Juvenile toxicity assessment of d,l-methylphenidate in rats

BACKGROUND: The oral administration of d,l‐methylphenidate (MPH) was designed to encompass the major part of postnatal development in the rat and to evaluate potential chronic effects. METHODS: Wistar Hannover rats were cross‐fostered on postpartum day 0 (day of birth) and were administered MPH at doses of 5, 50, and 100 mg/kg/day (mpkd) on postpartum days 7 to 70. Clinical signs, body weight, food consumption, developmental, behavioral, clinical/anatomic pathology, toxicokinetic, and fertility evaluations were conducted. RESULTS: MPH‐related effects on clinical signs, body weight, and behavior tests were noted. Increased locomotor activity and cage biting/chewing occurred at ≥5 mpkd (females) and ≥50 mpkd (males) and were absent after dosing ceased. Body weight parameters were decreased at ≥50 mpkd and were comparable to controls at 5 weeks' recovery. Open field motor activity tests conducted 2 weeks after dosing ceased revealed decreased peripheral beam breaks at ≥50 mpkd. Passive avoidance tests conducted 3 weeks after dosing ceased indicated decreased females reaching learning criterion at 100 mpkd. This is considered of nominal significance as there were no effects in the water maze test or retention in passive avoidance test. After multiple doses, females exhibited higher exposures than males and exposures were reduced in all groups in comparison to those after a single dose. CONCLUSIONS: These results suggest that MPH can produce enduring behavioral effects in rats. The no‐toxicologic‐effect‐level was 5 mpkd, associated with AUC_{(0–24 h)} racemate values in males and females, respectively, of 101 and 153 ng.h/mL after chronic dosing. Birth Defects Res (Part B) © 2008 Wiley‐Liss, Inc.     

Developmental toxicity evaluation of sodium thioglycolate administered topically to Sprague-Dawley (CD) rats and New Zealand White rabbits

BACKGROUND: Sodium thioglycolate, which has widespread occupational and consumer exposure to women from cosmetics and hair‐care products, was evaluated for developmental toxicity by topical exposure during the embryonic and fetal periods of pregnancy METHODS: Timed‐mated Sprague–Dawley rats (25/group) and New Zealand White (NZW) rabbits (24/group) were exposed to sodium thioglycolate in vehicle (95% ethanol:distilled water, 1:1) by unoccluded topical application on gestational days (GD) 6–19 (rats) or 6–29 (rabbits) for 6 hr/day, at 0, 50, 100, or 200 mg/kg body weight/day (rats) and 0, 10, 15, 25, or 65 mg/kg/day (rabbits). At termination (GD 20 rats; GD 30 rabbits), fetuses were examined for external, visceral, and skeletal malformations and variations. RESULTS: In rats, maternal topical exposure to sodium thioglycolate, at 200 mg/kg/day (the highest dose tested) on GD 6–19, resulted in maternal toxicity, including reduced body weights and weight gain, increased relative water consumption and one death. Treatment‐related increases in feed consumption and changes at the application site occurred at all doses, in the absence of increased body weights or body weight change. Fetal body weights/litter were decreased at 200 mg/kg/day, with no other embryo/fetal toxicity and no treatment‐related teratogenicity in any group. In rabbits, maternal topical exposure to sodium thioglycolate on GD 6–29 resulted in maternal dose‐related toxicity at the dosing site in all groups; no maternal systemic toxicity, embryo/fetal toxicity, or treatment‐related teratogenicity were observed in any group. CONCLUSIONS: A no observed adverse effect level (NOAEL) was not identified for maternal toxicity in either species with the dosages tested. The developmental toxicity NOAEL was 100 mg/kg/day (rats) and ≥65 mg/kg/day (rabbits; the highest dose tested). The clinical relevance of theses study results is uncertain because no data were available for levels, frequency, or duration of exposures in female workers or end users. Birth Defects Research Part B 68:144–161, 2003. © 2003 Wiley‐Liss, Inc.     

