Yoseph Caraco

CYP2C9 Genotype-guided Warfarin Prescribing Enhances the Efficacy and Safety of Anticoagulation : A Prospective Randomized Controlled Study

Warfarin anticoagulation effect is characterized by marked variability, some of which has been attributed to CYP2C9 polymorphisms. This study prospectively examines whether a priori knowledge of CYP2C9 genotype may improve warfarin therapy. Patients were randomly assigned to receive warfarin by a validated algorithm (“control”, 96 patients) or CYP2C9 genotype‐adjusted algorithms (“study”, 95 patients). The first therapeutic international normalized ratio and stable anticoagulation were reached 2.73 and 18.1 days earlier in the study group, respectively (P<0.001). The faster rate of initial anticoagulation was driven by a 28% higher daily dose in the study group (P<0.001). Study group patients spent more time within the therapeutic range (80.4 vs 63.4%, respectively, P<0.001) and experienced less minor bleeding (3.2 vs 12.5%, P<0.02, respectively). In conclusion, CYP2C9 genotype‐guided warfarin therapy is more efficient and safer than the “average‐dose” protocol. Future research should focus on construction of algorithms that incorporate other polymorphisms (VKORC1), host factors, and environmental influences.

Aceneuramic Acid Extended Release Administration Maintains Upper Limb Muscle Strength in a 48-week Study of Subjects with GNE Myopathy: Results from a Phase 2, Randomized, Controlled Study

Background: GNE Myopathy (GNEM) is a progressive adult-onset myopathy likely caused by deficiency of sialic acid (SA) biosynthesis. Objective: Evaluate the safety and efficacy of SA (delivered by aceneuramic acid extended-release [Ace-ER]) as treatment for GNEM. Methods: A Phase 2, randomized, double-blind, placebo-controlled study evaluating Ace-ER 3 g/day or 6 g/day versus placebo was conducted in GNEM subjects (n = 47). After the first 24 weeks, placebo subjects crossed over to 3 g/day or 6 g/day for 24 additional weeks (dose pre-assigned during initial randomization). Assessments included serum SA, muscle strength by dynamometry, functional assessments, clinician- and patient-reported outcomes, and safety. Results: Dose-dependent increases in serum SA levels were observed. Supplementation with Ace-ER resulted in maintenance of muscle strength in an upper extremity composite (UEC) score at 6 g/day compared with placebo at Week 24 (LS mean difference +2.33 kg, p = 0.040), and larger in a pre-specified subgroup able to walk ≥200 m at Screening (+3.10 kg, p = 0.040). After cross-over, a combined 6 g/day group showed significantly better UEC strength than a combined 3 g/day group (+3.46 kg, p = 0.0031). A similar dose-dependent response was demonstrated within the lower extremity composite score, but was not significant (+1.06 kg, p = 0.61). The GNEM-Functional Activity Scale demonstrated a trend improvement in UE function and mobility in a combined 6 g/day group compared with a combined 3 g/day group. Patients receiving Ace-ER tablets had predominantly mild-to-moderate AEs and no serious adverse events. Conclusions: This is the first clinical study to provide evidence that supplementation with SA delivered by Ace-ER may stabilize muscle strength in individuals with GNEM and initiating treatment earlier in the disease course may lead to better outcomes.

Long-Term Outcomes of Medication Intervention Using the Screening Tool of Older Persons Potentially Inappropriate Prescriptions Screening Tool to Alert Doctors to Right Treatment Criteria

To compare 24‐month outcomes of participants of a prospective randomized controlled trial (RCT) assigned to undergo a medication intervention of orally communicated recommendations based on Screening Tool of Older Persons potentially inappropriate Prescriptions (STOPP) and Screening Tool to Alert Doctors to Right Treatment (START) (intervention group) with outcomes of those assigned to undergo written medication review (control group).

Characterization of Strength and Function in Ambulatory Adults With Gne Myopathy

Objective: To characterize the pattern and extent of muscle weakness and impact on physical functioning in adults with GNEM. Methods: Strength and function were assessed in GNEM subjects (n = 47) using hand-held dynamometry, manual muscle testing, upper and lower extremity functional capacity tests, and the GNEM-Functional Activity Scale (GNEM-FAS). Results: Profound upper and lower muscle weakness was measured using hand-held dynamometry in a characteristic pattern, previously described. Functional tests and clinician-reported outcomes demonstrated the consequence of muscle weakness on physical functioning. Conclusions: The characteristic pattern of upper and lower muscle weakness associated with GNEM and the resulting functional limitations can be reliably measured using these clinical outcome assessments of muscle strength and function.

Characterization of Blood Glucose & Glycosuria following IV Trehalose (Cabaletta) administration for OPMD

CharaCTerizaTioN of Blood GluCoSe & GlyCoSuria followiNG iV TrehaloSe (CaBaleTTa) admiNiSTraTioN for oPmd H. Vornovitzki; S. Blotnick; I. Gliko-Kabir; Z. Argov; and Y. Caraco Clinical Pharmacology Unit, Hadassah University Hospital, Jerusalem, Israel; and Bioblast-Pharma Ltd., Tel-Aviv, Israel Background: Trehalose is a naturally occurring disaccharide that is currently being evaluated for the treatment of Oculopharyngeal Muscular Dystrophy (OPMD) and spinocerebellar ataxia 3. Objective: The purpose of this sub-study (part of OPMD phase 2 therapy trial) was to evaluate the extent of increase in blood glucose and the extent and duration of glycosuria associated with the intravenous administration of Trehalose. Methods: Fourteen OPMD patients received weekly intravenous 30 gr trehalose over a period of approximately 80 minutes. Just prior to and following the administration of the 3rd dose, blood were taken periodically over 5 hours for the evaluation of plasma concentration of trehalose using a validated high performance liquid chromatographic tandem mass spectrometry. On a different dosing day, plasma and urine samples were taken periodically over 8 hours for the evaluation of glucose concentration using hexokinase enzyme method on a chemistry analyzer. Results: Plasma concentration of trehalose exhibited more than 2-fold variation with AUC0→ 5 ranging from 2698 to 6103 μg*h/mL. A mild rise in plasma glucose was noted in 11 patients reaching a peak of (mean ± SD) 11.28 ± 7.27 mg% within 1-2 hours following Trehalose infusion. The rise in blood glucose was transient and it reverted back to pre-Trehalose concentrations within 1-4 hours (2.10 ± 1.29 hours). Some degree of glycosuria was noted in all patients. Maximal glucose urinary concentration varied ranging from 42 mg% and up to 1031 mg% (358 ± 341 mg%). Peak glycosuria was noted within 1-3 hours and it was evident only in 1 patient in the urine sample taken after 8 hours. Conclusions: The intravenous administration of 30 gr trehalose (Cabaletta) is associated with a subtle rise in blood glucose concentration and transient glycosuria. The presence of urinary glucose represents most probably in-situ renal activity of trehalase.

Phenytoin metabolic ratio (PMR) correlates with formation clearance of (S)‐7‐OH‐warfarin

To examine the correlation between PMR, a phenotypic marker of CYP2C9, and formation clearance (CLf) of (S)‐7‐OH‐warfarin (S7HW), the CYP2C9 mediated major metabolite of (S)‐warfarin, in order to evaluate whether PMR is predictive of warfarin (W) maintenance dose.