Growth curves of body weight and their relationship to sexual maturity in laboratory-bred male African green monkeys (Cercopithecus aethiops)

Nonlinear growth models having a three- or four-parameter family were applied to individual body weight data of 5 male African green monkeys for estimating their growth patterns. Body weight was measured from birth to six years of age and 58 to 114 data items per monkey were collected. The average body weight at birth was 360g with the standard deviation of +/- 25g, 4.54 +/- 0.29 kg at five years of age, and 4.50 +/- 0.12 kg at six years of age at which point body weight was judged to have reached a plateau. Five growth models (Gompertz, Logistic, Richards, Bertalanffy and Brody) were applied to the growth data in this study. As a result, two (Gompertz and Logistic) of the five models were found applicable to all data from the five monkeys. However, the coefficient of determination (R2) obtained by application of the two models were not so large (0.919 +/- 0.05 in Gompertz, 0.889 +/- 0.01 in Logistic). Therefore the data were divided into two groups according to monkey age: the first group being from monkeys between birth and 2 years 10 months of age and the second group was from monkeys older than 2 years 10 months of age. The Gompertz model fitted best the data of the first group in four of the five animals (R2 = 0.982 +/- 0.011). The age at the inflexion point in the Gompertz model nearly corresponded to the age of weaning. The Logistic model was most suitable for the date of the second group in all five animals (R2 = 0.955 +/- 0.038).(ABSTRACT TRUNCATED AT 250 WORDS)     

Beneficial effects of co-treatment with dextromethorphan on prenatally methadone-exposed offspring

Background

Heroin use among young women of reproductive age has drawn much attention around the world. Although methadone is widely used in maintenance therapy for heroin/morphine addiction, the long-term effects of prenatal exposure to methadone and preventative therapy remain unclear. For revealing this question, female pregnant Sprague–Dawley rats were sub-grouped to receive (1) vehicle, (2) methadone 5 mg/kg at embryonic day 3 (E3) and then 7 mg/kg from E4 to E20, (3) dextromethorphan (DM) 3 mg/kg, and (4) methadone + DM (the rats received methadone followed by DM treatment), subcutaneously, twice a day from E3 to E20. The body weight, natural withdrawal, pain sensitivity, ED50, conditioned place preference and water maze were conducted at different postnatal stages (P1 to P79) of offspring. The quantitative real-time RT-PCR and electrophysiology were also used to measure the gene expression of opioid receptors in the spinal cord and changes of LTP/LTD in the hippocampus, separately.

Results

Prenatal exposure to methadone or DM did not affect survival rate, body weight, water maze and LTP or LTD of offspring. However, prenatal methadone significantly increased the withdrawal symptoms, pain sensitivity, addiction liability and decreased the mRNA expression of pain related opioid receptors. Co-administration of DM with methadone in the maternal rats effectively prevented these abnormalities of offspring induced by methadone.

Conclusions

Our study clearly showed that co-administration of dextromethorphan with methadone in the maternal rats prevented the adverse effects induced by prenatal methadone exposure. It implies that dextromethorphan may have a potential to be used in combination with methadone for maintenance treatment in pregnant heroin-addicted women to prevent the adverse effects induced by methadone on offspring.

Electronic supplementary material

The online version of this article (doi:10.1186/s12929-015-0126-2) contains supplementary material, which is available to authorized users.     

Small weight gain is not associated with development of insulin resistance in healthy, physically active individuals.

We investigated whether weight gain alters insulin sensitivity and leptin levels in physically active individuals. Six (5 males and 1 female; age 26.6+/-1.0 years; BMI 21.5+/-0.9, body fat 17.4+/-2.2%) healthy individuals were enrolled in an overfeeding study (caloric surplus 22.5-26.5 kcal/kg/day) to achieve up to 10% weight gain over 4-6 week period with subsequent weight maintenance over additional 2 weeks. The participants were requested to maintain their previous physical activity which in all of them included 45-60 min training sessions at the gym 2-3 times/week. RESULTS: BMI increased to 23.4+/-0.9 (4.4 kg weight gain; p<0.05) and body fat to 21.0+/-2.8% (p < 0.05) over the period of active weight gain and remained stable over the two week period of weight maintenance; fasting plasma glucose and serum insulin remained unchanged; serum leptin nearly doubled (3.8+/-1.0 vs 6.4+/-1.9 ng/ mL; p < 0.05); insulin sensitivity, when expressed per kg of the total body (11.1+/-1.6 vs 12.4+/-2.1 mg/kg/min; p = NS), and lean body mass (13.4+/-1.9 vs 15.7+/-2.6 mg/kgLBM/min; p = NS), did not decrease after weight gain. On the contrary, insulin action had improved in 5 out of 6 individuals. In conclusion, the data presented in this preliminary report indicate that a small weight gain due to overfeeding in lean, healthy, physically active individuals is associated with rise in circulating leptin levels but not with worsening of insulin action.     

