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PubMed2004

Plasma and cerebrospinal fluid pharmacokinetics of depsipeptide (FR901228) in nonhuman primates.

PURPOSE: Acetylation of histones by histone acetyl transferases (HATs) leads to transcriptional activation, while histone deacetylase (HDAC) activity leads to transcriptional repression. Abnormalities of histone acetylation are associated with the malignant phenotype. Depsipeptide (FR901228) inhibits HDAC and has shown anticancer activity in preclinical models. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of depsipeptide in a nonhuman primate model that is highly predictive of human CSF penetration. DESIGN: Depsipeptide was administered intravenously at a dose of 10 mg/m(2) over 4 h to three different animals. Serial blood samples were obtained from all animals and serial CSF samples were obtained from two animals. Plasma and CSF concentrations of depsipeptide were measured using liquid chromatography/tandem mass spectrometry. Concentration-versus-time data were modeled using model-independent and model-dependent methods. RESULTS: The peak plasma concentration (median+/-SD) was 245+/-50 n M and occurred within the first 2 h of the infusion. The terminal half-life was 205+/-315 min, the AUC extrapolated to infinity was 50+/-15 micro M.min, and the total body clearance was 350+/-65 ml/min/m(2). In the two animals that had CSF sampling performed, the CSF peak concentration was 3.6 n M in one animal and 2.3 n M in the other, and the CSF half-lives were 250 and 325 min. The CSF penetration of depsipeptide (AUC(CSF):AUC(plasma)) was 2% in each animal. Observed changes included anorexia, fatigue, elevation of creatine phosphokinase (CPK) enzyme levels (muscle fraction), and transient early leukopenia. All animals recovered without sequelae. CONCLUSIONS: Although the CSF exposure to depsipeptide after intravenous administration was only 2%, CSF concentrations approached the IC(50) of depsipeptide in vitro for some tumors. Systemic administration of this agent may be useful for the treatment of leptomeningeal tumors.

Animals↗
PubMed2001

Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate.

INTRODUCTION: Phenylbutyrate (PB) and its metabolite phenylacetate (PA) demonstrate anticancer activity in vitro through promotion of cell differentiation, induction of apoptosis through the p21 pathway, inhibition of histone deacetylase, and in the case of PB, direct cytotoxicity. We studied the pharmacokinetics, metabolism, and cerebrospinal fluid (CSF) penetration of PA and PB after intravenous (i.v.) administration in the nonhuman primate. METHODS: Three animals received 85 mg/kg PA and 130 mg/kg PB as a 30-min infusion. Blood and CSF samples were obtained at 15, 30, 35, 45, 60 or 75 min, and at 1.5, 2.5, 3.5, 5.5, 6.5, 8.5, 10.5 and 24.5 h after the start of the infusion. Plasma was separated immediately, and plasma and CSF were frozen until HPLC analysis was performed. RESULTS: After i.v. PA administration, the plasma area under the concentration-time curve (AUC) of PA (median +/- SD) was 82 +/- 16 mg/ml.min, the CSF AUC was 24 +/- 7 mg/ml.min, clearance (Cl) was 1 +/- 0.3 ml/min per kg, and the AUCCSF:AUCplasma ratio was 28 +/- 19%. After i.v. PB administration, the plasma PB AUC was 19 +/- 3 mg/ml.min, the CSF PB AUC was 8 +/- 11 mg/ml.min, the PB Cl was 7 +/- 1 ml/min per kg, and the AUCCSF:AUCplasma ratio was 41 +/- 47%. The PA plasma AUC after i.v. PB administration was 50 +/- 9 mg/ml.min, the CSF AUC was 31 +/- 24 mg/ml.min, and the AUCCSF:AUCplasma ratio was 53 +/- 46%. CONCLUSIONS: These data indicate that PA and PB penetrate well into the CSF after i.v. administration. There may be an advantage to administration of PB over PA, since the administration of PB results in significant exposure to both active compounds. Clinical trials to evaluate the activity of PA and PB in pediatric central nervous system tumors are in progress.

Animals↗
PubMed1969

Vocal tract limitations on the vowel repertoires of rhesus monkey and other nonhuman primates.

