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Biomedical subjects

W Slikker

Publications and source records attributed to W Slikker.

At least 91 records · Page 5Linked to original sources
PubMed1994

The effect of dideoxycytidine on lymphocyte subpopulations in nonhuman primates.

In the present study, 2',3'-dideoxycytidine (ddC), which has antiretroviral activity, was given chronically to uninfected nonhuman primates to determine whether it produces adverse immunological or hematological effects. Nine healthy adult male rhesus monkeys were divided into three groups and given the following doses of ddC in a gelatin vehicle: group A, 0.06, 6.0, 3.0, and 1.5 mg/kg; group B, 0.6 mg/kg; group C, 0 mg/kg. Blood samples were collected for hematologic analysis and flow cytometric analyses of lymphocyte subpopulations. Chronic ddC exposure did not cause significant changes in the number of red blood cells, monocytes, or reticulocytes. The number of white blood cells and neutrophils increased and these changes were observed only in group A animals at the 1.5 mg/kg dose. The most significant alterations observed were decreases in the number of T helper cells (CD4) and B cells (CD20). CD4+ and CD20+ lymphocytes exhibited dose-related shifts that were reversible over time and after drug withdrawal. The results indicate that ddC has few hematologic effects but it does have profound but transient effects on the number of cells in lymphocyte subpopulations in normal primates.

Animals↗
PubMed1994

Acute effects of perinatal hypoxic insult on concentrations of dopamine, serotonin, and metabolites in fetal monkey brain.

Seven monkeys (Macaca mulatta) were laparotomized under general anesthesia (halothane, nitrous oxide, oxygen). Fetal hypoxia was induced in four monkeys by occlusion of the umbilical cord with a hydraulic occluder for 5-6 min. Three sham-operated fetuses served as controls. After unclamping, the fetuses were allowed to reperfuse for 20-30 min. To monitor hypoxia, the fetal electrocardiogram was recorded continuously. Hypoxic insult was associated with a decrease in fetal heart rate during the occlusion. After reperfusion, fetuses were immediately sacrificed and neocortex regions dissected on ice, frozen on dry ice and stored at -70 degrees C. Dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, serotonin, and 5-hydroxyindoleacetic acid were assayed by high performance liquid chromatography with electrochemical detection (HPLC/EC) in hippocampus, caudate nucleus and cortical regions. In the hippocampus, there was a significant increase in 5-hydroxyindoleacetic acid concentration. In prefrontal cortex, there was a trend toward an increase in serotonin but no effects on dopamine and homovanillic acid concentrations. Dopamine, serotonin and metabolites were not altered in the caudate nucleus. These data demonstrate that fetal hypoxia followed by reperfusion produced an increase in serotonin concentration measured within the hippocampus and selected cortical areas known to be targets of hypoxic injury.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Modeling for risk assessment of neurotoxic effects.

The regulation of noncancer toxicants, including neurotoxicants, has usually been based upon a reference dose (allowable daily intake). A reference dose is obtained by dividing a no-observed-effect level by uncertainty (safety) factors to account for intraspecies and interspecies sensitivities to a chemical. It is assumed that the risk at the reference dose is negligible, but no attempt generally is made to estimate the risk at the reference dose. A procedure is outlined that provides estimates of risk as a function of dose. The first step is to establish a mathematical relationship between a biological effect and the dose of a chemical. Knowledge of biological mechanisms and/or pharmacokinetics can assist in the choice of plausible mathematical models. The mathematical model provides estimates of average responses as a function of dose. Secondly, estimates of risk require selection of a distribution of individual responses about the average response given by the mathematical model. In the case of a normal or lognormal distribution, only an estimate of the standard deviation is needed. The third step is to define an adverse level for a response so that the probability (risk) of exceeding that level can be estimated as a function of dose. Because a firm response level often cannot be established at which adverse biological effects occur, it may be necessary to at least establish an abnormal response level that only a small proportion of individuals would exceed in an unexposed group. That is, if a normal range of responses can be established, then the probability (risk) of abnormal responses can be estimated.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Methylenedioxyamphetamine↗
PubMed1994

Identification of urinary metabolites of pyrilamine after oral administration to man.

1. The metabolism of pyrilamine, 2-[4-methoxybenzyl-(2-dimethylaminoethyl) amino] pyridine, was studied in adult male volunteers after a single oral dose of 50 mg. 2. Solvent extracts of urine obtained with or without enzyme hydrolysis were analysed by gc/ms after derivatization with MSTFA/TMSCI (N-methyl-N-trimethylsilyl-trifluoroacetamide/trimethyl chlorosilane). The structure of metabolites were determined based on EI mass spectra and confirmed with those of authentic standards. 3. Conjugated metabolites identified in the urine were pyrilamine, O-desmethylpyrilamine, and ring hydroxylated derivatives of pyrilamine. O-desmethylpyrilamine was also detected in low abundance as a free form. 4. These metabolites observed in human urine were quite different from those previously reported in rat.

