[Cardiovascular risk in gout - Role of allopurinol?] / Cardiovasculair risico bij jicht - rol voor allopurinol?

The treatment of gout is subject to different national and international guidelines. These guidelines differ in the extent to which they consider cardiovascular risk factors when deciding to start allopurinol. Observational studies and limited trial data suggest that treatment with allopurinol may reduce the risk of cardiovascular events in patients with gout. However, at this moment allopurinol remains an unproven strategy. There is need for a large randomized placebo-controlled trial with sufficient power and duration of follow-up.

The scientific basis of rational prescribing. A guide to precision clinical pharmacology based on the WHO 6-step method.

BACKGROUND AND METHODS: This opinion paper expanded on the WHO "six-step approach to optimal pharmacotherapy," by detailed exploration of the underlying pharmacological and pathophysiological principles. This exercise led to the identification of a large number of domains of research that should be addressed to make clinical pharmacology progress toward "precision clinical pharmacology," as a prerequisite for precision medicine. RESULT: In order to improve clinical efficacy and safety in patient groups (to guide drug development) as well as in individuals (to guide therapeutic options and optimize clinical outcome), developments in clinical pharmacology should at least tackle the following: (1) molecular diagnostic assays to guide drug design and development and allow physicians to identify the optimal targets for therapy in the individual patient in a quick and precise manner (to guide selection of the right drug for the right patient); (2) the setting up and validation of biomarkers of target engagement and modification as predictors of clinical efficacy and safety; (3) integration of physiological PK/PD models and intermediate markers of pharmacological effects with the natural evolution of the disease to predict the drug dose that most effectively improves clinical outcome in patient groups and individuals, making use of advanced modeling technologies (building on deterministic models, machine-learning, and deep learning algorithms); (4) methodology to validate human or humanized in vitro, ex vivo, and in vivo models for their ability to predict clinical outcome with investigational therapies, including nucleic acids or recombinant genes together with vectors (including viruses or nanoparticles), cell therapy, or therapeutic vaccines; (5) methodological complements to the gold-standard, large Phase 3 randomized clinical trial to provide clinically relevant and reliable data on the efficacy and safety of all treatment options at the population level (pragmatic clinical trials), as well as in small groups of patients (as low as n = 1); (6) regulatory science, so as to optimize the ethical review process, documentation, and monitoring of clinical trials, improve efficiency, and reduce costs of clinical drug development; (7) interventions to effectively improve patient compliance and to rationalize polypharmacy for the reduction of adverse effects and the enhancement of therapeutic interactions; and (8) appraisal of the ecological and societal impact of drug use to safeguard against environmental hazards (following the "One Health" concept) and to reduce drug resistance. DISCUSSION AND CONCLUSION: As can be seen, precision clinical pharmacology aims at being highly translational, which will require very large panels of complementary skills. Interdisciplinary collaborations, including non-clinical pharmacologists, will be key to achieve such an ambitious program.

Vascular Health in Patients in Remission of Cushing's Syndrome Is Comparable With That in BMI-Matched Controls.

CONTEXT: In active Cushing's syndrome (CS), patients suffer from endothelial dysfunction and premature atherosclerosis. However, it is uncertain to what extent vascular health recovers after long-term remission. This is highly relevant because this topic relates to future development of cardiovascular disease. OBJECTIVE: The objective of the study was to investigate whether micro- and macrovascular health is impaired after long-term remission of CS in patients with no or adequately treated comorbidities. DESIGN AND SETTING: This was a cross-sectional case-control study in two tertiary referral centers. PATIENTS AND MAIN OUTCOME MEASURES: Sixty-three patients (remission of CS for ≥ 4 y) and 63 healthy, well-matched controls were compared. In group A (58 patients and 58 controls), serum biomarkers associated with endothelial dysfunction, intima media thickness, pulse wave velocity, and pulse wave analysis were studied. In group B (14 patients and 14 controls), endothelium-dependent and -independent vasodilatation was studied in conduit arteries (flow mediated dilation of the brachial artery) and forearm skeletal muscle resistance arteries (vasodilator response to intraarterial acetylcholine, sodium-nitroprusside, and NG-monomethyl-L-arginine using venous occlusion plethysmography). RESULTS: There were no significant differences between the outcome measures of vascular health of patients and controls in groups A and B. CONCLUSION: The vascular health of patients in long-term remission of CS seems to be comparable with that of healthy gender-, age-, and body mass index-matched controls, provided that the patients have no, or adequately controlled, comorbidities. Therefore, the effects of hypercortisolism per se on the vasculature may be reversible. This accentuates the need for the stringent treatment of metabolic comorbidities in these patients.

