestinal capillariasis, enterobiasis, tricuriasis and hookworm
(Ancylostoma duodenale and Necator americanus) infection as single or mixed
infections. The drug is effective against both larval and adult stages of the nematodes that
cause these infections, and it is ovicidal for Ascaris and Trichuris. Immobilization and
death of susceptible gastrointestinal organisms occur slowly, and clearance from the
gastrointestinal tract may not be complete until a few days after treatment with
Mebendazole.

Pharmacokinetics.
Tablet formulations of Mebendazole are poorly and erratically absorbed and
concentrations of the drugs in plasma are low and do not reflect the dosage taken. The
low systemic bioavailability of mebendazole results from a combination of poor
absorption and rapid first-pass hepatic metabolism.
Mebendazole is about 95% bound to plasma protein and is extensively metabolized.

Toxicity and Side Effects
Mebendazole does not cause significant systemic toxicity in routine clinical use probably
as a result of its poor absorption, even in the presence of anemia and malnutrition.

Clinical Uses
Mebendazole is an excellent drug for the treatment of Trichuris trichura. It is highly
effective against infection with Ancylostoma duodenale just as pyrantel palmoate against
ascariasis, enterobiasis and Necator americanus infection. In the Philippines,
mebendazole has been used successfully in high dosage to treat intestinal capillariasis. In
even higher doses successful cure of hydatid disease has been reported, but surgery is
often required and additional clinical evaluation of both mebendazole and albendazole is
necessary for this refractory condition.

NICLOSAMIDE (YOMESIN)
Niclosamide is a halogenated salicylanilide derivative generally regarded as a very
effective agent for of most infections with cestodes in man and animals.




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Anthelmintic Actions
Niclosamide has prominent activity against most of the cestodes that infect man including
Enterobius(Oxyuris) vermicularis The principal action of the drug may be to inhibit
anaerobic phosphorylation of adenosine diphosphate(ADP) by the mitochondria of the
parasite, an energy producing process that is dependent on CO2 fixation.
Worms affected by this drug either in the gut or in vitro deteriorate , such that the scolex
and segments may be partially digested and become unrecognizable.


Toxicity and Side Effects
Niclosamide is quite free of undesired effects other than very occasional gastrointestinal
upset. No side effects were observed when niclosamide was given to debilitated or
pregnant patients.

Clinical Uses
Niclosamide can be considered an agent of choice in the treatment of Diphyllobothrium
latum, H. nana, T. saginata, and most other human intestinal cestodes infections. It is
also very effective in the treatment of T, solium infection.

PIPERAZINE
Clinically, this drug is highly effective against both Ascaris lumbricoides and Enterobius
(Oxyuris) vermicularis.

Anthelmintic Action
The predominant effect of piperizine on Ascaris is to cause a flaccid paralysis that
result in expulsion of the worm by peristalsis. Piperizine blocks the response of Ascaris
muscle to acetylcholine, apparently by altering the permeability of the cell membrane
to ions that are responsible for the maintenance of the resting potential, The drug
causes hyperpolorization and suppression of spontaneous spike potentials with
accompanying paralysis.

Toxicity and Side Effects
Piperizine is rapidly absorbed after an oral dose. About 20% is excreted unchanged in the
urine. Side effects associated with this drug include: (a) Very occasional gastrointestinal
upset (b) Transient neurological effects (c) Urticarial reactions.

Clinical Uses
Piperizine is particularly useful in treating combined ascariasis and oxyuriasis. Since the
worms are usually alive when passed, there is little chance of absorption of disintegrated
products.

 PRAZIQUANTEL
Praziquantel is a pyrazinoisoquinoline derivative clinically effective against a wide
spectrum of cestodes and trematodes infections in animals and humans; in contrast,
parasitic nematodes are relatively unaffected by the compound.




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Anthelmintic Action
Praziquantel is rapidly and reversibly taken up but not metabolized by helminthes in
vitro. The compound exerts two prompt action in susceptible organisms:
    1) At the lowest effective concentration, it causes increased muscular activity,
        followed by contraction and spastic paralysis.
    2) At slightly higher but still therapeutic concentrations, praziquantel causes
        vacuolization and vesiculation of the tegument.


