A cohort study of the universal neonatal urine screening for congenital cytomegalovirus infection

ObjectivesThis prospective cohort study aimed to evaluate the efficacy of the universal neonatal urine screening, followed by diagnosis, workup and antiviral therapy for symptomatic congenital cytomegalovirus (CMV) infection to reduce neurological impairments and sequelae.MethodsNeonates born in three facilities underwent the universal urine screening of PCR analyses for CMV-DNA. Neonates with symptomatic congenital CMV infection (cCMV) received oral valganciclovir (VGCV) of 32 mg/kg/day for six weeks or six months, and were evaluated for neurological outcomes including developmental quotient (DQ) and hearing function at around 18 months of corrected age.ResultscCMV was diagnosed in 56 (0.48%) of 11,736 neonates, consisting of 23 neonates with symptomatic and 33 with asymptomatic cCMV. The incidence of cCMV in the general perinatal medical center (0.69%) was higher than that in the primary maternity hospital (0.23%, p<0.01%). Twenty of the 23 infants with symptomatic cCMV received VGCV therapy, and 19 underwent neurological assessment. Eight neonates (42%) had severe sequelae of DQ < 70, bilateral hearing dysfunction, and/or epilepsy. Four neonates (21%) had mild sequelae of DQ 70–79 or unilateral hearing dysfunction only, and seven (37%) showed normal development without any impairment.ConclusionsThis study on a large scale demonstrated that a series of universal neonatal urine screening, diagnosis, workup, and VGCV therapy for neonates with symptomatic cCMV may decrease neurological impairments, because 58% of the treated infants had normal development or mild sequelae. The universal urine screening likely identifies subclinical symptomatic cCMV. Mothers with fetuses of cCMV seem to be selectively transferred to perinatal medical centers before deliveries.     

Amniotic fluid biomarkers predict the severity of congenital cytomegalovirus infection

BACKGROUNDCytomegalovirus (CMV) is the most common intrauterine infection, leading to infant brain damage. Prognostic assessment of CMV-infected fetuses has remained an ongoing challenge in prenatal care, in the absence of established prenatal biomarkers of congenital CMV (cCMV) infection severity. We aimed to identify prognostic biomarkers of cCMV-related fetal brain injury.METHODSWe performed global proteome analysis of mid-gestation amniotic fluid samples, comparing amniotic fluid of fetuses with severe cCMV with that of asymptomatic CMV-infected fetuses. The levels of selected differentially excreted proteins were further determined by specific immunoassays.RESULTSUsing unbiased proteome analysis in a discovery cohort, we identified amniotic fluid proteins related to inflammation and neurological disease pathways, which demonstrated distinct abundance in fetuses with severe cCMV. Amniotic fluid levels of 2 of these proteins — the immunomodulatory proteins retinoic acid receptor responder 2 (chemerin) and galectin-3–binding protein (Gal-3BP) — were highly predictive of the severity of cCMV in an independent validation cohort, differentiating between fetuses with severe (n = 17) and asymptomatic (n = 26) cCMV, with 100%–93.8% positive predictive value, and 92.9%–92.6% negative predictive value (for chemerin and Gal-3BP, respectively). CONCLUSIONAnalysis of chemerin and Gal-3BP levels in mid-gestation amniotic fluids could be used in the clinical setting to profoundly improve the prognostic assessment of CMV-infected fetuses.FUNDINGIsrael Science Foundation (530/18 and IPMP 3432/19); Research Fund – Hadassah Medical Organization.     