The effect of dipyridamole on the pharmacokinetics of metformin: a randomized crossover study in healthy volunteers.

PURPOSE: Concomitant treatment with the glucose-lowering drug metformin and the platelet aggregation inhibitor dipyridamole often occurs in patients with type 2 diabetes mellitus who have suffered a cerebrovascular event. The gastrointestinal uptake of metformin is mediated by the human equilibrative nucleoside transporter 4 (ENT4), which is inhibited by dipyridamole in preclinical studies. We hypothesized that dipyridamole lowers the plasma exposure to metformin. METHODS: Eighteen healthy volunteers (mean age 23 years; 9 male) were randomized in an open-label crossover study. Subjects were allocated to treatment with metformin 500 mg twice daily in combination with dipyridamole slow-release 200 mg twice daily or to metformin alone for 4 days. After a washout period of 10 days, the volunteers were crossed over to the alternative treatment arm. Blood samples were collected during a 10-h period after intake of the last metformin dose. The primary endpoint was the area under the plasma concentration-time curve (AUC0-12h) and the maximum plasma metformin concentration (C max). RESULTS: In healthy subjects, dipyridamole did not significantly affect Cmax nor AUC0-12h of metformin under steady-state conditions. CONCLUSIONS: Previous in vitro studies report that dipyridamole inhibits the ENT4 transporter that mediates gastrointestinal uptake of metformin. In contrast, co-administration of dipyridamole at therapeutic dosages to healthy volunteers does not have a clinically relevant effect on metformin plasma steady-state exposure. This observation is reassuring for patients who are treated with this combination of drugs.

Effect of dipyridamole on myocardial reperfusion injury: A double-blind randomized controlled trial in patients undergoing elective coronary artery bypass surgery.

Dipyridamole reduces reperfusion-injury in preclinical trials and may be beneficial in patients undergoing coronary angioplasty, but its effect on patients undergoing coronary artery bypass grafting (CABG) is unknown. We hypothesized that dipyridamole limits myocardial reperfusion-injury in patients undergoing CABG. The trial design was a double-blind trial randomizing between pretreatment with dipyridamole or placebo. In all, 94 patients undergoing elective on-pump CABG were recruited between February 2010 and June 2012. The primary endpoint was plasma high-sensitive (hs-) troponin-I at 6, 12, and 24 hours after reperfusion. Secondary endpoints were the occurrence of bleeding, arrhythmias, need for inotropic support, and intensive care unit length of stay. Finally, 79 patients (33 dipyridamole) were included in the per-protocol analysis. Dipyridamole did not significantly affect postoperative hs-troponin-I (change in plasma hs-troponin I -3% [95% confidence interval -23% to 36%]; P > 0.1). Secondary endpoints did not differ between groups. Dipyridamole prior to CABG does not significantly reduce postoperative hs-troponin release.

Ticagrelor Does Not Inhibit Adenosine Transport at Relevant Concentrations: A Randomized Cross-Over Study in Healthy Subjects In Vivo.

