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Biomedical subjects

A M Clark

Publications and source records attributed to A M Clark.

At least 127 records · Page 7Linked to original sources
PubMed1990

The metabolism of CGP-291: the use of microorganisms as models of mammalian metabolism.

CGP-291 is an investigational antiprotozoal agent with unknown metabolism. Microbial systems were utilized, as a model of mammalian metabolism, to predict the oxidative metabolic pathway of this nitroimidazole. Large-scale fermentation of CGP-291 with Beauvaria bassiana produced two major metabolites, IV and V. Structures of both were elucidated by comparing spectral data of metabolites to that of the starting material. The presence of two minor monohydroxylated metabolites was verified using LC-MS.

Chromatography, Thin Layer↗
PubMed1990

3-Methoxysampangine, a novel antifungal copyrine alkaloid from Cleistopholis patens.

Further examination of the active ethanolic extract of the root bark of Cleistopholis patens by using bioassay-directed fractionation resulted in the isolation of a new alkaloid, 3-methoxysampangine (compound I), together with three known alkaloids, eupolauridine (compound II), liriodenine (compound III), and eupolauridine N-oxide (compound IV). The proposed structure of compound I was based on its physicochemical properties and spectral data. 3-Methoxysampangine exhibited significant antifungal activity against Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans. This is the first report of the isolation of liriodenine (compound III) from the root bark of C. patens.

Alkaloids↗
PubMed1990

Effect of treatment with and subsequent withdrawal of exogenous porcine somatotropin on growth and reproductive characteristics of gilts.

Two experiments were conducted to examine responses of gilts to treatment with and withdrawal of exogenous porcine somatotropin (PST). In Exp. 1, 36 prepubertal gilts (79.7 +/- .9 kg; 159.1 +/- .7 d) were allotted randomly to receive daily either 0 micrograms PST (C) or 70 micrograms PST/kg initial BW for either 21 (PST-3) or 42 d (PST-6). Gilts were examined for estrus daily by a mature boar starting on d 22 and continuing for up to 50 d. Gilts that expressed estrus were mated and removed from treatment. PST-treated gilts had higher ADG (P less than .01) and lower feed/gain (P less than .02) than C gilts. Following initiation of boar exposure, C gilts (mean interval to estrus = 2.0 d) exhibited estrus earlier than PST-3 (24.8 d) and PST-6 (24.0 d) gilts (P less than .07); however, only two C gilts were observed in estrus compared with six PST-3 and six PST-6 gilts. In Exp. 2, 40 prepubertal gilts (72.6 +/- 1.0 kg; 141.1 +/- .7 d) were allotted randomly to receive daily either 0 mg PST (C) or 5 mg PST for 30 d. On d 31, half the gilts were comingled with unfamiliar penmates and examined for estrus daily by a mature boar for up to 45 d. Estrual gilts were removed from treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Effects of dose, age, inhibition of metabolism and elimination on the toxicokinetics of 2-butoxyethanol and its metabolites.

Acute exposure to 2-butoxyethanol (BE) causes dose- and age-dependent hemolytic anemia in rats. Recently, we have shown that butoxyacetic acid (BAA) is the proximate hemolytic agent and that inhibition of alcohol or aldehyde dehydrogenases protected rats against BE-induced hemolytic anemia. In the present investigations, the kinetics of 14C-BE metabolism and clearance were studied in control adult (3-4 months old) and old (12-13 months old) male F344 rats and in adult male F344 rats treated with pyrazole, cyanamide or probenecid. Our results showed that the area under the curve (AUC), maximum plasma concentration (Cmax) and systemic clearance (Cls) of BE were dose-dependent. In contrast, there was no effect of dose on half-life (T1/2) or volume of distribution (Vd) of BE. These results also showed that there was no age effect on T1/2, Vd or Cls of BE. However, Cmax and AUC of BE increased as a function of age. Also, analysis of variance indicated no significant interactions (P less than or equal to .05) between dose and age in relation to BE kinetics. As expected, inhibition of BE metabolism by pretreatment of rats with pyrazole or cyanamide resulted in a significant increase in the T1/2 and AUC of BE, whereas it caused a significant decrease in the Cls. Furthermore, pyrazole had no effect, whereas cyanamide had decreased Vd of BE. Analysis of the toxicokinetic parameters of BAA revealed that T1/2, AUC and Cmax of BAA were directly related to the age of the rats and the dose of BE administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1989

Comparative dermal absorption of 2,3,7,8-tetrachlorodibenzo-p-dioxin and three polychlorinated dibenzofurans.

