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H Boxenbaum

Publications and source records attributed to H Boxenbaum.

At least 19 recordsLinked to original sources
PubMed1999

Estimation of Ki in a competitive enzyme-inhibition model: comparisons among three methods of data analysis.

There are a variety of methods available to calculate the inhibition constant (Ki) that characterizes substrate inhibition by a competitive inhibitor. Linearized versions of the Michaelis-Menten equation (e.g., Lineweaver-Burk, Dixon, etc.) are frequently used, but they often produce substantial errors in parameter estimation. This study was conducted to compare three methods of analysis for the estimation of Ki: simultaneous nonlinear regression (SNLR); nonsimultaneous, nonlinear regression, "KM,app" method; and the Dixon method. Metabolite formation rates were simulated for a competitive inhibition model with random error (corresponding to 10% coefficient of variation). These rates were generated for a control (i.e., no inhibitor) and five inhibitor concentrations with six substrate concentrations per inhibitor and control. The KM/Ki ratios ranged from less than 0.1 to greater than 600. A total of 3 data sets for each of three KM/Ki ratios were generated (i.e., 108 rates/data set per KM/Ki ratio). The mean inhibition and control data were fit simultaneously (SNLR method) using the full competitive enzyme-inhibition equation. In the KM,app method, the mean inhibition and control data were fit separately to the Michaelis-Menten equation. The SNLR approach was the most robust, fastest, and easiest to implement. The KM,app method gave good estimates of Ki but was more time consuming. Both methods gave good recoveries of KM and VMAX values. The Dixon method gave widely ranging and inaccurate estimates of Ki. For reliable estimation of Ki values, the SNLR method is preferred.

Algorithms↗
PubMed1995

First-time-in-human dose selection: allometric thoughts and perspectives.

Some of the many factors that influence dose selection in first-time-in-human studies are examined. These include animal toxicology, toxicokinetics, allometric scaling, pharmacokinetics, body surface area correlations, and integration of preclinical pharmacologic and toxicologic data. Appropriate preclinical evaluation and analysis may reduce the frequency and severity of unexpected toxic events arising during single-dose, phase I testing. However, significant intrinsic uncertainties in this process presently exist and will continue to exist well into the foreseeable future. With our present state of knowledge, we cannot provide a realistic and reasonable algorithm for ascertaining first-time-in-human doses: any decision tree would be too unwieldy. There are several rules of thumb that do have a place in the evaluation and decision-making process, however.

Animals↗
PubMed1993

Human dolasetron pharmacokinetics: II. Absorption and disposition following single-dose oral administration to normal male subjects.

Dolasetron is a 5-hydroxytryptamine antagonist active at type III receptors; it is presently undergoing clinical evaluation for the reduction/prevention of cancer chemotherapy-induced nausea and vomiting. A previous study demonstrated that following intravenous administration to healthy male subjects, dolasetron disappeared extremely rapidly from plasma, and less than 1 per cent of the dose appeared in the urine. A major plasma metabolite, reduced dolasetron, peaked rapidly in the plasma. In this study, dolasetron was administered orally to healthy male subjects at doses ranging from 50 to 400 mg (mesylate monohydrate). Plasma concentrations of dolasetron were low and sporadic, and there was little excreted in urine; this prevented dolasetron pharmacokinetic analysis. Reduced metabolite concentrations peaked rapidly, with a median value of 1.00 h. The median terminal disposition half-life was 7.80 h. Median values for fraction of dose excreted in urine and renal clearance were 22.2 per cent and 2.56 ml min-1 kg-1. Whereas areas under the plasma concentration-time curves were proportional to dose, renal clearance increased with dose (p < 0.05). However, given dose proportionality to AUC, this is probably of little therapeutic consequence. Since reduced dolasetron has significant anti-emetic activity in the ferret model, it appears that this metabolite may play a significant role in pharmacodynamic activity.

Absorption↗
PubMed1992

Human dolasetron pharmacokinetics: I. Disposition following single-dose intravenous administration to normal male subjects.

