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PubMed2002

Interhemispheric intracranial pressure gradients in nonhuman primate stroke.

BACKGROUND: Although the development of significant interhemispheric intracranial pressure (ICP) gradients in the setting of unilateral stroke remains controversial, no study to date has investigated the existence of these gradients in a controlled, reproducible, clinically relevant model. Therefore, we used a primate model of reperfused hemispheric stroke to better characterize the development of these gradients. METHODS: Bilateral intraparenchymal ICP was continuously monitored in 7 adult male baboons subjected to left hemisphere reperfused stroke. Interhemispheric ICP gradients were calculated for each baboon and plotted over time. Infarct volume was determined using T2-weighted magnetic resonance imaging (MRI) at sacrifice. RESULTS: A bimodal distribution of interhemispheric ICP gradients was observed in animals with >20% infarct volume (22.1% +/- 0.9; range 21-23%) versus < or = 15% infarct volume (6.6% +/- 2.7; range 1-15%). In animals with >20% infarct volume, interhemispheric gradients developed early and persisted throughout the monitoring period. At 12 hours postreperfusion, animals with large infarcts demonstrated a mean pressure gradient of 13.8 +/- 4.3 mm Hg, compared to a mean gradient of -2.6 +/- 1.1 mm Hg for animals with < or =15% infarct volume. The difference in pressure gradients was statistically significant at all time points from 4 to 12 hours postreperfusion (p < 0.01). CONCLUSIONS: These data suggest that, in nonhuman primates, infarcts of a size approaching 20% of the hemisphere may be associated with significant ICP gradients. With these larger infarcts, ipsilateral monitoring is required if regional cerebral perfusion pressure is to be accurately assessed.

Animals↗
PubMed1997

Safety of airway gene transfer with Ad2/CFTR2: aerosol administration in the nonhuman primate.

In this study, the safety and efficacy of aerosol delivery to non-human primates of an adenoviral vector encoding the cystic fibrosis transmembrane conductance regulator protein (CFTR) were evaluated. The technique of concurrent flow spirometry was used to determine the deposited dose of Ad2/CFTR-2, which ranged from 3 to 8 x 10(10) I.U. Transgene DNA was detected by the polymerase chain reaction (PCR) in lung tissue from all treated animals, and human CFTR mRNA was detected on days 3, 7, and 21 post-exposure. The treatment was well tolerated, with no evidence of respiratory distress. Histologic changes in the lungs from Ad2/CFTR-2-treated animals were mild and, overall, indistinguishable from animals exposed to aerosolized vehicle. One vector-treated animal demonstrated an increase in lavage lymphocyte numbers 3 days after treatment and another had an abnormal chest radiograph 14 days after treatment. A third vector-treated animal had histologic evidence of a bronchointerstitial pneumonia 7 days after aerosol treatment that resolved by day 21. This study demonstrated that Ad2/CFTR-2 can effectively be delivered to the lungs of nonhuman primates and result in minimal adverse effects.

Adenoviruses, Human↗
PubMed2002

Hypertension induced by blockade of ET(B) receptors in conscious nonhuman primates: role of ET(A) receptors.

