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Biomedical subjects

W H Lawrence

Publications and source records attributed to W H Lawrence.

15 recordsLinked to original sources
PubMed1992

In vitro and in vivo activities of the novel antiplatelet agent alpha,alpha'-bis[3-(N,N-diethylcarbamoyl)piperidino]-p-xylene dihydrobromide.

In an effort to develop compounds with high antithrombotic activity and minimal toxicity, our laboratory has synthesized a number of nipecotamides. The effectiveness of one of these compounds, alpha,alpha'-bis[3-(N,N-diethylcarbamoyl)piperidino]-p-xylene dihydrobromide (A-1), in inhibiting both in vitro and in vivo platelet aggregation is reported here, along with its acute toxicity. The IC50 of A-1 in in vitro ADP- and PAF-induced platelet aggregation was 44.5 microM and 21.2 microM, respectively. Suppression of intraplatelet [Ca2+] is suggested as a likely mediator of the aggregation-inhibitory properties of A-1, since both the release of cytosolic Ca2+ and the influx of extracellular Ca2+ were decreased. The ED50 of A-1 in protecting mice against thromboembolism induced by a collagen-epinephrine challenge was 164 mumol/kg. The measurement of the acute toxicity of this compound as the LD50 was 691 mumol/kg, with the therapeutic index being 4.2. These data indicate that compounds in this family hold promise as clinically effective antithrombotic agents.

Adenosine Diphosphate↗
PubMed1990

Some novel inhibitors of platelet aggregation: acute toxicity in mice and its relationship to in vitro efficacy and toxicity. II. Nipecotoylaminoalkane and nipecotoylpiperazine congeners.

Four closely related nipecotoyl congeners are employed as molecular probes to evaluate the effects of systematic molecular changes upon lethal potency of the compounds. The in vivo toxicities, effected by changes in molecular structure, are compared to their in vitro concentrations inhibiting ADP-induced aggregation and epinephrine-induced primary aggregation of human blood platelets and their toxicities to mouse fibroblasts (L-929 cells) in culture. To assist in the selection of compounds which offer the greatest promise as therapeutic agents for further evaluation and to guide future development of optimal molecular structures, a ratio of acute ip LD50 (mumol/kg) [Tm] to concentration inhibiting 50% ADP-induced platelet aggregation (mumol/liter) [A] is calculated for each compound. These ratios range from 2.41 to 24.92 for the four compounds included in this study.

Alkanes↗
PubMed1976

Carcinogenic activity of a chlorinated polyether polyurethan.

On the basis of the results of an earlier study, a particular polyurethan sample (Y-238) was selected for further evaluation of its carcinogenic potential. This sample was subjected to physical and chemical tests for elucidation of its chemical structure, molecular weight, and molecular weight distribution. Additional biological tests were conducted on male NBR rats by implanting various quantities of the sample i.p., while others received an intrabronchus implant. Tumors, assessed histologically as malignant, were observed following both routes of implantation. The most common neoplasms of the pulmonary site was epidermoid carcinoma, while fibrosarcoma was the most common neoplasm in the peritoneal cavity. Data from the i.p. implantation suggested a dose-related incidence of cancers.

Animals↗
PubMed1975

Biological evaluation of polymers. I. Poly(methyl methacylate).

A series of poly(methyl methacrylate) formulations differing widely in chemical and physical properties was employed for the evaluation of primary screening methods for the assessment of acute toxicity. Materials and USP extracts of materials were tested in parallel. Tissue culture, hemolysis, intradermal irritation, systemic toxicity, muscle implant and histopathologic responses were determined for each of 27 formulations. A determination of the nonvolatile methanol extractable components was carried out on each formulation. The formulations varied with respect to percent, w/w, methyl methacrylate, N,N-dimethyl-p-toluidine, stannous octoate, 3, 4-diamino-toluene and, also, with respect to curing conditions. Volatile components, primarily methyl methacrylate, of three selected formulations were determined quantitatively by vacuum distillation and mass spectrographic analysis. Statistical analysis of the primary data indicated a significant correlation of residue weight (methanol extractable) with hemolytic activity (r = 0.93) and with the cumulative biological response (r = 0.9). Multiple linear regression analysis of residue weights with hemolysis and intradermal irriation responses gave the highest overall correlation (r = 0.96). Hemolytic activity and tissue culture responses were significantly correlated (r = 0.87). It was concluded that the observed variation of biological test results reflected significant differences in the toxicity of the test materials. The poly(methyl methacrylate) series examined was relatively low in toxicity and the biological tests examined, particularly the in vitro tests, were found to be responsive to formulation and curing conditions which indicated their suitability for primary toxicity screening.

Animals↗
PubMed1975

Maternal-fetal transfer of 14C-di-2-ethylhexyl phthalate and 14C-diethyl phthalate in rats.

14C-Di-2-ethylhexyl and 14C-diethyl phthalates were administered intraperitoneally to pregnant rats on either Day 5 or 10 of gestation. Rats were sacrificed at 24-hr intervals starting on Days 8 and 11, respectively; maternal blood, fetal tissue, amniotic fluid, and placentas (whenever possible) were obtained. The 14C-activity of each sample was determined by scintillation counting. It was found that both diesters and/or their metabolic products were present in each of these compartments throughout the gestation period, thus suggesting that the embryo-fetal toxicity and teratogenesis reported previously could be the results of a direct effect of the compound (or its metabolites) upon developing embryonic tissue. Additionally, the reduction in concentration of 14C from these tissues as a function of time was found to fit a first-order excretion curve. From this model curve, the half-life for both compounds was calculated; the average was about 2.33 days for di-2-ethylhexyl phthalate and 2.22 days for diethyl phthalate.

Amniotic Fluid↗
PubMed1975

Continuous vertical pendular eye movements after brain-stem hemorrhage.

Electro-oculographic studies are reported in a 33-year-old man with bilateral horizontal gaze palsies and continuous pendular eye movements in the vertical plane secondary to hemorrhage from a pontine arteriovenous malformation. The effects of pharmacologic and physiologic stimuli on the movements are described.

Adult↗
PubMed1975

Carcinogenesis from polyurethans.

Seventeen polyurethans, containing various substituent groups, and a polyethylene were implanted i.p. in groups of male black Bethesda rats and were evaluated for carcinogenesis over a 2-year period. Thirteen of the polyurethans and the polyethylene were similarly studied in females. Tumor development in these animals was expressed in terms of the incidence in the at-risk population, and the tumorigenic latent period was approximated for each sample. Twenty months after implantation, the relative tumorigenicity (area under the corrected cumulative tumor mortality versus time curve) in the males ranged from 0 (for the unimplanted controls) to 6.18 (for Y-238); for female rats this range was 0.29 (for unimplanted controls) to 5.72 (for Y-238). Estimated latent periods in the males ranged from 5 months (for Y-304) to 16 months (for Y-303), and 22.5 months for the unimplanted controls; for the females, the range was from 9 months (for Y-290) to 13.5 months (for Y-217), and 14 months for the unimplanted controls. The relative tumorigenicity of each sample was also compared to its in vitro activation energy for thermal decomposition. These data are discussed in terms of solid-state versus chemical carcinogenesis.

Animals↗