D-methylphenidate and D,L-methylphenidate are not developmental toxicants in rats and rabbits

BACKGROUND: D ,L ‐threo‐Methylphenidate (D ,L ‐MPH) is marketed currently for attention deficit hyperactivity disorder in children. D ‐threo‐methylphenidate (dexmethylphenidate; D ‐MPH) is a refined formulation of D ,L ‐methylphenidate containing only the active enantiomer and was recently approved in the U.S. for the same condition. D ‐Methylphenidate has been shown to be efficacious in patients at half the dose of D ,L ‐MPH with a potentially improved therapeutic profile. The developmental toxicity of both compounds was determined and compared in rats and rabbits according to current International Conference on Harmonization (ICH) guidelines. METHODS: Groups of pregnant rats were orally dosed twice daily 6 hr apart from Days 7 to 17 of presumed gestation (DG 7–17) for total daily doses of 2, 6 and 20 mg/kg D ‐MPH and 40 mg/kg D ,L ‐MPH. Groups of presumed pregnant rabbits were similarly dosed from DG 6 to 18 for total daily doses of 4, 20 and 100 mg/kg D ‐MPH and 200 mg/kg D ,L ‐MPH. Control groups for both studies were given water vehicle. Comprehensive clinical and developmental measurements were made. Satellite groups of animals were included in the main rat and rabbit studies for toxicokinetic assessment. RESULTS: No drug‐related mortality was seen in the F0 rats and rabbits. The number of rats with repetitive pawing, dilated pupil and aggression was significantly greater for the 40 mg/kg D ,L ‐MPH compared to the 20 mg/kg D ‐MPH dosed rats. Maternal body weight and body weight gain were significantly reduced for both D ‐MPH and D ,L ‐MPH groups compared to control. Maternal reproductive and litter parameters were unaffected by both drugs. No gross external, soft tissue, or skeletal alterations related to both compounds were seen in the fetuses. In rabbits, head‐bobbing and hyperpnea were significantly greater for the 200 mg/kg D ,L ‐MPH compared to 100 mg/kg D ‐MPH. No other maternal or fetal effects related to both compounds were seen. Exposure to D ‐MPH (as assessed by AUC) showed no teratogenic effects at exposures of up to 5.6 and 1.7 times for the rat and rabbit respectively compared to children taking the maximum therapeutic dose of 20 mg/day (10 mg twice a day). No teratogenic effects were seen for D ,L ‐MPH in rat and rabbit at exposures of up to 3.7 to 11.7 times that of the maximum therapeutic pediatric dose of 60 mg/day. CONCLUSIONS: Rats and rabbits dosed with D ,L ‐MPH exhibited significantly greater incidence of maternal clinical observations at twice the dose of D ‐MPH. Both D ‐MPH and D ,L ‐MPH were not teratogenic in rats and rabbits at higher exposure levels compared to humans. © 2003 Wiley‐Liss, Inc.     

Prenatal developmental toxicity of decabromodiphenyl ethane in the rat and rabbit

BACKGROUND: The potential embryotoxic and teratogenic effects of decabromodiphenyl ethane (DBDPEthane; CASRN 84852–53–9) were evaluated in prenatal developmental studies using rats and rabbits and performed in accordance with international guidelines and Good Laboratory Practice standards. Preliminary dose‐range‐finding studies were conducted, which indicated doses up to 1,250 mg/kg‐day were well tolerated by both rats and rabbits. METHODS: For the developmental studies, animals were administered DBDPEthane via gavage at dosage levels of 0, 125, 400, or 1,250 mg/kg‐day from gestation day (GD) 6 through 15 for rats and GDs 6 through 18 for rabbits. All female rats and rabbits were sacrificed on GD 20 or GD 29, respectively, and subjected to cesarean section. Fetuses were individually weighed, sexed, and examined for external, visceral and skeletal abnormalities. RESULTS: No treatment‐related mortality, abortions, or clinical signs of toxicity were observed during the study. Body weights, body weight gain, and food consumption were not affected by treatment. No significant internal abnormalities were observed in either species on necropsy. Cesarean section parameters were comparable between control and treated groups. No treatment‐induced malformations or developmental variations occurred. CONCLUSIONS: Based on these results, no evidence of maternal toxicity, developmental toxicity, or teratogenicity was observed in rats or rabbits treated with DBDPEthane at dosage levels up to 1,250 mg/kg‐day. Birth Defects Res (Part B) 89:139–146, 2010. © 2010 Wiley‐Liss, Inc.     

Developmental toxicity studies of lumefantrine and artemether in rats and rabbits

The combination of artemether plus lumefantrine is a type of artemisinin‐based combination therapy (ACT) recommended by the World Health Organization for uncomplicated falciparum malaria except in the first trimester of pregnancy. The first trimester restriction was based on the marked embryotoxicity in animals (including embryo death and cardiac and skeletal malformations) of artemisinins such as artesunate, dihydroartemisinin, and artemether. Before recommending ACTs for use in the first trimester, the World Health Organization has requested that all information relevant to the assessment of risk of ACTs to the embryo be made available to the public. This report describes the results of embryo‐fetal development studies of artemether alone, lumefantrine alone, and the combination in rats and rabbits as well as toxicokinetic studies of lumefantrine in pregnant rabbits. The developmental no‐effect levels for lumefantrine were 300 mg/kg/day in rats (based on a 25% decrease in litter size at 1000 mg/kg/day) and 1000 mg/kg/day in rabbits. The calculated safety margins based on human equivalent dose and plasma C_max and AUC values were in the range of 2.5‐ to 17‐fold. The developmental no‐effect levels for artemether were 3 mg/kg/day in rats and 25 mg/kg/day in rabbits. Lumefantrine caused no teratogenicity and was not a potent embryotoxin in rats and rabbits. Expected artemisinin‐like findings were seen with artemether alone and with artemether/lumefantrine combined except that no malformations were observed. There were no findings in pregnant rats and rabbits that would cause increased concern for the use of artemether–lumefantrine in the first trimester compared to other ACTs.     