The role of endothelin-B (ET(B)) receptors in circulatory homeostasis is ambiguous, reflecting vasodilator and constrictor effects ascribed to the receptor and diuretic and natriuretic responses that could oppose the hypertensive effects of ET excess. With the use of conscious, telemetry-instrumented cynomolgus monkeys, we characterized the hypertension produced by ET(B) blockade and the role of ET(A) receptors in mediating this response. Mean arterial pressure (MAP) and heart rate (HR) were measured 24 h/day for 24 days under control conditions and during administration of the ET(B)-selective antagonist A-192621 (0.1, 1.0, and 10 mg/kg bid, 4 days/dose) followed by coadministration of the ET(A) antagonist atrasentan (5 mg/kg bid) + A-192621 (10 mg/kg bid) for another 4 days. High-dose ET(B) blockade increased MAP from 79 +/- 3 (control) to 87 +/- 3 and 89 +/- 3 mmHg on the first and fourth day, respectively; HR was unchanged, and plasma ET-1 concentration increased from 2.1 +/- 0.3 pg/ml (control) to 7.24 +/- 0.99 and 11.03 +/- 2.37 pg/ml. Atrasentan + A-192621 (10 mg/kg) decreased MAP from hypertensive levels (89 +/- 3) to 75 +/- 2 and 71 +/- 4 mmHg on the first and fourth day, respectively; plasma ET-1 and HR increased to 26.64 +/- 3.72 and 28.65 +/- 2.89 pg/ml and 113 +/- 5 (control) to 132 +/- 5 and 133 +/- 7 beats/min. Thus systemic ET(B) blockade produces a sustained hypertension in conscious nonhuman primates, which is mediated by ET(A) receptors. These data suggest an importance clearance function for ET(B) receptors, one that influences arterial pressure homeostasis indirectly by reducing plasma ET-1 levels and minimizing ET(A) activation.

Animals↗
PubMed1991

Bone induction in nonhuman primates. An experimental study on the baboon.

Development leading to local bone differentiation in response to intramuscular and subcutaneous implantation of demineralized bone matrix has been predominantly investigated in rodents. To investigate bone differentiation by induction in primates, diaphyseal bone was harvested from ten male baboons and chemosterilized to obtain autolyzed, antigen-extracted allogeneic (AAA) bone containing the bone morphogenetic protein essential for osteoinduction. A total of 96 AAA bone diaphyseal cylinders were implanted intramuscularly in 24 adult male baboons and harvested at three, six, and nine months. Histologic analysis showed that the matrix had undergone considerable resorption, particularly at six and nine months. Seventy-three implants showed variable amounts of newly formed bone at the internal and external surfaces of the chemosterilized matrix. Numerous specimens showed florid bone formation, and newly formed woven bone persisted in association with the matrix for as long as nine months. Coating the AAA bone matrix with an allogeneic fibrin-fibronectin protein concentrate prepared from fresh-frozen baboon plasma did not significantly increase the amount of induced bone. Bone formation was confirmed by intravital double tetracycline labeling of the mineralization fronts. The unequivocal demonstration of bone formation by induction in a large series of adult nonhuman primates provides evidence that long-lived higher vertebrates retain the bone-inductive proteins in the extracellular matrix of bone and the crucial set of responding mesenchymal cells capable of transformation and differentiation into osteoblastic cell lines.

Animals↗
PubMed2001

Leridistim, a chimeric dual G-CSF and IL-3 receptor agonist, enhances multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression: effect of schedule, dose, and route of administration.

Leridistim is from the myelopoietin family of proteins, which are dual receptor agonists of the human interleukin-3 and G-CSF receptor complexes. This study investigated the effect of dosage, administration route, and schedule of leridistim to stimulate multilineage hematopoietic recovery in total body irradiated rhesus monkeys. Animals were x-irradiated on day 0 (600 cGy, 250 kVp) and then received, on day 1, leridistim s.c. in an abbreviated, every-other-day schedule at 200 microg/kg, or daily at 50 microg/kg, or i.v. daily or every-other-day schedules at 200 microg/kg dose. Other cohorts received G-CSF (Neupogen((R)) [Filgrastim]) in an every-other-day schedule at 100 microg/kg/day, or autologous serum (0.1%) s.c. daily. Hematopoietic recovery was assessed by bone marrow clonogenic activity, peripheral blood cell nadirs, duration of cytopenias, time to recovery to cellular thresholds, and requirements for clinical support. Leridistim, administered s.c. every other day, or i.v. daily, significantly improved neutrophil, platelet, and lymphocyte nadirs, shortened the respective durations of cytopenia, hastened trilineage hematopoietic recovery, and reduced antibiotic and transfusion requirements. A lower dose of leridistim administered daily s.c. enhanced recovery of neutrophil and platelet parameters but did not affect lymphocyte recovery relative to controls. Leridistim, a novel engineered hematopoietic growth factor administered at the appropriate dose, route and schedule, stimulates multilineage hematopoietic reconstitution in radiation-myelosuppressed nonhuman primates.

