Basic & clinical pharmacology & toxicology
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Basic Clin. Pharmacol. Toxicol. · Oct 2017
Observational StudyA 10-Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital-wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients?
A retrospective study was conducted to assess our 10-year experience of therapeutic drug monitoring (TDM) of linezolid in a large patient population to establish whether conventional dosing may result in adequate drug exposure in the majority of patients. Patients included in this study underwent TDM of linezolid trough concentration (Cmin ) during treatment with conventional doses of 600 mg every 12 hr in the period between January 2007 and June 2016. The desired range of Cmin was set between 2 and 7 mg/L (underexposure, Cmin < 2 mg/L; overexposure, Cmin > 7 mg/L). ⋯ Linezolid Cmin was not correlated linearly with CrCLC-G (R2 = 0.061). Variability in renal function explained only partially the very wide interindividual linezolid Cmin variability. Our study suggests that TDM could represent a valuable approach in optimizing linezolid exposure in the majority of patients.
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Basic Clin. Pharmacol. Toxicol. · Oct 2017
Case ReportsSevere Acute Valproic Acid Intoxication Successfully Treated with Liver Support Therapy.
Valproic acid (VPA) is widely used for the treatment of epilepsy. However, its overdose can cause intoxication and could be life-threatening. Due to the lack of specific antidote and poorness of endogenous clearance, extracorporeal treatment for severe intoxication cases is indicated. ⋯ In addition to standard therapy, she received two sessions of extracorporeal blood purification using a system based on fractionated plasma separation and adsorption mode integrated with continuous veno-venous haemofiltration (FPSA-CVVH), which is usually used for liver support therapy at our hospital. Her serum concentration of VPA decreased dramatically to 40.18 mg/L and her consciousness recovered completely within 24 hr after admission. Therefore, although haemodialysis has been reported to be effective in the treatment for VPA poisoning, FPSA-CVVH may provide an option for patients who require bedside therapy but have an unstable haemodynamic status or other conditions that result in inability to endure haemodialysis.
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Basic Clin. Pharmacol. Toxicol. · Jul 2017
Randomized Controlled TrialGenetic Influences of OPRM1, OPRD1 and COMT on Morphine Analgesia in a Multi-Modal, Multi-Tissue Human Experimental Pain Model.
Human studies on experimentally induced pain are of value to elucidate the genetic influence on morphine analgesia under controlled conditions. The aim of this study was to investigate whether genetic variants of mu-, kappa- and delta-opioid receptor genes (OPRM1, OPRK1 and OPRD1) and catechol-O-methyltransferase gene (COMT) are associated with the morphine analgesia. The study was a randomized, double-blind, two-way, crossover, single-dose study conducted in 40 healthy participants, where morphine was compared with placebo. ⋯ Moreover, in males, variability in morphine analgesia to rectal thermal stimulation was associated with OPRD1 polymorphisms: rs2234918 (p = 0.01) and rs533123 (p = 0.046). The study was explorative and hypothesis-generating due to the relatively small study size. However, results suggest that genetic variants in the COMT and OPRM1 irrespective of gender, and OPRD1 in males may contribute to the variability in morphine analgesia in experimental pain models.
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Basic Clin. Pharmacol. Toxicol. · Apr 2017
Case ReportsIdarucizumab for Reversal of Dabigatran Prior to Acute Surgery: A Schematic Approach Based on a Case Report.
Dabigatran, an oral direct thrombin inhibitor, is frequently used in treatment of venous thromboembolism and prevention of stroke in non-valvular atrial fibrillation. Recently, idarucizumab, a monoclonal antibody fragment that reverses the dabigatran effect, was introduced to the market to be used in case of life-threatening bleeding or acute surgery/invasive procedures. Whether usage should be guided by measurement of plasma dabigatran and/or other coagulation parameters is, however, still uncertain. ⋯ In this case, the decision to use idarucizumab was based on the clinical manifestations and other routine coagulation parameters, as the plasma dabigatran concentration was not available prior to administration. Due to challenges with the plasma dabigatran analysis and taking the safety of idarucizumab into consideration, it could be questioned whether a dabigatran measurement in general is necessary in this setting. Based on this case, we suggest a scheduled approach when considering requesting a plasma dabigatran measurement prior to administration of idarucizumab.
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Basic Clin. Pharmacol. Toxicol. · Mar 2017
A Novel Model of P-Glycoprotein Inhibitor Screening Using Human Small Intestinal Organoids.
P-glycoprotein (P-gp), an important efflux transporter in intestine, regulates the bioavailability of orally taken drugs. To develop an in vitro model that preferably mimics the physiological microenvironment of human intestine, we employed the three-dimensionally (3D) cultured organoids from human normal small intestinal epithelium. It was observed that the intestinal crypts could efficiently form cystic organoid structure with the extension of culture time. ⋯ Rhodamine 123 (Rh123), a typical substrate of P-gp, was actively transported across 3D organoids and accumulated in the luminal space. This transport process was also inhibited by verapamil and mitotane. In summary, the above-mentioned model based on human small intestinal 3D organoids is suitable to imitate the small intestinal epithelium and could be used as a novel in vitro model especially for P-gp inhibitor screening.