Cardiac and metabolic safety profile of antipsychotics in youths: A WHO safety database analysis.

A significant heterogeneity prevails in antipsychotics (APs) safety monitoring recommendations. Youths are deemed more vulnerable to cardiometabolic side effects. We aimed to assess age-dependent reporting of cardiac and metabolic disorders in youths, relying on the WHO safety database (VigiBase®). VigiBase® was queried for all reports of cardiac, glucose, lipid and nutritional disorders involving APs. Patients <18 years were classified as pediatric population. Disproportionality analyses relied on the Information Component (IC): the positivity of the lower end of its 95 % confidence interval was required to suspect a signal. We yielded 4,672 pediatric reports. In disproportionality analysis, nutritional disorders were leading in youths (IC 3.9 [3.9-4.0]). Among healthcare professionals' reports, stronger signals were detected in youths than in adults. Children had the greatest signal with nutritional disorders (IC 4.7 [4.6-4.8]). In adolescents, aripiprazole was ascribed to non-alcoholic steatohepatitis (NASH). Our findings, based on real-world data, support the hypothesis of a greater propensity for nutritional disorders in youths, despite limitations of pharmacovigilance studies. We suggest specific safety profiles, such as aripiprazole and NASH. Pending more answers from population-based studies, a careful anamnesis should seek for risk factors before AP initiation. A cautious monitoring is warranted to allow earlier identification of side effects.

[Peripheral neuropathy with hypervitaminosis B6 caused by self-medication]. / Neuropathie périphérique avec hypervitaminose B6 provoquée par l'automédication.

INTRODUCTION: Vitamin B6 is contained in a number of over-the-counter drugs and vitamin supplements. It may cause severe neurological troubles in case of overdosage. CASE REPORT: We report the case of a 92-year-old women with gait disorders. A diagnosis of peripheral neuropathy with both motor and sensitive deficits was established and investigated. Blood level of vitamin B6 was measured to investigate a potential deficiency. Unexpectedly, the results showed hypervitaminosis B6, which appears to be due to self-administration of an over-the-counter drug containing vitamin B6. Discontinuation of this drug was associated with decrease in vitamin B6 level as well as gait improvement. We also discuss the toxicity of vitamin B6. CONCLUSION: Hypervitaminosis B6 remains a possible cause of peripheral neuropathy and it may be caused by self-administration of over-the-counter vitamin-containing drugs.

Risks of the 'Sunshine pill' - a case of hypervitaminosis D.

Vitamin D is a fat-soluble vitamin essential for calcium homeostasis and bone health. Vitamin D toxicity or hypervitaminosis D is extremely rare. We describe the case of a 73-year-old man who presented with life-threatening hypervitaminosis D and hypercalcaemia resulting from self-medicated doses of vitamin D supplements. This case, alongside other global case reports, highlights the potential dangers of unlicensed vitamin D replacement. We discuss the evidence for vitamin D replacement and remind readers of the current guidance on daily intake and supplementation.

Metastatic mineralisation caused by vitamin D intoxication in hand-raised short-beaked echidnas (Tachyglossus aculeatus).

CASE REPORT: Two cases of metastatic mineralisation caused by dietary excess of vitamin D are reported in hand-raised short-beaked echidna (Tachyglossus aculeatus) puggles at the Australian Wildlife Health Centre. Oversupplementation was attributed to excessive levels of vitamin D in Wombaroo Echidna Milk Replacer fed to the puggles. No information exists regarding the naturally occurring vitamin D levels in echidna milk, but, given the low serum levels that have been observed in free-ranging animals, it is likely to be low. CONCLUSION: The vitamin D concentration in Wombaroo Echidna Milk Replacer has been reduced.

Reversible vascular calcifications associated with hypervitaminosis D.