Animals↗
PubMed1972

An outbreak of infection by Yersinia pseudotuberculosis in nonhuman primates.

Between October 1970 and June 1971, at the National Center for Primate Biology, Yersinia pseudotuberculosis of serotypes I-B and III was isolated from 9 monkeys (one during life and 8 at necropsy) of the following species: Macaca cynomolgus, Macaca nemestrina, Macaca radiata and Cercocebus fulliginosus. All these animals had characteristic gastrointestinal lesions consisting of superficial erosions or ulcerations with masses of gram-negative coccobacilli and an acute inflammatory exudate. Involvement of mesenteric nodes, livers and spleens by similar lesions was common. A more granulomatous reaction was rarely seen. Similar lesions without bacteriologic confirmation were found at necropsy in 20 other animals. When guinea pigs were inoculated intraperitoneally with our isolates, they developed focal splenic and hepatic necrosis resembling the septicemic form of the disease which is seen rarely in man. When inoculated intraperitoneally, they developed mesenteric lymphadenitis resembling human nonspecific mesenteric lymphadenitis; no intestinal lesions could be detected in the animals inoculated orally. The granulomatous component of the inflammatory response was better developed in guinea pigs than in the monkeys. It is concluded that infection by Yersinia pseudotuberculosis in nonhuman primates and probably also in other species, including man, is primarily a gastrointestinal disease. The primary intestinal lesions may be conspicuous, as in the monkeys, or inconspicuous, as in the guinea pig and man. The acuteness of the inflammatory response in the monkeys, when compared to the more granulomatous reaction in guinea pigs, suggests that the great majority of the monkeys died from an overwhelming infection before they could develop hypersensitivity to the organism.

Animals↗
PubMed2003

The safety and utility of recombinant human bone morphogenetic protein-2 for cranial procedures in a nonhuman primate model.

OBJECT: The goal of this study was to evaluate the safety and efficacy of recombinant human bone morphogenetic protein 2 (rhBMP-2) in cranial applications. METHODS: Critical-sized calvarial defects were created bilaterally in four rhesus monkeys, and bilateral rectangular bone flaps were created in six others. Control and rhBMP-2-treated sides were randomly chosen for each animal, and an absorbable collagen sponge was used to deliver the growth factor. Over a 6-month period postoperatively, the animals were serially evaluated for bone healing and adverse BMP-related consequences by using the following methods: computerized tomography (CT) scanning, magnetic resonance (MR) imaging, electroencephalography, histological investigations, and cerebrospinal fluid (CSF) analysis. The critical-sized defects for the rhBMP-2-treated and control sides attained 71 +/- 12% and 28 +/- 11% closure, respectively (four animals; p = 0.04). The CT scans demonstrated that the bone flaps treated with rhBMP-2 had complete osteointegration in five of six animals, whereas scans of the untreated bone flaps demonstrated uniformly poor osteointegration with the intact skull. Histological analysis confirmed well-formed bridges of bone on the rhBMP-2-treated sides. No epileptogenic activity was detected in any of the animals, and MR imaging revealed no evidence of adverse effects on the brain parenchyma. Meningitic irritation was not found on postoperative CSF sample analysis. CONCLUSIONS: Treatment of bone flaps and critical-sized cranial defects with rhBMP-2 leads to improved bone formation and osteointegration in nonhuman primates. Initial evaluation of rhBMP-2 appears to indicate a good safety profile for use in cranial procedures in primates.

Animals↗
PubMed1993

T- and B-cell functions and epitope expression in nonhuman primates immunized with simian immunodeficiency virus antigen by the rectal route.

