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PubMed2002

Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate.

PURPOSE: Vascular endothelial growth factor (VEGF) is a potent ischemia-upregulated angiogenic protein that has been implicated in diabetic retinopathy. Intravitreal VEGF injections have not previously been shown to produce preretinal neovascularization. The purpose of this study was to further characterize the angiopathic changes that occur after intravitreal injections in a nonhuman primate and determine if preretinal neovascularization develops. DESIGN: Experimental animal study. METHODS: Vascular endothelial growth factor 165 was injected into the eyes of normal cynomolgus monkeys at regular intervals. As a control, normal eyes were injected with phosphate buffered saline. Color photography and fluorescein angiography were performed at regular intervals. The retinas were incubated for adenosine diphosphatase (ADPase) activity to visualize retinal vessels. The retinas were flat-embedded and areas of potential preretinal neovascularization were identified en bloc and serially sectioned. RESULTS: Areas of capillary nonperfusion and vessel dilation and tortuousity were seen by angiography. In serial sections, the nonperfused areas were found to be associated with endothelial cell hyperplasia in vessel lumens. Preretinal neovascularization originating only from superficial veins and venules was observed throughout peripheral retina, but was not seen in the posterior pole. Lacunae-like veins were subdivided by the process of intussusception and endothelial cell bridging. Arterioles demonstrated endothelial cell hyperplasia and microaneurysms. CONCLUSION: Intraocular injections of VEGF were sufficient to produce preretinal neovascularization in the nonhuman primate. Most vasculopathic structures were associated with endothelial cell hyperplasia. These results demonstrate that VEGF alone can produce many features of both nonproliferative and proliferative diabetic retinopathy including the previously undescribed development of preretinal neovascularization. This well-characterized VEGF-induced primate model of retinal neovascularization may be useful as a means of testing new treatments for retinal neovascularization.

Animals↗
PubMed1988

Attenuation of bovine parainfluenza virus type 3 in nonhuman primates and its ability to confer immunity to human parainfluenza virus type 3 challenge.

Bovine parainfluenza virus type 3 (PIV-3) was evaluated as a candidate live-virus vaccine to protect against infection with human PIV-3. The level of replication of bovine and human PIV-3 and the efficacy of immunization with bovine PIV-3 in protecting against subsequent challenge with human PIV-3 was evaluated in nonhuman primates. The duration and magnitude of replication of human and bovine PIV-3 in the upper and lower respiratory tracts of New World monkeys was similar, and animals infected with bovine PIV-3 developed resistance to challenge with human PIV-3. The replication of two bovine strains of PIV-3 was restricted 100- to 1000-fold in Old World primates but was sufficient to induce high levels of neutralizing antibody to human PIV-3. The combined properties of restricted replication and induction of a protective immune response to human PIV-3 in nonhuman primates make bovine PIV-3 a promising candidate for a live-virus vaccine to protect humans against disease caused by PIV-3.

Animals↗
PubMed2003

Plasma and cerebrospinal fluid pharmacokinetics of SU5416 after intravenous administration in nonhuman primates.

PURPOSE: SU5416 is a small, lipophilic synthetic molecule that selectively inhibits the tyrosine kinase activity of the VEGF receptor Flk-1/KDR. The role of this agent in brain tumors is currently being investigated. Pharmacokinetic studies of SU5416 have been performed in humans; however, there have been no studies of its penetration in the cerebrospinal fluid (CSF). We studied the pharmacokinetics of SU5416 in plasma and CSF after intravenous (i.v.) administration using a nonhuman primate model that is highly predictive of the CSF penetration in humans. EXPERIMENTAL DESIGN: SU5416 (85 mg/m(2), about 3.8 mg/kg) was administered i.v. over 20 min to four nonhuman primates. Serial plasma and CSF samples were obtained prior to, during, and after completion of the infusion for determination of SU5416 concentrations. SU5416 was measured in plasma and CSF using high-performance liquid chromatography (HPLC). Concentration-versus-time data were modeled using model-independent and model-dependent methods. RESULTS: Peak plasma concentrations ranged from 6.3 to 14.5 microM and the mean plasma AUC was 620+/-180 microM.min. Disappearance of SU5416 from the plasma was best described by a one-compartment model with a half-life of 39+/-2.9 min. The volume of distribution was 36+/-11 l/m(2) and the clearance was 0.62+/-0.2 l/min per m(2). SU4516 was not quantifiable in the CSF. CONCLUSIONS: There is minimal penetration of SU5416 into the CSF after i.v. administration. The very low CNS exposure to SU5416 after i.v. dosing suggests that this agent is not optimal for the treatment of leptomeningeal tumors.

