Bitter orange (Citrus aurantium L.) extract subchronic 90-day safety study in rats.

Bitter orange (Citrus aurantium L.) extracts are widely used in dietary supplements and bitter oranges are used in various juices and food products. p-Synephrine, the primary active constituent, comprises approximately 90% of total protoalkaloids. This study, performed per OECD 408 guidance, examined the 90-day subchronic safety/toxicity of an extract standardized to 50% p-synephrine at doses of 100, 300 and 1000 mg/kg/day to male and female rats. No adverse effects were observed with respect to any of the observed parameters of clinical signs, functional observations of sensory reactivity, grip strength and motor activity, ophthalmology, body weights, hematology, food consumption, urinalysis, organ weights, as well as gross and microscopic pathology at termination at any of the doses in either sex. Treatment at 1000 mg/kg body weight/day of the extract resulted in non-adverse effects including fully reversible signs of repetitive head burrowing in the bedding material and piloerection for short periods of time in both sexes immediately after administration, which gradually disappeared by treatment day-81. A slight and reversible elevation of BUN and urea levels in male rats, and slight to mild increase in the relative but not absolute heart weights of male and female rats was observed. Based on these results, the no-observed-effect-level (NOEL) for this bitter orange extract standardized to 50% p-synephrine was 300 mg/kg, while the no-observed-adverse-effect-level (NOAEL) was 1000 mg/kg. The results indicate a high degree of safety for this bitter orange extract.

Citrus aurantium (bitter orange) extract: Safety assessment by acute and 14-day oral toxicity studies in rats and the Ames Test for mutagenicity.

The primary active constituent in bitter orange extract (BOE) is p-synephrine. This study assessed the safety of a BOE standardized to 50% p-synephrine following short-term exposure to rats and by the Ames Test. Following 5000 mg/kg of the extract orally to female rats all animals survived. Administration at 2000 mg/kg to female rats for four days yielded no signs of toxicity. Five male and five female rats were administered the BOE at 0, 250, 500, 1000 and 2000 mg/kg/day for 14 days. No significant effects were observed at any dose with respect to body weights, food intake, absolute and relative organ weights, hematology, clinical chemistry, and pathology. Two male rats died after 2000 mg/kg with gastrointestinal impaction at necropsy. During week two of 1000 mg/kg and 2000 mg/kg/day, rats exhibited transient signs of repetitive burrowing of heads in the bedding material (hypoactivity) for about 15 and 45 min, respectively. The no-observed-effect-level (NOEL) was 500 mg/kg/day. The mutagenic potential was assessed at and up to the limit dose of 5000 µg/plate in a Salmonella typhimurium reverse mutation (Ames) test, performed in duplicate as a pre-incubation assay in the presence and absence of metabolic activation (S9). The BOE did not induce an increase in the frequency of revertant colonies at any dose in the five tester strains, and was therefore non-mutagenic.

Suitability of PSA-detected localised prostate cancers for focal therapy: experience from the ProtecT study.

BACKGROUND: Contemporary screening for prostate cancer frequently identifies small volume, low-grade lesions. Some clinicians have advocated focal prostatic ablation as an alternative to more aggressive interventions to manage these lesions. To identify which patients might benefit from focal ablative techniques, we analysed the surgical specimens of a large sample of population-detected men undergoing radical prostatectomy as part of a randomised clinical trial. METHODS: Surgical specimens from 525 men who underwent prostatectomy within the ProtecT study were analysed to determine tumour volume, location and grade. These findings were compared with information available in the biopsy specimen to examine whether focal therapy could be provided appropriately. RESULTS: Solitary cancers were found in prostatectomy specimens from 19% (100 out of 525) of men. In addition, 73 out of 425 (17%) men had multiple cancers with a solitary significant tumour focus. Thus, 173 out of 525 (33%) men had tumours potentially suitable for focal therapy. The majority of these were small, well-differentiated lesions that appeared to be pathologically insignificant (38-66%). Criteria used to select patients for focal prostatic ablation underestimated the cancer's significance in 26% (34 out of 130) of men and resulted in overtreatment in more than half. Only 18% (24 out of 130) of men presumed eligible for focal therapy, actually had significant solitary lesions. CONCLUSION: Focal therapy appears inappropriate for the majority of men presenting with prostate-specific antigen-detected localised prostate cancer. Unifocal prostate cancers suitable for focal ablation are difficult to identify pre-operatively using biopsy alone. Most lesions meeting criteria for focal ablation were either more aggressive than expected or posed little threat of progression.