The electronic medication complete communication (EMC2) study: Rationale and methods for a randomized controlled trial of a strategy to promote medication safety in ambulatory care

BackgroundAdverse drug events (ADEs) affect millions of patients annually and place a significant burden on the healthcare system. The Food and Drug Administration (FDA) has developed patient safety information for high-risk medications that pose serious public health concerns. However, there are currently few assurances that patients receive this information or are able to identify or respond correctly to ADEs.ObjectiveTo evaluate the effectiveness of the Electronic Medication Complete Communication (EMC²) Strategy to promote safe medication use and reporting of ADEs in comparison to usual care.MethodsThe automated EMC² Strategy consists of: 1) provider alerts to counsel patients on medication risks, 2) the delivery of patient-friendly medication information via the electronic health record, and 3) an automated telephone assessment to identify potential medication concerns or ADEs. The study will take place in two community health centers in Chicago, IL. Adult, English or Spanish-speaking patients (N = 1200) who have been prescribed a high-risk medication will be enrolled and randomized to the intervention arm or usual care based upon practice location. The primary outcomes of the study are medication knowledge, proper medication use, and reporting of ADEs; these will be measured at baseline, 4 weeks, and three months. Intervention fidelity as well as barriers and costs of implementation will be evaluated.ConclusionsThe EMC² Strategy automates a patient-friendly risk communication and surveillance process to promote safe medication use while minimizing clinic burden. This trial seeks to evaluate the effectiveness and feasibility of this strategy in comparison to usual care.     

Moxifloxacin Pharmacokinetics and Pleural Fluid Penetration in Patients with Pleural Effusion

The aim of this study was to evaluate the pharmacokinetics and penetration of moxifloxacin (MXF) in patients with various types of pleural effusion. Twelve patients with empyema/parapneumonic effusion (PPE) and 12 patients with malignant pleural effusion were enrolled in the study. A single-dose pharmacokinetic study was performed after intravenous administration of 400 mg MXF. Serial plasma (PL) and pleural fluid (PF) samples were collected during a 24-h time interval after drug administration. The MXF concentration in PL and PF was determined by high-performance liquid chromatography, and main pharmacokinetic parameters were estimated. Penetration of MXF in PF was determined by the ratio of the area under the concentration-time curve from time zero to 24 h (AUC₂₄) in PF (AUC_24PF) to the AUC₂₄ in PL. No statistically significant differences in the pharmacokinetics in PL were observed between the two groups, despite the large interindividual variability in the volume of distribution, clearance, and elimination half-life. The maximum concentration in PF (Cmax_PF) in patients with empyema/PPE was 2.23 ± 1.31 mg/liter, and it was detected 7.50 ± 2.39 h after the initiation of the infusion. In patients with malignant effusion, Cmax_PF was 2.96 ± 1.45 mg/liter, but it was observed significantly earlier, at 3.58 ± 1.38 h (P < 0.001). Both groups revealed similar values of AUC_24PF (31.83 ± 23.52 versus 32.81 ± 12.66 mg · h/liter). Penetration of MXF into PF was similarly good in both patient groups (1.11 ± 0.74 versus 1.17 ± 0.39). Despite similar plasma pharmacokinetics, patients with empyema/parapneumonic effusion showed a significant delay in achievement of PF maximum MXF levels compared to those with malignant effusion. However, in both groups, the degree of MXF PF penetration and the on-site drug exposure, expressed by AUC_24PF, did not differ according to the type of pleural effusion.     

Risk Profiles for Sensorineural Hearing Loss in Patients with Head and Neck Cancer Receiving Cisplatin-based Chemoradiation

ObjectiveSensorineural hearing loss (SNHL) is a significant toxicity experienced by some patients undergoing cisplatin-based chemoradiation therapy for head and neck cancer. Therefore, SNHL risk profiles were created based on demographics, hearing thresholds, and treatment parameters.MethodsThirty-eight patients with squamous cell carcinoma of the head and neck, treated with postoperative or definitive cisplatin-based chemoradiation at the Princess Alexandra Hospital between 2010 and 2013, were retrospectively reviewed. Patients with pretreatment otologic problems were excluded. Regression models analysed the contributions of collected variables.ResultsAll patients (100%) received multiple audiological assessments, with 21 (55.3%) receiving baseline assessment. The mean hearing deterioration at pure-tone average 1–2–4 kHz was mild (range 22.4–27.6 dB). However, clinically significant SNHL was evident in 37 (97.3%), 24 (63.2%), and 14 (36.8%) patients at 8 kHz and pure-tone averages 0.5–1–2 kHz and 1–2–4 kHz, respectively. Principal component analysis indicated two profiles: (1) low or medium frequency SNHL and (2) high-frequency SNHL. Multivariate analysis demonstrated tobacco consumption (ρ < 0.006) and alcohol intake (ρ < 0.08) predicted high-frequency SNHL (F(3,33) = 3.59, ρ < 0.02, R² = 0.177), with cumulative cisplatin dose (ρ < 0.006) predicting low and medium frequency SNHL (F(3,34) = 14.81, ρ < 0.001, R² = 0.528).ConclusionsAlthough hearing loss rates may be under reported without routine audiological assessment, the incidence of cisplatin-based chemoradiation-induced SNHL, in this study, is high. The proposed predictive model can be used as a prognostic tool and potentially mitigate adverse outcomes.     

