Quaternary narcotic antagonists' relative ability to prevent antinociception and gastrointestinal transit inhibition in morphine-treated rats as an index of peripheral selectivity

Single doses of naloxone (0.025 to 0.5 mg/kg) or of one of four quaternary narcotic antagonists (i.e. nalorphine allobromide, nalorphine methobromide, naloxone methobromide or naltrexone methobromide, 1 to 60 mg/kg) were given s.c. to rats before morphine, 5 mg/kg i.v. In the absence of antagonists morphine reduced G.I. transit of a charcoal meal to about 15% of drug-free controls and consistently delayed nociceptive reactions (55°C hot plate) in all animals. Doses of antagonists slightly reducing morphine antinociception (centrally effective = A) and restoring G.I. transit to about 50% of drug-free rats (peripherally effective = B) were estimated. The A:B ratio, indicating peripheral selectivity, was at least 8 for any of the quaternary antagonists given 10 min before morphine, but prolonging this interval may have resulted in a lower figure (i.e. less peripheral selectivity) because of reduced A and increased B. This was definitely so for naltrexone methobromide (A:B, > 60 at 10 min, about 1 at 80 min) and was not apparent for nalorphine methobromide according to available data, which for nalorphine allobromide and to a lesser extent for naloxone methobromide showed only an increase in B at intervals longer than 10 min. Both morphine-induced antinociception and inhibition of G.I. transit were reduced by naloxone at the lower doses tested and were fully prevented at the higher. These findings indicate that, unlike naloxone, the investigated quaternary narcotic antagonists are interesting prototype drugs for selective blockade of opiate receptors outside the CNS, although certain critical aspects, possibly biological N-dealkylation to the corresponding tertiary antagonists, condition peripheral selectivity.     

Intraspecific polymorphism of sex chromosome heterochromatin in two species of the Anopheles gambiae complex

The Hoechst 33258 banding pattern of the mitotic chromosomes of several laboratory and natural populations of the sibling species A. gambiae and A. arabiensis has been analyzed. A clear intraspecific polymorphism of sex chromosome heterochromatin has been observed. Nevertheless in each species heterochromatic variations fall within a characteristic species-specific pattern. Moreover, while laboratory populations tend to be monomorphic for a given heterochromatic variant, natural populations exhibit a high degree of intrapopulation polymorphism. The possible role of sex chromosome heterochromatin in controlling fertility and mating behaviour of Anopheles mosquitoes is discussed.     

Syndrome +12p

Summary Familial 12/15 translocation with a child trisomic for the short arm of chromosome 12 (segment p 12.1pter) is reported. The clinical picture of the child is strikingly similar to previous reports of 12p trisomy. The main symptoms of 12p syndrome are defined.     

Role of adrenergic innervation in experimental renal hypertension

Renal hypertension was induced by ligation of the aorta between renal arteries in rats sympathectomized with 6-hydroxydopamine. In the early phase, equally severe hypertension developed in the denervated group as compared to innervated controls. Later, blood pressure was lower in the denervated rats. Initially, increases in plasma renin were seen in both groups; the levels, however, were markedly lower in the denervated rats. Later, the renin levels were similar and not different from baseline. It is concluded that adrenergic neural activity is not essential in the development of renal hypertension; the maintenance of the chronic state, however, depends in part on adrenergic innervation.     

Meningococcal Disease in California: Epidemiology and Management

Between 1969 and 1975 in California, 1,953 cases of meningococcal disease were reported. For cases reported in 1973, 1974 and 1975, detailed information about chemoprophylaxis of cases and contacts was obtained in addition to demographic and laboratory data. A review of data for the seven years showed a reduction in the case rate from 2.6 to 0.6 per 100,000 population, but this drop was due primarily to a very substantial decline in the military rate from 35.7 to 1.8 per 100,000 population. No reduction was apparent in the case fatality rate. Five groups of associated meningococcal disease cases were identified for a total of nine secondary or coprimary cases among 862 household contacts. Associated cases occurred in 10.4 per 1,000 household contacts—a rate several hundred times greater than that for the general population.The study findings indicate that many physicians are unaware of the following: (1) nonhousehold contacts are at little or no risk of contracting meningococcal disease; (2) prophylaxis should be offered only to household or intimate contacts immediately upon identification of an index case without waiting for test results for meningococcal carriage; (3) valid medical and epidemiologic indications exist for administering prophylaxis to household contacts who are culture negative as well as those who are culture positive; (4) the current drug of choice for prophylaxis is rifampin, but since no drug is completely effective, close medical observation remains the most important factor in the management of household or intimate contacts to meningococcal disease.     

Differences in blastema-associated proteins according to position along body axis in regenerating planarians

To test the hypothesis that neoblasts in different positions in regenerating pieces of planarians may be differentially responsive to diffusible stimuli through differentially expressed membrane receptors, we compared membrane surface proteins in blastemas induced at various positions along an anterior-posterior axis in Dugesia gonocephala (Dugès). The proteins were biotinylated and identified by molecular weight in SDS-PAGE (sodium-dodecylsulfate polyacrilamide gel electrophoresis). This SDS-PAGE pattern was then compared with that of N-glycosylated proteins incorporating ³H-mannose. One 20 kDa glycoprotein present in all blastemas at 3 d was absent from more anterior blastemas at 6 d irrespective of whether those blastemas were at the cephalic or the caudal end of the regenerating piece. The expression of this protein appears to be determined by the position of the blastema along the body axis rather than by its prospective fate.     

Diltiazem at high concentration increases the ionic permeability of biological membranes

Summary The effects of diltiazem, a drug which inhibits the calcium channels in cardiac muscle as well as the light-sensitive channels in photoreceptor cells, were studied on ionic fluxes in both membrane and intact cell preparations. Diltiazem nonselectively increased the ionic permeability to both anions and cations in photoreceptor rod outer segment and synaptic membrane vesicles as well as in intact erythrocytes. Under our conditions, the estimated threshold for the diltiazem effect varied between 12.5 and 200 m. In each case the concentration dependence exhibited the sigmoidal shape characteristic of positive cooperativity. The effect of diltiazem on ionic fluxes from phospholipid vesicles were strongly influenced by phospholipid composition and membrane charge. By contrast, diltiazem inhibited the efflux of⁸⁶Rb from photoreceptor cells of intact aspartate-isolated retina, an effect opposite to that of diltiazem on ionic permeabilities in photoreceptor membrane vesicle preparations.These data raise serious doubts on the specificity of diltiazem as a calcium channel blocker or as a cGMP channel blocker when used at concentrations higher than 10 m.