Search PubMed⌕ Search

Biomedical subjects

M A Goldsmith

Publications and source records attributed to M A Goldsmith.

78 records · Page 5Linked to original sources
PubMed1975

Quantitative prediction of drug toxicity in humans from toxicology in small and large animals.

The mouse, dog, and monkey toxicity data on 30 drugs was retrospectively analyzed in comparison with the actual clinical dose schedules used in man. Animal dose schedules were converted to the human schedule and comparisons were made of the human dose versus the large animal toxic dose low, toxic dose high, and lethal dose, the lethal doses for 10% and 90% of normal mice, and the optimal dose in tumor-bearing mice. If the starting dose in Phase 1 clinical trials had been selected by calculating one-third of the toxic dose low (in mg/sq m) in the most sensitive large animal species, 5 of the 30 drugs would have produced significant toxicity in the first patient. The lethal doses for 10 and 90% of normal mice and the optimal dose in L1210-bearing mice were found to offer good quantitative prediction of human toxicity. Determination of a safe and practical starting dose for Phase 1 studies should take into account not only dog and monkey data but also toxicology data in normal and tumor-bearing mice.

Animals↗
PubMedDate not supplied

Parallel evolution of CCR5-null phenotypes in humans and in a natural host of simian immunodeficiency virus.

The C-C chemokine receptor CCR5 in humans and rhesus macaques (Macaca mulatta) serves as the primary coreceptor for cellular entry by macrophagetropic strains of human immunodeficiency virus type 1 (HIV-1) and all reported strains of simian immunodeficiency virus (SIV) [1-6]. Humans homozygous for a 32 bp deletion allele of CCR5, resulting in a null phenotype, are highly resistant to infection by HIV-1 [7-9], prompting development of therapies and vaccines targeting CCR5. We now report a novel deletion allele of CCR5, with an allele frequency of 0.04, in sooty mangabey monkeys (Cercocebus torquatus atys), a natural host of SIV (SIVsmm) [10]. The mutant protein was not expressed at the cell surface and accordingly did not function as a viral coreceptor. Primary activated lymphocytes from mangabeys heterozygous for the deletion allele expressed significantly less CCR5 on the cell surface. Moreover, SIV seroprevalence and viremia were comparable among CCR5 heterozygotes and wild-type animals. Parallel evolution of CCR5-null alleles in humans and sooty mangabeys suggests that similar negative selection pressures have acted against CCR5, as would occur during epidemics of infectious agents that require CCR5 for pathogenesis. Sooty mangabeys bred to homozygosity for the deletion allele will be useful for experimental studies on the context-dependent role of CCR5 in host defense and microbial pathogenesis.

Animals↗