phenanthrenes and Fever

The clinical efficacy and tolerability of halofantrine, a new antimalarial schizontocide, was studied in a multi-centre trial involving 268 patients ranging in age from 6 months to 58 years. The patients were suffering from acute uncomplicated malaria due to either P. vivax or P. falciparum. Patients were treated orally with 3 doses of halofantrine hydrochloride, 500 mg/6-hourly in adults or 8 mg/kg body weight 6-hourly in children. The overall cure rate was 96.9%. The mean fever clearance time for different species was as follows: P. vivax--39.1 hours, P. falciparum--43.2 hours, mixed infection--60.0 hours, and the mean parasitaemia clearance times were 47.7, 55.1 and 72.0 hours, respectively. Recrudescence was reported in 11 (4.1%) patients, although all of them were parasite-free on Day 7 post-treatment. No haematological or biochemical abnormalities were noted. The drug was very well tolerated and no significant side-effects were reported. Halofantrine was found to be highly effective in acute malaria and offers an important alternative to existing medications.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Antimalarials; Body Weight; Child; Child, Preschool; Female; Fever; Humans; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Phenanthrenes; Recurrence; Time Factors; Treatment Outcome

Topics: Adolescent; Adult; Antibodies; Antimalarials; Clinical Trials as Topic; Ethanolamines; Fever; Follow-Up Studies; Hematocrit; Humans; Kidney Function Tests; Leukocyte Count; Liver Function Tests; Malaria; Male; Middle Aged; Parasite Egg Count; Phenanthrenes; Plasmodium falciparum; Quinine; Thailand

Prostaglandin E2 (PGE2), one of the terminal products in the cyclooxygenase pathway, plays an important role in various inflammatory responses. To determine whether selective inhibition of PGE2 may relieve these inflammatory symptoms, we synthesized a selective PGE2 synthesis inhibitor, compound A [1-(6-fluoro-5,7-dimethyl-1,3-benzothiazol-2-yl)-N-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]piperidine-4-carboxamide], then investigated the effects on pyrexia, arthritis and inflammatory pain in guinea pigs. In LPS-stimulated guinea pig macrophages, compound A selectively inhibited inducible PGE2 biosynthesis in a dose-dependent manner whereas enhanced the formation of thromboxane B2 (TXB2). Compound A suppressed yeast-evoked PGE2 production selectively and enhanced the production of TXB2 and 6-keto PGF1αin vivo. In addition, compound A relieved yeast-induced pyrexia and also suppressed paw swelling in an adjuvant-induced arthritis model. The effect on gastrointestinal (GI) ulcer formation was also evaluated and compound A showed a lower GI adverse effect than indomethacin. However, compound A failed to relieve yeast-induced thermal hyperalgesia. These results suggest that selective inhibition of PGE2 synthesis may have anti-pyretic and anti-inflammatory properties without GI side effect, but lack the analgesic efficacy.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Benzothiazoles; Depression, Chemical; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fever; Guinea Pigs; Imidazoles; Indomethacin; Inflammation; Macrophages; Pain; Peptic Ulcer; Phenanthrenes; Piperidines; Stimulation, Chemical; Thromboxane B2

Microsomal prostaglandin E synthase-1 (mPGES-1) is a terminal prostaglandin E(2) (PGE(2)) synthase in the cyclooxygenase pathway. Inhibitors of mPGES-1 may block PGE(2) production and relieve inflammatory symptoms. To test the hypothesis, we evaluated the antipyretic and analgesic properties of a novel and selective mPGES-1 inhibitor, MF63 [2-(6-chloro-1H-phenanthro-[9,10-d]imidazol-2-yl)isophthalonitrile], in animal models of inflammation. MF63 potently inhibited the human mPGES-1 enzyme (IC(50) = 1.3 nM), with a high degree (>1000-fold) of selectivity over other prostanoid synthases. In rodent species, MF63 strongly inhibited guinea pig mPGES-1 (IC(50) = 0.9 nM) but not the mouse or rat enzyme. When tested in the guinea pig and a knock-in (KI) mouse expressing human mPGES-1, the compound selectively suppressed the synthesis of PGE(2), but not other prostaglandins inhibitable by nonsteroidal anti-inflammatory drugs (NSAIDs), yet retained NSAID-like efficacy at inhibiting lipopolysaccharide-induced pyresis, hyperalgesia, and iodoacetate-induced osteoarthritic pain. In addition, MF63 did not cause NSAID-like gastrointestinal toxic effects, such as mucosal erosions or leakage in the KI mice or nonhuman primates, although it markedly inhibited PGE(2) synthesis in the KI mouse stomach. Our data demonstrate that mPGES-1 inhibition leads to effective relief of both pyresis and inflammatory pain in preclinical models of inflammation and may be a useful approach for treating inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Fever; Guinea Pigs; Humans; Imidazoles; Intramolecular Oxidoreductases; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microsomes; Pain; Phenanthrenes; Prostaglandin Antagonists; Prostaglandin-E Synthases; Rats; Saimiri

Topics: Antimalarials; Appendicitis; Diagnosis, Differential; Fever; Humans; Malaria; Male; Middle Aged; Phenanthrenes

Topics: Antimalarials; Butylamines; Ethanolamines; Fever; Humans; Malaria; Male; Methanol; Military Medicine; Phenanthrenes; Plasmodium falciparum; Quinine; Quinolines; Thailand; Vietnam

Topics: Bile Acids and Salts; Detergents; Fever; Medical Laboratory Science; Methods; Muramidase; Orthomyxoviridae; Phenanthrenes; Polymyxins; Sucrose; Vitamin A

Topics: Adult; Female; Fever; Humans; Phenanthrenes; Pregnancy; Puerperal Disorders