Key Learning Outcomes for Clinical Pharmacology and Therapeutics Education in Europe: A Modified Delphi Study.

Harmonizing clinical pharmacology and therapeutics (CPT) education in Europe is necessary to ensure that the prescribing competency of future doctors is of a uniform high standard. As there are currently no uniform requirements, our aim was to achieve consensus on key learning outcomes for undergraduate CPT education in Europe. We used a modified Delphi method consisting of three questionnaire rounds and a panel meeting. A total of 129 experts from 27 European countries were asked to rate 307 learning outcomes. In all, 92 experts (71%) completed all three questionnaire rounds, and 33 experts (26%) attended the meeting. 232 learning outcomes from the original list, 15 newly suggested and 5 rephrased outcomes were included. These 252 learning outcomes should be included in undergraduate CPT curricula to ensure that European graduates are able to prescribe safely and effectively. We provide a blueprint of a European core curriculum describing when and how the learning outcomes might be acquired

Comparison of Polyphenol-Enriched Tomato Juice and Standard Tomato Juice for Cardiovascular Benefits in Subjects with Stage 1 Hypertension: a Randomized Controlled Study

There is a growing body of evidence that tomato consumption reduces the risk of cardiovascular disease, through antioxidative, anti-inflammatory and hypotensive effects. We compared the effects of polyphenol-enriched and standard tomato juice on parameters of lipid and oxidative status and blood pressure in subjects with stage 1 hypertension. The experimental group (n=13) was supplemented with 200g of tomato fruit juice enriched with 1g of ethanolic extract of whole tomato fruit, while the control group (n=13) was consuming 200g tomato fruit juice. Before and after the treatment, blood samples were collected, and blood pressure was measured. Markers of oxidative stress and antioxidative defense: paraoxonase (PON1), thiobarbituric acid reactive substances (TBARS), total antioxidant status (TAS), total oxidant status (TOS), pro-oxidant-antioxidant balance (PAB) and C reactive protein (CRP) were determined in serum. Prothrombin time (PT) was measured in the whole blood samples. Parameters of lipid status, as well as susceptibility to copper-induced oxidation of LDL particles in vitro were also determined. There was a significant reduction in total cholesterol and LDL-C only in the control group at the end of the study. No significant differences were observed in the remainder of the assessed parameters along the study. In conclusion, tomato juice may have favorable effects on lipid metabolism, but polyphenol fortification does not constitute additional beneficial cardiovascular effects

Actual body weight-based vancomycin dosing in neonates

This study aimed to explore vancomycin pharmacokinetics and its covariates in critically ill neonates and to propose an easy applicable dosing nomogram for initial treatment. Individual vancomycin pharmacokinetic parameters were calculated based on therapeutic drug monitoring data using a one-compartmental model. A linear regression model was used for examination of covariates. The mean (SD) volume of distribution (Vd) and clearance (CL) for vancomycin were 0.73 (0.31) L/kg and 0.052 (0.020) L/h/kg, respectively. Vd was related to actual body weight (ABW), gestational and postmenstrual age. CL was also associated with ABW, gestational, postmenstrual age and also creatinine clearance. ABW was the strongest predictor for vancomycin pharmacokinetics and consequently dosing. Loading dose (mg) of 11.81 × ABW (kg) + 7.86 and maintenance dose (mg/day) of 40.92 × ABW (kg) -22.18 most closely approximated pharmacokinetic target. Vancomycin pharmacokinetics was mainly influenced by ABW in neonates and a practical ABW-based dosing algorithm was developed.status: publishe

Human urinary metabolomic profile of PPARalpha induced fatty acid beta-oxidation

Activation of the peroxisome proliferator-activated receptor alpha (PPARalpha) is associated with increased fatty acid catabolism and is commonly targeted for the treatment of hyperlipidemia. To identify latent, endogenous biomarkers of PPARalpha activation and hence increased fatty acid beta-oxidation, healthy human volunteers were given fenofibrate orally for 2 weeks and their urine was profiled by UPLC-QTOFMS. Biomarkers identified by the machine learning algorithm random forests included significant depletion by day 14 of both pantothenic acid (>5-fold) and acetylcarnitine (>20-fold), observations that are consistent with known targets of PPARalpha including pantothenate kinase and genes encoding proteins involved in the transport and synthesis of acylcarnitines. It was also concluded that serum cholesterol (-12.7%), triglycerides (-25.6%), uric acid (-34.7%), together with urinary propylcarnitine (>10-fold), isobutyrylcarnitine (>2.5-fold), (S)-(+)-2-methylbutyrylcarnitine (5-fold), and isovalerylcarnitine (>5-fold) were all reduced by day 14. Specificity of these biomarkers as indicators of PPARalpha activation was demonstrated using the Ppara-null mouse. Urinary pantothenic acid and acylcarnitines may prove useful indicators of PPARalpha-induced fatty acid beta-oxidation in humans. This study illustrates the utility of a pharmacometabolomic approach to understand drug effects on lipid metabolism in both human populations and in inbred mouse models