Safety of an oxygen-coordinated niacin-bound chromium(III) complex (NBC): II. Developmental toxicity study in rats.

The objective of the present study was to evaluate the teratogenic potential of a novel oxygen-coordinated niacin-bound chromium complex (NBC) in Sprague-Dawley rats. Due to its potential to affect fat synthesis and reduce food intake, processes which are often crucial in normal fetal development, this teratology study was undertaken as part of a multi-generation reproductive investigation. The animals in this study were selected randomly after weaning from each F(2b) litter of the F1 generation from the two-generation reproductive toxicity study. To start the teratology study, Sprague-Dawley rat pups ( approximately 30/sex/group) from the F(2b) generation were allowed to grow up to 10-12 weeks of age before mating. The rats in treatment group were exposed directly to NBC through feed. The dietary exposure levels were the same as those employed for the two-generation reproductive toxicity study, viz. 4, 15, or 60 ppm. Following mating at maturity, the pregnant rats were observed daily for clinical signs of adverse effects, and body weight and feed consumption were recorded. On the day 20th of the gestation, animals were subjected to a necropsy and caesarean section to examine the uterus, ovaries and fetuses for assessment of different parameters of pregnancy and embryo-fetal defects. In this study, no indications of maternal toxicity, adverse effects on the parameters evaluated for the gravid uteri, external abnormalities in the fetuses, soft tissue abnormalities in the fetuses, or skeletal abnormalities in the fetuses were noted. Based on the results of this developmental toxicity study, NBC was found to benon-teratogenic in Sprague-Dawley rat, at the dietary exposure levels of 4, 15, and 60 ppm, equivalent to the dose levels of 0.50, 2.0, or 8.0mg/kg/day, respectively.

Safety of a novel oxygen-coordinated niacin-bound chromium(III) complex (NBC): I. Two-generation reproduction toxicity study.

The objective of this study was to evaluate the effects of a novel oxygen-coordinated niacin-bound chromium(III) complex (NBC) on the reproductive systems of male and female rats, the postnatal maturation and reproductive capacity of their offspring, and possible cumulative effects through multiple generations. Sprague-Dawley rats were maintained on feed containing NBC at dose levels of 0, 4, 15, or 60ppm for 10weeks prior to mating, during mating, and, for females through gestation and lactation, across two generations. For the parents (F(0) and F(1)) and the offspring (F(1) and F(2a)), reproductive parameters such as fertility and mating, gestation, parturition, litters, lactation, sexual maturity and development of offspring were assessed. Results from the current study indicated that dietary exposure of NBC to parental male and female rats of both (F(0) and F(1)) the generations during the premating and mating periods, for both sexes, and during gestation and lactation in case of female rats, did not cause any significant incidence of mortality or abnormal clinical signs. Compared to respective controls, NBC exposure did not affect reproductive performance as evaluated by sexual maturity, fertility and mating, gestation, parturition, litter properties, lactation and development of the offspring. Based on the findings of this study, the parental as well as the offspring no-observed-adverse-effect level for NBC was determined to be greater than 60ppm in diet or equivalent to 7.80 and 8.31mg/kg body weight/day in male and female rats, respectively.

Upflow anaerobic filter for the degradation of adsorbable organic halides (AOX) from bleach composite wastewater of pulp and paper industry.

The removal of AOX from bleach plant effluent of pulp and paper industry was studied using upflow anaerobic filter. In this paper biodegradation of AOX at different concentrations and effect of electron donors like acetate and glucose thereon in an upflow anaerobic filter at 20 d HRT is described. Results showed significant improvement in AOX degradation when electron donors such as acetate and glucose were supplemented to the influent. AOX degradation was 88% at 28 mg AOX L(-1) and 28% at 42 mg AOX L(-1). The percent degradation efficiency was enhanced to 90.7, 90.2, and 93.0 at 28 mg AOX L(-1) when the influent was supplemented with glucose, acetate and both glucose and acetate, respectively. Similarly, the efficiency was 57, 56.6 and 79.6 at 42 mg AOX L(-1) when the influent was supplemented with glucose, acetate and both glucose and acetate, respectively. The GC-MS analysis data indicated that supplementation of the influent with electron donor increased the biodegradability of number of chlorinated organic compounds.