The role of maternal toxicity in lovastatin-induced developmental toxicity

The role of maternal toxicity in lovastatin-induced developmental toxicity in rats was examined in a series of studies. The first study administered lovastatin at 100, 200, 400, or 800 mg/kg/day (mkd) orally to mated rats from Gestation Day (GD) 6 through 20. Maternal toxicity was observed as transient dose-related body weight losses at the initiation of dosing; there were also deaths and/or morbidity at 400 and 800 mkd. These toxicities occurred in conjunction with forestomach lesions. Mean fetal weights were decreased in all groups (-5 to -16%), and the incidence of skeletal malformations, variations, and incomplete ossifications was increased. The 2 highest doses produced the most severe maternal and developmental effects. Using the same dosages, the second study avoided gestational maternal weight losses and morbidity by starting treatment 14 days before mating with dosing continued to GD 20. There were transient dose-related body weight losses after the start of dosing and deaths in the 400- and 800-mkd groups; however, there was no evidence of maternal toxicity during gestation. Developmental toxicity was evident only as slight, but generally significant (p< or =0.05) decreases in mean fetal weights in groups given > or =200 mkd (-2 to -5%). Significantly, no skeletal abnormalities were observed. A third study administered the pharmacologically active metabolite of lovastatin subcutaneously at dose levels that matched oral maternal drug exposures. In the high-dose group, maternal weight gain and mean fetal weight were slightly decreased but there were no treatment-related skeletal abnormalities. Finally, a series of toxicokinetic studies assessed whether the 2 different developmental toxicity profiles were due to differences in drug exposure between the developmentally toxic and non-toxic dosing regimes. The data showed that groups with no skeletal abnormalities had maternal and embryonic/fetal drug concentrations similar to or even greater than the groups with fetal abnormalities. These results indicate that fetal skeletal abnormalities observed at lovastatin dose levels > or =100 mkd are not due to a direct teratogenic effect, but are the result of excessive maternal toxicity, which most likely involves a nutritional deficiency associated with forestomach lesions and reduced maternal food intake.     

Developmental Toxicity of the HMG‐CoA Reductase Inhibitor (PPD10558) in Rats and Rabbits

PPD10558 is an orally active, lipid‐lowering 3–hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor (statin) being developed as a treatment for hypercholesterolemia in patients who have not been able to tolerate statins because of statin‐associated myalgia. We have studied the potential developmental toxicity effects of PPD10558 in pregnant rats and rabbits given daily oral doses during the period of organogenesis. Rats were dosed with 0, 20, 80, or 320 mg/kg/day from Gestation Day (GD) 6 to 17 and rabbits received dose levels of 0, 12.5, 25, or 50 mg/kg/day from GD 6 to 18. Additional groups in both studies served as toxicokinetic animals and received the PPD10558 in the same manner as the main study groups at the same dose levels. Blood samples were collected from toxicokinetic animals at designated time points on GD 6 and 17 in rats and GD 6 and 18 in rabbits. Fetal exposure in rats was assessed on GD 20. Maternal and developmental parameters were evaluated in rats and rabbits on GD 20 and GD 29, respectively. No maternal and developmental toxicity was observed at any of the dose levels used in the rat study. Evidence of fetal exposure was determined in fetal plasma with mean fetal concentrations of PPD10558 and the metabolite (PPD11901) found to be between 1 and 6% of the mean maternal concentrations. In rabbits, marked maternal toxicity including mortality (eight deaths; 1 dose at 25 and 7 at 50 mg/kg/day), abortions (2 at 25 mg/kg/day and 6 at 50 mg/kg/day) and reduction in gestation body weight, gestation body weight changes and decreased food consumption were observed. In addition, fetal body weights of the combined sexes were significantly reduced at 50 mg/kg/day in comparison with the controls. Mean peak exposure (Cmax) and total exposure (AUC(0–24)) of PPD11901 in both rats and rabbits were higher than that of PPD10558 on GD 6 and GD 17 at each of the three dose levels.. Based on the results of these studies, the no observed adverse effect level (NOAEL) for maternal and developmental toxicity in rats was considered to be ≥320 mg/kg/day, the highest dose level used in the study. The NOAEL for maternal and developmental toxicity in rabbits was 12.5 mg/kg/day and 25 mg/kg/day, respectively.     

