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Biomedical subjects

W Slikker

Publications and source records attributed to W Slikker.

At least 109 records · Page 6Linked to original sources
PubMed1991

Phenytoin teratogenicity and midgestational pharmacokinetics in mice.

Mice of the A/J and C57BL/6J (C57) strains were dosed with phenytoin (PHT) every 48 hr throughout pregnancy by gastric intubation to test the hypothesis that maternal plasma PHT concentration may be the significant factor in determining PHT reproductive and developmental toxicity. Serial serum samples were obtained from each mouse from gestation day (GD) 10-GD 12 for determination of individual dam PHT pharmacokinetics. Maximum PHT concentration and PHT AUC (area under-the-time-concentration curve) were regressed to laparotomy and fetal evaluation endpoints to determine whether significant association existed. Although serum PHT concentrations exceeded levels associated with teratogenicity (greater than 10 micrograms/ml), few major malformations were induced in either strain. However, in the A/J strain, there was a significant increased incidence of hydrocephaly and open eyelid. Regression of pharmacokinetic parameters with embryo and maternal endpoints indicated significant associations between gestational weight gain and maximum concentration measured (Cmax) or AUC in both strains. This association was also found for fetal weight in the C57 strain. In the A/J strain, the induction of decreased ossification of the sternebrae was also associated with maternal PHT concentration; however, linear regression of hydrocephaly and open eyelid to PHT concentration was not statistically significant. These results suggest that maternal plasma PHT concentration may be a quantifiable determinant of certain aspects of PHT developmental toxicity in the mouse.

Abnormalities, Drug-Induced↗
PubMed1991

Influence of dose and pharmaceutical formulation of vitamin A on plasma levels of retinyl esters and retinol and metabolic generation of retinoic acid compounds and beta-glucuronides in the cynomolgus monkey.

Retinoid concentrations were analyzed in plasma of nonpregnant female cynomolgus monkeys after oral administration of retinol or retinyl acetate at doses of 2, 10, or 50 mg (as retinol) per kilogram body weight dissolved in acetone/soybean oil (1/9) or acetone/Tween 20/water (1/5/4). All-trans-retinoic acid, 13-cis-retinoic acid, all-trans-4-oxoretinoic acid, and 13-cis-4-oxoretinoic acid as well as the conjugates of retinol and all-trans-retinoic acid with beta-D-glucuronic acid represented major polar plasma retinoids after high doses of vitamin A. The relative bioavailability of vitamin A as well as the biotransformation to more polar retinoids was independent of the molecular form of vitamin A (retinol or retinyl acetate) used for dosing. After administration of 2 mg/kg and, in particular, after a 10 mg/kg dose, the metabolic formation of polar retinoids in plasma was much more extensive with the detergent-based vehicle compared to the oil-based vehicle. At 50 mg/kg, comparable metabolism was observed for both forms. Polar metabolites of retinol were increased in a more than linear fashion with the detergent-based vitamin A preparations between 2 and 10 mg/kg and with the oil-based preparations between 10 and 50 mg/kg. Since retinoic acid compounds have previously been shown to be potent teratogens in various animal species and humans, their metabolic formation may be of significance for the teratogenic activity of high doses of vitamin A. In addition to the dose, the pharmaceutical preparation of vitamin A could therefore be a major determinant of the developmental toxicity of vitamin A.

Animals↗
PubMed1991

Acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on monoamines in rat caudate.

Extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and serotonin (5-HT) were assayed in the caudate of freely moving rats using microdialysis and high performance liquid chromatography with electrochemical detection (HPLC-EC) to detect changes in their release. Dialysates were assayed at 20-minute intervals for four hours after an intraperitoneal (IP) injection of MDMA (10 mg/kg). In a separate study to determine MDMA effects on total caudate levels of the above neurochemicals, animals were injected IP with MDMA (10 mg/kg) and then sacrificed at 20, 60, 120 and 180 minutes after treatment. Brains were quickly removed, and caudate nuclei were dissected for neurochemical analysis using HPLC-EC. MDMA elicited an amphetamine-like increase in DA release, followed by an increase in DA content. DOPAC and HVA were both reduced in homogenate. 5-HT release was also increased, followed by a drop in caudate homogenate levels by three hours. DA extracellular content was 686% of control at 80 minutes; caudate homogenate levels were 122% at 120 minutes. 5-HT extracellular release was 123% at 20 minutes, then decreased thereafter. It is concluded that the acute effect of MDMA on caudate is at least as great on the DA as it is on the 5-HT system.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Marijuana exposure and pulmonary alterations in primates.

As part of a large multidisciplinary study, we examined lungs from 24 periadolescent male rhesus monkeys that were sacrificed seven months after daily marijuana smoke inhalation of 12 months duration. Animals were divided into four exposure groups: A) high-dose (one marijuana cigarette 7 days/week), B) low-dose (one marijuana cigarette 2 days/week and sham smoke 5 days/week), C) placebo (one extracted marijuana cigarette 7 days/week), and D) sham (sham smoke 7 days/week). Lungs, removed intact, were formalin inflated, sectioned and examined. Several pathological alterations, including alveolitis, alveolar cell hyperplasia and granulomatous inflammation, were found with higher frequency in all cigarette-smoking groups. Other alterations, such as bronchiolitis, bronchiolar squamous metaplasia and interstitial fibrosis, were found most frequently in the marijuana-smoking groups. Alveolar cell hyperplasia with focal atypia was seen only in the marijuana-smoking animals. These changes represent mostly early alterations of small airways. Additional follow-up studies are needed to determine their long-term prognostic significance.

Animals↗
PubMed1991

Chronic marijuana smoke alters alveolar macrophage morphology and protein expression.

Male rhesus monkeys were subjected to chronic exposure to marijuana smoke. High dose animals (HI) were exposed 7 days/week to 1 MJ cigarette/day; low dose animals (LO) were exposed on 2 consecutive weekend days to 1 MJ cigarette/day; placebo animals (EM) were exposed to 1 ethanol-extracted MJ cigarette/day for 7 days/week; sham animals (SH) were exposed to sham smoking conditions 7 days/week. This regimen was maintained for 1 year and was followed by a 7 month rest period. Alveolar macrophages of animals exposed to the LO and HI dose smoking regimens exhibited irregular cell surface morphology, increased vacuolization, and a spherical conformation upon adherence to plastic. Gel protein profiles of purified macrophages from HI and LO animals showed marked differences in both constitutive and bacterial lipopolysaccharide-elicited protein expression when compared with those of macrophages from the EM or SH animals. These results indicate that chronic THC exposure alters macrophage morphology and protein expression to external stimuli even after a 7 month rest period.

Animals↗
PubMed1991

Chronic marijuana smoke exposure in the rhesus monkey. IV: Neurochemical effects and comparison to acute and chronic exposure to delta-9-tetrahydrocannabinol (THC) in rats.

THC is the major psychoactive constituent of marijuana and is known to produce psychopharmacological effects in humans. These studies were designed to determine whether acute or chronic exposure to marijuana smoke or THC produces in vitro or in vivo neurochemical alterations in rat or monkey brain. For the in vitro study, THC was added (1-100 nM) to membranes prepared from different regions of the rat brain and muscarinic cholinergic (MCh) receptor binding was measured. For the acute in vivo study, rats were injected IP with vehicle, 1, 3, 10, or 30 mg THC/kg and sacrificed 2 h later. For the chronic study, rats were gavaged with vehicle or 10 or 20 mg THC/kg daily, 5 days/week for 90 days and sacrificed either 24 h or 2 months later. Rhesus monkeys were exposed to the smoke of a single 2.6% THC cigarette once a day, 2 or 7 days a week for 1 year. Approximately 7 months after the last exposure, animals were sacrificed by overdose with pentobarbital for neurochemical analyses. In vitro exposure to THC produced a dose-dependent inhibition of MCh receptor binding in several brain areas. This inhibition of MCh receptor binding, however, was also observed with two other nonpsychoactive derivatives of marijuana, cannabidiol and cannabinol. In the rat in vivo study, we found no significant changes in MCh or other neurotransmitter receptor binding in hippocampus, frontal cortex or caudate nucleus after acute or chronic exposure to THC. In the monkey brain, we found no alterations in the concentration of neurotransmitters in caudate nucleus, frontal cortex, hypothalamus or brain stem.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Chronic marijuana smoke exposure in the rhesus monkey. I. Plasma cannabinoid and blood carboxyhemoglobin concentrations and clinical chemistry parameters.