 If sufficiently pronounced, this effect activates defense mechanisms and results in
destruction of worms. The molecular basis of the action of praziquantel is unknown. The
drug causes increased membrane permeability to certain monovalent and divalent cations,
particularly Ca 2+.

Pharmacokinetics
In man, praziquantel is readily absorbed after oral administration. Rapid first-pass
metabolism to many hydroxylated and conjugated products limits bioavailability of
praziquantel: its half-life in plasma is 5 hours.

 Toxicity and Side Effects
Untoward effects occurring shortly after drug administration include: (a) Abdominal
discomfort, nausea and malaise (b) Headache (c) Dizziness.
Fever, eosinophilia and skin rashes are occasionally observed. Extensive tests for
mutagenesis, carcinogenesis, and teratogenicity have been essentially negative.

Clinical Uses
Praziquantel is well tolerated, safe and effective when given in one to three doses the
same day for single or mixed infections with all species of schistosomes that affect man.

PYRANTEL PAMOATE
 Pyrantel palmoate is a broad-spectrum anthelmintic directed against pinworm,
roundworm, and hookworm. Oxantel palmoate, an m-oxyphenol, analog of pyrantel, is
effective for single for single dose treatment of trichuriasis.

Anthelmintic Action
Pyrantel and its analogs are depolarizing neuromuscular blocking agents. They induce
marked, persistent nicotinic activation, which results in spastic paralysis of the
worm. In contrast, piperazine causes hyperpolarizaton with reduction in spike-discharge
frequency and relaxation. Thus pyrantel and piperizine are mutually antagonistic in
Ascaris preparations.

Pharmacokinetics.
Pyrantel palmoate is poorly absorbed from the GIT, a property that contributes to its
selective action on gastrointestinal nematodes.




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Toxicity and Side Effects
Transient and mild gastrointestinal symptoms are occasionally observed as well as
headache, dizziness, rash and fever.

Clinical Uses
Pyrantel palmoate is an agent of choice in the treatment of ascariasis and enterobiasis
achieving high cure rates after single-dose.



SUMMARY OF TREATMENT OF HELMINTIC INFECTIONS.
Nematodes (Round worms). Ascaris lumbricoides
Both mebendazole and pyranteral pamoate are preferred agents. Piperizine is effective
but used less often because of occasional neurotoxicity and hypersensitivity reactions. If
ascariasis complicates hookworm infection, great care should be taken in treating the
latter to avoid promoting of the ascarids. In such cases, the roundworms may block the
lumen of the appendix producing symptoms of appendicitis.
In the treatment of such mixed infections the advantages lie with pyrantel pamoate and
mebendazole, because these agents are effective against Ascaris and both species of
hookworm. Preference should be given pyrantel pamoate because single-dose treatment
is effective and does not possess the teratogenic potential of mebendazole.

Hookworm: Necator americanus. Ancylostoma duodenale
Treatment of hookworm disease involves two related objectives:
 1. To restore the blood value to normal
 2. To expel the intestinal parasites.
Mebendazole and pyrantel pamoate are now drugs of first choice against both hookworm
species and have the advantage of effectiveness against other roundworms when there is
multiple infections.
Thiabendazole is the drug of choice for treating larva migrans or “creeping eruption”,
due most commonly to penetration of the skin of man by larva of the dog hookworm,
Ancylostoma brazilliense.

Trichuris trichura (Whipworm)
Trichuris infection is cosmopolitan especially in warm, humid climates. The worm is
usually asymptomatic except in heavily infected young children, who may exhibit mild
toxicity and some degree of anemia.
Mebendazole in a dosage of 100mg twice daily for 3 days is considered to be the safest,
most effective treatment against whipworm, either alone or in combination with Ascaris
and hookworm.
Thiabendazole, though quite toxic, is also effective in an appreciate proportion of cases.
Ivermectin shows promise in the treatment of this infection.




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Strongloides stercoralis (Threadworm)
Threadworm is frequently found in tropical and subtropical regions, often together with
other intestinal helminthes. Thiabendazole is highly effective and has been considered to
be the drug of choice.

Enterobius (Oxyuris) vermicularis (Pinworm)
The pinworm is cosmopolitan and the most common helminthic infection in the United
States, especially in school children. Both mebendazole and pyrantel pamoate are highly
effective and ivermectin shows great promise. Mebendazole should not be used during
pregnancy because of its teratogenic potential.