Animals↗
PubMed2006

Plasma and cerebrospinal fluid pharmacokinetics of nelarabine in nonhuman primates.

INTRODUCTION: Nelarabine is a water-soluble prodrug of the cytotoxic deoxyguanosine analog ara-G, to which it is rapidly converted in vivo by adenosine deaminase. Nelarabine has shown activity in the treatment of T-cell malignancies, especially T-cell acute lymphoblastic leukemia. Preliminary data suggested that nelarabine might penetrate into the CSF. We therefore studied the CSF penetration of nelarabine and ara-G in a nonhuman primate model that has been highly predictive of anticancer drug distribution in humans. METHODS: Nelarabine (35 mg/kg, approximately 700 mg/m2) was administered over 1 h through a surgically implanted central venous catheter to four nonhuman primates. Blood (four animals) and ventricular CSF (three animals) samples were obtained at intervals for 24 h for determination of nelarabine concentrations, which were measured by HPLC-mass spectrometry. RESULTS: The nelarabine plasma AUC (median+/-s.d.) was 2,820+/-1,140 microM min and the ara-G plasma AUC was 20,000+/-8,100 microM min. The terminal half-life of nelarabine in plasma was 25+/-5.2 min and clearance was 42+/-61 ml/min/kg. The terminal half-life of ara-G in plasma was 182+/-45 min. In CSF the terminal half-life of nelarabine was 77+/-28 min and of ara-G was 232+/-79 min. The AUCcsf:AUCplasma was 29+/-11% for nelarabine and 23+/-12% for ara-G. CONCLUSION: The excellent CSF penetration of nelarabine and ara-G supports further study of the contribution of nelarabine to the prevention and treatment of CNS leukemia.

Animals↗
PubMed1992

Expression and function of beta 2 integrins on alveolar macrophages from human and nonhuman primates.

The alveolar macrophage (AM) participates in diverse, adherence-related activities required for host defense and the inflammatory response. The beta 2 integrins (the CD11/CD18 heterodimer) mediate some of these activities on circulating leukocytes and peritoneal macrophages. We investigated expression of the CD11/CD18 leukocyte integrin subunits on AMs obtained by bronchoalveolar lavage of human and nonhuman primates. We also determined the role of the CD11/CD18 complex in AM chemotaxis and adherence to A549 alveolar epithelial cell monolayers. Immunofluorescence flow cytometry indicated that the CD11a/CD18 complex was expressed in high levels and CD11b/CD18 and CD11c/CD18 in lower levels on the AM surface. Northern blot analysis indicated the presence of CD11a, CD11c, and CD18 mRNA in the AMs. Smaller quantities of CD11b mRNA were also found. AM chemotaxis to zymosan-activated serum was markedly inhibited by a monoclonal antibody to CD18. In addition, adherence of AMs to A549 cells (stimulated by tumor necrosis factor to upregulate intercellular adhesion molecule-1 expression) was decreased from 30.3 +/- 5.0 to 20.8 +/- 2.4% (P less than 0.05) by the same monoclonal antibody. We conclude that: (1) AMs obtained from human and nonhuman primates constitutively express predominantly CD11a/CD18 surface antigen and mRNA, (2) chemotaxis of AMs is CD18 dependent, and (3) adhesion of AMs to an alveolar epithelial cell monolayer is partly but not completely dependent on the beta 2 integrins.

