Stereoselective handling of perhexiline:Implications regarding accumulation within the human myocardium

Purpose: Perhexiline is a prophylactic anti-ischaemic agent with weak calcium antagonist effect which has been increasingly utilised in the management of refractory angina. The metabolic clearance of perhexiline is modulated by CYP2D6 metaboliser status and stereoselectivity. The current study sought to (1) determine whether the acute accumulation of perhexiline in the myocardium is stereoselective and (2) investigate the relationship between duration of short-term therapy and the potential stereoselective effects of perhexiline within myocardium. Method: Patients (n = 129) from the active arm of a randomised controlled trial of preoperative perhexiline in cardiac surgery were treated with oral perhexiline for a median of 9 days. Correlates of atrial and ventricular concentrations of enantiomers were sought via univariate followed by multivariate analyses. Results: Myocardial uptake of both (+) and (−) perhexiline was greater in ventricles than in atria, and there was more rapid clearance of (−) than (+) perhexiline. The main determinants of atrial uptake of both (+) and (−) perhexiline were the plasma concentrations [(+) perhexiline: β = −0.256, p = 0.015; (−) perhexiline: β = −0.347, p = 0.001] and patients’ age [(+) perhexiline: β = 0.300, p = 0.004; (−) perhexiline: β = 0.288, p = 0.005]. Atrial uptake of (+) enantiomer also varied directly with duration of therapy (β = 0.228, p = 0.025), while atrial uptake of (−) perhexiline varied inversely with simultaneous heart rate (β = −0.240, p = 0.015). Conclusion: (1) Uptake of both perhexiline enantiomers into atrium is greater with advanced age and displays evidence of both saturability and minor stereoselectivity. (2) Atrial uptake of (−) perhexiline may selectively modulate heart rate reduction

Measurement of Cyclosporine A in Rat Tissues and Human Kidney Transplant Biopsies-A Method Suitable for Small (< 1 mg) Samples

Therapeutic drug monitoring is used to individualize cyclosporine A (CsA) dosing after transplantation. However, immunosuppressant concentrations within the graft may better predict clinical outcomes, including toxicity. This study aimed to develop a method suitable for CsA measurement using routine fine-needle biopsy samples. CsA was quantified retrospectively in kidney and liver tissues from 10 rats administered CsA, and 21 core needle kidney biopsies taken from renal transplant patients with suspected graft dysfunction. Dried biopsies were weighed (mean +/- SD weights of 0.22 +/- 0.18 mg), enzymatically solubilized, and then CsA was extracted and quantified using online 2-dimensional liquid chromatography-tandem mass spectrometry. The method was linear (r(2)>0.997, n = 10), accurate, and precise (quality control and calibrator coefficient of variation and bias 0.05). Similarly, in 16 transplant patients, for whom blood CsA concentrations (C2) were available within 1 day of the renal biopsy being performed, there was no significant correlation between CsA concentrations in blood and kidney tissue (Spearman r = 0.168, P>0.05). In situ CsA measurements acquired using this method could make an easy transition into clinical use due to their retrospective nature and minimal disruption to current clinical protocols and could provide an additional tool for optimizing clinical outcomes in the future

Cerebral blood volume lesion extent predicts functional outcome in patients with vertebral and basilar artery occlusion

Background CT perfusion may improve diagnostic accuracy in posterior circulation stroke. The posterior circulation Acute Stroke Prognosis Early CT score (pc-ASPECTS) on Computed Tomography Angiography source images (CTA-SI) predicts functional outcome in patients with basilar artery occlusion. Aims We assessed the prognostic value of pc-ASPECTS on CT perfusion in patients with vertebral and basilar artery occlusion (VBAO) in comparison with CTA-SI. Methods Whole-brain CT perfusion from consecutive stroke patients with VBAO at four stroke centers was retrospectively analyzed. pc-ASPECTS - a 10-point score assessing hypoattenuation on CTA-SI - was calculated from CT perfusion parameters as focally reduced cerebral blood flow or cerebral blood volume, focally increased time to peak of the deconvolved tissue residue function (Tmax) or mean transit time. Two investigators independently reviewed the images. Reliability was assessed with intraclass correlation coefficient. Good outcome was defined as modified Rankin scale ≤3 at three months. Results We included 60 patients with VBAO. After assessment of four CT perfusion maps simultaneously, area-under-ROC curve (AROC) was 0.83 (95%CI 0.72-0.93) for cerebral blood volume, 0.76 (95%CI 0.64-0.89) for cerebral blood flow, 0.77 (95%CI 0.64-0.89) for Tmax, 0.70 (95%CI 0.56-0.84) for mean transit time versus area-under-ROC curve 0.64 (95%CI 0.50-0.79) for CTA-SI. Cerebral blood volume had greater accuracy compared with CTA-SI for poor outcome (p = 0.04). In logistic regression analysis, cerebral blood volume pc-ASPECTS≤8 was independently associated with poor outcome (OR 9.3 95%CI 2.2-41; p = 0.003, adjusted for age and clinical severity). Inter-rater agreement was substantial for cerebral blood volume pc-ASPECTS (intraclass correlation coefficient 0.82 95%CI 0.71-0.90 versus 0.67 for CTA-SI 95%CI 0.43-0.81). Conclusions Cerebral blood volume pc-ASPECTS may identify VBAO patients at higher risk of disability