Micro‐computed tomographic evaluation of fetal skeletal changes induced by all‐trans‐retinoic acid in rats and rabbits

BACKGROUND: Our laboratory has been conducting positive control studies to evaluate the utility of micro‐computed tomography (micro‐CT) for qualitative evaluation of fetal skeletal morphology. All‐trans‐retinoic acid (atRA) was used to produce a different spectrum of defects compared to our previous studies with boric acid and hydroxyurea. METHODS: Groups of five mated Crl:CD(SD) female rats each were administered vehicle or atRA (2.5–50 mg/kg) on GD 10, and groups of four mated Dutch Belted rabbits each were dosed with vehicle or atRA (6.25–25 mg/kg) on GD 9. Cesarean sections were performed on GD 21 and 28, respectively. Following external examination the viscera were removed and fetuses scanned in a micro‐CT imaging system. Fetuses were subsequently stained with alizarin red. Skeletal morphology was evaluated by each method without the knowledge of treatment group. Total bone mineral content (BMC) of each fetus was quantitated using the micro‐CT images. RESULTS: In rats there were dose‐related increases in the incidence of extra lumbar vertebra and non‐dose‐related increases in supernumerary ribs at all dose levels. There were decreases in mean number of ossified sacrocaudal vertebra at ≥5 mg/kg, and increases in skull bone malformations at ≥10 mg/kg. Rabbits were less sensitive on a mg/kg basis since skeletal malformations and a decrease in mean number of ossified sacrocaudal vertebra were observed only in the 25‐mg/kg group. Micro‐CT evaluation detected essentially the same incidence of skeletal abnormalities as seen in alizarin red‐stained rat and rabbit fetuses. BMC analysis showed a trend toward slight decreases in atRA‐treated rats, but no notable changes in rabbits. CONCLUSIONS: These results add support to our previous work that demonstrates that micro‐CT imaging can effectively assess rat and rabbit fetal skeletal morphology. Birth Defects Res (Part B) 89:408–417, 2010. © 2010 Wiley‐Liss, Inc.     

TGF‐β1 monoclonal antibody: Assessment of embryo‐fetal toxicity in rats and rabbits

A humanized monoclonal antibody targeting transforming growth factor β1 (TGF‐β1 mab) has been used in development for the treatment of chronic kidney disease. Embryo‐fetal development studies were conducted in rats and rabbits using 30 and 25 animals per group, respectively. The TGF‐β1 mab was administered subcutaneously to rats at 0, 2, or 50 mg/kg/dose on gestation days (GDs) 6, 10, and 14 and intravenously to rabbits at 0 or 3 mg/kg/dose on GDs 7, 12 to 19, and at 30 mg/kg/dose on GDs 7, 12, 14, 16, and 18. Maternal reproductive endpoints and fetal viability, weight, and morphology were evaluated. There was no indication of maternal or embryo‐fetal toxicity in the rat. Effects in the rabbit were limited to the fetus where the 30 mg/kg TGF‐β1 mab dose produced a slight decrease in fetal weight and an increase in the incidence of retrocaval ureter and an absent and/or malpositioned kidney/ureter in two fetuses. In conclusion, TGF‐β1 mab produced no adverse maternal or embryo‐fetal findings in rats when administered ≤50 mg/kg on GDs 6, 10, and 14. TGF‐β1 mab did not demonstrate maternal toxicity or embryo‐fetal lethality at doses as high as 30 mg/kg when administered on GDs 7, 12, 14, 16, and 18 in rabbits. Fetal growth and morphology were affected only at 30 mg/kg; thus, the no observed adverse effect level was 3 mg/kg in rabbits. The margin of safety for both rats and rabbits was ≥37‐fold the clinical exposure level.     

