An assay of drug-induced emesis in the squirrel monkey (Saimiri sciureus).

BACKGROUND: Emesis has significant evolutionary value as a defense mechanism against ingested toxins; however, it is also one of the most common adverse symptoms associated with both disease and medical treatments of disease. The development of improved antiemetic pharmacotherapies has been impeded by a shortage of animal models. METHODS: The present studies characterized the responses of the squirrel monkey to pharmacologically diverse emetic drugs. Subjects were administered nicotine (0.032-0.56 mg/kg), lithium chloride (150-250 mg/kg), arecoline (0.01-0.32 mg/kg), or apomorphine (0.032-0.32 mg/kg) and observed for emesis and prodromal hypersalivation. RESULTS: Nicotine rapidly produced emesis and hypersalivation. Lithium chloride produced emesis with a longer time course without dose-dependent hypersalivation. Arecoline produced hypersalivation but not emesis. Apomorphine failed to produce emesis or hypersalivation. CONCLUSIONS: The squirrel monkey is sensitive to drug-induced emesis by a variety of pharmacological mechanisms and is well-positioned to examine antiemetic efficacy and clinically important side effects of candidate antiemetic pharmacotherapies.

Facial dysplasia in wild forest olive baboons (Papio anubis) in Sebitoli, Kibale National Park, Uganda: Use of camera traps to detect health defects.

BACKGROUND: Primate populations are in decline, mainly affected by agriculture leading to habitat loss, fragmentation but also chemical pollution. Kibale National Park (Uganda), Sebitoli forest, surrounded by tea and crop fields, is the home range of chimpanzees presenting congenital facial dysplasia. This study aimed to identify to what extent the same phenotypical features are observed in baboons (Papio anubis) of this area. METHODS: A total of 25 390 clips recorded by 14 camera traps between January 2017 and April 2018 were analyzed. RESULTS: We identified 30 immature and adult baboons of both sexes with nose and lip deformities. They were more frequently observed in the northwestern part of the area. CONCLUSIONS: A possible effect of pesticides used in crops at the border of their habitat is suspected to alter the embryonic development. This study emphasizes the importance of non-invasive methods to detect health problems in wild primates that can act as sentinels for human health.

Generalized convulsive seizures are associated with ketamine anesthesia in a rhesus macaque (Macaca mulatta) undergoing urodynamic studies and transcutaneous spinal cord stimulation.

A female rhesus macaque developed two episodes of generalized convulsions during transcutaneous spinal cord stimulation (TSCS) and urodynamic studies under ketamine anesthesia. The seizures took place in the absence of active TSCS and bladder pressure elevation. Ketamine anesthesia remains the primary risk factor for the convulsions during these experimental procedures.

Hypoxemia after single-shot anesthesia in common marmosets.

BACKGROUND: It remains unknown how single-shot anesthesia influences physical parameters, especially respiratory function and blood oxygen level of common marmosets (Callithrix jacchus) which came to be used for laboratory research. METHODS: We measured blood oxygen levels, both before and after oxygenation, in 13 common marmosets under two single-shot anesthesia conditions: ketamine/xylazine/atropine and alphaxalone. RESULTS AND CONCLUSIONS: We found that SpO2 values decreased to about 80% in the ketamine/xylazine/atropine protocol and fell just below 90% in the alphaxalone protocol. We observed a clear decrease in PaO2 values under the anesthetized condition compared to the awake condition. Our data indicate that single-shot anesthesia may cause hypoxemia in marmosets. Previous studies on other non-human primate have reported no SpO2 decrease and hypoxemia; thus, our experiment suggests that marmosets may have a more fragile respiratory system and require intensive veterinary care during anesthesia.

Cascading impacts of anthropogenically driven habitat loss: deforestation, flooding, and possible lead poisoning in howler monkeys (Alouatta pigra).

To construct informed conservation plans, researchers must go beyond understanding readily apparent threats such as habitat loss and bush-meat hunting. They must predict subtle and cascading effects of anthropogenic environmental modifications. This study considered a potential cascading effect of deforestation on the howler monkeys (Alouatta pigra) of Balancán, Mexico. Deforestation intensifies flooding. Thus, we predicted that increased flooding of the Usumacinta River, which creates large bodies of water that slowly evaporate, would produce increased lead content in the soils and plants, resulting in lead exposure in the howler monkeys. The average lead levels were 18.18 ± 6.76 ppm in the soils and 5.85 ± 4.37 ppm in the plants. However, the average lead content of the hair of 13 captured howler monkeys was 24.12 ± 5.84 ppm. The lead levels in the animals were correlated with 2 of 15 blood traits (lactate dehydrogenase and total bilirubin) previously documented to be associated with exposure to lead. Our research illustrates the urgent need to set reference values indicating when adverse impacts of high environmental lead levels occur, whether anthropogenic or natural, and the need to evaluate possible cascading effects of deforestation on primates.

