Chronic (60-week) toxicity study of DUROS leuprolide implants in dogs.

The toxicity and pharmacodynamics of leuprolide acetate delivered from subcutaneously implanted DUROS leuprolide implants were examined in sexually mature male beagle dogs. The DUROS leuprolide implant is a sterile, nonpyrogenic, nonerodible, single-use, implantable, osmotically driven, drug delivery system for the palliative treatment of advanced prostate cancer. It contains 65 mg of leuprolide and is designed to deliver leuprolide continuously at a nominal rate of 120 microg per day for at least 12 months. Serum drug and testosterone concentrations were compared to values from dogs receiving monthly intramuscular injections of Lupron Depot 3.75 mg or no treatment (sham-operated). The local tissue response induced by subcutaneously implanted DUROS leuprolide implants was also evaluated. Beagles were implanted with a DUROS leuprolide implant for 52 weeks followed by removal and implantation of a new DUROS leuprolide implant for an additional 8 weeks. No mortality or morbidity occurred in this study. No treatment-related changes occurred in mean body weights, blood chemistry, or hematology during the study. Treatment-related atrophy of the testes, epididymides, and prostate gland, consistent with the known pharmacological effects of the drug, was observed in all dogs receiving the DUROS leuprolide implant or the Lupron Depot. Histological examination of these organs showed no distinguishable difference between dogs treated with the DUROS leuprolide implant or Lupron Depot. Weekly serum samples from dogs with DUROS leuprolide implants indicated continuous leuprolide delivery over 60 weeks, while some samples from the Lupron Depot group fell below measurable concentrations. Analysis of serum samples collected every 28 days just before Lupron Depot injection showed that 80% of these samples had leuprolide concentrations below the limit of quantitation (0.1 ng/ml). Serum testosterone concentrations were below castrate levels (<50 ng/dl) by 4 weeks after implantation of DUROS leuprolide implant and remained so for the duration of the study. Lupron Depot 3.75 mg also effectively lowered serum testosterone concentrations, but required reinjection every 28 days. All local tissue reactions to the DUROS leuprolide implant at implant sites were classified as mild following macroscopic examination. Microscopic site scores were mild to moderate. The DUROS leuprolide implant was shown to be safe, to provide continuous leuprolide delivery, and to effectively lower serum testosterone concentrations below castrate levels.

Absorption, distribution and elimination of selenium as L-selenomethionine in non-human primates.

20 adult female macaques (Macaca fascicularis) were given oral doses of L-selenomethionine (L-SeMet) equivalent to 0, 25, 150, 300 and 600 micrograms selenium (Se)/kg body weight, and plasma, erythrocyte, hair, faecal and urine Se concentrations were determined. The macaques were scheduled for 30 daily oral doses of L-SeMet, but systemic toxicity necessitated dose reduction in several animals; two macaques given 600 micrograms Se/kg body weight/day for 10-15 days died, and the concentration of Se in their tissues was determined and compared with Se concentrations in tissues collected from one untreated animal. Circulating and urinary Se concentrations in control macaques were within the normal human ranges. Plasma, erythrocyte, hair and urinary Se concentrations were generally dependent on the dose of L-SeMet administered. Plasma Se reflected more immediately exposure to L-SeMet, whereas erythrocyte Se concentrations increased and decreased more slowly. In some cases, erythrocyte Se was still increasing or showed a plateau after L-SeMet treatment was discontinued. Plasma Se concentrations of 6.7-7.3 ppm were observed in the two animals that died due to acute toxicity to L-SeMet. Neither plasma nor erythrocyte GPx activity was influenced by a single L-SeMet dose, but an increase in erythrocyte GPx activity occurred with continuous exposure. Total tissue Se increased 13-28-fold in macaques given 600 micrograms Se/kg body weight/day for 10-15 days, with the liver and kidneys containing the the highest Se concentrations.

Developmental toxicity of L-selenomethionine in Macaca fascicularis.

Forty pregnant long-tailed macaques were dosed via nasogastric intubation with 0, 25, 150, or 300 micrograms/kg of L-selenomethionine (Se) daily during organogenesis [Gestational Day (GD) 20-50]. Clinical examination of the dams, maternal body weights, sonographic evaluations, clinical chemistry screens, and measures of serum progesterone and urinary estrone conjugates were used as indicators of maternal and fetal status in all animals. The pregnancies of two to three dams from each dose group were followed until term (approximately GD 165); the remainder (N = 7/dose group) were scheduled for hysterotomy on GD 100 +/- 2. A standard teratologic evaluation was performed including visceral and skeletal examinations. Fetal liver, kidney, skin, and smooth, cardiac, and skeletal muscles were examined by light microscopy; heart muscle was also evaluated by transmission electron microscopy. Neonates delivered at term remained with the dams and were removed periodically for morphometric, neurologic, behavioral, and ophthalmologic assessments on Days 1, 8, 15, 22, and 30 of age. Dose-dependent maternal toxicity as evidenced by anorexia, vomiting, and a significant reduction in body weight increased with increasing duration of Se exposure. One growth-retarded fetus was recovered on GD 131 from a compromised dam exposed to 25 micrograms/kg-day; one early embryonic death (GD 35) and two fetal deaths [GD 68 (followed by maternal death) and GD 123] occurred among animals dosed with 300 micrograms/kg-day. Pregnancy loss among treated animals was not significantly different from concurrent or historical controls. No statistically significant treatment-related effects were observed at necropsy on GD 100 +/- 2. One infant exposed to 150 micrograms/kg-day prenatally exhibited a unilateral cortical cataract, which may have been a spontaneous occurrence. The limited developmental effects observed and reported teratogenesis in nonmammalian species suggest that comparative pharmacokinetic studies are required before the full public health significance of elevated Se is understood.

