Dietary administration of colesevelam hydrochloride does not affect fertility or reproductive performance in rats

Colesevelam hydrochloride (HCl) (WelChol; Sankyo Pharma) is a novel, highly potent, bile acid-binding polymer used for the treatment of hypercholesterolemia. The primary aim of this study was to determine the effects of dietarily administered colesevelam HCl on fertility and reproductive performance parameters. To assess these effects, sexually mature Sprague-Dawley rats were randomized to one of five treatment groups: feed alone, feed plus control article (SigmaCell), or feed plus colesevelam HCl 200, 1000, or 2000 mg/kg/day. Male and female rats were administered the appropriate group agent for 28 and 15 days, respectively, and were subsequently paired together for cohabitation and mating. Females continued to receive the test agent in their dietary formulation through presumed gestation day (GD) 7. Presumed pregnant females underwent cesarean section on GD 20. Food consumption rate, body weight, gross necropsy, and standard preclinical tests for reproduction and fertility were performed for each test animal. No statistically significant differences were found between control and drug-treated groups for any tested endpoints of reproduction. All animals placed in cohabitation successfully mated. Uterine and litter end points were unaffected by dosages of colesevelam HCl as high as 2000 mg/kg/day. There were no significant differences between treatment group litter averages in the number of corpora lutea, implantation sites, litter size, live fetuses, body weights, early/late resorptions, and the number of dams with viable fetuses. In addition, no external alterations of fetal morphology were attributable to treatment with colesevelam HCl when administered up to the embryo implantation stage. In male animals, no significant differences were found between the colesevelam HCl and control study groups in the average caudal epididymal sperm count or sperm concentration, total number of motile and nonmotile sperm, and the total percentage of motile sperm. Based on these data, colesevelam HCl does not have any significant adverse reproductive or fertility effects in rats, even when administered at doses approximately 30 times greater than the approved clinical dose.     

Embryo–fetal toxicity assessment of vonoprazan in rats and rabbits

Vonoprazan is a new potassium‐competitive acid blocker to treat acid‐related diseases. However, its safety during pregnancy is unclear. The aim of the study was to investigate the potential reproductive toxicity on the embryo–fetal development of vonoprazan. Vonoprazan acetate was administered by intravenous injection to pregnant rats (0, 2, 6 and 20 mg kg^–1 day^–1) and rabbits (0, 1.2, 3.6 and 12 mg kg^–1 day^–1) during the organogenetic period (gestation day 6–15 [rats] and 6–18 [rabbits]). Maternal reproductive endpoints were evaluated, together with effects on fetal growth and morphological development. In rats, no treatment‐related effects were found in the highest dose group (20 mg kg^–1) and the maternal plasma exposure was ≥50‐fold the expected clinical human exposure. However, in rabbits, dose‐related clinical signs (soft or liquid feces) occurred in the 12 mg kg^–1 group, which was regarded as a maternal toxicity. Besides, decreased maternal weight gain also was considered as a minimal maternal toxicity. At 12 mg kg^–1, delayed fetal ossification was found as evidence of embryo–fetal growth retardation, which was related to decreased fetal and placental weights. There was no maternal and developmental toxicity in the 1.2 and 3.6 mg kg^–1 groups. Thus, the no‐observed‐adverse‐effect levels of vonoprazan acetate in rabbits are considered 3.6 mg kg^–1 day^–1, which produced plasma exposure that was about 18‐fold human clinical exposure.     

Dissociation between maternal and fetal toxicity of methyl isocyanate in mice and rats

The contribution of maternal hormonal changes and pulmonary damage on the fetal toxicity of methyl isocyanate (MIC) was studied in mice and rats. Exposure to MIC decreased maternal plasma progesterone levels in mice that lost but not in mice that retained pregnancy. Fetal toxicity of MIC was not related to changes in maternal plasma corticosterone levels. Neither chronic administration of progesterone nor the suppression of pulmonary edema with dexamethasone decreased fetal toxicity of MIC. Embryos exposed in utero or in vitro to MIC vapor exhibited a concentration-dependent decrease in growth in culture. An acute dose (3 mmol/kg) of the MIC metabolites (methylamine, dimethylamine, trimethylamine, dimethyl urea) did not exert fetal toxicity. These data suggest that the fetal toxicity of MIC is partly independent of maternal toxicity and may result from its transfer across the placenta and interaction with fetal tissues.     

