Constituents of Peucedanum zenkeri seeds and their antimicrobial effects.

The methanol extract of Peucedanum zenkeri L. seeds showed antimicrobial activity which is concentrated in the n-hexane fraction. Bioactivity-guided chromatographic fractionation of the seeds of P. zenkeri led to the isolation and characterization of five major coumarins, umbelliprenin, imperatorin, bergapten, isopimpinellin and byakangelicin, as well as two minor coumarins, 7-methoxy coumarin and 5-hydroxy-8-methoxy psoralen. Amongst the isolated compounds only imperatorin, bergapten and isopimpinellin were found to possess anti-microbial activity.

Stereoselective halofantrine disposition and effect: concentration-related QTc prolongation.

AIMS: 1) To characterize the variability of multiple-dose halofantrine pharmacokinetics over time in healthy adults, 2) to correlate the pharmacodynamic measure electrocardiographic (ECG) QT interval with (+)- and (-)-halofantrine plasma concentration and 3) to evaluate the safety and tolerance of halofantrine hydrochloride given over time to healthy adults. METHODS: Twenty-one healthy subjects were enrolled and 13 completed the study (180 days). Subjects received either 500 mg of racemic halofantrine once daily in the fasted state for 42 days, or placebo, and then halofantrine washout was documented for the following 138 days. Pharmacokinetic and pharmacodynamic (ECG QTc) measurements were obtained. RESULTS: Mean accumulation half-times (days) for halofantrine were: 7.0 +/- 4.8 [(+)-halofantrine] and 7.3 +/- 4.8 [(-)-halofantrine]. Mean steady-state concentrations were: 97.6 +/- 52.0 ng ml(-1) [(+)-halofantrine] and 48.5 +/- 20.8 [(-)-halofantrine]. Steady-state oral clearance was: 139 +/- 73 l h(-1) [(+)-halofantrine] and 265 +/- 135 l h(-1) [(-)-halofantrine]. Peak plasma concentrations of both (+)- and (-)-halofantrine were attained at 6 h and maximal ECG QTc prolongation was at 4-8 h following drug administration. Fourteen of 16 subjects who received active drug had ECG QTc prolongation that was positively correlated with both (+)- and (-)-halofantrine concentration. The five subjects who received placebo had no demonstrable change in ECG QTc throughout the study. Conclusions Halofantrine accumulates extensively and shows high intersubject pharmacokinetic variability, is associated with concentration-related ECG QTc prolongation in healthy subjects, and is clinically well tolerated in this subject group.

A new integrated program for natural product development and the value of an ethnomedical approach.

There is a need for less expensive alternative therapies, especially in the treatment of chronic illnesses. This presentation addresses the issues inherent in the use of natural products in a drug-discovery or development program and reviews a model program developed by the U.S. National Institutes of Health (NIH) and administered by the Fogarty International Center at the NIH. Eighty percent (80%) of the world's population relies on medicinal plants for their primary health care. The World Health Organization has been promoting traditional medicine as a source of less expensive, comprehensive medical care, especially in developing countries. Natural products have also been successful in drug development. Over 50% of the best-selling pharmaceuticals in use today are derived from natural products. In a natural-product drug development program, it is the diversity of the natural products that is especially interesting. Thanks to technologic advances, now is a good time to be looking for new drugs in the natural-product arena. But there are major hurdles to overcome in a natural-products development program, namely, time-to-lead, supply, and ownership. Time-to-lead is complex because most natural products are mixtures or crude extracts. It can be very difficult to isolate the active principles and elucidate their structures. The difficulty of obtaining sufficient supply is often given as a reason for not becoming involved in natural-product drug development or discovery. This presentation details some ways these seeming hurdles can be overcome. The concept of ownership has changed dramatically in recent years. Until recently, genetic resources were considered to belong to no one and to therefore be the heritage of everyone. The United Nations Convention on Biodiversity and the meetings in Rio de Janeiro in 1992, redefined biodiversity ownership. Genetic biodiversity has a potential value and belongs to the country of origin. The International Conservation of Biodiversity Groups (ICBGs) was founded in 1992 to address such issues. This presentation discusses the importance of integrating efforts in conservation, economic development, and drug development into one program. The presentation details a collaboration that includes an ICBG based at the Walter Reed Army Institute of Research and its four partner organizations and discusses the associated programs the collaboration has underway.