A 64-year-old man was hospitalized in 2002 with symptoms of stupor, weakness, and renal colic. The clinical examination indicated borderline hypertension, small masses in the glutei, and polyuria. Laboratory tests evidenced high serum concentrations of creatinine, calcium, and phosphate. Imaging assessments disclosed widespread vascular calcifications, gluteal calcifications, and pelvic ectasia. Subsequent lab tests indicated suppressed serum parathyroid hormone, extremely high serum 25-hydroxy vitamin D, and normal serum 1,25-dihydroxy vitamin D. Treatment was started with intravenous infusion of saline and furosemide due to the evidence of hypercalcemia. Prednisone and omeprazole were added given the evidence of hypervitaminosis D. The treatment improved serum calcium, kidney function, and consciousness. The medical history disclosed recent treatment with exceptionally high doses of slow-release intra-muscular cholecalciferol and the recent excretion of urinary stones. The patient was discharged when it was possible to stop the intravenous treatment. The post-discharge treatment included oral hydration, furosemide, prednisone and omeprazole for approximately 6 months up to complete resolution of the hypercalcemia. The patient came back 12 years later because of microhematuria. Lab tests were normal for calcium/phosphorus homeostasis and kidney function. Imaging tests indicated only minor vascular calcifications. This is the first evidence of reversible vascular calcifications secondary to hypervitaminosis D.

Effects of preventive versus "on-demand" nutritional support on paid labour productivity, physical exercise and performance status during PEG-interferon-containing treatment for hepatitis C.

BACKGROUND AND OBJECTIVE: Deterioration of nutritional status during PEG-interferon containing therapy for chronic hepatitis C can be ameliorated by preventive nutritional support. We aimed to explore whether such support also affects paid labour productivity, physical exercise and performance status. METHODS: In this prospective randomized controlled trial (J Hepatol 2012;57:1069-75), 53 patients with chronic hepatitis C had been allocated to "on demand" support (n=26: nutritional intervention if weight loss>5%) or preventive support (n=27: regular dietary advice plus energy- and protein-rich evening snack) during PEG-interferon-containing therapy. Paid labour productivity, physical exercise and performance status were evaluated at baseline, after 24 and (if applicable) after 48 weeks of treatment. RESULTS: At baseline, 46% of patients performed paid labour and 62% performed some kind of physical exercise. Furthermore, most patients were able to carry out normal activity with only minor symptoms of disease (mean Karnofsky performance score: 94). Decreases of paid labour productivity (-21% vs. -70%, P=0.003), physical exercise activity (-43% vs. -87%, P=0.005) and Karnofsky performance scores (-12% vs. -24%, P<0.001) were less in the preventive than in "on demand" group after 24 weeks of treatment. Effects of preventive nutritional support were even more pronounced after 48 weeks. CONCLUSIONS: Preventive nutritional support markedly ameliorates decreases of paid labour productivity, physical exercise and performance status during PEG-interferon-containing treatment for chronic hepatitis C.

Influence hypervitaminosis D3 on hemodynamic presentation of experimental copper intoxication.

As a component of various enzymes, it refers to copper essential trace elements, but the excessive consumption of the metal leads to the development of the pathogenic effects of xenobiotics on the functional condition of the cardiovascular system. However, the works devoted to the study of the effectiveness of prophylactic calcium in a copper toxicity, is not in the current literature. The purpose: study the effect of long-term toxicity of copper on the functional state of the cardiovascular system and its reactivity in experimental hypercalcemia. Methods: Experimental hypercalcemia model was created by forming a pilot hypervitaminosis D, by introducing «Akvadetrim¼ atraumatic preparation through a probe into the stomach in the dose 3000 IU (0.2 ml) / 100 g of body weight for 30 days. Chronic copper poisoning model created by intragastric administration of copper sulfate solution at a dosage of 20 mg/kg (in terms of metal) for 30 days, daily one time a day. The study of the functional state of the cardiovascular system is to determine the mean arterial pressure, specific peripheral vascular resistance, stroke index, cardiac index, the reactivity of the renin-angiotensin system and adrenoreactivity cardiovascular system. Results: The experimental study revealed that long-term copper poisoning leads to the development of hypertension due to an increase in total peripheral vascular resistance, along with the marked decline in the pumping function of the heart. Experimental hypercalcemia simulated by intragastric administration of vitamin D promotes more pronounced toxic effects of copper sulfate on the cardiovascular system. Conclusion: Copper poisoning of the body is characterized by the development of hypertension and the condition of artificial hypercalcemia potentiates the cardiotoxic effects of copper.

Hypervitaminosis D in guinea pigs with α-mannosidosis.

