Clin Transl Gastroenterol. 2021 Aug 16;12(8):e00391. doi: 10.14309/ctg.0000000000000391.

ABSTRACT

INTRODUCTION: We aim to evaluate the efficacy of 2 different 1-week quadruple therapies given back-to-back consecutive therapy in patients with difficult-to-treat Helicobacter pylori infection.

METHODS: Patients with proven H. pylori infection were recruited after >3 failed standard quadruple eradication. They received consecutive therapy consisting of esomeprazole 40 mg or rabeprazole 20 mg twice daily, amoxicillin 1,000 mg twice daily, tetracycline 500 mg 4 times daily, and furazolidone 100 mg 3 times daily for the first 7 days, followed by colloidal bismuth pectin 200 mg twice daily in place of furazolidone 100 mg for another 7 days. Eradication rates, treatment-emergent adverse events (TEAEs), and compliance were assessed.

RESULTS: Sixty-five patients were enrolled. The mean number of previous eradications was 3.6 (range: 3-7). The intention-to-treat and per-protocol eradication rates were 90.8% (59/65) and 95.1% (58/61). In total, 23.4% (15/64) of patients experienced drug-related TEAEs. No serious adverse events were observed. None of the patients required treatment for TEAEs, and 95.3% (61/64) showed good compliance. Overall, 51 patients (78.5%) were with the available antimicrobial susceptibility testing results. The resistance rates to clarithromycin, metronidazole, levofloxacin, and amoxicillin were 60.8% (31/51), 100% (51/51), 70.6% (36/51), and 2.0% (1/51), respectively. No resistance was detected to either furazolidone or tetracycline. However, in 54.9% of patients (28/51), H. pylori was resistant to 3 antibiotics (metronidazole, levofloxacin, and clarithromycin).

DISCUSSION: Consecutive therapy, including amoxicillin, tetracycline, and furazolidone, achieved a good eradication rate (>90%), with desirable compliance and tolerability in difficult-to-treat H. pylori infection.

PMID:34397042 | DOI:10.14309/ctg.0000000000000391

Clin Diabetes Endocrinol. 2021 Aug 15;7(1):16. doi: 10.1186/s40842-021-00130-x.

ABSTRACT

BACKGROUND: The study characterizes safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single rising doses of the 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) inhibitor BI 187004 in healthy men with overweight or obesity.

METHODS: This was a randomized, double-blind, parallel group, placebo-controlled study with administration of 2.5-360 mg BI 187004 or placebo once daily as single dose in 72 healthy male volunteers with overweight or obesity. Assessments included 11beta-HSD1 inhibition in the liver (assessed indirectly by urinary tetrahydrocortisol/tetrahydrocortisone ratio) and in subcutaneous adipose tissue ex vivo and determination of hypothalamus-pituitary-adrenal axis hormones.

RESULTS: BI 187004 was well tolerated and safe in all tested dose groups. The incidence of drug-related adverse events was 16.7% (n = 9) for all 9 BI 187004 dose groups and 5.9% (n = 1) for placebo. All treatment groups were similar concerning kind and intensity of adverse events. No clinically relevant deviations in clinical laboratory or ECG parameters were reported. Exposure of BI 187004 increased non-proportionally over the entire dose range tested. The geometric mean apparent terminal half-life decreased from 33.5 h (5 mg) to 14.5 h (160 mg) remaining stable up to 360 mg. Renal excretion of BI 187004 was low (3-5%). Urinary tetrahydrocortisol/tetrahydrocortisone ratio decreased, indicating liver 11beta-HSD1 inhibition. Median inhibition of 11beta-HSD1 in subcutaneous adipose tissue biopsies following single dosing ranged from 86.8% (10 mg) to 99.5% (360 mg) after 10 h and from 59.4% (10 mg) to 98.6% (360 mg) after 24 h.

CONCLUSIONS: BI 187004 as single dose was safe and well tolerated and is suitable for once daily dosing. There was significant, sustained 11beta-HSD1 inhibition in liver and adipose tissue.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT01587417 , registered on 26-Apr-2012.

PMID:34391480 | DOI:10.1186/s40842-021-00130-x

Thromb Res. 2021 Aug 2;206:18-28. doi: 10.1016/j.thromres.2021.07.016. Online ahead of print.