BACKGROUND AND PURPOSE: In patients with myocardial infarction, ticagrelor reduces cardiovascular and sepsis-related mortality, and can cause dyspnea. It is suggested that this is caused by adenosine receptor stimulation, because in preclinical studies, ticagrelor blocks the nucleoside transporter and increases cellular ATP release. We now investigated the effects of ticagrelor on the adenosine system in humans in vivo. EXPERIMENTAL APPROACH: In a double-blinded, placebo-controlled cross-over trial in 14 healthy subjects, we have tested whether ticagrelor (180 mg) affects adenosine- and dipyridamole-induced forearm vasodilation, as surrogates of nucleoside uptake inhibition and adenosine formation, respectively. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was measured. Primary endpoint was adenosine-induced vasodilation. KEY RESULTS: Ticagrelor did not affect adenosine- or dipyridamole-induced forearm vasodilation. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was not affected by ticagrelor. In vitro, ticagrelor dose-dependently inhibited nucleoside uptake, but only at supra-physiological concentrations. CONCLUSION AND IMPLICATIONS: In conclusion, at relevant plasma concentration, ticagrelor does not affect adenosine transport, nor adenosine formation in healthy subjects. Therefore, it is unlikely that this mechanism is a relevant pleiotropic effect of ticagrelor. TRIAL REGISTRATION: ClinicalTrials.gov NCT01996735.

Pharmacogenetics: from bench to byte--an update of guidelines.

Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, the Royal Dutch Association for the Advancement of Pharmacy established the Pharmacogenetics Working Group with the objective of developing pharmacogenetics-based therapeutic (dose) recommendations. After systematic review of the literature, recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine-S-methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA-B44, HLA-B*5701, CYP3A5, and factor V Leiden (FVL).

The Dutch vision of clinical pharmacology.

Recent position papers addressing the profession of clinical pharmacology have expressed concerns about the decline of interest in the field among clinicians and medical educators in the United Kingdom and other Western countries, whether clinical pharmacology is actually therapeutics, and whether the profession should be limited to physicians. The Dutch Society for Clinical Pharmacology and Biopharmacy offers answers to these questions and presents a new model for clinical pharmacology.

The role of the alpha-adrenergic receptor in the leg vasoconstrictor response to orthostatic stress.

AIM: The prompt increase in peripheral vascular resistance, mediated by sympathetic alpha-adrenergic stimulation, is believed to be the key event in blood pressure control during postural stress. However, despite the absence of central sympathetic control of the leg vasculature, postural leg vasoconstriction is preserved in spinal cord-injured individuals (SCI). This study aimed at assessing the contribution of both central and local sympathetically induced alpha-adrenergic leg vasoconstriction to head-up tilt (HUT) by including healthy individuals and SCI, who lack central sympathetic baroreflex control over the leg vascular bed. METHODS: In 10 controls and nine SCI the femoral artery was cannulated for drug infusion. Upper leg blood flow (LBF) was measured bilaterally using venous occlusion strain gauge plethysmography before and during 30 degrees HUT throughout intra-arterial infusion of saline or the non-selective alpha-adrenergic receptor antagonist phentolamine respectively. Additionally, in six controls the leg vascular response to the cold pressor test was assessed during continued infusion of phentolamine, in order to confirm complete alpha-adrenergic blockade by phentolamine. RESULTS: During infusion of phentolamine HUT still caused vasoconstriction in both groups: leg vascular resistance (mean arterial pressure/LBF) increased by 10 +/- 2 AU (compared with 12 +/- 2 AU during saline infusion), and 13 +/- 3 AU (compared with 7 +/- 3 AU during saline infusion) in controls and SCI respectively. CONCLUSION: Effective alpha-adrenergic blockade did not reduce HUT-induced vasoconstriction, regardless of intact baroreflex control of the leg vasculature. Apparently, redundant mechanisms compensate for the absence of sympathetic alpha-adrenoceptor leg vasoconstriction in response to postural stress.

Measurement of the endogenous adenosine concentration in humans in vivo: methodological considerations.