Antibiotic-associated adverse drug events at a Japanese academic hospital

IntroductionTo promote antimicrobial stewardship activity, an understanding of the incidence of antibiotic-associated adverse drug events (ADEs) is essential. In this study, we aimed to describe the occurrence of antibiotic-associated ADEs at our hospital.MethodsWe retrospectively searched the ADE registration system in Osaka University Hospital between 2010 and 2017. Registrations of ADEs were dependent on the patients' drug history and clinical course after hospitalization. We classified the data according to types of ADEs (gastrointestinal, hepatobiliary, renal, cardiac, respiratory, hematologic, neurologic, dermatologic, and musculoskeletal) and antibiotic class.ResultsDuring the study period, we found 707 cases of antibiotic-associated ADEs, accounting for 22.3% of all the cases. Beta-lactam antibiotics constitute more than half of the cases (51.3%). The most common ADE was dermatologic abnormalities (53.4%), followed by liver dysfunction (9.7%) and gastrointestinal symptoms (8.9%). Among all antibiotics, oral third-generation cephalosporins were frequently reported as offending drugs (107 cases), accounting for 29.5% of beta-lactam ADEs and 46.3% of cephem ADEs.ConclusionAntibiotic-associated ADEs covered approximately 20% of all the ADEs at our hospital. We believe that the data would be helpful in ensuring patient safety by promoting antimicrobial stewardship in hospitals.     

Hypoglycemic efficacy and safety of Momordica charantia (bitter melon) in patients with type 2 diabetes mellitus

IntroductionMomordica charantia (bitter melon) is widely used for its glucose-lowering effects. This study was conducted to assess the efficacy and safety of M. charantia as an adjuvant treatment in patients with type 2 diabetes.MethodsWe performed a randomized, placebo-controlled study. Blood glucose levels, lipid profile, and adverse events were investigated after 12 weeks of treatment. Ninety subjects were included in the final analysis for glucose lowering efficacy of bitter melon.ResultsThere were no differences in age, sex, or glycated hemoglobin (HbA1c) levels between the bitter melon extract and placebo groups. After treatment with bitter melon extract for 12 weeks, the HbA1c levels of the bitter melon and placebo groups remained unchanged; however, the average fasting glucose level of the bitter melon group decreased (p = 0.014). No serious adverse events were reported during the treatment period.ConclusionsOur data showed that bitter melon has effects of glucose lowering in patients with type 2 diabetes.     

Pharmacokinetics,toxicity and clinical efficacy of linezolid in Japanese pediatric patients