Transmission of human immunodeficiency virus (HIV) in North America and Europe occurs most commonly through the rectal mucosa during homosexual intercourse. The simian immunodeficiency virus (SIV) macaque model has been used to investigate rectal immunization. The vaccine used was a recombinant SIV gag p27 expressed as hybrid Ty virus-like particles (Ty-VLP). Sequential ororectal (OR) mucosal immunization was compared with i.m. immunization. Whereas both routes of immunization induced serum IgA and IgG p27 antibodies, only OR immunization induced rectal secretory IgA antibodies. Specific CD4+ T-cell proliferative responses to stimulation with p27 were found after i.m. immunization only in the blood and spleen, but after OR immunization they were found in the internal iliac and inferior mesenteric lymph nodes in addition to the blood and spleen. T-cell epitope mapping of the proliferative responses of short-term cell lines (STCLs) grown from peripheral blood or lymphoid cells revealed a major epitope within the polypeptide 121-150 after either route of immunization. Two minor T-cell epitopes were found within peptide 41-80 in STCLs from splenic and circulating cells. B-cell epitope mapping of serum or biliary IgA and IgG antibodies revealed two overlapping or adjacent immunodominant epitopes to the T-cell epitopes within the polypeptides 121-170 and 51-90. The results suggest that rectal augmented by oral immunization with a recombinant particulate antigen in nonhuman primates elicits secretory IgA and to a lesser extent IgG responses in the draining lymph nodes and the rectal mucosa, whereas systemic immunization targets predominantly splenic and circulating T- and B-cell responses. These findings may have important implications in the strategy of designing vaccines in prevention of homosexual transmission of HIV infection.

Administration, Rectal↗
PubMed2002

Induction of glioblastoma multiforme in nonhuman primates after therapeutic doses of fractionated whole-brain radiation therapy.

OBJECT: To determine the acute and long-term effects of a therapeutic dose of brain radiation in a primate model, the authors studied the clinical, laboratory, neuroimaging, molecular, and histological outcomes in rhesus monkeys that had received fractionated whole-brain radiation therapy (WBRT). METHODS: Twelve 3-year-old male primates (Macaca mulatta) underwent fractionated WBRT (350 cGy for 5 days/week for 2 weeks, total dose 3500 cGy). Animals were followed clinically and with laboratory studies and serial magnetic resonance (MR) imaging. They were killed when they developed medical problems or neurological symptoms, lesions appeared on MR imaging, or at study completion. Gross, histological, and molecular analyses were then performed. Nine (82%) of 11 animals that underwent long-term follow up (> 2.5 years) developed neurological symptoms and/or enhancing lesions on MR imaging, which were defined as glioblastoma multiforme (GBM), 2.9 to 8.3 years after radiation therapy. The GBMs were categorized as either unifocal (three) or multifocal (six), and were located in the supratentorial (six), infratentorial (two), or both (one) cranial regions. Histological examination revealed distant, noncontiguous tumor invasion within the white matter of all nine animals harboring GBMs. Novel interspecies comparative genomic hybridization (three animals) uniformly showed deletions in the GBMs that corresponded to chromosome 9 in humans. CONCLUSIONS: The high rate of GBM formation (82%) following a therapeutic dose of WBRT in nonhuman primates indicates that radioinduction of these neoplasms as a late complication of this therapy may occur more frequently than is currently recognized in human patients. The development of these tumors while monitoring the monkeys' conditions with clinical and serial MR imaging studies, and access to the tumor and the entire brain for histological and molecular analyses offers an opportunity to gather unique insights into the nature and development of GBMs.

Animals↗
PubMed1990

Effects of parenteral recombinant human macrophage colony-stimulating factor on monocyte number, phenotype, and antitumor cytotoxicity in nonhuman primates.