Trichinella spiralis
The trishna worm is ubiquitous, regardless of climate, and does live outside a host.
Thiabendazole in well-tolerated doses, has been shown to kill Trichinella larvae in the
muscles of experimental animals.

Filariae (Wuchereria bancrofti, Loa loa, Onchocerca volvulus)
Diethylcarbamazine is now the only agent for both suppression and cure of infections
with W, bancrofti, W. malayi and Loa loa. In longstanding elephantiasis, surgical
measures are required to improve lymph drainage and remove redundant tissue.
Ivermectin has replaced diethylcarbamazine as a drug of choice for the control of
onchocerciasis. Both agents only kill microfilaria of O. volvulus, but ivermectin
produces far milder systemic reactions and few if any, ocular complications.

Dracunculus medinensis (Guinea worm)
Traditional treatment for this disabling condition is to draw the adult female worm alive.
Satisfactory healing with either extrusion of the worm or, if no worm is extruded,
complete symptomatic and functional relief has been obtained by the administration of
metronidazole.

Cestodes
Taenia saginata.
Man is the definitive host for T. saginata, known as the beef tapeworm. Niclosamide and
praziquantel are the drugs of choice for treatment of infection with T. saginata. Cure can
however be assumed only if no further segments are detected by the end of 4 months.

Taenia solium (Pork tapeworm)
Praziquantel is preferred over niclosamide in the treatment of infection with T. solium
because the drug is also effective in combating cysticercosis.

Trematodes
Schistosoma haematobium. S.mansoni, S. japonica
Praziquantel is now considered the drug of choice for treating all species of schistosomes
that infect man. The drug is safe and effective when it is given in single or divided oral
doses on the same day. Oxamniquine has been proven to be effective for the treatment of



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S. mansoni infections although not clinically effective for the treatment of other
schistosome species. Metrifunate has been used with considerable success in the
treatment of S. haematobium infections, but the drug is not effective against S.
mansoni and S. japanicum.

Paragonimus westermoni (Lung flukes)
Following encouraging preliminary clinical results with praziquantel, three doses of
25mg/kg each are recommended daily for two consecutive days, but an optimal dosage
schedule is still to be established.




DRUGS USED IN THE CHEMOTHERAPY PROTOZOAL INFECTIONS
Amebiasis, Giardiasis and Trichomoniasis
Anaerobic protozoa of the genre Entamoeba, Gardia and Trichomonas are the causative
agents, respectfully of Amebiasis, gardiasis and trichomoniasis.

Amebiasis
Amebiasis caused by Entamoeba hystolytica has a cosmopolitan distribution, but it is
more severe in subtropical and tropical regions. It is transmitted by the fecal-oral route
and is particularly common under poor hygienic conditions in lower socioeconomic
groups, institutionalized individual and male homosexuals.
Trophozoites usually exist as commensals in the large intestines; i.e. they produce cysts
but otherwise cause little harm to the host.

Diagnosis
The diagnosis of amebiasis and its persistent is made by appropriate examination of rectal
scraping or of the stool.

Chemotherapy
Drugs used to treat amebiasis (amebicides) can be categorized Luminal, Systemic, or
Mixed.
Luminal amebicides such as diluxamine furoate and other dichloroacetamide derivatives,
are active only against the intestinal forms of amebae.
Systemic amebicides are effective against only invasive forms of amebiasis.
Mixed amebicides are effective against both effective intestinal and systemic forms of
amebiasis. Metronidazole, a nitroimidazole derivative, is the prototypical mixed
amebicides, and its use has revolutionized the treatment of this protozoan infection.
Antibiotics such as the amebicidal aminoglycocide paramomycin or tetracycline can be
used in conjunction with metronidazole to treat severe forms of intestinal amebiasis.

Giardiasis
Giardiasis, caused by the flagellated protozoan Giardia lamblia is the most commonly
reported intestinal protozoal infection in developed countries, including the United States.
Most infected individuals are asymptomatic.



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Cysts, in feces or in contaminated food or water, transmit the infection and the organism
does not require an intermediate host. Ingested cysts change into active trophozoites that
eventually reside and proliferate in the upper small intestine, where they may or may not
produce disease.