Multigeneration Reproductive Study of Hydroxyprogesterone Caproate (HPC) in the Rat: Laboratory Results and Clinical Significance

To demonstrate reproductive safety of a new commercial product for reducing the risk of preterm birth, HPC (17α‐hydroxyprogesterone caproate, Makena; manufactured by Baxter Pharmaceutical Solutions, Bloomington IN for Ther‐Rx Corporation, St. Louis, MO) was administered intramuscularly in Charles River LaboratoryCD strain rats. HPC was given at intervals equal to the half‐life measured in rats during three phases of embryo‐fetal development: during the period of ovarian development (RP1, days 8, 14, and 20), following implantation of the embryo (TP, days 6, 12, and 18), and, corresponding to the start of the drug in week 16 or later in humans, after gonadal formation including differentiation of the testes (RP2, day 17). Dose levels up to 30× the human therapeutic doses were utilized including 0 (vehicle), 5, 25, and 150 mg/kg (volume 0.6 ml/kg). Four groups of 25 time‐mated rats each were used for each phase. In addition, equal numbers of naïve (untreated) rats of opposite gender were used for F₁ breeding studies. HPC did not produce any consistent test‐article–related findings in the treated F₀ dams, their developing F₁ fetuses and did not affect the ability of the latter to produce a viable F₂ generation. The F₁ offspring did not evidence any adverse effects during their behavioral, sensory, and developmental assessments, including teratogenicity. Based on the cumulative data obtained from rats treated over two generations and during development in this study, the No‐observable‐effect‐level (NOEL) was established as 150 mg/kg. This study supports the absence of reproductive toxicity with HPC in published studies in animal models and in human clinical trials.     

中华硬蜱叮咬不同免疫力新西兰兔后中肠上皮组织的形态动态变化

通过光镜和电镜观察了中华硬蜱Ixodes sinensis叮咬初次和再次感染宿主新西兰兔后不同时间（叮咬后24 h、48 h、72 h以及第 5天、第8天）中肠上皮组织的形态学动态变化。结果显示： 中华硬蜱叮咬前中肠上皮主要由替代细胞和少量体积较大的消化细胞构成;替代细胞数量多、体积小、呈圆形、胞质染色浅 。中华硬蜱叮咬初次感染宿主后,消化细胞随叮咬时间延长而增多增大,微绒毛较密集,排列整齐,胞质内细胞器丰富,各单位膜结构清晰,并出现顶端小管、小泡、大量脂滴和高铁血红素颗粒;近基膜的细胞膜内褶形成发达的基底迷路系统。中华硬蜱叮咬再次感染宿主后,中肠可发生一系列明显的病理变化,中肠基膜出现变薄、松散和断裂现象,消化细胞破裂、空泡化,消化细胞数量减少;消化细胞微绒毛减少、变短、排列不整,线粒体肿大,体嵴减少、变短甚至髓样变,粗面内质网扩张,脂粒及高铁血红素颗粒减少,细胞膜吞饮、吞噬现象减弱,消化细胞内结构紊乱和破坏。该研究结果提示初次叮咬导致了宿主的免疫抗性,再次叮咬后蜱中肠是宿主免疫力的主要作用部位。     

Developmental toxicity of pentostatin (2'-deoxycoformycin) in rats and rabbits

The developmental toxicity of the potent adenosine deaminase (ADA) inhibitor, pentostatin (2'-deoxycoformycin), was investigated in pregnant rats and rabbits administered daily iv doses during organogenesis. Rats received 0, 0.01, 0.10, or 0.75 mg/kg on gestation days 6-15 and rabbits received 0, 0.005, 0.01, or 0.02 mg/kg on gestation days 6-18 and maternal and fetal parameters were evaluated on gestation day 21 (rats) or 30 (rabbits). Live fetuses were examined for external, visceral, and skeletal malformations and variations. In rats, maternal body weight gain and food consumption were significantly suppressed at doses of 0.10 and 0.75 mg/kg during the treatment period but returned to control levels during posttreatment. Increased postimplantation loss and decreased numbers of live fetuses, litter size, and fetal body weight were observed at 0.75 mg/kg. A statistically significant increase in the incidence of vertebral malformations occurred at 0.75 mg/kg. The incidence of certain skeletal variations (extra presacral vertebrae, extra ribs, hypoplastic vertebrae) was also increased at 0.75 mg/kg. Ossification of cervical centra was reduced at 0.75 mg/kg compared with controls. In rabbits, marked maternal toxicity (death, body weight loss, and decreased food consumption) and reproductive toxicity (abortion and premature delivery) occurred in all pentostatin-treated groups. However, there were no significant effects on number of live fetuses, pre- or postimplantation loss, litter size, or fetal body weights in the animals with live litters. There was also no apparent increase in the incidence of malformations or variations in the live fetuses of pentostatin-treated rabbits. Thus, these studies demonstrate developmental toxicity of pentostatin in rats and rabbits, and teratogenicity in rats, at maternally toxic doses.     