Demonstrating the validity of natural products as anti-infective drugs.

This presentation reviews the synthetic or classical development pathway of drug development and contrasts it with developing natural products as drugs. Also presented is an example of a traditional medicine that has been developed from a natural product and has become a "new/old" antiparasitic drug used in the treatment of malaria. The classic paradigm of synthetic drug development breaks down into drug discovery, drug design, preclinical studies, and clinical studies. This paradigm, constructed to weed out failures, results in a drug-development process that is high risk, time consuming, and expensive. The process requires screening an average of 10,000 active compounds to find a single compound that successfully makes its way through validation to drug approval and the marketplace. Following this paradigm, researchers progress from identifying a chemical lead to testing the compound in humans. The World Health Organization (WHO) Guidelines for the Assessment of Herbal Medicines are based on the classical guidelines and follow the classical approach to validating quality, safety, and efficacy--with one major difference. The starting point is to look at the natural product in humans. By taking into account the traditional experience with the product, the validation standard for safety and efficacy of natural products allows for the prolonged and apparently uneventful use of a substance to offer testimony of its safety. The reliance, then, is on experience--or what Western regulatory agencies would call "anecdotal information." Since most phytomedicines are a combination of several active ingredients, the WHO guidelines cover two kinds of combination products: Combinations that are already used in traditional medicine are considered "old" combination products. "New" combination products are well-known substances that are now being used in combination. Artemisia annua, a pervasive weed, has been referred to in Chinese medicine for thousands of years as a treatment for fever. In 1971, an extraction of artemisia yielded activity against Plasmodium berghei, a mouse model for malaria. The isolated compound, artemisinin, is an example of a traditional medicine that started out in humans, but which then provided a lead structure for a standard drug-development paradigm. Today, artemisinin derivatives are being used widely in combination therapy, especially in areas of the world where there is multidrug-resistant malaria.

Mechanism of cardiotoxicity of halofantrine.

OBJECTIVES AND METHODS: To further evaluate the scope and mechanism of potential cardiotoxicity associated with the antimalarial drug halofantrine, case reports submitted to the US Food and Drug Administration Spontaneous Reporting System were examined. Because halofantrine was associated with electrocardiographic prolongation of the QT interval and ventricular arrhythmias, in vitro cardiac electrophysiologic studies (isolated perfused cardiac model and isolated ventricular myocytes) were conducted to test the hypothesis that halofantrine or its metabolite is responsible for cardiotoxicity. RESULTS: Although it is difficult to ascertain causality and to estimate overall incidence, a significant number of adverse events related to the cardiovascular system were reported, including QT interval prolongation, life-threatening arrhythmias, and sudden death. The effect of halofantrine and its active metabolite (N-desbutylhalofantrine) on repolarization were examined in an isolated perfused heart model. Results indicate that halofantrine was able to prolong the QT interval, whereas N-desbutylhalofantrine had minimal effect on the QT interval relative to baseline. In an attempt to further elucidate the mechanism of QT interval prolongation, the effects of racemic halofantrine, its stereoisomers, and N-desbutylhalofantrine on repolarizing currents in isolated ventricular myocytes were studied with use of patch-clamp techniques. Halofantrine produced a stereoselective block of the delayed rectifier potassium channel in isolated feline myocytes. CONCLUSIONS: These results indicate that halofantrine is similar to quinidine and class III antiarrhythmics in its ability to prolong repolarization. We conclude that high plasma concentrations of halofantrine should be avoided, especially in women, and that N-desbutylhalofantrine may have potential as a safer antimalarial drug.

Randomized dose-ranging study of the safety and efficacy of WR 238605 (Tafenoquine) in the prevention of relapse of Plasmodium vivax malaria in Thailand.