The Role of Cryotherapy in Vitreous Concentrations of Topotecan Delivered by Episcleral Hydrogel Implant

Transscleral diffusion delivery of chemotherapy is a promising way to reach the vitreal seeds of retinoblastoma, the most common intraocular malignancy in childhood. In this in vivo study, the delivery of topotecan via lens-shaped, bi-layered hydrogel implants was combined with transconjunctival cryotherapy to assess whether cryotherapy leads to higher concentrations of topotecan in the vitreous. The study included 18 New Zealand albino rabbits; nine rabbits received a topotecan-loaded implant episclerally and another nine rabbits received transconjunctival cryotherapy superotemporally 2 weeks before implant administration. Median vitreous total topotecan exposures (area under the curve, AUC) were 455 ng·h/mL for the cryotherapy group and 281 ng·h/mL for the non-cryotherapy group, and were significantly higher in the cryotherapy group, similar to maximum levels. Median plasma AUC were 50 ng·h/mL and 34 ng·h/mL for the cryotherapy and non-cryotherapy groups, respectively, with no statistically significant differences between them. In both groups, AUC values in the vitreous were significantly higher than in plasma, with plasma exposure at only approximately 11–12% of the level of vitreous exposure. The results confirmed the important role of the choroidal vessels in the pharmacokinetics of topotecan during transscleral administration and showed a positive effect of cryotherapy on intravitreal penetration, resulting in a significantly higher total exposure in the vitreous

3,4-Dehydrodebrisoquine, a novel debrisoquine metabolite formed from 4-hydroxydebrisoquine that affects the CYP2D6 metabolic ratio

Considerable unexplained intersubject variability in the debrisoquine metabolic ratio (urinary debrisoquine/4-hydroxydebrisoquine) exists within individual CYP2D6 genotypes. We speculated that debrisoquine was converted to as yet undisclosed metabolites. Thirteen healthy young volunteers, nine CYP2D6*1 homozygotes [extensive metabolizers (EMs)] and four CYP2D6*4 homozygotes [poor metabolizers (PMs)] took 12.8 mg of debrisoquine hemisulfate by mouth and collected 0- to 8- and 8- to 24-h urines, which were analyzed by gas chromatography-mass spectrometry (GCMS) before and after treatment with beta-glucuronidase. Authentic 3,4-dehydrodebrisoquine was synthesized and characterized by GCMS, liquid chromatography-tandem mass spectrometry, and (1)H NMR. 3,4-Dehydrodebrisoquine is a novel metabolite of debrisoquine excreted variably in 0- to 24-h urine, both in EMs (3.1-27.6% of dose) and PMs (0-2.1% of dose). This metabolite is produced from 4-hydroxydebrisoquine in vitro by human and rat liver microsomes. A previously unstudied CYP2D6*1 homozygote was administered 10.2 mg of 4-hydroxydebrisoquine orally and also excreted 3,4-dehydrodebrisoquine. EMs excreted 6-hydroxydebrisoquine (0-4.8%) and 8-hydroxydebrisoquine (0-1.3%), but these phenolic metabolites were not detected in PM urine. Debrisoquine and 4-hydroxydebrisoquine glucuronides were excreted in a highly genotype-dependent manner. A microsomal activity that probably does not involve cytochrome P450 participates in the further metabolism of 4-hydroxydebrisoquine, which we speculate may also lead to the formation of 1- and 3-hydroxydebrisoquine and their ring-opened products. In conclusion, this study suggests that the traditional metabolic ratio is not a true measure of the debrisoquine 4-hydroxylation capacity of an individual and thus may, in part, explain the wide intragenotype variation in metabolic ratio