ANTIMALARIA. 117 good questions, nicely answered!

What are several drugs currently under tests for?

Several drugs are currently under tests for antimalarial activity. Positive results have been observed in animals and preliminary trials in humans.

What is lumefantrine and how is it used?

Lumefantrine, an aryl alcohol related to halofantrine, is available only as a fixed-dose combination with artemether (Coartem); now the first-line therapy for uncomplicated falciparum malaria in many countries.

What adverse events are associated with drug trials of Coartem?

Adverse events include gastrointestinal disturbances, headache, dizziness, rash, and pruritus; they have been due to malaria or concomitant medications rather than to Coartem.

What is unknown about Pyronaridine?

The mechanism of action of Pyronaridine is unknown. It is effective orally with low toxicity and active against P. falciparum and P. vivax.

What is Halofantrine hydrochloride and its effectiveness?

Halofantrine hydrochloride is a phenanthrene-methanol. It is effective against erythrocytic (but not other) stages of all four human malaria species. Oral absorption is variable and enhanced with food.

In which countries is Coartem approved, and what is its half-life?

Coartem is approved in many nonendemic countries, including the USA. The half-life is approximately 4 days.

When did the large scale trial of the first candidate vaccine begin?

The large scale trial of the first candidate vaccine began in 2009. Several drugs are currently under tests for antimalarial activity with positive results.

What is the activity of Clindamycin against erythrocytic schizonts?

Clindamycin is slowly active against erythrocytic schizonts. It is used after treatment courses of quinine, quinidine, or artesunate if doxycycline is not recommended (e.g., children and pregnant women).

What is the mechanism of action for Halofantrine?

The mechanism of action for Halofantrine is unknown. It is not available in the USA, although FDA approved, and is available in malaria-endemic countries.

How can drug levels of Coartem be affected?

Drug levels may be altered by interactions with other drugs, including those that affect CYP3A4 metabolism, but this area has not been well studied.

What is Azithromycin's role in antimalarial activity?

Azithromycin has antimalarial activity and is now under study as an alternative chemoprophylactic drug.

What is doxycycline used for in the treatment of falciparum malaria?

Doxycycline is used for the treatment of falciparum malaria in conjunction with quinine, which shortens the course of the drug.

What are the clinical uses of Halofantrine?

Halofantrine is used for the treatment of malaria due to most strains of P falciparum. It is limited by irregular absorption and cardiac toxicity and should not be used for chemoprophylaxis.

What should be considered regarding oral absorption of Coartem?

Oral absorption is highly variable and improved when the drug is taken with food. No dangerous toxicity concerns as for halofantrine - Coartem should be administered with fatty food to maximize antimalarial efficacy.

What are folate antagonists and sulfonamides in relation to antimalarials?

A number of antibiotics, in addition to the folate antagonists and sulfonamides, are modestly active antimalarials.

How is doxycycline used after the initial treatment of severe malaria?

It is used to complete treatment courses after initial treatment of severe malaria with intravenous quinine, quinidine, or artesunate.

What has been demonstrated about the antimalarial activity of fluoroquinolones?

Antimalarial activity of fluoroquinolones has been demonstrated, but with suboptimal efficacy for the therapy or chemoprophylaxis of malaria.

What are the adverse effects of Halofantrine?

Adverse effects include abdominal pain, diarrhea, vomiting, cough, rash, headache, pruritus, and elevated liver enzymes. The drug alters cardiac conduction, causing dangerous arrhythmias and deaths.

What effect does Coartem have on the QT interval?

Coartem can cause minor prolongation of the QT interval (clinically insignificant); carries no risk of dangerous arrhythmias (as with halofantrine and quinidine).

When is Halofantrine contraindicated?

Halofantrine is contraindicated in cases of cardiac conduction defects or who have recently taken mefloquine, and in pregnancy.

What type of drug is Atovaquone?

Atovaquone is a hydroxynaphthoquinone drug. It is used for the prophylactic treatment of malaria, treatment of malaria cases resistant to other drugs, and treatment of mild to moderate P. jiroveci pneumonia.

How do bacterial protein synthesis inhibitors act against malaria parasites?

The antibiotics that are bacterial protein synthesis inhibitors appear to act against malaria parasites by inhibiting protein synthesis in a plasmodial prokaryote-like organelle, the apicoplast.

What role does doxycycline play in chemoprophylaxis?

Doxycycline has become a standard chemoprophylactic drug, especially in areas of Southeast Asia with high rates of resistance to other antimalarials, including mefloquine.

What are the unwanted effects of artemesinin and related compounds?

