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PubMed1994

Therapeutic efficacy of recombinant interleukin-6 (IL-6) alone and combined with recombinant human IL-3 in a nonhuman primate model of high-dose, sublethal radiation-induced marrow aplasia.

Using a nonhuman-primate model of radiation-induced bone marrow aplasia, we examined whether the single, concomitant, or sequential administration of recombinant human interleukin-3 (IL-3) and IL-6 would promote bone marrow regeneration measured by an increase in circulating platelets (PLT) and neutrophils (PMN). Rhesus monkeys were irradiated at 450 cGy and were randomly assigned to one of five treatment protocols, receiving IL-6; IL-3; combined IL-6 and IL-3; sequential IL-3 and IL-6; or human serum albumin (HSA) as a control. Cytokines or HSA were administered at total dosages of 15 micrograms/kg/day. Complete blood counts and white blood cell differentials were monitored for 60 days postirradiation. Both IL-3 and IL-6 significantly enhanced the regeneration of PLTs and decreased the duration of thrombocytopenia (P = .005) without affecting PMN recovery. The radiation-induced anemia that was observed in the HSA-treated controls was less severe and resolved more quickly in the IL-6 treated animals. Sequential IL-3/IL-6 significantly increased the production of PLTs when compared with the HSA-treated controls (P = .003) and monkeys receiving concomitant IL-3/IL-6 (P = .041) but did not alter PMN levels significantly (P = .80). Coadministration of IL-6 and IL-3 did not enhance PLT but improved PMN recovery over IL-6 alone. In this primate model of marrow aplasia, IL-6 significantly enhanced the regeneration of PLTs but had no significant effect on PMN production, and did not exacerbate radiation-induced anemia. Furthermore, the use of sequentially administered IL-3 and IL-6 may improve PLT recovery as compared with concurrent IL-3/IL-6 administration, although this protocol is not significantly different in effect than either cytokine alone.

Anemia↗
PubMed1976

A simple restraining device for use with neonatal and small nonhuman primates.

A simple and inexpensive restraining device was designed for use with neonatal and small nonhuman primates weighing less than 2 kg. With this device a technician working alone can collect blood samples, fecal or vaginal smears, nasal or oral swabs, or perform a variety of routine procedures including physical examination and administration of medication.

Animals↗
PubMed2001

Three-dimensional analysis of nonhuman primate trabecular architecture using micro-computed tomography.

Until recently, detailed analyses of the architecture of nonhuman primate cancellous bone have not been possible due to a combination of methodological constraints, including poor resolution imaging or destructive protocols. The development of micro-computed tomography (microCT) and morphometric methods associated with this imaging modality offers anthropologists a new means to study the comparative architecture of cancellous bone. Specifically, microCT will allow anthropologists to investigate the relationship between locomotor behavior and trabecular structure. We conducted a preliminary study on the trabecular patterns in the proximal humerus and femur of Hylobates lar, Ateles paniscus, Macaca mulatta, and Papio anubis to investigate the quantitative differences in their trabecular architecture and evaluate the potential of microCT in anthropological inquiry. MicroCT allows the researcher to evaluate variables beyond simple two-dimensional orientations and radiographic densities. For example, this methodology facilitates the study of trabecular thickness and bone volume fraction using three-dimensional data. Results suggest that density-related parameters do not reliably differentiate suspensory-climbing species from quadrupedal species. However, preliminary results indicate that measurements of the degree of anisotropy, a measure of trabecular orientation uniformity, do distinguish suspensory-climbing taxa from more quadrupedal species. The microCT method is an advance over conventional radiography and medical CT because it can accurately resolve micron-sized struts that make up cancellous bone, and from these images a wide array of parameters that have been demonstrated to be related to cancellous bone mechanical properties can be measured. Methodological problems pertinent to any comparative microCT study of primate trabecular architecture are discussed.

Animals↗
PubMed2001

Nonhuman primates: a critical role in current disease research.

This review article emphasizes the critical role of nonhuman primates (NHPs) in biomedical research. It focuses on the most recent contributions that NHPs have made to the understanding, treatment, and prevention of important infectious diseases (e.g., acquired immunodeficiency syndrome, hepatitis, malaria) and chronic degenerative disorders of the central nervous system (e.g., Parkinson's and Alzheimer's diseases). The close phylogenetic relation of NHPs to humans not only opens avenues for testing the safety and efficacy of new drugs and vaccines but also offers promise for evaluating the potential of new gene-based treatments for human infectious and genetic diseases.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Species, diet, and gender differences in plasma postheparin lipolytic activities in nonhuman primates. Relationships with plasma lipids and high density lipoproteins.

