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H Boxenbaum

Publications and source records attributed to H Boxenbaum.

At least 37 records · Page 2Linked to original sources
PubMed1988

Physiological pharmacokinetic models: some aspects of theory, practice and potential.

Models are intellectual constructs that pattern selected relationships among the elements of one system to correspond in some way to elements of a second system. In pharmacokinetics, physiological models provide a clearly articulated, rational, explanatory basis for the integration of empirical data; they do this by partitioning the biological system into relevant components (tissues, organs, etc.) and linking them together through the circulatory system. Unlike conventional mammillary compartment models, there is a clear correspondence between model system elements and physiological entities. By virtue of their high degree of physical and biochemical relevance, these models can help provide deep insight into structure, function and mechanism. Pharmacokinetic (and potentially pharmacodynamic) response-time relationships can thus be understood in terms of interconnections and behavior of constituent subsystems. At their worst, these models provide stale or infertile views of reality and thus frustrate and alienate us with the triviality of their insights. At their best, they allow us to understand the accumulation of thought in pharmacokinetics and pharmacodynamics, and help with the integration of data and improvement of experimental design.

Animals↗
PubMed1988

A Gompertz age-specific mortality rate model of aging, hormesis, and toxicity: fixed-dose studies.

Based on the proposition that the logarithm of age-specific mortality rate (Gompertzian) is a linear measure of the mean intensity of injury for a homogeneous mammalian population in a uniform environment, a model was developed which characterizes mortality experience resulting from both toxic and hormetic actions. The mortality-reducing component (longevity hormesis) was assumed to be reversible; toxic effects, on the other hand, were assumed to accumulate irreversibly. Following chronic low-dose administration of selected toxic substances, it was demonstrated (in certain cases) that longevity hormesis could enhance lifespan, even in the presence of concomitant toxicity. Even when toxicity was evident, hormesis could ameliorate some of the mortality. The assumption that high-dose chronic toxicity studies can generate realistic estimates of risk at low doses is challenged.

Aging↗
PubMed1988

Hormesis, Gompertz functions, and risk assessment.

A historical survey of the literature indicates that benefits derived from low doses of toxic substances have been reported over many centuries. Hippocrates, Paracelsus, Arndt, Schulz, and Hahnemann (founder of homeopathy) have all reported that low doses of toxic substances may be "stimulatory" or otherwise beneficial. Assessment of mortality data from modern-day bioassay studies indicates that low-dose animal exposure to a variety of toxic agents can, through an unknown mechanism, also induce beneficial changes which promote health and prolong life (longevity hormesis). This nonspecific and apparently reversible phenomenon has been modeled kinetically through use of age-specific mortality rate and a generalized Gompertz function; the basic assumption is that mortality in an interval is a function of the weighted sum of intensities of physiologic injury during that interval. It was assumed that longevity-enhancing hormetic reduction in population injury may be decremented from life-shortening injury produced through the aging process and concomitant toxicity. At low exposure levels, a net reduction in age-specific mortality rate can sometimes be observed. The implications for risk assessment are significant. It is tacitly assumed in generating virtually all estimates of risk that toxic manifestations observed at higher doses are the sole effects elicited at lower doses. This appears to be qualitatively incorrect.

Animals↗
PubMed1987

Publication rates of pharmaceutical scientists: application of the waring distribution.

The publication frequency characteristics of 1984 Journal of Pharmaceutical Sciences reviewers were investigated to provide a perspective on the state of the pharmaceutical literature, its dynamics and some of its features. The average number of per capita total publications in 1984 was 3.56, with 26.9% of the reviewers not publishing at all during the year. The average number of per capita first-authorship publications in our survey was 1.17; the percentage of reviewers not publishing a paper as senior author increased to 50.4%. The so-called elite group of scientists--that is, the top group of scientists who publish 50% of the papers--consisted of 12.8% and 11.7% of the sample for total and senior-authored papers, respectively. Waring distributions were shown to adequately characterize the data. The conceptual scheme leading to the Waring distribution assumes three fundamental characteristics: (1) a "self-reproducing" property, viz., the rate of new entrants (potential publishing scientists) is proportional to community size; (2) a "cumulative advantage" or "success breeds success" property, viz., more highly published scientists; are more likely to publish their next article than are less-published scientists; and (3) a uniform "leakage" property, viz., all scientists, regardless of publication rates, have equal likelihood of dropping out of the publication community.

