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.     

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.     

Protection of photosensitized rats against long ultraviolet radiation by topical application of compounds with structures similar to that of dihydroxyacetone

Dihydroxyacetone (DHA), a browning agent, protects photosensitive rats and humans against long ultraviolet radiation (UVA, 320-400 nm) and visible (blue) light. The photoprotective efficacy of DHA and structurally similar compounds was assessed as prevention of edema in the paws of psoralen-sensitized rats, after exposure to blacklight fluorescent lamps. Methylglyoxal produced a yellow-brown color and provided nearly the same protection as DHA, whereas monohydroxyacetone did not color the skin and afforded little or no protection. Glyceraldehyde provided a moderate amount of protection, which was enhanced by prior exposure of the agent to alkaline pH. A solution of 5-hydroxymethylfurfuraldehyde was yellow and provided minimal protection by staining the skin rather than browning it. We conclude that the ability to produce a brown color in skin is a useful criterion for screening compounds for photoprotective efficacy against UVA radiation.     

VECURONIUM AND ATRACURIUM IN PATIENTS WITH END-STAGE RENAL FAILURE: A Comparative Study

Twenty patients with end-stage renal failure, undergoing kidneytransplantation, were assigned randomly to receive either vecuroniumor atracurium under evoked twitch tension control. The cumulative-dosetechnique was used to obtain 95% twitch depression (vecuronium:initial bolus 15 µg kg^–1, increments 6 µgkg^–1; atracurium: initial bolus 100 µg kg^–1,increments 40 µg kg^–1). Using ED₉₅ values derivedfrom the log-probit dose-response curves, vecuronium was 4.6times more potent than atracurium. The durations of action ofthe initial cumulativedoses (from end of injection of the lastincrement to 25% recovery) were 11.1± 3.3 min for vecuroniumand 16.2±3.9 min for atracurium (P < 0.05). In termsof duration of action of the maintenance doses (vecuronium one-quarterof the total incremental dose; atracurium one-third) some cumulationwas observed with vecuronium (interaction time x treatment;cumulation ratio 1.46 ±0.31 v. 0.98±0.10 for atracurium,P< 0.001). After 2 h of surgery, the mean recovery times(25% to 75% twitch height) did not differ (18.5±2.8 minand 16.7±4.4 min). It is concluded that vecuronium mightbe less safe than atracurium in patients with end-stage renalfailure undergoing prolonged operations.     

Risk factors for abruptio placentae

In a prospective study 90 patients who had confirmed abruption of the placenta were compared with a control group. Significantly more patients who had abruptio placentae were unmarried, smoked cigarettes, received no antenatal care, had coitus within the 48 hours preceding delivery, developed intrapartum hypertension and had a lower ponderal index than the controls. More patients with abruptio placentae had proteinuria and antepartum hypertension but statistical significance was not reached. In addition, the incidence of intra-uterine growth retardation was higher in these patients.