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ABSTRACT: CNTO 530is a biopharmaceutical consisting of a novel peptide that mimics the actions of erythropoietin, fused to the Fc fragment of human IgG4. Pharmacokinetic and pharmacodynamic studies showed that CNTO 530 produced sustained increases in red blood cell parameters in rats and rabbits and that the serum half life of CNTO 530 was 2 days in rabbits and 3 days in rats.
For the evaluation of embryofetal development, CNTO 530 was injected at loading doses of 0, 0.9/1, 6, or 60 mg/kg subcutaneously (SC) on gestation day (GD)7 followed by maintenance doses of 0, 0.3, 2, or 20 mg/kg SC every 3 days through GD16 in rats and every 2 days through GD19 in rabbits (GD0 was the day of mating). Rats were Caesarean sectioned on GD21, rabbits on GD29.
Administration of CNTO 530 was associated with an increase in hematocrit at all dose levels and a decrease in maternal body weight gains. Fetuses exhibited reduced body weight and delayed ossification. Soft tissue changes were limited to cardiovascular alterations in the high-dose rabbits only. Rat and rabbit fetuses were exposed to CNTO 530 in all dose groups.
These studies show that the embryo/fetal development effects observed following CNTO 530 treatment during organogenesis are qualitatively similar to those seen with other erythropoietin agonists and are likely a secondary consequence of increased hematocrit in the dams. Unlike other erythropoietin receptor agonists, CNTO 530 was able to cross the placental barrier, which was considered likely the result of FcRn-mediated transcytosis.
Birth Defects Research Part B Developmental and Reproductive Toxicology 04/2010; 89(2):87-96. · 1.93 Impact Factor
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ABSTRACT: Lenalidomide, a thalidomide analog, is indicated for treatment of patients with deletion-5q myelodysplastic syndromes or multiple myeloma. NZW rabbits were used because of sensitivity to thalidomide's teratogenicity.
Range-finding and pulse-dosing studies preceded a full developmental toxicity study in New Zealand white (NZW) rabbits (25/group) given lenalidomide (0, 3, 10, or 20 mg/kg/day) or thalidomide (180 mg/kg/day) by stomach tube on gestation days (GD) 7-19. Clinical signs, body weights, and feed consumption were recorded daily from GD 7. On GD 29, standard maternal necropsy, uterine content, and fetal evaluations were carried out.
In all studies, thalidomide was selectively toxic to development. In the pulse-dosing study, lenalidomide did not affect development at 100 mg/kg/day. Increases in C(max) and AUC(0-24 hr) values for lenalidomide were slightly less than dose-proportional; lenalidomide occurred in the fetuses. At 10 and 20 mg/kg/day, lenalidomide was maternally toxic (reduced body weight gain and feed consumption; at 20 mg/kg/day, weight loss and one abortion). Developmental toxicity at 10 and 20 mg/kg/day included reduced fetal body weights and increased postimplantation losses and fetal variations (morbidity/purple-discolored skin, undeveloped intermediate lung lobe, irregular nasal-frontal suture, and delayed metacarpal ossification). Thalidomide selectively reduced fetal body weight, increased postimplantation loss and caused characteristic limb and other dysmorphology.
The maternal and developmental NOAELs for lenalidomide are 3 mg/kg/day. Unlike thalidomide, lenalidomide affected embryo-fetal development only at maternally toxic dosages, confirming that structure-activity relationships may not predict maternal or developmental effects. No fetal malformations were attributable to lenalidomide.
