Is anti-factor Xa chromogenic assay for Rivaroxaban appropriate in clinical practice? Advantages and comparative drawbacks.

INTRODUCTION: No routine monitoring is required with factor Xa inhibitor rivaroxaban. Yet, its titration must be adapted, and its misuse may lead to increased risk of bleeding; therefore, therapeutic rivaroxaban monitoring might help in specific situations. MATERIAL AND METHODS: As asked by clinicians of our medical center, we measured rivaroxaban plasma concentrations in real conditions of use and checked their corresponding prescriptions. Measurement of 112 samples from 94 consecutive patients was performed with a Biophen LRT® anti-Xa chromogenic assay and compared blindly to the HPLC-MSMS "gold standard" method. Rivaroxaban was effectively given to 80 out of 94 patients but a mere 57% through an adequate prescription (within the scope of indications/titration). All chromogenic measurements were over the pre-specified 30ng/ml LOQ, whereas only 98 /114 samples had quantifiable rivaroxaban with HPLC-MSMS (LOQ 1ng/ml). Correlation between the two methods and linear regression were highly significant (p<0.0001). However, chromogenic values (mean 141.6ng/ml[96.6]) overestimated HPLC-MSMS values (119.7ng/ml[79.5]) by 22ng/ml according to Bland-Altman analysis (p<0.001). After re-assessing the chromogenic LOQ at 52ng/ml, 83 quantifiable samples had a mean concentration of 176.9ng/ml as compared to 158.5ng/ml with HPLC-MSMS, with no false positive anymore. CONCLUSIONS: In our medical center, rivaroxaban concentrations could be assessed by a rapid chromogenic method. Its pre-specified LOQ proved too high after being checked "on site" against HPLC-MSMS. Prescriptions for rivaroxaban were not optimal. An overestimated LOQ may impair observance monitoring or predispose patients to either risky thrombolysis or otherwise adjournable surgery in clinical practice.

An unusual case of death probably triggered by the association of buprenorphine at therapeutic dose with ethanol and benzodiazepines and with very low norbuprenorphine level.

Buprenorphine is largely prescribed for maintenance treatment in opioid dependence due to its safety profile. Nevertheless, fatalities at therapeutic dose have been described when associated with other central nervous system depressants, such as ethanol or benzodiazepines. Here, we report a case of death due to association of buprenorphine at therapeutic dose with benzodiazepines and ethanol. Although toxicity has been often attributed to its metabolite norbuprenorphine rather than to buprenorphine itself, in our case, norbuprenorphine was not detected in urine and bile and only in traces in blood. Moreover, the presence in blood of free buprenorphine but not of glucuronide metabolites argues for an unusual early death, at the beginning of buprenorphine metabolism. We propose that in the context of prior toxic impregnation, buprenorphine directly (and not via its metabolite norbuprenorphine) acted as a triggering factor by blocking the ventilatory response, rapidly leading to fatal respiratory depression.

Cafeteria diet induces obesity and insulin resistance associated with oxidative stress but not with inflammation: improvement by dietary supplementation with a melon superoxide dismutase.

Oxidative stress is involved in obesity. However, dietary antioxidants could prevent oxidative stress-induced damage. We have previously shown the preventive effects of a melon superoxide dismutase (SODB) on oxidative stress. However, the mechanism of action of SODB is still unknown. Here, we evaluated the effects of a 1-month curative supplementation with SODB on the liver of obese hamsters. Golden Syrian hamsters received either a standard diet or a cafeteria diet composed of high-fat, high-sugar, and high-salt supermarket products, for 15 weeks. This diet resulted in insulin resistance and in increased oxidative stress in the liver. However, inflammatory markers (IL-6, TNF-α, and NF-κB) were not enhanced and no liver steatosis was detected, although these are usually described in obesity-induced insulin resistance models. After the 1-month supplementation with SODB, body weight and insulin resistance induced by the cafeteria diet were reduced and hepatic oxidative stress was corrected. This could be due to the increased expression of the liver antioxidant defense proteins (manganese and copper/zinc superoxide dismutase, catalase, and glutathione peroxidase). Even though no inflammation was detected in the obese hamsters, inflammatory markers were decreased after SODB supplementation, probably through the reduction of oxidative stress. These findings suggest for the first time that SODB could exert its antioxidant properties by inducing the endogenous antioxidant defense. The mechanisms underlying this induction need to be further investigated.