This report is the first in a series about a large multidisciplinary study designed to determine whether chronic marijuana (MJ) smoke exposure results in residual behavioral and/or neuropathological alterations in the rhesus monkey. Prior to the initiation of a year of chronic MJ smoke exposure, 64 periadolescent male rhesus monkeys were trained for 1 year to perform five operant behavioral tasks and then divided, according to their performance in these tasks, into four exposure groups (n = 15-16/group): (1) a high dose (HI) group, exposed 7 days/week to the smoke of one standard MJ cigarette; (2) a low dose (LO) group, exposed on weekend days only to the smoke of a standard MJ cigarette; (3) an extracted MJ cigarette (EX) group, exposed 7 days/week to the smoke of one ethanol-extracted MJ cigarette; and (4) a sham group (SH), exposed 7 days/week to sham exposure conditions. Daily exposures for 1 year were accomplished using a mask that covered the subjects' nose and mouth. Average body weights (initially 3.7 +/- 0.5 kg, mean +/- SD) and rates of weight gain (approximately 0.1 kg/month) were the same for all groups throughout the entire experiment. During the first week of exposure, plasma concentrations of delta-9-tetrahydrocannabinol and 11-nor-9-carboxy-THC in the HI group were 59 +/- 7 (mean +/- SE) and 5.5 +/- 1.5 ng/ml, respectively, 45 min after MJ smoke administration and did not change significantly at similar times after exposure throughout the remainder of the year. Whole blood carboxyhemoglobin levels increased to approximately 13% 1 min after exposure to smoke in either the MJ or the EX groups. Comparison of blood chemistry and hematology values before, during, and after exposure indicated no differences for most parameters. During exposure, lymphocytes, alkaline phosphatase and gamma-glutamyl transferase were depressed in the HI group compared to in the SH group. During exposure, aspartate aminotransferase was elevated for both the HI and EX groups, suggesting a general effect of smoke exposure. Because these effects were transient and remained within the range of reported normal values, these data indicate that long-term, experimental exposure to MJ smoke is feasible and does not compromise the general health of the rhesus monkey.

Alkaline Phosphatase↗
PubMed1991

Effect of trimethyltin on amino acid concentrations in different regions of the mouse brain.

Trimethyltin (TMT) is a neurotoxic compound known to cause marked alterations in brain chemistry. We have previously demonstrated that a single oral dose of TMT produced a dose-dependent decrease in muscarinic cholinergic receptors in mouse brain and significantly elevated glutamine in several regions of the rat brain. This study was designed to determine if TMT produced dose- and time-related alterations in amino acid concentrations in the adult male C57BL/6N mouse brain and in peripheral organs and plasma. In the dose-response study, TMT was administered orally as a single dose of 0, 0.5, 1.0, 3.0 or 5.0 mg/kg and animals were sacrificed 24 hr after treatment. In the time-course study, mice were dosed with TMT at 3.0 mg/kg and sacrificed 4, 12, 24, 48 or 96 hr after dosing. Amino acid concentrations were quantified by HPLC/EC following precolumn derivatization with o-phthalaldehyde-tert-butylthiol. TMT produced dose-dependent increases in aspartate, glutamine and glycine in the caudate nucleus (CN), frontal cortex (FC) and hippocampus (HIP) at 3.0 and 5.0 mg/kg. TMT at 3.0 mg/kg produced significant increases of aspartate in FC and HIP after 48 hr. Glutamine concentrations were significantly increased at 24 and 48 hr in HIP and at 48 hr in CN. Glycine and GABA concentrations were significantly increased at 48 and 96 hr respectively in the HIP. Glutamine was increased in plasma at 4 and 12 hr and in liver at 24 hr. Hyperammonemia occurred in plasma after 8 hr and continued through 24 hr and was accompanied by an increase in serum urea nitrogen.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1991

