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At least 973 records · Page 54Linked to original sources
PubMed1996

Plasma and blood lead concentrations, lead absorption, and lead excretion in nonhuman primates.

In order to assess the comparability of lead disposition in the cynomolgus monkey to that in the human, we determined the relationships among blood lead concentration, plasma lead concentration, and lead excretion in monkeys. Six adult (3-5 kg) female cynomolgus monkeys (Macaca fascicularis) without previous experimental lead exposure were given single intravenous injections of from 750 to 3300 micrograms lead as lead nitrate, labeled with 210Pb, per kilogram body weight. Four additional monkeys, fasted overnight, were administered single oral doses of either 750 or 1500 micrograms lead as lead nitrate, labeled with 210 Pb, per kilogram for the assessment of fractional absorption. Blood and plasma lead concentrations (10 monkeys) and urinary and fecal excretion of lead (2 monkeys) were followed up for up to 16 days after lead administration. Fractional absorption from an oral dose was 44% at the lower of the two doses and 22-28% at the higher dose. The relationship between plasma and blood lead concentrations was found to be similar to that in humans, with plasma lead concentration at most a few percent of total blood lead concentration at low concentrations. Partitioning of lead across the red cell membrane in the 2 monkeys given exceptionally high doses (3300 micrograms/kg) intravenously was distinctly lower than that in the 4 monkeys given lower intravenous doses. Urinary clearance of lead in these 2 monkeys was 19% of the estimated glomerular filtration rate, within the range of efficiencies reported for humans. Fecal clearance, however, was anomalous and appeared to be an artifact of the very high dose. Examination of published data for urinary and fecal lead excretion in three adult baboons showed that both functions in the baboons were quantitatively similar to those in humans. Urinary clearance in the baboons was 14-24% of the estimated glomerular filtration rate, and fecal clearance was 78-85% of the urinary clearance. We conclude that nonhuman and human primates are comparable with respect to the relationship of plasma lead concentration to blood lead concentration and the relative efficiency of lead excretion in urine and feces.

Absorption↗
PubMed1999

Differential effects of administration of a human anti-CD4 monoclonal antibody, HM6G, in nonhuman primates.

A human sequence IgGkappa anti-CD4 monoclonal antibody (mAb), HM6G, originally isolated from a human immunoglobulin transgenic mouse was specific for and bound with high binding avidity to the CD4 antigen expressed on human, chimpanzee, and cynomolgus monkey T cells. Prior to testing this mAb in human clinical trials, a number of preclinical primate studies were performed. In chimpanzees, HM6G did not deplete circulating CD4(+) T cells and was cleared in a dose-dependent manner. In contrast, this mAb administered to cynomolgus monkeys depleted CD4(+) T cells (albeit only at high doses) and its clearance, which had reached saturation even at very low doses, was much slower. These differences were most likely due to the additional and rather substantial expression of the CD4 antigen on chimpanzee monocytes. In monkeys, the T cell depletion was mitigated by infusing the mAb over 30 min or longer (as opposed to 30 s) while only slightly altering the clearance. As expected, the human mAb did not induce an immune response in chimpanzees, although it did induce a low titer response in monkeys. These disparate pharmacokinetic and pharmacodynamic results suggest prudence when extrapolating results obtained in nonhuman models to humans.

Animals↗
PubMedDate not supplied

Oculomotor localization relies on a damped representation of saccadic eye displacement in human and nonhuman primates.

The oculomotor system has long been thought to rely on an accurate representation of eye displacement or position in a successful attempt to reconcile a stationary target's retinal instability (caused by motion of the eyes) with its corresponding spatial invariance. This is in stark contrast to perceptual localization, which has been shown to rely on a sluggish representation of eye displacement, achieving only partial compensation for the retinal displacement caused by saccadic eye movements. Recent studies, however, have begun to case doubt on the belief that the oculomotor system possess a signal of eye displacement superior to that of the perceptual system. To verify this, five humans and one monkey (Macaca nemestrina) served as subjects in this study of oculomotor localization abilities. Subjects were instructed to make eye movements, as accurately as possible, to the locations of three successive visual stimuli. Presentation of the third stimulus (2-ms duration) was timed so that it fell before, during, or after the subject's saccade from the first stimulus to the second. Localization errors in each subject (human and nonhuman) were consistent with the hypothesis that the oculomotor system has access to only a damped representation of eye displacement--a representation similar to that found in perceptual localization studies.

