Experimental Studies on Reproduction with the Lipid-Regulating Agent Gemfibrozil

Experimental Studies on Reproduction with the Lipid-RegulatingAgent Gemfibrozil. FITZGERALD, J. E., PETRERE, J. A., AND DELA IGLESIA, F. A. (1987). Fundam. Appl. Toxicol. 8, 454–464.Gemfibrozil, a new lipid-regulating agent, was evaluated inrats and rabbits for effects on various phases of the reproductionprocess. In teratology studies groups of pregnant rats and rabbitsreceived gemfibrozil at doses up to 200 mg/kg during organogenesis(rat, Days 6–15; rabbit, days 6–18). For peri- andpostnatal studies, groups of pregnant rats were given 92 or3 31 mg/kg from Day 15 of gestation through weaning. In fertilitystudies groups of sexually mature male rats were given 93 or326 mg/kg of gemfibrozil for 61 days and females were given94 or 318 mg/kg for 15 days prior to mating within treatmentgroups. Drug administration continued in females through gestationand weaning of the F₁ offspring. In subsequent fertility experiments,treated male rats were mated with untreated females and treatedfemales were cohabitated with untreated males. Gemfibrozil didnot elicit a teratogenic response in either rats or rabbitsup to doses that resulted in maternal toxicity. Reduced pupweights during the neonatal and weaning periods in the femalefertility study as well as in the perinatal–postnatalstudy were the only apparent drug effect. Treatment of femalerats prior to mating had no significant effects on general reproductiveparameters. Male rats given doses of about 300 mg/kg/day showedinconsistent and equivocal lower rates of fertility relativeto the concurrent controls. No adverse effects were seen inthe reproductive performance of offspring of gemfibrozil-treatedmale rats.     

Studies on Reproduction in Rats with Meclofenamate Sodium, a Nonsteroidal Anti-inflammatory Agent

Studies on Reproduction in Rats with Meclofenamate Sodium, aNonsteroidal Anti-inflammatory Agent. PETRERE, J. A., HUMPHREY,R. R., ANDERSON, J. A., FITZGERALD, J. E., AND DE LA IGLESIA,F. A. (1985). Fundam. Appl. Toxicol. 5, 665–671. Reproductionand teratology studies were performed in rats given meclofenamatesodium, a nonsteroidal anti-inflammatory agent. Dosages of 0,3, 6, and 9 mg/kg were administered orally as dietary admixturesin the Fertility and Perinatal-Postnatal studies. In the Teratologystudy, dosages of 10, 12, 15, and 20 mg/kg were administeredby intragastric intubation. In the Male-Fertility study no adverseeffects on fertility or litter and offspring parameters wereobserved in two generations. In the Female-Fertility and Perinatal-Postnatalstudies, maternal toxicity (death associated with intestinalulceration and adhesions) was particularly evident during lactation.Prolonged gestation periods, decreased weanling weights, andincreased weanling mortality were evident at dosages of 6 and9 mg/kg. Increased postimplantation loss occurred at 6 and 9mg/kg in the Term Sacrifice subgroup of the Female-Fertilitystudy. Fertility rates were unaffected and all other litterand offspring parameters of the F₁ and F₂ generations appearednormal. In the Teratology study no adverse effects on embryonicor fetal development were evident at maternally toxic dosagesup to 20 mg/kg. © 1985 Society of Texicology.     

Teratology Study in Rats with Amsacrine, an Antineoplastic Agent

Teratology Study in Rats with Amsacrine, an Antineoplastic Agent.ANDERSON, J. A., PETRERE, J. A., SAKOWSKI, R., FITZGERALD, J.E., AND DE LA IGLESIA, F. A. (1986). Fundam. Appl. Toxicol.7, 214–220. Amsacrine, an acndinylamino derivative usedin the treatment of refractory leukemias, was evaluated forits teratogenic potential in pregnant rats. The compound wasgiven by intrapentoneal (ip) administration on Days 6 to 9 ofgestation to groups of 20 female CD rats at levels of 0.5, 1.0,and 2.0 mg/kg. Appropriate vehicle and untreated controls wereincluded. Dams given 2.0 mg/kg lost weight during and afterthe treatment period. Food consumption was comparable to controlsat all dose levels except for the high dose group in the post-treatmentperiod. Decreased litter size, increased postimplantation loss,and reduced fetal weights occurred with doses of 2.0 mg/kg.Significantly reduced fetal body weight and increased incidenceof stunting were the only adverse findings at 0.5 and 1.0 mg/kg,respectively. Two fetuses at 2.0 mg/kg, one at 1.0 mg/kg, oneat 0.5 mg/kg, and two vehicle control fetuses had gross abnormalities.Fetotoxicity, manifested by inhibition of osteogenesis and minorskeletal abnormalities, occurred with doses of 0.5 mg/kg ormore. The results indicate that amsacrine was embryolethal torats at doses of 2.0 mg/kg and embryotoxic at lower dose levels.Teratogenicity was not evident at doses which did not affectfetal survival.     

