PharmVar GeneFocus: CYP4F2

\ua9 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.The Pharmacogene Variation Consortium (PharmVar) serves as a global repository providing star (*) allele nomenclature for the polymorphic human CYP4F2 gene. CYP4F2 genetic variation impacts the metabolism of vitamin K, which is associated with warfarin dose requirements, and the metabolism of drugs, such as imatinib or fingolimod, and certain endogenous compounds including vitamin E and eicosanoids. This GeneFocus provides a comprehensive overview and summary of CYP4F2 genetic variation including the characterization of 14 novel star alleles, CYP4F2*4 through *17. A description of how haplotype information cataloged by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) is also provided

Conservative treatment of idiopathic scoliosis according to FITS concept: presentation of the method and preliminary, short term radiological and clinical results based on SOSORT and SRS criteria

<p>Abstract</p> <p>Background</p> <p>Conservative scoliosis therapy according to the FITS Concept is applied as a unique treatment or in combination with corrective bracing. The aim of the study was to present author's method of diagnosis and therapy for idiopathic scoliosis FITS-Functional Individual Therapy of Scoliosis and to analyze the early results of FITS therapy in a series of consecutive patients.</p> <p>Methods</p> <p>The analysis comprised separately: (1) single structural thoracic, thoracolumbar or lumbar curves and (2) double structural scoliosis-thoracic and thoracolumbar or lumbar curves. The Cobb angle and Risser sign were analyzed at the initial stage and at the 2.8-year follow-up. The percentage of patients improved (defined as decrease of Cobb angle of more than 5 degrees), stable (+/- 5 degrees), and progressed (increase of Cobb angle of more than 5 degrees) was calculated. The clinical assessment comprised: the Angle of Trunk Rotation (ATR) initial and follow-up value, the plumb line imbalance, the scapulae level and the distance from the apical spinous process of the primary curve to the plumb line.</p> <p>Results</p> <p>In the Group A: (1) in single structural scoliosis 50,0% of patients improved, 46,2% were stable and 3,8% progressed, while (2) in double scoliosis 50,0% of patients improved, 30,8% were stable and 19,2% progressed. In the Group B: (1) in single scoliosis 20,0% of patients improved, 80,0% were stable, no patient progressed, while (2) in double scoliosis 28,1% of patients improved, 46,9% were stable and 25,0% progressed.</p> <p>Conclusion</p> <p>Best results were obtained in 10-25 degrees scoliosis which is a good indication to start therapy before more structural changes within the spine establish.</p

Physical therapy intervention studies on idiopathic scoliosis-review with the focus on inclusion criteria1

<p>Abstract</p> <p>Background</p> <p>Studies investigating the outcome of conservative scoliosis treatment differ widely with respect to the inclusion criteria used. This study has been performed to investigate the possibility to find useful inclusion criteria for future prospective studies on physiotherapy (PT).</p> <p>Materials and methods</p> <p>A PubMed search for outcome papers on PT was performed in order to detect study designs and inclusion criteria used.</p> <p>Results</p> <p>Real outcome papers (start of treatment in immature samples/end results after the end of growth; controlled studies in adults with scoliosis with a follow-up of more than 5 years) have not been found. Some papers investigated mid-term effects of exercises, most were retrospective, few prospective and many included patient samples with questionable treatment indications.</p> <p>Conclusion</p> <p>There is no outcome paper on PT in scoliosis with a patient sample at risk for being progressive in adults or in adolescents followed from premenarchial status until skeletal maturity. However, papers on bracing are more frequently found and bracing can be regarded as evidence-based in the conservative management and rehabilitation of idiopathic scoliosis in adolescents.</p

Solubility Measurements and Correlation of Modafinil in Neat Solvents and Binary Solvent Mixtures

