Individualized dosing of evinacumab is predicted to yield reductions in drug expenses

Background: Evinacumab is a first-in-class inhibitor of angiopoietin‐like protein 3 (ANGPTL3) for treatment of the rare disease homozygous familial hypercholesterolemia (HoFH). With projected drug costs of $450,000 per person per year, the question rises if cost-efficacy of evinacumab can be further improved. Objectives: To develop an individualized dosing regimen te reduce drug expenses. Methods: Using the clinical and pharmacological data as provided by the license holder, we developed an alternative dosing regimen in silico based on the principles of reduction of wastage by dosing based on weight bands rather than a linear milligram per kilogram body weight (mg/kg) dosing regimen, as well as dose individualization guided by low density lipoprotein cholesterol (LDL-C) response. Results: We found that the average quantity of drug used for a dose could be reduced by 34% without predicted loss in efficacy (LDL-C reduction 24 weeks after treatment initiation). Conclusion: Dose reductions without compromising efficacy seem feasible. We call for implementation and prospective evaluation of this strategy to reduce treatment costs of HoFH.</p

Diannexin Protects against Renal Ischemia Reperfusion Injury and Targets Phosphatidylserines in Ischemic Tissue

Renal ischemia/reperfusion injury (IRI) frequently complicates shock, renal transplantation and cardiac and aortic surgery, and has prognostic significance. The translocation of phosphatidylserines to cell surfaces is an important pro-inflammatory signal for cell-stress after IRI. We hypothesized that shielding of exposed phosphatidylserines by the annexin A5 (ANXA5) homodimer Diannexin protects against renal IRI. Protective effects of Diannexin on the kidney were studied in a mouse model of mild renal IRI. Diannexin treatment before renal IRI decreased proximal tubule damage and leukocyte influx, decreased transcription and expression of renal injury markers Neutrophil Gelatinase Associated Lipocalin and Kidney Injury Molecule-1 and improved renal function. A mouse model of ischemic hind limb exercise was used to assess Diannexin biodistribution and targeting. When comparing its biodistribution and elimination to ANXA5, Diannexin was found to have a distinct distribution pattern and longer blood half-life. Diannexin targeted specifically to the ischemic muscle and its affinity exceeded that of ANXA5. Targeting of both proteins was inhibited by pre-treatment with unlabeled ANXA5, suggesting that Diannexin targets specifically to ischemic tissues via phosphatidylserine-binding. This study emphasizes the importance of phosphatidylserine translocation in the pathophysiology of IRI. We show for the first time that Diannexin protects against renal IRI, making it a promising therapeutic tool to prevent IRI in a clinical setting. Our results indicate that Diannexin is a potential new imaging agent for the study of phosphatidylserine-exposing organs in vivo

Impact of lifelong exercise training on endothelial ischemia-reperfusion and ischemic preconditioning in humans.

Reperfusion is essential for ischemic tissue survival, but causes additional damage to the endothelium (i.e. ischemia-reperfusion [IR] injury). Ischemic preconditioning (IPC) refers to short repetitive episodes of ischemia that can protect against IR. However, IPC efficacy attenuates with older age. Whether physical inactivity contributes to the attenuated efficacy of IPC to protect against IR injury in older humans is unclear. We tested the hypotheses that lifelong exercise training relates to 1) attenuated endothelial IR and 2) maintained IPC efficacy that protects veteran athletes against endothelial IR. In 18 sedentary male individuals (SED, 20 years, 63±7 years) and 20 veteran male athletes (ATH, >5 exercise hours/week for >20 years, 63±6 years), we measured brachial artery endothelial function with flow-mediated dilation (FMD) before and after IR. We induced IR by 20-minutes of ischemia followed by 20-minutes of reperfusion. Randomized over 2 days, participants underwent either 35-minute rest or IPC (3 cycles of 5-minutes cuff inflation to 220 mmHg with 5-minutes of rest) before IR. In SED, FMD decreased after IR (median [interquartile range]): (3.0% [2.0-4.7] to 2.1% [1.5-3.9], P=0.046) and IPC did not prevent this decline (4.1% [2.6-5.2] to 2.8% [2.2-3.6],P=0.012). In ATH, FMD was preserved after IR (3.0% [1.7-5.4] to 3.0% [1.9-4.1], P=0.82) and when IPC preceded IR (3.2% [1.9-4.2] to 2.8% [1.4-4.6],P=0.18). These findings indicate that lifelong exercise training is associated with increased tolerance against endothelial IR. These protective, preconditioning effects of lifelong exercise against endothelial ischemia-reperfusion may contribute to the cardio-protective effects of exercise training

