Analysis of Combined Effect of CYP2C19 Genetic Polymorphism and Proton Pump Inhibitors Coadministration on Trough Concentration of Voriconazole.

PURPOSE: To analyze the combined effect of CYP2C19 genetic polymorphism and PPIs coadministration on voriconazole trough concentration (VCZ-Ctrough) in Chinese patients with hematological disorders. PATIENTS AND METHODS: A prospective observational study involved 250 plasma samples from 114 adult patients receiving voriconazole with or without PPIs were analyzed. Demographics and clinical characteristics were obtained from patient's records. A validated LC-MS/MS was used to quantify the plasma VCZ-Ctrough. Genotyping for CYP2C19*2 and CYP2C19*3 variant alleles was performed by PCR-RFLP followed by DNA sequencing. The combined total score (from 2 to 5) was calculated for each patient. The higher the score, the lesser the metabolism of the patient. FINDINGS: Fifty percent of patients administered with voriconazole were coadministered with PPIs, predominantly omeprazole or esomeprazole. Patients exhibiting CYP2C19 poor metabolizer phenotype showed a significantly higher median VCZ-Ctrough, (4.31µg/mL [IQR, 1.64µg/mL-7.36µg/mL]) than patients with normal metabolizer (1.38µg/mL, [IQR, 0.79µg/mL-2.14µg/mL], p < 0.0001). Similarly, patients co-administration with PPIs had higher median VCZ-Ctrough (2.86µg/mL [IQR 1.33µg/mL-4.66µg/mL]), than PPIs non-users (1.71µg/mL, [IQR, 0.86µg/mL-3.48µg/mL], p = 0.001). However, we noted that the median VCZ-Ctrough for each factor was ranging within the normal recommended therapeutic range in the Chinese population (0.5µg/mL-5µg/mL). But when the two factors were combined, the median VCZ-Ctrough was steadily increasing as the metabolic capacity (reflected by combined total score) was increasing. Importantly, the median VCZ-Ctrough in PM/PPIs user (total score 5) was significantly elevated to supra-therapeutic levels compared to NM/PPI non-user group (total score 2) (5.83µg/mL [IQR, 2.19µg/mL-9.51µg/mL] versus 1.13µg/mL [IQR, 0.67µg/mL-1.82µg/mL]), respectively, P < 0.0001. Furthermore, we observed that the elevation of median VCZ-Ctrough to supra-therapeutic levels was largely contributed by omeprazole or esomeprazole compared to lansoprazole or pantoprazole. CONCLUSION: Coadministration with PPIs significantly increased voriconazole trough concentrations and there was an additive effect in CYP2C19 PMs, who were most likely to have supra-therapeutic levels.

Feasibility Study for the Long-Term Management of Refractory Hyperkeratotic Eczema with Calcipotriol and Betamethasone Dipropionate (Daivobet®), Viaminate and Concomitant Conventional Therapies: A Retrospective Study.

BACKGROUND: The available treatments for refractory hyperkeratotic eczema are inadequate with frustrating results. We, therefore, incorporated Calcipotriol and Betamethasone Dipropionate (Daivobet®), and Viaminate into the mainstay treatment to improve the clinical symptoms. The study aimed to evaluate the efficacy of Daivobet ® and Viaminate as a potential treatment alternative for refractory hyperkeratotic eczema. PATIENTS AND METHODS: Between 2013 and 2015, 61 patients diagnosed with refractory hyperkeratotic eczema (RHE) who had shown inadequate response to conventional therapies were pooled from a single center. Besides, they were all treated with Daivobet ® , Viaminate, and an occlusive dressing mixture containing 5% salicylic acid ointment and 25% zinc oxide paste following inadequate response to conventional therapies (corticosteroids plus 25% zinc oxide paste and 5% salicylic acid ointment). Investigators Global Assessment (IGA) and Patient-Oriented Eczema Measure (POEM) assessed baseline and outcome measures for the degree of hyperkeratinization (0-clear; 3-moderate; 4-severe). RESULTS: Of the 61 patients, 49 (80.3%) patients presented with moderate RHE and 12 (19.7%) with severe RHE. After 24 weeks of treatment, the period for loss of keratinization was significantly lower in patients with moderate RHE (3.9±1.9 weeks) than those with severe RHE (10.8±1.0 weeks) with a P-value <0.01. Furthermore, they required a significantly shorter total treatment duration (10.6 ± 4.3 weeks) than those with severe RHE (20.3±3.6 weeks) with a P-value of <0.01. However, there were no significant differences in post hoc analysis at week 36 with P-values of 0.46 and 1.00 for IGA and POEM, respectively. CONCLUSION: Our results showed that the incorporation of Viaminate and Daivobet® into mainstay treatment was effective and safe for the long-term management of RHE.