Recombinant human macrophage colony-stimulating factor (rhM-CSF) was given to cynomolgus monkeys by continuous intravenous infusion or subcutaneous injection, at a dose of 50 to 100 micrograms/kg/d in repetitive 14-day cycles. Starting within 24 to 48 hours of initiation of rhM-CSF, there was a progressive increase in the number of circulating monocytes, from a baseline of 811 +/- 253 cells/microL to a peak of 3,495 +/- 712 cells/microL on day 5 to 7. Many of these cells were large, granular, and extensively vacuolated. The expanded cell population expressed HLA-DR, LFA3, CD11b (904), and CD14 (MY4), and was 77% CD16 (FcRIII) positive by two-color cytofluorometry. In functional assays, fresh monocytes showed little cytotoxicity against cultured human melanoma cells (SKMel-1), with or without prior rhM-CSF treatment. However, after 3 days of in vitro culture in rhM-CSF, monocytes from treated animals mediated efficient antibody-dependent cytotoxicity (ADCC) against SKMel-1 using the murine monoclonal antibody 3F8 (IgG3, anti-ganglioside GD2). Under the same conditions, monocytes from control animals showed little ADCC (17% versus 82%, P less than .05). Antitumor cytotoxicity in the absence of antibody was less efficient and was not significantly different between the two groups. There was a mild decrease in platelet count during rhM-CSF treatment, without clinical symptoms. No abnormalities of serum biochemical parameters were seen. We conclude that parenteral rhM-CSF increases the number of circulating monocytes in nonhuman primates, and that these monocytes mediate increased antitumor ADCC after a brief period of in vitro differentiation. This study has implications for the design of possible future clinical trials combining antitumor monoclonal antibodies and rhM-CSF.

Animals↗
PubMed2003

Suppressed complement activation in human decay accelerating factor transgenic porcine liver cross-circulated with nonhuman primates.

BACKGROUND: We developed an extracorporeal liver perfusion (ECLP) system as a liver-assist device. In this study, we evaluated the safety of the ECLP using human decay accelerating factor (hDAF) transgenic porcine livers in healthy baboons. METHODS: Livers were isolated from five hDAF transgenic pigs and five nontransgenic pigs for the ECLP. Ten cross-circulations between the ECLP and healthy baboons were performed without immunosuppressive agents. Cross-circulation was discontinued in any of the following circumstances: elevated hepatic arterial (>200 mm Hg) or portal (>60 mm Hg) perfusion pressure, massive exudate from the graft liver, mild macroscopic hemolysis, thrombocytopenia, or 24-hr well-conditioned cross-circulation. RESULTS: The cross-circulations with nontransgenic porcine livers were discontinued at 4.4+/-1.2 hr (mean+/-standard deviation) because of high perfusion pressure (n=2) or hemolysis (n=3). Three cross-circulations with hDAF transgenic porcine livers were performed for 24 hr; the other two cross-circulations were discontinued at 13 and 17 hr because of massive exudate and thrombocytopenia, respectively. The duration was 20.4+/-5.1 hr. Deposition of membrane attack complex in the hDAF transgenic porcine liver was less than that in the nontransgenic liver, although immunoglobulin-M deposition was comparable. The porcine livers showed no apparent interlobular bleeding or lobular necrosis. All porcine livers maintained bile production during the cross-circulation. No baboons showed any serious complications after the cross-circulation. CONCLUSION: The hDAF transgenic porcine liver reduced complement activation in xenoperfusion with healthy nonhuman primate blood and led to extended duration of cross-circulation.

Animals↗
PubMedDate not supplied

Nomegestrol acetate and vascular reactivity: nonhuman primate experiments.