Renal pigmentation due to chronic bismuth administration in a rhesus macaque (Macaca mulatta).

Renal pigmentation due to the administration of exogenous compounds is an uncommon finding in most species. This report describes renal pigmentation and intranuclear inclusions of the proximal convoluted tubules due to chronic bismuth administration in a rhesus macaque. An 11-year-old Indian-origin rhesus macaque with a medical history of chronic intermittent vomiting had been treated with bismuth subsalicylate, famotidine, and omeprazole singly or in combination over the course of 8 years. At necropsy, the renal cortices were diffusely dark green to black. Light and electron microscopy revealed intranuclear inclusions within the majority of renal proximal tubular epithelial cells. These inclusions appeared magenta to brown when stained with hematoxylin and eosin and were negative by the Ziehl-Neelsen acid-fast stain. Elemental analysis performed on frozen kidney measured bismuth levels to be markedly elevated at 110.6 ppm, approximately 500 to 1000 times acceptable limits. To our knowledge, this is the first report of renal bismuth deposition in a rhesus macaque resulting in renal pigmentation and intranuclear inclusions.

Selective serotonin reuptake inhibitor and bleeding in a cynomolgus macaque (Macaca fascicularis).

Selective serotonin reuptake inhibitors (SSRI) are associated with an increased bleeding risk in humans. This report describes a bleeding event in a cynomolgus macaque (Macaca fascicularis) treated with the SSRI sertraline HCl (Zoloft). During the treatment course, the subject presented with a maculopapular rash, cutaneous bleeding, epistaxis, bleeding from the eye, melena, and a severe thrombocytopenia. To our knowledge, this report is the first description of an SSRI-related adverse event in a nonhuman primate. This report demonstrates that the clinical presentation of SSRI-associated bleeding in cynomolgus macaques is consistent with that reported in humans and that complications from SSRI treatment should be considered as a differential diagnosis for maculopapular dermatitis or spontaneous bleeding in this species.

Spontaneous and experimental malignancies in non-human primates.

Contrary to earlier established opinion that tumors in monkeys are found rarely, now the large material confirms that monkey tumors are frequent phenomenon. Tumor incidence clearly increases with age. Frequencies of benign and malignant tumors of various locations and histogenesis are slightly different. Tumors of hematopoietic system are the most frequent. Sporadic cases and enzootic outbreaks of lymphomas are described for different kinds of monkeys, including apes, and probably are caused by viruses. Two viruses were isolated by us from sick monkeys - the retrovirus C-type STLV-1 and the herpes virus papio HVP. Inoculation of virus cultures into monkeys and rabbits induces neoplasms. Monkey neoplasms can be induced by exposure to various chemical agents, and by oncogenic and non-oncogenic viruses. There is no strict species specificity of tumor viruses. The role of polyoma viruses in neoplasms etiology is discussed.

Chronic cadmium treatment induces tubular nephropathy and osteomalacic osteopenia in ovariectomized cynomolgus monkeys.

In an attempt to establish a primate model of chronic cadmium toxicosis, we ovariectomized cynomolgus monkeys and treated them with CdCl2 by repeated intravenous injections for 13 to 15 months. The animals showed normocytic-normochromic anemia. The cadmium treatment resulted in increases of urinary enzyme activity indicative of renal tubular degeneration. Histopathology of the kidney revealed renal proximal tubular atrophy accompanied by interstitial fibrosis. Decreased bone mineral density was evident in the trabecular and cortical zones of the lumbar vertebra and femur, with osteoid accumulation around the trabeculae and Haversian canals. Iron deposition at the mineralization front and osteoclasts hyperplasia were indicative of impairment of bone mineralization and an increase of resorption. Blood inorganic phosphorus and 1α,25(OH)2 vitamin D3 levels decreased and urinary deoxypyridinoline level increased in cadmium-treated animals. The renal and bone lesions closely resemble those of itai-itai disease patients, the most severe case of cadmium toxicosis in terms of clinical chemistry and histopathology. Thus, ovariectomized monkeys chronically exposed to cadmium can serve as a primate itai-itai disease model, which is beneficial for developing novel therapeutic methods, investigating the mechanisms of the renal and bone lesions, and establishing more clearly defined criteria for diagnosing the disease.

Generalized seizure activity in an adult rhesus macaque (Macaca mulatta) during ketamine anesthesia and urodynamic studies.