ObjectivesThe aims of the present study were (a) to evaluate the pharmacokinetics of linezolid, and (b) to assess the toxicity and clinical efficacy of linezolid in Japanese pediatric patients.Patients and methodsRoutine clinical data including serum linezolid total and unbound concentrations were collected from 15 pediatric patients (0–13 years old). Pharmacokinetics of linezolid was assumed to follow one-compartment with the first-order absorption model. The relationship between risk for thrombocytopenia and linezolid concentrations, and the variations in C-reactive protein (CRP) concentrations and body temperatures were evaluated as clinical efficacy assessment.ResultsBody weight (WT) and maturation of body function were significant covariates for pharmacokinetics of linezolid in pediatric patients. The elimination half-life of linezolid in a pediatric patient with a WT of 9.9 kg and age of 24 months (median of this study) was 3.0 h. Thrombocytopenia was detected in three patients (21.4%), and the minimum concentrations (C_min) in these patients were significantly higher than those in patients without thrombocytopenia (P < 0.05). The CRP concentrations decreased more than 50% in all pediatric patients after the treatment with linezolid, however body temperatures at the end of treatment were higher than 37.5 °C in 6 patients (42.9%).ConclusionsAlthough dose adjustment based on body size was performed for pediatric patients, thrombocytopenia was detected in 21.4% of pediatric patients, and higher C_min was associated with the risk of thrombocytopenia. These results encourage the implementation of individual dose adjustment based on linezolid serum concentrations for safe and appropriate treatment with linezolid.     

The Economic Burden of Congenital Cytomegalovirus Disease in the First Year of Life: A Retrospective Analysis of Health Insurance Claims Data in the United States

PurposeCongenital cytomegalovirus (cCMV) infection is the most common congenital infection in the United States; however, limited data exist regarding the economic burden of cCMV disease (cCMVd) among newborns and infants. The purpose of this study was to compare health care resource utilization and costs between infants with cCMVd at birth and during the first year of life versus matched infants without diagnosed cCMVd.MethodsRetrospective analyses of health insurance claims data from the MarketScan Commercial Claims and Encounters and Multi-State Medicaid databases (January 1, 2011–December 31, 2016) were conducted. Infants with cCMV diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 771.1 or 078.5; International Classification of Diseases, Tenth Revision, Clinical Modification code P35.1 or B25) were included. Two mutually exclusive periods were examined: initial hospital stay at birth (“birth” analysis) and subsequent 12 months (“postbirth” analysis). Infants with cCMVd in both periods were matched 1:1 to infants without cCMVd based on demographic and clinical characteristics. All-cause costs for cCMVd in infants versus matched control infants were reported in 2016 US dollars. Multivariable regression analyses controlled for additional confounding factors.FindingsIn the birth analysis, 397 of 404 newborns with cCMVd (167 vaginal deliveries, 230 cesarean deliveries) were matched to control infants; newborns with cCMVd had an additional mean (95% CI) of 9.1 (5.8–12.3) and 9.0 (4.6–13.5) inpatient days and $24,274 (10,082–38,466) and $31,770 (9911–53,630) more unadjusted inpatient costs versus control infants for vaginal and cesarean deliveries, respectively. In the postbirth analysis, 678 of 679 infants with cCMVd were matched with control infants; infants with cCMVd had an additional $58,806 (95% CI, 41,247–76,365) in unadjusted costs versus control infants, with inpatient visits accounting for 85% of the difference. Newborns with cCMVd accrued costs at birth averaging 1.5 to 2.1 times greater than control infants for cesarean and vaginal deliveries. During the first year of life, infants with cCMVd had costs averaging 7 times greater than control infants.ImplicationscCMVd is associated with substantial economic burden from birth and during the first year of life. Our findings support the notion that developing effective prevention of cCMVd and increasing awareness of the disease among women should be a public health priority, given the economic burden of cCMVd.     

No implication of HIV coinfection on the plasma exposure to rifampicin,pyrazinamide, and ethambutol in tuberculosis patients