The vowel repertoire of a rhesus monkey (Macaca mulatta) was explored by means of a computer program that calculated formant frequencies from the area function of the animal's supralaryngeal vocal tract, which was systematically varied within the limits imposed by anatomical constraints. The resulting vowels were compared with those of humans and with recorded vocalizations of nonhuman primates. The computer model indicates that the acoustic "vowel space" of a rhesus monkey is quite restricted compared to that of the human. This limitation results from the lack of a pharyngeal region that can change its cross-sectional area. These animals thus lack the output mechanism necessary for production of human speech. Man's speech output mechanism is apparently species-specific.

Animals↗
PubMed1999

Differential expression of stress proteins in nonhuman primate lung and conducting airway after ozone exposure.

The presence of seven stress proteins including various heat shock proteins [27-kDa (HSP27), 60-kDa (HSP60), 70-kDa (HSP70) and its constitutive form HSC70, and 90-kDa (HSP90) HSPs] and two glucose-regulated proteins [75-kDa (GRP75) and 78-kDa (GRP78) GRPs] in ozone-exposed lungs of nonhuman primates and in cultured tracheobronchial epithelial cells was examined immunohistochemically by various monoclonal antibodies. Heat treatment (42 degrees C) resulted in increased HSP70, HSP60, and HSP27 and slightly increased HSC70 and GRP75 but no increase in GRP78 in primary cultures of monkey tracheobronchial epithelial cells. Ozone exposure did not elevate the expression of these HSPs and GRPs. All of these HSPs including HSP90, which was undetectable in vitro, were suppressed in vivo in monkey respiratory epithelial cells after ozone exposure. Both GRP75 and GRP78 were very low in control cells, and ozone exposure in vivo significantly elevated these proteins. These results suggest that the stress mechanism exerted on pulmonary epithelial cells by ozone is quite different from that induced by heat. Furthermore, differences between in vitro and in vivo with regard to activation of HSPs and GRPs suggest a secondary mechanism in vivo, perhaps related to inflammatory response after ozone exposure.

Animals↗
PubMed2000

Infection of nonhuman primate cells by pig endogenous retrovirus.

The ongoing shortage of human donor organs for transplantation has catalyzed new interest in the application of pig organs (xenotransplantation). One of the biggest concerns about the transplantation of porcine grafts into humans is the transmission of pig endogenous retroviruses (PERV) to the recipients or even to other members of the community. Although nonhuman primate models are excellently suited to mimic clinical xenotransplantation settings, their value for risk assessment of PERV transmission at xenotransplantation is questionable since all of the primate cell lines tested so far have been found to be nonpermissive for PERV infection. Here we demonstrate that human, gorilla, and Papio hamadryas primary skin fibroblasts and also baboon B-cell lines are permissive for PERV infection. This suggests that a reevaluation of the suitability of the baboon model for risk assessment in xenotransplantation is critical at this point.

Animals↗
PubMed2004

Paternal mitochondrial DNA transmission during nonhuman primate nuclear transfer.

Offspring produced by nuclear transfer (NT) have identical nuclear DNA (nDNA). However, mitochondrial DNA (mtDNA) inheritance could vary considerably. In sheep, homoplasmy is maintained since mtDNA is transmitted from the oocyte (recipient) only. In contrast, cattle are heteroplasmic, harboring a predominance of recipient mtDNA along with varying levels of donor mtDNA. We show that the two nonhuman primate Macaca mulatta offspring born by NT have mtDNA from three sources: (1) maternal mtDNA from the recipient egg, (2) maternal mtDNA from the egg contributing to the donor blastomere, and (3) paternal mtDNA from the sperm that fertilized the egg from which the donor blastomere was isolated. The introduction of foreign mtDNA into reconstructed recipient eggs has also been demonstrated in mice through pronuclear injection and in humans through cytoplasmic transfer. The mitochondrial triplasmy following M. mulatta NT reported here forces concerns regarding the parental origins of mtDNA in clinically reconstructed eggs. In addition, mtDNA heteroplasmy might result in the embryonic stem cell lines generated for experimental and therapeutic purposes ("therapeutic cloning").