WR 238605 is an 8-aminoquinoline developed for the radical cure of Plasmodium vivax. Forty-four P. vivax-infected patients were randomly assigned to 1 of 4 treatment regimens: 3 groups received a blood schizonticidal dose of chloroquine followed by WR 238605: group A (n=15) received 300 mg daily for 7 days; group B (n=11), 500 mg daily for 3 days, repeated 1 week after the initial dose; group C (n=9), 1 dose of 500 mg. A fourth group (D; n=9) received chloroquine only. Among patients who completed 2-6 months of follow-up (n=23), there was 1 relapse in group B (day 120) and 1 in group C (day 112). Among patients treated with chloroquine only, there were 4 relapses (days 40, 43, 49, and 84). WR 238605 was safe, well tolerated, and effective in preventing P. vivax relapse.

Successful topical treatment of murine cutaneous leishmaniasis with a combination of paromomycin (Aminosidine) and gentamicin.

Cutaneous leishmaniasis is presently treated with 20 days of parenteral therapy with a frequently toxic drug (antimony). Topical formulations of paromomycin (15%) plus methylbenzethonium chloride (MBCL, 12%) or plus urea (10%) in soft white paraffin have been tested for Old and New World disease in humans. We compared the efficacy of a new topical formulation, WR 279,396 (paromomycin [15%] plus gentamicin [0.5%]) to the clinical formulations in the treatment of cutaneous disease in BALB/c mice. Sixty-day-old lesions were treated twice a day for 10 days, and the response to therapy was determined over a further 70 days. For ulcers due to Leishmania major or to Leishmania mexicana, 100% of lesions in the WR 279,396 group healed by day 20 after therapy and did not relapse by day 70; 83% of lesions healed without relapse in the paromomycin-MBCL group. In the paromomycin-urea group, 100% of L. major lesions healed by day 30 but 30% relapsed. For ulcers due to Leishmania panamensis or Leishmania amazonensis, all lesions treated with WR 279,396 healed and did not relapse; < 50% of lesions treated with paromomycin-MBCL healed by day 30, and all lesions relapsed by day 70. In addition to being active, WR 279,396 was not toxic in this model and appears to have a cosmetic effect (promoting hair growth, healing, and limiting the size of the scar).

In vitro and in vivo reversal of chloroquine resistance in Plasmodium falciparum with promethazine.

The effect of combining promethazine with chloroquine was examined against Plasmodium falciparum in vitro in the Aotus-P. falciparum model and in bioassays from volunteers given promethazine. The combination of chloroquine plus promethazine (1 x 10(-6) M) reversed chloroquine resistance in standard P. falciparum clones and patient parasite isolates from Nigeria. The combination reduced the 50% inhibitory concentrations (IC50s) for chloroquine against resistant parasites by 32-92%. Coadministration of promethazine with chloroquine also demonstrated a dose-dependent effect in Aotus monkeys infected with chloroquine-resistant P. falciparum. Monkeys were given a chloroquine dose (20 mg/kg of body weight for seven days), which normally has no effect on parasitemia, plus 10, 20, 40, or 80 mg of promethazine/kg of body weight. In one monkey, parasitemia was suppressed at the lowest promethazine dose, but re-treatment with 20 mg/kg resulted in clearance of parasitemia. Initial treatment with chloroquine and 20 or 40 mg/kg of promethazine cleared parasitemia in some animals followed by recrudescence. Re-treatment at higher doses cured one monkey and resulted in initial clearance and delayed recrudescence 28 or 63 days after treatment in two monkeys. Recrudescent parasitemia in the two monkeys was low (10 parasites/microl of blood) and subsequently cleared without re-treatment. An in vitro bioassay model was developed to examine the effects of clinically achievable doses of promethazine on parasites susceptibilities in vitro. Plasma samples taken at hourly intervals from patients given a single oral dose of 25 mg of promethazine decreased the IC50 values for chloroquine by 20-58% with the most significant reductions occurring in plasma obtained from volunteers 3-4 hr after ingestion. Plasma obtained from two volunteers 6 hr after ingestion of the drug demonstrated no effect on chloroquine susceptibility, suggesting that study of the pharmacokinetic disposition and potential interaction is warranted to optimize the dose regimen in patients for antimalarial efficacy. Historic use of this drug combination for treatment or prevention of chloroquine-associated pruritus or as an antiemetic suggest that the combination is safe and effective when used at standard dosages. The results from this study demonstrate that promethazine is a potent modulator of chloroquine resistance. Clinical evaluation of therapeutic regimens is required to validate clinical efficacy of this promising combination for treatment of uncomplicated chloroquine-resistant malaria.