Evaluation of developmental toxicity in rats exposed to the environmental estrogen bisphenol A during pregnancy.

Bisphenol A (BPA) is an essential component of epoxy resins used in the lacquer lining of metal food cans, as a component of polycarbonates, and in dental sealants. The present study was conducted in an attempt to evaluate the adverse effects of the environmental estrogen BPA on initiation and maintenance of pregnancy and embryofetal development after maternal exposure during the entire period of pregnancy in Sprague-Dawley rats. The test chemical was administered by gavage to mated females from days 1 to 20 of gestation (sperm in varginal lavage = day 0) at dose levels of 0, 100, 300, and 1000 mg/kg. All females were subjected to caesarean section on day 21 of gestation and their fetuses were examined for external, visceral and skeletal abnormalities. In the 1000 mg/kg group, significant toxic effects including abnormal clinical signs, decreased maternal body weight and body weight gain, and reduced food consumption were observed in pregnant rats. An increase in pregnancy failure was also found in the successfully mated females. In addition, increased number of embryonal deaths, increased postimplantation loss, reduced litter size and fetal body weight, and decreased number of fetal ossification centers of several skeletal districts were seen. On the contrary, no significant changes induced by BPA were detected in the number of corpora lutea and implantation sites and by fetal morphological examinations. In the 300 mg/kg group, suppressed maternal body weight and body weight gain, decreased food intake and reduced body weight of male fetuses were seen. There were no adverse signs of either maternal toxicity or developmental toxicity in the 100 mg/kg group. It was concluded that BPA administration during the entire period of pregnancy in rats produced pregnancy failure, pre- and postimplantation loss, fetal developmental delay and severe maternal toxicity, but no embryo-fetal dysmorphogenesis at an oral exposure level of 1000 mg/kg.     

Repeated administration of naltrexone and diprenorphine decreases food intake and body weight in squirrel monkeys

Although chronic administration of naloxone has been reported to reduce food intake and body weight in rats, there have been no comparable investigations using a nonhuman primate. We examined the effects of repeated injections of two long acting opiate antagonists - naltrexone and diprenorphine - on the ad libitum intake of a nutritional complete liquid diet and on body weight in squirrel monkeys. Naltrexone binds with highest affinity to the mu opioid receptor whereas diprenorphine binds with equally high affinity to several subtypes of opioid receptor. Diprenorphine (ED50 = 0.01 mg/kg) was 22 times more potent than naltrexone (ED50 = 0.22 mg/kg) in decreasing 2 h food intake, suggesting that more than one opioid receptor subtype may be involved in the anorectic effects of opiate antagonists. A 1.0 mg/kg dose of drug reduced 24 h food intake by 50% and was associated with a weekly reduction in body weight of 4 and 5% for naltrexone and diprenorphine, respectively. Thus, in contrast with shorter time intervals, 24 h food intakes were similar for the two drugs, and this was associated with comparable body weight profiles. The decreases in food intake and body weight remained constant over the period of drug administration. Some monkeys showed profuse salivation and "wet dog shakes" after 4 days of treatment with the 1.0 mg/kg dose but not after 1 day. Therefore, opiate antagonists given chronically to monkeys reduced food intake and body weight in a dose-dependent manner with no evidence of tolerance to these effects.     

