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Cynomolgus Monkeys (cynomolgu + monkey)
Kinds of Cynomolgus Monkeys Selected AbstractsExperimental hepatitis A virus (HAV) infection in cynomolgus monkeys (Macaca fascicularis): evidence of active extrahepatic site of HAV replicationINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 1 2010Luciane A. Amado Summary This work studied the replication sites of hepatitis A virus (HAV) in cynomolgus monkeys (Macaca fascicularis) after intravenous inoculation. The cynomolgus monkeys were inoculated with the Brazilian hepatitis A virus strain (HAF-203). Monkeys were euthanized on days 15, 30, 45 and 60 postinoculation (pi). Liver samples, submandibular salivary gland, mesenteric lymph node and tonsils were removed for virological and pathological evaluation. Immunofluorescence analyses on liver and salivary gland sections using confocal laser scanning microscopy revealed the presence of HAV antigen (HAV Ag). The presence of HAV genome was monitored by real-time PCR. The HAV RNA was detected at 7 days postinoculation (dpi), concomitantly in serum, saliva and faeces. The highest HAV viral load was observed in faeces at 15 dpi (105 copies/ml), followed by serum viral load of 104 copies/ml at 20 dpi and saliva viral load of 103 copies/ml at 7 dpi. The animals showed first histological and biochemical signs of hepatitis at 15 dpi. The HAV antigen (Ag) was present from day 7 until day 60 pi in the liver and salivary glands. The HAV replicative intermediate was also detected in the liver (4.5 × 104 copies/mg), salivary glands (1.9 × 103 copies/mg), tonsils (4.2 × 101 copies/mg) and lymph nodes (3.4 × 101 copies/mg). Our data demonstrated that the salivary gland as an extrahepatic site of early HAV replication could create a potential risk of saliva transmitted infection. In addition, the cynomolgus monkey was confirmed as a suitable model to study the pathogenesis of HAV human infection. [source] Hematology and serum chemistry parameters in juvenile cynomolgus monkeys (Macaca fascicularis) of Mauritius origin: comparison between purpose-bred and captured animalsJOURNAL OF MEDICAL PRIMATOLOGY, Issue 4 2009Ugo Bonfanti Abstract Background, The vast majority of non-human primates used for experimental activities are purpose-bred. However, in case of particular procedures or specific projects, it may still be necessary to use animals captured in the wild. Methods, Sixty cynomolgus monkeys were randomly selected on the basis of breeding origin, and assigned to two groups, each of fifteen males and fifteen females. Analyses included the most frequently investigated parameters for hematology, coagulation, and biochemistry. Results, Differences were observed in some parameters, particularly in eosinophils, basophils and monocytes, and in fibrinogen, total protein, globulins, alanine amino-transferase, creatinine, aspartate amino-transferase, alkaline phosphatase, ,-glutamyl transferase, lactate dehydrogenase, ,-hydroxybutyrate dehydrogenase, iron, potassium, and phosphorus. Conclusions, Some values in the cynomolgus monkey may show significant differences according to the breeding background of the animals. Only data obtained from animals of similar origin have to be compared, to avoid misinterpretation during the evaluation of the experimental results. [source] Accelerating drug development: methodology to support first-in-man pharmacokinetic studies by the use of drug candidate microdosingDRUG DEVELOPMENT RESEARCH, Issue 1 2007Matthew A. McLean Abstract Microdosing of experimental therapeutics in humans offers a number of benefits to the drug development process. Microdosing, conducted under an exploratory Investigational New Drug (IND) application, entails administration of a sub-pharmacological dose of a new chemical entity (NCE) that allows for early evaluation of human pharmacokinetics. Such information can be pivotal for: (1) selecting a compound for full drug development from a small group of candidates; (2) defining the amount of material needed for early development; and (3) setting the initial Phase I dose regimen in humans. Appropriate safety studies must be conducted to support microdosing in humans, but the requirements are generally less extensive than those needed to support a traditional IND. To date, microdosing has not been broadly applied by the pharmaceutical industry due to concerns about analytical sensitivity and the possibility of non-linear pharmacokinetics at extremely low doses. The primary method for detecting analytes following microdosing until now has been accelerator mass spectrometry, which is expensive, not generally available, and requires test agents to be radiolabeled. Presented in this report is an example of pharmacokinetics analysis using LC/MS/MS following microdosing of an experimental agent in cynomolgus monkeys. The results show good linearity in plasma pharmacokinetics for oral doses of 10,mg/kg (therapeutic dose) and 0.0005,mg/kg (microdose) of the test agent. The results also demonstrate the feasibility of applying standard laboratory analytics to support microdosing in humans and raise the possibility of establishing an animal model to screen for compounds having non-linear pharmacokinetics at low dose levels. Drug Dev. Res. 68:14,22, 2007. © 2007 Wiley-Liss, Inc. [source] Pharmacodynamics and pharmacokinetics of YM128, a GPIIb/IIIa antagonist prodrugDRUG DEVELOPMENT RESEARCH, Issue 3 2002Ken-ichi Suzuki Abstract We examined the biochemical properties of YM-57029 ({4-[4-(4-Carbamimidoylphenyl)-3-oxopiperazin-1-yl]piperidino}acetic acid monohydrochloride trihydrate) and the pharmacodynamics and pharmacokinetics of its prodrug, YM128 (Ethyl (Z)-(4-{4-[4-(N2 -hydroxycarbamimidoyl)phenyl]-3-oxopiperazin-1-yl}piperidino)acetate), an orally-active glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist. YM-57029 strongly inhibited aggregation of human platelets induced by various agonists, with IC50 values ranging from 3.6 to 51 nM. YM-57029 specifically inhibited fibrinogen binding to purified GPIIb/IIIa about 1,000-fold more potently than Arg-Gly-Asp-Ser (RGDS). Moreover, YM-57029 effectively inhibited an Arg-Gly-Asp (RGD) peptide binding to platelets, suggesting that YM-57029 competed with the RGD sequence of ligand. YM-57029 or YM128 dose-dependently inhibited ex vivo platelet aggregation after iv bolus injection or oral administration to beagle dogs and cynomolgus monkeys. However, YM128 exerted more potent and prolonged inhibitory effects on platelet aggregation than YM-57029 after oral administration to cynomolgus monkeys. Furthermore, YM-57029 prolonged template bleeding time at a dose that inhibited ex vivo platelet aggregation during cumulative iv infusion