RESUMO

BACKGROUND: Nonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy. HYPOTHESIS/OBJECTIVES: The primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse-administered toceranib phosphate (TOC) combined with lomustine. ANIMALS: Forty-seven client-owned dogs with measurable MCT. METHODS: Toceranib phosphate was given PO on days 1, 3 and 5 of a 21-day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m(2) . All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone. RESULTS: The MTD of lomustine was established at 50 mg/m(2) when combined with pulse-administered TOC; the dose-limiting toxicity was neutropenia. Forty-one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression-free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy. CONCLUSIONS AND CLINICAL IMPORTANCE: Combined treatment with pulse-administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT.

Assuntos

RESUMO

The female squirrel monkey, Saimiri boliviensis, a New World monkey, has 10-day estrous cycles during the annual breeding season. Measurements of serum estradiol (E) concentrations in females housed with males in breeding pens revealed markedly higher levels than previously reported. Additionally, females in breeding pens appeared to have two distinct patterns of serum E peaks relative to the LH surge. Serum estrogen peaks averaging 5-fold greater than levels on the preceding day were observed on the same day as the LH surge, whereas other females had only a small E rise on the day of the LH surge followed by a 6-fold E rise on the next day. The serum progesterone (P) levels in all animals were depressed for 1-2 days before the LH surge but frequently started to rise on the day of the LH surge. The effect of the presence of a breeding male was examined by studying females housed in a group pen without exposure to a breeding male. In contrast to breeding-pen patterns, relatively small E rises were found in the 10 cycles observed. To further elucidate estrus-related E rises, a limited male-access paradigm was used to isolate mating-related hormone fluctuations. Pre-mating E levels had no marked rises; however, 4 h after mating, whether on the day of the LH surge or the next day, large E rises were found. These studies indicate that the LH surge in cycling squirrel monkeys is consistently preceded by a marked P nadir and associated with relatively small E rises.(ABSTRACT TRUNCATED AT 250 WORDS)

Assuntos

RESUMO

In the female Bolivian squirrel monkey a much greater elevation of serum estradiol (E2) was measured after mating than that observed in similary cycling monkeys that did not mate. This raised the possibility that cycling squirrel monkeys may not ovulate during nonmated cycles To test this hypothesis, we performed laparoscopies on nine isosexually housed, cycling monkeys to observe the ovaries after the luteinizing hormone (LH) surge, which was measured by mouse interstitial cell bioassay using LER 1909-2 as the standard. Single ovulatory stigmas were identified as well demarcated, red, punctate depressions at the center of dome-shaped elevations on the ovarian surface in eight monkeys, when laparoscopically examined 9-56 hr after the LH peak. One monkey examined laparoscopically prior to the LH surge had a large translucent cystic follicle, confirming the morphology of the mature prevulatory follicle. Mean progesterone (P) concentrations fell to a nadir 1 day prior to the LH surge and then began to rise on the LH surge. Peak P levels were found 2 days after the LH surge. In the ovulating animals in which periovulatory E2 levels were measured, no value was greater than 800 pg/ml, indicating that the presence of follicular rupture was not sufficient to account for the elevated E2 levels observed after mating. These data confirm ovulation and follicular rupture in the absence of mating and delineate the relationship between periovulatory LH, P, and E2 secretory patterns in cycling squirrel monkeys.

RESUMO

Serum measurements of chorionic gonadotropin (CG), estradiol (E-2) and progesterone (P) were used to describe patterns of hormonal change in Bolivian squirrel monkeys undergoing spontaneous abortion. During early pregnancy, serum CG levels gradually increased, reaching maximum levels at the end of the first 50 days of pregnancy (range: 200-1964 ug protein/ml). E-2 concentrations also increased to high levels (10-30 ng/ml) toward the end of pregnancy, while serum P remained fairly constant at levels above 100 ng/ml. A gradual decline in serum hormone concentrations was observed in aborting animals. CG levels declined to less than 100 ug protein/ml while E-2 and P decreased to concentrations characteristic of nonpregnant cycling animals, less than 500 pg/ml and 20 ng/ml respectively. The data suggest that two weekly measurements of CG and E-2 could be used to identify monkeys undergoing abortion and those which have already aborted.

Assuntos

RESUMO

To assess diurnal fluctuations of serum androgens and cortisol in adult male Bolivian squirrel monkeys, these steroids were measured at predetermined times (0300, 0900, and 2300 hours) during two separate 24-hour periods in the breeding season (January 1983 and late November 1983). A significant diurnal change in serum cortisol was noted, with a nadir of 99.9 ± 11.9 µg/dl (x̄ ± SEM) at 2300 hours and a peak of 168.9 ± 7.8 µg/dl at 0900 hours. Conversely, a nadir in serum testosterone was noted at 0900 hours (117 ± 26.5 ng/ml) increasing to a peak of 328.5 ± 57.9 ng/ml at 0300 hours. Serum androstenedione and dehydroepiandrosterone followed a pattern similar to testosterone, with a serum androstenedione (176.4 ± 34.9 ng/ml) and dehydroepiandrosterone (11.7 + 1.8 ng/ml) nadir at 0900 hours and a plasma androstenedione (494.5 ± 55.4 ng/ml) and dehydroepiandrosterone (32.5 ± 4.1 ng/ml) peak at 0300 hours. Parallel changes of testosterone, androstenedione, and dehydroepiandrosterone suggest a significant contribution of all three androgens from a common site, the testes. In contrast to old world primates and humans, serum androstenedione levels exceeded serum testosterone levels in this species.