The solubility of modafinil (MOD) form I, an antinarcoleptic drug, was measured at temperatures ranging from 278.15 to 333.15 K in ten neat solvents (acetone, acetonitrile, dimethylformamide, ethanol, ethyl acetate, methanol, methylethylketone, 1-propanol, 2-propanol, and water) and two binary solvent mixtures (acetone + water and methanol + water). The results employing the polythermal method demonstrate that the solubility increases with increasing temperature in the neat solvents and at constant composition in the binary solvent mixtures. Moreover, the MOD solubility decreases with an increasing mass fraction of water (antisolvent) in the binary solvent mixture methanol + water. In the binary solvent mixture acetone + water, the solubility exceeds its solubility in neat acetone and water, reaching a maximum at a water mass fraction of ∼20 wt %. Based on the calculated average relative deviation (ARD %), the experimental solubility data agree with the correlated data using the modified Apelblat and λh equations. Additionally, powder X-ray diffraction confirms that the recrystallized solid in the neat and binary solvent mixtures was the commercial MOD form I, except for 2-propanol. Thus, the presented solubility data provide a pathway to engineer crystallization processes for MOD toward integrated manufacturing from flow synthesis to crystallization

Efficacy of Rac and Cdc42 Inhibitor MBQ-167 in Triple-negative Breast Cancer

Abstract Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer, with a high predisposition for locally invasive and metastatic cancer. With the objective to reduce cancer metastasis, we developed small molecule inhibitors to target the drivers of metastasis, the Rho GTPases Rac and Cdc42. Of these, MBQ-167 inhibits both Rac and Cdc42 with IC50s of 103 and 78 nmol/L, respectively; and consequently, inhibits p21-activated kinase (PAK) signaling, metastatic cancer cell proliferation, migration, and mammosphere growth; induces cell-cycle arrest and apoptosis; and decreases HER2-type mammary fatpad tumor growth and metastasis (Humphries-Bickley and colleagues, 2017). Herein, we used nuclear magnetic resonance to show that MBQ-167 directly interacts with Rac1 to displace specific amino acids, and consequently inhibits Rac.GTP loading and viability in TNBC cell lines. Phosphokinome arrays in the MDA-MB-231 human TNBC cells show that phosphorylation status of kinases independent of the Rac/Cdc42/PAK pathway are not significantly changed following 200 nmol/L MBQ-167 treatment. Western blotting shows that initial increases in phospho-c-Jun and phospho-CREB in response to MBQ-167 are not sustained with prolonged exposure, as also confirmed by a decrease in their transcriptional targets. MBQ-167 inhibits tumor growth, and spontaneous and experimental metastasis in immunocompromised (human TNBC) and immunocompetent (mouse TNBC) models. Moreover, per oral administration of MBQ-167 at 100 mg/kg body weight is not toxic to immunocompetent BALB/c mice and has a half-life of 4.6 hours in plasma. These results highlight the specificity, potency, and bioavailability of MBQ-167, and support its clinical potential as a TNBC therapeutic.</jats:p

A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics

AIM:This study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to individually refine warfarin dosing in Caribbean Hispanic patients. PATIENTS & METHODS:A multiple linear regression analysis of effective warfarin doses versus relevant genotypes, admixture, clinical and demographic factors was performed in 255 patients and further validated externally in another cohort of 55 individuals. RESULTS:The admixture-adjusted, genotype-guided warfarin dosing refinement algorithm developed in Caribbean Hispanics showed better predictability (R2 = 0.70, MAE = 0.72mg/day) than a clinical algorithm that excluded genotypes and admixture (R2 = 0.60, MAE = 0.99mg/day), and outperformed two prior pharmacogenetic algorithms in predicting effective dose in this population. For patients at the highest risk of adverse events, 45.5% of the dose predictions using the developed pharmacogenetic model resulted in ideal dose as compared with only 29% when using the clinical non-genetic algorithm (p<0.001). The admixture-driven pharmacogenetic algorithm predicted 58% of warfarin dose variance when externally validated in 55 individuals from an independent validation cohort (MAE = 0.89 mg/day, 24% mean bias). CONCLUSIONS:Results supported our rationale to incorporate individual's genotypes and unique admixture metrics into pharmacogenetic refinement models in order to increase predictability when expanding them to admixed populations like Caribbean Hispanics. TRIAL REGISTRATION:ClinicalTrials.gov NCT01318057

Supplementary Figures from Efficacy of Rac and Cdc42 Inhibitor MBQ-167 in Triple-negative Breast Cancer

Supplementary Figures</p