A colony of guinea pigs (n = 9) with α-mannosidosis was fed a pelleted commercial laboratory guinea pig diet. Over 2 mo, all 9 guinea pigs unexpectedly showed anorexia and weight loss (11.7% to 30.0% of baseline weight), and 3 animals demonstrated transient polyuria and polydipsia. Blood chemistry panels in these 3 guinea pigs revealed high-normal total calcium, high-normal phosphate, and high ALP. Urine specific gravity was dilute (1.003, 1.009, 1.013) in the 3 animals tested. Postmortem examination of 7 animals that were euthanized after failing to respond to supportive care revealed renal interstitial fibrosis with tubular mineralization, soft tissue mineralization in multiple organs, hepatic lipidosis, and pneumonia. Analysis of the pelleted diet revealed that it had been formulated with a vitamin D3 content of more than 150 times the normal concentration. Ionized calcium and 25-hydroxyvitamin D values were both high in serum saved from 2 euthanized animals, confirming the diagnosis of hypervitaminosis D. This report discusses the clinical signs, blood chemistry results, and gross and histologic findings of hypervitaminosis D in a colony of guinea pigs. When unexpected signs occur colony-wide, dietary differentials should be investigated at an early time point.

Vitamin D3 quantification in a cod liver oil-based supplement.

A reliable, accurate and reproducible method to quantify vitamin D3 (Vit. D3) in oily dietary supplements was developed after three Vit. D3 intoxications were diagnosed as reasonably resulting from a dietary administration of a cod liver oil based supplement. Liquid chromatography coupled to mass spectrometry operating in atmospheric pressure chemical ionization conditions (LC-APCI) and by using a deuterium labelled internal standard resulted to be an effective technique to reach the analytical aim. Due to the complexity of the oily matrix, the new analytical approach required a solid phase extraction step prior to analysis. The amount of Vit. D3 declared on the label of the cod liver oil based supplement for each soft capsule is 1.5µg. Consequently, the method was developed to quantify Vit. D3 amounts in the range 1-5µg/mL. To improve reliability of obtained data, both MS and MS/MS acquisition methods were employed. The method was evaluated by measuring the characteristic parameters such as linearity, precision, accuracy and robustness and cross checked against a certified pharmaceutical preparation. The LC-APCI-MS and MS/MS methods were applied in order to assess the Vit. D3 content in the dietary supplements taken by the intoxicated patients, found about three order of magnitude higher than that declared. The Vit. D3 content of other batches of the same commercial product was found as declared.

Hepatotoxin-induced hypercreatinaemia and hypercreatinuria: their relationship to one another, to liver damage and to weakened nutritional status.

Hypercreatinuria is a well-known feature of liver and testicular toxicity and we have recently proposed that hepatotoxin-induced hypercreatinuria would arise as a consequence of increased cysteine synthesis associated with the provision of protective substances (glutathione and/or taurine). Here a direct relationship between hepatotoxin-induced hypercreatinaemia and hypercreatinuria is shown and the possible relationships of hepatotoxin-induced hypercreatinaemia and hypercreatinuria to hepatic damage and to weakened nutritional status are examined. Male Sprague-Dawley rats were dosed with a variety of model hepatotoxins at two dose levels per toxin. Blood plasma samples taken at 24 h post-dosing and urine samples collected from 24-31 h post-dosing were analysed by (1)H NMR spectroscopy. Both hypercreatinaemia and hypercreatinuria were found in rats dosed with allyl formate (75 mg/kg), chlorpromazine (30 and 60 mg/kg), alpha-naphthylisothiocyanate (ANIT, 100 mg/kg) and thioacetamide (200 mg/kg), whilst significant hypercreatinuria, but not hypercreatinaemia, was found after dosing with thioacetamide (50 mg/kg). Neither hypercreatinaemia nor hypercreatinuria were found after dosing with allyl formate (25 mg/kg), ethionine (300 and 1000 mg/kg) or ANIT (30 mg/kg). Reduced feeding is known to cause hypercreatinuria in rats and, of the four hepatotoxins that induced hypercreatinaemia and hypercreatinuria at the given time-points, two, chlorpromazine and ANIT, also affected nutritional status with ketosis being clearly identifiable from the plasma (1)H NMR spectra. Thus, the creatine changes induced by ANIT and chlorpromazine are potentially attributable, in whole or in part, to reduced feeding rather than to liver effects alone and, consequently, the results were examined with and without inclusion of the ANIT and chlorpromazine data. With all of the data included, there were eight out of ten points of correspondence between the incidence of hypercreatinaemia and/or hypercreatinuria and the incidence of increases in plasma alanine aminotransferase (ALT) activity. At the same time there were nine out of ten points of correspondence between the incidence of hypercreatinaemia and/or hypercreatinuria and the incidence of increases in plasma aspartate aminotransferase (AST) activity. However, with the ANIT and chlorpromazine data excluded there was complete (six out of six points) correspondence between the incidence of hypercreatinaemia and/or hypercreatinuria and the incidence of increases in plasma AST and ALT in the remaining data. Likewise, with all of the data included, there was some apparent correlation (correlation coefficient, r=0.80) between the group mean levels of plasma AST and plasma creatine when expressed relative to the mean values for controls sampled at the same time-point. However, with the ANIT and chlorpromazine data excluded, that correlation coefficient was increased to 0.95. The findings of these studies suggest that the ANIT- and chlorpromazine-induced creatine changes may have been caused by reduced feeding rather than by liver toxicity. The allyl formate and thioacetamide data indicate that hepatocellular necrosis is accompanied by increases in plasma and urinary creatine, and suggest the possibility of a quantitative relationship between the increases in plasma AST and the increases in plasma creatine that are associated with hepatocellular necrosis. The ethionine and ANIT data suggest that fatty liver (steatosis) and cholestatic damage may not be associated with hypercreatinaemia and hypercreatinuria.

