High ambient temperature increases the toxicity and lethality of 3,4-methylenedioxymethamphetamine and methcathinone.

RATIONALE: Methylenedioxymethamphetamine (MDMA) and methcathinone (MCAT) are abused psychostimulant drugs that produce adverse effects in human users that include hepatotoxicity and death. Recent work has suggested a connection between hepatotoxicity, elevations in plasma ammonia, and brain glutamate function for methamphetamine (METH)-induced neurotoxicity. OBJECTIVES: These experiments investigated the effect of ambient temperature on the toxicity and lethality produced by MDMA and MCAT in mice, and whether these effects might involve similar mechanisms to those described for METH neurotoxicity. RESULTS: Under low (room temperature) ambient temperature conditions, MDMA induced hepatotoxicity, elevated plasma ammonia levels, and induced lethality. Under the same conditions, even a very high dose of MCAT produced limited toxic or lethal effects. High ambient temperature conditions potentiated the toxic and lethal effects of both MDMA and MCAT. CONCLUSION: These studies suggest that hepatotoxicity, plasma ammonia, and brain glutamate function are involved in MDMA-induced lethality, as has been shown for METH neurotoxicity. The toxicity and lethality of both MDMA and MCAT were potentiated by high ambient temperatures. Although an initial mouse study reported that several cathinones were much less toxic than METH or MDMA, the present results suggest that it will be essential to assess the potential dangers posed by these drugs under high ambient temperatures.

Thiamine deficiency and oxidative stress induced by prolonged metronidazole therapy can explain its side effects of neurotoxicity and infertility in experimental animals: Effect of grapefruit co-therapy.

We aimed to explore the possible neurotoxicity and infertility mechanisms of prolonged metronidazole (MTZ) use and the effects of antioxidant grapefruit (GP) co-therapy on MTZ-induced complications. Sixty male albino Wistar rats were divided into four groups (n = 15 each). Group I (control group) received 1% dimethyl sulfoxide (27 ml/ kg/day), group II (MTZ group) received MTZ (400 mg/kg/day), group III (MTZ + GP) received MTZ (400 mg/kg/ day) plus GP juice (27 ml/kg/ day) and group IV (GP group) received GP juice (27 ml/kg) for 60 days. Semen analyses were performed. Free testosterone, gonadotrophin (follicle-stimulating hormone (FSH) and luteinizing hormone) and thiamine levels were measured. Samples of cerebellar, testicular and epididymal tissues were used for both colorimetric assays of oxidative stress markers and histopathological examinations. Significant decreases in the sperm count, percent total sperm motility, serum thiamine levels, free testosterone levels and FSH levels were observed in the MTZ and MTZ + GP groups (p < 0.05 for all parameters). Significantly higher oxidative stress levels (p < 0.05) were observed in the cerebellar and testicular tissue homogenates of these groups than in those of the control group, and associated disruptions in the cerebellar, testicular and epididymal structures were apparent compared to those of the control group. Although the GP group showed a significantly higher sperm count and significantly lower oxidative stress than the control group (p < 0.05), with histological similarity to the control group, the GP group exhibited significantly higher prolactin levels and lower free testosterone and FSH levels than the control group (p < 0.05). Oxidative stress and decreased thiamine levels could explain the MTZ-induced neurotoxicity and infertility side effects that aggravated by GP co-administration.

S-100ß in predicting the need of hyperbaric oxygen in CO-induced delayed neurological sequels.

BACKGROUND: Delayed neurological sequels (DNS) have been described after carbon monoxide (CO) poisoning. There is a need to find a new prognostic marker to guide the use of hyperbaric oxygen (HBO) therapy. AIM: To evaluate serum S-100ß level in patients presenting with acute CO poisoning as an indicator of poisoning severity and predictor of DNS occurrence and HBO need in those patients. METHODS: This prospective cohort study included patients with acute CO poisoning. On admission, carboxyhemoglobin (COHb) and S-100ß levels were measured. Patients were followed up for 6 months for signs of DNS. RESULTS: Out of 50 patients, 6 only developed DNS. The mean of S-100ß levels was significantly higher in patients with severe poisoning and those with DNS. Receiver operating characteristic curve analysis revealed that S-100ß had an area under the curve 0. 871; at a cutoff value ≥ 0.67 µg/L, its sensitivity and specificity were 100% and 77.3%, respectively. The sensitivity of S-100ß was significantly higher than that of COHb, while its specificity and overall accuracy were significantly higher than those of HBO criteria. CONCLUSION: Serum S-100ß level on admission could be a marker of poisoning severity and a predictor of CO-induced DNS development that guides the use of HBO therapy.