Animals↗
PubMed1980

The eye in accelerated hypertension. I. Elschnig's spots in nonhuman primates.

The acute form of Elschnig's spots was produced in a rhesus monkey with experimentally induced accelerated hypertension. Clinically, Elschnig's spots appeared within 24 hours of hypertension as discrete, whitish, subretinal lesions located in the temporal posterior poles of both fundi. The lesions leaked fluorescein. Morphologically, they consisted of complete obstruction of terminal choroidal arterioles and choriocapillaris by fibrin thrombi, necrosis of the retinal pigment epithelium, and fibrinous exudation into Bruch's membrane and into the subpigment epithelial and subretinal spaces. Most of the neurosensory retina was spared from morphologic damage. The differential susceptibility between choroidal and retinal vessels is explained by differences in anatomy and in autonomic nervous control.

Animals↗
PubMed1984

Refractive keratoplasty. Keratophakia in a nonhuman primate.

We performed 11 keratophakia procedures in a baboon (Papio cynocephalus) model using the same instruments and techniques that are presently clinically employed. We requested 10 diopters of correction in nine cases and 14 D in two cases. We were able to achieve a mean (+/- SD) keratometric steepening correction of 5.8 +/- 1.5 D using fresh and 9.3 +/- 5.0 D using prefrozen donor corneas. The overall change was 8.0 +/- 4.3 D. Morphologic results and corneal clarity were consistent with the excellent clinical results. The keratophakia lenticles were sparsely repopulated with keratocytes up to six months following surgery, but at 12 months, partial keratocyte repopulation of one lenticle did occur. We recommend that the baboon model be used for evaluation of all lamellar refractive surgical procedures.

Animals↗
PubMed1990

One-year refractive results of central photorefractive keratectomy for myopia in the nonhuman primate cornea.

Photorefractive keratectomy for the correction of myopia was performed in 32 eyes of 16 green monkeys. The corneas healed satisfactorily, with normal formation of basal lamina and hemidesmosomal attachments visible in 14-week histologic specimens. No recurrent erosions were observed clinically. After a transient period of faint haze, all corneas were clear at 17 weeks and remained clear through the 1-year follow-up. In terms of accuracy, all corneas demonstrated a significant flattening compared with preoperative values, but no significant difference was seen between the groups with different intended corrections (1.5 and 3 diopters). The changes in corneal shape stabilized by 17 weeks, as measured by keratometry. The clinical results suggest that mechanical removal of the epithelium is preferable to laser ablation of the epithelium. Overall, the results demonstrate that excimer laser ablation of the corneal stroma can produce a stable diptric change in the primate cornea with good healing and long-term corneal clarity.

Animals↗
PubMed1990

Refractive predictability of myopic hydrogel intracorneal lenses in nonhuman primate eyes.

The refractive predictability of myopic hydrogel intracorneal lenses made of lidofilcon A was evaluated in 24 monkey eyes following a microkeratome dissection. All eyes were examined monthly for refractive alteration and clinical appearance during a follow-up period of 7 to 33 months. The refractive yield was measured by retinoscopy and found to be a function of the implant depth. The mean +/- SD percent of the desired correction achieved averaged 70% +/- 24% at a 36% to 60% depth (n = 8), 54% +/- 22% at a 61% to 79% depth (n = 7), and 12% +/- 14% in implants deeper than at a 79% depth (n = 9). For eyes with implants at a 36% to 60% depth, the predicted vs achieved refractive alteration yielded a correlation coefficient of .97 (88% within +/- 3 diopters of the correlation). The refractive outcome remained stable throughout 7 months of follow-up, whereas deeply placed lenses (greater than or equal to 80%) exhibited significant regression in power during this time.