The endogenous nucleoside adenosine has profound tissue protective effects in situations of ischaemia or inflammation. Animal studies have shown that various drugs can activate this protective mechanism by interfering with the metabolism of adenosine. Translation of this concept to the clinical arena is hampered by the difficulties encountered in measuring the adenosine concentration, due to the rapid cellular uptake and degradation of adenosine, which continues unabated after blood sampling, and due to the metabolically active endothelial barrier for adenosine. In the current paper, we critically discuss the various methods to measure the adenosine concentration in humans in vivo. For the measurement of circulating adenosine, we conclude that the use of a pharmacological blocker solution (containing inhibitors of the enzymes ecto-5'-nucleotidase, adenosine deaminase, and adenosine kinase, and of the equilibrative nucleoside transporter) and a purpose-built syringe which mixes the blood with this solution immediately at the tip of the needle, seems to be the most sensitive technique. However, for the measurement of adenosine concentrations in interstitial tissue, microdialysis is a suitable method, when used with an appropriate method to determine the recovery of adenosine across the semipermeable membrane to calculate the absolute adenosine concentration. Consistent use of these methods could help in the comparison of the various studies focussed on endogenous adenosine and could help to facilitate the use of drugs that modulate the adenosine concentration to protect tissues in the clinical arena.

The effect of atazanavir and atazanavir/ritonavir on UDP-glucuronosyltransferase using lamotrigine as a phenotypic probe.

Atazanavir (ATV) is known to inhibit UGT1A1-mediated glucuronidation. Here we report the effect of ATV and ATV/ritonavir (RTV) on another UGT1A isoenzyme, UGT1A4. Twenty-one healthy volunteers received a single dose of 100 mg of oral lamotrigine on days 1, 13, and 27; on each occasion blood was sampled before the dose was administered and through 120 h after ingestion of the drug. On days 8-17 the subjects received oral ATV 400 mg q.d. On days 18-30 the subjects received oral ATV 300 mg plus oral RTV 100 mg q.d. Seventeen subjects were evaluable for pharmacokinetic analysis. Geometric mean ratios (+90% confidence intervals (CIs)) of lamotrigine area under the plasma concentration-time curve (AUC)(0-inf) and peak plasma concentration (C(max)) for ATV + lamotrigine and for lamotrigine alone were 0.88 (0.86-0.91) and 0.99 (0.95-1.02), respectively; the corresponding ratios for ATV/RTV and for lamotrigine were 0.68 (0.65-0.70) and 0.94 (0.90-0.97), respectively. The mean ratio of lamotrigine-2N-glucuronide to lamotrigine AUC(0-inf) increased from 0.45 for lamotrigine to 0.71 for ATV/RTV + lamotrigine. ATV alone does not significantly influence glucuronidation of lamotrigine. In contrast, ATV/RTV results in moderately decreased exposure to lamotrigine.

Dipyridamole enhances ischaemia-induced reactive hyperaemia by increased adenosine receptor stimulation.

BACKGROUND AND PURPOSE: Dipyridamole enhances post-occlusive reactive hyperaemia (PORH) in the human forearm vascular bed. We hypothesize that this effect is completely mediated by increased adenosine receptor stimulation. To test this hypothesis, the effect of caffeine (an adenosine receptor antagonist) on dipyridamole-induced augmentation of PORH was explored. EXPERIMENTAL APPROACH: The forearm vasodilator responses to three increasing periods of forearm ischaemia (2, 5 and 13 min) were determined during placebo infusion. Forty minutes after the last reperfusion period, this procedure was repeated during intra-arterial infusion of dipyridamole (7.4 nmol min(-1) per 100 ml forearm). At least 2 weeks later, this whole procedure was repeated, but now in the presence of caffeine (90 microg min(-1) per 100 ml volume). KEY RESULTS: After 2, 5 and 13 min of ischaemia, the average forearm blood flow increased to 5.6+/-0.7, 9.7+/-1.3 and 34.5+/-2.1 ml min(-1) per 100 ml. After infusion of dipyridamole into the brachial artery, these numbers were significantly increased to 7.7+/-0.8, 12.5+/-1.5 and 41.6+/-3.1 ml min(-1) per 100 ml. This response was abolished by the concomitant infusion of caffeine (6.6+/-0.5, 10.2+/-0.6, 35.1+/-2.2 (caffeine) versus 7.4+/-0.4, 10.5+/-0.6, 33.7+/-2.2 ml min(-1)per 100 ml (caffeine/dipyridamole)). CONCLUSIONS AND IMPLICATIONS: Caffeine prevented the augmenting effect of dipyridamole on PORH. This indicates that dipyridamole-induced augmentation of PORH is mediated via increased adenosine receptor stimulation as a result of elevated extracellular formation of adenosine during ischaemia.

