Case Report: The Clinical Toxicity of Dimethylamine Borane

Context: Dimethylamine borane (DMAB) is a reducing agent used in nonelectric plating of semiconductors. Exposures are usually through occupational contact. We report here four cases of people who suffered from work-related exposure to DMAB. Case presentation: Three patients exposed to DMAB decontaminated immediately by drinking a lot of water; they reported dizziness, nausea, diarrhea 6–8 hr later. The other patient did not decontaminate at once, and he suffered from more severe symptoms, including dizziness, nausea, limb numbness, slurred speech, irritable mood, and ataxia 13 hr later. Magnetic resonance imaging showed symmetric lesions with hyperintensity on T2WI and FLAIR in bilateral cerebellar dantate nuclei. This patient was readmitted to the hospital due to difficulty in walking and climbing 18 days after exposure. Lower leg weakness and drop foot were found bilaterally. A nerve conduction study revealed polyneuropathy with motor-predominant axonal degeneration. This patient receives regular outpatient followups and still walks with a clumsy gait and has difficulty with hand-grasping activity. Discussion: This case study demonstrates that DMAB is highly toxic to humans through any route of exposure, and dermal absorption is the major route of neurotoxicity. DMAB induces acute cortical and cerebellar injuries and delayed peripheral neuropathy. Relevance: Further investigation of the toxic mechanism of DMAB is warranted. Early decontamination with copious water is the best current treatment for exposure to DMAB

Sesamin: A Naturally Occurring Lignan Inhibits CYP3A4 by Antagonizing the Pregnane X Receptor Activation

Inconsistent expression and regulation of drug-metabolizing enzymes (DMEs) are common causes of adverse drug effects in some drugs with a narrow therapeutic index (TI). An important cytochrome, cytochrome P450 3A4 (CYP3A4), is predominantly regulated by a nuclear receptor, pregnane X receptor (PXR). Sesamin, a major lignan constituent in sesame seeds and oil, exhibits a variety of biological functions; however, the effect of sesamin on the modulation of CYP3A4 is not well understood. In this study, the effects of sesamin on the PXR-CYP3A4 pathway were characterized, as well as the underlying mechanisms of those effects. Sesamin potently attenuated CYP3A4 induction in a dose-dependent manner by blocking the activation of PXR. The PXR inducer-mediated inhibition of CYP3A4 was further evidenced by the ability of sesamin to attenuate the effects of several PXR ligands in the CYP3A4 reporter assay. Further mechanistic studies showed that sesamin inhibited PXR by interrupting the interacting with coregulators. These results may lead to the development of new therapeutic and dietary approaches to reduce the frequency of inducer-drug interaction. Sesamin was established as a novel inhibitor of PXR and may be useful for modulating DMEs expression and drug efficacies. Modification of CYP3A4 expression and activity by consumption of sesamin may have important implications for drug safety

Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry

Background and purpose: Prospectively collected data comparing the safety and effectiveness of individual non-vitamin K antagonists (NOACs) are lacking. Our objective was to directly compare the effectiveness and safety of NOACs in patients with newly diagnosed atrial fibrillation (AF). Methods: In GLORIA-AF, a large, prospective, global registry program, consecutive patients with newly diagnosed AF were followed for 3 years. The comparative analyses for (1) dabigatran vs rivaroxaban or apixaban and (2) rivaroxaban vs apixaban were performed on propensity score (PS)-matched patient sets. Proportional hazards regression was used to estimate hazard ratios (HRs) for outcomes of interest. Results: The GLORIA-AF Phase III registry enrolled 21,300 patients between January 2014 and December 2016. Of these, 3839 were prescribed dabigatran, 4015 rivaroxaban and 4505 apixaban, with median ages of 71.0, 71.0, and 73.0 years, respectively. In the PS-matched set, the adjusted HRs and 95% confidence intervals (CIs) for dabigatran vs rivaroxaban were, for stroke: 1.27 (0.79–2.03), major bleeding 0.59 (0.40–0.88), myocardial infarction 0.68 (0.40–1.16), and all-cause death 0.86 (0.67–1.10). For the comparison of dabigatran vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 1.16 (0.76–1.78), myocardial infarction 0.84 (0.48–1.46), major bleeding 0.98 (0.63–1.52) and all-cause death 1.01 (0.79–1.29). For the comparison of rivaroxaban vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 0.78 (0.52–1.19), myocardial infarction 0.96 (0.63–1.45), major bleeding 1.54 (1.14–2.08), and all-cause death 0.97 (0.80–1.19). Conclusions: Patients treated with dabigatran had a 41% lower risk of major bleeding compared with rivaroxaban, but similar risks of stroke, MI, and death. Relative to apixaban, patients treated with dabigatran had similar risks of stroke, major bleeding, MI, and death. Rivaroxaban relative to apixaban had increased risk for major bleeding, but similar risks for stroke, MI, and death. Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01468701, NCT01671007. Date of registration: September 2013