Animals↗
PubMed2000

Pharmacokinetics and cerebrospinal fluid penetration of CI-994 (N-acetyldinaline) in the nonhuman primate.

CI-994 is a substituted benzamide derivative that has demonstrated significant antitumor activity in vitro and in vivo against a broad spectrum of murine and human tumor models. Its mechanism of action is still unknown but seems to be novel compared with existing anticancer drugs. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of CI-994 in nonhuman primates. Three animals (total 4 doses) received an 80 mg/m2 dose of CI-994 administered over 20 min, and one animal received a dose of 100 mg/m2. Serial plasma and fourth ventricular CSF samples were obtained from 0 to 4320 min after administration of the 80-mg/m2 dose, and only plasma samples were obtained after the 100-mg/m2 dose. CI-994 was measured using a previously validated reverse-phase high-performance liquid chromatography assay. Elimination of CI-994 from plasma was triexponential (4 of 5 cases) or biexponential (1 of 5 cases), with a terminal half life (t1/2) of 7.4 +/- 2.5 h, volume of distribution of 15.5 +/- 1.8 L/m2, and clearance of 40 +/- 6 ml/min/m2. The area under the concentration-time curve (AUC) for the 80-mg/m2 dose was 125 +/- 17 microM x hr. CI-994 was first detected in CSF at the completion of the i.v. infusion. Peak concentrations of CI-994 in CSF were 3.4 +/- 0.3 microM. Elimination from CSF was monoexponential (2 of 4 cases) or biexponential (2 of 4 cases) with a terminal t1/2 in CSF of 12.9 +/- 2.5 h and AUC of 55 +/- 18 microM x hr. The AUC(CSF):AUCplasma ratio was 43 +/- 10%. This study demonstrates that there is excellent CSF penetration of CI-994 after i.v. administration. Additional studies are needed to evaluate the potential role of CI-994 in the treatment of central nervous system neoplasms.

Animals↗
PubMed2000

Psychophysical correlates of contralateral efferent suppression. I. The role of the medial olivocochlear system in "central masking" in nonhuman primates.

An extensive physiological literature, including experimental and clinical studies in humans, demonstrates that activation of the medial olivocochlear (MOC) efferent system, by either contralateral sound or electrical stimulation, can produce significant alterations in cochlear function and suggests a role for the MOC system in influencing the auditory behavior of binaural hearing. The present data are from psychophysical studies in nonhuman primates which seek to determine if the noted physiological changes in response to contralateral acoustic stimulation have a perceptual counterpart. Four juvenile Japanese macaques were trained to respond to the presence of 1-s sinusoids, presented to the test ear, in an operant reinforcement paradigm. Thresholds were compared for frequencies ranging from 1.0 to 4.0 kHz in quiet, with thresholds measured when continuous, two octave-band noise, centered on the test tone frequency, was presented in the contralateral ear. Contralateral noise was presented at levels of 10-60 dB above detection threshold for the test-tone frequency. While some variability was evident across subjects, both in the frequency distribution and magnitude (as a function of contralateral noise level), all subjects exhibited an increase, or suppression of thresholds in the presence of contralateral noise. On average, thresholds increased systematically with contralateral noise level, to a peak of 7 dB. In one subject, the threshold increase seen with contralateral noise was significantly reduced when the MOC was surgically sectioned on the floor of the IVth ventricle. The characteristics of the measured shifts in behavioral thresholds, in the presence of contralateral noise reported here, are qualitatively and quantitatively similar to both efferent physiological suppression effects and psychophysical central masking threshold shifts which have been reported previously. These data suggest that at least some aspects of "central masking" are efferent-mediated peripheral processes, and that the term "central masking" may be incorrect.

Acoustic Stimulation↗
PubMed1988

Collagen remodeling of the pressure-overloaded, hypertrophied nonhuman primate myocardium.

