A comparison of drug-induced cardiotoxicity in rat embryos cultured in human serum or protein free media.

INTRODUCTION: Although much reproductive toxicology research is performed in live animals there is increasing use of in vitro techniques primarily to identify potential hazards with human exposure. As many in vitro studies are undertaken using protein free media, the standard protocol is to compare the effect concentration determined in vitro with the predicted therapeutic free plasma concentration in humans. The aim of the present study was to test this rationale by comparing the effect of a small number of therapeutic drugs on heart rate of rodent embryos cultured in human sera or protein free serum. METHODS: Whole rat embryos were cultured in protein-free media or human serum to which drugs (amiodarone, citalopram, dofetilide, haloperidol, paroxetine, quetiapine, or trazodone) known to induce embryonic bradycardia were added. Embryonic heart rate was observed before and after addition of drugs. RESULTS: Most of the tested drugs (5/7) caused a greater decrease in embryonic heart rate in human sera than predicted based on the protein binding of the drug. DISCUSSION: The results suggest that there is less unbound drug in the protein free media and/or more unbound drug in the human sera than predicted. Variables such as saturated protein binding and pH cannot fully explain our results. Since the results did not validate the original rationale, reproductive toxicity results obtained using protein free in vitro techniques may not have the large safety factors predicted on the basis of protein binding.

Use of intravenous lipid emulsion in the resuscitation of a patient with cardiovascular collapse after a severe overdose of quetiapine.

BACKGROUND: Quetiapine is an atypical antipsychotic medication that is increasingly being used in the treatment of psychotic disorders and depression. An overdose of quetiapine is associated with hypotension, sinus tachycardia, and sedation. The clinical effects of its overdose are often mild to moderate, but a severe overdose can cause cardiovascular collapse and death.Intravenous lipid emulsion (ILE) is a proposed treatment for potentially lethal cardiotoxicity after severe overdoses with lipophilic drugs, such as quetiapine, mainly by the sequestration of the lipophilic toxin to an expanded intravascular lipid phase. OBJECTIVES: To report a case where ILE was successfully used in the resuscitation of a patient with cardiovascular collapse after a severe quetiapine overdose. CASE REPORT: A 42-year-old woman was admitted to the Emergency Department after being found unconscious at home, due to an estimated ingestion of 24 g of quetiapine (Seroquel). She was initially cardiorespiratory stable and unresponsive with a Glasgow Coma Scale of 3. The woman was immediately admitted to the Intensive Care Unit, where her condition quickly deteriorated. She was intubated, due to loss of airway. In addition, a gastric lavage was performed and activated charcoal was administered. The patient presented with cardiovascular collapse refractory to vasopressor treatment and volume resuscitation. ILE bolus followed by continuous infusion was administered. Her blood pressure started increasing 5 min after ILE was initiated and within an hour circulation was stabilized. The patient recovered completely without any residual symptoms, after 3 days in the ICU. CONCLUSIONS: ILE may potentially be life-saving in cases of severe quetiapine poisoning and should be considered as a treatment for severe cardiovascular instability resulting from quetiapine poisoning refractory to maximum conventional therapy.

Treatment of quetiapine overdose with intravenous lipid emulsion.

We report the case of a 29-year-old woman who attempted suicide by oral ingestion of potentially fatal doses of multiple drugs including quetiapine. Intravenous lipid emulsion (ILE) was administered at a dose higher than that used in the standard management of toxicity. Rapid improvement was observed in the patient's status, and no additional treatment was required during the period of observation. No adverse effect of lipid administration was observed. ILE treatment seems to have great potential in the management of lipophilic drug toxicity in the future.

The genotoxic potentials of some atypical antipsychotic drugs on human lymphocytes.

Olanzapine (OLZ), risperidone (RPD) and quetiapine (QTP) are atypical antipsychotic drugs and are commonly used for the treatments of schizophrenia and bipolar disorders. However, recent reports indicated that these drugs could exhibit toxic effects on nervous and cardiovascular systems. To our best knowledge, there are scarce data considering the genotoxic damage potentials of OLZ, RPD and QTP on human lymphocyte culture system. Therefore, in this study, the genotoxic potentials of OLZ, RPD and QTP (0-400 mg/L) have been evaluated in human whole blood cultures (WBCs; n = 4). The single cell gel electrophoresis (SCGE) and micronucleus (MN) assays were applied to estimate the DNA damage. The results of the present study indicated that the tested antipsychotic drug did not induce genotoxicity. In fact, the mean values of the total scores of cells showing DNA damage (for SCGE assay) and MN/1000 cell were not found significantly different from the control values (p > 0.05). However, the application of the highest drug concentrations (250 mg/L and above) caused the sterility in lymphocyte cultures. It is concluded that the tested three different atypical antipsychotic drugs can be used safely, but it is necessary to consider the cytotoxic effects that are likely to appear depending on the doses exposed.

Evaluation of NTF1836 as an inhibitor of the mycothiol biosynthetic enzyme MshC in growing and non-replicating Mycobacterium tuberculosis.

The mycothiol biosynthesis enzyme MshC catalyzes the ligation of cysteine with the pseudodisaccharide GlcN-Ins and has been identified as an essential enzyme in Mycobacterium tuberculosis. We now report on the development of NTF1836 as a micromolar inhibitor of MshC. Using commercial libraries, we conducted preliminary structure-activity relationship (SAR) studies on NTF1836. Based on this data, NTF1836 and five structurally related compounds showed similar activity towards clinical strains of M. tuberculosis. A gram scale synthesis was developed to provide ample material for biological studies. Using this material, we determined that inhibition of M. tuberculosis growth by NTF1836 was accompanied by a fall in mycothiol and an increase in GlcN-Ins consistent with the targeting of MshC. We also determined that NTF1836 kills non-replicating M. tuberculosis in the carbon starvation model of latency.