Prevention of coronary artery disease has been recognized as a major benefit of estrogen replacement therapy (ERT) in postmenopausal women. However, endometrial hyperplasia induced by unopposed ERT has raised important safety concerns. Progesterone or synthetic progestins have been used in combined hormone replacement therapy (HRT) to prevent endometrial cancer risk. Therefore, a major concern has been to ensure that the vascular beneficial effects of estrogens are not opposed when combined with progestins. Nomegestrol acetate (NOMAC) is an orally active progestin widely prescribed for HRT. Its vascular effects were evaluated in two models of coronary vascular reactivity in primates: 1) the paradoxical vasoconstriction to acetylcholine (Ach) coronary infusion after 5 months of mildly atherogenic diet in ovariectomized (OVX) Cynomolgus monkeys and 2) the pharmacologically evoked coronary vasospasm in the OVX Rhesus monkey. In the first model, after 3 months of continuous oral administration in the diet at 0.1 mg/kg/day, E2 prevented the paradoxical response to Ach, alone as well as combined with 0.25 mg/kg/day NOMAC, whereas NOMAC counteracted the endometrial stimulation. In the second model, after one artificial cycle consisting of 28 days of E2 subcutaneous (s.c.) implant and of daily oral gavage with 1 mg/kg/day of NOMAC for the last 14 days, no vasospasm (0 of 11 tested animals) occurred when the complete challenge protocol, including serotonin and the thromboxane agonist U46619, was administered to OVX Rhesus monkeys. In the balanced crossover design, identical artificial cycles with medroxyprogesterone acetate (MPA) at the same dose resulted in 7 vasospasms in 12 animals. In parallel, effective progestative activity was demonstrated by a secretory pattern in endometrial sections obtained at the end of the cycle. In these two nonhuman primate cardiovascular models, NOMAC did not have the negating effects observed with MPA.

Acetylcholine↗
PubMed1998

Immunization against natural Helicobacter pylori infection in nonhuman primates.

Helicobacter pylori infection is widespread in some breeding groups of a rhesus monkey colony (71% H. pylori positive by 1 year), and the rate of seroconversion is also high. As a result, these groups can be used to test the safety and efficacy of an anti-H. pylori vaccine. Nine-month-old female animals were randomized to receive either 8 mg of recombinant urease (rUre) plus 25 microg of Escherichia coli heat-labile enterotoxin (LT) (n = 26) or placebo plus LT (n = 29), given four times at 1-week intervals followed by a booster 1 month later. Ten months after the start of the immunization, the animals were subjected to endoscopy and biopsy samples were obtained. H. pylori negativity was defined as no H. pylori growth by culture and no H. pylori observed at histology. By this criterion, 2 (7%) of 29 animals receiving placebo and 8 (31%) of 26 immunized animals were H. pylori negative (P < 0.035). In addition, antral gastritis score was significantly less in H. pylori-negative immunized monkeys than in H. pylori-positive animals, whether they were given rUre plus LT or placebo plus LT (P < 0.02 or P < 0.01, respectively). Interestingly, antral gastritis was also significantly less in H. pylori-positive animals given rUre plus LT than in H. pylori-positive animals given placebo plus LT (P < 0.02). However, quantitative cultures did not demonstrate significant differences between the two latter groups. It is concluded that oral administration of rUre vaccine plus LT significantly protects nonhuman primates against H. pylori infection while not causing undesirable side effects.

Animals↗
PubMedDate not supplied

Cocaine impairs ovarian response to exogenous gonadotropins in nonhuman primates.

OBJECTIVE: Determine whether cocaine directly impairs ovarian steroid production and ovulation. METHODS: Normally cycling adult female rhesus monkeys received daily intravenous normal saline (control; n = 8) or cocaine (4 mg/kg; n = 8) through the follicular phase. Monkeys were injected daily with human menopausal gonadotropin (hMG; Pergonal) at a dose of 6 IU/kg intramuscularly beginning on cycle day 2. Daily blood samples were obtained, and serum estradiol (E(2)) and progesterone (P(4)) were measured by radioimmunoassay. When serum levels of E(2) declined, plateaued, or exceeded 600 pg/mL, laparoscopy was performed to count the number of follicles. If no new corpus luteum was present, monkeys were injected intramuscularly with 1000 IU of hCG. Laparoscopy was repeated 2 days later to document the number of ovulatory stigma. RESULTS: During ovarian stimulation, cocaine-treated monkeys required an average additional 1.5 days of hMG injections (P =.01), and this resulted in a greater total dose of hMG compared with control monkeys (351 +/- 16 IU versus 297 +/- 15 IU [mean +/- standard error of the mean], P =.03). For spontaneous and hCG-triggered ovulation, the number of ovulatory stigma was significantly lower (P <.003) in the cocaine-treated versus control monkeys (16 versus 31). Peak E(2) levels were significantly (P =.05) lower in cocaine-treated monkeys compared with controls. Luteal phase P(4) levels were lower in the cocaine-treated monkeys, but the difference was not statistically significant when compared with controls. CONCLUSION: Cocaine impaired ovarian responsiveness to exogenous gonadotropins and decreased ovulatory stigma in nonhuman primates. These findings suggest that cocaine has direct ovarian effects.