Algorithms↗
PubMed1984

A benzodiazepine receptor-mediated model of anxiety. Studies in nonhuman primates and clinical implications.

beta-Carboline-3-carboxylic acid ethyl ester (beta-CCE) binds with high affinity to brain benzodiazepine receptors and has potent behavioral and physiologic effects in primates. Dose-related increases in behavioral agitation, plasma cortisol level, BP, and heart rate were observed after administration of doses between 50 and 500 micrograms/kg of beta-CCE to rhesus monkeys. All of these effects were blocked by pretreatment with diazepam. Pretreatment with clonidine hydrochloride and propranolol hydrochloride, both of which have been reported to have anxiolytic actions in man, attenuated only selective aspects of the response to beta-CCE. The behavioral, endocrine, and physiologic effects of low doses of beta-CCE in monkeys are similar to those observed in anxious patients or normal subjects under anxiety-provoking or stressful situations. Administration of benzodiazepine receptor active antagonists such as beta-CCE to primates may, therefore, provide a valid and reproducible model of human anxiety that could be used to investigate specific biologic aspects of anxiety disorders.

Animals↗
PubMed1984

Fetal hydrocephalus. II. Amelioration of fetal porencephaly by in utero therapy in nonhuman primates.

The postnatal course of a form of infantile porencephaly under pressure in monkeys was evaluated by comparing brain development between animals that had received the hydrocephalic antenatal vent for intrauterine treatment and those that had not been treated antenatally. Brain development was assessed by computed tomographic scans. The studies showed asymmetric malformations and associated porencephalic lesions in infant monkeys not treated in utero, despite installation of a conventional postnatal ventriculoperitoneal shunt. In contrast, apparently normal development of brain tissue in infants given intrauterine therapy was observed.

Amnion↗
PubMed1996

Purkinje cell deficits in nonhuman primates following weekly exposure to ethanol during gestation.

The most serious features of fetal alcohol syndrome (FAS) are mental retardation and other behavioral problems resulting from alcohol-induced damage to the developing central nervous system (CNS). The mechanism by which alcohol induces its neuroteratogenic effects is unknown. One hypothesis is that gestational alcohol exposure results in a reduction in neuronal number. This study demonstrates that gestational exposure to ethanol in a non-human primate species induces permanent dose-related deficits in the number of cerebellar Purkinje cells. Ethanol was administered via nasogastric tube once per week to 15 gravid pigtailed macaques (Macaca nemistrina) in one of the following doses: 0.0 (intubated controls), 1.2, 1.8, 2.5, 3.3, and 4.1 g/kg/dose. Offspring were reared with parental surrogates and were sacrificed at 6 months of age; 8-microns-thick, parasagittal sections were cut through the paraffin-embedded cerebellar vermis. Purkinje cells were quantified, the length of the Purkinje cell line was determined stereologically, and Purkinje cell linear frequency was calculated. The number of Purkinje cells and their linear frequencies were significantly reduced in the alcohol-treated subjects, and the deficits were dose-dependent. The groups receiving 2.5 g/kg/dose and above were most severely affected and had an average deficit in Purkinje cell number of 11.8%, relative to controls. Alcohol had no effect on the length of the Purkinje cell line. The findings suggest that alcohol-induced reduction in neuronal number may be an important factor underlying the CNS dysfunction in FAS.

Animals↗
PubMed1999

Taste difference thresholds for sucrose in two species of nonhuman primates.

The purpose of this study was to determine taste difference thresholds for sucrose in frugivorous spider monkeys and omnivorous baboons. Using a two-bottle preference test of brief duration, we presented four Ateles geoffroyi and four Papio hamdryas anubis with six different reference concentrations (RCs) of 25, 50, 100, 200, 300, and 400 mM sucrose and tested their ability to discriminate these from lower concentrations of this carbohydrate. The just noticeable differences (JNDs), expressed as Weber ratios (delta/I), were found to range from 0.075-0.25 in the spider monkeys, with a tendency for lower values with higher RCs. In contrast, the baboons showed the reverse trend, with the lowest Weber ratio of 0.10 at the two lowest RCs and higher values of up to 0.25 with the highest RC tested. Thus, the JNDs were found to be generally similar in both species and at least as low as in humans. The results support the assumption that both spider monkeys and baboons may use sweetness as a criterion for food selection. The different patterns of differential sensitivity for sucrose across the range of concentrations tested suggest a correlation between the ability to discriminate between different concentrations of sucrose and the dietary habits of the two species.

Animals↗
PubMed1996

Effects of D2 dopamine receptor antagonists on Fos protein expression in the striatal complex and entorhinal cortex of the nonhuman primate.