Polychlorinated dibenzodioxins (PCDDs) and dibenzofurans (PCDFs) are toxic environmental contaminants which have the potential to accumulate in human tissues. In order to examine the potential for systemic exposure following dermal exposure, the absorption, distribution, and elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentachlorodibenzofuran (1PeCDF), and 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF) were evaluated in male F344 rats. TCDD (0.00015, 0.001, 0.01, 0.1, 0.5, and 1.0 mumol/kg) and the three PCDFs (0.1, 0.5, and 1.0 mumol/kg) were applied to a preclipped region on the back of the rat and covered with a perforated cap. The rats were held in individual metabolism cages for 3 days. In animals administered 0.1 mumol/kg, the absorption of TCDF was greater than that of 4PeCDF, 1PeCDF, and TCDD. Relative absorption (percentage of administered dose) declined with increasing dose while the absolute absorption (microgram/kg) increased nonlinearly with dose. Absorption of TCDF at 0.1 mumol/kg was 48% of the administered dose which was significantly greater than that of the other compounds. At this dose, absorption of 4PeCDF was greater than that of TCDD. Absorption at the higher doses was similar for all four compounds. Maximum relative absorption of TCDD (approximately 40% of the administered dose) was obtained at 0.001 and 0.00015 mumol/kg. Major tissue depots for these four chemicals included liver, adipose, skin, and muscle tissue; however, the liver:fat ratio for 4PeCDF was approximately fourfold higher than that for the other three compounds. When normalized to 100% of dose absorbed, the distribution of 4PeCDF-derived radioactivity in liver and adipose tissue was similar to that previously observed after oral and iv administration. In animals administered 0.1 mumol TCDF or 1PeCDF/kg, 56 and 32% of the respective absorbed dose was excreted as polar metabolites within 3 days. Very little of the absorbed dose of either TCDD (approximately 10%) or 4PeCDF (approximately 2%) was eliminated. Results indicate that the dermal absorption of these compounds is incomplete and that systemic toxicity following acute dermal exposure to levels found in the environment is unlikely.

Administration, Cutaneous↗
PubMed1989

Retinoic acid and 2,3,7,8-tetrachlorodibenzo-p-dioxin selectively enhance teratogenesis in C57BL/6N mice.

TCDD is one of the most toxic man-made compounds and an extremely potent teratogen in mice. Many of its toxic symptoms resemble those seen during vitamin A deficiency. Vitamin A and its derivatives, such as alltrans-retinoic acid (RA), are also teratogenic in mice, as well as many other species. Both TCDD and RA produce cleft palate in susceptible strains of mice. However, while TCDD produces hydronephrosis, RA does not, and TCDD does not produce limb bud defects while RA does. To determine whether TCDD and RA would enhance or antagonize the teratogenic effects of the other compound, C57BL/6N dams were treated po on Gestation Day (gd) 10 or 12 with 10 ml corn oil/kg containing TCDD (0-18 micrograms/kg), RA (0-200 mg/kg), or combinations of the two chemicals. Dams were killed on gd 18 and toxicity and teratogenicity assessed. Coadministration of TCDD and RA had no effect on maternal or fetal toxicity beyond what would be expected by either compound alone. Cleft palate was induced by RA at lower doses on gd 10 than on gd 12, but by TCDD at lower doses on gd 12 than on gd 10. Sensitivity to TCDD-induced hydronephrosis was similar on both gd 10 and 12. The limb bud defects were only observed when RA was administered on gd 10, not when given on gd 12. No other soft tissue or skeletal malformations were related to administration of TCDD or RA. No effect of TCDD was observed on the incidence or severity of limb bud defects induced by RA, nor did RA influence the incidence or severity of hydronephrosis induced by TCDD. However, the incidence of cleft palate was dramatically enhanced by coadministration of the xenobiotic and vitamin. On both gd 10 and 12, the dose-response curves for cleft palate induction were parallel, suggesting some similarities in mechanism between the two compounds. However, combination treatment resulted in a synergistic response that varied with the stage of development and was tissue specific.

Abnormalities, Drug-Induced↗
PubMed1989

Reproductive and growth responses of gilts to exogenous porcine pituitary growth hormone.