We report a case of a generalized seizure in an adult female rhesus macaque ( Macaca mulatta) undergoing a urodynamic evaluation while she was anesthetized with continuous-infusion ketamine. The seizure presented with generalized tonic-clonic activity during bladder infusion with saline. The tonic-clonic phase was self-limited and was followed by focal facial twitching, which was interrupted by bolus administration of intravenous diazepam. The ictal event was documented as pressure oscillations during cystometrogram recordings and a period of external urethral sphincter muscle activation, which was detectable by electromyography. An acute decrease in urethral pressure was demonstrated at the end of the generalized seizures. Ketamine anesthesia combined with relatively rapid infusion of saline into the bladder may have contributed to the onset of seizures. In addition, this case highlights the value of having a fast-acting benzodiazepine agent available to stop continuous or residual seizure activity during diagnostic or experimental procedures in anesthetized nonhuman primates.

Accidental induced seizures in three cynomologus macaques following administration of ceftriaxone dissolved in 1% lidocaine diluent.

Following initial signs of dural infection, or as prophylactic postoperative therapy, three cynomologus macaques were given an intramuscular or a subcutaneous injection of ceftriaxone dissolved in a 1% lidocaine diluent (CL). Two to 15 min later, all three monkeys experienced a long-lasting generalized apnoeic clonic convulsive seizure. The injected doses of lidocaine (0.7-2 mg/kg) were as low as 7-20-fold less than the experimental intravenous dosage (14.2 +/- 3.2 mg/kg) previously reported to induce seizure in healthy rhesus monkeys. Under different clinical conditions, the same three animals were either once (1 animal) or repeatedly given CL without any resultant neurological alterations. The monkeys had a cranial device implanted and two of them were craniotomized. This first report of accidental lidocaine-induced seizure in laboratory non-human primates following CL injection strongly suggests increased susceptibility when lidocaine administration is associated with central nervous system alteration. A novel hypothesis, the possible role of cytokine in lowering the lidocaine seizure threshold, is suggested.

High fat and high fructose diet induced intracranial atherosclerosis and enhanced vasoconstrictor responses in non-human primate.

The present study examined the effect of high fat and high fructose (HFF) diet on the development of atherosclerosis and vascular contractile responses in the cerebral artery and thoracic aorta in non-human primates. Female cynomolgus monkeys (age: 3 to 4 years) were divided into normal control diet (N=5) and HFF diet groups (N=5). Twenty-eight weeks after feeding the HFF diet, total cholesterol and low-density lipoprotein-cholesterol in serum were significantly increased in the HFF diet group compared to the control group. The ultrastructural analyses of the basilar artery and aorta demonstrated the infiltration of lipid-laden foam cells and the appearance of lipid droplet-filled smooth muscle cells in the monkeys fed with the HFF diet. In terms of vascular reactivity, there was significantly greater vasoconstriction of the aorta and basilar artery in response to 5-hydroxytryptamine in the HFF diet group compared to the normal diet-fed group. In addition, KCl-induced vasoconstriction of the basilar arteries was also significantly enhanced in the HFF diet group compared to the normal diet-fed monkeys. In all, our present study has demonstrated that changes in the vascular responsiveness of the cerebral artery and its cellular architecture may manifest into cerebrovascular complications consistent with a pathological state normally observed with the onset and progression of atherosclerosis.

Chronic cadmium treatment induces islet B cell injury in ovariectomized cynomolgus monkeys.

In an attempt to establish a primate model of chronic cadmium (Cd) toxicosis, we ovariectomized cynomolgus monkeys and treated with CdCl2 by repeated intravenous injections for 13 to 15 months. The animals showed an increase in blood glucose from Month 10 and a decrease in blood insulin at Month 11of the Cd-treatment. Histopathological examination of the Cd-treated animals revealed islet atrophy with reduction in islet number and vacuolation of the islet cells, whereas there was no remarkable change in the acinar cells of the exocrine pancreas. In histomorphometrical examination, insulin-positive areas in the islets were significantly decreased, accompanying a relative increase of glucagon-positive areas. Large amounts of Cd accumulated in the pancreas, and metallothionein (MT), a Cd binding protein, was localized in the islets of Cd-treated animals. The present study demonstrated that the chronic intravenous injection of Cd to cynomolgus monkeys induced the accumulation of the metal in the pancreas, degeneration of islet B cells and the diabetic clinical signs. Therefore the islet B cell is one of the major targets of the chronic Cd poisoning in monkeys.

Methylmercury poisoning in common marmosets--MRI findings and peripheral nerve lesions.

Common marmosets were used as model animals for methylmercury (MeHg) poisoning. Six marmosets were given MeHg of 5 ppm Hg in drinking water. The animals were divided into 3 groups of 2 each. The first group was examined for acute symptomatic MeHg poisoning. They were given MeHg for 70 and 90 days, respectively, to manifest severe symptoms. The second group was sacrificed after 38 days of MeHg exposure, when they had acute-subclinical MeHg poisoning. The third group of animals was exposed for 21 days, and then observed for 2.5 years without MeHg exposure. One of them showed typical symptoms of MeHg poisoning after MeHg exposure had ended, but the other one showed only slight symptoms without ataxia. This experiment demonstrated that MeHg causes pathological changes in neural tissues including the peripheral nerves in common marmosets. Furthermore, common marmosets were found to show MeHg-induced pathological changes similar to those in humans in the cerebrum and cerebellum.