Administration, Oral↗
PubMed1994

Age modulates the long-term but not the acute effects of the serotonergic neurotoxicant 3,4-methylenedioxymethamphetamine.

Tissue levels of serotonin (5-HT), levels of its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and populations of 5-HT reuptake sites were measured in the brains of rats exposed to 3,4-methylenedioxymethamphetamine (MDMA) at selected developmental ages. MDMA exposure at postnatal day (PND) 10 did not result in altered 5-HT or 5-HIAA levels 1 week after administration in any brain region examined. However, MDMA exposure at PND 40 and PND 70 resulted in dose-dependent reductions in 5-HT and 5-HIAA levels at 1 week in all brain regions examined. Time course studies revealed that at PND 10, MDMA acutely (< or = 24 hr) reduced 5-HT levels and that these levels later recovered to control levels. MDMA also acutely reduced 5-HT levels at PND 40 and PND 70, but at these ages the 5-HT levels were persistently depressed ( > or = 72 hr). Time course studies also revealed that MDMA acutely elevated dopamine levels in caudate putamen at PND 40 and PND 70, but no alterations in dopamine levels were observed at PND 10. Analysis of 5-HT reuptake site populations revealed that at PND 10 and PND 40, MDMA had little effect on reuptake site populations. At PND 70, however, MDMA reduced 5-HT reuptake site populations as early as 24 hr after administration. These experiments demonstrate not only that the biochemical effects of MDMA exposure are altered by the developmental status of the experimental animal, but also that each individual biochemical component may show differing sensitivities to alteration by MDMA at different developmental ages.

Age Factors↗
PubMed1994

Principles of developmental neurotoxicology.

With 4-8 percent of U.S. children exhibiting anatomical and/or functional deficits, and the occurrence of several tragic clinical syndromes resulting from developmental exposure to such agents as ethanol, lead and methylmercury, there is good reason to focus attention on the principles of developmental neurotoxicology. Various animal models have been used to confirm the developmental neurotoxicity that results from exposure to these agents, and along with clinical evidence, have implicated several other chemical classes such as antimitotics, insecticides, polyhalogenated hydrocarbons, psychoactive drugs, solvents and vitamins as specific agents with developmental neurotoxic potential. As for developmental toxicity in general, the nature and extent of neurotoxic effects are often dependent on the timing of exposure, and because stages of nervous system development can vary significantly between species in relation to the time of birth, variations in neurotoxic outcome across species are expected. There are several instances in which functional alterations (e.g., neuromotor development, locomotor activity, reactivity and/or habituation, learning and memory and sensory system modulation) have been observed at doses below those needed to produce other indicators of developmental toxicity. Neuroanatomical/neurohistological, neurochemical and neurophysiological endpoints have been used to substantiate these functional deficits and/or to describe adverse nervous system effects in the absence of functional data. As knowledge about the toxicological mechanisms underlying the expression of developmental neurotoxicity is increased, the ability to conduct quantitative risk assessments and protect human health will be enhanced.

Animals↗
PubMed1994

Further studies of the role of hyperthermia in methamphetamine neurotoxicity.

The depletion of striatal dopamine (DA) that can occur after methamphetamine (METH) administration has been linked to METH-induced hyperthermia. The relationship between METH-induced hyperthermia, neurotoxicity (striatal DA depletions) and compounds that protect against METH neurotoxicity was further investigated in this study. Typically, rats exposed to METH die when their body temperatures exceed 41.3 degrees C but such hyperthermic rats can be saved by hypothermic intervention. Subsequently, rats saved by hypothermic intervention have greater depletion of striatal DA at an earlier time of onset (18 hr or less post-METH) than do METH-exposed rats that do not attain such high temperatures. Striatal damage was present 3 days post-METH in these hyperthermic rats, as assessed by silver degeneration of terminals and increases in the astrocytes that express glial fibrillary acidic protein immunoreactivity. By contrast, alterations in the number of [3H]dizoclipine (MK-801) binding sites in cortical or striatal membranes at 1, 3 or 14 days post-METH were not detected. The experiments showed that mean and maximal body temperature correlated well with striatal DA concentrations 3 days post-METH (r = -0.77, n = 58), which suggests a role for hyperthermia in METH neurotoxicity. However, hyperthermia (alone or with haloperidol present) induced by high ambient temperatures did not deplete striatal DA in the absence of METH. Haloperidol, diazepam and MK-801 all reduced METH-induced striatal DA depletion to a degree predicted by their inhibition of hyperthermia and increased ambient temperature abolished their neuroprotection. Although an interleukin-1 receptor antagonist reduced maximal body temperature enough to lower the lethality rate, it did not reduce the temperature sufficiently to block METH neurotoxicity. It was concluded that short- and long-term decreases in striatal DA levels depend on the degree of hyperthermia produced during METH exposure but cannot be produced by hyperthermia alone. In addition, several agents that block DA depletions do so by inhibiting METH-induced hyperthermia. Finally, the results suggested a role for interleukin-1 in the extreme hyperthermia and lethality produced by METH.

