Nonhuman primates monkeys

This chapter will review some recently completed studies on the long-term effects of MDMA in nonhuman primates. The goals of these studies were to (1) determine if the neurotoxic effects of MDMA, which have been well documented in the rodent (see below), generalize to the primate (2) compare the relative sensitivity of primates and rodents to the neurotoxic effects of MDMA (3) ascertain if the toxic effects of MDMA in the monkey are restricted to nerve fibers (as they are in the rat), or if they involve cell bodies as well (4) evaluate how closely toxic doses of MDMA in the monkey approximate those used by humans and (5) examine whether 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) can be used to detect MDMA-induced serotonergic damage in the CNS of primates. Before presenting the results of these studies, previous results in the... 

Bergman, J., Madras, B.K., Johnson, S.E., and Spealman, R.D., Effects of cocaine and related drugs in nonhuman primates. III. Self-administration by squirrel monkeys, J. Pharmacol. Exp. Then, 251, 150, 1989. 

Data Adequacy Adequate lethality data were available for several species including nonhuman primates. Although the variability in response to the lethal effects of monomethylhydrazine among all species tested appeared to be relatively small (2- to 3-fold difference), the squirrel monkey appeared to be somewhat more sensitive. The AEGL values for monomethylhydrazine reflect the steep exposure-response relationship suggested by available data. ... 

In vitro TGN1412 caused a profound, polyclonal T-cell proliferation of human peripheral blood mononuclear cells, including those from patients with BCLL. It also induced a profound activation and proliferation of T-cell subsets including CD4+ and CD8+ T cells, naive and memory T cells, and regulatory T cells. TGN1412 was shown to induce a transient, well tolerated expansion of T cells in nonhuman primates treated with TGN1412 and efficacy was demonstrated in a rhesus monkey collagen-induced arthritis model. 

Nonhuman primates are often the nonrodent species of choice for safety assessment studies. There are over 500 species of nonhuman primates that differ widely from each other in size and physical characteristics. Most of the monkeys used in experimental research belong to the suborder Anthropoidea and especially to the superfamilies of Ceboidea (marmoset, squirrel monkey) and Cercopitcoidea (macaque, papio species, rhesus). These have been popular because of (1) assumed better concordance of effects seen to those in man and (2) smaller weights (and therefore reduced compound requirement). However, predominant factors leading to a decision whether or not to select primates as the nonrodent species for safety evaluation are summarized as follows (Hobson, 2000). 

Ebola—Ebola hemorrhagic fever (Ebola EF) is a severe, often-fatal disease in nonhuman primates such as monkeys, chimpanzees, and gorillas, and in humans. Ebola has appeared sporadically since 1976 when it was first recognized. 

In nonhuman primates, including humans, research which directly examines the hormonal regulation of parental care is virtually nonexistent (Rosenblatt, 1995 Corter and Fleming, 1995). However, behavioral observations of pregnant rhesus monkeys have indicated that primiparous (first-time) mothers may not show reliable increases in parental... 

The website continues, "The use of animal models to study neuro-developmental disorders has also been expanding, particularly here at UC Davis, which has schools of medicine and veterinary medieine, as well as a primate research center. Monkeys and other nonhuman primates have brains organized comparable to humans, making them ideal research models for the study of neuro-developmental disorders."... 

Key words Embryo fetal development. Nonhuman primate, Cynomolgus monkey, Fetus, Marmoset, Teratology... 

Key words Enhanced pre-and postnatal study, ePPND, Nonhuman primates, Cynomolgus monkey... 

Rodent models have been used successfully to study generalized anxiety, but, unfortunately, their applicability to the study of panic attacks is doubtful [File 1995]. In contrast, nonhuman primate models of both anxiety and panic have been developed in our own group and in other laboratories. These models, which typically involve the administration of a challenge agent to a singly caged animal, have been successful because fear and anxiety occur spontaneously in the primate, typically in response to social or environmental threat, and because monkeys exhibit much the same behavioral repertoire in their natural environment and in captivity [Higley and Suomi 1989 Kalin and Shelton 1989 Sapolsky 1990 Suomi 1982]. 

Pharmacokinetics and cerebrospinal fluid penetration of hypericin were studied after i.v. dose of 2 mg/kg in monkeys (Table 2) (70). Mean peak plasma concentration of hypericin following this dose was 71.7pg/mL (142 pM). Elimination of hypericin from plasma was biexponential, with an average terminal half-life of 26 14 hours. The 2 mg/kg dose in nonhuman primates was sufficient to maintain plasma concentrations above 5.1 pg/mL (10 pM) for up to 12 hours (the in vitro concentration required for growth inhibition of human glioma cell lines is greater than 10 pM). 

More recently, however, in cynomologous monkeys, a nonhuman primate, some limited responses to these compounds have been seen with a twofold increase in liver weight, hepatocyte hypertrophy, an increase in peroxisomes (2.7x), and an increase in mitochondria. However, no DNA damage was detected. With humans taking ciprofibrate, only limited peroxisome proliferation was seen, and there was no increase in acyl CoA oxidase. Thus, the question is, "are humans at risk " In order to understand this, the mechanism needs to be understood. 

Monkeys, in particular Rhesus macaque and squirrel monkey, have been considered as models for vaginal drug absorption because of the similarities between nonhuman primate and human anatomy. The vagina of rhesus macaques is characterized by connective tissue attachments, localization of steroid hormone receptors, duration, and cyclic changes in vaginal physiology similar to that of humans [119]. 

P5. Parks, J. S., and Rudel, L. L., Metabolism of the serum amyloid A proteins (SAA) in high-density lipoproteins and chylomicrons of nonhuman primates (vervet monkey). Am. /. Pathol. 112, 243-249 (1983). 

It should be noted that there are very few CROs that offer reproductive toxicity testing in nonhuman primates. To date, most of the reproductive toxicology studies in monkeys have been segment 2 (teratology) studies. Segment 1 (fertility) studies would be difficult to conduct. 

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