Anticoagulant selection in relation to the SAMe-TT2R2 score in patients with atrial fibrillation. the GLORIA-AF registry

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007

Association between antiepileptic drugs and hepatocellular carcinoma in patients with epilepsy: a population- based case–control study

[[abstract]]Background This study explored whether antiepileptic drugs (AEDs) use increases the risk of hepatocellular carcinoma (HCC). Methods We conducted a case–control study using data from the National Health Insurance system of Taiwan. The case group comprised 1,454 epilepsy patients with newly diagnosed HCC, and the control group comprised 1,448 epilepsy patients without HCC. Both groups had similar distributions of sex and age, and follow-up duration. Possible associations with the AEDs in Taiwan were examined. Results After adjusted for AEDs (phenobarbital and primidone, clonazepam, clorazepate and diazepam, and other AEDs), and for the comorbidities of diabetes, chronic liver disease and cirrhosis, hepatitis B and C virus infection, and alcoholism, the odds ratio (OR) of HCC was 1.22 (95% confidence interval [CI]: 1.01–1.47) for the group of phenytoin users compared with nonphenytoin users. An annual means of 61–120, 121–180, and >180 of defined daily doses (DDDs) of phenytoin (OR: 4.07, 95% CI: 2.03–8.18; OR: 7.51, 95% CI: 3.03–18.7, and OR: 14.6, 95% CI: 7.88–26.9, respectively) were significantly correlated with the risk of HCC but not with a DDD of ≤60. Compared with nonphenytoin users, HCC patients who had used phenytoin within 1 year of HCC diagnosis were at a greatest risk of HCC (adjusted OR: 2.29, 95% CI: 1.71–3.08), followed by who had used phenytoin within 2 years of diagnosis (adjusted OR: 1.92, 95% CI: 1.44–2.56). Conclusion The results indicate that high dose of phenytoin was associated with a statistically significant increased OR for HCC, which was not demonstrated for low-dose phenytoin

The Clinical Significance of Venom Detection in Patients of Cobra Snakebite

Cobra snakebites are one of the most frequent occurrences among the poisonous snakebites. The correlation between the serum concentrations of cobra venom in the victims with the severity of systemic and local symptoms after envenoming is still awaited for investigation. In this paper, we have developed an enzyme-linked immunosorbent assay (ELISA) to detect Taiwan cobra venom existed in the serum of the cobra snakebite victims. This established technique allowed us to detect as low as 1 ng/ml . Totally, 31 serum samples of 27 recognized and suspected cobra snakebite patients were analyzed by the developed ELISA technique. The highest venom level detected was 1270 ng/ml in a case 2 h after being envenomed. We found that the serum concentrations of the venom in the bitten patients were well correlated with the severity of local tissue destruction. Venom levels might remain high 48 h after snakebite. Two or more vials of specific antivenom administered soon after snakebite were effective in neutralizing the circulating venom as revealed by ELISA. Higher doses of antivenom may be indicated in cases of cobra venom-induced local tissue destruction. In conclusion, these results indicate that venom detection in snakebite victims is valuable in diagnosis and severity assessment of Taiwan cobra snakebite. (C) 2003 Elsevier Science Ltd. All rights reserved