Topiramate does not alter nicotine or cocaine discrimination in rats

The effects of topiramate, a potential treatment for drug dependence, were evaluated in two groups of rats trained to discriminate the administration of either 0.4 mg/kg nicotine or 10 mg/kg cocaine from that of saline, under a fixed-ratio 10 schedule of food delivery. Topiramate (1-60 mg/kg, intraperitoneal) did not produce any nicotine-like or cocaine-like discriminative effects by itself and did not produce any shift in the dose-response curves for nicotine or cocaine discrimination. Thus, the ability to discriminate the effects of nicotine or cocaine does not appear to be altered by topiramate administration. Furthermore, topiramate, given either alone or in combination with nicotine or cocaine, did not depress rates of responding. These experiments indicate that topiramate does not enhance or reduce the ability of rats to discriminate the effects of nicotine or cocaine.     

Teratogenic and fetal toxicity following intravenous theophylline administration in pregnant rabbits is related to maternal drug plasma levels

This study investigated the teratogenic and fetal toxicity of i.v. theophylline and its relationship to maternal plasma levels in pregnant rabbits. From days 6-18 of gestation, each dose of theophylline (15, 30 and 60 mg/kg/day at a rate of 0.5 ml/kg/min) was administered i.v. to pregnant rabbits using an automatic infusion pump. Theophylline showed reversible toxicity: accelerated respiration, sluggish startle reactions, dilation of the auricular vessels and polyuria were observed in dams treated with 60 mg/kg/day but not in animals given 15 or 30 mg/kg/day. Fetuses from the dam group treated with 60 mg/kg/day exhibited teratogenic toxicity such as cleft palate and skeletal variation of the 13th rib. Fetal toxicity was also observed including abortion, increased number of late deaths and decreased body weight appearing on day 29 of gestation. No toxicity was observed in fetuses from the dam group treated with 15 or 30 mg/kg/day. However, in the 30 and 60 mg/kg/day theophylline-treated groups, maternal plasma concentrations (Cmax) during the treatment period were approximately 56 and 106 micrograms/ml, respectively. It is therefore suggested that the risk of teratogenic and fetal toxicity caused by theophylline is dependent on its dosage. In conclusion, caution should be taken when administering theophylline or aminophylline to pregnant individuals at doses that could result in high neonate peak blood levels.     

Valproic acid is known to cause hypospadias in man but does not reduce anogenital distance or causes hypospadias in rats

The use of valproic acid during human pregnancy increases the risk of hypospadias in the offspring. Rats exposed in utero to valproic acid did not develop hypospadias and even had a slightly increased anogenital distance in males 3-4 days after birth. A classical antiandrogenic drug, flutamide, caused hypospadias as well as a reduction of the anogenital distance in males. At the age of 3 months, rats exposed in utero with either valproic acid or flutamide showed a reduced testicular weight and hypoplasia of tubules, which seemed not to be related to the antiandrogenic activity of flutamide as it did not correlate with the presence of hypospadias. The mechanism through which valproic acid causes hypospadias in man and affects testicular development in rat is unknown. Hypospadias caused by valproic acid in man is apparently not due to anti-androgenic properties of the drug.     