to cynomolgus monkeys. Metabolic and pharmacokinetic studies showed that YM128 effectively converted into YM-57029 in liver microsomes from humans as well as dogs and monkeys, and that bioavailabilities of YM128 in dogs and monkeys were 32.3 and 22.2%, respectively. These results suggest that YM128, a prodrug of YM-57029, may be a valuable GPIIb/IIIa antagonist with good bioavailability in humans. Drug Dev. Res. 55:149,161, 2002. © 2002 Wiley-Liss, Inc. [source] Experimental hepatitis A virus (HAV) infection in cynomolgus monkeys (Macaca fascicularis): evidence of active extrahepatic site of HAV replicationINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 1 2010Luciane A. Amado Summary This work studied the replication sites of hepatitis A virus (HAV) in cynomolgus monkeys (Macaca fascicularis) after intravenous inoculation. The cynomolgus monkeys were inoculated with the Brazilian hepatitis A virus strain (HAF-203). Monkeys were euthanized on days 15, 30, 45 and 60 postinoculation (pi). Liver samples, submandibular salivary gland, mesenteric lymph node and tonsils were removed for virological and pathological evaluation. Immunofluorescence analyses on liver and salivary gland sections using confocal laser scanning microscopy revealed the presence of HAV antigen (HAV Ag). The presence of HAV genome was monitored by real-time PCR. The HAV RNA was detected at 7 days postinoculation (dpi), concomitantly in serum, saliva and faeces. The highest HAV viral load was observed in faeces at 15 dpi (105 copies/ml), followed by serum viral load of 104 copies/ml at 20 dpi and saliva viral load of 103 copies/ml at 7 dpi. The animals showed first histological and biochemical signs of hepatitis at 15 dpi. The HAV antigen (Ag) was present from day 7 until day 60 pi in the liver and salivary glands. The HAV replicative intermediate was also detected in the liver (4.5 × 104 copies/mg), salivary glands (1.9 × 103 copies/mg), tonsils (4.2 × 101 copies/mg) and lymph nodes (3.4 × 101 copies/mg). Our data demonstrated that the salivary gland as an extrahepatic site of early HAV replication could create a potential risk of saliva transmitted infection. In addition, the cynomolgus monkey was confirmed as a suitable model to study the pathogenesis of HAV human infection. [source] Intermittently Administered Human Parathyroid Hormone(1,34) Treatment Increases Intracortical Bone Turnover and Porosity Without Reducing Bone Strength in the Humerus of Ovariectomized Cynomolgus MonkeysJOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2001David B. Burr Abstract Cortical porosity in patients with hyperparathyroidism has raised the concern that intermittent parathyroid hormone (PTH) given to treat osteoporotic patients may weaken cortical bone by increasing its porosity. We hypothesized that treatment of ovariectomized (OVX) cynomolgus monkeys for up to 18 months with recombinant human PTH(1,34) [hPTH(1,34)] LY333334 would significantly increase porosity in the midshaft of the humerus but would not have a significant effect on the strength or stiffness of the humerus. We also hypothesized that withdrawal of PTH for 6 months after a 12-month treatment period would return porosity to control OVX values. OVX female cynomolgus monkeys were given once daily subcutaneous (sc) injections of recombinant hPTH(1,34) LY333334 at 1.0 ,g/kg (PTH1), 5.0 ,g/kg (PTH5), or 0.1 ml/kg per day of phosphate-buffered saline (OVX). Sham OVX animals (sham) were also given vehicle. After 12 months, PTH treatment was withdrawn from half of the monkeys in each treatment group (PTH1-W and PTH5-W), and they were treated for the remaining 6 months with vehicle. Double calcein labels were given before death at 18 months. After death, static and dynamic histomorphometric measurements were made intracortically and on periosteal and endocortical surfaces of sections from the middiaphysis of the left humerus. Bone mechanical properties were measured in the right humeral middiaphysis. PTH dose dependently increased intracortical porosity. However, the increased porosity did not have a significant detrimental effect on the mechanical properties of the bone. Most porosity was concentrated near the endocortical surface where its mechanical effect is small. In PTH5 monkeys, cortical area (Ct.Ar) and cortical thickness (Ct.Th) increased because of a significantly increased endocortical mineralizing surface. After withdrawal of treatment, porosity in PTH1-W animals declined to sham values, but porosity in PTH5-W animals remained significantly elevated compared with OVX and sham. We conclude that intermittently administered PTH(1,34) increases intracortical porosity in a dose-dependent manner but does not reduce the strength or stiffness of cortical bone. [source] Hematology and serum chemistry parameters in juvenile cynomolgus monkeys (Macaca fascicularis) of Mauritius origin: comparison between purpose-bred and captured animalsJOURNAL OF MEDICAL PRIMATOLOGY, Issue 4 2009Ugo Bonfanti Abstract Background, The vast majority of non-human primates used for experimental activities are purpose-bred. However, in case of particular procedures or specific projects, it may still be necessary to use animals captured in the wild. Methods, Sixty cynomolgus monkeys were randomly selected on the basis of breeding origin, and assigned to two groups, each of fifteen males and fifteen females. Analyses included the most frequently investigated parameters for hematology, coagulation, and biochemistry. Results, Differences were observed in some parameters, particularly in eosinophils, basophils and monocytes, and in fibrinogen, total protein, globulins, alanine amino-transferase, creatinine, aspartate amino-transferase, alkaline phosphatase, ,-glutamyl transferase, lactate dehydrogenase, ,-hydroxybutyrate dehydrogenase, iron, potassium, and phosphorus. Conclusions, Some values in the cynomolgus monkey may show significant differences according to the breeding background of the animals. Only data obtained from animals of similar origin have to be compared, to avoid misinterpretation during the evaluation of the experimental results. [source] The effect of long-term streptozotocin-induced diabetes mellitus (STZ-DM) on cynomolgus (Macaca Fascicularis) monkeysJOURNAL OF MEDICAL PRIMATOLOGY, Issue 1 2009D. Wu Abstract Background, This study aimed to retrospectively analyze the effect of long-term streptozotocin-induced diabetes mellitus (STZ-DM) on adolescent cynomolgus monkeys. Methods, A total of 12 monkeys (six STZ-DM and six controls) were monitored for fasting glucose levels and locomotor activities, tested for hematological and serum parameters, measured for body weight and somatometric values. Results, Fasting glucose was