1. Anti-Protozoal Agents
Dr. Syed Md. Basheeruddin Asdaq, Ph.D
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2. Overview
The main protozoa that produce disease in humans are those causing
malaria,
amoebiasis,
leishmaniasis,
trypanosomiasis and
trichomoniasis.
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4. Malaria Caused by Plasmodium protozoa – 4 different species
Cause: the bite of an infected adult female anopheline mosquito
Also transmitted by infected individuals via blood transfusion, congenitally, or infected needles by drug abusers
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5. Plasmodium Life Cycle Asexual cycle: two phases Exoerythrocytic phase
Occurs “outside” the erythrocyte
Also known as the tissue phase
Erythrocytic phase
Occurs “inside” the erythrocyte
Also known as the blood phase
Erythrocytes = RBCs
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7. Malarial Parasite (Plasmodium)
Two interdependent life cycles
Sexual cycle: occurs in the mosquito
Asexual cycle: occurs in the human
Knowledge of the life cycles is essential in understanding antimalarial drug treatment
Drugs are effective only during the asexual cycle
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8. The chief species of human malaria parasites are as follows:
P. falciparum, which has an erythrocytic cycle of 48 hours in humans, produces malignant tertian malaria-'tertian' because the fever was believed to recur every third day, 'malignant' because it is the most severe form of malaria and can be fatal.
The plasmodium induces, on the infected red cell's membrane, receptors for the adhesion molecules on vascular endothelial cells. These parasitised red cells then stick to uninfected red cells forming clusters (rosettes).
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9. They also adhere to and pack the vessels of the microcirculation, interfering with tissue blood flow and causing organ dysfunction, for example renal failure and encephalopathy (cerebral malaria).
P. falciparum does not have an exoerythrocytic stage, so if the erythrocytic stage is eradicated, relapses do not occur.
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10. P. vivax produces benign tertian malaria-'benign' because it is less severe than falciparum malaria and rarely fatal. Exoerythrocytic forms may persist for years and cause relapses .
P. ovale, which has a 48-hour cycle and an exoerythrocytic stage, is the cause of a rare form of malaria .
P. malariae has a 72-hour cycle, causes quartan malaria and has no exoerythrocytic cycle.
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12. ANTIMALARIAL DRUGS
The best way to treat malaria is to avoid the disease in the first place by preventing mosquito bites.
Travellers to infected areas should always take simple precautions such as wearing clothes that cover much of the skin and using insect repellents in living, and especially in sleeping, areas since mosquitoes tend to bite between dusk and dawn.
Bed nets sprayed with insecticides such as permethrin can also be very effective.
Some drugs can be used prophylactically to prevent malaria while others are directed towards treating acute attacks.
In general, antimalarial drugs are classified in terms of the action against the different stages of the life cycle of the parasite .
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13. Antimalarial therapy and the parasite life cycle
Drugs used to treat the acute attack of malaria act on the parasites in the blood; they can cure infections with parasites (e.g. P. falciparum) that have no exoerythrocytic stage.
Drugs used for chemoprophylaxis (causal prophylactics) (i.e. to prevent malarial attacks when in a malarious area) act on merozoites emerging from liver cells.
Drugs used for radical cure are active against parasites in the liver.
Some drugs act on gametocytes and prevent transmission by the mosquito.
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14. 1.Drugs used to treat the acute attack
Blood schizonticidal agents are used to treat the acute attack
They are also known as drugs for suppressive or clinical cure.
They act on the erythrocytic forms of the plasmodium.
In infections with P. falciparum or P. malariae, which have no exoerythrocytic stage, these drugs effect a cure; with P. vivax or P. ovale, the drugs suppress the actual attack but exoerythrocytic forms can cause later relapses.
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15. Classifications quinoline-methanols (e.g. quinine and mefloquine),
4-aminoquinolines (e.g. chloroquine),
Phenanthrene halofantrine and agents that interfere either with the synthesis of folate (e.g. sulfones) or with its action (e.g. pyrimethamine and proguanil)
hydroxynaphthoquinone compound atovaquone.
Combinations of these agents are frequently used.
Some antibiotics, such as tetracycline and doxycycline, have proved useful when combined with the above agents.
Compounds derived from qinghaosu, for example artemether, arteflene and artesunate, have also proved effective.
