Metabolism and pharmacokinetic studies of misoprostol.

Absorption, metabolism and excretion of radiolabelled misoprostol were studied in laboratory animals and in humans. Dog and man were similar in terms of key parameters examined. Misoprostol itself was not present in plasma after its oral administration to humans. Misoprostol was rapidly converted by de-esterification to its free acid. This metabolite possesses significant desired pharmacological activity. Further metabolic conversion occurs over time via beta-oxidation of the alpha side chain, omega-oxidation of the beta side chain and reduction to the prostaglandin F analogs. The serum protein binding of the free acid metabolite of misoprostol was similar in young (81-88%) and elderly (81-89%) people. Binding was concentration-independent and was not altered by drugs which one would expect to be co-administered with misoprostol. In the rat, misoprostol neither inhibited nor induced drug metabolizing enzymes. A radio-immunological assay for measurement of the free acid metabolite in human plasma has been developed. This method has a sensitivity of 23 pg/ml and appears to be sufficiently sensitive for use in clinical trials.

Preclinical toxicology profile of misoprostol.

The toxicity of misoprostol has been extensively examined in a variety of in vitro and in vivo studies. Preclinical studies evaluated acute and chronic toxicity, mutagenicity and carcinogenicity, and reproductive toxicity. Single oral dose studies in rodents and non-rodents indicate a safety margin of at least 500 to 1000 fold between lethal doses in animals and therapeutic doses in humans. Chronic toxicity studies (52 weeks) have been performed at daily oral doses of up to 300 and 9000 micrograms/kg body weight in dogs and rats, respectively. Rectal temperatures were increased at 100 and 300 micrograms/kg in dogs and serum iron was increased at 9000 micrograms/kg in rats. Stomach weights were increased in dogs and rats in a dose-correlated manner related, at least in part, to an increase in the number of normal epithelial cells (gastric hyperplasia). When drug treatment was stopped rectal temperatures, serum iron and stomach weights reverted to normal. Electron microscope studies on hyperplastic tissue showed that the ultrastructure was not affected. Hyperostosis has been observed, mainly in female mice, following prolonged drug treatment at high doses. Histological studies of bone tissues of rats and dogs and radiological studies of long bones of dogs following chronic administration of misoprostol showed that bone development was normal in all respects. Mutagenicity studies were negative and misoprostol was not fetotoxic or teratogenic in rats at oral doses up to 10000 micrograms/kg body weight, or in rabbits at doses up to 1000 micrograms/kg body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

The concept of an artificial tympanic membrane.

A review is given of the development of the concept of an artificial tympanic membrane. Starting with homologous tympanic membranes we compared biodegradable collagen materials (homologous and heterologous) and biodegradable synthetic materials, poly-glycolic acid, poly-lactic acid and poly-alpha-amino acids. As a non-degradable material microporous PTFE and bisphenol-A poly (carbonate) were investigated. It is concluded that either poly-alpha-amino acid or PTFE with poly-alpha-amino acid maybe a suitable material for an artificial tympanic membrane.

New perspectives in myringoplasty.

Until 1950 the treatment of a perforated eardrum consisted of covering the drum permanently with artificial material. Since then a surgical technique to establish a functional reconstruction of the eardrum was developed (myringoplasty). A survey of the biological grafting materials used in this technique is given. Biodegradable and non-degradable synthetic materials may prove to be a valuable supplement of the existing biological grafting materials. Artificial eardrums made from several biodegradable poly(alpha-hydroxy acids) and poly(alpha-amino acids) and made from a number of microporous poly(tetrafluorethylene) membranes and from a microporous bisphenol-A poly(carbonate) membrane were implanted into the ears of rats and dogs and as a reference subcutaneously. The implants were histologically examined for periods up to one year. From the biodegradable polymers studied poly(beta-benzyl-L-aspartate-co-L-leucine) 50/50 evoked the least tissue reaction and the newly formed eardrums were the best in terms of thickness and overall integrity. The formation of a reinforced eardrum may be accomplished by the support of an inert, very thin, highly porous poly(tetrafluoroethylene membrane) preferably implanted as a composite graft with a biodegradable polymer.

Experimental myringoplasty.

Artificial eardrums made from biodegradable poly(D,L-lactic acid), poly(glycolic acid) and poly(beta-benzyl-L-aspartate-co-L-leucine) 50/50, and made from the microporous poly(tetrafluoroethylene) and bisphenol-A poly(carbonate) membranes were implanted into the ear and as a reference subcutaneously in rats. The implants were histologically examined for periods up to one year. From the biodegradable polymers studied the poly(beta-benzyl-L-aspartate-co-L-leucine) 50/50 evoked the least tissue reaction and the newly formed tympanic membranes are the best in terms of thickness and overall integrity. The microporous poly(tetrafluoroethylene) membrane can be considered as a valuable support for the formation of a reinforced tympanic membrane.

Comparative effects of repeated and prolonged inhalation exposure of beagle dogs and Cynomolgus monkeys to anaesthetic and subanaesthetic concentrations of enflurane and halothane.

Male and female Beagle dogs and Cynomolgus monkeys were exposed to anaesthetic (1.5 MAC) and subanaesthetic (1/100 MAC) levels of enflurane and halothane for 3 hours on alternate days for 4 weeks. One-half of the animals were killed following the last exposure and the remainder after 4 weeks of recovery. The animals' condition was assessed during anaesthetic periods by measuring respiration, ECG, blood pressure, temperature and EEG. Haematology, urinalysis and clinical chemistry parameters were evaluated. Gross and microscopic pathological examinations were conducted at the end of the exposure and recovery periods. Two female monkeys in the mid- and high-dose halothane groups died during the study. No deaths were observed in the enflurane group. No quantitative differences were observed in respiration rate, heart rate, blood pressure and EEG activity of animals anaesthetized with enflurane or halothane. Muscle twitches were observed in some mid- and high-dose dogs inhaling enflurane, but not in monkeys. A number of liver function tests became abnormal in mid- and high-dose halothane-treated dogs and high-dose halothane-treated monkeys. This was not observed with enflurane. Histopathologic alterations were confined to the liver of animals exposed to halothane. In dogs, the lesions were characterized by centrilobular hepatocyte degeneration and/or necrosis, fibroblastic proliferation, hepatocyte enlargement, fat deposition and glycogen depletion; and in mid- and high-dose monkeys by moderate to marked hepatocyte vacuolation and fat deposition. Except for one high-dose dog, these lesions were not seen in animals killed after 4 weeks of recovery. No histopathologic alterations were observed with enflurane.