Forty gilts (mean wt = 72 kg) were administered daily either vehicle (C = control) or 70 micrograms porcine growth hormone (pGH)/kg BW. After 30 d of treatment, eight gilts per group (Exp. 1) were slaughtered and blood, uteri and ovaries were collected. Follicular fluid (FFl) was collected and granulosa cells (GC) were cultured. The remaining gilts (Exp. 2) were treated for up to 35 additional days and examined twice daily for estrus. Estrusal gilts were removed from the experiment. Noncyclic gilts (n = 9 of 12 pGH; n = 4 of 12 C) were slaughtered on d 66 and their ovaries were examined. Ovarian weights were not different for pGH and C gilts in either Exp. 1 (P greater than .1) or Exp. 2 (P = .09). Uterine weights were greater for pGH-treated than for C gilts (P less than .007) in Exp. 1, but not in Exp. 2. Concentrations of estradiol (E2) in plasma and FF1 and of progesterone (P) in plasma and FF1 were not different for pGH and C gilts. Concentrations of insulin-like growth factor-I (IGF-I) in FF1 and in serum were greater for pGH than for C gilts (P less than .01). Concentration of P in serum-free medium of cultured GC was lower for GH than for C (P less than .05) in the presence or absence of gonadotropins in Exp. 1. The FSH-stimulated secretion of P was also lower for GC of pGH-treated gilts in Exp. 2, indicating a failure of GC to differentiate in culture. Only one pGH gilts in Exp. 2 manifested estrus, compared with seven C gilts (P less than .025). In Exp. 1, ADG was higher (P less than .03) and feed/gain lower (P less than .07) for pGH gilts. Longissimus muscle area (LMA) was not different (P = .19) between groups. Backfat thickness (BF) was lower (P less than .005) in pGH than in C in both Exp. 1 and 2. We conclude that exogenous pGH increased growth rate, improved feed efficiency and altered carcass traits in gilts. However, these effects were associated with impaired ovarian development of prepubertal gilts and a low incidence of estrus.

Animals↗
PubMed1987

In vivo efficacy of antifungal oxoaporphine alkaloids in experimental disseminated candidiasis.

The efficacy of three antifungal oxoaporphine alkaloids, liriodenine, liriodenine methiodide, and oxoglaucine methiodide, was determined in a mouse model of disseminated candidiasis. Mice infected with a lethal dose of Candida albicans NIH B311 were administered varying doses of each drug intraperitoneally or intravenously 7 hr postinfection. Reductions in the number of colony-forming units (CFU) recovered per milligram of kidney tissue were observed in drug-treated animals compared to vehicle-treated control mice. Significance was determined by the Wilcoxon nonparametric rank sum test. Intravenous administration of both liriodenine and liriodenine methiodide resulted in a significant reduction in the number of recovered CFU, while there was no significant response to treatment with oxoglaucine methiodide.

Animals↗
PubMed1986

Comprehensive antenatal care and education of young adolescents: beneficial effects on pregnancy and outcome.

Fifty-five consecutive adolescents, aged sixteen years or under at delivery, were cared for at a special antenatal clinic by one nurse and doctor and educated about pregnancy, health and reproduction. A philosophy of self-care and respect was engendered in these adolescents by the nurse and doctor. The effects of such care on the pregnancy and outcome were compared with a group of 55 consecutive patients (of similar age and background) cared for by the general clinic immediately prior to the introduction of the special care clinic. Urinary tract infection, anaemia, premature labour, fetal distress, operative delivery, primary postpartum haemorrhage, low birth weight infants, infant admission rate to neonatal unit and artificial feeding, were all significantly less common in the special clinic patients who also rarely missed outpatient appointments.

Adolescent↗
PubMed1986

Microbial metabolism of bornaprine, 3-(diethylamino)propyl 2-phenylbicyclo[2.2.1]heptane-2-carboxylate.

Metabolism studies of the anticholinergic drug, bornaprine [3-(diethylamino)propyl 2-phenylbicyclo[2.2.1]heptane-2-carboxylate, an epimeric mixture], in rats, dogs, and humans have been conducted previously, but the identities of the metabolites were not established. Using an in vitro microbial system to study the metabolism of bornaprine resulted in the isolation of four metabolites whose structures were rigorously established using spectroscopic techniques, especially 13C NMR. The four metabolites found were hydroxylated at C-5 or C-6 in the bicyclic ring.

Antiparkinson Agents↗
PubMed1986

Novel sulfur-containing microbial metabolite of primaquine.

Microbial metabolism studies of the antimalarial drug primaquine, using Streptomyces roseochromogenus (ATCC 13400) have produced an N-acetylated metabolite and a methylene-linked dimeric product, both of which have been previously reported, and a novel sulfur-containing microbial metabolite. The structure of the metabolite as a sulfur-linked dimer was proposed on the basis of spectral and chemical data. The molecular formula C34H44N6O4S was established from field-desorption mass spectroscopy and analytical data. The 1H- and 13C-nuclear magnetic resonance spectral data firmly established that the novel metabolite was a symmetrically substituted dimer of primaquine N-acetate with a sulfur atom linking the two units at C-5. The metabolite has been shown to be a mixture of stereoisomers which can equilibrate in solution. This observation was confirmed by microbial synthesis of the metabolite from optically active primaquine.