Unwanted effects include transient heart block, neutropenia, and fever.

What are the adverse effects associated with doxycycline?

Adverse effects include gastrointestinal symptoms, candidal vaginitis, and photosensitivity.

How does Atovaquone work?

It inhibits the parasite’s mitochondrial electron transport chain, possibly by mimicking the natural substrate ubiquinone. It is used in combination with the antifolate drug proguanil, acting synergistically.

Why should no antibiotic be used as single agents in the treatment of malaria?

No antibiotic should be used as single agents in the treatment of malaria because their action is much slower than that of standard antimalarials.

What are sesquiterpene lactones and their origin?

Sesquiterpene lactones are derivatives of a Chinese herb, quing hao, used for malaria remedy.

How does artemesinin interact with other drugs in rodents?

Artemesinin potentiated the effects of mefloquine, primaquine, and tetracycline; it has additive effects with chloroquine and antagonises sulphonamides and other folate antagonists.

What are the unwanted effects of Atovaquone in combination?

Unwanted effects include abdominal pain, vomiting, and nausea. Pregnant and lactating women should not take atovaquone. Resistance as a single drug is common; in combination, it is less common.

What is the activity of tetracycline and doxycycline against malaria parasites?

Tetracycline and doxycycline are active against erythrocytic schizonts - all human malaria parasites, but not active against liver stages.

What is the half-life of Primaquine and how is Tefenoquine metabolized?

Primaquine has a short half-life of 3-6 hrs; Tefenoquine is metabolised slowly and has a weekly dosing schedule.

Describe the effectiveness of Artemisinin in treating malaria.

Artemisinin is a fast acting blood schizonticide, effective in treating acute attack of malaria, including chloroquine-resistant and cerebral malaria.

In what way are artemesinin derivatives used with other anti-malarial drugs?

Artemesinin derivatives are used in combination with other anti-malarial drugs, e.g., lumefantrine.

What are the derivatives and synthetic analogues of Artemisinin?

Artesunate (water soluble derivative); synthetic analogues - artemether and arteether.

What type of compound is Primaquine?

Primaquine is an 8-aminoquinolone. It is active against liver hypnozoites and is used in combination with other drugs, e.g., chloroquine. Resistance is rare.

What are the unwanted effects of Primaquine related to GIT and methemoglobinemia?

Unwanted effects include GIT effects (dose related) and methemoglobinemia with cyanosis.

What is the clinical use of artemesinin and its derivatives in sub-Saharan Africa?

Artemesinin and its derivatives are used in the treatment of multi-drug resistant P. falciparum in sub-Saharan Africa.

What are the adverse effects of drugs affecting folate metabolism?

Gastrointestinal symptoms, skin rashes, itching (rare)
Mouth ulcers, alopecia (proguanil)
Severe cutaneous reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis (fansidar)
Hematologic, gastrointestinal, central nervous system, dermatologic, renal toxicity (single fansidar dose)
High rates of agranulocytosis (maloprim)

What are the analogues of Primaquine?

Analogues of Primaquine include Tafenoquine and Etaquine. These analogues are more active and slowly metabolised. They are used for the radical cure of P. vivax and P. ovale malaria.

What genetic condition is associated with haemolysis due to Primaquine?

Haemolysis is linked to glucose-6-phosphate dehydrogenase deficiency, an X chromosome genetic condition. Red cells can't regenerate NADPH, depleted by oxidant metabolites of Primaquine.

How is multi-drug resistant P. falciparum treated in south-east Asia?

Treatment of multi-drug resistant P. falciparum in south-east Asia involves combination with mefloquine.

What was Fansidar's role in treating uncomplicated falciparum malaria?

Fansidar was the first-line treatment for uncomplicated falciparum malaria. It is no longer recommended due to resistance. It should not be used for severe malaria.

What caution should be taken with drugs affecting folate metabolism?

Use cautiously with renal or hepatic dysfunction
Pyrimethamine is teratogenic (animals), fansidar safe in pregnancy (humans)
Proguanil safe in pregnancy, folate supplements given routinely
Fansidar preventive therapy in pregnancy, high folate supplementation (5 mg daily) should be avoided

What action does Primaquine have on parasites?

Primaquine has gametocidal action. It is the most effective antimalarial drug for preventing disease transmission in all the 4 plasmodia species. It has no action on sporozoites and erythrocytic stages.

Why is it important to estimate enzyme activity before administering Primaquine?

It's important to estimate enzyme activity because red cells are unable to regenerate NADPH, which is depleted by oxidant metabolic derivatives of Primaquine.