多囊卵巢综合征猕猴的生殖特性(英文)

多囊卵巢综合征(PCOS)是临床上常见的一种内分泌失调性疾病,也是造成无排卵性不孕的重要原因。对多囊卵巢综合征动物模型的研究有10余年,迄今尚未建立起较为理想的模型动物。该研究的目的在于构建猕猴多囊卵巢综合征动物模型,并分析该模型动物的一些主要生殖特性。将6只成年雌性猕猴(6～10a)平均分成2组:PCOS模型组和对照组。模型组动物的建立方法是:在月经周期的第1、3、5天,分别皮下注射丙酸睾丸酮一次,剂量为3.5mg/kg体重;接着在第7、9、11天,分别肌注人绒毛膜促性腺激素一次,剂量是350IU/kg体重;连续注射2个月经周期。对照组动物注射生理盐水。结果显示:PCOS模型组动物呈现出高血清LH和T,分别为(5.35±0.17)IU/L和(7.58±0.14)ng/mL,而且血清LH/FSH值(5.35/1.30=4.12);模型组动物血清FSH、E2和P的含量与对照组无显著差异。腹部B超扫描结果提示,模型组动物卵巢多囊化。对两组动物进行超排处理后,模型组动物卵巢呈明显的过刺激现象,模型组动物胚胎体外培养的囊胚率为23.53%,显著低于对照组(66.67%)(P<0.05),即用丙酸睾丸酮联合人绒毛膜促性腺激素,能够建立PCOS猕猴模型,该模型动物的一些主要生殖特性与人类PCOS相似。     

Effect of continuous infusions of dexfenfluramine on food intake, body weight and brain amines in rats

The present experiments describe the effects of continuous SC infusion, via osmotic minipump, of dexfenfluramine on food intake and body weight of male and female rats. It was found that the food intake of male rats was reduced by infusions of both 3 and 6 mg/kg/day although tolerance developed within 2-4 days at the lower dose. Further, these rats showed tolerance to an acute anorectic test dose of dexfenfluramine. Body weight loss was sustained by both groups. In older (6-8 mo old) female rats, some of which had previously nursed three litters, the anorectic effects of dexfenfluramine (3 and 6 mg/kg/day) were sustained throughout the 6 day infusion, and weight loss was substantial. The effects did not differ between bred and virgin rats of comparable age. The lower dose of dexfenfluramine produced no depletion of brain serotonin (5HT), although 5HIAA was reduced. Both compounds were depleted by the higher dose. The 3 mg/kg/day dose, in select rat populations, may be a close model for the mode of dexfenfluramine administration to humans.     

Developmental and reproductive toxicity studies on artemisone

BACKGROUND: In order to justify clinical studies in women of child-bearing age with artemisone, a new artimisinin derivative, studies to assess fertility and early embryonic development in rats, developmental toxicity in rats and rabbits, and peri-post natal development in rats were performed. METHODS AND RESULTS: In the study on fertility and early embryonic development (dose levels 0-5-20-80 mg/kg bw/day), doses inducing clinical and organ toxicity were used. Only in severe toxicity conditions, a reduction of the number of estruses, a prolonged time to insemination, decreased numbers of corpora lutea, implantation sites, and viable fetuses were found. Two developmental toxicity studies were performed in rats (dose levels 0-1-2 mg/kg bw/day) and rabbits (dose levels 0-2.5-5.0-7.5 mg/kg bw/day). It was shown that rats were about 5 times more sensitive than rabbits. In rats, artemisone induced total litter loss (late resorptions) at 2 mg/kg body weight and above with an increased incidence of a common vascular variation and retarded ossification at this dose. In rabbits, maternal toxicity, abortion and a slightly increased incidence of cardiac ventricular septal defects was observed at 7.5 mg/kg body weight. In a pre- and postnatal developmental toxicity study in rats (dose levels 0-1-2-4 mg/kg bw/day), 4 mg/kg body weight artemisone induced clinical symptoms and affected postnatal survival, body weight gain in the F1 pups, and motor activity. CONCLUSIONS: In summary, artemisone was shown to be embryo- and fetotoxic and induced cardiac ventricular septal defects and retarded ossification in dosages where total litter loss and abortions were observed. However, no effect on reproductive and developmental parameters below severe toxic dosages could be observed. Birth Defects Res (Part B)86: 131-143, 2009. © 2009 Wiley-Liss, Inc.     