Thiamine deficiency, oxidative metabolic pathways and ethanol-induced neurotoxicity: how poor nutrition contributes to the alcoholic syndrome, as Marchiafava-Bignami disease.

Ethanol is an important risk factor for the occurrence of several brain disorders that depend on the amount, period and frequency of its consumption. Chronic use of ethanol often leads to the development of neurodegenerative syndromes, which cause morphological and functional impairments such as foetal alcohol syndrome in newborns exposed to ethanol during pregnancy, Wernicke-Korsakoff Syndrome and, more rarely, Marchiafava-Bignami disease (MBD). MBD is characterized by primary degeneration of the corpus callosum, without inflammation and is associated with oxidative stress and hypovitaminosis, as well as altered mental status, to mention dementia, seizures, depression and so on. This review discusses MBD and poor nutrition as a risk factor for the development of such alcoholic syndrome, with focus on diagnosis, pathogenic aspects, signs and symptoms, as well as therapeutic perspectives. On the basis of the inclusion/exclusion criteria adopted, the performed search in scientific databases (Pubmed, Scielo and Google Scholar) resulted in 100 studies that are being presented and discussed in the present work. Review, case-control and cohort studies on alcoholism-associated hypovitaminosis, oxidative stress, MBD and ethanol metabolism pathways were admitted as relevant. We highlight that MBD is a poorly described, diagnosed, insidious and progressive condition, for which evidence suggests a synergism between ethanol-induced neurotoxic effects and hypovitaminosis B. Present treatment consists of vitamin B1(thiamine) supplementation. Nonetheless, other strategies such as the inclusion of antidepressants or steroidal anti-inflammatories as add-on therapies have been employed as an attempt to improve the damage. Indeed, both the diagnosis and treatment are difficult, and death occurs within few years.

Naringin regulates glutamate-nitric oxide cGMP pathway in ammonium chloride induced neurotoxicity.

Naringin, plant bioflavonoid extracted mainly from grapefruit and other related citrus species. This study was designed to assess the neuroprotective effect of naringin on ammonium chloride (NH4Cl) induced hyperammonemic rats. Experimental hyperammonemia was induced by intraperitonial injection (i.p) of NH4Cl (100mg/kg body weight (b.w.)) thrice a week for 8 consecutive weeks. Hyperammonemic rats were treated with naringin (80mg/kg b.w.) via oral gavage. Naringin administration drastically restored the levels of blood ammonia, plasma urea, nitric oxide (NO), glutamate, glutamine, lipid peroxidation, lipid profile, activities of liver marker enzymes, antioxidant status and sodium/potassium-ATPase (Na+/K+-ATPase). In addition, naringin supplementation reverted back the pathological changes of liver, brain and kidney tissues, the expressions of Glutamine synthetase (GS), Na+/K+-ATPase, neuronal nitric oxide (nNOS) and soluble guanylate cyclase (sGC) in hyperammonemic rats. Hence, this study suggested that nargingin exhibited their protective effect against NH4Cl induced toxicity via enhancing the activities of antioxidant enzymes and inhibiting the lipid peroxidation process. Take together, this study provides data that naingin effectively reduced neurotoxicity by attenuating hyperammonemia, suggesting that naringin act as a potential therapeutic agent to treat hyperammonemic rats.

Electromyographic and laboratory findings in acute Solanum torvum poisoning.

CONTEXT: Solanum torvum berries, known as susumber or turkey berries, are prepared as part of traditional Jamaican dishes usually served with cod and rice. Poisoning is rare. Although toxic compounds have never been definitively isolated, previous reports suggest toxicity results from inhibition of acetylcholinesterases. We present a case of susumber berry poisoning with detailed electromyographic studies and laboratory analysis. CASE DETAILS: A 54-year-old woman presented to the Emergency Department (ED) complaining of vision, speech, and gait changes; emesis; and diffuse myalgias following consumption of susumber berries. The physical examination demonstrated an intact, lucid mental status, miosis, opsoclonus, severe dysarthria, dysmetria, mild extremity tenderness and weakness, and inability to ambulate. Her symptom constellation was interpreted as a stroke. DISCUSSION: Electromyography demonstrated a pattern of early full recruitment as well as myotonia during the period of acute toxicity. Additionally, solanaceous compounds, in particular solasonine and solanidine, were identified in leftover berries and the patient's serum. Store-bought commercial berries and subsequent serum samples were free of such toxic compounds. EMG studies, together with a laboratory analysis of berries or serum can assist in the differential diagnosis of stroke, and provide both a prognostic screening and confirmation of suspected glycoside toxicity.