There are contrasting findings regarding the effect of HIV on the pharmacokinetics of first‐line anti‐tubercular drugs (FLATDs) due to a lack of prospective controlled clinical studies, including patients with tuberculosis (TB) and patients with TB living with HIV. This study aims to assess the effect of HIV coinfection and antiviral therapy on the plasma exposure to FLATDs in patients with TB. HIV negative (TB‐HIV− group; n = 15) and HIV positive (TB‐HIV+ group; n = 18) adult patients with TB were enrolled during the second month of FLATDs treatment. All TB‐HIV+ patients were on treatment with lamivudine, tenofovir (or zidovudine), and raltegravir (or efavirenz). Serial blood sampling was collected over 24 h and FLATDs pharmacokinetic parameters were evaluated using noncompartmental methods. In the TB‐HIV+ patients, dose‐normalized plasma exposure area under the curve from zero to 24 h (nAUC_0–24; geometric mean and 95% confidence interval [CI]) values at steady‐state to rifampicin, pyrazinamide, and ethambutol were 18.38 (95% CI 13.74–24.59), 238.21 (95% CI 191.09–296.95), and 18.33 (95% CI 14.56–23.09) µg∙h/ml, respectively. Similar plasma exposure was found in the TB‐HIV− patients. The geometric mean and 90% CI of the ratios between TB‐HIV− and TB‐HIV+ groups suggest no significant pharmacokinetic interaction between the selected antivirals and FLATDs. Likewise, HIV coinfection itself does not appear to have any effect on the plasma exposure to FLATDs.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

First‐line anti‐tubercular drugs (FLATDs) plasma exposure is an important variable of tuberculosis (TB) outcome; however, there are contrasting findings regarding the effect of HIV on the pharmacokinetics of FLATDs due to a lack of prospective controlled clinical studies, including HIV positive and HIV negative patients with TB.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluates the effect of HIV coinfection on the pharmacokinetics of rifampicin, pyrazinamide, and ethambutol in patients who are on stable therapy in the second month of FLATDs treatment.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study shows no evidence that the pharmacokinetics of rifampicin, pyrazinamide, and ethambutol in patients with TB are affected by HIV coinfection or by any of the standard of care HIV comedications allowed in the study (lamivudine, zidovudine, tenofovir, efavirenz, or raltegravir).

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

HIV coinfection does not require dose adjustment of rifampicin, pyrazinamide, and ethambutol in patients with TB.     

Pharmacist- versus physician-initiated admission medication reconciliation: impact on adverse drug events

BackgroundMedication reconciliation (MR) has proven to be a problematic task for many hospitals to accomplish. It is important to know the clinical impact of physician- versus pharmacist-initiated MR in the resource-limited hospital environment.MethodsThis quasi-experimental study took place from December 2005 to February 2006 at an urban US Veterans Affairs hospital. MR was implemented on 2 similar general medical units: one received physician-initiated MR and the other received pharmacist-initiated MR. Adverse drug events (ADEs) and a 72-hour medication-prescribing risk score were ascertained by research pharmacists for all admitted patients by structured record review. Multivariable models were tested for intervention effect, accounting for quasi-experimental design and clustered observations, and were adjusted for patient and encounter covariates.ResultsPharmacists completed the MR process in 102 admissions and physicians completed the process in 116 admissions. In completing the MR process, pharmacists documented statistically more admission medication changes than physicians (3.6 vs 0.8; P < 0.001). The adjusted odds of an ADE caused by an admission prescribing change with pharmacist-initiated MR compared with a physician-initiated MR were 1.04 with a 95% CI of 0.53 to 2.0. The adjusted odds of an ADE caused by an admission prescribing change that was a prescribing error with pharmacist-initiated MR compared with a physician-initiated MR were 0.38 with a confidence interval of 0.14 to 1.05. No difference was observed in 72-hour prescribing risk score (coefficient = 0.10; 95% CI, ?0.54 to 0.75).ConclusionMR performed by pharmacists versus physicians was more comprehensive and was followed by lower odds of ADEs from admission prescribing errors but with similar odds of all types of ADEs. Further research is warranted to examine how MR tasks may be optimally divided among clinicians and the mechanisms by which MR affects the likelihood of subsequent ADEs. ClinicalTrials.gov identifier: NCT00370916.     