Effects of feeding level and protein content of milk replacer on the performance of dairy herd replacements

It has been suggested that United Kingdom recommendations for feeding the neonatal calf (500 g milk replacer (MR)/day; 200-230 g CP/kg milk powder) are inadequate to sustain optimal growth rates in early life. The current study was undertaken with 153 high genetic merit, male and female Holstein-Friesian calves (PIN2000 = ￡48) born between September and March, with heifers reared and bred to calve at 24 months of age. Calves were allocated to one of four pre-weaning dietary treatments arranged in a 2 MR feeding level (5 v. 10 l/day) × 2 MR protein content (210 v. 270 g CP/kg dry matter (DM)) factorial design. MR was reconstituted at a rate of 120 g/l of water, throughout, and was offered via computerised automated milk feeders. Calves were introduced to pre-weaning diets at 5 days of age and weaned at day 56. During the first 56 days of life, calves offered 10 l MR/day had significantly higher liveweight gains (P < 0.001) than calves fed 5 l MR/day. No significant differences in liveweight gain were found between calves fed 210 g CP/kg DM MR and those fed 270 g CP/kg DM MR from birth to day 56. Differences in live weight and body size due to feeding level disappeared by day 90. Neither MR feeding level nor MR CP content affected age at first service or age at successful service, and with no milk production effects, the results indicate no post-weaning benefits of increased nutrition during the milk-feeding period in dairy heifers.     

Deposition of copper, iron, manganese and zinc in the empty body of growing lambs of the breed German Merino Landsheep

A growth experiment with 108 lambs (breed: German Merino Landsheep) was carried out to examine the effect of gender, body weight (BW) and feeding intensity on the deposition of Fe, Zn, Cu and Mn in the empty body (whole animal minus contents of the gastrointestinal tract and bladder). The lambs (50% female and 50% male animals) were fed at three feeding levels ('low', 'medium' and 'high' by varying daily amounts of concentrate and hay) and slaughtered at different final BWs (30, 45 or 55 kg). Six male and six female animals were killed at a BW of 18 kg representing the animals' BW at the beginning of the comparative slaughter experiment. There were significant main effects for the treatments growth rate and final weight on the daily rate of accretion of the trace elements examined. Feeding intensity had a marked influence on the accretion rate for Fe (P < 0.001), Zn (P < 0.001), Cu (P < 0.001) and Mn (P = 0.003). With increasing feeding intensity (low, medium, high) the daily deposition of these trace elements increased (4.4, 5.2, 6.6 mg/day for Fe; 4.9, 5.5, 6.9 mg/day for Zn; 0.20, 0.36, 0.44 mg/day for Cu; 0.14, 0.16, 0.21 mg/day for Mn). Heavier final BW led to increased daily retention of Zn (P < 0.001) and Mn (P = 0.002). Gender had a marked influence only on the accretion rate for Zn (P < 0.001). Ram lambs had a higher daily deposition of this element than female lambs. Related to 1000 g empty body gain, the following concentrations were found for the trace elements examined: Fe 26.1 mg, Zn 30.0 mg, Cu 1.41 mg and Mn 1.04 mg. A feeding influence was given for Zn (P < 0.001) and Cu (P = 0.039). Feeding level low had higher Zn and lower Cu concentrations. Male animals showed less Fe (P < 0.001) and Zn (P = 0.034) per kg empty body gain than females.     

Maternal and developmental toxicity of low doses of cytosine arabinoside in mice

1-beta-D-Arabinofuranosylcytosine (Ara-C), an effective drug for the treatment of leukemia and breast cancer, was evaluated for developmental toxicity in pregnant Swiss mice. Ara-C was administered by intraperitoneal injection on gestational days 6-15 at doses of 0, 0.5, 2, and 8 mg/kg/day. Maternal observations included clinical signs, body weight change, food consumption, and gross evaluation of organs and uterine contents at necropsy (day 18). Live fetuses were examined for external, visceral, and skeletal alterations. Maternal toxicity was observed at 2 and 8 mg/kg/day, as evidenced by a significant decrease in body weight gain and food consumption during the treatment period. Significantly increased early and late resorptions and reduced number of live fetuses per liter as well as decreased fetal body weight were observed at 8 mg/kg/day. At 2 mg/kg/day, the incidence of cleft palate, renoureteral agenesis or hypoplasia, and poly- or oligodactyly was significantly increased, whereas fetal weight was reduced at 0.5 mg/kg/day. Thus, the developmental no-observed-adverse-effect-level (NOAEL) of Ara-C in the pregnant mouse is lower than 0.5 mg/kg/day, while the NOAEL for maternal toxicity is 0.5 mg/kg/day. We believe that exposure to this agent ought to be avoided during organogenesis.     