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16. 2. Drugs that effect radical cure
Tissue schizonticidal agents effect a radical cure by acting on the parasites in the liver
Only the 8-aminoquinolines (e.g. primaquine and tafenoquine) have this action.
These drugs also destroy gametocytes and thus reduce the spread of infection.
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17. 3. Drugs used for chemoprophylaxis
Drugs used for chemoprophylaxis block the link between the exoerythrocytic stage and the erythrocytic stage and thus prevent the development of malarial attacks.
Prevention of the development of clinical attacks can, however, be effected by chemoprophylactic drugs that kill the parasites when they emerge from the liver after the pre-erythrocytic stage.
The drugs used for this purpose are chloroquine, mefloquine, proguanil, pyrimethamine, dapsone and doxycycline. They are often used in combinations.
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18. Summary of drugs used for treatment and chemoprophylaxis of malaria
Infections
Drugs for the treatment of the clinical attack
Drugs for chemoprophylaxis
All plasmodial infections except chloroquine-resistant P. falciparum
Oral chloroquine or sulfadoxine-pyrimethamine
Oral chloroquine or proguanil
Infection with chloroquine-resistant P. falciparum
Oral quinine plus:
(i) tetracycline or
(ii) doxycycline or oral halofantrine or oral mefloquine
Oral chloroquine plus:
(i) proguanil or
(ii) doxycycline or
(iii) pyrimethamine-
dapsone or oral mefloquine
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19. Chemoprophylactic agents are given to individuals who intend travelling to an area where malaria is endemic.
Administration should start 1 week before entering the area and should be continued throughout the stay and for at least a month afterwards.
No chemoprophylactic regimen is 100% effective and the choice of drug is difficult.
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20. 4. Drugs used to prevent transmission
Some drugs (e.g. primaquine, proguanil and pyrimethamine) have the additional action of destroying the gametocytes, preventing transmission by the mosquito and thus preventing the increase of the human reservoir of the disease-but they are rarely used for this action alone.
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21. 4-AMINOQUINOLINES
The main 4-aminoquinoline used clinically is chloroquine
Amodiaquine has very similar action to chloroquine, It was withdrawn several years ago because it caused agranulocytosis but has now been re-introduced in several areas of the world where chloroquine resistance is endemic.
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22. Resistance Pharmacological actions
P. falciparum is now resistant to chloroquine in most parts of the world.
Resistance appears to result from enhanced efflux of the drug from parasitic vesicles as a result of increased expression of the human multidrug resistance transporter P-glycoprotein.
Resistance of P. vivax to chloroquine is also a growing problem in many parts of the world.
Pharmacological actions
Chloroquine is a disease-modifying antirheumatoid drug and also has some quinidine-like actions on the heart.
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23. Administration and pharmacokinetic aspects
Chloroquine is given orally, is completely absorbed, is extensively distributed throughout the tissues and is concentrated in parasitised red cells.
Given IM or slow SC of small doses
As explained above, chloroquine concentrates particularly in parasitised red cells. It is released slowly from the tissues and metabolised in the liver.
It is excreted in the urine, 70% as unchanged drug and 30% as metabolites. Elimination is slow, the major phase having a half-life of 50 hours, and a residue persists for weeks or months.
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24. Unwanted effects
Chloroquine has few adverse effects when given for chemoprophylaxis. With the larger doses used to treat the clinical attack of malaria, unwanted effects can occasionally occur, including nausea and vomiting, dizziness and blurring of vision, headache, and urticarial symptoms.
Large doses have sometimes resulted in retinopathies. Bolus intravenous injections of chloroquine can cause hypotension and, if high doses are used, fatal dysrhythmias.
Chloroquine is considered to be safe for use by pregnant women.
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25. QUINOLINE-METHANOLS Quinine
The two most widely used quinoline-methanols are quinine and mefloquine .
Quinine
Quinine is an alkaloid derived from cinchona bark. It is a blood schizonticidal drug effective against the erythrocytic forms of all four species of plasmodium, but it has no effect on exoerythrocytic forms or on the gametocytes of P. falciparum.
Its mechanism of action is, like that of chloroquine, associated with inhibition of the parasite's haem polymerase; but quinine is not so extensively concentrated in the plasmodium as chloroquine so other mechanisms could also be involved.
With the emergence and spread of chloroquine resistance, quinine is now the main chemotherapeutic agent for P. falciparum.