Animals↗
PubMed1993

Domoic acid-treated cynomolgus monkeys (M. fascicularis): effects of dose on hippocampal neuronal and terminal degeneration.

Domoic acid is a tricarboxylic amino acid (structurally related to kainic acid and glutamic acid) that is found in the environment as a contaminant of some seafood. To determine the nature of any neurological damage caused by domoate, as well as the minimum neurotoxic dose, juvenile and adult monkeys were dosed intravenously with domoate at one of a range of doses from 0.25 to 4 mg/kg. When animals were perfused one week later, histochemical staining using a silver method to reveal degenerating axons and cell bodies showed two distinct types of hippocampal lesions. One lesion, termed 'Type A', was a small focal area of silver grains restricted to CA2 stratum lucidum, the site of greatest kainic acid receptor concentration in the brain. Type A lesions occurred over a dose range of 0.5 to 2.0 mg/kg in juvenile animals and 0.5 to 1.0 mg/kg in adult animals. No mortality occurred in any of the juvenile monkeys, but one juvenile animal that received 4.0 mg/kg sustained a second type of lesion, termed 'Type B', characterized by widespread damage to pyramidal neurons and axon terminals of CA4, CA3, CA2, CA1, and subiculum subfields of the hippocampus. Doses of more than 1.0 mg/kg in the adult monkeys either proved lethal or resulted in Type B lesions. Induction of c-fos protein had occurred in the hippocampal dentate gyrus and CA1 regions of moribund animals perfused within hours of their initial dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Intracranial injection of Fluoro-Gold results in the degeneration of local but not retrogradely labeled neurons.

Small volumes of either Fluoro-Gold (hydroxy-stilbamidine) or physiological saline were pressure injected into the striatum of adult rats. This paradigm is essentially the same as that used by neuroscientists who inject small quantities of Fluoro-Gold into brain structures to reveal neuronal connections. Using a modified de Olmos' cupric-silver technique, virtually no degeneration could be detected as the result of saline injection at any time point examined. However, comparable injections of Fluoro-Gold resulted in conspicuous cell body and terminal degeneration within the striatum 1-10 days post injection. Terminal degeneration within the substantia nigra pars reticulata could also be seen 2-10 days after injection. Examination of cells of the compacta region revealed conspicuous retrograde uptake of Fluoro-Gold, although none of these cells exhibited any evidence of neuronal degeneration at any postoperative time examined.

Animals↗
PubMed1993

Development of dopamine and N-methyl-D-aspartate systems in rat brain: the effect of prenatal phencyclidine exposure.

Phencyclidine (PCP) inhibits the uptake of the neurotransmitter dopamine (DA), and blocks N-methyl-D-aspartate (NMDA) receptor-regulated ion channels. PCP also binds to sigma receptors in vivo and in vitro in rat brain. Prolonged exposure to PCP in adults has been observed to reduce the number of PCP binding sites in brain. We designed these experiments to evaluate whether prolonged prenatal exposure to PCP produces alterations in the development of DA and NMDA systems in brain. To do so, we characterized the normal course of development of basal and stimulated DA release in striatal slices, the ontogeny of striatal DA concentrations, and the development of NMDA receptor channels and associated glutamate binding sites in frontal cortex. We compared these developmental profiles to those in rats exposed to prenatal PCP, in an attempt to characterize the effect of prenatal PCP exposure on the pattern of brain development. Pregnant CD rats were injected s.c. with either 0, 10 or 20 mg/kg PCP daily on gestational days 8 through 20. On postnatal days (PND) 8, 21, 45, or 100, rats were sacrificed and brain tissues isolated for in vitro assessment. In vitro [3H]DA release from striatal slices evoked by either 40 microM glutamate or 15 mM K+ increased over 250% from PND 8 to PND 45, and glutamate-stimulated release was still significantly below adult levels at PND 45. In contrast, D-methamphetamine (D-METH)-evoked [3H]DA release, frontal cortical glutamate binding sites and NMDA channels developed early, reaching adult levels on or before PND 21.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Effects of a cold environment or age on methamphetamine-induced dopamine release in the caudate putamen of female rats.