Fertility and Developmental Toxicity Assessment in Rats and Rabbits with LY500307, a Selective Estrogen Receptor Beta (ERβ) Agonist

LY500307 is a selective estrogen receptor beta (ERβ) agonist that was developed for the treatment of benign prostatic hyperplasia. The in vitro functional selectivity of LY500307 for ERβ agonist activity is 32‐fold above the activity at the alpha receptor (ERα). LY500307 was evaluated in a series of male (M) and female (F) rat fertility and rat and rabbit embryo‐fetal development (EFD) studies, using 20 or 25 animals/group. LY500307 was administered daily by oral gavage starting 2 weeks (F) or 10 weeks (M) before mating, during cohabitation, until necropsy (M) or through gestation day (GD) 6 (F) in the fertility studies and from GD 6 to 17 (rats) or GD 7 to 19 (rabbits) in the EFD studies. Dosage levels of LY500307 ranged from 0.03 to 10 mg/kg/day for rats and from 1 to 25 mg/kg/day for rabbits. Fertility, estrous, maternal reproductive endpoints, conceptus viability, sperm parameters, organ weights, and histopathology were evaluated in the fertility studies. Maternal reproductive endpoints and fetal viability, weight, and morphology were evaluated in the EFD studies. Toxicokinetics were assessed in satellite animals. At 10 mg/kg/day in the male fertility study, findings included decreased body weight (BW); food consumption (FC); fertility, mating, and conception indices; sperm concentration; and reproductive tissue weight (associated with atrophic histologic changes). In the female fertility study, effects included decreased BW and FC at ≥0.3 mg/kg/day and persistent diestrus, delayed mating, and reduced fertility/conception indices at 3 mg/kg/day. In the rat EFD study, findings included decreased maternal BW and FC and increased incidences of adverse clinical signs, abortion, maternal mortality/moribundity, postimplantation loss, and fetal skeletal variations at 3 mg/kg/day. Effects in the rabbit EFD study were limited to decreases in maternal BW and FC at 25 mg/kg/day. In general, systemic maternal exposure increased proportionally with dosage in rats, but less than proportionally in rabbits. In conclusion, the no‐observed adverse effect levels following LY500307 administration were 1 mg/kg/day for male rat fertility, 0.3 mg/kg/day for female rat fertility and EFD, and 25 mg/kg/day for rabbit EFD. Adverse reproductive and developmental effects only occurred at or above parentally toxic dosage levels and were considered predominantly due to off‐target ERα effects.     

On systematics of mites of the genus Syringophiloidus (Acari: Syringophilidae) from the european part of Russia

A new species Syringophiloidus delichonum sp. n. (Acari: Syringophilidae) is described from quills of Delichon urbica (Hirundinidae) and S. glandarii (Fritsch, 1958) from Garrulus glandarius (Corvidae) is redescribed. Syringophiloidus glandarii, female: body length 650-680, width 160-180. Peritremes: longitudinal branch with 11-14 chambers, lateral--with 2 chambers. All propodosomal setae slightly serrate. Length of setae: vi 33-36, ve 87-96, sci 150-180, sce 180-240, h 200-230, dl 210-230, d2 140-170, d4 25-32, d5 33-40, l1 190-210, l2 150-170, l4 250-280, l5 310-320, pg1 140-150, pg2 120-160, pg3 190-200, g1, g2 40-45, a1, a2 25-33. Male. Body length 500-520, width 150-170. Peritremes: longitudinal branch with 13-14 chambers, lateral with 4 chambers. Length of setae: vi 32-36, ve 50-56, sci 74-80, sce 120-135, h 90-100, d1 135-140, d2 13-22, d5 20-22, l1 24-45, l2 13-22, l5 180-200, pg1 90-110, pg2 70-90. S. glandarii is closely related to S. presentalis Chirov et Kravsova, 1995. It is distinguished from the latter species by following characters. In female S. glandarii, setae vi, ve are thick and serrate, ve 87-96 in length. In female S. presentalis, setae vi, ve are thin and nude, ve 40-70 in length. Syringophiloidus delichonum sp. n., female (holotype): body length 900, width 135. Peritremes: longitudinal branch with 8 chambers, lateral--with 1-2 chambers. All setae nude. Length of setae: vi 45, ve 90, sci 200, sce 200, h 225, d2 90, d4 35, d5 33, l1 140, l2 ?, 155-160 in paratypes, l4 230, l5 320, pg1 135, pg2 120, pg3 170, g1, g2 40, a1, a2 17. Male Body length 506, width 135. Peritremes: longitudinal branch with 9 chambers, lateral with 2 chambers. Length of setae; vi 33, ve 78, sci 90, sce 123, h 130, d1 135, d2 15, d5 17, l1 22, l2 15, l5 180, pg1 105, pg2 45. S. delichonum sp. n. is closely related to S. presentalis, but differs by following characters. In female S. delichonum sp. n., body length is 850-920; longitudinal branch of peritreme includes 6-8 chambers; setae ve 85-90 in length; in male, longitudinal branch of peritreme include 9 chambers. In female S. glandarii, body length 630-700; longitudinal branch of peritreme include 10-11 chambers; setae ve 40-70 in length; in male, longitudinal branch of peritreme include 11-13 chambers.     