First-time-in-humans safety and pharmacokinetics of WR 238605, a new antimalarial.

WR 238605 is an 8-aminoquinoline drug currently under development for prophylaxis and treatment of malaria. Preclinical studies have demonstrated that it has greater efficacy and less toxicity compared with primaquine. In this first-time-in-human randomized, double-blind, placebo-controlled study designed to evaluate the safety, tolerance and pharmacokinetics, WR 238605 was administered to 48 men in single oral doses ranging from four to 600 mg (base). It was well tolerated, with gastrointestinal disturbances as possible side effects. Linear kinetics were demonstrated at these doses. WR 238605 has a long absorption phase and is slowly metabolized, with a tmax of 12 hr and an elimination half-life of 14 days. These safety, efficacy and pharmacokinetic properties make this drug an excellent candidate for further testing as a prophylactic, radical curative, and terminal eradication drug.

Prophylaxis of Plasmodium falciparum infection in a human challenge model with WR 238605, a new 8-aminoquinoline antimalarial.

The prophylactic efficacy of WR 238605, a primaquine analog, was studied with a human Plasmodium falciparum challenge model. A single oral dose of 600 mg, administered 1 day prior to challenge, successfully protected three of four subjects. The fourth subject developed mild, oligosymptomatic malaria on day 31, with drug concentrations one-half of those in the protected individuals. WR 238605 appears to be a promising prophylactic drug for P. falciparum malaria.

Population pharmacokinetics and pharmacodynamics of pyridostigmine bromide for prophylaxis against nerve agents in humans.

This study was conducted to determine the pharmacokinetics and pharmacodynamics of pyridostigmine given as 30 mg of pyridostigmine bromide every 8 hours in healthy subjects. Plasma pyridostigmine concentration and red blood cell acetylcholinesterase activity were measured in blood samples collected during a 3-week period. Population analysis was performed using standard pharmacokinetic and pharmacodynamic models with the nonlinear mixed-effect modeling software (NONMEM). The pharmacokinetic model that best fit the pyridostigmine plasma levels was a two-compartment open model with first-order absorption, a lag time, and first-order elimination from the central compartment. The pharmacodynamic model that best fit red blood cell acetylcholinesterase activity was an inhibitory Emax model with an effect compartment linked to the central compartment. The results showed that the pharmacokinetics of pyridostigmine bromide are both gender and weight dependent. The pharmacodynamic effect does not lag significantly from the plasma concentration and returns to near normal within 8 hours. With the present dosage regimen of 30 mg every 8 hours, 30% of individuals may not have red blood cell acetylcholinesterase inhibition > 10% at the time of the trough.

Critical analysis of the pharmaceutical care research literature.