Neonatal bilirubin binding capacity discerns risk of neurological dysfunction.

BACKGROUND: Bilirubin binding capacity (BBC) defines the dynamic relationship between an infant's level of unbound or "free" bilirubin and his/her ability to "tolerate" increasing bilirubin loads. BBC is not synonymous with albumin (Alb) levels because Alb binding of bilirubin is confounded by a variety of molecular, biologic, and metabolic factors. METHODS: We utilized a novel modification of a previously developed hematofluorometric method to directly assay BBC in whole blood from preterm and term neonates and then combined these data with an archived database. Total bilirubin (TB) was also measured, and multiple regression modeling was used to determine whether BBC in combination with TB measurements can assess an infant's risk for developing bilirubin-induced neurotoxicity. RESULTS: TB and BBC levels ranged from 0.7-22.8 to 6.3-47.5 mg/dl, respectively. Gestational age (GA) correlated with BBC (r = 0.54; P < 0.0002) with a slope of 0.93 mg/dl/wk by logistic regression. Our calculations demonstrate that recently recommended GA-modulated TB thresholds for phototherapy and exchange transfusion correspond to 45 and 67% saturation of our observed regression line, respectively. CONCLUSION: We speculate that the spread of BBC levels around the regression line (± 5.8 mg/dl) suggests that individualized BBC assays would provide a robust approach to gauge risk of bilirubin neurotoxicity compared with TB and GA.

Evaluating the effects and safety of intravenous lipid emulsion on haloperidol-induced neurotoxicity in rabbit.

There are many reports on the effect of intravenous lipid emulsion (ILE) as an antidote in drugs related toxicities. We determined the effects of ILE on neurotoxicity of haloperidol (HA), a highly lipophilic antipsychotic, as a model of antipsychotics poisoning. We used six groups of five male rabbits. Two groups received distilled water intravenously followed by infusions of either 18 mL/kg of normal saline or ILE 20%, after 30 minutes. The third group received 18 mL/kg of normal saline after HA (2.6 mg/kg) administration. The three other groups received ILE 20% solution (6, 12, and 18 mL/kg) following HA injection. Catalepsy scores, temperature, pupil size, and mortality rate were measured at 0, 0.5, 1, 2, 3, 4, 8, and 24 hours after HA administration began. Blood and tissue samples were taken from all animals at 24 hours or at death time for biochemical, cell count, and pathological studies. ILE reversed cataleptic scores, miotic pupils, and hypothermia of HA intoxication much faster than normal saline (P < 0.001). Biochemical complications and mortality rate of the animals were significantly higher in the HA + 18 mL/Kg ILE group. ILE reversed sings of HA neurotoxicity; however, synergistic effect of high dose of ILE and HA increased complications and mortality.

Serum myoglobin, but not lipopolysaccharides, is predictive of AMPH-induced striatal neurotoxicity.

Determinants of amphetamine (AMPH)-induced neurotoxicity are poorly understood. The role of lipopolysaccharides (LPS) and organ injury in AMPH-induced neurotoxicity was examined in adult male Sprague-Dawley rats that were give AMPH and became hyperthermic during the exposure. Environmentally-induced hyperthermia (EIH) in the rat was compared to AMPH to determine whether AMPH-induced increases in LPS and peripheral toxicities were solely attributable to hyperthermia. Muscle, liver, and kidney function were determined biochemically at 3h or 1 day after AMPH or EIH exposure and histopathology at 1 day after treatment. Circulating levels of LPS were monitored (via limulus amoebocyte coagulation assay) during AMPH or EIH exposure. Blood LPS levels were detected in 40-50% of the AMPH and EIH rats, but the presence of LPS in the serum had no effect on organ damage or striatal dopamine depletions (neurotoxicity). In both CR and NCTR rats, serum bound urea nitrogen and creatinine levels increased at 3h after EIH or AMPH (2- to 3-fold above control) but subsided by 1 day. Alanine transaminase was increased (indicating liver dysfunction) by both AMPH and EIH at 3 h (2- to 10-fold above control) in CR rats, but the levels were not significantly different between the control and AMPH groups in NCTR animals. Mild liver necrosis was detected in 1 of 7 rats examined in the AMPH group and in 1 of 5 rats examined in the EIH group (only NCTR rats were examined). Serum myoglobin increased (indicating muscle damage) in both CR and NCTR rats at 3h and was more pronounced with AMPH (≈5-fold above control) than EIH. Our results indicate that: (1) "free" blood borne LPS often increases with EIH and AMPH but may not be necessary for striatal neurotoxicity and CNS immune responses; (2) liver or kidney dysfunction may result from muscle damage; however, it is not sufficient nor necessary to produce, but may exacerbate, neurotoxicity; (3) AMPH-induced serum myoglobin release is a potential biomarker and possibly a factor in AMPH-induced toxicity processes.