Cutaneous manifestations of chikungunya fever: observations made during a recent outbreak in south India.

UNLABELLED: BACKGROUND; Chikungunya fever is an Aedes mosquito-borne Arbo viral illness with significant morbidity. METHODS: In a recent outbreak of the disease in south India, the dermatologic manifestations of 145 patients attending a tertiary care hospital were recorded. RESULTS: All age groups were affected, including newborns. Some of the cutaneous features were observed during the acute stage of the illness, and others during convalescence or thereafter. Pigmentary changes were found to be the most common cutaneous finding (42%), followed by maculopapular eruption (33%) and intertriginous aphthous-like ulcers (21.37%). Lesions with significant morbidity were generalized vesiculobullous eruptions (2.75%), found only in infants, lymphedema, and intertriginous aphthous-like ulcers. Exacerbation of existing dermatoses, such as psoriasis, and unmasking of undiagnosed Hansen's disease were observed. A perivascular lymphocytic infiltrate was a consistent histopathologic finding in all types of skin lesions. All patients responded well to symptomatic, conservative treatment. CONCLUSIONS: The cutaneous findings hitherto not reported may be the result of the African genotype of the virus detected during this outbreak in India.

Safety of a Novel Calcium/Potassium Salt of Hydroxycitric Acid (HCA-SX): I. Two-Generation Reproduction Toxicity Study.

ABSTRACT (-)-Hydroxycitric acid (HCA), a natural plant extract from the dried fruit rind of Garcinia cambogia, has been reported to inhibit fat synthesis and reduce food intake. The objective of this study was to evaluate the effects of a novel calcium/potassium salt of (-)-hydroxycitric acid (HCA-SX) on the reproductive systems of male and female rats, the postnatal maturation and reproductive capacity of their offspring, and possible cumulative effects through multiple generations. Sprague-Dawley rats (30/sex/group) were maintained on feed containing HCA-SX at dose levels of 0, 1000, 3000, or 10,000 ppm for 10 weeks prior to mating, during mating, and, for females, through gestation and lactation, across two generations. During the period of study, animals were examined daily for signs of clinical toxicity and their body weight and feed consumption were recorded twice a week. For the parents (F(0) and F(1)) and the offspring (F(1) and F(2a)), reproductive parameters such as fertility and mating, gestation, parturition, litters, lactation, sexual maturity, and development of offspring were assessed. At termination, necropsy and histopathological examinations were performed on all animals. Dietary exposure of HCA-SX to parental male and female rats of both (F(0) and F(1)) the generations during the premating and mating periods, for both sexes, and during gestation and lactation in case of female rats, did not reveal any remarkable incidence of mortality or abnormal clinical signs. Compared to respective controls, HCA-SX exposure did not affect feed consumption or body weight at any of the exposure levels. HCA-SX exposure did not affect reproductive performance as evaluated by sexual maturity, fertility and mating, gestation, parturition, litter properties, lactation, and development of the offspring. Based on the results of this study, the parental as well as the offspring no-observed-adverse-effect level for HCA-SX was determined to be greater than 10,000 ppm in diet or equivalent to 1018 and 1524 mg/kg body weight/day in male and female rats, respectively.

Safety of a Novel Calcium/Potassium Saltof (-)-Hydroxycitric Acid (HCA-SX): II.Developmental Toxicity Study in Rats.

