Evaluation of a novel ECG lead placement method in telemetered freely moving cynomolgus monkeys: assessment of an intravascular biopotential lead.

INTRODUCTION: ECG is considered as a critical biomarker of cardiac safety pharmacology. ECG signal quality is essential for accurate interval quantification and automated arrhythmia detection. METHODS: We evaluated ECG signal quality over a 6 month period from 15 cynomolgus monkeys with radiotelemetry transmitters using biopotential leads where the negative lead was inserted in the jugular vein and advanced to the superior vena cava (intravascular lead) and the positive lead was placed on the diaphragm at the apex of the heart (diaphragmatic lead). Signal noise and signal-to-noise ratio from this implantation methodology were compared with signals obtained from animals with subcutaneous ECG lead. Macroscopic pathology and histopathology associated with the intravascular lead were evaluated at 6 months post-implantation in six monkeys. RESULTS: The ECG morphology obtained with the intravascular/diaphragmatic lead placement was comparable to conventional subcutaneous ECG (emulating Lead II) but presented higher amplitudes (P-wave +50.0%; R-wave +30.0%). Signal noise showed a circadian cycle of changes in magnitude for subcutaneous ECG leads that was not observed with this method. The intravascular/diaphragmatic lead placement presented a higher signal-to-noise ratio than subcutaneous ECG leads. No macroscopic abnormality was observed to be associated with the intravascular lead. Mild thickening of the intima/subintima with mild intimal proliferation of the cranial vena cava surrounding the intravascular lead were noted at histopathological examination. DISCUSSION: The intravascular/diaphragmatic ECG lead placement in cynomolgus monkeys provided reduced signal noise and elevated P-QRS-T amplitudes. The intravascular lead was well tolerated and appeared suitable for chronically instrumented cardiovascular safety pharmacology studies. Further assessments would be warranted to evaluate the potential of this methodology in other species.

Intrapulmonary and intravenous administrations of dihydroergotamine mesylate have similar cardiovascular effects in the conscious dog.

BACKGROUND AND PURPOSE: The effects of intrapulmonary artery (i.p.a.) administration of dihydroergotamine mesylate (DHE) were evaluated. EXPERIMENTAL APPROACH: Conscious beagle dogs (n=4) were given DHE via the i.p.a. or i.v. route as two 0.014 mg kg(-1) doses and a 0.14 mg kg(-1) dose given 60 min apart. A recovery period of > or =45 h occurred before crossover to the alternative route. Physiological parameters were monitored by telemetry or direct measurement, and venous blood samples were collected for pharmacokinetic assessments. KEY RESULTS: No meaningful differences between i.v. and i.p.a. treatments were observed for heart rate, systemic pressures and vascular pressures. Aortic resistance increased 8, 27 and 70%, respectively, following three doses of i.v. DHE compared with 11, 37 and 57%, respectively, with i.p.a. DHE. Carotid artery resistance increased 22, 40 and 87%, respectively, following three doses of i.v. DHE, compared with 17, 45 and 67%, respectively, following i.p.a. DHE. Increases in coronary artery resistance were of similar magnitude following i.v. and i.p.a. DHE administration. Increases in left ventricular systolic and diastolic pressures were seen following all doses of i.v. and i.p.a. DHE. Changes following DHE 0.014 mg kg(-1) were minimal and not clinically significant. With DHE 0.14 mg kg(-1) by either route, emesis was the most common adverse event. CONCLUSIONS AND IMPLICATIONS: DHE has comparable effects delivered via simulated deep inhalation (i.p.a.) or i.v. administration. The risk of cardiovascular complications is unlikely to be greater following inhalation of DHE.

Evidence that colitis is initiated by environmental stress and sustained by fecal factors in the cotton-top tamarin (Saguinus oedipus).