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26. Pharmacological actions
Pharmacological actions on host tissue include a depressant action on the heart, a mild oxytocic effect on the uterus in pregnancy, a slight blocking action on the neuromuscular junction and a weak antipyretic effect.
Pharmacokinetic aspects
Quinine is usually given orally in a 7-day course, but it can be given by slow IV infusion for severe P. falciparum infections and in patients who are vomiting. The half life is 10 hours.
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27. Unwanted effects
Given orally, quinine is bitter, so compliance is poor. It is irritant to the gastric mucosa and can cause nausea and vomiting.
If the concentration in the plasma exceeds μmol/l, 'cinchonism' is likely to occur-nausea, dizziness, tinnitus, headache and blurring of vision.
Excessive plasma levels of quinine can result in hypotension, cardiac dysrhythmias and severe central nervous system (CNS) disturbances such as delirium and coma.
Other rarer unwanted reactions that have been reported are hypoglycaemia, blood dyscrasias (especially thrombocytopenia) and hypersensitivity reactions.
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28. Quinine can stimulate insulin release
Quinine can stimulate insulin release. Patients with marked falciparum parasitaemia can have low blood sugar for this reason and also because of glucose consumption by the parasite. This can cause diagnostic confusion between coma caused by cerebral malaria and hypoglycaemic coma-which responds to glucose.
Blackwater fever, a severe and often fatal condition in which acute haemolytic anaemia is associated with renal failure, is a rare result of treating malaria with quinine or of erratic and inappropriate use of quinine for a 'fever'.
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29. Resistance
Some degree of resistance is developing. Like chloroquine, resistance is conferred by increased expression of P-glycoprotein, which effectively pumps the drug out of the parasite.
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30. Tinnitus, dizziness, blurred vision, and headache are indicative of toxicity to which one of the following antimalarial drugs?
A. Primaquine.
B. Quinine.
C. Pyrimethamine.
D. Chloroquine.
E. Sulfadoxine.
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31. Mefloquine
Mefloquine is a blood schizonticidal quinoline-methanol compound, active against P. falciparum and P. vivax; however, it has no effect on hepatic forms of the parasites, so treatment of P. vivax infections should be followed by a course of primaquine to eradicate the hypnozoites.
Mefloquine is frequently combined with pyrimethamine.
The antiparasite action is associated with inhibition of the haem polymerase; however, since mefloquine, like quinine, is not as extensively concentrated in the parasite as chloroquine, other mechanisms might also be involved.
Resistance has occurred in P. falciparum in some areas-particularly in southeast Asia-and is thought to be caused, as with quinine, by increased expression in the parasite of the P-glycoprotein.
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32. Pharmacokinetic aspects
Mefloquine is given orally and is rapidly absorbed. It has a slow onset of action and a very long plasma half-life (up to 30 days), which may be the result of enterohepatic cycling or tissue storage.
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33. Gastrointestinal disturbances (50%)
Unwanted effects
Gastrointestinal disturbances (50%)
Transient CNS toxicity-giddiness, confusion, dysphoria and insomnia-can occur and there have been a few reports of aberrant atrioventricular conduction and serious, but rare, skin diseases.
Mefloquine may rarely provoke severe neuropsychiatric reactions.
Mefloquine is contraindicated in pregnant women and in women liable to become pregnant within 3 months of stopping the drug, because of its long half-life and uncertainty about its possible teratogenicity.
When used for chemoprophylaxis the unwanted actions are usually milder, but the drug should not be used in this way unless there is a high risk of acquiring chloroquine-resistant malaria.
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34. PHENANTHRENE-METHANOLS, Halofantrine -
Halofantrine is a blood schizonticidal drug. It is one of a group of compounds that were studied during the Second World War and found to have antimalarial activity but were not developed when chloroquine was found to be successful.
However, as chloroquine resistance developed, halofantrine came in from the cold.
It is active against strains of P. falciparum that are resistant to chloroquine, pyrimethamine and quinine. It is effective against the erythrocytic form of P. vivax but not the hypnozoites.
However, it is not usually used for vivax malaria since this is generally susceptible to chloroquine.
Cross-resistance between halofantrine and mefloquine in falciparum infections has been reported. Its mechanism of action is not known.
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35. Pharmacokinetic aspects Halofantrine is given orally.
peak plasma concentration approximately 4-6 hrs and a half-life of 1-2 days, though its main metabolite, which has equal potency, has a half-life of 3-5 days.
