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Biomedical subjects

M H Dong

Publications and source records attributed to M H Dong.

15 recordsLinked to original sources

Microcomputer programs for physiologically-based pharmacokinetic (PB-PK) modeling.

Physiologically-based pharmacokinetic (PB-PK) models are each defined as a set of mathematical equations offering a fairly comprehensive time course of a chemical's disposition in several pre-selected anatomical compartments. Each of these compartments has its characteristic blood flow, volume, tissue-blood partition coefficient, and metabolic or clearance rate constants that together are deemed responsible for a chemical's disposition in that region. Numerous investigators have used these models to predict tissue dose in the animal or human body in recent years. This simulation technique, if proven effective, will eventually reduce the large number of animals that are required in the costly classic, in vivo studies to be conducted for chemical disposition or metabolism. This communication offers 2 affordable micro-computer programs which can be used as a practical simulation tool in further exploring the application of PB-PK modeling in chemical risk assessment. These 2 programs are written especially for investigators who prefer to have some appreciation of the required computer simulation first before committing themselves to using more advanced, expensive simulation software packages that are commercially available.

Administration, Cutaneous

Computations of adjusted rates and lifetime risks from occupational cohort data: a program package using FORTRAN and GLIM.

A program package using FORTRAN and GLIM is presented to compute lifetime risks of dying from a particular cause of death for a worker subjected to specific risk exposures using death rates adjusted for selected covariates (risk factors). Calculations of the exposure index and adjusted rates depend on several commonly used procedures. Tests of homogeneity and trend for adjusted rates are provided. Lifetime risks are calculated in two different ways: adjusting or ignoring competing causes of death.

Cohort Studies

Solid phase synthesis of human growth hormone-releasing factor analogs containing a bicyclic beta-turn dipeptide.

Three analogs derived from the N-terminal 29-residue fragment of human growth hormone-releasing factor (hGRF) which contained a bicyclic beta-turn dipeptide (BTD) at 7-8, 8-9, and 9-10 positions were synthesized by solid phase methodology to ascertain if the beta-turns are important for the biological activity of hGRF and also to show the applicability of the BTD unit to solid phase synthesis. All three analogs were obtained in good yield and purity indicating that the BTD unit can be used in the usual condition of solid phase synthesis. The capacity of these analogs to release growth hormone (GH) was tested in an in vitro bioassay using rat anterior pituitary cells. All three BTD-containing analogs showed the same maximal GH secretion with parallel dose-response curves to that of hGRF(1-29)NH2, except their relative potencies were very low.

Amino Acid Sequence

Synthetic analogs of growth hormone-releasing factor with antagonistic activity in vitro.

Analogs of human and rat growth hormone-releasing factor (hGRF and rGRF), related to [D-Arg2]hGRF(1-29)NH2, were synthesized by solid phase methodology. Their capacity to inhibit growth hormone secretion stimulated by hGRF(1-44)NH2 was tested on rat anterior pituitary cells in monolayer culture. Among the analogs of hGRF, [D-Arg2,29,Arg30]hGRF(1-30)NH2 showed the highest antagonistic potency of 3.64 relative to [D-Arg2]hGRF(1-29)NH2 = 1. However, the most potent analog synthesized thus far was [N-Ac-His1,D-Arg2,Ala15]rGRF(1-29)NH2, which showed a relative potency of 27.7.

Amino Acid Sequence

Competing risk analysis of life table data: application to lifetime risk computation.

In this pedagogic note we propose to assess the safety of treatment in a clinical trial, or the effect of risk exposure in a chronic animal study, in terms of two lifetime risks. These risks are computable from life table type data and take into account the effects of competing risks. We first describe their computational procedures in detail to demonstrate the need for their implementation in a computer program. We then illustrate their practical application through use of the data obtained from an actual clinical study.

Health Status Indicators

Microcomputer programs for complex epidemiologic procedures. I. Computation of adjusted rates.

In epidemiological cohort studies one measure of association based directly on incidence or mortality rates is the excess rate. This measure is defined as the excess in these rates between two groups with different exposure experience. At times the computation of these excess rates separately for each of the categories of a risk factor is crucial, as with these rates we can then determine whether the factor exerts a dose-response effect that may implicate a causal relation. Recently an indirect method of standardization has been reported, which computes the excess rates for a factor that are adjusted for the confounding effects of several other factors. The method involves a complex iterative procedure that cannot be carried out easily without the aid of a computer. The objective of this communication is to make available a microcomputer program that has been written to implement this laborious computation. In this pedagogic note the adjustment method is described and the application of the microcomputer program is illustrated.

Epidemiologic Methods

Microcomputer programs for complex epidemiologic procedures. II. Test for equality and trend of adjusted rates.

The microcomputer program presented in Part I of this series (M. H. Dong, Comput. Biomed. Res. 22, 349 (1989)) is useful for computing adjusted excess rates. That program, however, does not provide a means for a quantitative analysis of the adjusted rates computed for the categories of a risk factor. At times it is crucial for us to determine whether after adjustment a factor exerts a dose-response effect that is statistically significant. Recently a hypothesis test for analyzing such an effect has been reported. The test is based on score statistics obtained directly from a product model assumed for the excess rate. The objective of this second part is to continue to make available a microcomputer program that has been written to implement the computation of these score statistics, which likewise entails a complex and lengthy iterative procedure. In this communication the test is described and the application of the microcomputer program is illustrated.

