Effects of an antagonist of neurokinin receptors 1, 2 and 3 on reproductive hormones in male beagle dogs.

BACKGROUND: SCH 206272, a neurokinin 1, 2, and 3 receptor antagonist, administered to beagle dogs results in testicular toxicity. Therefore, a series of experiments were conducted to determine whether this observed toxicity was associated with changes in reproductive hormones and hypothalamic gonadotrophin releasing hormone (GnRH) levels. METHODS: Male beagle dogs were administered 30 mg/kg SCH 206272 for up to 7 days. Blood samples were collected at the end of the dosing period for reproductive hormone analysis. Male reproductive organs were stained with hematoxylin and eosin and the hypothalamus was stained for GnRH. RESULTS: Intact male dogs exhibited SCH 206272-related decreases in pulsatility and magnitude of luteinizing hormone (LH) and testosterone, which were associated with seminiferous tubule degeneration, oligospermia, and epithelial atrophy in the prostate gland. Neutered dogs also exhibited SCH 206272-related decreases in LH and FSH. In a subsequent reversibility study, intact male dogs exhibited decreased LH, testosterone, and FSH, which exhibited recovery by 2 weeks post-dosing; however, seminiferous tubule degeneration and oligospermia did not exhibit recovery by 2 weeks post-dosing. Dogs administered SCH 206272 also exhibited an increase in mean number of GnRH-containing neurons in the hypothalamus and an increase in GnRH mRNA/neuron, which exhibited recovery by 2 weeks post-dosing. CONCLUSIONS: SCH 206272-dosed dogs exhibited rapid decreases in reproductive hormones and subsequent testicular pathology. Collectively, these changes in hormone levels suggest that the observed SCH 206272-related reproductive tract findings are the result of alterations in hypothalamic-pituitary-gonadal function. However, a direct effect on the testes cannot be definitively ruled out.

Myocardial and reproductive system toxicity of SCH 351591, a selective phosphodiesterase-4 inhibitor, in CD-1 mice.

This report describes the findings of preclinical testing of SCH 351591, a selective phosphodiesterase 4 inhibitor, in CD-1 mice over a wide range of doses, in which the heart and reproductive organs of both sexes demonstrated toxic effects. Repeat-dose toxicity studies assessed 5, 15, 50, 100, 200, 400, and 800 mg/kg/day, orally by gavage, for one or three months. Findings included higher testes and ovary weights and lower uterus weights (> or =200 mg/kg), small ovaries/uterus (> or =400 mg/kg), and histopathologic changes of large corpora lutea and ovarian atrophy at 200 and 800 mg/kg, respectively. In addition, chronic myocardial inflammation of the heart base occurred at 100 mg/kg. Vaginal staging of the estrous cycle revealed persistent diestrus. There was no histopathologic correlate or morphometric change to explain higher testes weights. A pilot fertility and early embryonic developmental toxicity study assessing doses of 100, 200, 400, and 800 mg/kg/day produced complementary results. Females had prolonged or abnormal estrous cycles, fewer successful pregnancies, increased ovarian corpora lutea, and decreased size of live litters owing to fetal resorptions. Male fertility was not affected. However, males had a 25% increase in testes weights at all doses. The pharmacology of specific PDE4 isoenzymes may explain both the reproductive and cardiac findings.

Administration of an antagonist of neurokinin receptors 1, 2, and 3 results in reproductive tract changes in beagle dogs, but not rats.

SCH 206272, an antagonist of neurokinin receptors 1, 2, and 3, was administered orally by gavage for 1 month to 8- to 10-month-old dogs at doses of 0, 15, 30, or 60 mg/kg, and to 6-week-old rats at doses of 0, 30, 100, or 300 mg/kg. The most important changes occurred in the reproductive tract of the dogs at all doses. Absolute and relative group mean organ weights for the testes, prostate gland, epididymides, ovaries, and uterus were 33-86% lower than concurrent controls in groups receiving SCH 206272. Organ weight changes were not dose-related. Microscopic changes that correlated with the organ weight changes occurred in all groups receiving SCH 206272. For males, they included minimal to severe atrophy of the testes, epididymides, and prostate gland. In addition, the epididymides exhibited severe oligospermia or aspermia, minimal epithelial apoptosis and mild epithelial vacuolation. In female dogs, the ovaries and uteri appeared immature. Microscopic changes were similar in incidence and severity in dogs receiving 30 or 60 mg/kg, but were slightly less in dogs receiving 15 mg/kg. In contrast, similar findings were not observed in the reproductive tract of male or female rats, despite overlapping systemic, hypothalamic, and pituitary gland concentrations of SCH 206272.

The toxicity of SCH 351591, a novel phosphodiesterase-4 inhibitor, in Cynomolgus monkeys.

SCH351591, a novel phosphodiesterase-4 inhibitor under investigation as a potential therapeutic for asthma and chronic obstructive pulmonary disease (COPD), was evaluated in a 3-month rising-dose study in Cynomolgus monkeys. Four groups, containing four monkeys/sex, received vehicle control or rising doses up to 12, 24, or 48 mg/kg of SCH351591 daily. Although initial exposure produced clinical signs of emesis, reduced food intake, and reduced body weight, tachyphylaxis to the emesis allowed dose escalation up to 48 mg/kg/day. Two monkeys died and 3 were sacrificed in moribund condition over the course of the study. Early mortality, involving monkeys dosed with 12 or 24 mg/kg, was attributed to sepsis (2 monkeys) or colon inflammation (3 monkeys). Leukocyte function assays on low- and mid-dose group survivors revealed an inhibition of T lymphocyte proliferation for 12 mg/kg group males and 24 mg/kg group monkeys of both sexes. Necropsy findings, unassociated with early mortality, included reduced size and weight of the thymus, depletion of body fat, red discoloration of the gastric mucosa, and perivascular hemorrhage of the stomach and heart. Stomach and heart gross findings were present in the high-dose group only. Histopathologic lesions, in addition to those attributed to concurrent bacterial infection, included thymic atrophy, serous atrophy of fat, myocardial degeneration and acute to chronic inflammation of small to medium-sized arteries in various organs and tissues including the heart, kidneys, stomach, salivary glands, pancreas, esophagus, gallbladder, and mesentery. The findings of this study demonstrate the potential of a PDE4 inhibitor to alter immunologic response as well as to produce arteriopathy in nonhuman primates.

