Cassondra Bauer

Validation of lower body negative pressure as an experimental model of hemorrhage.

Lower body negative pressure (LBNP), a model of hemorrhage (Hem), shifts blood to the legs and elicits central hypovolemia. This study compared responses to LBNP and actual Hem in sedated baboons. Arterial pressure, pulse pressure (PP), central venous pressure (CVP), heart rate, stroke volume (SV), and +dP/dt were measured. Hem steps were 6.25%, 12.5%, 18.75%, and 25% of total estimated blood volume. Shed blood was returned, and 4 wk after Hem, the same animals were subjected to four LBNP levels which elicited equivalent changes in PP and CVP observed during Hem. Blood gases, hematocrit (Hct), hemoglobin (Hb), plasma renin activity (PRA), vasopressin (AVP), epinephrine (EPI), and norepinephrine (NE) were measured at baseline and maximum Hem or LBNP. LBNP levels matched with 6.25%, 12.5%, 18.75%, and 25% hemorrhage were -22 ± 6, -41 ± 7, -54 ± 10, and -71 ± 7 mmHg, respectively (mean ± SD). Hemodynamic responses to Hem and LBNP were similar. SV decreased linearly such that 25% Hem and matching LBNP caused a 50% reduction in SV. Hem caused a decrease in Hct, Hb, and central venous oxygen saturation (ScvO2). In contrast, LBNP increased Hct and Hb, while ScvO2 remained unchanged. Hem caused greater elevations in AVP and NE than LBNP, while PRA, EPI, and other hematologic indexes did not differ between studies. These results indicate that while LBNP does not elicit the same effect on blood cell loss as Hem, LBNP mimics the integrative cardiovascular response to Hem, and validates the use of LBNP as an experimental model of central hypovolemia associated with Hem.

Transgene expression up to 7 years in nonhuman primates following hepatic transduction with helper-dependent adenoviral vectors

Helper-dependent adenoviral vectors (HDAd) have been shown to mediate a considerably longer duration of transgene expression than first-generation adenoviral vectors. We have previously shown that transgene expression from HDAd-transduced hepatocytes can persist at high levels for up to 2.6 years in nonhuman primates following a single-vector administration. Because duration of transgene expression and long-term toxicity are critical for risk:benefit assessment, we have continued to monitor these animals. We report here that transgene expression has persisted for the entire observation period of up to 7 years for all animals without long-term adverse effects. However, in all cases, transgene expression level slowly declined over time to less than 10% of peak values by the end of the observation period but remained 2.3-111-fold above baseline values. These results will provide important information for a more informed risk:benefit assessment before clinical application of HDAd.

A preliminary report on the feeding of cynomolgus monkeys (Macaca fascicularis) with a high-sugar high-fat diet for 33 weeks

Background  The metabolic syndrome is common in populations exposed to a typical Western diet. There is a lack of an animal model that mimics this condition.

The baboon (Papio sp.) as a model for female reproduction studies

BIOLOGY AND REPRODUCTION Due to their size and anatomical similarity to humans, baboons make an excellent model for reproductive studies. Baboons have a simple short cervix, muscular uterus, ovaries just lateral to the uterus and similar vasculature to that of humans. Because of the size of the animals, instruments designed for use in women can be readily used on baboons. Noninvasive determination of phase of estrous cycle is readily made by observation of changes in perineal sexual skin turgor and color. ADVANTAGES Some advantages of use of baboons compared to other nonhuman primates is that they are nonseasonal breeders allowing for studies to be conducted year round, have minimal infectious disease risks to humans as they do not carry Herpes B and have a social structure allowing for easy group formation. Baboons serve as good models for many conditions in humans and should be considered for studies investigating reproductive issues.

Characterization of tubal occlusion after transcervical polidocanol foam (PF) infusion in baboons

OBJECTIVE Our long-term goal is to develop a nonsurgical method of fallopian tubal occlusion for the purpose of permanent contraception. We have previously demonstrated that transcervical administration of 5% polidocanol foam (PF) can create tubal occlusion in macaques but that multiple treatments are required. In this study, we assessed the efficacy of various regimens of PF with and without depomedroxyprogesterone acetate (DMPA) (to control ovarian cycle phase) in the baboon. STUDY DESIGN Adult cycling female baboons were evaluated for tubal patency by hysterosalpingography and then received a transcervical infusion of PF with (+) or without (-) an intramuscular injection of DMPA (3.5 mg/kg). Two concentrations of PF were compared: 1% [(+) DMPA, n=5; (-) DMPA, n=3] and 5% [(+) DMPA, n=4; (-) DMPA, n=3]. Controls received (+) DMPA (n=2) or (-) DMPA, (n=3) only. The reproductive tracts were removed 1-3 months after treatment for examination. RESULTS No fallopian tubal occlusion was observed in negative controls (±DMPA). Histologic complete tubal occlusion was observed in 3/8 of females treated with 1% PF and in 6/7 treated with 5% PF. Histologic evaluation suggested that 1% PF is associated with prolonged chronic inflammation (more than 2-3 months), while 5% treatment eliminates the epithelial lining, at least focally, and resolves into complete occlusion within 1-2 months. This pattern of complete occlusion was seen in all 4 females that received 5% PF (+DMPA) and in 2/3 that received 5% PF (-DMPA). CONCLUSION In a baboon model of transcervical permanent contraception, a single treatment with 5% PF resulted in complete tubal occlusion more reliably (85%) than 1% PF (38%). Cotreatment with DMPA may improve treatment results with 5% PF but requires additional study. IMPLICATIONS A finding that a single transcervical treatment with 5% PF can occlude the fallopian tubes of baboon supports further study of this approach as a novel strategy for permanent contraception for women.