Animals↗
PubMed1999

Effect of chronic high-dose exogenous cortisol on hippocampal neuronal number in aged nonhuman primates.

Chronic exposure to increased glucocorticoid concentrations appears to lower the threshold for hippocampal neuronal degeneration in the old rat. It has been proposed that increased brain exposure to glucocorticoids may lower the threshold for hippocampal neuronal degeneration in human aging and Alzheimer's disease. Here, we asked whether chronic administration of high-dose cortisol to older nonhuman primates decreases hippocampal neuronal number as assessed by unbiased stereological counting methodology. Sixteen Macaca nemestrina (pigtailed macaques) from 18 to 29 years of age were age-, sex-, and weight-matched into pairs and randomized to receive either high-dose oral hydrocortisone (cortisol) acetate (4-6 mg/kg/d) or placebo in twice daily palatable treats for 12 months. Hypothalamic-pituitary-adrenal activity was monitored by measuring plasma adrenocorticotropin and cortisol, 24 hr urinary cortisol, and CSF cortisol. Urinary, plasma, and CSF cortisol were elevated, and plasma adrenocorticotropin was reduced in the active treatment group. Total hippocampal volume, subfield volumes, subfield neuronal density, and subfield total neuronal number did not differ between the experimental groups. These findings suggest that chronically elevated cortisol concentrations, in the absence of stress, do not produce hippocampal neuronal loss in nonhuman primates.

Aging↗
PubMed2005

Preliminary results of fetal cardiac bypass in nonhuman primates.

OBJECTIVE: Fetal cardiac surgery has potential benefits for treatment of some congenital heart defects. However, placental dysfunction as a result of fetal bypass, fetal stress, and fetal exposure to external milieu needs to be overcome to optimize the outcomes of fetal cardiac bypass. In this study we evaluated the technical feasibility of cardiac bypass in the nonhuman primate fetus and the efficacy of different anesthetic approaches. METHODS: Twelve baboon fetuses, average gestation 146 +/- 8 days and weight 696 +/- 184 g, were used. Three fetuses were excluded from the study because of nuchal cord presentations. The animals were separated into two anesthesia groups: isoflurane (n = 6) and fentanyl and midazolam (n = 3). A miniature roller pump circuit without oxygenator was used for fetal bypass for 30 minutes. No blood transfusion was performed. Fetal blood gas samples were collected before bypass, during bypass, and at 15 and 60 minutes after bypass. RESULTS: All fetuses in the isoflurane group were successfully placed on the cardiac bypass circuit. However, 2 animals in the fentanyl and midazolam group were not placed on the bypass circuit because of sustained elevation in maternal uterine tone. All maternal baboons survived. Of the 6 fetuses in the isoflurane group, 5 survived for 60 minutes; however, placental function continued to deteriorate after bypass (Pa o 2 33 +/- 3 mm Hg before bypass, 23 +/- 6 mm Hg 15 minutes after, and 18 +/- 9 mm Hg 60 minutes after). CONCLUSION: The technical feasibility of cardiac bypass in nonhuman primate fetuses weighing less than 1000 g was confirmed. Isoflurane anesthesia appears to be superior to fentanyl and midazolam anesthesia for fetal cardiac surgery because of adequate uterine relaxation.

Anesthesia, General↗
PubMed2006

Long-term doxycycline-regulated transgene expression in the retina of nonhuman primates following subretinal injection of recombinant AAV vectors.

