Antimalarials, history

The success of quinine inspired the search for other antimalarials. The greatest impetus for the development of synthetic dmgs came this century when the two World Wars intermpted the supply of cinchona bark to the combatants. A stmcturally related 4-quinolinemethanol is mefloquine (65, Lariam [51773-92-3]) which now serves as an effective alternative agent for chloroquine-resistant P. falciparum. This is a potent substance that requires less than one-tenth the dose of quinine to effect cures. There are some untoward side effects associated with this dmg such as gastrointestinal upset and dizziness, but they tend to be transient. Mefloquine is not recommended for use by those using beta-blockers, those whose job requires fine coordination and spatial discrimination, or those with a history of epilepsy or psychiatric disorders. A combination of mefloquine with Fansidar (a mixture of pyrimethamine and sulfadoxine) is known as Fansimef but its use is not recommended. Resistance to mefloquine has been reported even though the compound has not been in wide use. 

Include a careful travel history of patient and physical findings (e.g., splenomegaly) and details of antimalarial chemoprophylaxis, when obtainable. 

Colitis, concurrent use of antimalarials, immunosuppressive agents, penicillamine, or phenylbutazone, congestive heart failure (CHF), exfoliative dermatitis, history of blood dyscrasias, severe liver or renal impairment, systemic lupus erythematosus... 

BUPROPION 1. ANTIBIOTICS - fluoroquinolones 2. ANTICANCER AND IMMUNO-MODULATING DRUGS-corticosteroids, interferons 3. ANTIDEPRESSANTS-TCAs 4. ANTIMALARIALS - chloroquine, mefloquine 5. ANTIPSYCHOTICS 6. BRONCHODILATORS -theophylline 7. CNS STIMULANTS 8. PARASYMPATHOMIMETICS T risk of seizures. This risk is marked in elderly people, in patients with a history of seizures, with addiction to opiates/cocaine/ stimulants, and in diabetics treated with oral hypoglycaemics or insulin Bupropion is associated with a dose-related risk of seizures. These drugs, which lower seizure threshold, are individually epileptogenic. Additive effects occur when combined Extreme caution. The dose of bupropion should not exceed 4S0 mg/day (or 150 mg/day in patients with severe hepatic cirrhosis)... 

Cinchona species (Rubiaceae) are sources of quinine and quinidine, containing a quinoline nucleus and derived through the extensive elaboration of strictosidine (Fig. 42). The intriguing history of the antimalarial quinine and its role in world politics over the past 350 years are legendary. It is frequently the only antimalarial drug to which patients are not resistant. Its widest use, however, is in the beverage industry in tonic water. Quinidine, an isomer of quinine, is used to treat cardiac arrythmias. 

In a single-arm, open, prospective study between 1990 and 1995 (before HAART) the prophylactic efficacy of Fansidar was evaluated in 95 HIV-infected patients with successfully treated Pneumocystis proved pneumonia and no history of Toxoplasma encephalitis (3). Patients took Fansidar with folinic acid (15 mg) twice weekly and were followed for a median of 19 (range 1-72) months. Five patients had a Pneumocystis relapse, but three had not taken their therapy. Of the 69 patients positive for. r. t. -Toxoplasma IgG antibodies, only one developed toxoplasma encephalitis after 50 months. A rash developed in 16 patients after a median of 3 weeks, and required withdrawal in six. Two developed Stevens-Johnson syndrome after three or four doses. There was no significantly increased risk of adverse reactions to Fansidar in patients with previous hypersensitivity reactions to co-tri-moxazole. The results of this study are of particular relevance to areas in which HAART is unavailable and where the antimalarial activity of Fansidar may confer additional benefit. 

The study of natural products, or Nature s Combinatorial Library , has had a long history as a source of drugs, and plants have historically been at the forefront of natural product drug discovery. In the anticancer area, for example, vinblastine and vincristine, etoposide, paclitaxel (Taxol), docetaxel, topotecan, and irinotecan, among others, are all plant-derived natural products or modified versions of plant compounds, while antimalarial therapy would be much poorer without quinine and artemisinin and the drugs derived from these plant products. This chapter provides an overview of the major medicinal agents that are themselves natural products isolated from plants or are chemical modifications of such lead compounds. It covers the therapeutic areas of cancer, HIV, malaria, cardiovascular, and central nervous system (CNS) diseases. Natural plant products have also made contributions in areas such as immunomodulatory and antibiotic activities," and the reader is referred to the cited reviews for information on these areas. 

Penicillamine is contraindicated in patients with a history of penicillamine-related aplastic anemia or agranulo-cystosis in patients with significant renal or hepatic insufficiency in pregnant women and in patients receiving gold salts, immunosuppressants, antimalarials, or phenylbutazone because of the increased risk of serious hematologic effects. 

Mefloquine hydrochloride (lariam) is available for oral administration only. Tablets marketed in the U.S. contain 250 mg mefloquine hydrochloride, equivalent to 228 mg mefloquine base (this may vary in Canada and elsewhere). The dosing below is expressed in mg salt. Adults and children >45 kg body weight take 250 mg weekly starting 1-2 weeks before entering an endemic area and ending 4 weeks after leaving. Pediatric doses, taken by the same schedule, are 5 mg/kg for children up to 15 kg (may have to be prepared by a pharmacist) 62.5 mg (1/4 tablet) for 15-19 kg 125 mg (V2 tablet) for 20-30 kg 187.5 mg /k tablet) for 31 5 kg. Note Mefloquine is not recommended for children weighing <5 kg or individuals with a history of seizures, severe neuropsychiatric disturbances, sensitivity to quinoline antimalarials, or cardiac conduction abnormalities. 

Febrifugine has a history as a malaria remedy which dates back to the first recorded use of Ch ang Shan in China, 200 B.C. It is an alkaloid which is apparently fairly widely distributed in the roots and leaves of plants of the family Saxifragaceae, and has been isolated both from the leaves of the common hydrangea in the United States and from the roots of Dichroa febrifuga Lour. The alleged antimalarial activity of the latter crude plant material has been confirmed by a number of modem investigators (93, 96-99). As a consequence of the careful and independent studies of both American and Chinese workers (100-106), the active alkaloid has been... 

Fever and malaria can induce a psychosis, but in this case, fever was an unlikely cause, as fever-induced psychosis is usually polymorphic and associated with some alteration of consciousness and orientation, which were absent there was also no past history of an altered mental state after febrile illnesses. Falciparum malaria leading to psychiatric sequelae usually presents with cerebral malaria, which has well-defined neurological signs. Antimalarial drugs such as chloroquine, mefloquine, and quinine can cause psychoses, and given substantial evidence of neurotoxicity after exposure to artemisinin compounds. 

---