Absence of embryo-fetal toxicity in rats or rabbits following oral dosing with nelfinavir

The potential for nelfinavir mesylate (VIRACEPT) to induce maternal and embryo-fetal toxicity was evaluated in rats and rabbits following oral administration. The drug was administered by gavage to rats at doses of 200, 500, or 1000mg/kg/day on days 6-17 of gestation and to rabbits at doses of 200, 400, or 1000mg/kg/day on days 7-20 of gestation. Dams and does were euthanized on GD20 and 29, respectively, and the offspring were weighed and examined for external, visceral, and skeletal alterations. Maximum plasma nelfinavir concentrations (C(max)) in rats were comparable to C(max) values in humans and were 3- to 6-fold higher than the reported human trough levels, while plasma nelfinavir levels in rabbits were approximately 0.13-0.17x the human C(max) and 0.25-0.5x the human trough. In rats, no treatment-related maternal or embryo-fetal toxicity was observed at any dose level and the NOAEL for both maternal and fetal toxicity was considered to be 1000mg/kg/day. Two rabbits in the 400mg/kg/day group died prior to scheduled termination. Because no deaths occurred in the high dose group and there were no other treatment-related signs of clinical toxicity in any dose group, these deaths were considered unrelated to nelfinavir. Group mean body weight loss in rabbits was observed at 1000mg/kg/day on gestation days 7-10. Food consumption was also reduced in this treatment group throughout the dosing period. There were no treatment-related findings in other maternal or fetal parameters. Thus, the no-observed-adverse-effect-level (NOAEL) for maternal toxicity in the rabbit was considered to be 400mg/kg/day (based on maternal body weight loss in the high dose group), while the NOAEL for embryo-fetal toxicity in the rabbit was considered to be 1000mg/kg/day. Thus, under the conditions of this study, nelfinavir was not considered to be toxic to the rat or rabbit conceptus.     

Correlation between maternal toxicity and embryo/fetal effects

It has been widely debated whether embryo/fetal toxicity is secondary to maternal toxicity. This argument has led to great difficulties for administrative decision makers involved in public health evaluation of drugs or chemicals. The present study sought to characterize whether there is a correlation between maternal toxicity and embryo/fetal toxicity. Developmental data from control and treated animals in our laboratory were collected and evaluated. Maternal toxicity, defined here as maternal body weight change, was statistically correlated with embryo/fetal parameters. The result showed that embryo/fetal parameters did not correlate with the body weight change. It can be concluded that maternal toxicity does not always lead to embryo/fetal toxicity; therefore, findings should be handled on a case by case basis and causal relationships should be established.     

Kava feeding in rats does not cause liver injury nor enhance galactosamine-induced hepatitis.

Kava, like a number of herbals, has been associated with causing liver damage based on limited evidence. In contrast, the present study found that in rats, 3 mo feedings of two types of kava extracts (an acetone extract and an ethanol extract of the Samoan kava cultivar Ava Laau) at three different doses (31.25, 62.5 and 133 mg/kg diet) produced no liver injury based on serum markers of liver damage (sorbitol dehydrogenase activities, bile acid concentrations, and beta-glucuronidase activities) and serum lipid peroxide readings. In fact, for some measurements and some kava doses, the injury marker readings were below control values. Moreover, for these same parameters, kava feeding did not enhance the effects of the hepatotoxin galacatosamine (500 mg/kg ip); some kava doses even showed modest protection against liver injury. Liver histology analysis showed no signs of kava causing or enhancing liver injury. Thus, this study does not support the concept that kava produces or aggravates liver injury.     

Bolus maternal cocaine administration does not produce a large increase in fetal sheep cerebral cortical glutamate concentration

Human cocaine use during pregnancy may result in postnatal neurologic dysfunction and abnormal behavior. L-Glutamate, the major excitatory neurotransmitter in the brain, plays an important role in cerebral cortical development. An optimal level of glutamate is required for normal neuronal development. We tested whether acute cocaine exposure produces large increases in glutamate release in the intact cerebral cortex of the near-term fetal sheep. Cocaine 3.0 mg kg(-1) IV bolus produced the expected increase in maternal and fetal mean arterial pressure, increase in fetal heart rate, decrease in uterine blood flow, and decrease in fetal arterial blood pO2 (N = 5). The percentage increases in extracellular glutamate concentration in the fetal cerebral cortex measured by in utero microdialysis were 7%, 15%, 17%, 17%, and 43% in each fetus (upper 95% confidence bound for the median = 43%). We conclude that if cocaine increases glutamate concentration in the developing cerebral cortex, the increase in magnitude is small relative to the changes produced by other interventions such as ethanol or umbilical cord occlusion. Mechanisms other than increases in cerebral cortical glutamate concentration probably contribute to the neurologic injury associated with prenatal cocaine exposure.     