Adeno-associated viral gene therapy has shown promise for the treatment of inherited and acquired retinal disorders. In most applications, regulation of expression is a critical concern for both safety and efficacy. The purpose of our study was to evaluate the ability of the tetracycline-regulatable system to establish long-term transgene regulation in the retina of nonhuman primates. Three rAAV vectors expressing the tetracycline-dependent transactivator (rtTA) under the control of either the ubiquitous CAG promoter or the specific RPE65 promoter (AAV2/5.CAG.TetOn.epo, AAV2/4.CAG.TetOn.epo, and AAV2/4.RPE65.TetOn.epo) were generated and administered subretinally to seven macaques. We demonstrated that repeated inductions of transgene expression in the nonhuman primate retina can be achieved using a Tet-inducible system via rAAV vector administration over a long period (2.5 years). Maximum erythropoietin (EPO) secretion in the anterior chamber depends upon the rAAV serotype and the nature of the promoter driving rtTA expression. We observed that the EPO isoforms produced in the retina differ from one another based on the transduced cell type of origin within the retina and also differ from both the physiological EPO isoforms and the isoforms produced by AAV-transduced skeletal muscle.

Animals↗
PubMed2002

Intracytoplasmic injection of frozen-thawed epididymal spermatozoa in a nonhuman primate model, the cynomolgus monkey (Macaca fascicularis).

Intracytoplasmic sperm injection (ICSI) with frozen-thawed epididymal spermatozoa was performed in the cynomolgus monkey (Macacafascicularis) to produce embryos in vitro. Eleven sexually mature females were hyperstimulated with an GnRH agonist (1.8 mg active triptorelin per 2 kg body weight), followed (2 weeks later) by rFSH (37.5 IU per 2 kg daily) for 12 days, and finally 1000 IU of hCG. Epididymal spermatozoa were collected from a single adult male monkey. The first stimulation cycle resulted in 90 oocytes; 70% of which were metaphase II (MII). Sixty-four percent of these MII oocytes were fertilized. Comparing ovarian response of five monkeys that underwent a second stimulation cycle there was an increase in oocyte quantity (13.2 versus 9.2 oocytes per monkey) but the percentage of MII oocytes remained the same at 58%. Fertilization and cleavage rates were also reduced but there was an increase in the number of embryos available for transfer. Overall, four monkeys became pregnant resulting in the birth of two healthy infants and two abortions. These findings show that ovarian stimulation by GnRH-rFSH did not compromise the developmental competence of the oocytes; effective combination of cryopreservation of epididymal spermatozoa and ICSI is possible in nonhuman primate reproduction, and thus has potential application in the conservation of highly endangered nonhuman primate species, and the cynomolgus monkey is a reliable biomedical research model to study the potential risks and benefits associated with assisted reproductive techniques prior to approval for clinical trials on humans.

Animals↗
PubMed1989

Myocardial fibrosis in nonhuman primate with pressure overload hypertrophy.

Characteristics of pressure overload hypertrophy are known to include an accumulation of collagen (or fibrosis) and a biochemical remodeling of fibrillar type I and III collagens. The corresponding structural nature of myocardial fibrosis is less clear. This light morphologic study was undertaken to address this issue in the hypertrophied left ventricle of the nonhuman primate with experimental hypertension. For this purpose, the picrosirius red technique and polarization microscopy were used to examine the myocardium during the evolutionary, early, and late phases of established hypertrophy corresponding to 4, 35, and 88 weeks of experimental hypertension. Evidence of increased thin perimysial fiber formation, together with collagen fiber disruption and edema at 4 weeks of hypertrophy, was found when the chamber volume to left ventricular mass ratio was reduced. After 35 weeks, when this ratio was again normal, a greater number of intermuscular spaces contained both thick and thin perimysial fibers. In addition to this interstitial fibrosis, a reactive fibrosis consisting of a meshwork of thick and thin perimysial fibers was seen extending over muscle fibers. Finally, at 88 weeks, this fibrous meshwork had encircled muscle and there now was evidence of cell necrosis. The accompanying replacement fibrosis consisted of yet another distinctive orthogonal grid of thick and thin collagen fibers. Thus, a continuum of fibrillar collagen remodeling was seen in pressure overload hypertrophy in the nonhuman primate myocardium. Structurally distinct patterns of myocardial fibrosis were recognized based on the alignment of perimysial fibers with muscle that may explain the cellular remodeling and altered mechanical behavior of the concentrically hypertrophied myocardium.