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines

Despite advances in the field of pharmacogenetics (PGx), clinical acceptance has remained limited. The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of three anti-cancer drugs (fluoropyrimidines: 5-fluorouracil, capecitabine and tegafur) to decrease the risk of severe, potentially fatal, toxicity (such as diarrhoea, hand-foot syndrome, mucositis or myelosuppression). Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) enzyme deficiency increases risk of fluoropyrimidine-induced toxicity. The DPYD-gene activity score, determined by four DPYD variants, predicts DPD activity and can be used to optimize an individual's starting dose. The gene activity score ranges from 0 (no DPD activity) to 2 (normal DPD activity). In case it is not possible to calculate the gene activity score based on DPYD genotype, we recommend to determine the DPD activity and adjust the initial dose based on available data. For patients initiating 5-fluorouracil or capecitabine: subjects with a gene activity score of 0 are recommended to avoid systemic and cutaneous 5-fluorouracil or capecitabine; subjects with a gene activity score of 1 or 1.5 are recommended to initiate therapy with 50% the standard dose of 5-fluorouracil or capecitabine. For subjects initiating tegafur: subjects with a gene activity score of 0, 1 or 1.5 are recommended to avoid tegafur. Subjects with a gene activity score of 2 (reference) should receive a standard dose. Based on the DPWG clinical implication score, DPYD genotyping is considered "essential", therefore directing DPYD testing prior to initiating fluoropyrimidines

Leg blood flow measurements using venous occlusion plethysmography during head-up tilt

We tested whether venous occlusion plethysmography (VOP) is an appropriate method to measure calf blood flow (CBF) during head-up tilt (HUT). CBF measured with VOP was compared with superficial femoral artery blood flow as measured by Doppler ultrasound during incremental tilt angles. Measurements of both methods correlated well (r = 0.86). Reproducibility of VOP was fair in supine position and 30° HUT (CV: 11%–15%). This indicates that VOP is an applicable tool to measure leg blood flow during HUT, especially up to 30° HUT

Ischemic Preconditioning in the Animal Kidney, a Systematic Review and Meta-Analysis

Ischemic preconditioning (IPC) is a potent renoprotective strategy which has not yet been translated successfully into clinical practice, in spite of promising results in animal studies. We performed a unique systematic review and meta-analysis of animal studies to identify factors modifying IPC efficacy in renal ischemia/reperfusion injury (IRI), in order to enhance the design of future (clinical) studies. An electronic literature search for animal studies on IPC in renal IRI yielded fifty-eight studies which met our inclusion criteria. We extracted data for serum creatinine, blood urea nitrogen and histological renal damage, as well as study quality indicators. Meta-analysis showed that IPC reduces serum creatinine (SMD 1.54 [95%CI 1.16, 1.93]), blood urea nitrogen (SMD 1.42 [95% CI 0.97, 1.87]) and histological renal damage (SMD 1.12 [95% CI 0.89, 1.35]) after IRI as compared to controls. Factors influencing IPC efficacy were the window of protection (<24 h = early vs. ≥24 h = late) and animal species (rat vs. mouse). No difference in efficacy between local and remote IPC was observed. In conclusion, our findings show that IPC effectively reduces renal damage after IRI, with higher efficacy in the late window of protection. However, there is a large gap in study data concerning the optimal window of protection, and IPC efficacy may differ per animal species. Moreover, current clinical trials on RIPC may not be optimally designed, and our findings identify a need for further standardization of animal experiments

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene–drug interaction of DPYD and fluoropyrimidines

Despite advances in the field of pharmacogenetics (PGx), clinical acceptance has remained limited. The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of three anti-cancer drugs (fluoropyrimidines: 5-fluorouracil, capecitabine and tegafur) to decrease the risk of severe, potentially fatal, toxicity (such as diarrhoea, hand-foot syndrome, mucositis or myelosuppression). Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) enzyme deficiency increases risk of fluoropyrimidine-induced toxicity. The DPYD-gene activity score, determined by four DPYD variants, predicts DPD activity and can be used to optimize an individual’s starting dose. The gene activity score ranges from 0 (no DPD activity) to 2 (normal DPD activity). In case it is not possible to calculate the gene activity score based on DPYD genotype, we recommend to determine the DPD activity and adjust the initial dose based on available data. For patients initiating 5-fluorouracil or capecitabine: subjects with a gene activity score of 0 are recommended to avoid systemic and cutaneous 5-fluorouracil or capecitabine; subjects with a gene activity score of 1 or 1.5 are recommended to initiate therap

Reflex systemic sympatho-neural response to brachial adenosine infusion in treated heart failure

Item does not contain fulltextAIMS: In healthy men, brachial artery adenosine infusion elicits a reflex increase in total body norepinephrine (NE) spillover (TBS) that is blunted by oral angiotensin AT(1) receptor blockade. Our objectives were to determine whether a similar reflex is active in treated heart failure (HF) patients and attenuated by ARB. METHODS AND RESULTS: In this double-blind study, 12 patients with an ejection fraction </=40% were randomized to 2 weeks of oral candesartan up-titrated to 32 mg/day or placebo. Forearm blood flow was measured bilaterally by venous occlusion plethysmography. Total body NE spillover was determined following infusion of tritiated NE. After saline was infused into the non-dominant brachial artery to establish baseline values, adenosine and nitroprusside (as vasodilator control) were administered in random order. Both caused dose-dependent increases in ipsilateral but not contralateral blood flow. Nitroprusside had no TBS effect, whereas adenosine reduced TBS from 3967 (SD 2362) to 3293 pmol/min (SD 2093) (P = 0.03). This decrease was not augmented in candesartan-treated subjects [-1096 (SD 726) vs. -253 pmol/min (SD 1094); placebo vs. candesartan; P = 0.22]. CONCLUSIONS: In contrast to healthy men, in treated HF patients, locally infused adenosine does not elicit a reflex sympatho-excitatory response mediated by angiotensin AT(1)-modulated neurotransmission