Studies were done in selected groups of nonhuman primates in which the diet (low fat and high fat as either polyunsaturated or saturated fat), gender, and species (African green monkeys and cynomolgus monkeys) were varied. Large differences in plasma lipid and lipoprotein concentrations were found among these groups, providing the opportunity to examine their relationships to postheparin lipolytic activities (PHLA) including lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL). PHLA was measured in plasma drawn 20 minutes after injection of heparin (100 units/kg). The assay was done with a radioactive triglyceride emulsion, and LPL and HTGL activities were estimated after 1 M NaCl inhibition of the former. LPL activity was high in both species of monkeys, and HTGL activity was low; the ratio of HTGL/LPL was consistently less than 0.5. The mean values for LPL activity did not vary significantly among experimental groups, but significant negative correlations between LPL activity and plasma triglyceride concentration were found. Statistically significant diet, species, and gender differences in HTGL activities were found. In high-fat-fed compared to low-fat-fed animals, HTGL activities were higher, and high density lipoprotein (HDL) cholesterol concentrations and the percentages of HDL2b were also higher. African green monkeys had consistently higher HTGL activities than cynomolgus monkeys and had higher concentrations of HDL cholesterol and a greater proportion of HDL as the larger HDL2b subfraction. Significantly lower HTGL activities were found in females compared to males fed the low-fat diets, and females had a significantly greater proportion of total HDL in the HDL2b subfraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Immediate and long-term safety of recombinant adeno-associated virus injection into the nonhuman primate muscle.

Previous studies on distribution and toxicity of viral vectors administered in monkeys indicated that the nonhuman primate model has a reasonable predictive value for clinical applications. In this study, eight macaques were injected intramuscularly with recombinant adeno-associated virus (rAAV) at doses similar to those administered to hemophilia B patients, and followed to analyze the dissemination and shedding in biological samples and long-term persistence in distant organs. Following rAAV delivery, we found vector genome in various biological fluids for up to 6 days and infectious particles exclusively in the serum during the first 48-72 hours. rAAV sequences were detected in peripheral blood mononuclear cells (PBMC) for up to 10 months. At necropsy, 8 to 18 months after rAAV delivery, rAAV sequences were found in lymph nodes and livers but never in the gonads. Tissue examination, of liver in particular, showed no abnormalities. We concluded that during our experimental time frame, rAAV-mediated gene transfer into skeletal muscle of macaques seemed to be safe with respect to the recipient and the environment. However, it was associated with a transient viremia and the persistence of rAAV sequences in PBMC, lymph nodes, and liver, the long-term consequences of which remain unknown.

Animals↗
PubMedDate not supplied

Nonhuman primates in behavioral toxicology: issues of validity, ethics and public health.

The small, but vital, niche of nonhuman primates in neurotoxicology is examined. Several models of sensory and cognitive function have been especially useful with primates. Their sensitivity to low doses is clear. The validity of data from these models is indicated by their high correlation with data from intoxicated and normal humans, by the degree to which they approximate job functions and other vital human performances, and by their ability to document specific changes in behavioral function which correlate well with morphological and biochemical effects. The use of primates for this research is justified by the absence of adequate alternatives using nonprimate species, in vitro tests or computer programs. A series of experiments on the effects of methylmercury is used to illustrate ethical and scientific issues concerning research with primates. Recent trends are illustrated by data with trimethyltin.

Animal Experimentation↗
PubMed2005

Serotonin and aggressive behavior in rodents and nonhuman primates: predispositions and plasticity.

This review analyzes psychosocial and genetic determinants of aggressive behavior in rodents and nonhuman primates and the role of the serotonin (5-HT) system on aggressive behaviors in order to trace possible evolutionary common origins between psychopathological and adaptive forms of aggression. Studies in primates suggest that deficit in serotonin activity, as indicated by the levels of the cerebrospinal fluid (CSF) serotonin major metabolite 5-hydroxyindoleacetic acid (5-HIAA) correlates with impulsive and aggressive behavior. It is possible that CSF 5-HIAA reflects the prevailing serotonergic tone and may be related to an aggressive trait. Superimposed on this tone are phasic serotonin changes that may be related to the inhibition of aggressive acts. Genetic factors determine aggressive behaviors as demonstrated by classic selection and strain comparison studies. Manipulations of genes targeting 5-HT receptors, transporters and enzymes can influence aggression. Some of these genes related to the serotonin transporter (5-HTT) and the monoamine oxidase A (MAO-A) show a polymorphism that may predispose, under specific environmental conditions, certain individuals to display pathological forms of aggression.

Aggression↗
PubMed1991

Manual laterality in nonhuman primates: a distinction between handedness and manual specialization.