OBJECTIVE: To describe and evaluate published pharmaceutical care research and make recommendations to improve the quality of the literature. DATA SOURCES: MEDLINE and International Pharmaceutical Abstracts using the key word "pharmaceutical care," limited to research articles published January 1988-December 1996. STUDY SELECTION: Articles that evaluated the provision of pharmaceutical care in a defined population. DATA EXTRACTION: Citations (title and abstract) identified were reviewed. Articles potentially meeting the inclusion criteria were screened and scored according to the Pharmaceutical Care Research Checklist for the presence of criteria including pharmaceutical care process, methodology, and measures/outcomes. RESULTS: A total of 979 citations were identified. Of 57 abstracts identified as potentially meeting the inclusion criteria, 43 articles were eliminated, 2 were rejected, and 12 were accepted for analysis. Deficiencies identified included: a lack of research in community practice (n = 2), randomized controlled trials (n = 3), workload measurement (n = 6), and patient satisfaction (n = 1). Scoring according to the Pharmaceutical Care Research Checklist also identified the following deficiencies (maximum Composite Criterion Score [CCS] of 24): description of population sample (CCS 17), dropouts (CCS 13), informed consent (CCS 8), pharmacist training/qualifications (CCS 9), instrument validity (CCS 10), structure criteria (CCS 4), patient outcomes (CCS 11), and economic outcomes (CCS 12). The mean total checklist score was 37 of 50 (range 31-46). CONCLUSIONS: Few research studies have evaluated the provision of pharmaceutical care in a defined population. Deficiencies identified by low CCSs demonstrated the need for quality research design and a clear description of the pharmaceutical care process to evaluate the impact of pharmaceutical care. Recommendations for improvement in research design were made.

Plasmodium falciparum: evaluation of lactate dehydrogenase in monitoring therapeutic responses to standard antimalarial drugs in Nigeria.

The correlation of P. falciparum lactate dehydrogenase (pLDH) activities and patent infections was evaluated for monitoring therapeutic responses and drug resistance in 70 patients with microscopically confirmed P. falciparum malaria in Nigeria. Each patient was treated with standard dosages of artemether (53 patients), chloroquine (7 patients), sulfadoxine-pyrimethamine (6 patients), or halofantrine (4 patients). Response of infection to treatment was monitored by microscopic examination of thick and thin blood smears, clinical symptoms, and levels of pLDH activities in blood products. pLDH activity was determined using an antibody capture technique and 3-acetyl pyridine adenine dinucleotide developed to enhance sensitivity of the enzyme detection. All patients treated with artemether were cured while 5 patients treated with chloroquine, 1 treated with sulfadoxine-pyrimethamine, and 2 treated with halofantrine suffered recrudescent infections after treatment. pLDH activity was detected in blood products obtained from patients with patent or recrudescent infections determined by microscopy and clinical symptoms. Levels of pLDH activities in whole blood and packed cells from the patients correlated with qualitative detection of parasites in blood smears and in patients with high gametocyte counts. Gametocyte counts in the patients after treatment ranged from 40 gametocytes/microliter of blood to 4923 gametocytes/microliter of blood. There is a consistent relationship between patent infection and pLDH activities that could easily be determined in whole blood and packed cells from the patients. Further development of the procedure will enhance its valuable application in clinical management of drug-resistant malaria in the endemic areas.

Prophylaxis of Plasmodium falciparum malaria with azithromycin administered to volunteers.

OBJECTIVE: To determine whether azithromycin, 250 mg/d, is effective prophylaxis for liver infection or for both liver and subsequent blood infection with Plasmodium falciparum. DESIGN: Controlled phase II trial with two cohorts entered sequentially. SETTING: Clinical trials center of Walter Reed Army Institute of Research, Washington, D.C. PATIENTS: Each of the two cohorts consisted of 12 normal adult volunteers who had not had malaria during the previous 2 years: 10 who received azithromycin prophylaxis and 2 controls who did not received treatment. INTERVENTION: For cohort 1, prophylactic efficacy against liver infection alone during the initial 7 days of the infection was determined by loading participants with azithromycin before challenge with P. falciparum-infected mosquitoes on day 0 and by then giving the drug for 7 days after the challenge. The regimen was 500 mg on day 14 before the challenge, followed by 250 mg/d from day 13 before the challenge through day 7 after the challenge. For cohort 2, prophylactic efficacy against both the liver infection and the subsequent blood infection was determined by continuing drug administration for 28 days after the challenge. MEASUREMENTS: Plasmodium falciparum infection was diagnosed through peripheral blood smears obtained up to 70 days after challenge. Malarial symptoms and adverse drug reactions were also monitored. RESULTS: In cohort 1, 4 of 10 volunteers who received azithromycin prophylaxis (40%) did not develop parasitemia. In cohort 2, none of the 10 volunteers receiving azithromycin prophylaxis (100%) developed parasitemia. For each cohort, both control volunteers became parasitemic on days 9 through 13 after the challenge. Adverse drug reactions were few and mild. CONCLUSIONS: In this model, prophylaxis with azithromycin (250 mg/d) was partially effective against liver parasites and completely successful against the combination of liver and blood parasites. These data suggest that azithromycin has the potential to be an effective, well-tolerated clinical prophylactic agent for P. falciparum malaria.

