Comparison of meclizine levels in the plasma of rats and dogs after intranasal, intravenous, and oral administration.

Meclizine, used prophylactically for the prevention of motion sickness and vertigo, is presently available only in oral form. We report herein that, when given intranasally, meclizine dihydrochloride is absorbed in rats about half as effectively as when given intravenously, but about six times more effectively than after oral administration, as estimated by the area under the plasma concentration-time curve. The mean times to peak levels in plasma are about 8.5 min after an intranasal dose and 49.0 min after oral delivery. We extended these studies to a second species, the beagle dog, and achieved qualitatively similar results with a new formulation (Mecnazone; Nastech Pharmaceutical Co., Inc.). The fraction absorbed intranasally was about 0.89 that of an equivalent intravenous dose but about four times that of an equivalent oral administration. In these studies, the mean times to peak levels in plasma was 11.9 min after an intranasal dose and 70.0 min after an oral dose. Terminal elimination kinetics were the same for all routes within each species. Intranasal delivery of meclizine therefore appears to be superior to the oral route for the more rapid achievement of substantial levels in plasma at a reduced dose.

Studies of the effects of alpha-difluoromethylornithine and ethanol on the pathogenesis of bleomycin-induced pulmonary fibrosis in mice.

Both DL-alpha-difluoromethylornithine (DFMO) and ethanol have been reported to inhibit the growth of fibroblasts in cell culture. The objectives of the present study were to determine whether these compounds could be used to inhibit the growth of fibroblasts in vivo, with a bleomycin-induced mouse model of pulmonary fibrosis. DBA/2J mice were given a single endotracheal injection of bleomycin, 10 nmol. In addition to bleomycin (BLM), groups of animals received 2% DFMO in drinking water for 4 days prior to BLM and 18 days after (BLM DFMO), 6% ethanol in drinking water for 7 days prior to BLM and 21 days after (BLM E7), 6% ethanol in drinking water for 21 days initiated on the day of BLM intubation (BLM E), or DFMO, E7, and BLM in combination (BLM DFMO E7). Animals died or were killed 21 days after bleomycin treatment and lungs were evaluated by histopathologic criteria. DFMO failed to alter the incidence or severity of fibrotic lesions, increased the severity of epithelial metaplasia (p less than 0.05), and reduced the lung disease index (from 56.3 to 42.1%, p less than 0.05) and mortality from 83.3 to 41.7% (p less than 0.025). In contrast to the unsatisfactory response to DFMO, pretreatment with ethanol (BLM E7) reduced the incidence of interstitial fibrosis from 91.3 to 71.4% (p less than 0.05) and confluent fibrosis from 73.9 to 20.0% (p less than 0.005). The severity of lesions was also reduced by ethanol, resulting in an 18.5% decrease in interstitial fibrosis, a 25.9% decrease in epithelial metaplasia, and a 55.4% reduction in the lung disease index (all p less than 0.01). However, when ethanol and DFMO were administered in combination, the beneficial effects of ethanol alone were not observed, and only the lung disease index was decreased.

Streptozotocin treatment of streptozotocin-induced islet cell adenomas in rats.

Hypoglycemic rats bearing insulin-secreting islet-cell adenomas produced by the combined action of streptozotocin and nicotinamide were treated with streptozotocin. Antitumor response was demonstrated by elevation of blood glucose, reduction in plasma and tumor IRI, and histopathologic changes in the beta-cell neoplasm. The rodent tumor model may serve as a predictive system for selection and investigation of mechanisms of action of future antitumor agents to be used in the treatment of malignant insulinoma in man.

Modification of renal tumorigenic effect of streptozotocin by nicotinamide: spontaneous reversibility of streptozotocin diabetes.

The renal oncogenic activity of streptozotocin in male Holtzman rats was significantly decreased by nicotinamide. Adenomas of the kidney were noted in 77% (21/28) of the animals treated with single iv dose of the streptozotocin, 50 mg/kg, while only 18% (5/28) of animals given nicotinamide ip, 350 mg/kg, 10 min before and 180 min after the same dose of streptozotocin had demonstrable renal tumors. Moreover, the renal adenomas induced by streptozotocin alone occurred sooner and were generally larger when compared with those in the animals treated with the nicotinamide-streptozotocin combination. The 50 mg/kg dose of streptozotocin was diabetogenic in all rats, but the diabetic state was not permanent. Spontaneous recovery from the diabetes was first noted after 8 and 10 months of followup, and after 16 months none of the surviving rats were diabetic.

Studies on the inhibition of clearance of organic dyes by Saramycetin.

1. Saramycetin, a polypeptide antifungal antibiotic has been found to retard the clearance of sulphobromophthalein (BSP) in man. An explanation for this observation was sought in several lower species.2. Doses of Saramycetin without effect on the other standard tests of hepatic function or on hepatic morphology profoundly altered the disposition of BSP and several other dyes in mice and dogs.3. Saramycetin strongly inhibited the hepatic enzyme which conjugates BSP to reduced glutathione, provoked a regurgitation of BSP from the liver into the bloodstream, and was anticholeretic in the dog.4. These diverse actions of Saramycetin may, in concert, explain the altered clearance of BSP. It is suggested that low doses of Saramycetin exert a pharmacological effect on certain hepatic excretory processes, whereas high doses are toxic.