This article examines individual and group manual lateralization in nonhuman primates as a function of task's demands. It is suggested to distinguish low- from high-level manual activities with respect to the novelty variable and to the spatiotemporal scale of the movements. This review shows that low-level tasks lead to (a) symmetrical distributions of hand biases for the group and (b) manual preferences that are not indicative of the specialization of the contralateral hemisphere. In contrast, behaviors expressed in high-level tasks (a) show asymmetrical distribution of hand biases for the group and (b) seem to be related to a specialization of the contralateral hemisphere. Two types of lateralization, handedness and manual specialization, correspond to the 2 levels of tasks that are distinguished.

Animals↗
PubMed2006

Lack of correlation between SIV-Nef evolution and rapid disease progression in morphine-dependent nonhuman primate model of AIDS.

Six morphine-dependent and two control macaques were infected in an SIV/SHIV nonhuman primate model of AIDS. Three animals in the morphine group rapidly developed clinical disease and died within the timeframe of this study. The sequence evolution of nef in plasma virus was assessed at 4, 12, and 20 weeks postinfection. Cloned sequences were compared phylogenetically against each other as well as against the inoculum virus clones to determine the effect of morphine and rate of disease progression on diversity and divergence, respectively. Unlike our earlier studies of tat and env, nef evolution was not affected by morphine abuse or by rapid disease progression. The results suggest that although the evolution of other loci is inversely correlated to the onset and rate of clinical disease, differential evolution of nef is related neither to drug abuse nor to rapid progression within the first 20 weeks of infection.

Animals↗
PubMed2003

Nonhuman primate model for Listeria monocytogenes-induced stillbirths.

Listeria monocytogenes, isolated from outbreaks in either human or nonhuman primate populations, was administered orally at doses ranging from 10(6) to 10(10) CFU. Four of 10 treated animals delivered stillborn infants. L. monocytogenes was isolated from fetal tissue, and the pathology was consistent with L. monocytogenes infection as the cause of pregnancy loss. For all pregnancies resulting in stillbirths, L. monocytogenes was isolated from maternal feces, indicating that L. monocytogenes had survived and had probably colonized the gastrointestinal tract. Antibodies and antigen-specific lymphocyte proliferation against Listeria increased in animals that had stillbirths.

Animals↗
PubMed1980

Microscopic examination of stools from nonhuman primates as a way of predicting the presence of Shigella.

Microscopic examination of stool samples from captive nonhuman primates with diarrhea for the presence or absence of leukocytes or erythrocytes or both as a means of predicting the presence of Shigella spp. was performed. Analysis of the data multivariately by means of a log linear model did not show a three-way association between diarrhea, Shigella, and the presence or absence of cells.

Animals↗
PubMed2006

Placental growth factor-1 potentiates hematopoietic progenitor cell mobilization induced by granulocyte colony-stimulating factor in mice and nonhuman primates.

The complex hematopoietic effects of placental growth factor (PlGF) prompted us to test in mice and nonhuman primates the mobilization of peripheral blood progenitor cells (PBPCs) elicited by recombinant mouse PlGF-2 (rmPlGF-2) and recombinant human PlGF-1 (rhPlGF-1). PBPC mobilization was evaluated by assaying colony-forming cells (CFCs), high-proliferative potential-CFCs (HPP-CFCs), and long-term culture-initiating cells (LTC-ICs). In mice, both rmPlGF-2 and rhPlGF-1 used as single agents failed to mobilize PBPCs, whereas the combination of rhPlGF-1 and granulocyte colony-stimulating factor (rhG-CSF) increased CFCs and LTC-ICs per milliliter of blood by four- and eightfold, respectively, as compared with rhG-CSF alone. rhPlGF-1 plus rhG-CSF significantly increased matrix metalloproteinase-9 plasma levels over rhG-CSF alone, suggesting a mechanistic explanation for rhPlGF-1/rhG-CSF synergism. In rhesus monkeys, rhPlGF-1 alone had no mobilization effect, whereas rhPlGF-1 (260 microg/kg per day) plus rhG-CSF (100 microg/kg per day) increased rhG-CSF-elicited mobilization of CFCs, HPP-CFCs, and LTC-ICs per milliliter of blood by 5-, 7-, and 15-fold, respectively. No specific toxicity was associated with the administration of rhPlGF-1 alone or in combination. In conclusion, our data demonstrate that rhPlGF-1 significantly increases rhG-CSF-elicited hematopoietic mobilization and provide a preclinical rationale for evaluating rhPlGF-1 in the clinical setting.

Animals↗
PubMed2005

Application of autologous hematopoietic cell therapy to a nonhuman primate model of heterogeneous high-dose irradiation.

