Hypericin is a natural derivative of the common St. Johns wort plant, Hypericum perforatum. It has in vitro activity against several viruses, including bovine diarrhea virus, a pestivirus with structural similarities to hepatitis C virus (HCV). We conducted a phase I dose escalation study to determine the safety and antiviral activity of hypericin in patients with chronic HCV infection. The first 12 patients received an 8-week course of 0.05 mg of hypericin per kg of body weight orally once a day; 7 patients received an 8-week course of 0.10 mg/kg orally once a day. At the end of the 8-week period of treatment, no subject had a change of plasma HCV RNA level of more than 1.0 log 10 . Five of 12 subjects receiving the 0.05-mg/kg/day dosing schedule and 6 of 7 subjects receiving the 0.10-mg/kg/day dosing schedule developed phototoxic reactions. No other serious adverse events associated with hypericin use occurred. The pharmacokinetic data revealed a long elimination half-life (mean values of 36.1 and 33.8 h, respectively, for the doses of 0.05 and 0.1 mg/kg) and mean area under the curve determinations of 1.5 and 3.1 g/ml ؋ hr, respectively. In sum, hypericin given orally in doses of 0.05 and 0.10 mg/kg/d caused considerable phototoxicity and had no detectable anti-HCV activity in patients with chronic HCV infection.

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Comparative studies in beagle dogs suggested that the pharmacokinetic profiles of BB-K8 and kanamycin are similar. After intravenous (iv) administration to dogs, BB-K8 and kanamycin were rapidly distributed in plasma and tissue fluids; their "apparent" volumes of distribution comprised approximately 23% of the total body volume. Like kanamycin, BB-K8 had a plasma half-life of about 0.8 h which paralleled the urinary excretion rate. Approximately 92% of the dose was excreted as unchanged drug within 6 h of dosing, and clearance appeared to be primarily by glomerular filtration. After intramuscular (im) administration to dogs, BB-K8 and kanamycin were totally and rapidly absorbed; peak concentrations in the plasma occurred 0.5 to 1.0 h after dosing. The kinetic parameters goveming the distribution and elimination of BB-K8 and kanamycin after an im dose were similar to those obtained for iv dosing and indicate desirable dose-independent kinetics. A human pharmacokinetic study indicated that the kinetic profiles of BB-K8 and kanamycin are similar in man after im dosing. Like kanamycin, BB-K8 is rapidly absorbed, yielding peak serum concentrations of about 20 gg/ml at 1 h after a 500-mg im dose. The plasma half-life of these two drugs was approximately 2.3 h. Clearance in man was primarily by glomerular filtration, and the urinary excretion of BB-K8 and kanamycin accounted for 83% of the dose.BB-K8 is a new semisynthetic aminoglycosidic antibiotic derived from kanamycin A (H. Kawaguchi et al., J. Antibiot. [Tokyo], in press) which exhibits broad-spectrum antimicrobial activity, including potent antipseudomonal activity (K. E. Price et al., J. Antibiot.[Tokyo], in press) and activity against some kanamycin-resistant and gentamicin-resistant clinical isolates of Enterobacteriaceae. In recent studies with cats (J. C. Reiffenstein et al., in preparation), BB-K8 produced a degree of ototoxicity and renal toxicity similar to that produced by kanamycin when dosed on a weight basis over a 7-day period. In a study based on blood chemistry and histopathology (S. W. Holmes et al., Abstr. 12th Intersci. Conf. Antimicrob. Ag. Chemother., p. 7, 1972), BB-K8 was found to be approximately five times less nephrotoxic than gentamicin, and, in contrast to gentamicin, BB-K8 produced vestibular dysfunction only at the high doses which produced cochlear toxicity.This report presents a pharmacokinetic comparison of BB-K8 and kanamycin in dogs and humans after parenteral administration. MATERIALS AND METHODSIn a complete crossover design, BB-K8 and kanamycin were administered intravenously and intramuscularly to four beagle dogs (mean weight, 8.2 0.2 kg) at a dose of 25 mg/kg. Blood samples were taken from an intravenous catheter (Bardic Intracath) implanted into the saphenous vein. Urine was collected cumulatively over a 6-to 8-h period by means of Lucite-coated stainless-steel cannulae surgically implanted within the bladder of the dogs. The urine was collected into flasks placed in an ice bath, and the plasma and urine specimens were k...

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Comparative drug disposition studies in mice, rats, dogs, and humans indicate that cephapirin, a new semisynthetic cephalosporin antibiotic that exhibits broad-spectrum antimicrobial activity, is metabolized to desacetylcephapirin in these species. Pharmacokinetic analyses of the concentrations of cephapirin and desacetylcephapirin in plasma and urine reveal that the rate and extent of deacetylation decreases from rodents to dogs to humans. The kinetic analyses also suggest that the kidney performs a role not only in the excretion but also in the metabolism of cephapirin to desacetylcephapirin.Cephapirin, sodium 7-(pyrid-4-yl-thioacetamido)cephalosporante ( Fig. 1), is a new semisynthetic 7-aminocephalosporanic acid derivative that exhibits a broad spectrum of antimicrobial activity (2,3,5) and in humans exhibits a similar pharmacokinetic profile to that of cephalothin (1). These results (1) were based on total bioactivity in serum, as determined by the cup-plate assay (6), and failed to take into account any possible differences in drug metabolism. In mice, rats, dogs, and humans, cephapirin has been shown to be metabolized to a bioactive desacetyl metabolite, and it has been suggested that the kidney performs a role not only in the excretion of the parent compound and desacetyl metabolite but also in the metabolism of cephapirin to desacetylcephapirin (B. E. Cabana and D. R. Van Harken, 5th Int. Congr., Pharmacol., San Francisco, Calif., Abstr. 209, p. 35, 1972 metabolism cages. In dogs, blood samples were taken from the saphenous vein by means of an intravenous (i.v.) catheter (Bardic, Intercath). The dogs were fasted overnight and hydrated (30 ml/kg) 15 to 30 min prior to drug administration. Continuous urine collection was achieved by means of Lucitecoated, stainless-steel cannulae surgically implanted within the bladder of the female dogs. The bladder cannulae were permanently implanted in dogs within 1 to 2 months of running the studies. The dogs had normal creatinine clearance (4 ml/min per kg) at the time of the study.Ten fasted, healthy male volunteers (mean weight, 66 kg) were employed for the human metabolic studies. The drug was administered by the i.v. route into the median cubital vein over a 5-min period. Blood specimens (20 ml) were drawn immediately before and at 5 min, 0.5, 1.0, 1.5, 2, 3, and 4 h after drug administration, and urine was collected at 1, 2, 4, and 6 h after drug administration. A water diuresis was maintained throughout the urine collection period by oral administration of 600 ml of tap water 20 min prior to drug administration and subsequent administration of 300 ml of water at 1 and 3 h after dosing.Blood specimens taken from the laboratory animals and men were placed in heparinized tubes (Vacutainers) and kept in an ice bath until centrifuged. Shortly thereafter, the blood specimens were spun down at approximately 1,000 x g in a refrigerated centrifuge (5°C), and the plasma samples were quickly frozen in a dry ice-acetone bath and kept frozen until bioassayed. The urine spe...