Aldehyde oxidase and its contribution to the metabolism of a structurally novel, functionally selective GABAA alpha5-subtype inverse agonist.

(3-Tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)pyrazolo[1,5-d] [1,2,4]triazine was recently identified as a functionally selective, inverse agonist at the benzodiazepine site of GABA(A) alpha5-containing receptors, which enhances performance in animal models of cognition. The routes of metabolism of this compound in rat, dog, rhesus monkey and human in vitro systems, and in vivo in rat, dog and rhesus monkey have been characterized. The current study demonstrates that both a cytosolic oxidative reaction and cytochrome P450 play important roles in the metabolism of the compound. Chemical inhibition studies showed the oxidation in human cytosol to be catalysed predominantly by aldehyde oxidase rather than the related enzyme, xanthine oxidase. The aldehyde oxidase-mediated metabolites were present in vitro and in vivo in both rat and rhesus monkey, and also in vitro in man. They were absent both in vitro and in vivo in dog.

7-Methoxybenzofuran-4-carboxamides as PDE 4 inhibitors: a potential treatment for asthma.

The synthesis and pharmacological profile of a novel series of 7-methoxybenzofuran-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).

3-(4-Piperidinyl)- and 3-(8-aza-bicyclo[3.2.1]oct-3-yl)-2-phenyl-1H-indoles as bioavailable h5-HT2A antagonists.

A series of 3-(4-piperidinyl)- and 3-(8-aza-bicyclo[3.2.1]oct-3-yl)-2-phenyl-1H-indoles have been prepared and evaluated as ligands for the h5-HT2A receptor. 3-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-phenyl-1H-indole is a high-affinity (1.2nM), selective (>800 fold over h5-HT2C and hD2 receptors) antagonist at the h5-HT2A receptor with oral bioavailability in rats.

Aryl sulfonamides as selective PDE4 inhibitors.

A series of novel selective phosphodiesterase 4 (PDE4) inhibitors has been developed which displays activity both in vitro and in vivo. These compounds possess good selectivity for the catalytic site of PDE4 over the high affinity Rolipram binding site. In vivo studies demonstrate a reduced propensity to display the emetic side effects which are commonly observed with PDE4 inhibitors.

Improved training techniques and UltraBag system resulted in lowered peritonitis rate in an inner-city population.

Fifteen continuous ambulatory peritoneal dialysis (CAPD) patients from our dialysis unit were studied while using two different types of exchange systems: a snap-disconnect Y-set system and the Baxter UltraBag system. The incidence of peritonitis in the snap-disconnect Y-system was found to be 32 cases in 187 months, or a rate of 1 case of peritonitis every 5.8 months. When these patients switched to the Baxter UltraBag system, the incidence of peritonitis dropped to 4 cases in 175 months, or 1 case every 43.8 months, a highly significant difference. We conclude, therefore, that the UltraBag system is highly effective in reducing the incidence of peritonitis in CAPD patients.

BAY u9773, a novel antagonist of cysteinyl-leukotrienes with activity against two receptor subtypes.

The effects of BAY u9773 (6(R)-(4'-carboxyphenylthio)-5(S)-hydroxy-7(E),9(E), 11(Z),14(Z)-eicosatetraenoic acid), a cysteinyl-leukotriene analogue, were investigated on a variety of smooth muscle preparations in order to determine its profile as a cysteinyl-leukotriene receptor antagonist. The tissues were contracted with leukotriene C4 or leukotriene D4 and their receptor characteristics defined as either 'typical' or 'atypical' according to the activity or inactivity, respectively, of the selective antagonists ICI 198615, MK 571 and SKF 104353. BAY u9773 antagonised 'typical' cysteinyl-leukotriene receptors with pA2 (or pKB) values in the range 6.8-7.4 and also antagonised 'atypical' receptors with pA2 values in the range 6.8-7.7. However, BAY u9773 had no effect at 10(-6) M against a selection of non-leukotriene stimuli in the same preparations. BAY u9773 competitively displaced [3H]leukotriene D4 binding to guinea-pig lung homogenate, with a pKi of 7.0 +/- 0.1. In the guinea-pig lung strip, BAY u9773 was found to be inactive at 10(-6)M against leukotriene C4- and leukotriene D4-induced contractions, which may suggest the existence of a third type of cysteinyl-leukotriene receptor. These data demonstrate that BAY u9773 is a selective cysteinyl-leukotriene receptor antagonist with comparable activity at both 'typical' and 'atypical' receptors and as such represents a valuable tool for the study of cysteinyl-leukotriene receptors.

Residual concentrations of propanil, TCAB, and other pesticides in rice-growing of soils in the United States, 1972.

Ninety-nine soil samples from the rice-growing states of Arkansas, California, Louisiana, Mississippi, and Texas were collected, primarily to monitor the herbicide propanil. No residual concentrations of propanil were detected in any of these samples, but TCAB, a propanil transformation product, was detected in six samples at concentrations ranging from 0.01 ppm to 0.05 ppm. Organochlorine and organphosphorus pesticide determinations were also performed. The compounds dieldrin, aldrin, and DDT and its metabolites were found more frequently; endrin and chlordane were found less frequently. The organophosphorus pesticides diazinon and parathion were detected occasionally.

Proposal for prevention and treatment of hypertension and renal failure in Zimbabwe

Zimbabwe has made great strides in the development of a national health care system to provide care to all of its citizens. It has embarked on an extensive program to provide access to basic health services to the entire population. The Government of Zimbabwe established a Health Manpower Department within the Ministry of Health to facilitate the attainment of its health objectives in the most cost effective and efficient manner. The result is a commitment to an increase in all health services with an accompanied need not only for more manpower; and productivity in all existing disciplines; but also for the development of new essential specialties. Over the last few years there has been increased awareness of the devastating consequences that occur as a result of untreated or undiagonosed hypertension. Major sequelae that occur with hypertension include cerebral vascular accident; hypertensive cardiovascular disease; and renal failure. Appropriately; special emphasis has been placed on detection and treatment of hypertension so as to prevent the morbidity and mortality of this disease. The Health Department Institute (HDI); established in 1984; provides health care training; health risk management; hepertension screening; prevention education; and medical treatment for many in the greater Los Angeles area. HDI; and its affiliated companies; manage both hospital based hemodialysis units and free-standing hemodialysis and peritoneal dialysis units. HDI trains patent care technicians and nurses to provide care at these facilities; and participates in curriculm development and training of medical students and physicians at university based hypertension/renal training programs. [abstract terminated]