Contrast-enhanced transrectal ultrasonography of a novel canine prostate cancer model.

OBJECTIVE: This study evaluated the utility of a new animal model for prostate cancer imaging using a new ultrasonographic contrast agent (Sonazoid [NC100100]; Amersham Health, Oslo, Norway), for prostate cancer detection. METHODS: Twenty-four dogs had a canine transmissible venereal sarcoma cell line injected (50 million cells/mL) directly into the prostate, producing a neoplasm in 15 to 40 days. Transrectal ultrasonography was performed in power Doppler mode on 8 dogs (phase I) and in gray scale phase inversion harmonic imaging mode on 16 animals (including control animals without tumors; phase II). Evaluations were repeated after intravenous injections of the contrast agent (dose, 0.00625-0.20 microL/kg). Histopathologic examination was performed after each study. For the phase II experiments, sensitivity, specificity, and accuracy were calculated. RESULTS: The contrast agent improved visualization of the prostate cancer vascularity and delineation of tumor size and shape in both power Doppler and phase inversion harmonic imaging modes. Canine transmissible venereal sarcoma tumors ranging from 3 x 5 to 40 x 50 mm were detected. The accuracy for detecting the number of prostate tumors increased (in phase II) from 67% to 87% with the addition of the contrast agent. Histopathologic examination confirmed the ultrasonographic findings and revealed typical canine transmissible venereal sarcoma cells infiltrating the prostate with moderate neovascularity. CONCLUSIONS: The novel canine tumor model was useful for evaluating ultrasonographic prostate imaging techniques. Improved detection of prostate tumors in dogs was possible with gray scale phase inversion harmonic imaging of the contrast agent. The accuracy of lesion detection increased from 67% to 87%.

Chronic toxicity and oncogenicity study with glutaraldehyde dosed in the drinking water of Fischer 344 rats.

Glutaraldehyde (GA) has a wide spectrum of industrial, scientific and biomedical applications. Its potential to produce chronic toxic and/or oncogenic effects was investigated in Fischer 344 rats (100/sex/group) given GA in drinking water for a maximum of 104 weeks. GA concentrations were 0 (control), 50,250 and 1000 ppm, resulting in average daily GA consumptions, respectively, of 0, 4, 17 and 64 mg/kg for males and 0, 6, 25 and 86 mg/kg for females. Interim euthanasia (10/sex/group) was performed at 52 and 78 weeks. Parameters evaluated were clinical signs, body weight, food and water consumption, hematology, serum chemistry, urinalysis, organ weights, gross and microscopic pathology. There were no treatment-related effects on mortality. Absolute body weights and body weight gains of the 250 and 1000 ppm males and females were reduced over the study in a dosage-related manner. Food and water consumption by the 250 and 1000 ppm groups were decreased in a statistically significant dose-related manner over the study, and mean water consumption by the 50 ppm animals was slightly reduced but not with statistical significance. The 250 and 1000 ppm groups had a dose-related decrease in urine volume with increased osmolality, and pH was slightly reduced. Absolute kidney weights were increased in the 250 and 1000 ppm groups at the 52 and 78 week sacrifices, and decreased at 104 weeks. Relative kidney weights were increased at all sacrifice times for the 1000 ppm group, at 52 weeks for the 250 ppm group, and at 72 weeks for the 50 ppm group. The urinalysis and renal weight changes are compatible with a physiological compensatory adaptation to reduced water consumption. Gross and histological evidence for gastric irritation was observed principally in the 1000 ppm rats euthanized at 104 weeks and in animals that died during the study. Bone marrow hyperplasia and renal tubular pigmentation, seen in rats that died and the 104 week euthanasia animals, may have been secondary to a low grade hemolytic anemia in animals with large granular lymphocytic leukemia (LGLL). The only neoplasm that showed a statistically significant increase was LGLL, which occurred at a high incidence in both sexes and all groups, including the controls, for both animals that died and at the 104 week euthanasia. A few instances of LGLL were observed at 78 weeks. The overall incidence of LGLL in the spleen for the 0, 50, 250 and 1000 ppm groups was, respectively, 43, 51, 40 and 46% for males, and 24, 41, 41 and 53% for females. Statistical analyses indicated that the severity of LGLL was associated with the higher dosages of GA in female, but not male, rats. Due to the background and variable incidence of LGLL in the Fischer 344 rat, the finding of a statistical significance only for female rats, and because, there was no clear dose-response relationship, the biological significance of the LGLL findings is unclear. There is the possibility that the significance was a statistical artifact due to the low incidence of LGLL in the female control animals as a result of biological variability within the study. It is also considered to be possible that the chronic dosage of GA in the drinking water resulted in a modification of one or more of the factors responsible for the expression of this common and spontaneously occurring neoplasm in the Fischer 344 rat.