Parallel changes in spontaneously occurring inflammation in colonic Thiry-Vella loops and the in-line colon of cotton-top tamarins were studied in a colitis-inducing environment at 8 and 15 months following surgical preparation of the loops. Gross disease severity and numbers of inflammatory/immune cells per unit area of lamina propria in histological sections from endoscopic biopsies were analyzed. Cell counts and severity of colitis declined over time in the Thiry-Villa loops while the disease followed its characteristic course in the remaining large bowel and in the colons of controls. Perfusion of the loops with the animals' feces increased the density of the cellular infiltrate in the lamina propria in parallel with increased severity of inflammation. Electron micrographs of the colonic mucosa showed invasion by microorganisms. The predominant microorganism had characteristics of Helicobacter sp. The results implicate the fecal stream as a factor in the persistence of colitis in the tamarin model. Nevertheless, fecal factors appear not to be the primary trigger, as evidenced by findings that the disease is not expressed in wild-living tamarins and that it enters remission when affected animals are transferred to natural conditions from a colitis-inducing environment. Both an adverse environment and the fecal contents appear to be required for expression of the disease.

Inhalation chemotherapy for macroscopic primary or metastatic lung tumors: proof of principle using dogs with spontaneously occurring tumors as a model.

This study represents part of an effort to determine the safety and efficacy of inhaled antineoplastic drugs, using pet dogs with spontaneously arising primary and metastatic lung cancers (including sarcoma, carcinoma, and malignant melanoma) as a model. Dogs received new formulations of either paclitaxel (PTX) or doxorubicin (DOX) by the inhalation route every 2 weeks using a specially designed aerosol device. Response was assessed radiographically using the indices of tumor nodule number and volume measurement of discrete pulmonary nodules. Dogs experiencing progressive disease after two consecutive treatments were crossed over to receive the alternate compound. In 24 dogs, 6 (25%) responses were noted including 5 partial responses (PR) and 1 complete response. These include 4 (22.2%) of 18 responses to DOX and 2 (13.3%) of 15 responses to PTX. Responses were noted with osteosarcoma (including three dogs with metastatic osteosarcoma that had failed prior systemic chemotherapy), liposarcoma, hemangiosarcoma, and undifferentiated sarcoma. One dog with mammary carcinoma experienced a 47% reduction in volume after PTX inhalation, just shy of PR criteria. One dog with liposarcoma is experiencing a long-term (>12 months) stabilization of disease on PTX. To date, no systemic toxicities have been observed with either PTX or DOX inhalations. Local (pulmonary) toxicity was not observed with PTX; however, changes consistent with pneumonitis/fibrosis were observed in some dogs receiving DOX. Only one of these dogs showed clinical signs, which were responsive to steroid and antitussive therapy. These data represent "proof of principle" for the avoidance of systemic toxicity while delivering efficacious local drug levels by the inhalation route.

Colitis and colon cancer in cotton-top tamarins (Saguinus oedipus oedipus) living wild in their natural habitat.

The cotton-top tamarin is a nonhuman primate noted for susceptibility to juvenile onset colitis and subsequent colon cancer. About 80% develop colitis in captive environments outside the tropics. The aim was to determine the prevalence of colitis and colorectal cancer in tamarins living wild in their tropical habitat. Endoscopic biopsy was used to compare severity of colitis, inflammatory/immune cell densities, mucosal dysplasia, and occurrence of cancer in wild tamarins in a tropical habitat with tamarins living captive in a temperate climate. Six colon biopsies from each of 69 captives showed severe colitis in 64.5% of biopsies and moderate colitis in 19.5%. Severe colitis was not found in 88 wild tamarins; 13% had moderate colitis. Densities of polymorphonuclear leukocytes, plasma cells, and mononuclear cells in the lamina propria were related directly to the severity of four grades of colitis (normal, mild, moderate, and severe). Histologic or gross signs of carcinoma were detected in 12 captives and low- or high-grade dysplasia in 15. Neither cancer nor dysplasia was found in any of the wild tamarins. The observations suggest that colitis and cancer in the tamarin model are linked to environmental factors.