Transcervical administration of polidocanol foam prevents pregnancy in female baboons

Background Our objective was to conduct a pilot study to determine if transcervical administration of polidocanol foam (PF) with or without doxycycline or benzalkonium chloride (BZK) would prevent pregnancy in baboons. Methods In study phase 1, adult cycling baboons underwent a hysterosalpingogram to evaluate tubal patency prior to transcervical infusion of 20 mL of 5% PF followed by 1 mL of saline containing 100 mg doxycycline (5%/doxy; n=5), 3% PF plus doxycycline (3%/doxy; n=4), 3% PF with 0.01% BZK (3%/BZK; n=4) or no additional treatment (control; n=9). Immediately following treatment, animals received intramuscular depot medroxyprogesterone acetate (DMPA, 2 mg/kg) to suppress cyclicity during healing and were then socially housed with males of proven fertility. The primary outcome was pregnancy within six cycles of resumption of menses (efficacy phase 1). During study phase 2, PF-treated females from study phase 1 contributed additional cycles (6–8) of exposure (efficacy phase 2), and 5 control females who had recovered from medical abortion (after study phase 1 pregnancy) were subsequently treated with 5% PF (with DMPA) and exposed to breeding (efficacy phase 1; n=3 six cycles, n=2 five cycles). Results All females resumed normal menstrual cycles and mating activity after DMPA. During efficacy phase 1, 7/9 (78%) control females became pregnant. In contrast, fewer pregnancies occurred in PF-treated females: 5% PF 0/5 (0%), 5%/doxy 1/5 (20%), 3%/doxy 1/4 (25%) and 3%/BZK 1/4 (25%). During efficacy phase 2, only one additional pregnancy occurred (3%/BZK). Conclusions A single transcervical treatment with 5% PF prevented pregnancy in most baboons. Cotreatment with doxycycline or BZK did not improve results. Implications Transcervical intrauterine administration of PF resulted in a high rate of tubal occlusion with prevention of pregnancy; refinements are needed to increase the contraceptive rate following a single treatment to near 100%.

Metabolism and Disposition of Bupropion in Pregnant Baboons (Papio cynocephalus)

Recent in vitro data obtained in our laboratory revealed similarities between baboons and humans in the biotransformation of bupropion (BUP) by both hepatic and placental microsomes. These data supported the use of baboons to study BUP biotransformation during pregnancy. The aim of this investigation was to determine the pharmacokinetics of BUP in baboons during pregnancy and postpartum, as well as fetal exposure to the drug after intravenous administration. Pregnant baboons (n = 5) received a single intravenous bolus dose of bupropion hydrochloride (1 mg/kg) at gestational ages 94–108 days (midpregnancy), 142–156 days (late pregnancy), and 6 weeks postpartum. Blood and urine samples were collected for 12 and 24 hours, respectively. The concentrations of BUP, hydroxybupropion (OH-BUP), threohydrobupropion, and erythrohydrobupropion in plasma were determined by liquid chromatography–tandem mass spectrometry. Relative to the postpartum period, the average midpregnancy clearance of BUP trended higher (3.6 ± 0.15 versus 2.7 ± 0.28 l/h per kg) and the average Cmax (294 ± 91 versus 361 ± 64 ng/ml) and the area under the curve (AUC) of BUP values (288 ± 22 versus 382 ± 42 h·ng/ml) trended lower. AUCOH-BUP also tended to be lower midpregnancy compared with postpartum (194 ± 76 versus 353 ± 165 h·ng/ml). Whereas the observed trend toward increased clearance of BUP during baboon pregnancy could be associated with a pregnancy-induced increase in its biotransformation, the trend toward increased renal elimination of OH-BUP may overshadow any corresponding change in the hydroxylation activity of CYP2B.

Serum prostate specific antigen changes in cynomolgus monkeys (Macaca fascicularis) on a high sugar high fat diet

An inverse relationship between serum prostate specific antigen (PSA) levels and body mass index (BMI) has been reported in men but not in any animal model.

Abstract 970: Effect of feeding a high fat, high simple carbohydrate diet on serum prostate specific antigen (PSA) in cynomolgus monkeys

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Introduction The prostate specific antigen (PSA) test is used for screening and monitoring of prostate cancer. However, PSA has clinical limitations as it is elevated in other pathological conditions other than prostate cancer. PSA is also influenced by other physiological and environmental variables like genetics and diet. The aim of this study was to investigate the effect of feeding a high fat, high simple carbohydrate (HFHSC) diet on serum PSA in a nonhuman primate species. Methods Fifteen cynomolgus monkeys (Macaca fascicularis) were fed an HFHSC diet for 4 months. Body weight and Dual energy X-ray absorptiometry (DEXA) measurements were done at 0, 8 and 16 weeks. Blood was also drawn from these animals and used to assay serum PSA and serum insulin levels. Results View this table: Conclusions Feeding cynomolgus monkeys with an HFHSC diet for 4 months resulted in a significant increase in serum PSA levels. The mechanisms underlying this change in serum PSA is still under investigation, however, chronic hyper-insulinemia as indicated in this study might be one of the contributing factors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 970.