Transplacental passage of a human relaxin administered to rhesus monkeys.

A synthetic version of the human relaxin encoded by the human gene 2 (hR1x-2) was administered to pregnant rhesus monkeys (Macaca mulatta) on gestational days 141-158. Monkeys (three per group) received doses of 100 micrograms/kg or 2000 micrograms/kg as a continuous i.v. infusion over 2 h into a radial vein. One monkey in the low-dose group received, along with the unlabelled hR1x-2, 25.5 microCi/kg of the test material internally labelled with [35S]cysteine. Immunoreactive hR1x-2, as measured by enzyme-linked immunosorbent assay, appeared in all fetuses within 30 min (the first sampling time) of beginning the infusions. Peak fetal plasma levels of hR1x-2 were only 0.8-1.5% of the maternal values. Only 8-15% of the fetal serum radioactivity was hR1x-2. Radioactivity from maternal urine pooled over the 4-h experiment did not elute at the volume corresponding to hR1x-2, but near the column volume.

Animals↗
PubMed1991

Interactions of MK-801 with glutamate-, glutamine- and methamphetamine-evoked release of [3H]dopamine from striatal slices.

The interactions of MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine], glutamate and glutamine with methamphetamine (METH)-evoked release of [3H]dopamine were assessed in vitro to determine whether MK-801 inhibition of METH neurotoxicity might be mediated presynaptically, and to evaluate the effects of glutamatergic stimulation on METH-evoked dopamine release. MK-801 inhibition of glutamate- or METH-evoked dopamine release might reduce synaptic dopamine levels during METH exposure and decrease the formation of 6-hydroxydopamine or other related neurotoxins. Without Mg++ present, 40 microM and 1 mM glutamate evoked a N-methyl-D-aspartate receptor-mediated [3H]dopamine and [3H]metabolite (tritium) release of 3 to 6 and 12 to 16% of total tritium stores, respectively, from striatal slices. With 1.50 mM Mg++ present, 10 mM glutamate alone or in combination with the dopamine uptake blocker nomifensine released only 2.1 or 4.2%, respectively, of total tritium stores, and release was only partially dependent on N-methyl-D-aspartate-type glutamate receptors. With or without 1.50 mM Mg++ present, 0.5 or 5 microM METH evoked a substantial release of tritium (5-8 or 12-21% of total stores, respectively). METH-evoked dopamine release was not affected by 5 microM MK-801 but METH-evoked release was additive with glutamate-evoked release. Without Mg++ present, 1 mM glutamine increased glutamate release and induced the release of [3H]dopamine and metabolites. Both 0.5 and 5 microM METH also increased tritium release with 1 mM glutamine present. When striatal slices were exposed to 5 microM METH this glutamine-evoked release of glutamate was increased more than 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Biogenic amines as biomarkers for neurotoxicity.

There has been a surge of interest over the past several years in the use of neurochemical endpoints to contribute to our understanding of the mechanism of action of neurotoxicants. In our present presentation, two biogenic amine systems were selected as examples of biomarkers for neurotoxicity. To investigate these neurochemical endpoints, two prototype neurotoxicants were evaluated in experimental animals. One agent, reserpine, was used to assess developmental neurotoxicity and administered prenatally, while the other, MDMA, was used in the adult animal. The neurochemical biomarkers measured were dopamine, serotonin, and their metabolite (DOPAC and 5-HIAA) concentrations by HPLC/EC and dopamine receptor binding by radioligand receptor techniques. A review of the background, experimental design, and results are presented in this article. Our findings indicate that components of the biogenic amine systems can be used as sensitive neurochemical biomarkers of neurotoxicity. These neurochemical biomarkers can be correlated with neuropathological and behavioral biomarkers to aid in the understanding of mechanisms of neurotoxicity.