ABSTRACT (-)-Hydroxycitric acid (HCA), active constituent (10%-30%) of the dried fruit rind of Garcinia cambogia, is commonly used as a dietary supplement for weight management. The objective of the present study was to evaluate the teratogenic potential of a novel calcium/potassium salt of HCA (HCA-SX) in Sprague-Dawley rats. Due to its potential to affect fat synthesis and reduce food intake, processes that are often crucial in normal fetal development, this teratology study was undertaken as part of a multigeneration reproductive investigation. The animals in this study were selected randomly after weaning from each F(2b) litter of the F(1) generation from the two-generation reproductive toxicity study. To start the teratology study, Sprague-Dawley rat pups ( approximately 30/sex/group) from the F(2b) generation were allowed to grow up to 10 to 12 weeks of age before mating. The rats in the treatment group were exposed directly to HCA-SX through feed, while prior to their weaning, they had indirect exposure to the test material during lactation. The dietary exposure levels were the same as those employed for the two-generation reproductive toxicity study, viz. 1000, 3000, or 10,000 ppm. Following mating at maturity, the pregnant rats were observed daily for clinical signs of adverse effects, and body weight and feed consumption were recorded. On day 20 of gestation, animals were subjected to a necropsy and cesarean section to examine the uterus, ovaries, and fetuses for assessment of different parameters of pregnancy and embryo-fetal defects. Despite a slight (13%) lowering of maternal body weight gain during gestation period in the group receiving 10,000 ppm HCA-SX, no evidence of maternal toxicity, adverse effects on the parameters evaluated for the gravid uteri, external abnormalities in the fetuses, soft tissue abnormalities in the fetuses, or skeletal abnormalities in the fetuses were noted. Based on the results of this developmental toxicity study, conducted in continuation of a two-generation reproductive toxicity study, HCA-SX was not found to be teratogenic in the Sprague-Dawley rat at the dietary exposure levels of 1000, 3000, and 10,000 ppm, equivalent to the dose levels of 103, 352, or 1240 mg/kg/day, respectively.

Safety evaluation of a standardized phytochemical composition extracted from Bacopa monnieri in Sprague--Dawley rats.

BacoMind is an enriched phytochemical composition derived from Bacopa monnieri, a common medicinal plant having multiple uses in the traditional system of medicine and particularly used as a memory enhancing agent for centuries. The plant and its extracts have been evaluated for anti-inflammatory, cardio tonic, sedative and neuro-muscular blocking activities. In view of the extensive use of this plant, BacoMind , standardized to bioactive compounds was evaluated in a series of toxicity studies, to confirm the safety of its usage. BacoMind , on single oral administration had a median lethal dose of 2,400 mg/kg in Sprague-Dawley rats. In a 14 day repeated dose oral toxicity study in rats, except for mild lowering in body weight gain in male rats, it was found to be tolerated well up to the dose of 500 mg/kg. A subchronic oral toxicity study for 90 days in rats at the dose levels of 85, 210 and 500 mg/kg did not reveal any evidence of toxicity with respect to clinical signs, neurological examination, food consumption, body weight gain, haematological and blood biochemistry parameters. The absolute and relative organ weight of vital organs did not differ significantly from that of the control. Necropsy and histopathological examination, did not reveal any remarkable and treatment related changes. A no-observed adverse effect level of 500 mg/kg body weight was established in rats.

Vascular endothelial growth factor expression in osteosarcoma.

UNLABELLED: Vascular endothelial growth factor expression by osteosarcomas at biopsy has been shown to have a negative influence on survival. Whether it continues to be expressed and influence outcome in tumors after neoadjuvant chemotherapy has not been determined. To determine if a high-degree of vascular endothelial growth factor expression by the surviving osteosarcoma cells in the resected tumor has a negative influence on prognosis, we retrospectively reviewed 52 patients with Stage IIB osteosarcoma around the knee, 48 of whom received neoadjuvant chemotherapy. Vascular endothelial growth factor expression by the surviving tumor cells in the surgically resected specimens was determined by immunohistochemical staining. Followup was for a minimum of 92 months. The presence of vascular endothelial growth factor expression in greater than 25% of tumor cells was independently associated with a reduced overall and disease-free survival rate. LEVEL OF EVIDENCE: Prognostic study, Level II (retrospective study). See the Guidelines for Authors for a complete description of levels of evidence.

Generalized anetoderma in a patient with HIV and dual mycobacterial infection.

A middle-aged HIV infected man receiving treatment for pulmonary tuberculosis, presented with a febrile illness along with evanescent, erythematous nodular lesions all over the body. On examination, he had features suggestive of lepromatous leprosy with lesions of erythema nodosum leprosum. In addition, there were multiple small, circumscribed areas of slack skin, clinically and histopathologically suggestive of anetoderma. Both leprosy and HIV infection are known to give rise to lesions of anetoderma. Pathogenesis of anetoderma in these infectious conditions is discussed.

Greither's disease.

A 14-year-old girl with diffuse palmoplantar keratoderma with hyperhidrosis and progressive extension of keratoderma to the dorsum of the hands and feet is reported. The inheritance pattern was autosomal dominant.