Absorption is substantially increased by a fatty meal and elimination is in the faeces.
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36. Unwanted effects
Abdominal pain, gastrointestinal disturbances, headache, a transient rise in hepatic enzymes and cough occur. Pruritus is reported but is less marked than with chloroquine.
Halofantrine can produce changes in cardiac rhythm (most notably a lengthening of the Q-T interval) particularly if given with other dysrhythmia-inducing drugs. It has caused sudden cardiac death.
Rarer reactions are haemolytic anaemia and convulsions.
Because of such unwanted actions, halofantrine is no longer used for 'standby' treatment of malaria and it is now reserved for infections caused by resistant organisms.
However, even in this case, decreasing sensitivity and resistance of P. falciparum have been reported.
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37. DRUGS AFFECTING THE SYNTHESIS OR UTILISATION OF FOLATE
Antifolate drugs are classified into type 1 and type 2 compounds.
The type 1 antifolates are the sulfonamides and the sulfones, which inhibit the synthesis of folate by competing with p-Amino benzoic acid.
The type 2 antifolates are drugs such as pyrimethamine and proguanil, which prevent the utilisation of folate by inhibiting the conversion of dihydrofolate to tetrahydrofolate by dihydrofolate reductase.
Combinations of folate antagonists (type 2) with drugs inhibiting folate synthesis (type 1) cause sequential blockade, affecting the same pathway at different points; these combinations thus have synergistic action.
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38. Pyrimethamine is a 2,4, diaminopyrimidine and is similar in structure to trimethoprim.
The structure of proguanil is different but it can assume a configuration similar to that of pyrimethamine.
Both (pyrimethamine, proguanil) have a greater affinity for the plasmodial enzyme than for the human enzyme.
Pyrimethamine is only used in combination with either dapsone or a sulfonamide.
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39. The main sulfonamide used in malaria treatment is sulfadoxine and the only sulfone used is dapsone.
The sulfonamides and sulfones are active against the erythrocytic forms of P. falciparum but are less active against those of P. vivax; they have no activity against the sporozoite or hypnozoite forms of the plasmodia.
Pyrimethamine-sulfadoxine has been extensively used for chloroquine-resistant malaria but resistance to this combination has developed in many areas.
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40. Pharmacokinetic aspects
Both pyrimethamine and proguanil are given orally and are well absorbed, though the process is slow.
Pyrimethamine has a plasma half-life of 4 days and effective 'suppressive' plasma concentrations may last for 14 days; it is taken once a week.
The half-life of proguanil is 16 hours. It is a pro-drug, metabolised in the liver to its active form, cycloguanil, which is excreted mainly in the urine. It must be taken daily.
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41. Unwanted effects
Larger doses of the pyrimethamine-dapsone combination can cause serious reactions such as haemolytic anaemia, agranulocytosis and eosinophilic alveolitis.
The pyrimethamine-sulfadoxine combination can cause serious skin reactions, blood dyscrasias and allergic alveolitis; it is no longer recommended for chemoprophylaxis.
In high doses, pyrimethamine may inhibit mammalian dihydrofolate reductase and cause a megaloblastic anaemia; folic acid supplements should be given if this drug is used during pregnancy.
Resistance to antifolate drugs arises from single point mutations in the genes encoding parasite dihydrofolate reductase.
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42. 8-AMINOQUINOLINES
The only 8-aminoquinoline licensed for current use is primaquine.
Etaquine and tafenoquine are more active and slowly metabolised analogues of primaquine and are currently undergoing clinical evaluation.
The mechanism of action of these compounds is not known.
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43. The antimalarial action of these drugs is exerted against the liver hypnozoites and they can effect a radical cure of those forms of malaria in which the parasites have a dormant stage in the liver-P. vivax and P. ovale.
Primaquine does not affect sporozoites and has little if any action against the erythrocytic stage of the parasite.
However, it has a gametocidal action and is the most effective antimalarial drug for preventing transmission of the disease in all four species of plasmodia.
It is almost invariably used in combination with another drug, usually chloroquine.
Resistance to primaquine is rare, though evidence of a decreased sensitivity of some P. vivax strains has been reported.
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44. Pharmacokinetic aspects
Primaquine is given orally and is well absorbed. Its metabolism is rapid and very little drug is present in the body after hours.