Cardiac muscle is tethered within a fibrillar collagen matrix that serves to maximize force generation. In the human pressure-overloaded, hypertrophied left ventricle, collagen concentration is known to be increased; however, the structural and biochemical remodeling of collagen and its relation to cell necrosis and myocardial mechanics is less clear. Accordingly, this study was undertaken in a nonhuman primate model of left ventricular hypertrophy caused by gradual onset experimental hypertension. The amount of collagen, its light microscopic features, and proportions of collagen types I, III, and V were determined together with diastolic and systolic mechanics of the intact ventricle during the evolutionary, early, and late phases of established left ventricular hypertrophy (4, 35, and 88 weeks, respectively). In comparison to controls, we found 1) increased collagen at 4 weeks, as well as a greater proportion of type III, in the absence of myocyte necrosis; 2) collagen septae were thick and dense at 35 weeks, while the proportion of types I and III had converted to control; 3) necrosis was evident at 88 weeks, and the structural remodeling and proportion of collagen types I and III reflected the extent of scar formation; and 4) unlike diastolic myocardial stiffness, which was unchanged at 4, 35, or 88 weeks, the systolic stress-strain relation of the myocardium was altered in either a beneficial or detrimental manner in accordance with structural remodeling of collagen and scar formation. Thus, early in left ventricular hypertrophy, reactive fibrosis and collagen remodeling occur in the absence of necrosis while, later on, reparative fibrosis is present.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Microdialysis and SPECT measurements of amphetamine-induced dopamine release in nonhuman primates.

The competition between endogenous transmitters and radiolabeled ligands for in vivo binding to neuroreceptors might provide a method to measure endogenous transmitter release in the living human brain with noninvasive techniques such as positron emission tomography (PET) or single photon emission computerized tomography (SPECT). In this study, we validated the measure of amphetamine-induced dopamine release with SPECT in nonhuman primates. Microdialysis experiments were conducted to establish the dose-response curve of amphetamine-induced dopamine release and to document how pretreatment with the dopamine depleter alpha-methyl-para-tyrosine (alpha MPT) affects this response. SPECT experiments were performed with two iodinated benzamides, [123I]IBZM and [123I]IBF, under sustained equilibrium condition. Both radio-tracers are specific D2 antagonists, but the affinity of [123I]IBZM (KD-0.4 nM) is lower than that of [123I]IBF (KD 0.1 nM). With both tracers, we observed a prolonged reduction in binding to D2 receptors following amphetamine injection. [123I]IBZM binding to D2 receptors was more affected than [123I]IBF by high doses of amphetamine, indicating that a lower affinity increases the vulnerability of a tracer to endogenous competition. With [123I]IBZM, we observed an excellent correlation between reduction of D2 receptor binding measured with SPECT and peak dopamine release measured with microdialysis after various doses of amphetamine. Pretreatment with alpha MPT significantly reduced the effect of amphetamine on [123I]IBZM binding to D2 receptors, confirming that this effect was mediated by intrasynaptic dopamine release. Together, these results validate the use of this SPECT paradigm as a noninvasive measurement of intrasynaptic dopamine release in the living brain.

Amphetamine↗
PubMed1999

The use of fMRI for determining the topographic organization of cortical fields in human and nonhuman primates.

In this study, we demonstrate activation of somatosensory cortex in the anesthetized macaque monkey and awake human using fMRI, and confirm the topographic organization of somatosensory cortex previously described in both species. The macaque model provides an efficient means of addressing questions regarding the capabilities and neurophysiological relevance of fMRI, and serves as an interface between established invasive electrophysiological methods in nonhuman primates, and noninvasive imaging assays of functional activation in humans.

Anesthetics↗
PubMed2001

Evidence of infection with simian type D retrovirus in persons occupationally exposed to nonhuman primates.

Simian type D retrovirus (SRV) is enzootic in many populations of Asian monkeys of the genus Macaca and is associated with immunodeficiency diseases. However, the zoonotic potential of this agent has not been well defined. Screening for antibodies to SRV was performed as part of an ongoing study looking for evidence of infection with simian retroviruses among persons occupationally exposed to nonhuman primates (NHPs). Of 231 persons tested, 2 (0.9%) were found to be strongly seropositive, showing reactivity against multiple SRV antigens representing gag, pol, and env gene products by Western immunoblotting. Persistent long-standing seropositivity, as well as neutralizing antibody specific to SRV type 2, was documented in one individual (subject 1), while waning antibody with eventual seroreversion was observed in a second (subject 2). Repeated attempts to detect SRV by isolation in tissue culture and by using sensitive PCR assays for amplification of two SRV gene regions (gag and pol) were negative. Both individuals remain apparently healthy. We were also unable to transmit this seropositivity to an SRV-negative macaque by using inoculation of whole blood from subject 1. The results of this study provide evidence that occupational exposure to NHPs may increase the risk of infection with SRV and underscore the importance of both occupational safety practices and efforts to eliminate this virus from established macaque colonies.

