We examined the effects of PF1022A, newly developing in Japan, on adult Angiostrongylus cantonensis in the pulmonary arteries of rats. Following five and ten successive oral doses at 10 mg/kg per day, the first-stage larvae in rat faeces disappeared completely at 2 weeks after treatment. The treatment completely killed the female worms, but not the male worms. However, numbers of male worms were also decreased after the administration of either five successive oral doses at 10 mg/kg per day for four courses or five successive intraperitoneal doses at 0.5 mg/kg per day. Next, we examined the effects of PF1022A on larval A. cantonensis migrating into the central nervous system (CNS) of rats. Following five successive oral doses at 5 or 10 mg/kg per day and five successive intraperitoneal doses at 0.5 mg/kg per day, lesser killing effects were observed on male as well as female worms. On the basis of these results it is apparent that PF1022A will become a promising anthelmintic available as treatment for tissue-dwelling as well as intestinal nematodes.
To enhance the bioavailability of PF1022A (cyclo(D-lactyl-L-N-methylleucyl-D-3-phenyllactyl-L-N-met hylleucyl-D-lactyl-L-N-methylleucyl-D-3-phenyllactyl-L-N- methylleucyl)), a newly developed antinematode drug, we examined whether the new drug has polymorphism or not. First, four forms of PF1022A, designated as form alpha, form I, form II and form III of PF1022A, were prepared. By examining physicochemical properties of these forms by various methods including X-ray powder diffractometry and differential scanning calorimetry, it became apparent that PF1022A had one amorphous (form alpha) and three crystalline polymorphic forms, form I, form II and form III. Secondly, a dissolution study was carried out, and form alpha and form III were found to have higher solubility than form I and form II. Thirdly, anti-larval effects of the 4 forms of PF1022A on tissue-dwelling nematode, Angiostrongylus costaricensis, in mice were compared when given orally for 5 successive days at 10 or 40 mg/kg/day. Significant effects were observed in almost all parameters in host mice and worms in the groups treated with form alpha or form III, each at 40 mg/kg, but form I and form II had little effect. The present results suggest that PF1022A has polymorphism and that the form alpha and form III were more effective against tissue-dwelling nematodes than the form I and form II when given orally.
Abstract:The combination effects of chloroquine with Cepharanthin " or minocycline hydrochloride were evaluated against a blood-induced infection with chloroquine-resistant P. berghei NK 65 in ICR mice. The infected mice in an untreated control group showed a progressively increasing parasitemia leading to mouse death. A twoday dosage of 20 mg base/kg of chloroquine alone produced little effect against P. berghei NK 65 infection, and all mice died from day 13 to 15 with an increasing parasitemia. A four-day dosage of 4 mg/kg of Cepharanthin " alone produced no antimalarial activity, and all mice died by day 10. A four-day dosage of 50 mg/kg of minocycline hydrochloride alone produced a slight effect, but all mice died by day 18. Furthermore, mice given chloroquine in combination with Cepharanthin " died from day 14 to 15. Mice given Cepharanthin " plus minocycline hydrochloride also died from day 15 to 17. On the other hand, infected mice treated with chloroquine plus minocycline hydrochloride survived during the experiment. All mice treated with chloroquine alone, minocycline hydrochloride alone, chloroquine plus Cepharanthin " or Cepharanthin " plus minocycline hydrochloride showed low parasitemia levels during drug administration and a few subsequent days, but then malaria parasites re-increased in the bloodstream of the treated mice until death. On the other hand, malaria parasites in the mice given chloroquine plus minocycline hydrochloride decreased on day 6 and then could not be detected by microscopic examination during the observation period. This finding strongly suggests that the combination effects of chloroquine and minocycline hydrochloride are worthy of evaluation in human malaria. The results also clearly demonstrate the necessity and importance of in vivo experiments in estimating the activities of drugs.
IntroductionInternational norms and ethical standards have suggested that compensation for research-related injury should be provided to injured research volunteers. However, statistical data of incidence of compensation claims and the rate of awarding them have been rarely reported.MethodQuestionnaire surveys were sent to pharmaceutical companies and medical institutions, focusing on industry-initiated clinical trials aiming at new drug applications (NDAs) on patient volunteers in Japan.ResultsWith the answers from pharmaceutical companies, the incidence of compensation was 0.8%, including 0.06% of monetary compensation. Of the cases of compensation claims, 99% were awarded. In turn, with the answers from medical institutions, the incidence of compensation was 0.6%, including 0.4% of serious but not death cases, and 0.04% of death cases. Furthermore, most claims for compensation were initiated by medical institutions, rather than by the patients. On the other hand, with the answers from clinical trial volunteers, 3% of respondents received compensations. These compensated cases were 25% of the injuries which cannot be ruled out from the scope of compensation.ConclusionOur study results demonstrated that Japanese pharmaceutical companies have provided a high rate of compensation for clinical trial-related injuries despite the possibility of overestimation. In the era of global clinical development, our study indicates the importance of further surveys to find each country's compensation policy by determining how it is being implemented based on a survey of the actual status of compensation coming from statistical data.
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