Diagnosis
The diagnosis of giardiasis is made by identification of cysts or trophozoites in fecal
specimens.

Chemotherapy
Treatment with metronidazole or quinacrine is usually successful.


Trichomoniasis
Trichomoniasis is caused by flagellated protozoan Trichomonas vaginalis. This organism
inhabits the genitourinary tract of human host, where it can produce vaginitis in women
and urethritis in men.

Chemotherapy
Proper treatment of both partners with either metronidazole or related nitroimidazole
compounds is nearly always successful.

Chloroquine.
Chlo1roquine is now used as a amebicide to treat hepatic amebiasis only when treatment
with is unsuccessful or contraindicated. The clinical response to chloroquine in patients
with hepatic amebiasis is often prompt, and there is no evidence that ameba develops
resistance to this agent. The drug is much less effective in amebiasis, partly because it
attains a much less lower concentration in the intestinal wall than in the liver and partly
because it is almost absorbed from the small bowel.

Diloxanide Furoate (Furamide)
Diloxanide is a dichloroacetamide derivative shown to be effective in cyst-passing
patients, but ineffective in the treatment of acute intestinal amebiasis

Toxicity and Side effects
Side effects are mild. Flatulence is most commonly reported; vomiting, pruritus and
urticaria occur occasionally.

Clinical Uses
Administered alone, diloxanide furoate is the drug of choice in the treatment of
asymptomatic passers of cysts though its efficacy in the treatment of acute amebiasis with
frank dysentery is controversial. However treatment with diloxanide furoate resulted in
high percentage of cure in trials carried out on asymptomatic subjects or on patients with
nondysenteric, symptomatic intestinal amebiasis.




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Emetine and Dihydroemetine
Emetine is an alkaloid obtained from ipecac (“Brazil root”) used as direct-acting systemic
amebicide in the treatment of severe invasive intestinal amebiasis, amebic hepatitis and
amebic abscesses. Dihydroemetine has similar pharmacological properties, but it is
considered to be less toxic. Both drugs have largely been replaced by mixed amebicides
of the nitroimidazole class which are as effective but far safer. Disadvantage of these
alkaloids is that require parenteral administration.



METRONIDAZOLE
Metronidazole {1-(β-hydroxyethyl)-2-nitromidazole} has an extremely broad spectrum of
protozoal and antimicrobial activity which is used to clinical advantage.
 Antiparasitic and Antimicrobial Effects
Metronidazole is directly trichomonacidal. Sensitive isolates of T. vaginalis are killed by
<0.01μg/ ml of the drug under anaerobic conditions; higher concentrations are required
when 1% oxygen is present or with isolates from patients who displayed a poor
therapeutic response to metronidazole. The drug is also potent against E. histolytica under
xenic and axenic conditions.
Metronidazole also displays antibacterial activity against all amebic cocci and both
anaerobic gram-negative bacilli, including Bacteroides species, and anaerobic spore-
forming gram-positive bacilli. Nonsporulating gram-positive bacilli are often resistant, as
are aerobic and facultative anaerobic bacteria.
Metronidazole is clinically effective in trichomoniasis, amebiasis, and giardiasis as well
as in a variety of infections caused by obligate anaerobic bacteria, including Bacteroides
fragillis. Other effects of nitroimidazoles include suppression of cellular immunity,
mutagenesis, carcinogenesis and sensitization of hypoxic cells to radiation.

Mechanism of Action
  1. The nitro group of metronidazole accepts electrons from electron-transport
     proteins such as flavoproteins in mammalian cells and ferredoxins or their
     equivalents in bacteria and diverts them from normal energy-yielding pathways.
  2. Metronidazole inhibits DNA synthesis in T. vaginalis and Clostridium
     bifermentans and causes degradation of existing DNA in the latter
     microorganism.
  3. Studies with mammalian DNA indicate that reduced metronidazole causes a loss
     of the helical structure of DNA, strand breakage, and an accompanying
     impairment of its function.

Pharmacokinetics
The drug is usually completely and promptly absorbed after oral administration, reaching
concentrations in plasma of about 10 μg/ ml approximately 1 hour after a single 500-mg
dose. Repeated doses every 6 to 8 hours result in some accumulation of the drug. The
half-life of metronidazole is about 8 hours, and its volume of distribution is
approximately that of total body water. Metronidazole penetrates well into body tissues
and fluids, including vaginal secretions, seminal fluid, saliva and breast milk.