Animals↗
PubMedDate not supplied

Alteration of high density lipoprotein subfractions of nonhuman primates fed fish-oil diets. Selective lowering of HDL subfractions of intermediate size and density.

Two groups of adult male African green grivet monkeys (12 animals in each group) were fed atherogenic diets containing 40% of total calories as fat with half of the fat calories derived from lard or menhaden oil and 0.8 mg cholesterol/kcal for a period of 10 months to ascertain the effect of such diets on lipoprotein concentrations, composition, and distribution. After 8 months on this diet, the animals' lipoproteins were isolated from their plasma by ultracentrifugation and agarose column chromatography, and these were characterized chemically. Compared with the lard-fed group, the menhaden oil-fed animals had significantly lower total plasma cholesterol (decreases 33%), HDL cholesterol (decreases 33%) and apo A-I (decreases 30%) concentrations and LDL molecular weights (decreases 15%). Although the fish-oil diets resulted in an average similar reduction of LDL cholesterol concentrations (decreases 34%), the decrease was not statistically significant. The lipid and apoprotein compositions of plasma LDL and HDL were similar between the two groups of animals. The distribution of HDL subfractions was determined by gradient gel electrophoresis and density gradient ultracentrifugation. The fish-oil group had a significant reduction in protein (decreases 46%) of HDL subfractions of intermediate size (80 to 88 A) compared to the lard-fed group. By density gradient ultracentrifugation, there was a 35% to 40% lower concentration of protein in the d = 1.10-1.13 g/ml subfraction of fish-oil-fed monkeys. Thus, feeding fish oil to nonhuman primates results in a selective decrease in the concentration of HDL subfractions of intermediate size and density compared to lard-fed animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Eplerenone inhibits atherosclerosis in nonhuman primates.

Aldosterone may be involved in the pathogenesis of atherosclerosis. We investigated the effect of eplerenone, a selective mineralocorticoid receptor blocker, on atherosclerosis in monkeys fed a high-cholesterol diet. Monkeys fed a high-cholesterol diet for 9 months were divided into 3 groups: those treated with a low dose of eplerenone (30 mg/kg per day); those treated with a high dose of eplerenone (60 mg/kg per day); and the placebo-treated group. The normal group consisted of monkeys fed a normal diet. There were no significant differences in blood pressure and cholesterol levels between the placebo- and eplerenone-treated groups. On the other hand, monocyte chemoattractant protein-1 and malondialdehyde-modified LDL were significantly higher in the placebo-treated group than in the normal group, whereas they were suppressed in the eplerenone-treated groups. The ratio of intimal volume to total volume by intravascular ultrasound analysis imaging of the aortas was dose-dependently lower in the eplerenone-treated groups than in the placebo-treated group. Acetylcholine-induced vasorelaxation was significantly weaker in the placebo-treated group than in the normal group, but the vasorelaxation was strengthened in the eplerenone-treated groups. A significant upregulation of angiotensin-converting enzyme activity was observed in the placebo-treated group, but the activity was suppressed in the eplerenone-treated groups. In conclusion, eplerenone may strengthen the endothelium-dependent relaxation and suppress angiotensin-converting enzyme activity in the vasculature, thus preventing the development of atherosclerosis in nonhuman primates.