Studies on Reproduction in Rats with Pirmenol, an Antiarrhythmic Agent

Studies on Reproduction in Rats with Pirmenol, an AntiarrhythmicAgent. ANDERSON, J. A., PETRERE, J. A., FITZGERALD, J. E., DELA IGLESIA, F. (1986). Fundam. Appl. Toxicol. 7, 221-227. Fertilityand perinatal-postnatal studies were performed in CD rats givenpirmenol, an antiarrhythmic agent, at dosages of 0, 25, 50,and 100 mg/kg. The drug was administered orally as diet admixturesin all studies. In the male fertility study, mature male ratswere treated for 61 days prior to mating with virgin, untreatedfemale rats. In the female fertility study, mature virgin femalerats were treated for 15 days prior to mating with untreatedpartners with treatment continuing throughout mating, pregnancy,parturition, and weaning of the litters. In both studies, one-halfof the dams in each group were killed on Day 21 of pregnancyand the remaining dams were allowed to deliver and wean theiroffspring and postnatal development was monitored. At weaning,two males and two females were arbitrarily selected from eachlitter, allowed to mature on unmedicated diet, and then matedwithin treatment groups to produce the F2 generation. In theperinatal-postnatal study, pregnant females were treated continuouslyfrom Day 15 of pregnancy until weaning of the litters on Day21 postbirth. No adverse effects on fertility, general reproductiveparameters, or offspring survival and development were evidentat doses employed in these studies.     

Teratogenesis of Calcium Valproate in Rats

Teratogenesis of Calcium Valproate in Rats. Ong, Lina L., Schardein,James L., Petrere, Judith A., Sakowski, Raymond, Jordan, Hollis,Humphrey, Ronald R., Fitzgerald James E., and de la Iglesia,Felix A. (1983). Fundam. Appl. Toxicol. 3:121-126. Studies wereconducted to determine the teratogenic potential of the calciumsalt of valproic acid in rats when given orally at doses of600, 150, and 50 mg/kg on days 6–15 of gestation. Thesodium salt of valproic acid was used as a reference agent ata dose level of 600 mg/kg. The administration of 600 mg/kg/dayof either calcium or sodium valproate resulted in transient,severe sedation in the dams. Four dams receiving 600 mg/kg ofeither salt died during the experiment, with deaths occurringbetween day 7 and 11 of gestation. Food consumption and bodyweight gain were significantly reduced during the dosing periodwith both salts at dose levels of 600 mg/kg. Embryotoxicityat the high doses(600 mg/kg) with either salt was manifestedby increases in fetal resorption, reduced body weights, andsignificantly increased Incidence of supernumerary ribs andbifid vertebral centra among the surviving fetuses. A teratogeniceffect was evident at 600 mg/kg with either salt of valproicacid. Seven of 16 fetuses from dams given the calcium salt wereabnormal. Findings included one with omphalocele and six otherswith skeletal malformations. Eleven of 24 fetuses from damsgiven the sodium salt were abnormal: three littermates had bilateralectrodactyly of the rear feet and malformed vertebral centraand eight others had skeletal malformations. No teratogeniceffect was evident among the fetuses from dams given 150 mg/kgcalcium salt. Embryotoxicity was demonstrated by a significantincrease in the incidence of supernumerary ribs. No adverseeffect was observed among the fetuses from dams given 50 mg/kgof the calcium salt.     

Developmental Toxicity Studies in Mice, Rats, and Rabbits with the Anticonvulsant Gabapentin

The developmental toxicity of the anticonvulsant agent gabapentinwas evaluated in mice, rats, and rabbits treated by gavage throughoutorganogenesis. Mice received 500, 1000, or 3000 mg/kg on gestationdays (GD) 6–15 and rats and rabbits received 60, 300,or 1500 mg/kg on GD 6–15 (rats) or 6–18 (rabbits).Additional groups received an equivalent volume of the vehicle,0.8% methylcellulose, or remained untreated. All dams were observeddaily for clinical signs of toxicity. In mice, body weightsand food consumption were recorded on GD 0, 6, 12, 15, and 18while in rats and rabbits these parameters were evaluated daily.Near term (mouse, GD 18; rat, GD 20; and rabbit, GD 29) eachfemale was euthanatized, necropsies were performed, and litterand fetal data were collected. Live fetuses were examined forexternal, visceral, and skeletal variations and malformations.No adverse maternal or fetal effects were observed in mice orrats given doses up to 1500 or 3000 mg/kg, respectively. Notreatment-related maternal or fetal effects were apparent inrabbits given 60 or 300 mg/kg. At 1500 mg/kg, one rabbit died,four others aborted, and reduced food consumption and body weightgain were observed. No other reproductive, litter, or fetalparameters were affected, except that the incidence of visceralvariations in rat fetuses was slightly but statistically significantlyincreased at 1500 mg/kg due to a slight increase in the incidenceof dilated renal pelvis. This finding was not considered biologicallysignificant because this degree of variability has been seenin this strain of rats. In conclusion, no evidence of teratogenicitywas found for gabapentin at doses up to 3000 mg/kg in the mouseand up to 1500 mg/kg in the rat and rabbit.     