Animals↗
PubMed1995

A 60 Hz electric and magnetic field exposure facility for nonhuman primates: design and operational data during experiments.

A unique exposure facility was designed and constructed to generate large-scale vertical electric fields (EF) of up to 65 kV/m and horizontal magnetic fields (MF) of up to 100 microT (1G), so that the behavioral and neuroendocrine effects of 60 Hz EF or combined electric and magnetic field (E/MF) exposure could be examined using nonhuman primates as subjects. Facility design and operational problems and their solutions are presented, and representative operational data from four sets of experiments are provided. A specially designed, optically isolated, 4 cm spherical-dipole EF probe and a commercially available MF probe were used to map the EF and MF within the fiberglass animal cages. In addition, amplifiers, signal conditioners, and A/D converters provided EF, MF, and transformer signals to a microcomputer at 15 min intervals. The apparatus produced homogeneous, stable E/MF at the desired intensities, and the fiberglass cages did not produce appreciable distortion or attenuation. Levels of recognized EF artifacts such as corona and ozone were negligible. The facility worked as intended, providing a well-characterized and artifact-controlled environment for experiments with baboons (Papio cynocephalus).

Animals↗
PubMed2000

Dopa-induced blood flow responses in nonhuman primates.

Initially, treatment with the dopamine precursor levodopa provides substantial symptomatic relief for patients with Parkinson's disease (PD). However, as the disease progresses, side effects such as involuntary movements or psychosis may accompany the response to medication. The mechanisms underlying these actions of levodopa remain unclear. To develop methodology for longitudinal studies of the effects of PD and levodopa treatment in living nonhuman primates, we first studied the effects of an acute dose of levodopa on regional brain activity in sedated baboons using positron emission tomography. We found that levodopa significantly decreased regional cerebral blood flow (rCBF) bilaterally in putamen and right cingulate and increased rCBF in right lateral temporal cortex and bilateral frontal cortex. We then performed similar studies on a nemestrina in awake and sedated states to determine whether these responses were affected by sedation. Interestingly, the directions of the rCBF responses in the putamen and temporal cortex were reversed depending on the presence or absence of sedation. Specifically, responses were decreased in sedated animals, but increased dose-dependently in the awake nemestrina. These findings have important implications for the interpretation of studies that use anesthesia. The responses in the awake nemestrina were most similar to those reported in humans and thus may be the most useful model system. Future imaging studies using selective dopaminergic agents in awake animals may permit the identification of relatively specific agonist-mediated pathways and may help separate the mechanisms that mediate levodopa's benefit from those that produce its unwanted side effects.

Anesthetics, Dissociative↗
PubMed2005

Modeling human methamphetamine exposure in nonhuman primates: chronic dosing in the rhesus macaque leads to behavioral and physiological abnormalities.

Acute high dose methamphetamine (METH) dosing regimens are frequently used in animal studies, however, these regimens can lead to considerable toxicity and even death in experimental animals. Acute high dosing regimens are quite distinct from the chronic usage patterns found in many human METH abusers. Furthermore, such doses, especially in nonhuman primates, can result in unexpected death, which is unacceptable, especially when such deaths fail to accurately model effects of human usage. As a model of chronic human METH abuse we have developed a nonlethal chronic METH administration procedure for the rhesus macaque that utilizes an escalating dose protocol. This protocol slowly increases the METH dosage from 0.1 to 0.7 mg/kg b.i.d. over a period of 4 weeks, followed by a period of chronic METH administration at 0.75 mg/kg b.i.d. (= total daily METH administration of 1.5 mg/kg). In parallel to human usage patterns, METH injections were given 20-23 times a month. This regimen produced a number of behavioral and physiological effects including decreased food intake and a significant increase in urinary cortisol excretion.