Occurrence and fate of fetal lumbar rib induced by Scutellariae radix in rats

BACKGROUND: This study was conducted to evaluate the occurrence and fate of fetal lumbar rib induced by Scutellariae radix (SR) in rats. METHODS: Water extracts of SR were orally administered to pregnant rats from day 7 to day 17 of gestation at a dose of 186 mg/kg/day, equivalent to 25 g/kg of starting material, representing a 100‐fold increase over typical human intake level. RESULTS: The incidence of fetal lumbar rib in the SR‐treated group was increased on gestational day 20 and then decreased on postnatal day 50. The weight of fetuses in the SR‐treated group tended to be less than that in the control group. Alkaline phosphatase in SR‐treated dams was increased on gestational day 20, but was decreased on postnatal day 50. There were no significant differences between the vehicle control and SR‐treated groups in maternal body weight, embryological, histopathological, hematological, and serum biochemical changes. CONCLUSIONS: The present data suggest that the appearance of lumbar rib induced by SR is a transient fetal variation rather than teratogenicity or maternal toxicity. Birth Defects Res (Part B) 89:201–206, 2010. © 2010 Wiley‐Liss, Inc.     

Evaluation of the developmental toxicity of lenalidomide in rabbits

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Betel Nut Chewing Is Strongly Associated With General and Central Obesity in Chinese Male Middle‐aged Adults

Betel nut chewing has been reported to increase the risk of cardiovascular disease and all‐cause mortality. The reason is unclear. In this study, we investigated the association between betel nut chewing and general obesity (BMI ≥25 kg/m²) and central obesity (waist circumference (WC) ≥90 cm). A total of 1,049 male subjects, aged ≥40 years, were recruited from Taichung city in Taiwan in 2004. The relationships between betel nut chewing and general and central obesity were studied by multiple linear and logistic regression analyses. The prevalence of current and former betel nut chewing was 7.0 and 10.5% in our male Taiwanese cohort. Current/former betel nut chewers had a higher prevalence of general and central obesity when compared with individuals who had never chewed betel nut. Adjusted for age, diabetes, hypertension, lipids, smoking, alcohol drinking, physical activity, income, and education level, the odds ratios (ORs; 95% confidence intervals) of general and central obesity among the lower consumption of betel nut chewers were 1.78 (1.07, 2.96) and 1.19 (0.70, 2.02), respectively, compared to 2.01 (1.18, 3.41) and 1.89 (1.10, 3.23), respectively, among higher consumption chewers compared to individuals who had never chewed betel nut. The increasing ORs of general and central obesity with higher betel nut consumption revealed dose–response effects. Using multiple linear regression analyses, after adjusting for potential confounders, betel nut consumption was statistically significantly associated with BMI and WC. In conclusion, betel nut chewing was independently associated with general and central obesity in Taiwanese men. Dose–response effects of the association between betel nut consumption and general obesity as well as central obesity were found.     

Different embryo-fetal toxicity effects for three VLA-4 antagonists

BACKGROUND: VLA‐4 (Very late antigen 4, integrin α₄β₁) plays an important role in cell‐cell interactions that are critical for development. Homozygous null knockouts of the α₄subunit of VLA‐4 or VCAM‐1 (cell surface ligand to VLA‐4) in mice result in abnormal placental and cardiac development and embryo lethality. Objectives of the current study were to assess and compare the teratogenic potential of three VLA‐4 antagonists. METHODS: IVL745, HMR1031, and IVL984 were each evaluated by the subcutaneous route in standard embryo‐fetal developmental toxicity studies in rats and rabbits. IVL984 was also evaluated in mice. Fetuses were examined externally, viscerally, and skeletally. RESULTS: IVL745 did not cause significant maternal or fetal effects at doses up to 100 or 250 mg/kg/day in rats or rabbits, respectively. HMR1031 treatment resulted in marked maternal toxicity and slight fetal toxicity at the highest tested doses of 200 and 75 mg/kg/day in rats and rabbits, respectively. HMR1031 embryo‐fetal effects consisted of slightly lower body weight and crown‐rump length in rats and minor sternebral defects in rabbits. IVL984 treatment resulted in minimal maternal effects at doses up to 40, 15, and 100 mg/kg/day in rats, rabbits, and mice, respectively (excluding abortions in rabbits). However, marked developmental effects were observed at the lowest tested IVL984 doses, 1, 0.2, and 3 mg/kg/day in rats, rabbits, and mice, respectively. IVL984 embryo‐fetal effects consisted of increased total post‐implantation loss due to early resorptions and high incidences of cardiac malformations and skeletal malformations and/or variations. Notably, spiral septal defects were observed in up to 76% of rat fetuses and up to 58% of rabbit fetuses. CONCLUSIONS: Dramatic differences in teratogenic potential were observed: IVL745 was not teratogenic, HMR1031 caused slight embryo‐fetal effects at maternally‐toxic doses, and IVL984 was a potent teratogen at doses where direct maternal toxicity was limited to abortions in rabbits. Prominent effects of IVL984 included embryo lethality and cardiac malformations including spiral septal defects in three species. Birth Defects Res B 71:55–68, 2004. © 2004 Wiley‐Liss, Inc.     