正常婴幼儿耳蜗导水管的HRCT表现及其径线与感音神经性耳聋患儿的差异

目的 分析正常婴幼儿耳蜗导水管（CA）的HRCT表现特点,观察其径线与感音神经性耳聋（SNHL）患儿的差异。方法 收集无听力异常的婴幼儿颞骨HRCT资料129例（258耳）作为正常组,以58例（116耳）经临床诊断为感音神经性聋（SNHL）、内耳结构正常的儿童颞骨CT资料作为SNHL组,并将2组均分为1岁、2岁、3岁亚组,分别测量2组CA长径及外口宽径,并进行统计学分析。结果 正常组CA长径及外口宽径无侧别和性别间差异（P均>0.05）。2组同年龄亚组CA长径差异无统计学意义（t=0.160、0.979、0.432,P均> 0.05）。SNHL组各亚组CA外口宽径均小于正常组对应年龄亚组（t=3.722、3.101、3.336,P均<0.01）。结论 正常婴幼儿CA长径和外口宽径随年龄增长而增大;CA外口宽径偏小可能与SNHL的发生有关。     

Steady-State Pharmacokinetics of Oral Voriconazole and Its Primary Metabolite,N-Oxide Voriconazole,Pre- and Post-Autologous Peripheral Stem Cell Transplantation

Voriconazole (VCZ) is frequently utilized for prevention and treatment of invasive fungal infections in peripheral stem cell transplant (PSCT) patients. We performed an open-label pharmacokinetic study to compare VCZ and N-oxide voriconazole (N-oxide VCZ) pharmacokinetics in patients pre- and post-PSCT. Ten patients completed both sampling periods. The pharmacokinetics of VCZ were unchanged; however, those of N-oxide VCZ were significantly different pre- and post-PSCT.     

Pharmacokinetics of flomoxef in plasma,peritoneal fluid,peritoneum, and subcutaneous adipose tissue of patients undergoing lower gastrointestinal surgery: Dosing considerations based on site-specific pharmacodynamic target attainment

IntroductionFlomoxef is generally used to treat abdominal infections and as antibiotic prophylaxis during lower gastrointestinal surgery. It is reportedly effective against extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and an increasingly valuable alternative to carbapenems. However, its abdominal pharmacokinetics remain unclear. Herein, pharmacokinetic analysis of flomoxef in the abdominal tissue was conducted to simulate dosing regimens for pharmacodynamic target attainment in abdominal sites.MethodsFlomoxef (1 g) was administered intravenously to a patient 30 min before commencing elective lower gastrointestinal surgery. Samples of plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue were collected during surgery. The flomoxef tissue concentrations were measured. Accordingly, non-compartmental and compartmental pharmacokinetic parameters were calculated, and simulations were conducted to evaluate site-specific pharmacodynamic target values.ResultsOverall, 41 plasma samples, 34 peritoneal fluid samples, 38 peritoneum samples, and 41 subcutaneous adipose samples from 10 patients were collected. The mean peritoneal fluid-to-plasma ratio in the areas under the drug concentration-time curve was 0.68, the mean peritoneum-to-plasma ratio was 0.40, and the mean subcutaneous adipose tissue-to-plasma was 0.16. The simulation based on these results showed the dosing regimens (q8h [3 g/day] and q6h [4 g/day]) achieved the bactericidal effect (% T > minimum inhibitory concentration [MIC] = 40%) in all tissues at an MIC of 1 mg/L.ConclusionsWe elucidated the pharmacokinetics of flomoxef and simulated pharmacodynamics target attainment in the abdominal tissue. This study provides evidence concerning the use of optimal dosing regimens for treating abdominal infection caused by strains like ESBL-producing bacteria.     

A Randomized Controlled Trial on the Effects of Low-Dose Extracorporeal Shockwave Therapy in Patients With Knee Osteoarthritis