Extracellular levels of dopamine (DA) and metabolites as well as serotonin [5-hydroxytryptamine (5-HT)] and 5-hydroxyindoleacetic acid (5-HIAA) were determined in the caudate putamen (CPU) of either 6- or 12-month-old female rats using microdialysis and high-performance liquid chromatography with electrochemical detection (HPLC-ED) before, during, and after four consecutive injections (given at 2-h intervals) of methamphetamine (METH). In 6-month-old rats administered 4 x 5 mg/kg METH at an environmental temperature (ET) of 23 degrees C, peak extracellular DA levels (between 50 and 150 rho g/10 microliters) were attained 30-45 min after each dose of METH while dihydroxyphenylacetic acid (DOPAC) decreased steadily after the first doses of METH until it reached a plateau at 50% of control (550-700 pg/10 microliters) levels. Increases in 5-HT levels during METH administrations paralleled DA increases while 5-HIAA decreases paralleled DOPAC decreases. The total CPU DA and 5-HT content of these rats was about 65% of control at 3 days post-METH. Reducing the ET to 4 degrees C during dosing decreased the peak and average DA levels attained during the 4 x 5 mg/kg METH administration to about 50% of that observed at a 23 degrees C ET. Increasing the dose to 4 x 10 mg/kg METH (4 degrees C ET) increased peak and average CPU DA levels to 200% that observed during 4 x 5 mg/kg METH at a 23 degrees C ET. However, no significant decreases in total CPU DA content of any rats dosed with METH at a 4 degrees C ET were observed 3 days post-METH. In 12-month-old rats dosed with 4 x 5 mg/kg METH (23 degrees C ET), the peak and average extracellular DA levels were only 30-60% that of 6-month-old rats. However, the CPU DA content of older rats was significantly decreased both 3 (30% control) and 14 (60% control) days post-METH. In summary, METH toxicity may not be predicted solely by the extracellular levels of DA attained during METH administration; age and ET also greatly influence METH neurotoxicity.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Quantitative plasma disposition of retinol and retinyl esters after high-dose oral vitamin A administration in the cynomolgus monkey.

A solid-phase extraction technique followed by automated high-performance liquid chromatography sample elution was successfully used to evaluate the effect of three pharmaceutical parameters on the plasma profile of various forms of vitamin A after an oral dose to cynomolgus monkeys. The three parameters evaluated were the chemical form of vitamin A (retinol versus retinyl acetate), the vehicle (acetone/Tween 20/water versus acetone/soybean oil), and the retinol dose (2, 10, and 50 x 10(3) retinol equivalents/kg). The form of the administered compound, retinol or retinyl acetate, appeared to have no major effect on the formation of nonpolar retinoids. The ester profile in plasma differed depending on whether the dose was administered in the water-based or the oil-based vehicle. Irrespective of the vehicle type the predominant retinoid formed was retinyl palmitate/oleate. However, retinol doses in the water-based vehicle formed relatively high concentrations of retinyl laurate and retinyl myristate but no retinyl linolenate. The retinol dose in the oil-based vehicle formed consistent, but relatively minor, concentrations of retinyl linolenate, higher relative concentrations of retinyl linoleate, and no retinyl laurate or myristate. The dose of retinol administered had an impact on the diversity of the nonpolar retinoid profile. The low dose led to the presence of almost exclusively retinyl palmitate/oleate and retinyl stearate, whereas at higher doses the other retinyl esters became major retinol constituents.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

No increase in carcinogen-DNA adducts in the lungs of monkeys exposed chronically to marijuana smoke.

Rhesus monkeys exposed to marijuana smoke either 7 or 2 days/weeks (HI and LO groups, respectively), or ethanol-extracted marijuana smoke for 7 days/week (EM) or sham treatment (SH) for 1 year were sacrificed 7 months following the last exposure. Pulmonary levels of carcinogen-DNA adducts were determined. Although mean or median adduct levels were not statistically different, 15 of 22 adduct measures were highest in the EM group and lowest 12 of 22 times in the SH group. The levels of aromatic carcinogen-DNA adducts seem no higher in the lungs of animals exposed to marijuana smoke than in untreated animals. Ethanol-extracted marijuana may have effects greater than marijuana itself.