Dolasetron is a 5-hydroxytryptamine antagonist active at type III receptors; it is presently undergoing clinical evaluation for the reduction/prevention of cancer chemotherapy-induced nausea and vomiting. Following intravenous administration to healthy male subjects of doses ranging from 0.6 to 5 mg kg-1, dolasetron disappeared extremely rapidly from plasma; concentrations were generally measurable for only 2-4 h. Less than 1 per cent of the dose was excreted intact in urine. A major plasma metabolite, reduced dolasetron, peaked rapidly at approximately 0.625 h (median). Its median terminal disposition half-life was 7.56 h; median values for fraction of dose excreted in urine and renal clearance were 31.0 per cent and 2.68 ml min-1 kg-1, respectively. Over the dose-range covered, pharmacokinetics of both dolasetron and reduced metabolite appeared to be independent of dose. The median ratio of the areas under the plasma concentration-time curves for metabolite relative to dolasetron was 11.9. As a result of its activity and significant plasma concentrations, reduced dolasetron may play a significant role in pharmacodynamic activity.

Adult↗
PubMed1992

Pharmacokinetics: philosophy of modeling.

Generally speaking, there are two extremes of scientific personality types: sharpeners and levelers. Sharpeners, highly attuned to system differences and nuances, and always alert to distinctions, try hard to let nothing slip by them unnoticed. Levelers, on the other hand, attempt to submerge system differences, reveal uniform patterns, and condense disparate elements. This paper is one leveler's attempt to address the following philosophical questions confronting pharmacokinetic modelers: (1) What is the nature of reality? (2) What is a model? (3) Why do we model? (4) What are the different types of models? (5) How do we model? (6) What are the properties and characteristics of models? (7) How do we evaluate models? (8) What are some of the tricks and traps of modeling? And (9), what are some of the psychological characteristics of modelers?

Animals↗
PubMed1991

Scientific creativity: a review.

Aside from possession of the relevant knowledge, skills, and intelligence, what seems to characterize the creative scientist is his imagination, originality, and ingenuity in combining existing knowledge into a new and unified scheme. This creativity frequently emerges from an aesthetic, poetic sense of freedom derived from work, an uninhibited playful activity of exploring a medium for its own sake. We speculate thus: With a preference for irregularities and disorder, the creative scientist temporarily takes leave of his senses, permitting expression of unconfigurated forces of his irrational unconscious. This amounts to a kind of internal "wagering," in which the scientist pits himself against uncertain circumstances, a situation in which his individual effort can be the deciding factor. When working on a difficult problem, there frequently occurs a "creative worrying" in which the problem is consciously and unconsciously carried around while doing other tasks. This period is attended by frustrations, tensions, and false inspirations. Dream and reality are wedded in a largely unconscious process of undefined emotional turmoil. When a uniquely gratifying association is realized, the unconscious deposits its collection of insights into the fringe consciousness, whereupon the full consciousness seizes on it and releases it as a flash of insight. Because the creative scientist possesses a strong and exacting self-concept, he can organize, integrate, and even exploit the conflict within himself. By compensating in fantasy for what is missing in reality, creativeness can be an expressive outlet ameliorating the universal, annoying split between a man's inner unconscious world and his outer conscious world. Although there is a divergence of opinion as to whether creativity can be taught, there is agreement that it can be fostered. However, parents, teachers, and institutions must display considerably more flexibility and tolerance towards individually minded persons who behave in seemingly nonconformist ways.

Creativity↗
PubMed1990

Biphasic mortality response of chipmunks in the wild to single doses of ionizing radiation: toxicity and longevity hormesis.

Based on survivalship data from Tryon and Snyder, wild chipmunks (Tamias striatus), captured, exposed to single doses of either 200 or 400 rad ionizing radiation, and subsequently returned to their natural habitat, exhibited a biphasic response in age-specific mortality rate (omega x). On the one hand, a residuum of unrepaired toxicity (injury) appeared to persist and manifest itself throughout life (enhancement of omega x values). A second response, termed longevity hormesis (of unknown mechanism), was also observed. This phenomenon initially reduced omega x values but was reversible. A relatively simple mathematical model characterizing differences in mortality experience between control and irradiated populations was formulated and tested. Although there were some shortcomings, the model characterized the data reasonably well.