Activity of azithromycin as a blood schizonticide against rodent and human plasmodia in vivo.

We compared the efficacy of azithromycin to the clinical antimalarial doxycycline in Plasmodium berghei-infected mice and in P. falciparum-infected Aotus monkeys. When mice were administered drug orally twice a day for three days, the minimum total dose of azithromycin that cured all mice was 768 mg/kg. Doxycycline at a dose of 1,536 mg/kg cured no mice. The efficacy of fast-acting blood schizonticides (quinine, halofantrine, artemisinin) against P. berghei was augmented by azithromycin. In monkey experiments in which there were two animals per experimental group, azithromycin (100 mg/kg/day for seven days) eliminated parasitemia; azithromycin (30 mg/kg/day) initially cleared 99.8-100% of the parasites with recrudescence in the one completely cleared case. Doxycycline (30 mg/kg/day) cleared 100% of the parasites with recrudescence in both cleared cases. Since azithromycin can be clinically administered at a somewhat higher daily dosage than doxycycline, the data suggest that it may be possible to replace drugs of the tetracycline class with azithromycin in combination with fast-acting blood schizonticides for the treatment of P. falciparum infection.

Probable ticlopidine-induced cholestatic hepatitis.

OBJECTIVE: To report a case of probable ticlopidine-induced cholestatic hepatitis. CASE SUMMARY: A 76-year-old man with no known history of liver disease developed painless jaundice approximately 3 weeks after starting ticlopidine 250 mg bid. After ticlopidine was discontinued, the jaundice resolved and serum liver enzyme concentrations returned toward normal. A diagnosis of probable ticlopidine-induced cholestatic hepatitis was made. The patient was not rechallenged with ticlopidine. DISCUSSION: A literature search produced 6 case reports describing 7 patients in whom probable ticlopidine-induced cholestatic hepatitis had been diagnosed. Only 1 of these reports appeared in the North American literature. Jaundice developed within 1 to 3 months of starting ticlopidine at less than or equal to the recommended daily dose. In all cases, jaundice resolved and serum liver enzyme concentrations normalized over a period of months after drug discontinuation. CONCLUSIONS: Routine monitoring of serum liver enzyme concentrations is not recommended. However, patients should be instructed to watch for signs and symptoms of liver injury. Should they occur, patients should stop taking the ticlopidine and consult their physician immediately.

Fatal neurotoxicity of arteether and artemether.

Artemisinin (qinghaosu) and several derivatives have been developed and are in use as antimalarial drugs but scant information is available regarding animal or human toxicity. Following a eight-day, multiple-dose, pharmacokinetic study of arteether (AE) (10 mg/kg/day [n = 6] and 20 mg/kg/day [n = 6]) in dogs, all high-dose animals displayed a progressive syndrome of clinical neurologic defects with progressive cardiorespiratory collapse and death in five of six animals. Neurologic findings included gait disturbances, loss of spinal and pain response reflexes, and prominent loss of brain stem and eye reflexes. Animals had prolongation of QT interval corrected for rate (QTc) on electrocardiograms (ECGs) with bizarre ST-T segment changes. Prominent neuropathic lesions were noted to be primarily limited to the pons and medulla. Similar lesions with dose-related severity were noted in eight other dogs studied in a second study with intramuscular (IM) administration of AE in sesame oil during a 28-day, dose-ranging study using 5, 10, 15, and 20 mg/kg/day. Injury, graded by a pathologist blinded to the dose group, showed a dose-related, region-specific injury in all animals that was most pronounced in the pons. Further studies in Sprague-Dawley rats using IM administration of AE and artemether (AM) at a dose of 12.5-50 mg/kg/day for 28 days confirmed the onset of a clinical neurologic syndrome with dose-related changes in body weight, activity, and seizure-like activity, stereotypic movement disorders, and ECG changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Antimalarial activity of WR 243251, a Dihydroacridinedione.