30-day oral toxicity study of L-selenomethionine in female long-tailed macaques (Macaca fascicularis).

Twenty female long-tailed macaques received nasogastric intubation of 0-600 micrograms/kg-day L-selenomethionine for up to 30 consecutive days. Selenium ingestion was well tolerated at all dose levels until the second to third week of the study at which time two animals given 600 micrograms/kg-day died. One animal from the 300 micrograms/kg-day group was removed from study on Treatment Day 19 due to selenium-induced hypothermia. In some cases, administered doses were reduced at the 300 and 600 micrograms/kg-day levels such that the final time-weighted average doses were 0, 25, 62-117, 150, 188-203, and 300 micrograms/kg-day. Six animals at the 188 micrograms/kg-day level or greater required nonscheduled fruit and dietary supplementation to prevent their impending demise. As the dose and duration of exposure increased, the incidence of anorexia, gastrointestinal distress, mucocutaneous toxicity, and frequency of reduced body temperature also increased. A dose-dependent reduction in body weight was also observed. At the greater doses, disturbances in menstrual function were evident, and were accompanied by the absence of serum progesterone concentrations above 1.0 ng/ml, reduced luteal phase lengths, increased intermenstrual intervals, and lowered estrogen excretion. A maximum tolerated dose of 150 micrograms/kg-day L-selenomethionine for 30 days was identified based on mean body weight reduction, hypothermia, dermatitis, xerosis, cheilitis, disturbances in menstruation, and the necessity of dietary intervention to prevent death at doses of 188 micrograms/kg-day or greater.

Embryotoxicity studies of norfloxacin in cynomolgus monkeys: I. Teratology studies and norfloxacin plasma concentration in pregnant and nonpregnant monkeys.

Norfloxacin, a new orally active antibiotic, was investigated in cynomolgus monkeys for potential developmental toxicity. Fifty-seven monkeys were administered a control vehicle or norfloxacin by nasogastric gavage during the major period of organogenesis on gestational days (GD) 21 through 50 at doses of 0, 50, 100, 150, or 200/300 mg/kg/day. There was no evidence of teratogenicity at any dose level. Maternotoxicity and a significant increase in embryolethality occurred following doses of 200/300 mg/kg/day. The maternotoxicity was not expected based on range-finding studies in nonpregnant female monkeys, which showed no signs of toxicity in doses up to 500 mg/kg/day. Additional studies were conducted to determine if norfloxacin caused similar toxicity later in gestation. Forty-six pregnant monkeys were dosed with a control vehicle or 200 mg/kg/day norfloxacin for one of three 10-day periods on GD 36-45, 71-80, or 111-120. There were no maternotoxic, embryotoxic, or fetotoxic effects observed. Plasma concentrations of norfloxacin in five cynomolgus monkeys following 50 and 200 mg/kg oral doses were not dose-proportionate. However, at a given dose, administered in cross-over fashion, plasma concentrations of norfloxacin were higher in nonpregnant females (approximately 20-40%) than during pregnancy when the same subject was compared. At the no-observed-effect dose for maternal and embryotoxicity (50 mg/kg), peak plasma concentrations of norfloxacin in pregnant cynomolgus monkeys are approximately threefold higher than those observed in human volunteers receiving norfloxacin at the maximum recommended therapeutic dose of 400 mg (5.7 mg/kg based on 70 kg body weight) twice per day.

Valproic acid developmental toxicity and pharmacokinetics in the rhesus monkey: an interspecies comparison.

This study was undertaken to assess the developmental toxicity and drug distributional and metabolic characteristics of prenatal valproic acid (VPA) exposure in rhesus monkeys. Oral administration of 20-600 mg/kg/day VPA (approximately 1-15 X human therapeutic dose) to 33 animals on variable gestational days (GD) during organogenesis resulted in dose-dependent developmental toxicity manifested as increased embryo/fetal mortality, intrauterine growth retardation, and craniofacial and skeletal defects. Biphasic plasma elimination curves were observed for total and free VPA on the first (GD 21) and last (GD 50) days of treatment in the 100- and 200-mg/kg/day dose groups. VPA exhibited dose-independent elimination kinetics at the plasma concentrations observed in this study. There was no significant change in pharmacokinetic parameters (maternal plasma elimination rate, area under the curve, peak plasma concentration) between the first and last days of treatment at either dose level. Placental transfer studies indicated that embryos were exposed to half the free VPA concentrations present in maternal plasma on GD 37. Comparisons of interspecies sensitivity to VPA-induced developmental toxicity in the mouse, rat, monkey, and man are made.