Flow-mediated dilatation in the superficial femoral artery is nitric oxide mediated in humans.

Flow-mediated dilatation (FMD) of the brachial and radial arteries is an important research tool for assessment of endothelial function in vivo, and is nitric oxide (NO) dependent. The leg skeletal muscle vascular bed is an important territory for studies in exercise physiology. However, the role of endothelial NO in the FMD response of lower limb arteries has never been investigated. The purpose of this study was to examine the contribution of NO to FMD in the superficial femoral artery in healthy subjects. Since physical inactivity may affect endothelial function, and therefore NO availability, spinal cord-injured (SCI) individuals were included as a model of extreme deconditioning. In eight healthy men (34 +/- 13 years) and six SCI individuals (37 +/- 10 years), the 5 min FMD response in the superficial femoral artery was assessed by echo-Doppler, both during infusion of saline and during infusion of the NO synthase blocker N(G)-monomethyl-L-arginine (L-NMMA). In a subset of the controls (n = 6), the 10 min FMD response was also examined using the same procedure. The 5 min FMD response in controls (4.2 +/- 0.3%) was significantly diminished during L-NMMA infusion (1.0 +/- 0.2%, P < 0.001). In SCI, L-NMMA also significantly decreased the FMD response (from 8.2 +/- 0.4% during saline to 2.4 +/- 0.5% during L-NMMA infusion). The hyperaemic flow response during the first 45 s after cuff deflation was lower in both groups during infusion of L-NMMA, but the effect of L-NMMA on FMD persisted in both groups after correction for the shear stress stimulus. The 10 min FMD was not affected by L-NMMA (saline: 5.4 +/- 1.6%, L-NMMA: 5.6 +/- 1.5%). Superficial femoral artery FMD in response to distal arterial occlusion for a period of 5 min is predominantly mediated by NO in healthy men and in the extremely deconditioned legs of SCI individuals.

Physical (in)activity and endothelium-derived constricting factors: overlooked adaptations.

The inner surrounding of arterial vessels, the endothelium, is optimally located to detect changes in blood characteristics or blood flow that may result from changes in physical activity or from diseases. In response to physical stimuli, the endothelium varies its release of circulating vasoactive substances and serves as a source of local and systemic endothelium-derived dilator and vasoconstrictor factors. Endothelial dysfunction is one of the earliest markers of vascular abnormalities observed in cardiovascular disease and ageing. Exercise training is an efficient therapeutic strategy to improve endothelial function. Traditionally, studies on endothelial dysfunction and physical (in)activity-related effects on vascular adaptations are primarily focused on vasodilator substances (i.e. nitric oxide). One may suggest that augmentation of vasoconstrictor pathways (such as endothelin-1 and angiotensin II) contributes to the endothelial dysfunction observed after physical inactivity. Moreover, these pathways may also explain the exercise-induced beneficial cardiovascular adaptations. This review summarizes the current knowledge on the effects of physical (in)activity on several endothelium-derived vasoconstrictor substances.

Local vasoconstriction in spinal cord-injured and able-bodied individuals.