Animals↗
PubMed2005

Safety of direct administration of AAV2(CU)hCLN2, a candidate treatment for the central nervous system manifestations of late infantile neuronal ceroid lipofuscinosis, to the brain of rats and nonhuman primates.

Late infantile neuronal ceroid lipofuscinosis (LINCL), a pediatric autosomal recessive neurodegenerative lysosomal storage disorder, results from mutations in the CLN2 gene and consequent deficiency in tripeptidyl-peptidase I (TPP-I) and progressive destruction of neurons. We have previously demonstrated that CNS gene transfer of AAV2(CU)hCLN2 (an AAV2-based vector expressing the human CLN2 cDNA) in rats and nonhuman primates mediates long-term TPP-I expression in the CNS neurons [Sondhi, D., Peterson, D.A., Giannaris, E.L., Sanders, C.T., Mendez, B.S., De, B., Rostkowski, A., Blancard, B., Bjugstad, K., Sladek, J.R., Redmond, D.E., Leopold, P.L., Kaminsky, S.M., Hackett, N.R., and Crystal, R.G. (2005). Gene Ther. 12, 1618-1632]. The present study tests the hypothesis that direct CNS administration of a clinical-grade AAV2(CU)hCLN2 vector to the CNS of rats and nonhuman primates at doses scalable to humans has a long-term safety profile acceptable for initiating clinical trials. Fischer 344 rats were injected bilaterally via the striatum with 2 x 10(10) particle units (PU) of AAV2(CU)hCLN2, using saline as a control. At 13, 26, and 52 weeks, vector and phosphate-buffered salineinjected rats were killed (n = 6 per time point), and blood, brain, and distant organs were assessed. There were no biologically significant differences between control and vector groups for complete blood count, serum chemistry, and neutralizing anti-AAV2 antibody levels. CNS administration of AAV2 CUhCLN2 did not result in any pathological changes in the brain that were attributable to the vector, although microscopic changes were observed along the track consistent with needle trauma. A total dose of 3.6 x 10(10) or 3.6 x 10(11) PU of AAV2(CU)hCLN2 was administered to the CNS of African Green monkeys at 12 locations, targeting the caudate nucleus, hippocampus, and overlying cortices. Monkeys (n = 3 at each dose) were killed 1, 13, 26, or 52 weeks after injection. Controls included sham-injected, saline-injected, and AAV2(CU)Null-injected (3.6 x 10(11) PU) monkeys. There were no biologically significant differences among vector-injected and control groups in any parameter of the general assessment, complete blood count, or serum chemistry assessed at multiple time points after vector administration. Importantly, no abnormal behavior was observed in any group in videotaped neurological assessment, where behaviors were quantified before administration and at multiple time points afterward. Histopathological examination of the CNS demonstrated that 1 week after administration, AAV2(CU)hCLN2 produced transient minor white matter edema with reactive glial cells in the corona radiata of the cerebrum along the injection track and in the surrounding white matter. This abnormality was not observed at 13, 26, or 52 weeks. Together with the long-term gene expression after gene transfer, these findings supported the initiation of clinical trials to assess the safety of AAV2(CU)hCLN2 administration to individuals with LINCL.

Animals↗
PubMed2004

Nonhuman primate models for islet transplantation in type 1 diabetes research.

