Effects of pinacidil upon penile erectile tissue, in vitro and in vivo

The effect of pinacidil, a new antihypertensive vasodilator, was studied in vitro upon human and porcine Corpus cavernosum and in vivo upon simian Corpus cavernosum. In vitro, pinacidil incubation (10(-5)-10(-3) M) was found to induce a concentration-dependent inhibition of the tissue response to norepinephrine (NE) and high potassium (K+). Likewise a concentration-related relaxation of the tissue, precontracted with either NE or K+, was seen using pinacidil 10(-5)-10(-3) M. Depending on the concentration applied, spontaneous activity as well as tone and amplitude of the contractions were reduced until total relaxation of the tissue was obtained with a pinacidil incubation of 10(-3) M. In vivo, 5 mg pinacidil in 0.3 ml solution was injected intracavernosally in 17 monkeys. Sixteen monkeys developed tumescence and 10, rigidity of the penis as well. Only one of 5 showed a decrease in the systemic blood pressure. Pinacidil might be of clinical interest as an agent facilitating erection when given intravernosally.     

Synthetic inhibitors of serine proteinases. 32. Inhibition of trypsin, plasmin and thrombin by amides of N-alpha-substituted 4-amidinophenylalanine. Effect of various amino acids and blocking groups of the n-alpha residue on inhibitory activity

Cyclic amides of N alpha-arylsulfonylated 4-amidinophenylalanine are specific, highly potent inhibitors of thrombin. Introduction of amino acids between the arylsulfonyl blocking group and amino nitrogen influence particularly the antithrombin activity. By the use of glycine as spacer the compounds become tight binding thrombin inhibitors, while introduction of other omega-amino acids, Gly-Gly, L-Pro, Gly-L-Pro or L-Pro-Gly, reduces the specificity and potency of thrombin inhibition. Substitution of the arylsulfonyl blocking group for a heteroarylsulfonyl residue or an aryl residue causes a decrease in antithrombin activity, while substitution for a benzoyloxycarbonyl blocking group has only slight influence. It is concluded that the N alpha-moiety is of decisive importance for the antithrombin activity of derivatives of 4-amidinophenylalanine.     

Reepithelialization of experimental scalds effected by topically applied superoxide dismutase: controlled animal studies

Highly reactive metabolites, such as oxygen free radicals, initiate a cascade of inflammatory processes in thermally damaged skin, leading to enhanced tissue loss and delayed wound healing. The extent of tissue necrosis in the zone of stasis is of prognostic significance in the wound healing process. In this study, the effect of oxygen free radical removal by recombinant human-Cu/Zn-superoxide dismutase, given in three different formulations during the inflammatory postburn phase and wound repair, was examined. Recombinant human superoxide dismutase was either injected directly into the lesions, spread as enzyme-containing gel onto the burned tissue, or encapsulated into liposomes consisting of 1,2 dipalmitoy-sn-glycero-3-phosphocholine, cholesterol and stearylamine, suspended into a hydrophilic gel and administered to burned animals immediately after trauma. Controls were treated with plain gel or kept untreated. Edema formation, size of lesions, deepening of necrosis, and reepithelialization were examined. Results indicate that superoxide dismutase treatment resulted in reduced and faster recruitment of edema formation, smaller wound sizes, and minor tissue necrosis compared to the controls, thus resulting in significantly faster reepithelialization after 3 weeks. These animal studies on the efficacy of liposomal oxygen free radical scavenger showed accelerated wound healing in all parameters tested.     

Sialyltransferase activity and hepatic tumor growth in a nude mouse model of colorectal cancer metastases.

Sialyltransferase activity (EC 2.4.99.6) was measured in the microsomal fraction of colorectal cancer cell lines using an assay based on the incorporation of [14C]CMP-sialic acid into asialofetuin. In the poorly differentiated lines MIP101 and Clone A, sialyltransferase activity had a Vmax of 0.36 and 0.31 nmol/mg protein/h, respectively, while the moderately differentiated to well-differentiated cell lines HT-29, CCL188, and CX-1 had Vmaxs of 2.46, 1.05, and 1.24 nmol/mg protein/h, respectively. All cell lines tested had a Km of 15.4 (+/- 0.7)(SD) mumol/liter. The better differentiated cells had higher levels of sialyltransferase activity, which correlated with their higher levels of sialic acid and their enhanced ability to form liver metastases in the nude mouse following intrasplenic injection compared to the poorly differentiated cell lines. Treatment of the cell lines with KI-8110, a CMP-sialic acid derivative which prevents incorporation of sialic acid into glycoconjugates, resulted in reduced formation of hepatic metastases by the colorectal carcinoma cell lines in the nude mouse model. It is suggested that reduced sialylation of adhesion molecules such as carcinoembryonic antigen may change the biology of the tumor cell, one consequence of which is the prevention of implantation of the cells into distant sites, resulting in a reduced incidence of metastases.     

Pharmacokinetics of moxonidine after single and repeated daily doses in healthy volunteers

The pharmacokinetics of the centrally acting alpha-2 agonist moxonidine were investigated in 12 healthy male subjects after single and repeated oral doses (q12h for five days) of moxonidine 0.2 mg. Plasma concentration-time data followed the general characteristics of a one-compartment model with first-order absorption. Peak plasma concentrations of 1.29 +/- 0.32 ng/mL were achieved 0.74 +/- 0.35 hours after ingestion of a 0.2-mg tablet. The terminal half-life of elimination was 2.12 +/- 0.58 hours. The oral clearance (CL/F) amounted to 830 +/- 171 mL/min with renal elimination being the major route of elimination. No significant differences in pharmacokinetic parameters could be observed following repeated dosing over five days.     

In vivo gene transfer: focus on the kidney

Renal gene transfer techniques are being developed as a novelexperimental approach to understand the pathogenesis of renaldisease and to potentially develop new therapeutic tools. Wereview the currently available technology to introduce foreigngenetic material into renal tissue, i.e., retroviral, adenoviral,and liposomal transfer systems with their respective advantagesand caveats. Today, the transfer efficiency of these methodsappears to be sufficiently high to study the effects of transducedgenes on renal function and morphology in rat kidney. This willallow (i) the elucidation of the function of genes on the courseof renal disease in experimental animal models and (ii) themodulation of local expression of endogenous genes which presumptivelycontribute to renal pathology in these models. One strategyto accomplish this aim is the use of recombinant DNA technologyto design antisense DNA constructs or oligonucleotides, whichinterfere with the renal expression of target genes. We willalso discuss some of the shortcomings of the currently usedtechniques with respect to potential therapeutic use of genetransfer systems and gene modulation.     

The National Occupational Research Agenda: a model of broad stakeholder input into priority setting.

OBJECTIVES: No single organization has the resources necessary to conduct occupational safety and health research to adequately serve the needs of workers in the United States. The National Institute for Occupational Safety and Health (NIOSH) undertook the task of setting research priorities in response to a broadly perceived need to systematically address those topics most pressing and most likely to yield gains to workers and to the nation. METHODS: NIOSH and its public and private partners used a consensus-building process to set priorities for the next decade for occupational safety and health research--the National Occupational Research Agenda. RESULTS: The process resulted in the identification of 21 research priorities grouped into 3 categories: disease and injury, work environment and workforce, and research tools and approaches. CONCLUSIONS: Although the field of occupational safety and health is often contentious and adversarial, these research priorities reflect a remarkable degree of concurrence among a broad range of stakeholders who provided input into a clearly defined and open process.