maintained at high levels in STZ-DM monkeys. At the age when normal adolescent monkeys dramatically increased their weight, STZ-DM led to the retardation of weight increase in diabetic monkeys. Moreover, STZ-DM monkeys showed abnormal lipid levels and somatometric measurements. In locomotor activity test, STZ-DM monkeys were more active than control ones. Conclusions, Long-term STZ-DM disrupts the normal growth of young monkeys and interferes with some aspects of hormone, lipid metabolism and physical activities. Mean plasma glucose (MPG) appeared to be an important factor in physical activity abnormalities of STZ-DM monkeys. [source] Effect of vaccination with recombinant modified vaccinia virus Ankara expressing structural and regulatory genes of SIVmacJ5 on the kinetics of SIV replication in cynomolgus monkeysJOURNAL OF MEDICAL PRIMATOLOGY, Issue 4 2001Donatella R.M. Negri The efficacy of a multicomponent vaccination with modified vaccinia Ankara constructs (rMVA) expressing structural and regulatory genes of simian immunodeficiency virus (SIVmac251/32H/J5) was investigated in cynomolgus monkeys, following challenge with a pathogenic SIV. Vaccination with rMVA-J5 performed at week 0, 12, and 24 induced a moderate proliferative response to whole SIV, a detectable humoral response to all but Nef SIV antigens, and failed to induce neutralizing antibodies. Two months after the last boost, the monkeys were challenged intravenously with 50 MID50 of SIVmac251. All control monkeys, previously inoculated with non-recombinant MVA, were infected by week two and seroconverted by weeks four to eight. In contrast a sharp increase of both humoral and proliferative responses at two weeks post-challenge was observed in vaccinated monkeys compared to control monkeys. Although all vaccinated monkeys were infected, vaccination with rMVA-J5 appeared to partially control viral replication during the acute and late phase of infection as judged by cell- and plasma-associated viral load. [source] Ultrasound detection of non-Hodgkin's lymphoma in three cynomolgus monkeys after renal transplantation and cyclosporine immunosuppressionJOURNAL OF MEDICAL PRIMATOLOGY, Issue 2 2001Lorrie Gaschen Purpose: To describe the early detection of non-Hodgkin's lymphoma (NHL) with ultrasound in three clinically normal cynomolgus monkeys post-renal transplantation and immunosuppression with cyclosporine. Materials and methods: The monkeys in this report were treated with cyclosporine (Neoral®) after receiving renal transplants. In addition to clinical and laboratory (hematology, serum chemistry) monitoring, renal allografts were monitored every 2 weeks with ultrasound and ultrasound-guided allograft biopsies were performed. Results: Enlarged renal hilar and mesenteric lymph nodes were detected with ultrasound in three monkeys on days 36, 49 and 134 post-transplantation. Sonographically the lymph nodes were inhomogeneous, of low echogenity and rounded. In two animals, the spleen was sonographically enlarged and inhomogeneous. All three monkeys were symptom-free at the time of ultrasound detection and NHL was diagnosed histologically. Conclusion: Ultrasound provides a rapid, non-invasive means of early detection of NHL in animal transplantation models prior to the onset of clinical symptoms of disease. [source] SHIV89.6P pathogenicity in cynomolgus monkeys and control of viral replication and disease onset by human immunodeficiency virus type 1 Tat vaccineJOURNAL OF MEDICAL PRIMATOLOGY, Issue 3-4 2000Aurelio Cafaro The Tat protein of human immunodeficiency virus (HIV) is produced very early after infection, plays a key role in the virus life cycle and in acquired immunodeficiency syndrome (AIDS) pathogenesis, is immunogenic and well conserved among all virus clades. Notably, a Tat-specific immune response correlates with non-progression to AIDS. Here, we show that a vaccine based on the Tat protein of HIV blocks primary infection with the simian/human immunodeficiency virus (SHIV)89.6P and prevents the CD4 T cell decline and disease onset in cynomolgus monkeys. No signs of virus replication were found in five out of seven vaccinated macaques for almost 1 year of follow-up. Since the inoculated virus (derived from rhesus or from cynomolgus macaques) is shown to be highly pathogenic in cynomolgus macaques, the results indicate efficacy of Tat vaccination in protection against highly pathogenic virus challenge. Finally, the studies of the Tat-specific immunological responses indicate a correlation of protection with a cytotoxic T cell response. Thus, a Tat-based vaccine is a promising candidate for preventive and therapeutic vaccination in humans. [source] The species differences of intestinal drug absorption and first-pass metabolism between cynomolgus monkeys and humansJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 11 2009Masayuki Takahashi Abstract In order to elucidate the causes of the species differences in the oral bioavailability (BA) between cynomolgus monkeys and humans, the contributions of first-pass metabolism and intestinal absorption were investigated. Typical substrates of cytochrome P450 enzymes, UDP-glucuronosyltransferase enzymes and efflux transporters were selected, and the BA, the hepatic availability (Fh) and the fraction dose absorbed from gastro-intestinal tract (Fa*Fg) were calculated from pharmacokinetic analysis after oral and intravenous administration in cynomolgus monkeys. In addition, in vitro metabolism was investigated using liver and intestinal microsomes to evaluate the relationship between in vivo and in vitro results. The BA of cynomolgus monkeys was low compared with that in humans with most of the drugs tested, and not only Fh but also Fa*Fg contributed significantly to the low BA in cynomolgus monkeys. When Fh was evaluated in in vitro experiments, it correlated well with the in vivo Fh. However, although the metabolic activities of CYP3A4 substrates were high in cynomolgus monkey intestinal microsomes, those of the other substrates were low or not detected. These findings suggested that the species differences and low BA in cynomolgus monkeys could be mostly attributed not only to hepatic first-pass metabolism but also to the intestinal absorption process. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4343,4353, 2009 [source] Differential Effects of Ethanol on Serum GABAergic 3,,5,/3,,5, Neuroactive Steroids in Mice, Rats, Cynomolgus Monkeys, and HumansALCOHOLISM, Issue 3 2010Patrizia Porcu Background:, Acute ethanol administration increases plasma and brain levels of progesterone and deoxycorticosterone-derived neuroactive steroids (3,,5,)-3-hydroxypregnan-20-one (3,,5,-THP) and (3,,5,)-3,21-dihydroxypregnan-20-one (3,,5,-THDOC) in rats. However, little is known about ethanol effects on GABAergic neuroactive steroids in mice, nonhuman primates, or humans. We investigated the effects of ethanol on plasma levels of 3,,5,- and 3,,5,-reduced GABAergic neuroactive steroids derived from progesterone, deoxycorticosterone, dehydroepiandrosterone, and testosterone using gas chromatography-mass spectrometry. Methods:, Serum levels of GABAergic neuroactive steroids and pregnenolone were measured in male rats, C57BL/6J and DBA/2J mice, cynomolgus monkeys, and humans following ethanol administration. Rats and mice were injected with ethanol (0.8 to 2.0 g/kg), cynomolgus monkeys received ethanol (1.5 g/kg) intragastrically, and healthy men consumed a beverage containing 0.8 g/kg ethanol. Steroids were measured after 60 minutes in all species and also after 120 minutes in monkeys and humans. Results:, Ethanol administration to rats increased levels of 3,,5,-THP, 3,,5,-THDOC, and pregnenolone at the doses of 1.5 g/kg (+228, +134, and +860%, respectively, p < 0.001) and 2.0 g/kg (+399, +174, and +1125%, respectively, p < 0.001), but not at the dose of 0.8 g/kg. Ethanol did not alter levels of the other neuroactive steroids. In contrast, C57BL/6J mice exhibited a 27% decrease in serum 3,,5,-THP levels (p < 0.01), while DBA/2J mice showed no significant effect of ethanol, although both mouse strains exhibited substantial increases in precursor steroids. Ethanol did not alter any of the neuroactive steroids in cynomolgus monkeys at doses comparable to those studied in rats. Finally, no effect of ethanol (0.8 g/kg) was observed in men. Conclusions:, These studies show clear species differences among rats, mice, and cynomolgus monkeys in the effects of ethanol administration on circulating neuroactive steroids. Rats are unique in their pronounced elevation of GABAergic neuroactive steroids, while this effect was not observed in mice or cynomolgus monkeys at comparable ethanol doses. [source] Zolpidem Generalization and Antagonism in Male and Female Cynomolgus Monkeys Trained to Discriminate 1.0 or 2.0 g,/,kg EthanolALCOHOLISM, Issue 7 2008Christa M. Helms Background:, The subtypes of , -aminobutyric acid (GABA)A receptors mediating the discriminative stimulus effects of ethanol in nonhuman primates are not completely identified. The GABAA receptor positive modulator zolpidem has high, intermediate, and low activity at receptors containing ,1, ,2/3, and ,5 subunits, respectively, and partially generalizes from ethanol in several species. The partial inverse agonist Ro15-4513 has the greatest affinity for ,4/6 -containing receptors, higher affinity for ,5 - and lower, but equal, affinity for ,1 - and ,2/3 -, containing GABAA receptors, and antagonizes the discriminative stimulus effects of ethanol. Methods:, This study assessed Ro15-4513 antagonism of the generalization of zolpidem from ethanol in male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 g/kg (n = 10) or 2.0 g/kg (n = 7) ethanol (i.g.) from water with a 30-minute pretreatment interval. Results:, Zolpidem (0.017 to 5.6 mg/kg, i.m.) completely generalized from ethanol (,80% of total session responses on the ethanol-appropriate lever) for 6/7 monkeys trained to discriminate 2.0 g/kg and 4/10 monkeys trained to discriminate 1.0 g/kg ethanol. Zolpidem partially generalized from 1.0 or 2.0 g/kg ethanol in 6/7 remaining monkeys. Ro15-4513 (0.003 to 0.30 mg/kg, i.m., 5-minute pretreatment) shifted the zolpidem dose,response curve to the right in all monkeys showing generalization. Analysis of apparent pKB from antagonism tests suggested that the discriminative stimulus effects of ethanol common with zolpidem are mediated by low-affinity Ro15-4513 binding sites. Main effects of sex and training dose indicated greater potency of Ro15-4513 in males and in monkeys trained to discriminate 1.0 g/kg ethanol. Conclusions:, Ethanol and zolpidem share similar discriminative stimulus effects most likely through GABAA receptors that contain ,1 subunits, however, antagonism by Ro15-4513 of zolpidem generalization from the lower training dose of ethanol (1.0 g/kg) may involve additional zolpidem-sensitive GABAA receptor subtypes (e.g., ,2/3 and ,5). [source] Ethanol Self-Administration and Alterations in the Livers of the Cynomolgus Monkey, Macaca fascicularisALCOHOLISM, Issue 1 2007Priscilla Ivester Background: Most of the studies of alcoholic liver disease use models in which animals undergo involuntary administration of high amounts of ethanol and consume diets that are often high in polyunsaturated fatty acids. The objectives of this study were (1) to evaluate whether cynomolgus monkeys (Macaca fascicularis) drinking ethanol voluntarily and consuming a diet with moderate amounts of lipid would demonstrate any indices of alcoholic liver disease past the fatty liver stage and (2) to determine whether these alterations were accompanied by oxidative stress. Methods: Six adult male and 6 adult female cynomolgus monkeys were allowed to consume ethanol voluntarily for 18 to 19 months. Additional monkeys were maintained on the same consumption protocol, but were not provided with ethanol. During the course of the study, liver biopsy samples were monitored for lipid deposition and inflammation, serum for levels of liver enzymes, and urine for concentrations of the isoprostane (IsoP) metabolite, 2,3-dinor-5,6-dihydro-15-F2t -IsoP, a biomarker for oxidative stress. Liver mitochondria were monitored for respiratory control and liver for concentrations of neutral lipids, adenine nucleotides, esterified F2 isoprostanes, oxidized proteins, 4-hydroxynonenal (HNE)-protein adducts, and protein levels of cytochrome P-450 2E1 and 3A4. Results: Ethanol consumption ranged from 0.9 to 4.05 g/kg/d over the period of the study. Serum levels of aspartate amino transferase were elevated in heavy-consuming animals compared with those in ethanol-naïve or moderate drinkers. Many of the ethanol consumers developed fatty liver and most showed loci of inflammation. Both hepatic energy charge and phosphorylation potential were decreased and NADH-linked respiration was slightly, but significantly depressed in coupled mitochondria as a result of heavy ethanol consumption. The urinary concentrations of 2,3-dinor-5,6-dihydro-15-F2t -IsoP increased as high as 33-fold over that observed in ethanol-abstinent animals. Liver cytochrome P-450 2E1 concentrations increased in ethanol consumers, but there were no ethanol-elicited increases in hepatic concentrations of the esterified F2 isoprostanes, oxidized proteins, or HNE-protein adducts. Conclusion: Our studies show that cynomolgus monkeys undergoing voluntary ethanol consumption for 1.5 years exhibit many of the features observed in the early