Effect of chronic infusion of olanzapine and clozapine on food intake and body weight gain in male and female rats

Many antipsychotics cause weight gain in humans, but usually not in rats, when injected once or twice daily. Since blood antipsychotic half-lives are short in rats, compared to humans, chronic administration by constant infusion may be necessary to see consistent weight gain in rats. Male and female rats were implanted with mini-pumps for constant infusion of olanzapine (5 mg/kg/day), clozapine (10 mg/kg/day) or vehicle for 11 days. Food intake and body weight were measured; blood drug levels were measured by HPLC. Olanzapine increased food intake and body weight in female, but not male rats. Serum olanzapine concentrations were 30-35 ng/ml. Clozapine had no effect on food intake or body weight in female or male rats. Serum clozapine concentrations were about 75 ng/ml. Single-dose pharmacokinetic analysis revealed a serum terminal half-life of 1.2-1.5 h for each drug, with no sex differences. Despite the fact that olanzapine and clozapine promote weight gain in humans, these drugs appear to have minimal effects on body weight and food intake in rats, except for a modest effect of olanzapine in female rats, even though therapeutic levels of olanzapine are achieved in serum during chronic infusion. Hence, the rapid clearance of drug following single administration in previous studies cannot explain the weak or absent effects of antipsychotics on weight gain in this species. The rat thus appears to be an inadequate model of weight gain produced by some antipsychotics in humans.     

Influence of maternal nicotine exposure on neonatal rat bone: protective effect of pentoxifylline

Limited research in young adults and immature animals suggests a detrimental effect of tobacco on bone during growth. The aim of this study was to determine the adverse effects of maternal nicotine exposure during pregnancy and lactation on neonatal rat bone development, and to determine a protective effect of pentoxifylline (PTX). Gravid rats were assigned into four groups, one control (group I) and three experimental (groups II, III, and IV). In group II, pregnant rats received 3 mg/kg/day nicotine alone, subcutaneously, until 21 days postnatal. In group III, pregnant rats received nicotine (3 mg/kg/day) and PTX (60 mg/kg/day). In group IV, pregnant rats received PTX alone (60 mg/kg/day). Whole body mineral density (BMD), content (BMC), area (BA), and histopathologic and morphologic findings of the femur were determined at 21 days of age. The study revealed that nicotine exposure (group II) decreased birth weight, pregnancy weight gain, and length of femur compared with other groups (P < 0.01). Birth weight was higher in groups III (PTX + nicotine) and IV (PTX) than in group II (nicotine). Body weight at 21 days of age was higher (P = 0.009) in the PTX alone group (group IV) compared with the other groups. BMD was higher (P < 0.001) in the PTX-treated groups (group III and IV) compared with other groups. In addition, there were more apoptotic chondrocytes in the hypertrophic zone of rats exposed to nicotine alone (group II) compared with the other groups (P < 0.001). In conclusion, maternal nicotine exposure resulted in decreased birth weight, pregnancy weight gain, and bone lengthening, and increased apoptosis. Pentoxifylline supplementation was found to prevent the adverse effects of maternal nicotine exposure on BMD and birth weight.     

Prevention of diet-induced obesity and impaired glucose tolerance in rats following administration of leptin to their mothers

Absence of leptin is known to disrupt the development of energy balance regulatory mechanisms. We investigated whether administration of leptin to normally nourished rats affects energy balance in their offspring. Leptin (2 mg.kg(-1).day(-1)) was administered from day 14 of pregnancy and throughout lactation. Male and female offspring were fed either on chow or on high-fat diets that elicited similar levels of obesity in the sexes from 6 wk to 15 mo of age. Treatment of the dams with leptin prevented diet-induced increases in the rate of weight gain, retroperitoneal fat pad weight, area under the intraperitoneal glucose tolerance curve, and fasting plasma insulin concentration in female offspring. In the male offspring, the diet-induced increase in weight gain was prevented and increased fat pad weight was reduced. Energy intake per rat was higher in response to the obesogenic diet in male offspring of saline-treated but not leptin-treated dams. A similar trend was seen in 3-mo-old female offspring. Energy expenditure at 3 mo of age was higher for a given body weight in female offspring of leptin-treated compared with saline-treated dams when these animals were fed on the obesogenic diet. A similar trend was seen for male rats fed on the obesogenic diet. Thus leptin levels during pregnancy and lactation can affect the development of energy balance regulatory systems in their offspring.     