WR 243251 is a dihydroacridinedione that was evaluated for antimalarial blood schizonticidal activity in vitro and in vivo. The in vitro doses calculated to kill 50% of organisms were 11 nM for a chloroquine-susceptible, mefloquine-resistant standard strain and 25 nM for a chloroquine- and pyrimethamine-resistant standard strain. The total dose needed to cure 100% of mice infected with a drug-susceptible strain of Plasmodium berghei was 12 to 20 mg/kg of body weight for both oral and subcutaneous administration. The regimen needed to cure 100% of Aotus monkeys infected with Plasmodium falciparum was 8 mg/kg/day for 3 days (chloroquine-susceptible strain) and 16 mg/kg/day for 3 days (chloroquine-resistant strain). The 100% curative doses for Aotus monkeys did not increase for parasites previously exposed to subcurative doses. The absolute value of the curative doses of WR 243251 was comparable to or lower than the values for clinical antimalarial agents. The high absolute activity, comparability of activities against susceptible and resistant parasites, and inability to induce resistance by exposure to subcurative doses suggest that WR 243251 has strong potential as a blood schizonticidal agent.

Efficacy of azithromycin as a causal prophylactic agent against murine malaria.

The efficacy of the newly marketed azalide azithromycin was compared with that of the clinical agent doxycycline in a murine model of sporozoite-induced malaria. Drug was administered once; Plasmodium yoelii sporozoites were administered 2 h later; survival at day 60 was determined. For parenterally administered drug, 160 mg of azithromycin or doxycycline per kg of body weight was 100% effective; 40 mg of azithromycin per kg was 80% effective, but 40 mg of doxycycline per kg was 40% effective. Orally administered azithromycin was somewhat less effective than parenterally administered drug, consistent with the 37% clinical oral bioavailability of this agent. For orally administered azithromycin, 160 mg/kg was 100% effective and 40 mg/kg was 40% effective. The efficacy of azithromycin in comparison with that of doxycycline and the known prolonged levels of azithromycin in the livers of humans suggest that azithromycin has potential as a clinical causal prophylactic agent for malaria.

Neurotoxicity in animals due to arteether and artemether.

Several artemisinin (qinghaosu) derivatives have been developed and are in use as antimalarial drugs but scant animal or human toxicity data are available. We noted a progressive syndrome of clinical neurological defects with cardio-respiratory collapse and death in 5/6 dogs dosed daily for 8 d with intramuscular arteether (AE) at 20 mg/kg/d in a pharmacokinetic study. Neurological findings included gait disturbances, loss of spinal reflexes, pain response reflexes and prominent loss of brain-stem and eye reflexes. Electrocardiography showed prolongation of the QT interval corrected for rate (QTc). Prominent neuropathic lesions were sharply limited to the pons and medulla. Neurological injury, graded by a pathologist 'blinded' to dose group, showed a dose-related region-specific injury which was most pronounced in the pons and medulla in all animals. Rats treated with AE and artemether (AM) at 12.5 to 50 mg/kg/d for 28 d confirmed clinical neurological abnormalities with high doses (> 25 mg/kg/d) after 6-14 d. Neuropathological examination of rat brain sections at 5 levels from the rostral cerebrum to the caudal medulla showed a dose-related pattern of injury characterized by hyalinized neuron cell bodies and loss of Nissl substance; changes congruent with those noted in dogs. No significant difference was noted in the extent, type, or distribution of lesions in the brains of rats treated with equivalent doses of AE or AM.(ABSTRACT TRUNCATED AT 250 WORDS)