Embryotoxicity and fetal toxicity of nickel in rats

Embryotoxicity and fetal toxicity of nickel chloride (NiCl₂) and nickel subsulfide (Ni₃S₂) were studied in Fischer rats. Injection of NiCl₂ (16 mg of Ni/kg, im) on Day 8 of gestation reduced the mean number of liver pups per dam and resulted in diminished body weights of fetuses on Day 20 of gestation and of weanlings at 4 to 8 weeks after birth. Injection of Ni₃S₂ (80 mg of Ni/kg, im) on Day 6 of gestation reduced the mean number of live pups per dam. No congenital anomalies were found in fetuses from any Ni-treated dams, including dams that received 10 im injections of NiCl₂ (2 mg of Ni/kg, twice daily, on Days 6–10 of gestation). ⁶³NiCl₂ (12 mg of Ni/kg, im) was administered to a group of nonpregnant female rats and to groups of pregnant rats on Day 8 or 18 of gestation. After 24 hr, the relative concentrations of ⁶³Ni in tissues were: kidney > serum > adrenal ? lung ? ovary > spleen ? heart ? liver > skeletal muscle. Pituitary ⁶³Ni concentrations were much higher in pregnant rats than in nonpregnant females. ⁶³Ni concentrations in products of conception (embryos and embryonic membranes) on Day 9 and in placentas on Day 19 were equivalent to ⁶³Ni concentrations in adrenal, lung, and ovary tissues of the dams. Autoradiography of fetuses and placentas on Day 19 of gestation showed ⁶³Ni localization in fetal urinary bladders and in the basal laminae and yolk sacs of the placentas. These studies show (a) that im injection of NiCl₂ and Ni₃S₂ during early gestation causes embryonic mortality at dosages that do not cause maternal mortality, and (b) that ⁶³Ni(II) can cross the feto-maternal barriers and enter the fetuses during late gestation.     

Omeprazole does not change the oral bioavailability or pharmacokinetics of vinpocetine in rats

Previous studies proved that food strongly enhanced the bioavailability of vinpocetine. Food may change the pharmacokinetics of a drug by affecting various factors, including gastrointestinal pH. However, the influence of proton pump inhibitor-induced pH alterations on vinpocetine pharmacokinetics is not known. The aim was to evaluate the influence of omeprazole on the pharmacokinetics of oral vinpocetine. One group of male Wistar rats received single oral doses of vinpocetine (2 mg/kg - regimen V). In the second group, omeprazole (10 mg/kg) was administered intraperitoneally for 5 days before vinpocetine administration (regimen OV). For analysis of vinpocetine pharmacokinetics, blood samples were obtained before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 h after vinpocetine administration. Vinpocetine concentrations were measured by high performance liquid chromatography (HPLC). The mean values of AUC(0-t), AUC(0-inf) and C(max) in regimen V were very similar to respective values in regimen OV. The mean T(max) in both regimens was estimated for 1.5 h. There were no statistically significant differences between both regimens. In conclusion, omeprazole did not affect the pharmacokinetic profile of vinpocetine.     

Chronic intrauterine exposure to endotoxin does not alter fetal nephron number or glomerular size

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Thirteen-week oral toxicity study of L-lysine hydrochloride in rats