3,4-Methylenedioxyamphetamine↗
PubMed1990

Characterization of oxidized and glucuronidated metabolites of retinol in monkey plasma by thermospray liquid chromatography/mass spectrometry.

Eight metabolites of retinol were isolated by high-performance liquid chromatography (HPLC) from the plasma of the non-human primate Macaca fascicularis after acute exposure to 150,000 IU of vitamin A per kilogram body weight. After enrichment and further chromatographic purification, the metabolites were reinjected individually into a second HPLC system which was connected on-line by a thermospray interface to a mass spectrometer operated in the positive ionization mode. Six retinoids were identified by (i) a comparison of their retention times with those of appropriate reference compounds in the two chromatographic systems and (ii) by comparison of their mass spectra with those of reference compounds. These retinoids were: 13-cis-4-oxoretinoic acid, all-trans-4-oxoretinoic acid, 13-cis-retinoic acid, all-trans-retinoic acid, all-trans-retinoyl beta-glucuronide and all-trans-retinyl beta-glucuronide. One further metabolite could be identified for the first time as all-trans-4-oxoretinoyl beta-glucuronide by its mass spectrum and, after treatment of the unknown metabolite with beta-glucuronidase, by its hydrolysis product all-trans-4-oxoretinoic acid. The molecular structure of one metabolite could not be elucidated. A major metabolic pathway of high-dose vitamin A in the non-human primate is apparently the oxidation of the primary alcohol group of retinol resulting in the formation of all-trans-retinoic acid. Subsequently, a broad spectrum of various metabolites of all-trans-retinoic acid, including beta-glucuronides and retinoids with a 13-cis configuration, appear in the plasma.

Animals↗
PubMed1990

Risk assessment for neurotoxic effects.

Regulation of neurotoxicants is generally based on setting allowable doses (exposures) by dividing a no observed adverse effect level (NOAEL) by uncertainty factors that hopefully account for interspecies and intraspecies differences for extrapolations of experimental results obtained in animals to humans. This procedure makes no use of estimates of risk as a function of dose or does it acknowledge any risk at the NOAEL. The purpose of this paper is to illustrate how bioassay data can be used to estimate the risk of neurotoxic effects as a function of dose. In the absence of direct measurements of neurotoxic effects, biomarkers associated with neurotoxic effects can be used as measures of toxicity. In the absence of a definition of an adverse effect, an abnormal level for a measure of toxicity can be established which occurs only in a small fraction of a population which is not exposed to the substance under investigation. Risk is defined as the proportion of a population whose levels of a measure of toxicity equal or exceeds the abnormal level of the measure under study. The procedure is illustrated using data for neurochemical, neurohistological, and behavioral effects of methylenedioxymethamphetamine (MDMA) administered to rats or monkeys. This procedure is more versatile than the NOAEL/uncertainty factor approach since it provides estimates of risk as a function of dose of a potential neurotoxic substance.

3,4-Methylenedioxyamphetamine↗
PubMed1990

Thallium intoxication produces neurochemical alterations in rat brain.