Comparison of the behavioral teratogenic potential of phenytoin, mephenytoin, ethotoin, and hydantoin in rats.

Pregnant Sprague-Dawley CD rats were orally administered either phenytoin (PHT, 200 mg/kg), mephenytoin (MPH, 100 mg/kg), ethotoin (ETH, 600 mg/kg), hydantoin (HYD, 1,200 mg/kg) or vehicle (propylene glycol) on days 7-18 of gestation. Mean (+/- S.E.) maternal serum concentrations of PHT, MPH, and ETH 1 hour after dosing on gestational day 18 were 16.0 +/- 3.3, 10.7 +/- 3.0, and 65.2 +/- 10.45, respectively, and free fractions were 16%, 18%, and 11% respectively. The free fraction for PHT is similar, but was lower for both MPH and ETH than that seen in humans. Preweaning mortality for PHT, MPH, ETH, HYD, and controls was 25%, 6.3%, 12.5%, 2.0% and 0.8%, respectively. The MPH and ETH-exposed animals weighed approximately 6.6% less than controls throughout the study; the other groups did not differ significantly. PHT offspring showed increased early locomotor activity. Only PHT-exposed animals (27%) exhibited abnormal circling behavior after weaning. PHT-circlers accounted for higher levels of activity in an open-field test and for longer straight channel swimming times. PHT-circlers and noncirclers differed from one another and controls on performance of a complex (Cincinnati) maze and on the development of the air-righting reflex. Offspring prenatally exposed to MPH showed an early delay in air-righting. ETH and HYD offspring were not consistently different from controls in behavior. The data suggest the following ordinal relationship among the drugs for behavioral teratogenesis: PHT much greater than MPH greater than ETH congruent to HYD congruent to CON. The effects of PHT are consistent with previous findings. Data on the other drugs suggest that other hydantoins do not possess the behavioral teratogenic efficacy of PHT and that PHT may be unique in its effects on CNS development.     

Monitoring and assessment of ingestive chewing sounds for prediction of herbage intake rate in grazing cattle

Accurate measurement of herbage intake rate is critical to advance knowledge of the ecology of grazing ruminants. This experiment tested the integration of behavioral and acoustic measurements of chewing and biting to estimate herbage dry matter intake (DMI) in dairy cows offered micro-swards of contrasting plant structure. Micro-swards constructed with plastic pots were offered to three lactating Holstein cows (608±24.9 kg of BW) in individual grazing sessions (n=48). Treatments were a factorial combination of two forage species (alfalfa and fescue) and two plant heights (tall=25±3.8 cm and short=12±1.9 cm) and were offered on a gradient of increasing herbage mass (10 to 30 pots) and number of bites (~10 to 40 bites). During each grazing session, sounds of biting and chewing were recorded with a wireless microphone placed on the cows’ foreheads and a digital video camera to allow synchronized audio and video recordings. Dry matter intake rate was higher in tall alfalfa than in the other three treatments (32±1.6 v. 19±1.2 g/min). A high proportion of jaw movements in every grazing session (23 to 36%) were compound jaw movements (chew-bites) that appeared to be a key component of chewing and biting efficiency and of the ability of cows to regulate intake rate. Dry matter intake was accurately predicted based on easily observable behavioral and acoustic variables. Chewing sound energy measured as energy flux density (EFD) was linearly related to DMI, with 74% of EFD variation explained by DMI. Total chewing EFD, number of chew-bites and plant height (tall v. short) were the most important predictors of DMI. The best model explained 91% of the variation in DMI with a coefficient of variation of 17%. Ingestive sounds integrate valuable information to remotely monitor feeding behavior and predict DMI in grazing cows.