L-Lysine hydrochloride (Lys) is an essential amino acid in humans and animals, and it is used in animal feeds, in prevention of herpes simplex recurrence, and cereal fortification in some developing countries. This study evaluated toxicological and behavioral effects of Lys during a dosing study with male and female Sprague-Dawley rats. The amino acid was incorporated into a standard diet at doses equal to 1.25%, 2.5%, and 5.0% (w/w). A control group of rats received a standard diet. All diets were administered ad libitum for 13 consecutive weeks. To examine stability of any potential effects, the administration period was followed by a 5-week recovery period, during which only the standard diet was provided to all animals. In male and female rats in each concentration group, treatment-related changes were not observed in the clinical signs, body weights, diet consumption, water intake, ophthalmology, gross pathology, organ weights, or histology. A Lys-related drop in serum concentration and an increase in urine excretion of chlorides was a compensatory reaction to the ingested hydrochloride. No functional, biochemical, or histological changes in renal function were found. The no-observed-adverse-effect level (NOAEL) for Lys was estimated at 5.0% for both genders (male, 3.36 +/- 0.12 g/kg/day; female, 3.99 +/- 0.28 g/kg/day).     

Chronic intrathecal morphine treatment does not cause down-regulation of spinal adenosine A1 receptors in rats

We have shown previously that systemic chronic morphine treatment causes down-regulation of spinal adenosine A₁ receptors in rats. Recently, we have found that chronic supraspinal morphine treatment also causes this effect. In the present study, we investigated whether chronic spinal morphine treatment has the same effect of down-regulation of spinal adenosine A₁ receptors. Adult male Sprague-Dawley rats were rendered tolerant to morphine either by multiple intrathecal (i.t.) injections or continuous Lt. infusion by osmotic pump administration for 2 or 4 days. Spinal A₁-adenosine receptor binding activity was measured by using the selective A₁ adenosine agonist [³H]cyclohexyladenosine. No significant decrease in [³H]cyclohexyladenosine binding was found in the spinal cord after 2 or 4 days of multiple Lt. injections of morphine. There was also no significant change in the amount of spinal [³H]cyclohexyladenosine bound after 4 days of continuous Lt. infusion of morphine by osmotic pump. From these and our previous results, it is concluded that only supraspinal chronic morphine treatment down regulates the spinal A₁ adenosine receptor and this may play a role in the mechanism of supraspinal morphine tolerance but not spinal morphine tolerance.     

Dermal irritation of petrolatum in rabbits but not in mice,rats or minipigs

Petrolatum is widely used in cosmetics, topical pharmaceuticals and also as a vehicle in dermal toxicity studies. New Zealand white rabbits treated with white petrolatum (vehicle control) in a 2‐week dermal irritation study exhibited moderate to severe erythema starting on Day 7 that subsided towards the end of the study. Histological examination of abraded and non‐abraded petrolatum‐treated skin obtained at termination (Day 15) revealed mild acanthosis, hyperkeratosis, dermal edema with mixed inflammatory cells in the dermis. Macroscopic and microscopic features noted in rabbits were consistent with dermal irritation to petrolatum. Wistar‐Han rats, CD1 mice, C57/Bl/6J mice and Göttingen minipigs treated topically with white petrolatum did not exhibit clinical or histologic evidence of dermal irritation. Therapeutic agents developed for topical application are generally tested in rabbits during some point in development. Interpretation of skin irritation data from a single species can impact risk assessment for humans and on product labeling. Copyright © 2013 John Wiley & Sons, Ltd.     

The disposition of benzoylecgonine in maternal and fetal rats.

We tested our hypothesis that pregnancy alters the pharmacokinetic profile of benzoylecgonine, and that this metabolite accumulates in the fetus longer than in the mother. Chronically catheterized near-term pregnant and nonpregnant female Sprague-Dawley rats received an intravenous infusion of benzoylecgonine over a period of 30 min. Adult or fetal blood and tissue samples were obtained either at the end of the infusion or 6 h postinfusion for analysis of benzoylecgonine and other cocaine metabolite concentrations via gas chromatography/mass spectrometry (GC/MS). Pregnancy altered benzoylecgonine pharmacokinetics. At the end of the infusion, benzoylecgonine concentration in the fetal plasma was markedly lower than in the maternal plasma with a fetal/maternal ratio of 0.14+/-0.01. A significantly lower concentration of benzoylecgonine was found in both maternal and fetal brain at 0 h postinfusion, with tissue/plasma concentration ratios of 0.04 and 0.24, respectively, suggesting that benzoylecgonine does not readily penetrate into the brain. At 6 h, the fetal concentration of benzoylecgonine was significantly higher than in the corresponding maternal blood and tissues. Ecgonine methyl ester, a metabolite of benzoylecgonine was found in the maternal liver, but not in the fetus. In addition, the amniotic fluid concentration of benzoylecgonine became significantly higher in the 6-h postinfusion samples as compared to the end of infusion value, suggesting that repeated intrauterine exposure to cocaine may cause an accumulation of benzoylecgonine in the fetus.     