Animals↗
PubMed1992

Metabolism of methapyrilene by Fischer-344 rat and B6C3F1 mouse hepatocytes.

1. Suspension cultures of freshly isolated F344 rat and B6C3F1 mouse hepatocytes were compared for their ability to transform various concentrations of methapyrilene (MP). 2. MP metabolites were isolated and purified by h.p.l.c., and were identified by comparing their chromatographic and mass spectral properties with those of authentic standards. 3. Both rat and mouse hepatocytes transformed MP to tentatively identified 2-thiophenecarboxylic acid (I), and definitively identified mono-N-desmethyl methapyrilene glucuronide (II), methapyrilene glucuronide (III), methapyrilene N-oxide (V), and mono-N-desmethyl methapyrilene (VII).

Animals↗
PubMed1992

The influence of environmental temperature on the transient effects of methamphetamine on dopamine levels and dopamine release in rat striatum.

When male rats were injected four times (once every 2 hr) with 5 mg/kg methamphetamine (METH) at an environmental temperature of 23 degrees C, transient changes occurred in the levels of striatal dopamine (DA) and the regulation of striatal DA release. Striatal DA levels were minimally affected 1 day after METH treatment, but 3 days after METH treatment, striatal DA levels decreased to approximately 40% of control. DA levels returned to 70% of control 2 weeks after METH. Similarly, striatal tyrosine hydroxylase (TH) activity decreased to approximately 50% of control activity 3 days after METH treatment at 23 degrees C, but did not differ from controls at 1 or 14 days after METH treatment. No changes in striatal DA levels were observed in rats treated with four doses of 5 mg/kg METH at an environmental temperature of 4 degrees C. Striatal DA levels decreased modestly to approximately 70% of controls 3 days after treatment with four doses of 10 mg/kg METH at 4 degrees C, but DA levels returned to control levels 14 days after METH treatment. Furthermore, striatal TH activity was not affected by 10 mg/kg METH at 4 degrees C. Thus, a cold environmental temperature (4 degrees C) reduced the effects of METH on striatal DA levels and striatal TH activity. Changes in the presynaptic regulation of DA release after either 5 mg/kg (23 degrees C) or 10 mg/kg (4 degrees C) METH treatment were determined in vitro using striatal slices.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Chronic marijuana smoke exposure in the rhesus monkey. II: Effects on progressive ratio and conditioned position responding.

Sixty-two male rhesus monkeys were trained to respond in an operant test battery that included tasks thought to allow measurement of aspects of motivation and color and position discrimination. Subjects were assigned to eight treatment groups (n = 7-8) based upon behavioral performance. There were two behavioral groups: ACTIVE = behavior assessed throughout the 365 days of active exposure and beyond, and RESIDUAL = behavior assessed beginning 2 months after the last exposure. Each behavioral group had four dose groups: HI = smoke from one marijuana (MJ) cigarette/day 7 days/week; LO = MJ smoke only on weekends; EX = smoke from one extracted MJ (placebo) cigarette/day 7 days/week; SH = sham exposure 7 days/week. For the motivation task, both HI and LO ACTIVE groups earned significantly fewer reinforcers than did both ACTIVE control groups during the last several months of exposure. These effects disappeared within 2 to 3 months of cessation of treatment, and no similar effect was present when RESIDUAL groups were tested. Performance of the color and position discrimination task was adversely affected in one of eight HI ACTIVE subjects throughout most of the chronic exposure, and there was a trend toward residual deficits in performance of this task in the HI RESIDUAL group compared to both SH and EX RESIDUAL controls. These data could be interpreted to mean that during periods of chronic use, MJ produces an amotivational-like syndrome in rhesus monkeys and that this syndrome disappears only several weeks to months after the last exposure.

Animals↗
PubMed1991

Chronic exposure to delta 9-tetrahydrocannabinol fails to irreversibly alter brain cannabinoid receptors.

The effects of chronic delta 9-tetrahydrocannabinol (delta 9-THC) and marijuana administration on the properties of brain cannabinoid receptor populations of the rat and monkey, respectively, were examined in this study. It was determined that the properties of the cannabinoid receptors in the striatum, cerebral cortex, cerebellum, hippocampus, and brainstem/spinal cord of the rat do not appear to be irreversibly altered by chronic exposure to delta 9-THC. Similarly, the cannabinoid receptors in the caudate, prefrontal cortex, and cerebellum of the monkey do not appear to be irreversibly altered by chronic exposure to marijuana smoke.

Analgesics↗