stages of human alcoholic liver disease. Ethanol-elicited fatty liver, inflammation, and elevated serum aspartate amino transferase were evident with a diet that contained modest amounts of polyunsaturated lipids. The dramatic increases in urinary IsoP demonstrated that the animals were being subjected to significant oxidative stress that correlated with their level of ethanol consumption. [source] Induction and Maintenance of Ethanol Self-Administration in Cynomolgus Monkeys (Macaca fascicularis): Long-Term Characterization of Sex and Individual DifferencesALCOHOLISM, Issue 8 2001J. A. Vivian Background: Investigations of oral ethanol self-administration in nonhuman primates have revealed important parallels with human alcohol use and abuse, yet many fundamental questions concerning the individual risk to, and the biological basis of, excessive ethanol consumption remain unanswered. Moreover, many conditions of access to ethanol in nonhuman primate research are largely unexplored. This set of experiments extends within- and across-session exposure to ethanol to more fully characterize individual differences in oral ethanol self-administration. Methods: Eight male and eight female adult cynomolgus monkeys (Macaca fascicularis) were exposed to daily oral ethanol self-administration sessions for approximately 9 months. During the first 3 months, a fixed-time (FT) schedule of food delivery was used to induce the consumption of an allotted dose of ethanol in 16-hr sessions. Subsequently, the FT schedule was suspended, and ethanol was available ad libitum for 6 months in 16- or 22-hr sessions. Results: Cynomolgus monkeys varied greatly in their propensity to self-administer ethanol, with sex and individual differences apparent within 10 days of ethanol exposure. Over the last 3 months of ethanol access, individual average ethanol intakes ranged from 0.6 to 4.0 g/kg/day, resulting in blood ethanol concentrations from 5 to 235 mg/dl. Males drank approximately 1.5-fold more than females. In addition, heavy-, moderate-, and light-drinking phenotypes were identified by using daily ethanol intake and the percentage of daily calories obtained from ethanol as criteria. Conclusions: Cynomolgus monkeys displayed a wide intersubject range of oral ethanol self-administration with a procedure that used a uniform and prolonged induction that restricted early exposure to ethanol and subsequently allowed unlimited access to ethanol. There were sex and stable individual differences in the propensity of monkeys to consume ethanol, indicating that this species will be important in characterizing risk factors associated with heavy-drinking phenotypes. [source] Ex vivo inhibition of thrombus formation by an anti-glycoprotein VI Fab fragment in non-human primates without modification of glycoprotein VI expressionJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2008P. OHLMANN Summary.,Objectives:,Glycoprotein (GP)VI is an attractive target for the development of new antithrombotic drugs. Its deficiency protects animals in several models of thrombosis, arterial stenosis and ischemia-,reperfusion while inducing no major bleeding tendency. The Fab fragment of one anti-GPVI monoclonal antibody (9O12.2) inhibits all GPVI functions in vitro. The aim of this study was to determine the ex vivo effects of 9O12.2 Fab on hemostasis, coagulation and thrombosis in non-human primates. Methods and results:,Blood samples were collected from cynomolgus monkeys before and after (30, 90 and 150 min, 1 and 7 days) a bolus injection of 9O12.2 Fab (4 mg kg,1) or vehicle. Platelet counts and coagulation tests (prothrombin time, activated partial thromboplastin time) were not modified following Fab injection. The PFA-100 closure time increased during the first hours and returned to initial values on day + 1. Platelet-bound Fab was detected from 30 min to 24 h after Fab injection without GPVI depletion at any time. Collagen-induced platelet aggregation was selectively and fully inhibited at 30 min. Thrombus formation on collagen in flowing whole blood (1500 s,1) was delayed and decreased, and collagen-induced or tissue factor-induced thrombin generation in platelet-rich plasma was profoundly inhibited. Conclusion:,The anti-GPVI 9O12.2 Fab inhibits thrombus formation ex vivo in non-human primates with a composite effect on platelet activation and thrombin generation in the absence of GPVI depletion. [source] Estrogen/isoflavone interactions in cynomolgus macaques (Macaca fascicularis)AMERICAN JOURNAL OF PRIMATOLOGY, Issue 9 2009J. Mark Cline Abstract Soy isoflavones are phytoestrogenic components of dietary soy, which are widely consumed for their potential health benefits. Soy isoflavones appear to decrease breast and endometrial cancer risk in human observational studies, but paradoxically stimulate growth of breast cancer cells in culture and uterine enlargement in rodents. We have shown that these compounds are not estrogenic in cynomolgus monkeys even at relatively high doses, but that they reduce estrogen-induced proliferative responses of the breast and endometrium. This effect may be mediated through estrogen receptor interactions and/or modulation of endogenous estrogen metabolism. Interindividual variation in isoflavone absorption and metabolism contributes to the degree of estrogen antagonistic effect. Our recent studies have also shown that individual isoflavone metabolites such as glyceollins may have unique selective estrogen receptor modulator-like activity, acting as tissue-specific antagonists without agonist activity. Rodent studies and human epidemiologic data suggest that timing of exposure and dose relative to endogenous estrogen concentrations are important determinants of effect, and studies of dietary soy on breast development and pubertal maturation are under way. Because soy isoflavones are both abundant in standard monkey chow diets and widely available as dietary supplements for human beings, these findings have broad relevance to the health of human and nonhuman primates. Am. J. Primatol. 