Repeated maternal separation does not alter sucrose-reinforced and open-field behaviors

Repeated separation of rat pups from their mothers has been reported to increase behavioral fearfulness and hypothalamic-pituitary-adrenal (HPA) response to stress. Recently, it was suggested that it might also alter behavioral responses to natural and drug rewards. Here, we studied whether maternal separation (MS) would alter behavioral responses to a sucrose reward. We also tested whether MS would alter behavioral responses in an open-field test using a novel method of analysis [Software for the Exploration of Exploration (SEE)]. Long-Evans rat pups were exposed to either 180 min of MS, 15 min of separation [early handling (EH)] or left undisturbed [nonhandled (NH)] from postnatal day (PND) 3 to 14. The adult male offspring were tested for sucrose solution preference using a two-bottle free-choice test, operant response for sucrose under fixed ratio and progressive ratio (PR) schedules of reinforcement and response to a novel environment (open-field test). MS had no effect on sucrose preference or operant responding for sucrose reward. In the open-field test, NH rats showed a brief decrease in locomotor response, but MS rats did not differ from the NH and EH groups in the other behavioral measures. Thus, under the conditions of the present study, MS did not appear to alter reward-related processes and also had a minimal effect on open-field behavior.     

Developmental toxicity study of pure trans-capsaicin in rats and rabbits

Human environmental and dietary exposure to trans-capsaicin--the pungent ingredient in chili peppers--is ubiquitous. Moreover, based on the highly selective agonism of trans-capsaicin for TRPV1 receptors, drug products containing high concentrations of trans-capsaicin are under development as analgesics. For instance, a high-concentration (8% w/w) pure trans-capsaicin dermal patch (designated NGX-4010) is in advanced clinical evaluation for the management of neuropathic pain of peripheral origin. Our objective was to investigate effects of trans-capsaicin on embryo/fetal development, consequent to maternal exposure, from implantation to closure of the hard palate. trans-Capsaicin was delivered systemically by means of either a patch [NGX-4010 (25, 37.5, or 50 cm(2))] to pregnant Sprague-Dawley rats on days of presumed gestation (DGs) 7 through 17, or via a 10% w/v capsaicin liquid formulation (CLF), at dosages of 3, 6.5 or 13 mul/cm(2) applied to a 200-cm(2) area on the back on DGs 7 though 19 to timed-mated New Zealand white rabbits. In rats, the maternal no-observable-effect level (NOEL) was less than 25 cm(2) but no cesarean-sectioning or litter parameters were affected by application of NGX-4010 at patch sizes as high as 50 cm(2). The only test article-related observations were delays in skeletal ossification, evident as significant reductions in the average number of metatarsals and ossified hindlimb and forelimb phalanges that occurred in the 50 cm(2) NGX-4010 dose group. Although the values for ossified metatarsals were outside the historical control range, ossified hindlimb and forelimb phalanges were within historical control ranges. No other gross external, soft tissue, or skeletal fetal alterations (malformations or variations) were caused by application of the NGX-4010. In rabbits, the maternal NOEL was less than 3 mul/cm(2) CLF (or 0.3 mg/cm(2)trans-capsaicin) per 200 cm(2), but no cesarean-sectioning or litter parameters were affected. No fetal alterations (malformations or variations) were caused by dosages of CLF as high as 13 mul/cm(2) (or 1.3 mg/cm(2)trans-capsaicin). Taken together, these data suggest that tran s-capsaicin should not be considered a developmental toxicant.