Mitochondrial energy metabolism in a model of undernutrition induced by dexamethasone.

The present investigation was undertaken to evaluate whether mitochondrial energy metabolism is altered in a model of malnutrition induced by dexamethasone (DEX) treatment (1.5 mg/kg per d for 5 d). The gastrocnemius and liver mitochondria were isolated from DEX-treated, pair-fed (PF) and control (CON) rats. Body weight was reduced significantly more in the DEX-treated group (-16%) than in the PF group (-9%). DEX treatment increased liver mass (+59% v. PF, +23% v. CON) and decreased gastrocnemius mass. Moreover, in DEX-treated rats, liver mitochondria had an increased rate of non-phosphorylative O2 consumption with all substrates (approximately +42%). There was no difference in enzymatic complex activities in liver mitochondria between rat groups. Collectively, these results suggest an increased proton leak and/or redox slipping in the liver mitochondria of DEX-treated rats. In addition, DEX decreased the thermodynamic coupling and efficiency of oxidative phosphorylation. We therefore suggest that this increase in the proton leak and/or redox slip in the liver is responsible for the decrease in the thermodynamic efficiency of energy conversion. In contrast, none of the variables of energy metabolism determined in gastrocnemius mitochondria was altered by DEX treatment. Therefore, it appears that DEX specifically affects mitochondrial energy metabolism in the liver.

Alcohol abuse and dependence: psychopathology, medical management and dental implications.

BACKGROUND: The authors review the clinical features, epidemiology, pathophysiology, medical management, dental findings and dental treatment of patients with alcoholism. LITERATURE REVIEWED: The authors conducted a MEDLINE search for 1995 through 2001 using the key terms of alcoholism, epidemiology, pathophysiology, treatment and dentistry. Reports selected for further review included those published in English in peer-reviewed journals. The authors gave preference to articles reporting randomized, controlled trials. CONCLUSIONS: Alcoholism is a chronic and progressive psychiatric illness that afflicts more than 14 million Americans. It is characterized by a loss of control over the use of alcohol, resulting in impaired social functioning, and the consequent development of medical illnesses. The disease arises in genetically vulnerable people when they are overwhelmed by their cravings for the alcohol-associated euphoria that results from the actions of several neurotransmitter systems in the brain's pleasure center. New medications to counteract alcohol-induced neurotransmission imbalance may assist patients in reducing their craving. CLINICAL IMPLICATIONS: The prevalence of dental disease usually is extensive because of a disinterest in performing appropriate oral hygiene techniques and diminished salivary flow. Concurrent abuse of tobacco products worsens dental disease and heightens the risk of developing oral cancer. Identification of the alcohol-abusing patient, a cancer-screening examination, preventive dental education, and use of saliva substitutes and anticaries agents are indicated. Special precautions must be taken when performing surgery and when prescribing or administering analgesics, antibiotics or sedative agents that are likely to have an adverse interaction with alcohol or psychiatric medications.