Explain the mechanism of action of Artemisinin.

Inhibition of parasite Ca2+ dependent ATPase. And may need iron so that it can be activated and give its action.

Against which stage of malaria does Artemisinin show no activity?

No activity against: liver hypnozoites.

What is no longer recommended for chemoprophylaxis due to resistance?

Single folate antagonists are no longer recommended for chemoprophylaxis due to resistance. Combination regimens were common but are no longer recommended due to resistance to both agents.

Why should Fansidar not be used for severe malaria?

Fansidar should not be used for severe malaria because it is slower-acting than other agents. It is not reliably effective in vivax malaria and its usefulness against P ovale and P malariae is not adequately studied.

What is the recommended dosage of folate supplementation with Fansidar?

Standard recommended dosage of 0.4-0.6 mg daily is less likely to affect Fansidar’s protective efficacy.

What is the first-line therapy for toxoplasmosis?

Pyrimethamine, in combination with sulfadiazine, is the first-line therapy in the treatment of toxoplasmosis.

What is the similarity between primethamine and trimethoprim?

Primethamine is similar to trimethoprim, an antibacterial drug. Both drugs have greater affinity for plasmodial enzyme than for the human enzyme. Action is slow against erythrocytic forms of the parasite.

Why is the combination of chloroquine and proguanil no longer recommended?

Chloroquine (500 mg weekly) and proguanil (200 mg daily) combination was common but is no longer recommended due to resistance to both agents.

What is the first-line therapy for pneumocystosis?

The first-line therapy of pneumocystosis is trimethoprim plus sulfamethoxazole.

What is the main action of sulfonamides and sulfones in folate metabolism?

Sulfonamides and sulfones are antibacterial drugs that inhibit the synthesis of folate by competing with p-aminobenzoic acid. They are used to treat malaria and other infections.

What are the effects of proguanil on initial hepatic stages?

Proguanil has addition effects on initial hepatic stages but no effects on hypnozoites of P. vivax.

What is the status of Fansidar and Maloprim in chemoprophylaxis?

Fansidar (sulfadoxine and pyrimethamine) and Maloprim (dapsone+pyrimethamine) with weekly dosing are no longer recommended due to resistance and toxicity.

What type of drug is lumefantrine related to?

Lumefantrine is an aryl amino alcohol drug related to the elder compound, halofantrine, which is seldomly used.

Which sulfonamide is mainly used for malaria treatment?

The main sulfonamide used for malaria treatment is sulfadoxine. Sulfone, used only as dapsone, is also mentioned in the context of folate metabolism.

What is the half-life of pyrimethamine and its effect on plasma concentration?

The half-life of pyrimethamine is 4 days with suppressive plasma concentration up to 14 days.

What are some adverse effects of Mefloquine?

Nausea, vomiting, dizziness, sleep and behavioral disturbances.
Epigastric pain, diarrhea, abdominal pain, headache, rash, and dizziness.
Leukocytosis, thrombocytopenia, and aminotransferase elevations.
Neuropsychiatric symptoms: depression, confusion, acute psychosis, or seizures.
Alteration of cardiac conduction, arrhythmias, and bradycardia.

Against which forms of malaria is sulfadoxine active?

Sulfadoxine is active against erythrocytic forms of P. falciparum, less so against P. vivax, and has no activity against sporozoites or hypnozoites (parasite).

What is the half-life of proguanil and how is it metabolized?

Proguanil has a half-life of 16 hours and is a prodrug metabolised to an active form, cycloguanil, in the liver.

What is Intermittent Preventive Therapy and who typically receives it?

Intermittent Preventive Therapy is a new strategy for malaria control where high-risk patients receive intermittent treatment for malaria, regardless of infection status, typically with Fansidar.

What is the mode of action of lumefantrine?

The mode of action of lumefantrine is to prevent parasite detoxification of haem.

What are the clinical uses of Mefloquine for chemoprophylaxis?

Mefloquine is effective against most strains of P. falciparum and probably all other human malarial species. It is recommended in chloroquine resistance.

What are the contraindications and cautions for Mefloquine?

Contraindicated: epilepsy, psychiatric disorders, arrhythmia, cardiac conduction defects, or sensitivity to related drugs.
Do not co-administer with quinine, quinidine, or halofantrine.
Caution: If quinine or quinidine is used to treat malaria after mefloquine chemoprophylaxis.

How is Intermittent Preventive Therapy administered to pregnant women?

Pregnant women receive single doses of Fansidar during the second and third trimesters as part of Intermittent Preventive Therapy.