The half-life is 3-6 hours.
Tafenoquine is broken down much more slowly and, therefore, has the advantage that it can be given on a weekly basis.
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45. Unwanted effects
Dose-related gastrointestinal symptoms can occur and large doses may cause methaemoglobinaemia with cyanosis.
This antimalarial drug can, however, cause haemolysis in individuals with an X-chromosome-linked genetic metabolic condition-a deficiency of glucose 6-phosphate dehydrogenase in the red cells.
When this deficiency is present, the red cells are not able to regenerate NADPH, its concentration being reduced by the oxidant metabolic derivatives of primaquine. As a consequence, the metabolic functions of the red cells are impaired and haemolysis occurs. Primaquine metabolites have greater haemolytic activity than the parent compound.
The deficiency of the enzyme occurs in up to 15% of Black males and is also fairly common in some other ethnic groups. Glucose 6-phosphate dehydrogenase activity should be estimated before giving primaquine.
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46. A 36-year-old male of Lebanese ancestry is being treated for Plasmodium vivax malaria. He experiences severe fatigue, back pain, and darkened urine. Which one of the following antimalarial drugs is most likely to have caused his symptoms?
A. Pyrimethamine.
B. Artemisinin.
C. Chloroquine.
D. Quinine.
E. Primaquine.
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47. ANTIBIOTICS USED IN MALARIA
Some antibiotics, for example doxycycline and tetracycline, have a place in the treatment of the acute attack of malaria and in chemoprophylaxis;
QINGHAOSU (ARTEMISININ) AND RELATED COMPOUNDS
The qinghaosu-based compounds are derived from the herb qing hao, a traditional Chinese remedy for malaria. The scientific name, conferred on the herb by Linnaeus, is Artemisia.
Artemisinin, a chemical extract from Artemisia, is poorly soluble in water and a fast-acting blood schizonticide effective in treating the acute attack of malaria (including chloroquine-resistant and cerebral malaria).
Artesunate, a water-soluble derivative, and the synthetic analogues artemether and artether have higher activity and are better absorbed.
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48. The compounds are concentrated in parasitised red cells.
It may involve damage to the parasite membrane by carbon-centred free radicals (generated by the breakdown of ferrous protoporphyrin IX) or covalent alkylation of proteins.
These compounds do not have any effect on liver hypnozoites and are not useful for chemoprophylaxis.
Artemisinin can be given orally, IM, or by suppository,
Artemether orally or IM,
Artesunate intramuscularly or intravenously.
They are rapidly absorbed and widely distributed, and are converted in the liver to the active metabolite dihydroartemisinin.
The half-life of artemisinin is about 4 hours, of artesunate 45 minutes and of artemether 4-11 hours.
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49. Unwanted effects
There have been few unwanted effects reported to date. Transient heart block, decrease in blood neutrophil count and brief episodes of fever have been reported.
In animal studies, artemisinin causes an unusual injury to some brainstem nuclei, particularly those involved in auditory function. However, there have been no reported incidences of neurotoxicity in humans.
So far, there have also been no reported cases of resistance.
In rodent studies, artemisinin potentiated the effects of mefloquine, primaquine, and tetracycline, was additive with chloroquine and antagonised the sulfonamides and the folate antagonists. For this reason, artemisinin derivatives are frequently used in combination with other antimalarial drugs.
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50. In randomised trials, the qinghaosu compounds have cured attacks of malaria, including cerebral malaria, more rapidly and with fewer unwanted effects than other antimalarial agents.
Artemisinin and derivatives are effective against multidrug-resistant P. falciparum in sub-Saharan Africa and, combined with mefloquine, against multidrug-resistant P. falciparum in southeast Asia.
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51. D. Sodium stibogluconate. E. Primaquine.
Which of the following drugs is recommended for the treatment of severe, multidrug-resistant Plasmodium falciparum malaria?
A. Artemisinin.
B. Chloroquine.
C. Quinine.
D. Sodium stibogluconate.
E. Primaquine.
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52. HYDROXYNAPHTHOQUINONE DRUGS
Atavaquone is used for the treatment of malaria and has some ability to prevent its development. It acts primarily to inhibit the parasite's mitochondrial electron transport chain, possibly by mimicking the natural substrate ubiquinone.