ABSTRACT

INTRODUCTION: Oral anticoagulant (OAC)-related adverse events are high post-hospitalization. We planned to develop and validate a prediction model for OAC-related harm within 30 days of hospitalization.

METHODS: We undertook a population-based study of adults aged ≥66 years who were discharged from hospital on an OAC from September 2010 to March 2015 in Ontario, Canada. The primary outcome was a composite of time to first hospitalization or emergency department visit for a hemorrhagic or thromboembolic event, or mortality within 30 days of hospital discharge. Cox proportional hazards regression was used to build the model.

RESULTS: We included 120,721 patients of which 5423 experienced the outcome. Most patients were aged ≥75 years (59.5%) and were female (55.6%). Sixty percent of the cohort had a follow-up visit with a healthcare provider within 7 days of discharge. Patients discharged on a direct acting OAC versus warfarin (apixaban: Hazard Ratio [HR] 0.82, 95% confidence interval [CI] 0.71-0.94; dabigatran: HR 0.73, 95% CI 0.63-0.84; rivaroxaban: HR 0.79, 95% CI 0.71-0.88), were prevalent users of the dispensed OAC versus incident users (HR 0.82, 95% CI 0.69-0.96), had a joint replacement in the past 35 days (HR 0.40, 95% CI 0.33-0.50) or major surgery during index hospital stay (HR 0.69, 95% CI 0.60-0.80) had a lower risk for the outcome. The Cox model was stable with acceptable discrimination but poor goodness-of-fit.

CONCLUSIONS: A model for OAC-related harm in the early post-discharge period was developed. External validation studies are required to understand the model's poor calibration.

PMID:34391064 | DOI:10.1016/j.thromres.2021.07.016

J Immunother Cancer. 2021 Aug;9(8):e002863. doi: 10.1136/jitc-2021-002863.

ABSTRACT

BACKGROUND: GWN323 is an IgG1 monoclonal antibody (mAb) against the glucocorticoid-induced tumor necrosis factor receptor-related protein. This first-in-human, open-label phase I/Ib study aimed to investigate the safety and tolerability and to identify the recommended doses of GWN323 with/without spartalizumab, an anti-programmed cell death receptor-1 agent, for future studies. Pharmacokinetics, preliminary efficacy and efficacy biomarkers were also assessed.

METHODS: Patients (aged ≥18 years) with advanced/metastatic solid tumors with Eastern Cooperative Oncology Group performance status of ≤2 were included. GWN323 (10-1500 mg) or GWN323+spartalizumab (GWN323 10-750 mg+spartalizumab 100-300 mg) were administered intravenously at various dose levels and schedules during the dose-escalation phase. Dose-limiting toxicities (DLTs) were assessed during the first 21 days in a single-agent arm and 42 days in a combination arm. Adverse events (AEs) were graded per National Cancer Institute-Common Toxicity Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors V.1.1.

RESULTS: Overall, 92 patients (single-agent, n=39; combination, n=53) were included. The maximum administered doses (MADs) in the single-agent and combination arms were GWN323 1500 mg every 3 weeks (q3w) and GWN323 750 mg+spartalizumab 300 mg q3w, respectively. No DLTs were observed with single-agent treatment. Three DLTs (6%, all grade ≥3) were noted with combination treatment: blood creatine phosphokinase increase, respiratory failure and small intestinal obstruction. Serious AEs were reported in 30.8% and 34.0%, and drug-related AEs were reported in 82.1% and 77.4% of patients with single-agent and combination treatments, respectively. Disease was stable in 7 patients and progressed in 26 patients with single-agent treatment. In combination arm patients, 1 had complete response (endometrial cancer); 3, partial response (rectal cancer, adenocarcinoma of colon and melanoma); 14, stable disease; and 27, disease progression. GWN323 exhibited a pharmacokinetic profile typical of mAbs with a dose-dependent increase in the pharmacokinetic exposure. Inconsistent decreases in regulatory T cells and increases in CD8+ T cells were observed in the combination arm. Gene expression analyses showed no significant effect of GWN323 on interferon-γ or natural killer-cell signatures.

CONCLUSIONS: GWN323, as a single agent and in combination, was well tolerated in patients with relapsed/refractory solid tumors. The MAD was 1500 mg q3w for single-agent and GWN323 750 mg+spartalizumab 300 mg q3w for combination treatments. Minimal single-agent activity and modest clinical benefit were observed with the spartalizumab combination.