71:722,731, 2009. © 2009 Wiley-Liss, Inc. [source] The relationship between social status and atherosclerosis in male and female monkeys as revealed by meta-analysisAMERICAN JOURNAL OF PRIMATOLOGY, Issue 9 2009Jay R. Kaplan Abstract More than 25 years ago our laboratory reported sex-dependent relationships between social status and coronary artery atherosclerosis among cholesterol-fed cynomolgus monkeys (Macaca fascicularis) maintained in social groups of four to six animals each. Dominant males developed more atherosclerosis than subordinates, but only if housed in recurrently reorganized social groups. In contrast, dominant females developed significantly less atherosclerosis than subordinates, irrespective of social setting. Although we have continued to study these associations, no confirmatory investigations have been reported by other laboratories or using other atherosclerosis-susceptible monkey species. Accordingly, we conducted a meta-analysis of all relevant data sources developed in our laboratory since 1982 to determine whether the originally reported relationships between social status and atherosclerosis reflected robust associations. The sentinel (first) studies were composed of 16 females and 27 males. The current meta-analysis encompassed 419 animals (200 females and 219 males) derived from 11 separate investigations. The results confirmed that, among males, dominant individuals developed more extensive atherosclerosis than subordinates when housed in recurrently reorganized (unstable) social groups in which an estrogen-implanted female was also present. Dominant males in stable social groups tended to have less atherosclerosis than similarly housed subordinates, but this effect was not significant. On the contrary, we found that dominant females developed reliably less atherosclerosis than subordinates. Am. J. Primatol. 71:732,741, 2009. © 2009 Wiley-Liss, Inc. [source] Social stress, visceral obesity, and coronary artery atherosclerosis: product of a primate adaptationAMERICAN JOURNAL OF PRIMATOLOGY, Issue 9 2009Carol A. Shively Abstract Abdominal obesity is prevalent and often accompanied by an array of metabolic perturbations including elevated blood pressure, dyslipidemia, impaired glucose tolerance or insulin resistance, a prothrombotic state, and a proinflammatory state, together referred to as the metabolic syndrome. The metabolic syndrome greatly increases coronary heart disease (CHD) risk. Social stress also increases CHD although the mechanisms through which this occurs are not completely understood. Chronic stress may result in sustained glucocorticoid production, which is thought to promote visceral obesity. Thus, one hypothesis is that social stress may cause visceral fat deposition and the metabolic syndrome, which, in turn increases CHD. CHD is caused by coronary artery atherosclerosis (CAA) and its sequelae. Cynomolgus monkeys (Macaca fascicularis) are a well-established models of CAA. Social subordination may be stressful to cynomolgus monkeys and result in hypercortisolemia and exacerbated CAA in females. Herein is reviewed a body of literature which suggests that social stress increases visceral fat deposition in cynomolgus monkeys, that subordinate females are more likely than dominants to have visceral obesity, that females with visceral obesity have behavioral and physiological characteristics consistent with a stressed state, and that females with high ratios of visceral to subcutaneous abdominal fat develop more CAA. While these relationships have been most extensively studied in cynomolgus macaques, obesity-related metabolic disturbances are also observed in other primate species. Taken together, these observations support the view that the current obesity epidemic is the result of a primate adaptation involving the coevolution with encephalization of elaborate physiological systems to protect against starvation and defend stored body fat in order to feed a large and metabolically demanding brain. Social stress may be engaging these same physiological systems, increasing the visceral deposition of fat and its sequelae, which increase CHD risk. Am. J. Primatol. 71:742,751, 2009. © 2009 Wiley-Liss, Inc. [source] Primate models in women's health: inflammation and atherogenesis in female cynomolgus macaques (Macaca fascicularis)AMERICAN JOURNAL OF PRIMATOLOGY, Issue 9 2009Thomas C. Register Abstract Female cynomolgus monkeys are excellent models for understanding cardiovascular disease and the relationships between inflammatory processes and conditions such as atherogenesis. This review summarizes published research findings obtained through comprehensive, multidisciplinary, multi-investigator studies in nonhuman primates over the past two decades. These studies examined the effects of exogenous estrogens and dietary soy protein/isoflavones (IFs) on atherosclerosis, circulating biomarkers, and tissue inflammation in pre- and postmenopausal female cynomolgus monkeys. Inflammation may play a role in the initiation and progression of disease, be a consequence of the disease, or both. Circulating and tissue biomarkers with inflammatory and anti-inflammatory characteristics (including adhesion molecules such as e-selectin, VCAM-1, and ICAM-1, chemokines such as MCP-1, cytokines such as interleukins, and acute phase reactants such as CRP, and others) may be useful indicators of disease status. Treatment of postmenopausal subjects with estrogen resulted in significant reductions in several key inflammatory mediators as well as atherosclerosis, while dietary IF had a more limited effect on inflammation and atherogenesis. Circulating concentrations of key inflammatory proteins, including monocyte-chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6), were associated with atherosclerosis and lesion characteristics in these animals. In premenopausal female monkeys, a diet enriched in soy protein reduced arterial inflammation as well as atherogenesis in comparison to a diet enriched in casein-lactalbumin. Expression levels of arterial inflammation associated genes (MCP-1, ICAM-1) and markers for inflammatory cell types (macrophages and T cells) correlated with plaque size, were differentially influenced by treatments, and represent potential targets for interventions. Arterial expression of estrogen receptor ,, the key mediator of estrogenic effects, was inversely correlated with plaque size and indices of inflammation, suggestive of an atheroprotective role. The findings provide additional evidence that circulating inflammatory markers (particularly MCP-1) may be useful indicators of atherosclerotic disease progression and responses to treatment in female primates, and that estrogens and dietary soy may inhibit atherogenesis in part through anti-inflammatory mechanisms. Am. J. Primatol. 