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The liver is the main site of metabolism, and this accounts for over 50% of the systemic
clearance of metronidazole. The two principal metabolites result from oxidation of side
chains; both have antitrichomonal activity. Oxidative metabolism of metronidazole is
inducible by phenobarbital and possibly by ethanol.


Preparations, Routes of Administration and Dosage.
Metronidazole (Flagyl and others) is formulated as 250 mg and 500 mg tablets for oral
administration and in forms for intravenous infusion. In cases necessitating repeated
courses and higher doses, it is recommended that intervals of 4 to 6 weeks elapse between
courses. In such cases, leukocytes counts should be carried out before, during and after
each course of treatment.
Reinfection by an infected male partner may also cause an unsatisfactory response.
Trichomonads are demonstrated in the urogenital tract in over 30% of male partners of
infected women. The male may be treated by oral administration of 250 mg , three times
daily for seven days or with a single 2-g dose. For amebiasis, 750mg of metronidazole,
three times daily for 5 to 10 days is recommended. Treatment with metronidazole is
least effective when the drug is administered to the asymptomatic passers of cysts.
Metronidazole is a drug of choice in the treatment of giardiasis. It is also considered to be
helpful for the elimination of guinea worm in dracunculiasis, even though it has no direct
effect on the parasite.
Metronidazole is also extremely useful for the treatment of serious infection due to
susceptible anaerobic bacteria, including Bacteroides, Clostridium, and Fusobacterium.
The recommended intravenous dosage regimen for anaerobic infections includes a
loading dose (15mg/kg), followed 6 hours later by a maintenance dose of 7.5 mg/kg
every 6 hours, usually for 7 to 10 days.

Toxicity and Drug Interactions
Side effects are usually not severe to cause discontinuation of treatment. The most
common are: (a) Headache (b) Nausea (c) Dry mouth (d) A metallic taste
Occasionally experienced include (a) Vomiting (b) Diarrhea (c) Abdominal distress
Furry tongue, glossitis and stomatitis may occur during therapy and be associated with a
sudden intensification of moniliasis. Neurotoxic effects of metronidazole have been
observed. Dizziness, vertigo, and rarely encephalopathy, convulsion, and incordination,
and ataxia may appear. Numbness or paresthesia of an extremity occurs occasionally, and
the drug should be discontinued when this happens.
Metronidazole has a well-documented disulfiram-like effect, such that some patients
experience abdominal distress, vomiting, flushing and headache if they drink alcohol
beverages during a course of treatment. Confusional and psychotic states may also occur
during concurrent administration of metronidazole and disulfiram.
Metronidazole is contraindicated in patients with active disease of the CNS. The dosage
should be reduced in patients with severe obstructive hepatic disease, alcoholic cirrhosis,
or severe renal dysfunction. Its use during the first trimester of pregnancy is not
recommended.




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Clinical Uses
   1. Metronidazole cures genital infections with T. vaginalis in both males and
       females in a high percentage of cases
   2. Metronidazole is an effective amebicide for the treatment of all symptomatic
       forms of amebiasis.
   3. The drug also kills G. lamblia and has been shown to be effective in the treatment
       of giardiasis.
   4. The drug is an alternative to clindamycin, certain beta-lactam antibiotics, and
       chloramphenicol for the treatment of infections with various anaerobic bacteria.

QUINACRINE
Quinacrine is an acridine derivative whose major indication is for the treatment of
giardiasis. The metabolic fate of quinacrine is incompletely understood. 100mg given
three times daily for 5 to 7 days is the recommended dose for the treatment of giardiasis.

Side Effects
Frequent side effects include (a) Headache (b) Dizziness (c) Vomiting (d) Blood
dyscrasias (e) Urticaria (f) Exfoliative dermatitis.

Antibiotics Amebicides
Some amebicides have been successfully used in the treatment of intestinal amoebiasis
especially paramomycin, some of the tetracycline and erythromycin. Paramomycin is
directly amebicidal while others act by interfering with the flora essential for the
proliferation of pathogenic amebae. Paramomycin is effective in the treatment of
infection with various tapeworms.