[Effects of secretory and osmotic diarrhea on rats intestinal function and morphology]. / Efectos de la diarrhea secretora y osmótica sobre la función y morfología del intestino en ratas.

In order to compare intestinal morphology and function, diarrhea was produced in rats using laxatives in the diet. The 14 day study included two groups of rats with diarrhea (osmotic or secretory), two groups without diarrhea but with a degree of malnutrition which was similar to that seen in the rats with diarrhea (malnourished without diarrhea) and a well-nourished group (control). The inclusion of laxatives(lactose or bisoxatin acetate) cause a reduction in food intake, diarrhea an malnutrition. It also caused a reduction in dietary protein and fat digestibility which was proportional to the severity of diarrhea and more pronounced in secretory diarrhea. In the malnourished rats without diarrhea, malnutrition did not affect their absorptive function. Both in the rats with secretory and osmotic diarrhea an intestinal hypertrophy was observed. This hypertrophy was proportional to the severity of diarrhea and independent of its aetiology. In the intestines of the rats with both types of diarrhea there was inflammation, a greater number of mitotic figures but the flattening of the villi seen in the malnourished rats without diarrhea was not seen. In osmotic diarrhea there was, in addition, a patchy damage of the surface of the jejunal mucosa and an increment in the number of goblet cells, indicating a more severe intestinal deterioration. Since despite this greater deterioration, these rats absorbed more protein and fat we concluded that the alterations in intestinal morphology seen in this study was not predictive of intestinal function. The study also showed that diarrhea had a trophic effect on the intestine which did not occur in malnourished rats without diarrhea.

The genetic consequences of our sweet tooth.

First reported in 1956, hereditary fructose intolerance (HFI) illustrates vividly how interactions between genes and nutrients can influence taste preferences; the disease also reflects the ascendancy of sucrose and fructose as energy sources and as the world's principal sweeteners. However, HFI is not the only genetic ill to have emerged from our obsession with sugar: the slave trade, which had such a key part in the development of the sugar industry, also included major genetic consequences in its haunting legacy.

Hungry for tobacco: an analysis of the economic impact of tobacco consumption on the poor in Bangladesh.

OBJECTIVE: To investigate the extent of tobacco expenditures in Bangladesh and to compare those costs with potential investment in food and other essential items. DESIGN: Review of available statistics and calculations based thereon. RESULTS: Expenditure on tobacco, particularly cigarettes, represents a major burden for impoverished Bangladeshis. The poorest (household income of less than $24/month) are twice as likely to smoke as the wealthiest (household income of more than $118/month). Average male cigarette smokers spend more than twice as much on cigarettes as per capita expenditure on clothing, housing, health and education combined. The typical poor smoker could easily add over 500 calories to the diet of one or two children with his or her daily tobacco expenditure. An estimated 10.5 million people currently malnourished could have an adequate diet if money on tobacco were spent on food instead. The lives of 350 children could be saved each day. CONCLUSION: Tobacco expenditures exacerbate the effects of poverty and cause significant deterioration in living standards among the poor. This aspect of tobacco use has been largely neglected by those working in poverty and tobacco control. Strong tobacco control measures could have immediate impact on the health of the poor by decreasing tobacco expenditures and thus significantly increasing the resources of the poor. Addressing the issue of tobacco and poverty together could make tobacco control a higher priority for poor countries.

Nutrition and alcohol neurotoxicity.

Neurological complications of alcoholism such as Wernicke-Korsakoff syndrome and polyneuropathy often originate from interactive factors involving direct nervous system toxicity of ethanol and nutrient deficiencies associated to heavy drinking. Not all patients are equally susceptible to these disorders and a genetic predisposition to thiamine deficiency has been described in subjects with Wernicke's encephalopathy. At moderate alcohol dosages, nutrient abnormalities may be marginal, inducing no obvious manifestations until other neurotoxic agents are absorbed. Examples are presented illustrating the interaction of ethanol and styrene on brain glutathione metabolism in rats, and cases of methanol poisoning in alcoholics. In these patients, ethanol-induced folate deficiency can potentiate visual toxicity of methanol due to impairment of the folate-dependent pathway involved in formate detoxication. The notion that nutritional deficiencies and ethanol toxicity may act synergistically in the nervous system outlines the importance of adequate nutritional strategies in the treatment of alcoholism and also indicates that methodological flaws may result during experimental studies from failure to control for nutritional variables.