Comparison of QTc data analysis methods recommended by the ICH E14 guidance and exposure-response analysis: case study of a thorough QT study of asenapine.

An assessment of the effects of asenapine on QTc interval in patients with schizophrenia revealed a discrepancy between the results obtained by two different methods: an intersection-union test (IUT) (as recommended in the International Conference on Harmonisation E14 guidance) and an exposure-response (E-R) analysis. Simulations were performed in order to understand and reconcile this discrepancy. Although estimates of the time-matched, placebo-corrected mean change in QTc from baseline (ddQTc) at peak plasma concentrations from the E-R analysis ranged from 2 to 5 ms per dose level, the IUT applied to simulated data from the E-R model yielded maximum ddQTc estimates of 7-10 ms for the various doses of asenapine. These results indicate that the IUT can produce biased estimates that may induce a high false-positive rate in individual thorough QTc trials. In such cases, simulations from an E-R model can aid in reconciling the results from the two methods and may support the use of E-R results as a basis for labeling.

Antipsychotics in pregnancy.

Women who are pregnant and who have a history of psychosis are commonly managed with antipsychotic medications. The evidence regarding the use of antipsychotics in pregnancy has been insufficient to provide adequate support for this practice and is a concern for clinicians and women alike. This review presents literature surrounding the use of antipsychotic medications in pregnancy, providing an overview of the historical and contemporary perspectives which influence clinicians prescribing practices. Data were sourced from Medline, CINAHL, PsycINFo, using the terms antipsychotics with pregnancy and psychosis or schizophrenia. This was expanded to include the most common atypical antipsychotics: olanzapine, risperidone, clozapine, quetiapine, ziprasidone and aripiprazole. Literature was found reporting the use of antipsychotic medications in pregnancy since the introduction of antipsychotics in the 1950s, comprising mainly of authors' reviews of the literature, case studies, retrospective reports, drug company registries and more recently a prospective comparative study. This review identifies that the literature provides no clear answer for clinicians as to the risk associated with the use of antipsychotics in pregnancy. To this effect, recently in Australia, the National Register of Antipsychotic Medications in Pregnancy was established to prospectively collect information regarding outcomes for mother and baby, when antipsychotic medications have been used during pregnancy.

Comparing acute toxicity of first- and second-generation antipsychotic drugs: a 10-year, retrospective cohort study.

OBJECTIVE: Second-generation antipsychotics (SGAs) are far more commonly used in the United States compared to first-generation antipsychotics (FGAs), but the relative safety of SGAs compared to FGAs following acute toxic ingestions has not been studied. METHOD: A retrospective cohort study was performed by chart review of the California Poison Control System electronic database of 1975 cases from the 10-year period 1997 to 2006 involving patients aged 18 to 65 years who ingested a single SGA or FGA. Cases were coded for overall severity of adverse outcome as defined by the American Association of Poison Control Centers criteria and for presence of specific symptoms and treatments. Odds ratios were calculated between SGAs and FGAs for various symptoms, treatments, and outcome severity. RESULTS: Odds of a major adverse outcome or death were significantly higher for SGAs than FGAs (OR = 1.71, 95% CI = 1.09 to 2.71). Patients taking SGAs had higher odds of respiratory depression (OR = 2.39, 95% CI = 1.09 to 5.26), coma (OR = 2.18, 95% CI = 1.30 to 3.65), and hypotension (OR = 1.80, 95% CI = 1.23 to 2.63) compared to those taking FGAs but lower odds of dystonia (OR = 0.12, 95% CI = 0.08 to 0.19) or rigidity (OR = 0.30, 95% CI = 0.10 to 0.90). CONCLUSION: SGAs appear no safer than FGAs in acute overdose. While neuromuscular symptoms appear less frequently with SGAs compared to FGAs, the relatively greater rates of central nervous system depression associated with SGA overdose may be more dangerous.

Acute oxcarbazepine and atomoxetine overdose with quetiapine.

We present a case of acute oxcarbazepine and atomoxetine overdose combined with excess quetiapine in a 19-y-old male. The patient ingested approximately 36 g oxcarbazepine (514 mg/kg), 1.2 g atomoxetine (17 mg/kg), and 9 mg Quetiapine (128 mg/kg). Central nervous system (CNS) depression with initial unresponsiveness developed within 1 h of ingestion, necessitating intubation for airway protection. Despite aggressive therapy with whole bowel irrigation and charcoal administration, the patient's somnolence persisted for 4 d, punctuated by occasional violent outbursts. Prolonged QTc was noted initially, but normalized within 4 d. This case suggests that acute overdose of oxcarbazepine and atomoxetine combined with quetiapine is associated with rapid and prolonged CNS depression.

Synthesis and anticonvulsant activity of new dibenzo[1,2]thiazepine S,S-dioxides.

A new series of 11-substituted 6,11-dihydro-6-methyl-dibenzo[c,f]-[1,2]thiazepine S,S-dioxides was synthesized. Some of the components show significant anticonvulsant activity in the MES, pentetrazol and strychnine tests. The more active compounds are devoid of neurotoxic effects.