Growth retardation in premenarchial female rhesus monkeys during chronic administration of a GnRH agonist (leuprolide acetate)

Abstract: Leuprolide acetate in depot form (0.75 mg/kg body weight/month, im) was administered to four female rhesus monkeys from 18–30 months of age, a period that includes the premenarchial growth spurt. They were compared to eight age matched controls. As anticipated, sexual maturation was blocked in the Leuprolide group and menarche did not occur. Growth was also severely retarded; no weight gain occurred during the study in the Leuprolide group as compared to a 25% weight gain (P = .004) in the control group. The Leuprolide group also lost muscle mass. Food intake normalized for body weight was not affected. Linear growth averaged 35% less in the Leuprolide group. Serum IGF-1 concentrations increased from 486±84 to 965±47 ng/mL (P = .0025) in the Leuprolide group and from 838±139 to 3,006±545 ng/mL (P = .0016) in the control group. These data suggest that premenarchial pituitary/gonadal suppression results in a distinctive pattern of growth retardation in monkeys.     

Increased Food Intake and Energy Expenditure Following Administration of Olanzapine to Healthy Men

Atypical antipsychotic medications like olanzapine (OLZ) induce weight gain and increase the risk of diabetes in patients with schizophrenia. The goal of this study was to assess potential mechanisms of OLZ‐induced weight gain and accompanying metabolic effects. Healthy, lean, male volunteers received OLZ and placebo (PBO) in a randomized, double‐blind, crossover study. In periods 1 and 2, subjects received OLZ (5 mg for 3 days then OLZ 10 mg for 12 days) or matching PBO separated by a minimum 12‐day washout. Twenty‐four hour food intake (FI), resting energy expenditure (REE), activity level, metabolic markers, and insulin sensitivity (IS) were assessed. In total, 30 subjects were enrolled and 21 completed both periods. Mean age and BMI were 27 years (range: 18–49 years) and 22.6 ± 2.2 kg/m², respectively. Relative to PBO, OLZ resulted in a 2.62 vs. 0.08 kg increase in body weight (P < 0.001) and 18% (P = 0.052 or 345 kcal) increase in FI. Excluding one subject with nausea and dizziness on the day of OLZ FI measurement, the increase in FI was 547 kcal, (P < 0.05). OLZ increased REE relative to PBO (113 kcal/day, P = 0.003). Significant increases in triglycerides, plasminogen activator inhibitor‐I (PAI‐I), leptin, and tumor necrosis factor‐α (TNF‐α) were observed. No significant differences in activity level or IS were observed. This study provides evidence that OLZ pharmacology drives the early increase in weight through increased FI, without evidence of decreased energy expenditure (EE), activity level, or short‐term perturbations in IS.     

Exogenous hypercortisolism and epididymal fat cell count in young rats.

The influence of two different grades of exogenous hypercortisolism on body weight, epididymal fat pad weight and the total number of fat cells in epididymal fat pads was investigated in young, growing rats. Cortisol, 4-5 mg/kg/day orally from the 7th to the 9th week, reduced body weight gain, whereas epididymal fat pad weight and fat cell content did not differ from those of the control rats. Cortisone acetate, 2.5 mg per 100 g, given subcutaneously for 2 weeks to rats 4-11 week of age caused in the young rat (4-6 weeks) a partial inhibition of the normal increase in body weight, whereas in the young-adult rat (6 weeks and older) an actual decrease of body weight was seen. At both dose levels and - with respect to the higher dose level- in all age groups studied, the weight and fat cell content of the epididymal fat pad were not changed by the cortisone (cortisol) treatment.     

Complications of systemic corticosteroid therapy for problematic hemangioma.