Thallium, a rodenticide, has been shown to produce several neurological symptoms including motor weakness, ataxia, tremor, convulsion, coma and death. The present study was designed to evaluate the effects of acute or subacute exposure to thallium on several neurochemical biomarkers in rat brain. In the acute study, adult male CD rats were treated with 0 or 20 mg thallium/kg intraperitoneally (ip) and sacrificed 2, 6, or 24 hr after exposure. In the subacute study, animals were treated with 0 or 5 mg thallium/kg ip daily for 10 days and sacrificed 24 hr after the last dose. Acute injections of thallium produced in the frontal cortex significant increases in glutamine concentration after 6 hr and in taurine after 6 and 24 hr. In hippocampus, significant decreases in aspartic acid and taurine concentrations were found after 6 hr. Subacute exposure to thallium produced significant increases of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and serotonin (5-HT) in amygdala and increases in 5-HT concentration in hypothalamus. DA or muscarinic cholinergic (MCh) receptor binding did not show any significant alterations in caudate nucleus or frontal cortex after acute or subacute exposure to thallium. However, when membranes prepared from control caudate nuclei were incubated with thallium (1-100 microM) in vitro, we observed a dose-dependent decrease in DA and MCh receptor binding. These data suggest that the neurotoxicity produced by thallium exposure may be associated with changes in the concentrations of amino acids and other neurotransmitters in various regions of the rat brain.

Amino Acids↗
PubMed1989

Altered hepatic microsomal function and elevated protooncogene expression as residual effects in rats exposed to delta-9-tetrahydrocannabinol.

The microsomal activation of the potent hepatocarcinogen aflatoxin B1 (AFB1) and the expression of selected protooncogenes were investigated in the livers of rats exposed to delta 9-tetrahydrocannabinol (THC). At equimolar levels of cytochrome P-450, the microsome-mediated binding of AFB1 to DNA was significantly lower (56% of the controls) in preparations from drug exposed rats. Hepatic expression of the c-k-ras protooncogene was 3-fold higher in THC exposed animals. These results suggest the possible occurrence of long lasting residual effects in the rats exposed to THC.

Aflatoxin B1↗
PubMed1989

Fast-atom bombardment and thermospray mass spectrometry for the characterization of two glucuronide metabolites of methapyrilene.

Two conjugated metabolites of methapyrilene hydrochloride isolated from mouse-hepatocytes were examined by mass spectrometry using fast-atom bombardment (FAB) and thermospray ionization. The major metabolite, methapyrilene glucuronide, was identified based on a prominent peak due to the protonated molecule as well as the loss of the dimethylamine and sugar moieties. Identification of the second metabolite was complicated by large signals associated with the biological sample matrix. The complementary nature of the fragmentation observed in the mass spectra using FAB and thermospray ionization allowed this metabolite to be identified as the desmethylmethapyrilene glucuronide. The fragmentation observed using FAB ionization was not greatly affected by the presence of the glucuronide moiety. While loss of the sugar moiety indicated a glucuronide, additional fragmentation confirmed the presence of the underlying ethylenediamine substructure which is characteristic of this class of antihistamines.

Animals↗
PubMed1989

Acute effects of marijuana smoke on complex operant behavior in rhesus monkeys.

The acute behavioral effects of marijuana smoke were assessed in rhesus monkeys using a battery of food-reinforced complex operant tasks that included incremental repeated acquisition (IRA, n = 9), conditioned position responding (CPR, n = 8), progressive ratio (PR, n = 8), delayed matching to sample (DMTS, n = 6), and temporal response differentiation responding (TRD, n = 3). Marijuana or placebo smoke was delivered by a specialized face mask 15-min before sessions at exposure levels of 1, 5, 10, and 15 puffs (35cc/puff) or one cigarette smoked to a butt length of approximately 10 mm (approximately 20 puffs). Marijuana smoke caused significant disruptions of performance in all tests except PR after exposure to 10 or more puffs. Generally, response rates decreased or latencies to respond increased. Performance in the PR test was not consistently affected by marijuana exposure. Accuracy of responding was not altered by marijuana smoke at doses lower than those that decreased response rates in the IRA or CPR tests. In the three animals performing under all five schedules, the relative sensitivities for detecting marijuana behavioral effects were DMTS = TRD greater than IRA = CPR greater than PR. These results suggest that performance under operant schedules that are thought to represent some aspect of time perception, short-term memory, learning, motivation, and position discrimination show differential sensitivity to disruption by marijuana smoke, a finding similar to that noted previously for iv THC administration.

Animals↗