Insulin-dependent diabetes mellitus is an autoimmune disease that causes a progressive destruction of the pancreatic beta cells. As a result, the patient requires exogenous insulin to maintain normal blood glucose levels. Both the pancreas and the islets of Langerhans have been transplanted successfully in humans and in animal models, resulting in full normalization of glucose homeostasis. However, insulin independence, transient or persistent, was documented in only a small fraction of cases until recently. The chronic immunosuppression required to avoid immunological rejection appears to be toxic to the islets and adds the risk of lymphoproliferative disease reported earlier. For islet transplantation to become the method of choice, it is essential first to identify islet-friendly immunosuppressive regimens and/or to develop methods that induce donor-specific tolerance and improve islet isolation and transplantation protocols. Indeed, researchers have already successfully allografted islets in the presence of nonsteroidal immunosuppression in a process known as the Edmonton protocol. An alternative method, gene therapy, could replace these other methods and better meet the insulin requirement of an individual without requiring pancreatic or islet transplantation. This alternative, however, requires animal models to develop and test clinical protocols and to demonstrate the feasibility of preclinical trials. Nonhuman primates are ideally suited to achieve these goals. The efforts toward developing a nonhuman primate diabetic model with demonstrable insulin dependence are discussed and include pancreatic and islet transplant trials to reverse the diabetic state and achieve insulin independence. Also described are the various protocols that have been tested in primates to circumvent immunosuppression by using tolerance induction strategies in lieu of immunosuppression, thus exploring the field of donor-specific tolerance that extends beyond islet transplantation.

Animals↗
PubMed1992

Nonhuman primate models for HIV vaccine development.

Animal models will be essential in developing a vaccine to protect against human immunodeficiency virus (HIV) infection. While HIV-1 infects great apes, it induces no disease in these species. Some simian immunodeficiency virus (SIV) isolates cause an AIDS-like disease in macaque monkeys. The SIV/macaque model has proven a valuable system for exploring AIDS pathogenesis and assessing strategies for HIV vaccination. Studies in nonhuman primates have shown that a variety of vaccine approaches transiently elicit immunity which can protect against a very small intravenous challenge of cell-free virus. Longstanding immunity which protects against cell-associated or mucosal virus challenge has not yet been achieved. Nonhuman primate models will be essential for achieving this goal.

AIDS Vaccines↗
PubMed2002

Efficacy of the oxygen-charged static two-layer method for short-term pancreas preservation and islet isolation from nonhuman primate and human pancreata.

Previous reports indicate that the two-layer method (TLM) of human pancreas preservation is superior to University of Wisconsin solution (UW) when pancreata are preserved for extended periods (i.e., >24 h) prior to islet isolation. In this study, the efficacy of using the TLM for preserving pancreata for short periods (i.e., <13 h) was evaluated using both nonhuman primate and human pancreata preserved with a TLM kit precharged with oxygen. An oxygen precharged TLM (static TLM) was established and compared with the original TLM with continuous oxygen supply. For the static TLM, the perfluorochemical was fully oxygenated and the oxygen supply removed prior to pancreas preservation. In the primate model, pancreata were preserved by the static TLM, the original TLM, and UW for 5 h prior to islet isolation. In the human model, pancreata were preserved with the static TLM or the original TLM or UW for 4-13 h. Both primate and human pancreata were processed by intraductal collagenase injection and digestion followed by continuous density gradient purification to isolate islets. Islets were assessed for islet yield, purity, viability, and in vitro functionality. In the primate model, islet yield, viability, and in vitro functionality were significantly improved by both the static TLM and the original TLM with similar results. Postculture islet yields were 23,877 +/- 3619 IE/g in the static TLM, 21,895 +/- 3742 IE/g in the original TLM, and 6773 +/- 735 IE/g in UW. In the human model, both the static TLM and the original TLM significantly increased islet yield compared with UW with postculture islet yields of 2659 +/- 549 IE/g in the static TLM, 2244 +/- 557 IE/g in the original TLM, and 1293 +/- 451 IE/g in UW. Nonhuman primate and human pancreata stored in the static TLM, immediately upon procurement, yield isolated islets of a substantially higher quantity than when pancreata are stored in UW. Thus, the use of the static TLM should replace the use of UW for storage of pancreata during transport prior to islet isolation.