Atavaquone and the antifolate drug proguanil are usually used in combination since they act together to cause a synergistic antimalarial effect. When combined with proguanil, atavaquone is highly effective and well tolerated.
Few side-effects of such combination treatment have been reported, but abdominal pain, nausea and vomiting can occur. Pregnant or breastfeeding women should not take atavaquone.
Resistance to atavaquone is rapid and results from a single point mutation in the gene for cytochrome b. Resistance to combined treatment with atavaquone and proguanil is less common.
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53. POTENTIAL NEW ANTIMALARIAL DRUGS
Several new drugs are currently under test for antimalarial activity with positive results in animals and in preliminary trials in humans.
One of these, pyonaridine, has been used in China for almost 10 years. It is active against P. falciparum and P. vivax and is also active in chloroquine-resistant P. falciparum. It is effective orally and has low toxicity.
Lumefantrine is structurally related to quinine and is effective against P. falciparum particularly when combined with either mefloquine or artemisinin derivatives.
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54. AMOEBIASIS AND AMOEBICIDAL DRUGS
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55. Amoebiasis is an infection with Entamoeba histolytica produced by the ingestion of cysts of this organism.
In the intestine, the cysts develop into trophozoites that adhere to colonic epithelial cells by means of a lectin on the parasite membrane, which has similarity to host adherence proteins.
The trophozoite then lyses the host cell (hence histolytica) and invades the submucosa, where it may secrete a factor that inhibits IFNγ-activated macrophages, which would otherwise kill it.
These processes may result in dysentery, though in many subjects a chronic intestinal infection can be present in the absence of dysentery.
The parasite may invade the liver, leading to the development of liver abscesses, and in some subjects an amoebic granuloma (an amoeboma) develops in the intestinal wall.
Some individuals are 'carriers'-they harbour the parasite without developing overt disease, but the cysts are present in their faeces and they can infect other individuals. The cysts can survive outside the body for at least a week in a moist and cool environment.
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56. for chronic intestinal amoebiasis: diloxanide
The main drugs currently used are metronidazole, tinidazole and diloxanide. These agents may be used in combination.
The drugs of choice for the various forms of amoebiasis are as follows:
for acute invasive intestinal amoebiasis resulting in acute severe amoebic dysentery: metronidazole (or tinidazole) followed by diloxanide
for chronic intestinal amoebiasis: diloxanide
for hepatic amoebiasis: metronidazole followed by diloxanide
for the carrier state: diloxanide.
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57. Metronidazole
Metronidazole kills the trophozoites of E. histolytica but has no effect on the cysts. It is the most effective drug available for invasive amoebiasis involving the intestine or the liver, but it is less effective against organisms in the lumen of the gut.
The action of metronidazole is thought to be through damage to the DNA of the trophozoite by toxic oxygen products generated from the drug by the parasite.
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58. Pharmacokinetic aspects
Metronidazole is usually given orally and is rapidly and completely absorbed, giving peak plasma concentration in 1-3 hours, with a half-life of about 7 hours.
Rectal and intravenous preparations are also available.
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59. Unwanted effects
There are few unwanted effects with therapeutic doses. It has a metallic, bitter taste in the mouth.
Minor gastrointestinal disturbances have been reported as have CNS symptoms (dizziness, headache, sensory neuropathies).
The drug interferes with alcohol metabolism and alcohol should be strictly avoided.
Metronidazole should not be used in pregnancy.
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60. A 22-year-old man, who frequently backpacks, complains of diarrhea and fatigue. Examination of stool specimens shows binucleate organisms with four flagellae. Which one of the following drugs would be effective in treating this patient's infestation?
A. Metronidazole.
B. Quinidine.
C. Pentamidine.
D. Sulfadoxine.
E. Stibogluconate.
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61. Unwanted effects are similar to those seen with metronidazole.
Tinidazole and nimorazole are similar to metronidazole. Tinidazole is eliminated more slowly than metronidazole, having a half-life of hours.
Unwanted effects are similar to those seen with metronidazole.
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62. It has no serious adverse effects.
Diloxanide
Both diloxanide itself and, more particularly, an insoluble ester, diloxanide furoate, are effective against the non-invasive intestinal parasite.
The drugs have a direct amoebicidal action, affecting the amoebae before encystment.
Diloxanide furoate is given orally, the unabsorbed moiety being the amoebicidal agent.
It has no serious adverse effects.
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63. QUESTIONS ?
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