Models, Theoretical↗
PubMed1986

Time concepts in physics, biology, and pharmacokinetics.

Three major types of time relativity are discussed: physical, biological, and psychological. Physical relativity illustrates how the same distant event may occur in the past of one observer and in the future of another. Moreover, space and time variables are not viewed in isolation from one another, but rather are blended together into a static, four-dimensional "block universe." Biological relativities arise through coordinate transformations of physical time-scales such that relevant processes become invariant in space-time. Because pharmacokinetic processes are integrated through a common, highly coordinated series of systems, relations between mammalian species may be probed through empiric allometric coordinate transformations. Psychological time relativity deals with a creature's awareness of its own duration and location within a restricted range of reality; it involves the transformation of perceived sequences (stimuli) into durations.

Animals↗
PubMed1985

Pharmacokinetic interaction of disulfiram and antidepressants.

Intravenous imipramine and desipramine were administered to two detoxified alcoholics before and during disulfiram treatment. Tricyclic pharmacokinetic parameters, determined from plasma samples over 48 hours, indicated decreased total body clearance, increased elimination half-life, and higher peak plasma levels during disulfiram treatment.

Adult↗
PubMed1984

Alcoholism and mortality kinetics.

Gompertz plots of age-specific mortality rates versus age were compared in alcoholics and the general population. Alcoholism had a dual effect, apparently increasing vulnerability to death while slowing the aging rate (longevity is a two-dimensional function). It was hypothesized that the apparent slowing of the aging rate was an artifact, resulting from population heterogeneity in vulnerability. It is recommended that in future studies, attempts be made to categorize alcoholic subjects with respect to alcoholic habit. Longitudinal studies would also be useful.

Adult↗
PubMed1983

Interspecies pharmacokinetic scaling and the Dedrick plots.

Interspecies variations in pharmacokinetics are frequently the consequence of organisms living in different time domains. Whereas species' parameter values differ when referenced to chronological time, scaling of data with respect to active mass (ergosomes) and to ideal (mathematical) pharmacokinetic space time (mesochrons, kallynochrons, or apolysichrons) removes the astronomical time dependency. A theory of pharmacokinetic similarities is presented which states that both physiological and pharmacokinetic processes are biologically interrelated and governed by a master synchronization mechanism; consequently interspecies pharmacokinetic events frequently may be expressed as invariant values; e.g., hexobarbital disposition half-life is approximately the duration of 1,680 gut beats (time standard) regardless of mammalian species. The depletion theory hypothesis of aging that each mammalian organism of set mass is genetically endowed with a set total energy or metabolism (lebenszeitliche Kraft) is found to be adaptable at the microscopic pharmacokinetic level; thus it is hypothesized that each mammalian organism has a genetically determined and finite quantity of phase I hepatic pharmacokinetic stuff (activity) to expend during a lifetime and that this pharmacokinetic stuff (ml cleared X kg-1 X maximum life-span potential-1) is a constant. The rate at which this pharmacokinetic stuff is utilized (comparative pharmacokinetics) is presumed to be regulated by a pharmacokinetic clock, which may undergo either acute or chronic perturbations having either a genetic or environmental origin.

Animals↗
PubMed1982

Literature growth in pharmacokinetics.