71:766,775, 2009. © 2009 Wiley-Liss, Inc. [source] First description of the surgical anatomy of the cynomolgus monkey liverAMERICAN JOURNAL OF PRIMATOLOGY, Issue 5 2009Corinne Vons Abstract No detailed description of nonhuman primate liver anatomy has been reported and little is known about the similarity between such livers and human liver. The cynomolgus monkey (Macaca fascicularis) was used to establish a preclinical model of genetically modified hepatocytes auto transplantation. Here, we report information gleaned from careful observation and notes obtained from 59 female cynomolgus monkeys undergoing 44 anatomical hepatic resections, 12 main portal vein division dissections and selective branch ligations, and 46 portographies. Additionally, three anatomical liver dissections after total resection at autopsy were performed and served to confirm peroperative observations and for photography to provide illustrations. Our results indicate that the cynomolgus monkey liver has four lobes: the median (the largest), the right and left lateral, and the caudate lobes. In 60% (N=20) of individuals the portal bifurcates into right and left portal veins, in the remaining 40% (N=14) the portal vein trifurcates into right anterior, right posterior, and left portal veins. The anatomy and branching pattern of the hepatic artery and bile ducts closely follow those of the portal branches. Functionally, the cynomolgus monkey liver can be divided into eight independent segments. Thus, we report the first detailed description of the hepatic and portal surgical anatomy of the cynomolgus monkey. The cynomolgus monkey liver is more similar to the human liver than are livers of any small or large nonprimate mammals that have been described. Am. J. Primatol. 71:400,408, 2009. © 2009 Wiley-Liss, Inc. [source] Comparative studies with six extenders for sperm cryopreservation in the cynomolgus monkey (Macaca fascicularis) and rhesus monkey (Macaca mulatta)AMERICAN JOURNAL OF PRIMATOLOGY, Issue 1 2006Yahui Li Abstract Ejaculated spermatozoa from cynomolgus monkeys and rhesus monkeys were frozen in straws with six different extenders (TTE, DM, mDM, LG-DM, G-DM, and TCG) containing glycerol. Sperm motility and head membrane and acrosomal integrity were evaluated after freezing and thawing, and the cryoprotective effects were compared among the extenders and the two species studied. The results showed that sperm motility and motility recovery with the six extenders were comparable for the cynomolgus and rhesus monkeys. There was no significant difference in sperm motility and head membrane integrity among the six extenders in either the cynomolgus or rhesus monkeys (P>0.05). However, a slightly but statistically lower percentage of acrosomal integrity was found with TCG in both species compared to the other extenders (P<0.05). These findings demonstrate that TTE, DM, mDM, LG-DM, G-DM, and TCG are equally suitable extenders for the cryopreservation of spermatozoa from cynomolgus and rhesus monkeys. Am. J. Primatol. 68:39,49, © 2006 Wiley-Liss, Inc. [source] Influence of estradiol on cortisol secretion in ovariectomized cynomolgus macaques (Macaca fascicularis)AMERICAN JOURNAL OF PRIMATOLOGY, Issue 1 2003R.C. Stavisky Abstract In an investigation of cortisol secretion in fully mature, ovariectomized cynomolgus monkeys (Macaca fascicularis), we compared monkeys that were given either placebo (OVX, n = 26) or 17, estradiol (E2 ) (EST, n = 26) in a daily oral dose. Serum cortisol concentrations were measured prior to the experimental manipulation and 3, 6, 9, and 12 months following initiation of treatment. Pretreatment cortisol values did not differ between groups. Assessment of the treatment period values revealed that cortisol concentrations were significantly higher (,10%) in the EST than in the OVX monkeys. Cortisol also varied significantly across periods of sampling. This time-dependent variation was attributable to elevations in months 6 and 9 (when daylight was generally long), relative to months 3 and 12 (when daylight was relatively short). The modest stimulatory effect of estrogen on corticosteroid production observed in this study is consistent with what has been seen in women, and contrasts with the more robust effects observed in New World monkeys. The possible relationship between season and cortisol secretion observed here has not been previously described in monkeys. Am. J. Primatol. 60:17,22, 2003. © 2003 Wiley-Liss, Inc. [source] Investigation of Lymphocyte Depletion and Repopulation Using Alemtuzumab (Campath-1H) in Cynomolgus MonkeysAMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2010D. J. Van Der Windt As the target CD52 molecule is expressed on erythrocytes of most nonhuman primate strains, using alemtuzumab in these species would cause massive hemolysis. Six cynomolgus monkeys of Indonesian origin, screened by agglutination assay for absence of CD52 on erythrocytes, were administered alemtuzumab in a cumulative dose to a maximum of 60 mg/kg. In two monkeys, mycophenolate mofetil (MMF) was added as maintenance therapy. Complete depletion of T and B lymphocytes (>99.5%) was achieved with 20 mg/kg alemtuzumab and was more profound than in monkeys treated with antithymocyte globulin (n = 5), as quantified by flow cytometry. Repopulation was suppressed by weekly injections of 10 mg/kg. Without MMF, repopulation of CD20+B cells and CD8+T cells was complete within 2 and 3 months, respectively, and repopulation of CD4+T cells was 67% after 1 year. MMF significantly delayed CD4+T-cell repopulation. Among repopulating CD4+ and CD8+ T cells, a phenotypic shift was observed from CD45RAhiCD62Lhi naïve cells toward CD45RAloCD62Llo effector memory cells. In lymph nodes, the depletion of naïve cells was more profound than of memory cells, which may have initiated a proliferation of memory cells. This model offers opportunities to investigate lymphocyte depletion/repopulation phenomena, as well as the efficacy of alemtuzumab in preclinical transplantation models. [source] Long-Term Survival of Nonhuman Primate Islets Implanted in an Omental Pouch on a Biodegradable ScaffoldAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2009D. M. Berman The aim of this study was to test whether an omental pouch can be used as an alternative site for islet implantation in diabetic monkeys. Here we report the successful engraftment of islets in diabetic cynomolgus monkeys when loaded on a synthetic biodegradable scaffold and placed in an omental pouch. One autologous and five allogeneic diabetic monkey transplants under the cover of steroid-free immune suppression (SFIS) were undertaken. Fasting blood glucose (FBG) and C-peptide (CP), exogenous insulin requirements (EIR), intravenous glucose tolerance test (IVGTT), A1C and histopathology were used to assess islet engraftment and survival. All animals achieved CP levels > 1.0 ng/mL following transplant, a 66,92% posttransplant decrease in EIR and reduced A1C. Following graft removal, CP became negative and histopathological analysis of the explanted grafts demonstrated well-granulated and well-vascularized, insulin-positive islets, surrounded by T-cell subsets and macrophages. Compared to intrahepatic allogeneic islet transplants (n = 20), there was a delayed engraftment for omental pouch recipients but similar levels of CP