Factors influencing left ventricular ejection fraction in patients with coronary microvascular disease and obstructive coronary artery disease.

OBJECTIVE: The aim of our research was to evaluate the relationship involving left ventricular ejection fraction, low density lipoprotein, B-type natriuretic peptide, Troponin I and coronary flow reserve, and to determine the predictors of left ventricular ejection fraction in patients with coronary microvascular disease and obstructive coronary artery disease, and in patients with coronary microvascular disease. RESULTS: The mean age was 58.5 ± 12.5 years. In patients with obstructive coronary disease and coronary microvascular disease we found low density lipoprotein-c had significant inverse relationship with left ventricular ejection fraction, left ventricular ejection fraction also had significant negative relationship with B-type natriuretic peptide, and Troponin-I. While a significant direct relationship turned out to be observed linking left ventricular ejection fraction with coronary flow reserve. Left ventricular ejection fraction had significant negative relationship with low density lipoprotein, and B-type natriuretic peptide in patients with obstructive coronary artery disease only. Age, blood pressure, lipid levels, red cell distribution width, glycated hemoglobin, symptoms, New York heart association classification, alcohol drinking, hypertension, diabetes mellitus, troponin levels and B-type natriuretic peptide were the predictors for left ventricular ejection fraction in coronary microvascular disease patients.

The variation of superior semicircular canal bone thickness in relation to age and gender.

BACKGROUND: Superior semicircular canal dehiscence syndrome (SSCD) is a current diagnosis that is due to a loss of bone covering the superior semicircular canal (SSC). This results in pressure-/sound- induced vertigo and oscillopsia. OBJECTIVE: To find the variation of the thickness of the bone that covers the Superior Semicircular Canal with relation to age and gender among the Chinese descents. MATERIALS AND METHODS: Three hundred and eleven temporal bone Cone Beam Computed Tomography (CBCT) images of patients who attended Otology clinic at Second Hospital of Shandong University from January, 2017 to April, 2018 were retrospectively studied. The images were reconstructed in the line of Poschl and the thinnest area of the bone covering the SSC was taken. RESULTS: We included 172 (55.31%) females and 139 (44.69%) males. Mean age was 41 years. Overall mean difference in thickness was found to be -0.0210. There was no significant difference between the female and male bone thickness (p = .7113). With age the mean difference was 0.0801 (p = .1557) which was not statistically significant. CONCLUSION AND SIGNIFICANCE: There was no significant change in bone thickness with advancing age. CBCT is the best method of assessing SSCD.

The Influence of Proinflammatory Cytokines on Voriconazole Trough Concentration in Patients With Different Forms of Hematologic Disorders.

Even though multiple factors are involved in the high fluctuation of voriconazole (VCZ) plasma concentration, little is known regarding the influence of proinflammatory cytokines on VCZ concentration. The aim of this study was to investigate the influence of proinflammatory cytokines, namely, interleukin (IL)-1ß, IL-6, IL-18, interferon-γ, tumor necrosis factor-α, and transforming growth factor (TGF)-ß1 on VCZ trough concentration (VCZ-Cmin ) in Chinese patients with different forms of hematologic disorders. A total of 250 plasma samples from 113 patients were analyzed for VCZ-Cmin and proinflammatory cytokines using a validated liquid chromatography-tandem mass spectrometry and enzyme-linked immunosorbent assay methods, respectively. Patient demographics and clinical characteristics were obtained from hospital records. VCZ-Cmin was significantly correlated with IL-18 in acute myeloid leukemia (r = 0.456; P ˂ .0001), acute lymphoblastic leukemia (r = 0.317; P = .019), and chronic myeloid leukemia (r = 0.737; P = .004) while VCZ-Cmin and TGF-ß1 were correlated (r = 0.436; P ˂ .001) in acute myeloid leukemia patients only. VCZ-Cmin at different concentration range showed significant inhibitory effect of IL-6. A backward multiple linear regression model revealed patient age (coefficient [ß] = 0.025; P = .04), gamma-glutamyl transferase (ß = 0.003; P = .023), IL-6 (ß = -0.001; P = .024), proton pump inhibitor coadministration (ß = 1.518; P = .002), and cytochrome P450 (CYP) 2C19 polymorphism as predictors of VCZ-Cmin ; however, these factors explained only 29% of VCZ-Cmin variation. In conclusion, IL-18 and TGF-ß1 have correlation with VCZ-Cmin in Chinese patients with leukemia. Apparently, VCZ may have an inhibitory effect on IL-6 levels. Furthermore, patient age, gamma-glutamyl transferase, IL-6, PPI coadministration, and cytochrome P450 2C19 polymormorphism partially predicted the VCZ-Cmin . Therapeutic drug monitoring of VCZ in Chinese patients is highly encouraged.