Fecal short-chain fatty acids associated with inflammation in cotton-top tamarin model for idiopathic colitis.

This study measured fecal levels of short-chain fatty acids (SCFAs) relative to the severity of colitis in the cotton-top tamarin model of colitis and colon cancer. Severity of colitis was classified as mild, moderate, or severe by subjective scoring of colonic mucosal biopsies and quantification of inflammatory cell infiltrates in the lamina propria. SCFAs were determined by gas chromatography of SCFAs extracted from fresh feces. Tamarins with moderate or severe colitis had significantly reduced levels of fecal SCFAs. The percent dry matter of feces declined significantly in moderate and severe colitis, while total dry matter output per day increased, indicating that moderate and severe colitis in tamarins was associated with diarrhea and increased fecal water loss. In conclusion, this study found colitis in the tamarin model was associated with decreased fecal SCFA levels and progressive inflammation in a pattern similar to human colitis.

Temperature-metabolism relations in the cotton-top tamarin (Saguinus oedipus) model for ulcerative colitis.

Examination of temperature-metabolism relations found no significant differences between thermoregulation of temperature housed laboratory cotton-top tamarins (Saguinus oedipus) and wild tamarins in Colombia, S.A. The results indicate that tamarins do not acclimate to a temperature environment and are metabolically stressed at Ta less than 32 degrees C. This is consistent with an hypothesis of chronic metabolic stress as a factor in the etiology of cotton-top tamarin colitis, which is restricted to captive populations and not found in wild tamarins.

Gestation and placentation in two New World opossums: Didelphis virginiana and Monodelphis domestica.

Estrus, gestation, and placentation were studied in the Virginia opossum (Didelphis virginiana) and the gray short-tailed oppossum (Monodelphis domestica), representatives of the prototypic, New World marsupial family Didelphidae. Didelphis is a large (3,000 g), pouched opossum that exhibits a 28-day estrous cycle, spontaneous estrus and ovulation, and a high ovulation rate (60 ova per cycle). Monodelphis is a small (100 g), pouchless opossum with male-induced estrus and ovulation and a moderate ovulation rate (12 ova per cycle). Implantation occurs on day 10 of the 13-day gestation period in Didelphis and on day 12 of the 15-day gestation in Monodelphis. Gestation and placentation, including the ultrastructural features of trophoblastic apposition to the uterine mucosa, are very similar in Didelphis and Monodelphis. Differences, such as a larger increase in uterine volume and a more highly folded endometrium following implantation in Monodelphis are minor. They appear to be related to the smaller maternal body size and the relatively larger uterine load of embryos in Monodelphis. Because body size is one of the major variables among New World marsupials, the descriptions of gestation and placentation presented here for Didelphis and Monodelphis, provide a basis for comparison in future studies of didelphid marsupials.

Sexual maturation in female gray short-tailed opossums, Monodelphis domestica, is dependent upon male stimuli.

The development of physiological responsiveness to male stimuli in peripubertal female gray short-tailed opossums was examined in this study. Prepubertal females were exposed directly or indirectly to male chemicals (odors) or to no male stimuli. All females exposed directly to deposited male stimuli (22/22) showed estrus at a mean (+/- SEM) age of 127 +/- 2 days. Only 59% (13/22) of females exposed indirectly showed estrus, and at an older mean age of 162 +/- 5 days (p less than 0.01). Vaginal estrus was not observed in any of the females isolated from male stimuli (0/11). Direct exposure of prepubertal females to male odors was associated with higher uterine weights compared to those of indirectly exposed and isolated females. Reproductive success, measured as litter production, of peripubertal females greater than 140 days old was comparable to adult reproductive success. This study has shown that reproductive maturation in pubertal female opossums requires male stimuli, that this stimulus appears to be pheromonal, and that direct exposure to deposited male odors is the most effective stimulus for female reproductive maturation.