Birth Defects Research Part B Developmental and Reproductive Toxicology 07/2007; 80(3):188-207. · 1.93 Impact Factor
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ABSTRACT: D-methylphenidate is an enantiomer of D,L-methylphenidate and was developed as an improved treatment for attention deficit hyperactivity disorder in children. The current study was performed to determine and compare the toxicity of 2-50 mg/kg per day D-MPH and 100 mg/kg per day D,L-MPH for 90 days in rats with the top D-MPH dose being equimolar to 100 mg/kg D,L-MPH. The top D-MPH and D,L-MPH doses were at least 67 times that of the human dose and produced systemic exposures that were over 10 times higher than those typically achieved in children. During the course of the study, one male each from the 50 mg/kg per day and D,L-MPH groups and one female from the 50 mg/kg group died. Incidences of material around nose/eyes, scabbing, foot swelling, alopecia and abrasions were evident at 50 mg/kg per day D-MPH and 100 mg/kg per day D,L-MPH doses. Body weight and its changes decreased in a dose-dependent manner for D-MPH males. There were significant changes in some clinical chemistry measurements at the terminal bleed in the high dose groups of both sexes although most of these changes were resolved by the recovery bleed. Differences in absolute and relative body and certain organ weights for high dose D-MPH and D,L-MPH groups were seen at terminal necropsy with the differences no longer present after the recovery period. No abnormal or gross histopathological changes were associated with any of these organ weight changes reported for the terminal and recovery periods. Based on body weight changes, the no observed adverse effect level for D-MPH in rats was 20 mg/kg. Overall, the toxicity profile observed in rats with 50 mg/kg per day D-MPH was comparable to that of an equimolar dose of D,L-MPH (100 mg/kg per day) when given repeatedly for 90 days using a twice a day dosing regimen.
Toxicology 11/2002; 179(3):183-96. · 3.68 Impact Factor
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ABSTRACT: Pediatric evaluations are useful only when the animal model and human neonate have similar timing in system development. The objective of this study was to compare the growth of 24-hour-old swine provided 3 different feeding regimens of a simulated sow milk formula for 3 weeks. Three groups of three swine per sex were used. Group 1 was fed every 4 hours for weeks 1 through 3. Group 2 was fed every 3 hours during week 1 and every 4 hours during weeks 2 and 3. Group 3 (as close to ad libitum as possible) was fed every 2 hours for the first 2 days; every 2.5 hours for the next 2 days; every 3 hours for the next 3 days; and every 4 hours during weeks 2 and 3. No mortality occurred. Body weights were within normal limits. Organ weights, physical and ophthalmologic examinations, hematology and serum chemistry parameters, gross necropsy observations, and microscopic evaluation of the brain, liver, and kidneys were not affected by the three feeding regimens. Day 21 body weight gain of group 3 was greater than that for groups 1 or 2. Mean formula consumption (ounces/day) over 21 days was significantly increased (p < .01) for group 3 (males and combined sexes) compared to the two other groups, supporting the greater weight gain of group 3 versus groups 1 and 2 over the 21-day feeding period. Body weights of the piglets fed simulated sow milk and historical control 21-day-old suckling pigs were within the same range. Only the labor-intensive feeding of simulated sow milk in a regimen close to ad libitum produced maximal weight gain in 24-hour-old piglets during the initial 3 weeks postpartum.
International Journal of Toxicology 21(5):361-70. · 1.28 Impact Factor
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ABSTRACT: 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.
International Journal of Toxicology 25(3):205-17. · 1.28 Impact Factor
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ABSTRACT: Monoclonal antibodies directed against tumor necrosis factor alpha (TNFalpha) are currently employed in the treatment of various immune-mediated diseases. These studies were designed to evaluate potential effects of anti-TNFalpha treatment in mice during pregnancy and lactation on the development of the immune system in the F1 generation. Pregnant CD-1 mice were treated with vehicle or with 10 or 40 mg/kg of an anti-mouse TNFalpha monoclonal antibody (mAb) (cV1q) on days 6, 12, and 18 of gestation and on days 3, 9, and 15 of lactation. Evaluation of immune system functionality was conducted in F1 generation mice at 11 weeks of age. Immune function was evaluated by splenocyte phenotyping, immunoglobulin M (IgM) antibody response to sheep red blood cells (SRBCs), spleen cell proliferative response to anti-CD3, and natural killer cell activity. Treatment of pregnant mice with cV1q produced no adverse effects in the dams and no adverse effects in the F1 generation. In general, the functioning of the immune system of the F1 generation did not appear to be adversely affected following exposure to cV1q in utero and during lactation. The only statistically significant change was a slight (approximately 20%) reduction in the spleen cell expansion in response to SRBC immunization in the female F1 mice from the 40 mg/kg cV1q treatment group. In conclusion, administration of a monoclonal antibody against mouse TNFalpha during pregnancy and lactation had little or no effect on selected immune parameters in mice, with only a possible minor attenuation of spleen cell response to immunization noted in the female F1 generation at 11 weeks of age.
International Journal of Toxicology 27(4):341-7. · 1.28 Impact Factor