Recent studies have reported that acute administration of dopamine D2 receptor antagonists increases expression of the immediate early gene c-fos in the rat striatal complex. There have been no corresponding studies of the effects of D2 antagonists in primate species. Since all clinically effective antipsychotic drugs share D2 receptor antagonism, it is important to define the extent to which these drugs may alter expression of c-fos or its protein product, Fos, in primates. We therefore examined the effects of administration of two D2 receptor antagonists, haloperidol and metoclopramide, on Fos expression in the striatum and temporal cortices of the vervet monkey. Metoclopramide does not appear to possess significant antipsychotic efficacy but potently produces extra-pyramidal side effects, while haloperidol is an effective antipsychotic drug that produces extrapyramidal side effects. Both drugs increased the number of Fos-like immunoreactive (Fos-li) neurons in the caudate nucleus and putamen; the numbers of Fos-li neurons in these regions were increased in both the patch and matrix compartments. Haloperidol but not metoclopramide increased the number of Fos-li neurons in the nucleus accumbens shell. Similarly, haloperidol but not metoclopramide increased the number of Fos-li neurons in the entorhinal cortex. Neither drug altered Fos expression in the inferior temporal cortex. These data suggest that the dorsolateral caudate nucleus and putamen may be sites at which D2 receptor antagonists elicit extrapyramidal side effects, and the nucleus accumbens shell and entorhinal cortex may be loci at which the therapeutic actions of antipsychotic drugs are manifested.

Animals↗
PubMed1997

L-DOPA modulates striatal dopaminergic function in vivo: evidence from PET investigations in nonhuman primates.

Significant increases in striatal L-[11C]DOPA retention were observed in adult female rhesus monkeys with positron emission tomography (PET) following administration of drugs that increase cerebral L-DOPA concentrations. The monkeys were scanned twice: at baseline (using 10-50 micrograms of tracer substance) and during continuous administration of L-DOPA (3 or 15 mg/kg/h) and 6-R-Erythro-4,5,6,7-tetrahydrobiopterin (6R-BH4) (5 mg/kg/h) and during combined administration of both drugs. PET scans of L-[11C]DOPA distribution were obtained in GE2048-15B or GE4096-15WB Plus positron tomographs. In all studies the specific striatal L-[11C]DOPA influx rate increased by an average of 17-20%. These increases were significantly higher than the retest variability obtained with saline infusions under identical experimental conditions. In individual monkeys the magnitude of increase in the striatal L-[11C]DOPA influx rate varied from no effect of the drug infusion to a 45% increase. Taken together, the results of this study demonstrate that L-DOPA in itself can affect dopaminergic neurotransmission in vivo and also adds further evidence that the neuromodulatory effects of the amino acid are predominantly autoreceptor antagonist-like. The findings most likely have importance for the further understanding of the dopaminergic system in neurodegenerative and psychiatric disorders.

Animals↗
PubMed1997

Imaging of cholinergic terminals using the radiotracer [18F](+)-4-fluorobenzyltrozamicol: in vitro binding studies and positron emission tomography studies in nonhuman primates.

The goal of the present set of studies was to characterize the in vitro binding properties and in vivo tissue kinetics for the vesicular acetylcholine transporter (VAcChT) radiotracer, [18F](+)-4-fluorobenzyltrozamicol ([18F](+)-FBT). In vitro binding studies were conducted in order to determine the affinity of the (+)- and (-)-stereoisomers of FBT for the VAcChT as well as sigma (sigma 1 and sigma 2) receptors. (+)-FBT was found to have a high affinity (Ki = 0.22 nM) for the VAcChT and lower affinities for sigma 1 (21.6 nM) and sigma 2 (35.9 nM) receptors, whereas (-)-FBT had similar affinities for the VAcChT and sigma 1 receptors (approximately 20 nM) and a lower affinity for sigma 2 (110 nM) receptors. PET imaging studies were conducted in rhesus monkeys (n = 3) with [18F](+)-FBT. [18F](+)-FBT was found to have a high accumulation and slow rate of washout from the basal ganglia, which is consistent with the labeling of cholinergic interneurons in this brain region. [18F](+)-FBT also displayed reversible binding kinetics during the 3 h time course of PET and produced radiolabeled metabolites that did not cross the blood-brain barrier. The results from the current in vitro and in vivo studies indicate that [18F](+)-FBT is a promising ligand for studying cholinergic terminal density, with PET, via the VAcChT.

Animals↗