What are the unwanted effects of lumefantrine?

Unwanted effects of lumefantrine include gastrointestinal and CNS symptoms.

What type of compound is Mefloquine and what is its activity against parasites?

Mefloquine is a blood schizonticidal compound. It is active against P. falciparum and P. vivax but has no effect on hepatic forms of the parasite.

How is Mefloquine used in the treatment of malaria?

Mefloquine is used for most falciparum malaria. It is not recommended for severe or complicated malaria since quinine, quinidine, and artemisinins are more rapidly active.

What is the mode of action of pyrimethamine and proguanil?

Pyrimethamine and proguanil inhibit dihydrofolate reductase, preventing the utilization of folate in DNA synthesis. They are used in combination to block the folate pathway synergistically.

When do young children receive Intermittent Preventive Therapy?

Young children receive monthly doses during scheduled immunizations or in areas with seasonal malaria, as part of Intermittent Preventive Therapy during the transmission season.

Describe the chemical nature of Mefloquine.

Mefloquine is a synthetic 4-quinoline methanol that is chemically related to quinine.

What are the symptoms of cinchonism caused by quinine?

Symptoms of cinchonism include:

Ringing in ears
Nausea
Vomiting (due to gastric irritation and CTZ stimulation)
Headache
Mental confusion
Vertigo
Difficulty in hearing and visual defects (due to neurotoxicity and constriction of vessels).

What are the pharmacological actions of quinine?

Quinine has oxytocic effects on the uterus during pregnancy, slight blocking effects at the neuromuscular junction, and weak antipyretic effects.

What are some adverse effects of quinine related to the cardiovascular system?

Adverse effects include:

Hypotension
Cardiac arrhythmias (rapid i.v. injection — the patient may die)
Hypersensitive reactions.

What is Quinine derived from?

Methanol Quinolone, Quinine is derived from Cinchona Bark. It is a blood schizonticidal drug effective against erythrocytic forms of all species of plasmodium.

How is quinine used for malaria?

Quinine is used for uncomplicated chloroquine-resistant malaria orally and for complicated/cerebral malaria (chloroquine sensitive or resistant) intravenously.

What are the adverse effects of quinine related to skin and blood?

Adverse effects include:

Purpura
Rashes
Itching
Angioedema of face and bronchoconstriction
Haemoglobinuria (black water fever)
Kidney damage.

Where is resistance to Mefloquine found and what is it associated with?

Resistance to Mefloquine is found only in regions of Southeast Asia with high rates of multidrug resistance. It is associated with resistance to quinine and halofantrine but not with resistance to chloroquine.

What are the contraindications for Chloroquine?

Chloroquine is contraindicated in:

Psoriasis or porphyria (may precipitate acute attacks)
Retinal or visual field abnormalities
Myopathy

What is the benefit of quinine for nocturnal muscle cramps?

Quinine benefits some cases of nocturnal muscle cramps and is effective in myotonia congenita, but not in all cases.

How should quinine be used during pregnancy?

Quinine should be used only for life-threatening infection with special care to prevent hypoglycaemia during pregnancy.

What is the resistance pattern of chloroquine?

Resistance is very common among strains of P. falciparum; uncommon but increasing for P. vivax.

What should be used with caution when taking Chloroquine?

Use caution with Chloroquine if there is a history of:

Liver disease
Neurologic disorders
Hematologic disorders

How does Quinine act in the body?

It acts by concentrating in parasite food vacuoles, preventing the biocrystallization of the hemoglobin breakdown product, heme, into hemozoin, thus eliciting parasite toxicity due to the buildup of free heme.

Why is quinine not recommended for the diagnosis of myasthenia gravis?

Quinine precipitates weakness in myasthenia gravis, and the provocative test is dangerous, so it is not recommended.

What are some symptoms of quinine overdose related to the central nervous system?

Symptoms include:

Delirium
Fever
Tachypnoea followed by respiratory depression
Marked weakness
Prostration.

How is quinine used for varicose veins?

Quinine is injected with urethane, causing thrombosis and fibrosis of the varicose vein mass.

What type of compound is Chloroquine?

Chloroquine is a 4-aminoquinoline. It is used as a blood schizonticidal agent. It is effective against erythrocytic forms of all 4 plasmodial species (cases - no resistance).

What are the clinical uses of chloroquine?

Treatment: Drug of choice for non-falciparum and sensitive falciparum malaria.
Chemoprophylactic agent: Malarious regions without resistant falciparum malaria.

What drug interactions should be avoided with Chloroquine?