Adenosine↗
PubMed2003

Identification of natural antibodies to interleukin-18 in the sera of normal humans and three nonhuman primate species.

Natural antibodies to cytokines can be found in the sera of normal healthy individuals in the absence of specific immunostimulation. However, the function, impact, and purpose of natural antibody development have yet to be fully elucidated. Interleukin (IL)-18 is a cytokine that exerts proinflammatory activities and induces natural killer (NK) cell activity. Recombinant human IL-18 (rHuIL-18) is currently in development as a cancer immunotherapy. In this study, the presence of natural antibodies to IL-18 in the sera of normal humans and three nonhuman primate species was evaluated by electrochemiluminescence immunoassay (ECLIA). Of the human sera tested, 6 of 47 samples were positive for natural antibodies to IL-18. Of the nonhuman primate sera tested, 22 of 80 cynomolgus monkey samples, 4 of 31 rhesus monkey samples, and 2 of 20 chimpanzee samples were positive for natural antibodies to IL-18. Natural anti-IL-18 antibodies were neutralizing in 5 of 22 cynomolgus and 2 of 4 rhesus sera. None of the chimpanzee or human sera were able to neutralize IL-18 induction of interferon (IFN)-gamma in vitro. In vivo activity of rHuIL-18 was compared in IL-18 natural antibody-positive and -negative cynomolgus monkeys. The presence of natural antibodies to IL-18 did not alter rHuIL-18 systemic exposure levels, induction of neopterin, or induction of treatment-induced antibodies following intravenous administration of rHuIL-18. In conclusion, our data indicate that, as has been found with other cytokines, natural anti-IL-18 antibodies are relatively common. Moreover, natural anti-IL-18 antibodies do not appear to influence rHuIL-18 activity in vivo and are not predictive of a heightened immune response, suggesting that natural anti-IL-18 antibodies do not impact IL-18 therapy. Finally, our data suggest that the ability to detect natural anti-cytokine antibodies may be a useful measure of the adequacy of an assay for deployment in clinical trials.

Animals↗
PubMed2001

Quantification of serotonin transporters in nonhuman primates using [(123)I]ADAM and SPECT.

UNLABELLED: We reported recently a highly selective radioligand, 2-([2-([dimethylamino]methyl)phenyl]thio)-5-[(123)I]iodophenylamine (ADAM), for SPECT imaging of serotonin transporters (SERT). In this article we describe the kinetic modeling of [(123)I]ADAM and its ability to quantitatively and reproducibly measure the concentrations of SERT in the nonhuman primate brain. We also investigate simplified models of tracer behavior that do not require invasive arterial blood sampling. METHODS: Three female baboons each underwent 3 [(123)I]ADAM SPECT studies. The studies consisted of a dynamic sequence of seventy-two 5-min scans after injection of 330 +/- 50 MBq (mean +/- SD) [(123)I]ADAM. Rapid arterial blood samples were obtained and corrected for the presence of labeled metabolites. Dynamic imaging and metabolite-corrected plasma data were analyzed using graphic analysis to give the distribution volumes (DVs) of different brain regions. DV ratios (DVRs) of target to cerebellum were derived and compared against a kinetic reference tissue model and simple target-to-background ratio. RESULTS: Averaged over all 9 scans, the mean DV in the midbrain was 4.86 +/- 1.06 mL/mL and the mean DV in the cerebellum was 2.25 +/- 0.48 mL/mL. The mean test-retest repeatability of the midbrain DV was 14.5%. The reference tissue model gave a mean midbrain DVR of 2.01 +/- 0.17 and correlated strongly with the DVR calculated from the full kinetic model (correlation coefficient [R(2)] = 0.94; P < 0.001), but with much improved repeatability (test-retest, 5.4%; intersubject variability, 5.2%). Similarly, the simple ratio method gave strong correlations with the full kinetic model (R(2) = 0.89; P < 0.001) and a test-retest of 7.6%. CONCLUSION: Accurate, repeatable quantification of SERT in the nonhuman primate brain is possible using kinetic modeling of dynamic [(123)I]ADAM SPECT scans. Simplified models, which do not require arterial blood sampling, gave accurate results that correlated strongly with the full kinetic model. The test-retest reliability of the simplified reference region models was excellent. Quantification of SERT is possible using full kinetic modeling and also with simpler reference region methods.