Acetylcholine↗
PubMedDate not supplied

Bone formation and osseointegration stimulated by rhBMP-2 following subantral augmentation procedures in nonhuman primates.

The purpose of this study was to evaluate bone formation and osseointegration using titanium dental implants in the subantral space following surgical implantation of recombinant human bone morphogenetic protein-2 (rhBMP-2). In each of four cynomolgus monkeys, one subantral site was treated with rhBMP-2 (0.19 mg per implant) in an absorbable collagen sponge (ACS). The contralateral site was treated with vehicle in ACS (control). Three months later, two screw-type titanium dental implants were placed into each augmented sinus, and one additional implant was placed immediately anterior to the sinus. Thus, each animal had three experimental sites: rhBMP-2, control, and nonsinus. Animals were sacrificed after an additional 3 months, and block sections were harvested and prepared for histometric analysis. Analysis of variance and t tests were used to evaluate differences between experimental conditions. Mean (+/- SD) vertical bone gain was significantly greater in rhBMP-2 than in control sites (6.0 +/- 0.3 versus 2.6 +/- 0.3 mm; P < .002). Bone density in rhBMP-2 sites averaged 14.4 +/- 2.9% versus 13.9 +/- 4.6% and 14.1 +/- 3.6% for control and nonsinus sites, respectively, without significant differences between experimental conditions. Bone-implant contact in rhBMP-2 sites (41.4 +/- 7.7%) was not significantly different from that in control (38.9 +/- 12.4%) and nonsinus sites (46.8 +/- 10.6%). The present study provides evidence for considerable vertical bone gain in the subantral space following surgical implantation of rhBMP-2, thus allowing placement of dental implants. The newly formed bone appears to be of similar quality and to be as suitable for osseointegration as the residual bone in this nonhuman primate model. Thus, surgical implantation of rhBMP-2 appears to have clinical utility and may provide a realistic alternative to autogenous bone grafts for subantral augmentation procedures.

Analysis of Variance↗
PubMed1997

Preclinical evaluation in nonhuman primates of murine monoclonal anti-idiotype antibody that mimics the disialoganglioside GD2.

The antiganglioside GD2 monoclonal antibody 14G2a (Ab1) served as an immunogen to generate the anti-idiotype (anti-Id) 1A7 (IgG1,kappa), which mimics GD2 both antigenically and biologically. Anti-Id 1A7 induced anti-GD2 antibodies in mice and rabbits. In this preclinical study, a pair of cynomolgus monkeys, immunized with 1A7 that had been mixed with QS-21 adjuvant, produced anti-anti-Id antibodies (Ab3), which reacted with the GD2-positive melanoma cell line M21/P6 cells but not with GD2-negative LS174-T cells. The Ab3 shared Ids with mAb 14G2a (Ab1), as demonstrated by their ability to inhibit binding of 1A7 to this Ab1. The Ab3 bound specifically to purified GD2 antigen and competed with the Ab1 14G2a in binding to a GD2-positive melanoma cell line or to purified GD2, suggesting that Ab1 and Ab3 may bind to the same epitope and may behave as an Ab1-like antibody (Ab1'). The isotype of the GD2-specific antibodies was mostly IgG in nature. The specificity of the antibodies for GD2 was further confirmed by dot blot analysis. These antisera also specifically lysed GD2-positive target cells in an antibody-dependent cellular cytotoxicity assay. The induction of anti-GD2 responses in monkeys did not cause any apparent side effects, despite the fact that GD2 antigen is expressed by many normal tissues of these animals. Taken together, these results suggest that anti-Id 1A7 can induce GD2-specific antibodies in nonhuman primates and can thus serve as a potential network antigen for triggering active anti-GD2 antibodies in patients with GD2-positive neuroectodermal tumors.

Adjuvants, Immunologic↗