Does olanzapine inhibit the psychomimetic effects of Δ9-tetrahydrocannabinol?

Δ9-Tetrahydrocannabinol (THC) produces transient psychomimetic effects in healthy volunteers, constituting a pharmacological model for psychosis. The dopaminergic antagonist haloperidol has previously been shown to reduce these effects. This placebo-controlled, cross-over study in 49 healthy, male, mild cannabis users aimed to further explore this model by examining the effect of a single oral dose of olanzapine (with dopaminergic, serotonergic, adrenergic, muscarinergic and histaminergic properties) or two oral doses of diphenhydramine (histamine antagonist) on the effects of intrapulmonarily administered THC. Transient psychomimetic symptoms were seen after THC administration, as measured on the positive and negative syndrome scale (20.6% increase on positive subscale, p<0.001) and the visual analogue scale for psychedelic effects (increase of 10.7 mm on feeling high). Following the combination of THC and olanzapine, the positive subscale increased by only 13.7% and feeling high by only 8.7 mm. This reduction of THC effects on the positive subscale failed to reach statistical significance (p=0.066). However, one-third of the subjects did not show an increase in psychomimetic symptoms after THC alone. Within responders, olanzapine reduced the effects of THC on the positive subscale (p=0.005). Other outcome measures included pharmacokinetics, eye movements, postural stability, pupil/iris ratio, and serum concentrations of cortisol and prolactin.

Safety and pharmacokinetics of intrathecal administration of pemetrexed in rats.

PURPOSE: Leptomeningeal carcinomatosis is a devastating complication of malignant disease. In this study, we evaluated the safety and pharmacokinetics of intrathecally administered pemetrexed in rats. METHODS: Three levels of pemetrexed (0.3, 1, and 3 mg/kg) were administered to 15 rats per level (45 rats in total) twice a week for 2 weeks through specifically designed indwelling subarachnoid catheters. Presence of clinical and pathological neurotoxicity was evaluated. To evaluate the pharmacokinetics of pemetrexed, independent cohorts of 30 rats were treated with 1 mg/kg of pemetrexed and its concentration in cerebrospinal fluid (CSF) and blood was measured using UPLC/MS/MS. RESULTS: There were no cases of clinical or pathologic neurotoxicity after intrathecal administrations of pemetrexed at levels of 0.3 and 1 mg/kg; however, 5 of 15 (33%) rats died after administration of 3 mg/kg pemetrexed. The distribution/elimination of pemetrexed in CSF was best described by a two-compartment model, with initial and terminal half-lives of 0.43 and 1.43 h, respectively. The predicted maximal concentration in CSF was 588 µM, and high levels of pemetrexed appeared to be maintained for a long time. Area under the curve and volume of distribution at steady state were 560 µM h and 1.14 ml, respectively. CONCLUSIONS: The no observed adverse effect level of intrathecal administration of pemetrexed was 1 mg/kg in rats. At this level, therapeutically high and durable pemetrexed concentrations could be achieved. Based on these results, further research on intrathecal pemetrexed in humans or non-human primates should be considered.

[Lithium intoxications at normal serum levels]. / Schwere lithiumintoxikationen bei normalen serumspiegeln.

OBJECTIVE: Lithium is known to be neurotoxic at higher serum levels. In rare cases patients develop symptoms of intoxication or full blown intoxications even when lithium levels are normal. Our aim was to detect predicting factors of lithium neurotoxicity at normal serum lithium levels in order to allow prevention of those constellations. METHODS: We report two cases of severe lithium intoxications at normal serum lithium levels and review the current literature concerning lithium neurotoxicity at normal serum levels. RESULTS: It appears that the probability of developing signs of lithium intoxications in patients treated with lithium is increased with advanced age, co-morbidity with pre-existing neurological or other general diseases, especially those associated with fever, and in combination with the use of antipsychotics, antidepressants or mood stabilizers. The serum lithium level does not necessarily detect an intoxication. CONCLUSIONS: In patients developing signs of intoxication under lithium therapy, further investigations should include serum levels and an EEG. Because intoxications can occur even in normal serum levels, discontinuation of lithium medication should be taken into account on the basis of clinical signs of intoxication.