Leishmaniasis, Trypanosomiasis and Other Protozoal Infections.
Caused by members of the order kinetoplastida, trypanosomiasis and Leishmaniasis in
their protein forms can be especially difficult to prevent and cure. Effective drugs are
simply not available to treat some form of these infections. Moreover, agents with
established clinical efficacy are either too toxic or impractical for wide-scale
administration.

Trypanosomiasis
African Trypanosomiasis is transmitted by tsetse flies of the genus Glossinia and is
caused by subspecies of hemoflagellate Trypanosoma brucei. The parasite is detectable in
the blood, lymph and spinal fluid of the host. Two main types of human trypanosomal
disease exist:
    1. The Rhodesian trypanosomiasis (T. brucei rhodensiense) which produces a
       progressive and usually fatal form of disease marked by an early involvement of
       the central nervous system (CNS) and terminal cardiac failure.
    2. The Gambian trypanosomiasis (T. brucei gambiense) which causes the so-called
       sleeping sickness characterized by later involvement of the CNS and prolonged
       term course.




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Chemotherapy
Treatment with standard but toxic agents such as suramin, penthamidine and melasoprol
is inadequate; therapy must be given parenterally over extended periods and is often
unsuccessful.

American Trypanosomiasis
Also known as Chagas’ disease – a zoonosis caused by T. cruzi transmitted by
bloodsucking triatomid bugs, and affects about 24 million people from Southern
California to Argentina and Chile where the chronic form of the disease in adults is a
major cause of cardiomyopathy, megaesophagus, megacolon and death. Metacyclic
trypomastigotes enter host cells and proliferate as intracellular amastigotes which
differentiate and then released into the circulation.
Chronic disease of the heart and gastrointestinal tract eventually results from destruction
of myocardial cells and neurons of mesenteric plexus.

Chemotherapy
Although nitroheterocyclic drugs such as nifurtimox and benznidazole can suppress
parasitaemia and possibly cure or ameliorate the acute phase of Chagas’ disease, they
have little effect on the chronic disease.

Leishmaniasis
Human leishmaniasis is caused by protozoal species and subspecies of the genus
Leishmania and family Trypanasomatidae transmitted to man most often by the bites of
infected phlebotamine sand flies.
In increasing order of systemic involvement and clinical severity, human leishmaniasis
can be classified into; (a) Cutaneous (b) Mucocutaneous (c) Visceral (Kala azar) form. It
now appears that the cutaneous forms of leishmaniasis are self-limiting, whereas the
Mucocutaneous and visceral forms are not.

Chemotherapy
Initial treatment with pentavalent antimonials according to the regimens based on
collective empirical experience appears safe and effective in over 90% of cases. Second-
line drugs such as penthamidine and amphotericin B, are less satisfactory because of
unacceptable toxicity at effective therapeutic doses.

Other Protozoal Infections-Toxoplasmosis
Toxoplasmosis caused by the intracellular protozoan Toxoplasma gondii, is a zoonosis
that is a common cause of latent human infection worldwide. Acute infection is
particularly threatening to the fetus and immunocompromised host. The treatment of
choice is pyrimethamine and a sulfonamide. About 70 to 80% of patients with the
acquired immunodeficiency syndrome (AIDS) develop this serious complication; despite
treatment, the mortality rate is about 20% per episode.
Standard therapy for this condition is either trimethoprin-sulfamethoxazole or parenteral
penthamidine. Examples of less common protozoal infections affecting man are



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babesiosis, balantidiasis and coccidiosis. While balantidiasis responds to tetracyclines,
the other two infections are quite refractory to specific chemotherapy.


MELARSOPROL
Melarsoprol is a dimercaprol derivative of melarsen oxide. Of considerable importance
was the finding that trypanocidal arsenicals of the melamine type were effective against
trypasamide-resistant strains of trypanosomes.

Antiprotozoal Effects
It is the arsenoxide form of an organic arsenical that account for both its rapid lethal
effect on African trypanosomes and its toxicity to the host. The mechanism by which
melarsoprol is lethal to parasites is probably responsible for its toxicity to host tissues.