Growth retardation in premenarchial female rhesus monkeys during chronic administration of GnRH agonist (leuprolide acetate).

Leuprolide acetate in depot form (0.75 mg/kg body weight/month, i.m.) was administered to four female rhesus monkeys from 18-30 months of age, a period that includes the premenarchial growth spurt. They were compared to eight age matched controls. As anticipated, sexual maturation was blocked in the Leuprolide group and menarche did not occur. Growth was also severely retarded; no weight gain occurred during the study in the Leuprolide group as compared to a 25% weight gain (P = .044) in the control group. The Leuprolide group also lost muscle mass. Food intake normalized for body weight was not affected. Linear growth averaged 35% less in the Leuprolide group. Serum IGF-1 concentrations increased from 486 +/- 84 to 965 +/- 47 ng/mL (P = .0025) in the Leuprolide group and from 838 +/- 139 to 3,006 +/- 545 ng/mL (P = .0016) in the control group. These data suggest that premenarchial pituitary/gonadal suppression results in a distinctive pattern of growth retardation in monkeys.

Lesions of acute inhaled lethal ricin intoxication in rhesus monkeys.

Five unimmunized adult rhesus monkeys weighing 5.9-6.3 kg were challenged with a precalculated, inhaled dose of 20.95-41.8 micrograms/kg of aerosolized ricin. Two males and three females either died or were killed at the onset of respiratory distress between 36 and 48 hours post-ricin inhalation and were necropsied. Consistent gross and microscopic lesions were confined to the thoracic cavity. All monkeys had multifocal to coalescing fibrinopurulent pneumonia, diffuse necrosis, and acute inflammation of airways, and nearly diffuse alveolar flooding, with peribronchovascular edema. All monkeys also had purulent tracheitis, fibrinopurulent pleuritis, and purulent mediastinal lymphadenitis. One male monkey and one female monkey had bilateral adrenocortical necrosis. We attributed the cause of death to asphyxiation following massive pulmonary alveolar flooding. The lesions of acute inhaled ricin intoxication in rhesus monkeys closely resembled those lesions reported in rats with acute inhaled ricin intoxication.

Production of premature delivery in pregnant rhesus monkeys by androstenedione infusion.

The endocrine mechanism involved in term and preterm delivery in primates, including pregnant women, are poorly understood. In the term monkey, fetal plasma androgen concentration rises to two hundred times the maternal concentration which remains unchanged. Placental conversion of androgen to estrogen results in increased maternal plasma estrogen concentration at term in both pregnant nonhuman primates and women. In the present study, continuous infusion of androstenedione to 0.8 gestation monkeys resulted in the premature occurrence of labor-type myometrial activity and increases in maternal plasma estrogen, oxytocin and amnion fibronectin concentrations similar to those measured at normal-term labor. Androstenedione induction of these normal-term biochemical and endocrine changes accompanied by fetal membrane rupture, cervical dilatation and live delivery provides a rich opportunity to study the molecular and physiological mechanisms of both term and preterm labor in primates.

Topical anesthetic-induced methemoglobinemia and sulfhemoglobinemia in macaques: a comparison of benzocaine and lidocaine.

Benzocaine (BNZ) and lidocaine (LC) are commonly used topical (spray) anesthetics approved for use in humans. Benzocaine has structural similarities to methemoglobin (MHb)-forming drugs that are current candidates for cyanide prophylaxis, while LC has been reported to increase MHb in man. In this study, we compared MHb and sulfhemoglobin (SHb) production in three groups of Macaques (Chinese rhesus and Indian rhesus (Macaca mulatta) and pig-tailed macaques (Macaca nemestrina)) after exposure to BNZ and LC. Formation of SHb, unlike MHb, is not thought to be reversible and therefore is considered to be of greater toxic significance. Both MHb and SHb levels were measured periodically on a CO-Oximeter. All rhesus macaques (n = 8) were administered an intratracheal/intranasal) dose of 56 mg (low dose) or 280 mg (high dose) of BNZ or 40 mg of LC in a randomized cross-over design (all animals received all three treatments). Pig-tailed macaques (n = 6) were given an intranasal dose of 56 mg of BNZ and 40 mg of LC. As no differences in the peak MHb or time to peak (mean +/- SD) were observed among the three macaque subspecies, the data were pooled. Lidocaine did not cause MHb or SHb formation above baseline in any monkey. In contrast, all monkeys (n = 14) had a significant elevation in peak MHb formation after 56 mg of BNZ, which ranged from 4.0% to 19.4% with an average of 8.6 +/- 4.0% (mean +/- SD), with peak MHb levels reached at 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)