Inhibition of CYP2D6 with low dose (5 mg) paroxetine in patients with high 10-hydroxynortriptyline serum levels-A prospective pharmacokinetic study

The antidepressant nortriptyline is metabolized by cytochrome P450 2D6 (CYP2D6) to the less active and more cardiotoxic drug metabolite, 10-hydroxynortriptyline. High serum levels of this metabolite (>200 μg/L) may lead to withdrawal of nortriptyline therapy. Adding CYP2D6 inhibitors reduce the metabolic activity of CYP2D6 (phenoconversion) and so decrease the forming of hydroxynortriptyline. In this study, 5 mg paroxetine is administered to patients with high hydroxynortriptyline concentrations (>200 μg/L). The shift in number of patients to therapeutic nortriptyline (50-150 μg/L) and safe hydroxynortriptyline (<200 μg/L) concentrations, and the degree of phenoconversion, expressed as the change in ratio nortriptyline/hydroxynortriptyline concentrations before and after paroxetine addition, are prospectively observed and described. After paroxetine addition, 12 patients (80%) had therapeutic nortriptyline and safe hydroxynortriptyline concentrations. Hydroxynortriptyline concentrations decreased in all patients. The average nortriptyline/hydroxynortriptyline concentrations ratio increased from 0.32 to 0.59. This study shows that 5 mg paroxetine addition is able to lower high hydroxynortriptyline serum levels to safe ranges

Conversion of STOPP/START version 2 into coded algorithms for software implementation: A multidisciplinary consensus procedure

Background: The rapid digitalization of medical practice has attracted growing interest in developing software applications for clinical guidelines and explicit screening tools to detect potentially inappropriate prescribing, such as STOPP/START criteria. The aim of the current study was to develop and provide logically unambiguous algorithms of STOPP/START criteria version 2, encoded with international disease and medication classification codes, to facilitate the development of software applications for multiple purposes. Methods: A four round multidisciplinary consensus and validation procedure was conducted to develop implementable coded algorithms for software applications of STOPP/START criteria version 2, based on ICD, ICPC, LOINC and ATC classification databases. Results: Consensus was reached for all 34 START criteria and 76 out of 80 STOPP criteria. The resulting 110 algorithms, modeled as inference rules in decision tables, are provided as supplementary data. Conclusion: This is the first study providing implementable algorithms for software applications based on STOPP/START version 2, validated in a computer decision support system. These algorithms could serve as a template for applying STOPP/START criteria version 2 to any software application, allowing for adaptations of the included ICD, ICPC and ATC codes and changing the cut-off levels for laboratory measurements to match local guidelines or clinical expertise