Avoid coadministration with:

Antidiarrheal agent kaolin
Calcium-containing antacids
Magnesium-containing antacids

These interfere with Chloroquine absorption.

How is Quinine different from chloroquine in terms of concentration?

Quinine is not extensively concentrated in plasmodium as chloroquine; thus other mechanisms could be involved. It is a main chemoprophylactic agent for P. falciparum.

What are the safety concerns for Chloroquine?

Safety concerns for Chloroquine include:

Pregnancy
Use in young children

What are the drugs used to prevent transmission?

Drugs: Primaquine, proguanil, and pyrimethamine.
Destroy gametocytes to prevent transmission by mosquitoes.
Human reservoir of disease.
Used for other purposes as well.

Against which forms is Chloroquine not effective?

Chloroquine is not effective against sporozoites, hypnozoites, or gametocytes. It is effective against erythrocytic forms of all 4 plasmodial species in cases with no resistance.

How is chloroquine used in amebic liver abscess cases?

Used in amebic liver abscess that fails initial therapy with metronidazole, as chloroquine reaches very high liver concentrations.

What is the purpose of tissue schizonticidal agents in radical cure?

Tissue schizonticidal agents effect a 'radical' cure by eradicating P. vivax and P. ovale in the liver. Drugs include 8-aminoquinolines like primaquine and tafenoquine. They destroy gametocytes, reducing the spread of infection.

How does Chloroquine interact with parasite pH levels?

In parasites, Chloroquine remains uncharged at neutral pH and freely diffuses into parasite lysosomes. In lysosomes with acid pH, it becomes protonated and trapped.

What are the adverse effects of chloroquine?

Pruritus (common, primarily in Africans); nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision, and urticaria are uncommon.

What are artemisinin and related compounds used for?

Artemisinin and related compounds are used to treat acute attacks and are usually used in combinations. They are part of the classification of drugs for treating acute attacks.

What is the role of drugs used for chemoprophylaxis?

Drugs used for chemoprophylaxis kill the parasite as they emerge from the liver, after the preerythrocytic stage. Drugs include artemisinin derivatives, chloroquine, lumefantrine, mefloquine, proguanil, pyrimethamine, dapsone, doxycycline, used in combinations.

What is the first stage in the lifecycle depicted?

The first stage involves a mosquito biting the skin, initiating the exoerythrocytic stage. This stage is crucial for the lifecycle progression.

Name some quinolone-methanols used to treat acute attacks.

Quinolone-methanols used to treat acute attacks include quinine and mefloquine. Various 4-aminoquinolines like chloroquine are also used in this classification.

What causes malaria and what are the four main species of plasmodia that infect humans?

Malaria is caused by parasites belonging to the genus Plasmodium. The four main species of plasmodia that infect humans are Plasmodium vivax, Plasmodium falciparum, Plasmodium ovale, and Plasmodium malariae.

What occurs during the sporozoites stage?

During the sporozoites stage, sporozoites are introduced into the host's body. This stage is essential for the infection process.

What drugs interfere with the synthesis of folate or its action?

Drugs interfering with either the synthesis of folate or its action include pyrimethamine and proguanil. These drugs are used to treat acute attacks.

What is the insect vector for malaria and where does it breed?

The insect vector for malaria is a female Anopheles mosquito, which breeds in stagnant water.

What happens after the infected hepatocyte stage?

After the infected hepatocyte stage, hepatic schizonts form and eventually rupture, releasing merozoites into the bloodstream.

Which drug affects mitochondrion function in treating acute attacks?

Atovaquone is the drug that affects mitochondrion function in treating acute attacks. It is part of the classification of drugs used for this purpose.

According to the WHO report in 2008, how significant is malaria as a public health problem?

According to the WHO report in 2008, malaria is a significant public health problem in 90 countries, affecting 50% of the world population.

Describe the erythrocytic stage in the lifecycle.

The erythrocytic stage involves merozoites infecting RBC's, progressing through early and late trophozoite stages, and forming blood-stage schizonts.

What antibiotics are useful in combination with other agents for treating acute attacks?

Antibiotics like tetracycline, doxycycline, and clindamycin are useful in combinations with above agents for treating acute attacks. They are part of the classification of drugs used for this purpose.

What were the impacts of malaria in 2006?

In 2006, malaria caused 880 million acute illnesses each year, resulted in 1 million deaths, and it was estimated that it kills a child every second in Africa.

What is the final stage in this lifecycle?

The final stage involves the formation of gametocytes, which are taken up by mosquitoes, completing the lifecycle.

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