Disposition of a new tetrahydrocarbazole analgesic drug in laboratory animals and man

1. The disposition of AY-30,068 (I), a new tetrahydrocarbazole analgesic drug, was studied in mice, rats, dogs, rhesus monkeys, and man. 2. Oral doses of the 14C-labelled drug in aqueous solution were well absorbed in rodents, but absorption of oral doses of the crystalline drug in dogs was poor. Due to the virtual absence of serum metabolites in rats and dogs, the bioavailability of I was nearly identical to the extent of absorption. Although a small first-pass effect was observed in mice, unchanged I represented a major portion of serum radioactivity. 3. A linear increase in the serum concentrations of I occurred at doses between 0.05 and 25 mg/kg in rats, 0.1 and 50 mg/kg in dogs, and 1-160 mg in man. In rhesus monkeys given a 0.5 mg/kg oral dose, the Cmax and AUC of I were similar to values obtained following a corresponding dose in dogs. 4. After i.v. administration of a 1.0 mg/kg dose the terminal elimination half-life (t1/2 beta) of I was 4 h in mice and 9-10 h in rats and dogs. In rodents, dogs, and several human subjects, the elimination of I was interrupted by secondary peaks. Enterohepatic circulation was confirmed in bile duct cannulated rats, where the t1/2 beta of I was decreased to 2.4 h. In rodents the serum clearance and apparent volume of distribution of I were 0.04-0.2 l/kg.h and 0.5-0.8 l/kg, respectively, and 0.6 l/kg.h and 9.8 l/kg in dogs. 5. In rodents and dogs dosed with 14C-labelled I, radioactivity was excreted almost entirely in the faeces. No unchanged I was detected in rat bile, while about 70% of the radioactivity corresponded to conjugates of parent drug.     

In vitro/in vivo functionality of Catapres-TTS

The in vitro and in vivo functionality of Catapres-TTS, a transdermal therapeutic system that delivers the alpha adrenergic receptor agonist clonidine, is discussed in terms of the drug transport kinetics and resultant plasma drug concentration profiles. The design of Catapres-TTS is presented as an optimization by which the best combination of system performance characteristics is obtained within the inherent limitations of the transdermal drug transport properties and the known pharmacokinetic and pharmacodynamic properties of the drug. Clonidine is a potent antihypertensive agent with a relatively low therapeutic index. For Catapres-TTS, the majority of control over the drug input rate resides within the system, rather than within the skin, which significantly reduces the variability in drug input rate and resulting plasma drug concentration both within and between patients. Moreover, the presence of a rate-control element in the system allows for patterning of the drug release rate. An initial bolus of drug is placed in the contact adhesive layer, where its transport into the skin is not inhibited by the rate control element in the system, for reduction in the time needed to achieve steady state drug input. The selection of the loading dose of drug is described as an optimization between the minimization of the lag time and the maintenance of constant plasma drug concentrations during the crossover period between system applications in chronic therapy.     

Tower Hamlets Health Authority Measles Immunisation Initiative 1987-88

Measles as a cause of childhood death and disability can be prevented by vaccination of 95% of the pre-school population, as in the United States, where proof of measles immunisation is required for school entry. An inner-city London Health Authority used the 1987 World Immunisation Day as the occasion to invite heads of nursery and infant schools to join in a pilot scheme to increase the number of new pupils who were protected. A small but growing number of the schools now include a question about immunisation in their admission routine. The computerised appointment system for child health clinic vaccinations was shown to be unable to give sufficient appointments for older children. School nurses and health visitors organised extra immunisation sessions during the 1988 epidemic.     

Enucleation combined with orbital implants for malignant melanoma of the uvea

Advanced malignant melanomas of the uvea unsuited for an eye salvaging approach require enucleation of the tumor containing eye. A series of 68 patients is reported who underwent enucleation combined with insertion of a spherical dura-encased implant after 30 Gray pre-irridiation therapy of the orbit. Postoperative results with special attention to cosmetic outcome and motility of the prosthesis suggest that the insertion of an orbital implant should be preferred to the enucleation with no implant.     

Fatal and non-fatal stingray envenomation

A fatality occurred in a previously healthy 12-year-old boy after a penetrating chest injury from a stingray barb. The injury occurred under freak circumstances. Death was a result of cardiac tamponade which was secondary to venom-induced, localized myocardial necrosis and spontaneous perforation, six days after the direct penetration of the right ventricle by the barb. Three other cases of less serious stingray envenomation are described which illustrate the significant localized morbidity that may occur without immediate wound exploration and toilet after adequate anaesthesia. We also report a study of a series of 100 minor stingray envenomations which, when treated, resulted in no morbidity. It is possible that local infiltration with 1% plain lignocaine may have a direct counteraction against stingray venom that remains in the wound area. Stingray venom has insidious, but powerful, localized tissue necrosing properties in humans.