ObjectiveTo test the efficacy of low-dose extracorporeal shockwave therapy (ESWT) on osteoarthritis knee pain, lower limb function, and cartilage alteration for patients with knee osteoarthritis.DesignRandomized controlled trial with placebo control.SettingOutpatient physical therapy clinics within a hospital network.ParticipantsEligible volunteers (N=63) with knee osteoarthritis (Kellgren-Lawrence grade II or III) were randomly assigned to 2 groups.InterventionsPatients in the experimental group received low-dose ESWT for 4 weeks while those in the placebo group got sham shockwave therapy. Both groups maintained a usual level of home exercise.Main Outcome MeasuresKnee pain and physical function were measured using a visual analog scale (VAS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the Lequesne index at baseline, 5 weeks, and 12 weeks. Cartilage alteration was measured analyzing the transverse relaxation time (T2) mapping.ResultsThe VAS score, WOMAC, and Lequesne index of the ESWT group were significantly better than those of the placebo group at 5 and 12 weeks (P<.05). Both groups showed improvement in pain and disability scores over the 12-week follow-up period (P<.05). In terms of imaging results, there was no significant difference in T2 values between groups during the trial, although T2 values of the ESWT group at 12 weeks significantly increased compared to those at baseline (P=.004). The number and prevalence of adverse effects were similar between the 2 groups, and no serious side effects were found.ConclusionsA 4-week treatment of low-dose ESWT was superior to placebo for pain easement and functional improvement in patients with mild to moderate knee osteoarthritis but had some negative effects on articular cartilage.     

Pharmacokinetics and Pharmacodynamics of Setrobuvir,an Orally Administered Hepatitis C Virus Non-Nucleoside Analogue Inhibitor

PurposeNew antiviral agents with activity against hepatitis C virus (HCV) are needed to optimize treatment for chronic hepatitis C (CHC). We evaluated the pharmacokinetics of setrobuvir (a non-nucleoside HCV polymerase inhibitor) in healthy volunteers (study 1 & 2) and its antiviral efficacy in patients with genotype 1, noncirrhotic treatment-naive CHC (study 3).MethodsThree studies investigated the pharmacokinetics and pharmacodynamics of setrobuvir. First, sequential cohorts of volunteers were randomly assigned to receive single oral doses of setrobuvir 400 to 3000 mg or placebo in a double-blind, ascending dose study. In the second study, volunteers were randomly assigned to receive multiple doses of setrobuvir (400 or 800 mg once daily [QD] or 600 mg twice a day [BID]). In the third study, patients with genotype 1 CHC received setrobuvir (200, 400, or 800 mg) or placebo BID for 3 days.FindingsAfter single doses of setrobuvir (400–3000 mg) to volunteers in a fasted state, peak C_max and AUC_0–∞ increased in a less than dose-proportional manner. The mean apparent t_½z ranged from 22.0 to 31.3 hours and was not dose related. C_max and AUC increased significantly (4.3- and 6.3-fold, respectively) in volunteers who received 2000 mg with a high-fat meal versus fasting. After multiple oral doses, steady state was achieved after 7 days of dosing (400 or 800 mg QD and 600 mg BID) and accumulation was dose-independent. Mean day 14 plasma exposure increased in a less than dose-proportional manner in volunteers who received 400 and 800 mg QD, but it was more than dose-proportional in volunteers receiving 600 mg BID. Dose did not affect the mean t_½z (range, 24.1–26.6 hours), apparent oral clearance (0.254–0.516 L/h), or apparent volume of distribution (9.60–18.1 L). In patients with CHC, dose-related reductions in HCV RNA concentration were apparent within 24 hours of the start of treatment. Reductions from baseline to the end of treatment (day 3) in patients treated with setrobuvir 200, 400, and 800 mg BID were –2.1, –2.2, and –2.9 log₁₀ IU/mL, respectively (vs ≤0.1 log₁₀ IU/mL with placebo). Reductions in HCV RNA were greater in patients with genotype 1b (range, –2.7 to –3.1 log₁₀ IU/mL) than in patients with genotype 1a (range, –1.3 to –2.7 log₁₀ IU/mL). Setrobuvir was well tolerated, with no serious adverse events.ImplicationsThe steady state pharmacokinetics of setrobuvir appear to be dose proportional, and setrobuvir produces a mean reduction of 2.9 log₁₀ IU/mL in HCV RNA over 3 days in patients with genotype 1 (a and b) treated with 800 mg BID. ClinicalTrials.gov identifier: NCT00782353     

Efficacy and Safety of Fenofibrate-Statin Combination Therapy in Patients With Inadequately Controlled Triglyceride Levels Despite Previous Statin Monotherapy: A Multicenter,Randomized, Double-blind,Phase IV Study