Food Restriction during Organogenesis in Rabbits: Effects on Reproduction and the Offspring

Food Restriction during Organogenesis in Rabbits: Effects onReproduction and the Offspring. PETRERE, J. A., ROHN, W. R.,GRANTHAM, L. E., II, AND ANDERSON, J. A. (1993). Fundam. Appl.Toxicol. 21, 517–522. To assess the effects of markedly restricted food intake versusad libitum feeding or a slightly restricted feeding regimenduring the period of organogenesis we fed groups of 16–18pregnant rabbits Purina Certified High Fiber Chow ad libitum,150 g/day, 75 g/day, or 15 g/day on Gestation Days 6 to 18 inclusive.Prior to and after organogenesis the animals were provided foodad libitum (ad lib). Clinical observations, body weights, andfood and water consumption were recorded daily. On GestationDay 30 each doe was euthanatized and necropsied, and maternaland fetal data were collected. Each fetus was examined for external,visceral, and skeletal variations and malformations. Ossificationparameters were also evaluated. Statistical analyses were conductedin two ways, first comparing the restricted groups to the adlib group and second comparing the 15 and 75 g/day groups tothe 150 g/day group. During Days 6–18, the 15 and 75 g/daygroups had significantly decreased weight gain (actual weightloss), compared to the groups fed 150 g/day or ad lib. Waterconsumption was also significantly decreased in the 15 g/daygroup during this period, compared to the ad lib group. Whenfood was provided ad lib on Days 19–30 to the restrictedgroups, weight gain was significantly higher in the 15 and 75g/day groups than the group previously given 150 g/day and thead lib group. There were no differences in water consumptionduring that period. Abortion occurred in three 15 g/day animals.Pregnancy rate and numbers of corpora lutea, implantation sites,live and dead fetuses and resorptions, pre- and postimplantationloss, and placental weights were similar among groups. Fetalsex ratio and survival at term were comparable between the adlib group and the restricted groups. In the 15 g/day group,mean fetal weights were lower than those in the 150 g/day andthe ad lib groups. None of the fetuses from food-restricteddoes had external or visceral malformations, whereas two littermatesfrom the ad lib group had malformations of the heart or gallbladder.Except for a significant increase in the percentage of litterswith external or visceral variations in the 15 g/day group comparedto the 150 g/day group, there were no significant differencesbetween groups in the incidences of variations or malformations.Our findings agree with those in the literature in that abortionis increased and fetal weights are reduced when maternal foodintake is severely restricted during organogenesis. Contraryto a previous report also using 15 g/day during organogenesis[R. L. Clark, R. T. Robertson, C. P. Peter, J. A. Bland, T.E. Nolan, L. Oppenheimer, and D. L. Bokelman (1986). Fundam.Appl. Toxicol. 7, 292–286], we did not have an increasedincidence of fetal malformations. This study indicates thatthe influence of reduced food intake and body weight loss duringorganogenesis is equivocal in the induction of teratogenicityin rabbits.     

Preclinical Toxicology Studies with the Lipid-Regulating Agent Gemcadiol

Preclinical Toxicology Studies with the Lipid-Regulating AgentGemcadiol. FITZGERALD, J. E., PETRERE, J. A., MCGUIRE, E. J.,AND DE LA IGLESIA, F. A. (1986). Fundam. Appl. Toxicol. 6,520–531.Gemcadiol is a medium-length diol moiety with lipid-regulatingproperties in animals and man. The compound was not toxic whensingle doses were administered to rodents with the lethal dosegreater than 7000 mg/kg in rats and mice. Rats treated for 13or 52 weeks with 30 to 300 mg/kg had reversible food intakesuppression and weight gain inhibition, decreased blood cholesterol,slight anemia, and generally dose-related but reversible decreasesin glucose, and increases in alkaline phosphatase and bloodurea nitrogen. Liver weights were increased, and there was accompanyinghypertrophy and increased cytoplasmic eosinophilia of hepatocyteswith associated peroxisome proliferation. Rats treated for 52weeks also had mild renal tubular dilatation. Dogs given 25to 300 mg/kg of gemcadiol for up to 52 weeks tolerated the compoundbetter than rats. Effects related to compound administrationwere elevated serum alanine aminotransferase activity in femaleanimals only, and microscopic cytoplasmic vacuolation and hyalinebody formation in both sexes. Monkeys given 25 to 300 mg/kggemcadiol for 13 weeks had slightly decreased serum cholesteroland slightly increased serum creatine phosphokinase. Teratologystudies in rats or rabbits indicated no teratogenic response.Gemcadiol affects principally the liver, and the hepatic alterationsseen in rats and dogs may reflect compensatory manifestationsof altered metabolism related to the lipid-regulating activityof the compound.