Chemical Phenomena↗
PubMed1984

Excretion, distribution, and metabolism of primaquine in rats.

The metabolism of the 8-aminoquinoline antimalarial drug, primaquine (I) was studied using rats. The drug was administered intravenously, intraperitoneally, and orally, and blood samples were collected at various time intervals. Primaquine was metabolized by oxidative deamination to give 8-(3-carboxy-l- methylpropylamino )-6- methoxyquinoline (III). The plasma levels of both primaquine and its metabolite were determined by HPLC. The tissue distributions of radioactive primaquine after intravenous, intraperitoneal, and oral administrations were also determined. Significant concentrations of radioactivity were found in the lungs, adrenal glands, and liver. In addition, a significant portion of the dose was found to be excreted in the feces within 24 h after administration of the drug by either of the three routes.

Administration, Oral↗
PubMed1984

Microbial transformation of primaquine by Candida tropicalis.

The microbial metabolism of primaquine, a 6-methoxy-8-aminoquinoline antimalarial agent, was investigated. The yeast Candida tropicalis was found to convert primaquine to the previously reported N-acetylated derivative. On continued incubation of C. tropicalis in the presence of the N-acetylated derivative, a minor dimeric metabolite was formed. The proposed structure of the metabolite was based primarily on the analysis of its spectroscopic properties (1H and 13C nuclear magnetic resonance spectra and field-desorption mass spectrum). The structure of the metabolite was proven by direct comparison with an authentic sample of the minor dimeric metabolite prepared by treatment of the N-acetylated derivative with formaldehyde in the presence of formic acid in methanol.

Acetylation↗
PubMed1984

Production of a novel dimeric metabolite of primaquine by Streptomyces rimosus.

Primaquine, an 8-amino-6-methoxyquinoline antimalarial agent, was subjected to metabolic studies with microorganisms. Streptomyces rimosus converted primaquine to the previously reported N-acetyl derivative. Continued incubation of S. rimosus resulted in the formation of a minor dimeric metabolite. The structure of the minor dimeric metabolite was proposed based primarily on its spectral data (1H and 13C nuclear magnetic resonance spectra and mass spectrum). The proposed structure of the metabolite was confirmed by synthesis of the dimer by treatment of primaquine-N-acetate with potassium ferricyanide in a biphasic chloroform-aqueous sodium bicarbonate system with a phase-transfer catalyst. Since (+/-)-primaquine was used for both the microbial transformation and synthesis, a diastereomeric mixture of symmetrical dimers was formed in each case. The metabolite sample was identical to the synthetic sample, as shown by direct comparison (thin-layer chromatography, co-thin-layer chromatography, high-pressure liquid chromatography, co-high-pressure liquid chromatography, 1H nuclear magnetic resonance spectra, and mass spectrum).

Chromatography, High Pressure Liquid↗
PubMed1983

Demethylation of imipramine by enteric bacteria.

The ability of a number of aerobic and anaerobic bacteria to N-demethylate imipramine (I) to desipramine (II) has been investigated. Of the bacteria investigated, almost half were known inhabitants of the human GI tract. More than half of the enteric bacteria studied were capable of N-demethylating imipramine (I) to desipramine (II) to some extent in at least one medium. It was found that the medium in which the organism was grown had a significant effect on the N-demethylase activity observed.

Bacteria, Aerobic↗
PubMed1983

Behavior of life-shortening genes in genetic mosaics of Drosophila melanogaster.

Genetic mosaics of two life-shortening (adult lethal) genes in Drosophila melanogaster were analyzed with respect to the location and extent of external tissues which exhibited the life-shortening genotype. It was hoped by this method to localize the site of action of each gene. For one mutant, AL 2, no correlation was found between the site of the adult lethal genotype and the adult life span of the mosaic fly. However, there was a direct correlation between the total amount of tissue exhibiting the adult lethal genotype and length of adult life. For the other mutant, AL 4, a more direct correlation could be made between location of adult lethal tissue and a shortened adult life span. Its focus was oriented toward the cephalic region. Like AL 2, it exhibited a direct correlation between total adult lethal tissue and length of adult life. The importance of this method of genetic analysis for the understanding of the action of life-shortening genes is discussed.

Animals↗