Aging↗
PubMed1989

Gompertzian mortality derived from competition between cell-types: congenital, toxicologic and biometric determinants of longevity.

Gompertz-Makeham kinetics of population mortality is derived in terms of competition between hypothetical life-prolonging and life-shortening regulatory elements (cells) interacting in each organism by generalized Volterra-type competitive exclusion. The model is developed on two levels, the first applicable to homogeneous populations, and the second, a statistical generalization, applicable to inhomogeneous populations. It offers a natural classification of effects of exogeneous agents on longevity, including hormetic and paradoxical effects of toxic substances, thus relating to problems of risk assessment by extrapolation from high to low doses. Two applications, concerning the effects of radiation on mice and Drosophila imagos, respectively, are used to illustrate the flexibility of the model in the analysis and interpretation of observational data.

Animals↗
PubMed1989

A Gompertz age-specific mortality rate model of aging: modification by dietary restriction in rats.

A Gompertz age-specific mortality rate model characterizing actuarial effects of food restriction in rats was developed based on mortality data from the study of Yu et al. (J. Gerontol. 40: 657-670, 1985). Results indicated that in the presence of adequate nutrition, food restriction reduces the aging rate parameter in a consistent manner, regardless of the age at which food restriction is initiated.

Aging↗
PubMed1988

Human serum and plasma protein binding of enoximone and its sulfoxide metabolite.

Experimental factors and determinants of the protein binding of enoximone (a new cardiotonic agent) were investigated in human serum from healthy, drug-free subjects using a rapid ultrafiltration method; these factors and determinants included nonspecific binding to the apparatus, ultrafiltrate volume, temperature, serum pH, enoximone serum concentration, and enoximone sulfoxide (metabolite) concentration. It was demonstrated from mass balance experiments that nonspecific binding to the apparatus did not occur. Within the range investigated, ultrafiltrate volume did not affect the binding result. However, serum pH and temperature were critical variables. At pH 7.4 and 37 degrees C, enoximone serum binding occurred to the extent of approximately 70%; over the therapeutic serum concentration range, this binding was concentration independent. Experiments with purified albumin solutions indicated that much of the serum binding could be accounted for by albumin. At concentrations exceeding those observed clinically, enoximone sulfoxide did not affect enoximone serum binding. In another experiment, enoximone binding to serum was compared with that from plasma containing either heparin or disodium EDTA. There were essentially no differences. Enoximone sulfoxide serum protein binding was also investigated in serum from healthy, drug-free human subjects; binding occurred to the extent of approximately 5%.

Animals↗
PubMed1988

Quantitative structure-activity study on human pharmacokinetic parameters of benzodiazepines using the graph theoretical approach.

The graph theoretical indices for a series of 13 benzodiazepines were calculated using a graph-path topological method. The total molecule, the ring fragments, and combinations of ring fragments were subjected to a quantitative structure-activity analysis using eight pharmacokinetic parameters. The metabolic clearance and the blood-to-plasma concentration ratios were most highly correlated with the graph theoretical indices, with R values of 0.975 and 0.938, respectively. These correlations were found when the diazepine + benzo fragment and phenyl fragment were used to calculate the graph-path indices. Terminal disposition half-life was correlated with the benzo + diazepine fragment, with R = 0.969. Truncating the graph-path codes by eliminating cycles in the total molecule markedly improved the correlation coefficients. When compared to the graph-path indices for the total molecule, the correlation coefficients for the terminal disposition half-life and metabolic clearance data rose from 0.721 to 0.935 and from 0.770 to 0.968, respectively, using the graph-path indices of the truncated molecule. Intrinsic clearance of unbound drug also was poorly correlated with the total molecule (r less than 0.7) but rose significantly using the graph-path indices of the truncated molecule (r = 0.971 and 0.975 for the well-stirred and parallel-tube models, respectively).

Anti-Anxiety Agents↗