Systemic corticosteroid therapy has been used to treat hemangiomas for 30 years; yet, there are no studies of possible complications. We reviewed the database of the Vascular Anomalies Center at the Boston Children's Hospital and gathered information on short- and long-term side effects in children who were given systemic corticosteroids for problematic hemangiomas. In addition, a questionnaire regarding early and late consequences was sent to the families of children who were treated with corticosteroids from 1983 to 1997. Of 300 patients with hemangiomas, 80 children were identified as having received a full course of systemic corticosteroids for problematic tumors. Complete data were collected on 62 of these children. The response rate to the questionnaire was 78 percent (n = 62 of 80). The initial dose of corticosteroid varied from 2 to 3 mg/kg/ day. Duration of therapy ranged from 2 to 21 months (mean, 7.9 months; median, 6.5 months). The follow-up interval from the cessation of therapy ranged from 6 months to 15 years (mean, 4 years; median, 3 years). Short-term complications included cushingoid facies (n = 44; 71 percent), personality changes (n = 18; 29 percent), gastric irritation (n = 13; 21 percent), fungal (oral or perineal) infection (n = 4; 6 percent), and diminished gain of height (n = 22; 35 percent) and weight (n = 26; 42 percent). A total of 91 percent of children who had diminished gain of height (n = 20) returned to their pretreatment growth curve for height by 24 months of age. One child, who was treated at another institution with a dose of 20 mg/kg/day for 6.5 months that was slowly tapered over 18 months, was petite 6 years after ending therapy. Another child treated with an initial dose of 2 mg/kg/day for 5 months was smaller than predicted at the age of 6 years, but she was born prematurely and was on ventilatory support for respiratory distress. Three children treated with the standard dose and duration were at a low percentile for weight 4, 5, and 10 years after the cessation of therapy. Statistical analysis showed a correlation between diminished gain of height with duration of therapy and age at initiation of treatment. One child had corticosteroid myopathy that resolved with cessation of therapy. We found no evidence for immunologic suppression, i.e., there was no increase in the number of bacterial infections during corticosteroid administration. In conclusion, systemic corticosteroids can be safely given to treat endangering hemangiomas in infants at doses of 2 to 3 mg/kg/day, which are slowly tapered and stopped before the age of 1 year. Short-term side effects were minor and transient, and no serious long-term complications occurred.     

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

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

Antioxidant effects of Emblica officinalis and Zingiber officinalis on arsenic and lead induced toxicity on Albino rats

It is of interest to document the effect of Emblica officinalis (E. officinalis) and Zingiber officinalae (Z. officinalae) leaf extract on reactive oxygen species, antioxidant potential changes in arsenic and lead-induced toxicity in male rats. We used 8 groups of adult male Wistar rats with 1 control group for this study. The animals were divided into Group I: Control and Group II: Lead and sodium arsenite induced rats (animals were induced for metal toxicity by the combined administration of arsenic (13.8 mg/ kg body weight) and lead (116.4 mg/kg body weight). These doses were administered by gastric intubation during 14 consecutive days using known standard procedures. Arsenic and lead induced rats treated with ethanolic extract of Emblica officinalis (60 mg/kg body weight/day, orally for 45 days) are group III rats. Group IV animals are arsenic and lead induced rats treated orally with ethanolic extracts of E. officinalis (120 mg/kg body weight/day for 45 days). Group V animals are arsenic and lead induced rats treated orally with ethanolic extracts of Z. officinalae (60 mg/kg body weight/day for 45 days). Group VI animals are arsenic and lead induced rats orally treated with ethanolic extracts of Zingiber officinalis (120 mg/kg body weight/day for 45 days). Group VII animals are arsenic and lead induced rats treated orally with ethanolic extracts of E. officinalis and Z. officinalae (60 + 60 mg/kg body weight/day for 45 days). Group VIII animals are arsenic and lead induced rats treated orally with ethanolic extracts of E. officinalis and Z. officinalae (120 + 120 mg/kg body weight/day, orally for 45 days). Normal Control animals were treated orally with ethanolic extracts of E. officinalis (120mg/kg body weight) + Z. officinalae (120mg/kg body weight) for 45 days. The control and experimental animals were then subjected to analysis for oxidative stress markers such as H2O2, *OH, and lipid peroxidation (LPO), antioxidant enzymes in addition to liver and kidney function markers. Results: Arsenic and lead induced rats showed a significant increase in the levels of reactive oxygen species (H2O2, OH* and LPO) with concomitant alterations in the renal and liver tissues. However, enzymic and non-enzymic antioxidant levels were decreased. Nevertheless, an oral effective dose of E. officinalis and Z. officinalae (120 + 120 mg/kg body weight/day increased the antioxidant enzymes and retrieved the altered levels of ROS and LPO that were induced by arsenic and lead. Thus, we show that E. officinalis and Z. officinalae leaf extract exhibits nephroprotective and hepatoprotective role through the restoration of reactive oxygen species and antioxidant enzymes in the kidney and liver tissue of Arsenic and Lead-induced nephrotoxicity and hepatotoxicity in rats. Hence, E. officinalis and Z. officinalae leaf extract are potential therapeutic options for the treatment of metal toxicity-induced kidney and liver diseases.