Local vasoconstriction plays an important role in maintaining blood pressure in spinal cord-injured individuals (SCI). We aimed to unravel the mechanisms of local vasoconstriction [venoarteriolar reflex (VAR) and myogenic response] using both limb dependency and cuff inflation in SCI and compare these with control subjects. Limb blood flow was measured in 11 male SCI (age: 24-55 yr old) and 9 male controls (age: 23-56 yr old) using venous occlusion plethysmography in forearm and calf during three levels of 1) limb dependency, and 2) cuff inflation. During limb dependency, vasoconstriction relies on both the VAR and the myogenic response. During cuff inflation, the decrease in blood flow is caused by the VAR and by a decrease in arteriovenous pressure difference, whereas the myogenic response does not play a role. At the highest level of leg dependency, the percent increase in calf vascular resistance (mean arterial pressure/calf blood flow) was more pronounced in SCI than in controls (SCI 186 +/- 53%; controls 51 +/- 17%; P = 0.032). In contrast, during cuff inflation, no differences were found between SCI and controls (SCI 17 +/- 17%; controls 14 +/- 10%). Percent changes in forearm vascular resistance in response to either forearm dependency or forearm cuff inflation were equal in both groups. Thus local vasoconstriction during dependency of the paralyzed leg in SCI is enhanced. The contribution of the VAR to local vasoconstriction does not differ between the groups, since no differences between groups existed for cuff inflation. Therefore, the augmented local vasoconstriction in SCI during leg dependency relies, most likely, on the myogenic response.

[Subglottal stenosis as the first symptom of Wegener's granulomatosis]. / Subglottische stenose als eerste uiting van de ziekte van Wegener.

A 51-year-old woman presented with a sore throat, hoarseness and difficulty in swallowing. On physical examination she was found to have stridor. Laryngoscopy revealed a subglottal stenosis. Infection was thought to be the cause but this was not confirmed by sputum or laryngeal cultures. Because of the clinical course and the presence of antineutrophil cytoplasmic proteinase-3 antibodies, Wegener's granulomatosis was diagnosed. Immunosuppressive therapy led to improvement. At 4-year follow-up the patient had scleritis but no ENT problems. Wegener's granulomatosis should always be considered in a patient with a subglottal stenosis; it can be the first symptom of this disease.

Methotrexate modulates the kinetics of adenosine in humans in vivo.

BACKGROUND: Animal studies suggest that the anti-inflammatory effect of methotrexate (MTX) is mediated by increased adenosine concentrations. OBJECTIVE: To assess the effect of MTX on the vasodilator effects of adenosine and the nucleoside uptake inhibitor, dipyridamole, in humans in vivo as a marker for changes in adenosine kinetics. METHODS: Ten patients with active arthritis were treated with MTX (15 mg/week). Measurements were performed before and after 12 weeks of treatment. At these time points, the activity of adenosine deaminase was measured in isolated lymphocytes, and forearm blood flow (FBF) was determined by venous occlusion plethysmography during administration of adenosine and dipyridamole into the brachial artery. RESULTS: The Vmax of adenosine deaminase in lymphocytes was reduced by MTX treatment (p<0.05). MTX significantly enhanced vasodilator response to adenosine (0.5 and 1.5 microg/min/dl of forearm tissue; mean (SE) FBF ratio increased from 1.2 (0.2) to 1.4 (0.2) and 2.2 (0.2) ml/dl/min, respectively, before and from 1.3 (0.1) to 1.8 (0.2) and 3.2 (0.5) ml/dl/min during MTX treatment; p<0.05). Also, dipyridamole-induced vasodilatation (30 and 100 microg/min/dl) was enhanced by MTX (FBF ratio increased from 1.2 (0.2) to 1.5 (0.3) and 1.8 (0.2), respectively, before and from 1.3 (0.1) to 1.8 (0.2) and 2.4 (0.4) during MTX treatment; p<0.05). CONCLUSIONS: MTX treatment inhibits deamination of adenosine and potentiates adenosine-induced vasodilatation. Also dipyridamole-induced vasodilatation is enhanced by MTX treatment, suggesting an increased extracellular formation of adenosine. These effects on the adenosine kinetics in humans may contribute to the therapeutic efficacy of MTX.