Animals↗
PubMed2000

DNA of nonhuman primates harbors hepatitis C-virus-specific sequences of its 5'-non-coding region (5'-NCR).

The DNA from PBMCs of both hepatitis C virus (HCV)-positive patients and healthy HCV-negative human individuals tested thus far contains essential parts--up to 272/341 nucleotides--of the HCV 5'-non-coding region (5'-NCR). These findings bring up the question of the possible evolutionary background of these sequences. Therefore, using the same methodology, we looked for the same sequences in animals closely related to man, i.e., in nonhuman primates (two chimpanzees, one orang-utan, one Debrazza monkey, two New World monkey species and a prosimian). The DNA from PBMCs of the studied animals belonging to nonhuman primates contains essential parts--up to 272/341 nucleotides--of the HCV 5'-non-coding region (5'-NCR). A common sequence of 82 nucleotides is contained in the DNA of all the tested animals but only the chimpanzee's DNA harbors the same, longer sequence region of 272/341 nucleotides of the 5'-NCR found in human DNA. The results may provide a clue as to the possible origin of parts of the IRES containing sequence area of the HCV.

Animals↗
PubMed1998

Pharmacokinetics of O6-benzylguanine and its active metabolite 8-oxo-O6-benzylguanine in plasma and cerebrospinal fluid after intrathecal administration of O6-benzylguanine in the nonhuman primate.

O6-Benzylguanine (O6BG) irreversibly inactivates the single-turnover DNA repair protein alkylguanine-alkyltransferase. Thus, O6BG increases tumor-cell sensitivity to alkylating agents such as carmustine, lomustine, procarbazine, and temozolomide. We investigated the pharmacokinetic behavior of O6BG and O6-benzyl-8-oxoguanine (8-oxo-O6BG) in cerebrospinal fluid (CSF) and plasma after intraventricular administration of O6BG in a nonhuman primate model. In our study, three animals received a single 1-mg dose of O6BG into the lateral ventricle. CSF from the 4th ventricle and plasma samples were collected after administration, and O6BG and 8-oxo-O6BG concentrations were measured by high-performance liquid chromatography. Four additional animals received 1 mg of O6BG via the intralumbar route weekly for 6 weeks to assess the feasibility and toxicity of this route of administration. The peak O6BG CSF concentration was 412+/-86 microM, the t1/2 was 0.52+/-0.02 h, the clearance was 0.22+/-0.01 ml/min, and the area under the concentration-time curve was 319+/-15 microM x h in 4th ventricular CSF. The peak CSF concentration of 8-oxo-O6BG in CSF was 1.9+/-0.4 microM, the t1/2 was 0.76+/-0.03 h, and the area under the concentration-time curve was 5.0+/-1.1 microM x h. Both O6BG and 8-oxo-O6BG were detected in the plasma 0.5-3 h after intraventricular O6BG administration. The plasma peak concentration of O6BG was 0.4 microM at 30 min, and the concentration was <0.1 microM by 3 h. The plasma concentration of 8-oxo-O6BG was 0.2 microM at 30 min and 0.6 microM at 3 h. The animals tolerated the single intraventricular dose and 6 weekly intralumbar doses of O6BG without toxicity. We concluded that intrathecal administration of O6BG is well tolerated in the nonhuman primate and seems to have a substantial pharmacokinetic advantage over systemic administration for meningeal tumors.

Animals↗