The literature growth in pharmacokinetics and bioavailability between the years 1964 and 1980 is analyzed. During much of this period, the literature doubled approximately every 1.6 years. However, during the period 1978-1980, little or no growth was observed. During the period 1950-1967, the total chemical literature increased exponentially with a half-life of 8.28 years; between 1968 and 1980, the half-life was 12.4 years. Thus, the pharmacokinetic literature increased at a much more rapid pace than did the total chemical literature in general. The subject of growth is considered in a general context, particularly as influenced by psychological, sociological, political, and economic factors. It is concluded that while mathematical functions may adequately describe past literature trends, they have little if any utility in predicting future trends in specific research areas such as pharmacokinetics.

Abstracting and Indexing↗
PubMed1982

Comparative pharmacokinetics of benzodiazepines in dog and man.

The pharmacokinetic parameters disposition half-life, metabolic clearance, volume of distribution, intrinsic clearance of unbound drug, and (distributive tissue volume/unbound fraction in tissue) were compared for 12 benzodiazepines in dog and man. With the exception of volume of distribution, statistically significant correlations were obtained when parameters were plotted on a double logarithmic grid. In general, benzodiazepines were metabolized more rapidly and exhibited greater tissue distribution in dog than in man. The variability in parameters was such, however, as to make extrapolations from one species to another subject to considerable error.

Animals↗
PubMed1982

Publication trends in the drug dependence literature.

Publications dealing with psychotropic drug use and dependence were analyzed for the years 1960-1980 using the numbers of articles cited in each yearly edition of Cumulated Index Medicus. The following headings were reviewed: drug abuse, drug dependence, alcoholism, smoking, heroin addiction, cannabis, cannabinoids, cocaine, phencyclidine, lysergic acid diethylamide, diazepam, and meprobamate. The number of citations for a given year was used to calculate the percentage of the literature for that year which fell under each of those headings. In general, it appears that the growth of the scientific literature included under many of these headings has been more rapid than the overall growth of the literature.

Humans↗
PubMed1980

Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance: extrapolation of data to benzodiazepines and phenytoin.

The literature was reviewed to obtain data from 11 mammalian species on liver weight, hepatic blood flow, and antipyrine intrinsic clearance. It was demonstrated that liver weight and hepatic blood flow in all species could be readily related to body weight by a simple equation. Additionally, hepatic blood flow in all species was directly proportional to liver weight. With the exception of man, antipyrine intrinsic clearance was also directly proportional to liver weight. Man's intrinsic clearance was approximately one-seventh of that which would be predicted from other species. Data on benzodiazepines and phenytoin showed a similar pattern.

Animals↗
PubMed1978

(-)-2-Hydroxy-n-cyclopropylmethylmorphinan: radioimmunoassay and phamacokinetic profile.

The pharmacokinetic profile of (-)-2-hydroxy-N-cyclopropylmethylmorphinan (HCMM), a narcotic antagonist and analgesic, has been evaluated in man following administration of 25 to 50 mg of the drug orally and 10 to 15 mg intramuscularly. A specific radioimmunoassay procedure was developed for the determination of HCMM in plasma and urine. The drug had a mean "apparent" elimination half-life in plasma of about 11 hr following both routes of administration. A mean of 47% of the oral dose was excreted in the urine as unconjugated and conjugated HCMM and only 5% of the dose was excreted as intact HCMM. In one subject studied, the plasma levels of conjugated HCMM were as much as 5-fold higher than the levels of unconjugated drug. Although there was considerable intersubject variability following both routes of administration, the overall pharmacokinetic parameters suggest that oral and intramuscular doses are bioequivalent.

Administration, Oral↗
PubMedDate not supplied

Scaling of antipyrine intrinsic clearance of unbound drug in 15 mammalian species.

The intrinsic clearance of unbound drug (CLuint) for antipyrine in 15 mammalian species was characterized by an equation of the form, CLuint = theta 1 (body weight) theta 2 (brain weight) theta 3, where thetas are constants. Maximum lifespan potential in mammals can also be characterized by an equation of this form. It is suggested that the set of genetic mechanisms regulating longevity and other constitutional characteristics in species is also linked to rates of drug metabolism. The ability to scale interspecies data in pharmacokinetics is taken as an expression of this design principle.

Animals↗