We developed a model of heterogeneous irradiation in a nonhuman primate to test the feasibility of autologous hematopoietic cell therapy for the treatment of radiation accident victims. Animals were irradiated either with 8 Gy to the body with the right arm shielded to obtain 3.4 Gy irradiation or with 10 Gy total body and 4.4 Gy to the arm. Bone marrow mononuclear cells were harvested either before irradiation or after irradiation from an underexposed area of the arm and were expanded in previously defined culture conditions. We showed that hematopoietic cells harvested after irradiation were able to expand and to engraft when reinjected 7 days after irradiation. Recovery was observed in all 8-Gy-irradiated animals, and evidence for a partial recovery was observed in 10-Gy-irradiated animals. However, in 10-Gy-irradiated animals, digestive disease was observed from day 16 and resulted in the death of two animals. Immunohistological examinations showed damage to the intestine, lungs, liver and kidneys and suggested radiation damage to endothelial cells. Overall, our results provide evidence that such an in vivo model of heterogeneous irradiation may be representative of accidental radiation exposures and may help to define the efficacy of therapeutic interventions such as autologous cell therapy in radiation accident victims.

Animals↗
PubMed2001

Perspectives on using nonhuman primates to understand the etiology and treatment of postmenopausal osteoporosis.

The reproductive physiology and skeletal anatomy of nonhuman primates are very similar to those of women and these similarities have prompted studies of the effects of ovariectomy in monkeys on bone metabolism. Following ovariectomy, monkey bone exhibits increases in remodeling activity resulting in bone loss. Since similar bone changes occur after menopause in women, ovariectomized monkeys provide an excellent model of the early skeletal events following menopause and have been employed to study the skeletal actions of drugs designed to treat postmenopausal osteoporosis. This review describes the motivations for examining monkeys, practical aspects of working with monkeys, comparisons of human and monkey bone anatomy, endocrinological aspects of monkey bone metabolism, and the available data obtained in monkeys related to postmenopausal and other forms of osteoporosis.

Journal Article↗
PubMed1977

Nonhuman primates: laboratory animals of choice for neurophysiologic studies of sleep.

A systematic study was made of several nonhuman primates to learn more about their relative usefulness for studies of sleep. Species studied included the Guinea baboon (Papio papio), Kenya or yellow baboon (P cynocephalus), olive baboon (P anubis), sacred baboon (P hamadryas), vervet monkey (Cercopithecus aethiops), rhesus monkey (Macaca mulatta), bonnet monkey (M radiata), crab-eating monkey (M fascicularis), patas monkey (Erythrocebus patas), chimpanzee (Pan troglodytes), mongoose lemur (Lemur mongoz), black lemur (Lemur macaco fulvus), and bushbaby (Galago senegalensis). Comparisons were made of electroencephalographic activity, states of vigilance, and responses to sleep-waking drugs. The results showed that there were major similarities among the genera studied as well as individual intrageneric and intraspecies differences. It was concluded that the chimpanzee, olive baboon, and rhesus monkey were the best species for comparative studies, and that the rhesus monkey was the best single model because of its well defined sleep organization and ease of handling and housing.

5-Hydroxytryptophan↗
PubMed2006

Translation of nondopaminergic treatments for levodopa-induced dyskinesia from MPTP-lesioned nonhuman primates to phase IIa clinical studies: keys to success and roads to failure.

Studies in MPTP-lesioned nonhuman primates have demonstrated the potential of nondopaminergic drugs in reducing the problems of levodopa-induced dyskinesia (LID). Here we review the process of translating findings from the monkey to man. Agents targeting glutamate, adensosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid transmitter systems have been assessed for antidyskinetic potential in human studies. Eleven nondopaminergic drugs with antidyskinetic efficacy in the MPTP primate have been advanced to proof-of-concept phase IIa trials in PD patients (amantadine, istradefylline, idazoxan, fipamezole, sarizotan, quetiapine, clozapine, nabilone, rimonabant, naloxone, and naltrexone). For all six nondopaminergic transmitter systems reviewed, the MPTP-lesioned primate correctly predicted phase II efficacy of at least one drug. Of the 11 specific molecules tested in both monkeys and humans, 8 showed clear antidyskinetic properties in both human and monkey. In the instances where the primate studies did not, or did not consistently, predict the outcome of the human studies, the discrepancy may reflect limitations in the validity of the model or limitations in the design of either the clinical or the preclinical studies. We find that the major determinant of success in predicting efficacy is to ensure that primate studies are conducted in a statistically rigorous way and incorporate designs and outcome measures with clinical applicability. On the other hand, phase IIa trials should strive to replicate the preclinical study, especially in terms of protocol, drug dose equivalence, and outcome measure, so as to test the same hypothesis. Failure to meet these criteria carries the risk of false negative conclusions in phase IIa trials.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
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↗