Amphetamine-Related Disorders↗
PubMed2005

Nonhuman primate models of asthma.

Asthma is a complex human disease that does not have an accurate counterpart in any common model organism. Most of our understanding of the immune mechanisms underlying asthma comes from studies in man and mouse. However, there are fundamental differences between the spontaneous disease in man and the experimentally induced counterparts in mice. We advocate more extensive use of nonhuman primate asthma models to reconcile these differences between man and mouse.

Animals↗
PubMed2006

Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates.

There is a remarkable heterogeneity in the functional profile (quality) of T cell responses. Importantly, the magnitude and/or quality of a response required for protection may be different depending on the infection. Here, we assessed the capacity of different Toll like receptor (TLR)-binding compounds to influence T helper cell (Th)1 and CD8+ T cell responses when used as adjuvants in nonhuman primates (NHP) with HIV Gag as a model antigen. NHP were immunized with HIV Gag protein emulsified in Montanide ISA 51, an oil-based adjuvant, with or without a TLR7/8 agonist, a TLR8 agonist, or the TLR9 ligand cytosine phosphate guanosine oligodeoxynucleotides (CpG ODN), and boosted 12 wk later with a replication-defective adenovirus-expressing HIV-Gag (rAD-Gag). Animals vaccinated with HIV Gag protein/Montanide and CpG ODN or the TLR7/8 agonist had higher frequencies of Th1 responses after primary immunization compared to all other vaccine groups. Although the rAD-Gag boost did not elevate the frequency of Th1 memory cytokine responses, there was a striking increase in HIV Gag-specific CD8+ T cell responses after the boost in all animals that had received a primary immunization with any of the TLR adjuvants. Importantly, the presence and type of TLR adjuvant used during primary immunization conferred stability and dramatically influenced the magnitude and quality of the Th1 and CD8+ T cell responses after the rAD-Gag boost. These data provide insights for designing prime-boost immunization regimens to optimize Th1 and CD8+ T cell responses.

Adjuvants, Immunologic↗
PubMed2004

Spinal cord involvement in the nonhuman primate model of Lyme disease.

Lyme borreliosis is a multisystemic disease caused by infection with various genospecies of the spirochete Borrelia burgdorferi. The organs most often affected are the skin, joints, the heart, and the central and peripheral nervous systems. Multiple neurological complications can occur, including aseptic meningitis, encephalopathy, facial nerve palsy, radiculitis, myelitis, and peripheral neuropathy. To investigate spinal cord involvement in the nonhuman primate (NHP) model of Lyme borreliosis, we inoculated 25 adult Macaca mulatta with B. burgdorferi sensu strictu strains N40 by needle (N=9) or by tick (N=4) or 297 by needle (N=2), or with B. burgdorferi genospecies garinii strains Pbi (N=4), 793 (N=2), or Pli (N=4) by needle. Immunosuppression either transiently (TISP) or permanently (IS) was used to facilitate establishment of infection. Tissues and fluids were collected at necropsy 7-24 weeks later. Hematoxylin and eosin staining was used to study inflammation, and immunohistochemistry and digital image analysis to measure inflammation and localize spirochetes. The spirochetal load and C1q expression were measured by TaqMan RT-PCR. The results showed meningoradiculitis developed in only one of the 25 NHP's examined, TISP NHP 321 inoculated with B. garinii strain Pbi. Inflammation was localized to nerve roots, dorsal root ganglia, and leptomeninges but rarely to the spinal cord parenchyma itself. T cells and plasma cells were the predominant inflammatory cells. Significantly increased amounts of IgG, IgM, and C1q were found in inflamed spinal cord. Taqman RT-PCR found spirochetes in the spinal cord only in IS-NHP's, mostly in nerve roots and ganglia rather than in the cord parenchyma. C1q mRNA expression was significantly increased in inflamed spinal cord. This is the first comprehensive study of spinal cord involvement in Lyme borreliosis.

Animals↗