Biometry

A multistage approach to the cohort analysis of lifetime lung cancer risk among steelworkers exposed to coke oven emissions.

A cohort analysis was performed to predict the lifetime lung cancer risk to a US or Canadian nonwhite male steelworker exposed to coke oven emissions. The procedure employed required that the lung cancer mortality (used for risk assessment) be estimated by addition of the excess to the background rates. The age-specific excess rates were obtained following selection of the proper excess risk function as implied by the multistage theory of carcinogenesis. A quantitative approach based on model fitting was used for selection of the excess risk function. The results show no evidence that coke oven emissions have a late stage carcinogenic effect. The indication that the agent acts as an initiator is moderate to weak. The number of carcinogenic stages involved was estimated to be four. Based on the assumption that exposure was set at a high concentration for 40 years with a starting age of 20 years, it was estimated that the lifetime risk through age 85+ years for a hypothetical US or Canadian nonwhite male oven worker could be as high as 0.40. This represents a 15-fold increase of the baseline risk.

Adult

Synthesis and in vitro bioactivity of human growth hormone-releasing factor analogs substituted with a single D-amino acid.

Fifty-four analogs of human growth hormone-releasing factor (hGRF) substituted with a single D-amino acid were synthesized by solid phase methodology. Their capacity to release growth hormone was tested on rat anterior pituitary cells in monolayer culture. Among the series of 28 analogs, which had the amino acid at each position of hGRF (1-29)NH2, except glycine at position 15, substituted by the corresponding D-isomer, [D-Ala2]-, [D-Asp3]-, [D-Asn8]-, [D-Tyr10]-, [D-Asp25]-, [D-Met27]-, [D-Ser28]-, and [D-Arg29]hGRF(1-29)NH2 were as potent as hGRF(1-29)NH2, while [D-Ile5]-, [D-Phe6]-, [D-Thr7]-, and [D-Val13]hGRF(1-29)NH2 showed quite low potencies. Effects of substitution with other D-amino acids in positions 2,3,8,9,10 and 11 were also studied. In most cases, the resulting analogs showed decreased potency, but still retained high intrinsic activity. Only [D-Arg2]hGRF(1-29)NH2 showed very low intrinsic activity and some antagonistic property.

Animals

Determination of urinary thiamin by the thiochrome method.

A modified procedure for the determination of thiamin in human urine by the thiochrome fluorescent method was used to examine the effects of three oxidizing agents. Urinary thiamin values obtained with the use of HgCl2 as the oxidizing agent were lower than those found with the use of either BrCN or K3Fe(CN)6. This may be due to a difference in the reactivity of interfering compounds with the specific oxidizing agent used. Recovery values were acceptable for each of these three oxidizing agents, although BrCN appears to be slightly superior. In addition to the recovery values, the linear response for the thiamin standards used in this study supports the use of a smaller resin column for the pretreatment of urine samples; this was found to be more economical and convenient to use.

Chemical Phenomena

Influence of dietary thiamine on pulmonary, renal, and hepatic drug metabolism in the mouse.

The effect of dietary thiamine status on the in vitro metabolism of drugs in mouse lung, kidney, and liver was investigated. Administration of a diet deficient in thiamine resulted in a tendency toward an elevated hepatic and pulmonary microsomal content of cytochrome P-450 and elevated activities of aminopyrine demethylase and aniline hydroxylase compared to those in similar mice fed 5 or 20 mg of thiamine per kilogram of diet. There was also a tendency for renal drug metabolism to be inversely related to dietary thiamine status. The effect of dietary thiamine on the induction of drug metabolism by phenobarbital in hepatic and extrahepatic tissues was also studied. In general, there was little to no difference in the percent induction as a function of thiamine status. These studies suggest that dietary thiamine is an important determinate in drug metabolism, and the metabolism varies with different tissues.

Animals

Thiamin, riboflavin, and vitamin B6 contents of selected foods as served.

Information of thiamin, riboflavin, and vitamin B6 contents of eighty-one food items is presented. The data represent over two hundred samples collected from serving lines in dining halls of two military installations. Ninety per cent of the vitamin B6 values and 35 per cent of the thiamin and riboflavin diata are not available in the current literature. In contrast to most previously published data, the emphasis in this study was on the vitamin contents of prepared food items on an "as served" basis.

Cooking

Results with commercial radioassay kits compared with microbiological assay of folate in serum and whole-blood.

We compared results with three commercial folate radioassay kits [Bio-Rad, New England Nuclear (NEN), and RIA Products] with those by microbiological assay for more than 200 samples of human serum and whole blood. All but one kit (NEN) compared favorably with the microbiological assay for serum samples, although there were notable diagnostic discrepancies. Two kits (NEN and Bio-Rad) were tested on whole-blood samples; both yielded values significantly higher than those by microbiological assay. The frequency distributions of erythrocyte folate data differed strikingly between the two kits; the NEN method yielded a much narrower range of normal values than did either the Bio-Rad or the microbiological assay. Radioassay kits appear to be suitable diagnostic agents for serum folate, if the behavior of a particular kit is investigated thoroughly before its routine use. However, the diagnostic value of radioassays of erythrocyte folate needs to be validated.

Biological Assay