Toxicity and Side Effects
Toxicity is common during treatment with melarsoprol. The most serious complications
involve the nervous system. Manifestations include; (a) Convulsions associated with
acute cerebral edema (b) Rapidly progressive coma (c) Acute nonlethal mental
disturbances without neurological signs.

Clinical Uses
Melarsoprol is the drug of choice for the treatment of the meningocephalitic stage of
African trypanosomiasis because of its ability to enter the cerebrospinal fluid. It is
effective in both Gambian and Rhodesian varieties of the disease.

NIFURTIMOX
Nifurtimox,        3-methyl-4(5’-nitrofurfurylidene-amino)-tetrahydo-4H-1,4-thiazide-1,1-
dioxide, is a nitrofuran quite effective clinically in Chagas’ infection.

Antiprotozoal Effects
Nifurtimox is trypanocidal against both the trypomastigate and the amastigote forms of T.
cruzi causing damage and inhibiting their development in vitro. Its trypanocidal action
appears to be related to its ability to undergo partial reduction to form chemically reactive
radicals that cause production of toxic, partially reduced products of oxygen e.g.
superoxide, H2O2 and hydroxyradicals.

Pharmacokinetics
Nifurtimox is well absorbed after oral administration.

Toxicity and Side Effects
 Common side effects include; (a) Dermatitis (b) Fever (c) Icterus (d) Pulmonary
infiltrates (e) Anaphylaxis (f) Nausea (g) Myalgia (h) Weakness.
Peripheral neuropathy and gastrointestinal symptoms are particularly common after
prolonged treatment and later complications may lead to weight loss. Headache, psychic
disturbances, paresthesias, polyneuritis and CNS excitation are less frequent.




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Clinical Uses
Nifurtimox is effective in the acute and, to some questionable extent in the chronic stages
of T.cruzi infections.


PENTAMIDINE
Pentamidine (4,4’-diamidinophenoxy pentate)*

SURAMIN
Suramin is used primarily for the treatment of African trypanosomiasis. Although
suramin is effective in clearing adult filariae of onchocerciasis, it has largely been
replaced by Ivermectin for the treatment of that infection. Because of its inhibiting
activity of retroviral reverse transcriptase, it was recently tested unsuccessfully for
treatment of patients with AIDS. Interest has also been stimulated in the efficacy of
suramin in metastastic adrenocortical carcinoma and adrenocortical hyperfunction by
drug-related adrenal insufficiency observed in clinical studies and animal models.

Antiprotozoal Effects
The primary mechanism of suramin is not established which is not surprising taking its
general toxicity in consideration. Suramin is known however, to inhibit many
trypanosomal enzymes, particularly glycerol oxidase, a parasite enzyme involved with
energy metabolism as observed in suramin-tested animals.

Pharmacokinetics
Suramin must be given parenterally. Following its intravenous administration, its plasma
concentration falls fairly rapidly for a few hours, then more slowly for a few days with a
half-life of about 48 hours, and then finally very slowly with a terminal elimination half-
life of about 50 days.
The persistence of suramin in the circulation is due to extremely tight binding to plasma
protein and explains why the drug has proven valuable in the prophylaxis of
trypanosomiasis.

Route of Administration and Dosage
Treatment of active African trypanosomiasis should not be started until 24 hours after
diagnostic lumbar puncture, and caution required if the patient has onchocerciasis.

Toxicity and Side Effects
   1) The most serious immediate reaction consists of; (a) Nausea (b) Vomiting (c)
       Shock (d) Loss of consciousness
   2) Other common reactions include; (a) Fever (b) Erythematous skin rashes (c)
       Neurological complications ( headache, metallic taste, paresthesiae and peripheral
       neuropathy)
   3) Laboratory abnormalities noted in 12 to 26% of AIDS patients include leucopenia
       and occasional agranulocytosis, thrombocytopenia, proteinuria and elevation of
       plasma creatinine, transaminases and bilirubin.




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Clinical Uses
Suramin is used to treat African trypanosomiasis but is not of value in South American
trypanosomiasis caused by T. cruzi, Because only small amounts of the drug enter the
cerebrospinal fluid, suramin is more effective in the treatment of T. gambiense than those
with T, rhodensiense.

Chemotherapy
The treatment of choice is pyrimethamine and a sulfonamide.




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