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H Boxenbaum

Publications and source records attributed to H Boxenbaum.

43 records · Page 3Linked to original sources
PubMedDate not supplied

Gompertz mortality analysis: aging, longevity hormesis and toxicity.

The hazard function, denoted h(x), is the probability of death during an interval of time [Formula: see text], assuming survival to the beginning of the interval. Brues and Sacher provided both theoretical and experimental support for the assumption that h(x) is an exponential function of the mean intensity of physiologic injury for a homogeneous mammalian population provided an adequate diet, kept free of preventable disease and maintained under favorable, uniform conditions. Consequently, the Napierian logarithm of the hazard function, the 'Gompertzian', is proportional to the mean intensity of physiologic injury under the aforementioned conditions. Investigation of Gompertzian values therefore affords a simple and convenient measure of the mean population time course of aging, toxicity and beneficial life-enhancing effects (e.g., longevity hormesis and slowing of the aging process). (The word 'hormesis' has been applied to various forms of 'stimulation' elicited by low doses of otherwise toxic agents.) Using this method of analysis, reversible toxicity, reversible reduction in physiologic injury (longevity 'hormesis'), irreversible toxicity and irreversible reduction in aging (via caloric restriction) are all reviewed. It is demonstrated that these effects may superimpose upon one another, the most common combination following administration of mild to moderate doses of a toxic agent being irreversible toxicity combining with longevity hormesis.

Journal Article↗
PubMedDate not supplied

Cytochrome P450 3A4 in vivo ketoconazole competitive inhibition: determination of Ki and dangers associated with high clearance drugs in general.

Assuming complete hepatic substrate metabolism and system linearity, quantitative effects of in vivo competitive inhibition are investigated. Following oral administration of a substrate in the presence of a competitive inhibitor, determination of the inhibition constant (Ki) is possible when plasma concentration-time profiles of both substrate and inhibitor are available. When triazolam is the P450 3A4 substrate and ketoconazole the competitive inhibitor, Ki approximately 1.2 microg/mL in humans. The effects of competitive inhibition can be divided into two components: first-pass hepatic metabolism and systemic metabolism. For drugs with high hepatic extraction ratios, the impact of competitive inhibition on hepatic first-pass metabolism can be particularly dramatic. For example, human terfenadine hepatic extraction goes from 95% in the absence of a competitive inhibitor to 35% in the presence of one (ketoconazole, 200 mg po Q 12 h dosed to steady-state). First-pass extraction therefore goes from 5% in the absence of the inhibitor to 65% in its presence. The combined effect on first-pass and systemic metabolism produces an approximate 37 fold increase in terfenadine area under the plasma concentration-time curve. Assuming intact drug is active and/or toxic, development of metabolized drugs with extensive first-pass metabolism should be avoided if possible, since inhibition of metabolism may lead to profound increases in exposure.

Alprazolam↗
PubMedDate not supplied

Human in vivo competitive inhibition of P450 substrates: increased plasma concentrations as a function of hepatic extraction ratio and percent inhibition.

The purpose of this note is to posit and discuss the concept of "competitive inhibition potential" (CIP), which is an in vivo index of the ability of a competitive inhibitor to elevate plasma concentrations of drug substrates, when the competitive inhibitor is administered at its usual and customary dose.

Binding, Competitive↗