production were ultimately achieved, with a broad range of IEQ/kg transplanted in both sites. Our results suggest this extrahepatic transplantation site has potential as an alternative site for clinical islet cell transplantation. [source] Engraftment of Adult Porcine Islet Xenografts in Diabetic Nonhuman Primates Through Targeting of Costimulation PathwaysAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2007K. Cardona Recent advances in human allogeneic islet transplantation have established ,-cell replacement therapy as a potentially viable treatment option for individuals afflicted with Type 1 diabetes. Two recent successes, one involving neonatal porcine islet xenografts transplanted into diabetic rhesus macaques treated with a costimulation blockade-based regimen and the other involving diabetic cynomolgus monkeys transplanted with adult porcine islet xenografts treated with an alternative multidrug immunosuppressive regimen have demonstrated the feasibility of porcine islet xenotransplantation in nonhuman primate models. In the current study, we assessed whether transplantation of adult porcine islet xenografts into pancreatectomized macaques, under the cover of a costimulation blockade-based immunosuppressive regimen (CD28 and CD154 blockade), could correct hyperglycemia. Our findings suggest that the adult porcine islets transplanted into rhesus macaques receiving a costimulation blockade-based regimen are not uniformly subject to hyperacute rejection, can engraft (2/5 recipients), and have the potential to provide sustained normoglycemia. These results provide further evidence to suggest that porcine islet xenotransplantation may be an attainable strategy to alleviate the islet supply crisis that is one of the principal obstacles to large-scale application of islet replacement therapy in the treatment of Type 1 diabetes. [source] Treatment by Mycophenolate Mofetil of Advanced Graft Vascular Disease in Non-Human Primate Recipients of Orthotopic Aortic AllograftsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2003Jochen Klupp Failure to control chronic graft dysfunction [e.g. graft vascular disease (GVD)] is the primary cause of immunologic graft failure. This is the first study of mycophenolate mofetil (MMF) for the treatment of GVD in non-human primate recipients of aortic allografts. Abdominal aortic allografts were exchanged between mixed leukocyte reaction (MLR) -mismatched, blood-group-compatible cynomolgus monkeys. Six control recipients were untreated. Individualized treatment with frequent dose adjustments of MMF insured that treatment was close to the maximum tolerated dose (mean 99.2 mg/kg/day). Immune-mediated injury proceeded unhindered until day 45, after which MMF treatment began. Changes in intimal volume (IV) were quantified by intravascular ultrasound (IVUS) and compared to histology on day 105. Serial IVUS measurements of IV (mm3) in controls showed progressive GVD. In four out of six animals, MMF was well tolerated, thus enabling optimum treatment; in all these animals, IV was significantly less than in the control animals (p = 0.02). In the two remaining animals, high doses were not tolerated; at day 105, there was no significant difference in IV between them and the controls. We found a significant correlation between the mean MMF tolerated dose and the inhibition of progression of IV (r = ,0.88, p = 0.015). When high MMF doses were tolerated, MMF slowed progression of GVD. [source] Safety Pharmacology, Toxicology and Pharmacokinetic Assessment of Recombinant Human ,-Interferon Produced from CHO-SS CellsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 1 2006Victor E. Buckwold Here we provide an overview of our preclinical safety evaluation of the fully-glycosylated human IFN-, produced from CHO-SS cells that is currently being evaluated clinically. IFN-, was not associated with any biologically-relevant adverse effects in a series of 10 safety pharmacology experiments, in the Ames mutagenicity test, in the micronucleus test, or in intraarterial, intravenous, paravenous or subcutaneous local tolerance studies. Acute, subacute, subchronic and reproductive toxicity studies performed in cynomolgus monkeys and rats showed a toxicity profile similar to that of human , interferon (IFN-,). Except for the acute (single-dose) toxicology study, all of the other toxicity studies showed evidence for the formation of anti-IFN-, antibodies over time in the animals. These antibodies were found to neutralize IFN-, antiviral activity in vitro in a dose-dependent manner. The average pharmacokinetic parameters following a single subcutaneous dose of IFN-, in rabbits, rats and monkeys were determined and found to be similar to that of human IFN-,. These findings demonstrate that IFN-, has a safety profile consistent with that required for its use in man. IFN-, might be beneficial for the treatment of patients infected with hepatitis C virus who fail to respond to IFN-, or as a first-line treatment option. [source] The prediction of human response to ONO-4641, a sphingosine 1-phosphate receptor modulator, from preclinical data based on pharmacokinetic,pharmacodynamic modelingBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2010Tomoya Ohno Abstract The pharmacokinetic (PK) and pharmacodynamic (PD) parameters of ONO-4641 in humans were estimated using preclinical data in order to provide essential information to better design future clinical studies. The characterization of PK/PD was measured in terms of decreased lymphocyte counts in blood after administration of ONO-4641, a sphingosine 1-phosphate receptor modulator. Using a two-compartment model, human PK parameters were estimated from preclinical PK data of cynomolgus monkey and in vitro human metabolism data. To estimate human PD parameters, the relationship between lymphocyte counts and plasma concentrations of ONO-4641 in cynomolgus monkeys was determined. The relationship between lymphocyte counts and plasma concentrations of ONO-4641 was described by an indirect-response model. The indirect-response model had an Imax value of 0.828 and an IC50 value of 1.29,ng/ml based on the cynomolgus monkey data. These parameters were used to represent human PD parameters for the simulation of lymphocyte counts. Other human PD parameters such as input and output rate constants for lymphocytes were obtained from the literature. Based on these estimated human PK and PD parameters, human lymphocyte counts after administration of ONO-4641 were simulated. In conclusion, the simulation of human lymphocyte counts based on preclinical data led to the acquisition of useful information for designing future clinical studies. Copyright © 2010 John Wiley & Sons, Ltd. [source] | ||||||||||