PurposeResidual cardiovascular risk reduction by fenofibrate in patients with high serum triglyceride (TG) levels despite previous statin monotherapy is not well characterized. The purpose of this study was to evaluate the efficacy and safety of a combination of choline fenofibrate and statin in patients with inadequately controlled TG levels despite previous statin monotherapy.MethodsThis prospective, multicenter, randomized, double-blind study was conducted in Korea. A total of 133 patients with controlled LDL-C but elevated TG levels, already receiving statin monotherapy, were enrolled in the study, which was conducted from July 2018 to December 2019. Patients were randomly assigned to receive combination therapy with choline fenofibrate and statin or statin monotherapy in a 1:1 ratio. After 8 weeks of treatment, the lipid profiles and safety parameters of the patients in the 2 groups were compared.FindingsThe study included 127 patients (64 in the combination group and 63 in the control group) older than 19 years. After 8 weeks of therapy, mean serum TG levels significantly decreased from 269.8 to 145.5 mg/dL (P < 0.0001) in the combination therapy group, whereas no significant changes occurred in the statin monotherapy group (from 271.1 to 280.5 mg/dL). Contrarily, the mean serum HDLC levels significantly increased from 45.0 to 50.4 mg/dL (P = 0.0004) in the combination therapy group, whereas there were no significant changes in the monotherapy group (from 44.3 to 44.7 mg/dL). There were no additional serious adverse events in the combination therapy group compared with the statin monotherapy group.ImplicationsThe combination therapy using choline fenofibrate and statin was found to be effective in serum TG control and likely tolerable in patients with high TG levels despite statin monotherapy. A larger study, conducted for a longer duration, is needed to evaluate the effectiveness of this combination in reducing cardiovascular risk. ClinicalTrials.gov identifier: NCT03874260.     

A Prospective,Observational Study of Use Combination Silodosin 8 mg Plus Serenoa Repens,Urtica Dioica,Cucurbita Pepo (Rotaprost) Compared With Silodosin 8 mg Alone in Treatment Patients with Benign Prostate Hyperplasia

BackgroundBenign prostatic hyperplasia (BPH) is one of the most common causes of lower urinary tract symptoms (LUTS) in older men. Nowadays, there are several plant extracts used for the treatment of LUTS due to BPH.ObjectiveThe aim of this study is to compare the effect of combining silodosin 8 mg with Serenoa repens, Urtica dioica, Cucurbita pepo (Rotaprost 530 mg) compared to silodosin 8 mg and Rotaprost 530 mg alone in patients with LUTS/BPH.MethodsFour hundred five men with symptomatic BPH were recruited for the study from June 2020 to January 2021. Three hundred eighty-nine patients were followed up for 6 months. All participants provided written informed consent. This prospective study included analysis of three treatment groups: Group I patients (n = 130) received a combination of silodosin 8 mg and Rotaprost 530 mg (containing a dry extract of Serenoa repens 80 mg, a dry extract of Urtica dioica 150 mg, a dry extract of Cucurbita pepo seeds 200 mg, zinc (in the form of zinc picolinate) 0.105 mg, and selenium (as sodium selenite) 22.5 µg); the group II (n = 129) received silodosin 8 mg alone, and the group III (n = 130) received Rotaprost 530 mg alone. Outcomes were measured by changes from baseline in International Prostate Symptom Score (IPPS) total score, PSA value, prostate volume, residual urine after urination, and maximum flow rate. Statistical significance was set at P < 0.05.ResultsIn group I, IPSS, prostate volume, and maximum urinary flow rate (Qmax) improved significantly (P < 0.05) compared with groups II and III during follow-up. Prostate volume in group I showed a significant decrease only during 6 months of therapy (P < 0.05). No serious adverse effects were registered in the three groups.ConclusionCombination therapy with silodosin 8 mg significantly reduced LUTS/BPH, Qmax, and prostate volume compared with silodosin 8 mg alone. Rotaprost 530 mg can also reduce PSA by at least 20.6?25.7% after 6-months of treatment.