TRIAL REGISTRATION NUMBER: NCT02740270.

PMID:34389618 | DOI:10.1136/jitc-2021-002863

Eur J Cancer. 2021 Aug 10;155:179-190. doi: 10.1016/j.ejca.2021.06.055. Online ahead of print.

ABSTRACT

BACKGROUND: The REGOMA trial showed that regorafenib significantly improved overall survival in patients with recurrent glioblastoma compared with lomustine. Patients treated with regorafenib experienced a higher occurrence of grade 3-4 drug-related adverse events than those receiving the standard treatment. Because this safety profile was expected, it was considered of great importance to assess the patient point of view regarding the disease and treatment impact on different aspects of life and patient well-being. We here report the final results of the health-related quality of life (HRQoL) assessment, a secondary end-point of the study. This trial is registered with ClinicalTrials.gov, NCT02926222.

METHODS: Patient-reported outcomes were assessed, within a prospective, randomised, multicentre, open-label phase II trial, by the European Organisation for Research and Treatment of Cancer core questionnaire and brain module at baseline and every 8-weekly neuroradiological assessment till disease progression. Mixed-effect linear models were fitted for each of the HRQoL domain to examine the change over progression-free time within and between arms. Furthermore, differences were also classified as clinically meaningful changes. To correct for multiple comparisons and avoid type I errors, the level of significance was set at P = 0.01 (2-sided).

RESULTS: Of 119 enrolled patients, 56/59 (95%) patients and 58/60 (97%) patients treated with regorafenib and lomustime completed questionnaires at baseline, respectively. No significant differences were observed in any generic or cancer-specific domain during treatment in both arms, or between the two arms, except for the appetite loss and diarrhoea scales which were significantly worse in patients treated with regorafenib. The rate of patients with a clinically meaningful worsening for appetite loss, diarrhoea and for any other domain was not statistically different between the two arms.

CONCLUSIONS: Regorafenib did not negatively affect HRQoL in patients with recurrent glioblastoma. These data combined with the survival benefit shown in the REGOMA trial support the use of regorafenib as a treatment option for these patients.

PMID:34388515 | DOI:10.1016/j.ejca.2021.06.055

Lancet Gastroenterol Hepatol. 2021 Aug 10:S2468-1253(21)00252-1. doi: 10.1016/S2468-1253(21)00252-1. Online ahead of print.

ABSTRACT

BACKGROUND: BI 695501 is a biosimilar that has demonstrated similar efficacy, safety, and immunogenicity to adalimumab reference product in patients with rheumatoid arthritis and chronic plaque psoriasis. The VOLTAIRE-CD study aimed to compare the efficacy and safety of BI 695501 with adalimumab reference product in patients with Crohn's disease.

METHODS: This phase 3, randomised, double-blind study was done at 92 centres in 12 countries across Europe and the USA in patients aged 18-80 years with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score 220-450). Patients were randomly assigned 1:1 using an interactive response technology system to the BI 695501 group or adalimumab reference product group, stratified by previous exposure to infliximab (yes vs no) and simple endoscopic score for Crohn's disease at screening (<16 vs ≥16). All investigators involved in trial assessments or procedures and all patients were masked to treatment allocation until week 24. Patients received BI 695501 (40 mg/0·8 mL formulation) or adalimumab reference product (either 40 mg/0·4 mL citrate-free or 40 mg/0·8 mL) 160 mg on day 1 and 80 mg on day 15, followed by 40 mg every 2 weeks, via subcutaneous injection. The primary endpoint was the proportion of patients with clinical response (CDAI decrease ≥70 points) at week 4, with an exploratory non-inferiority margin of 0·76 for the lower limit of the two-sided 90% CI of the risk ratio (RR). The primary analysis was done in a modified full analysis set of all patients who received at least one dose of study medication and had a baseline and at least one post-baseline CDAI assessment. Safety was assessed in all patients who received at least one dose of study medication. After week 4, responders were treated until week 46; those randomly assigned to adalimumab reference product switched to BI 695501 at week 24. This study is registered at ClinicalTrials.gov (NCT02871635) and EudraCT (2016-000612-14).

FINDINGS: Between Jan 4, 2017, and April 5, 2018, 147 patients were enrolled and randomly assigned to BI 695501 (n=72) or adalimumab reference product (n=75). At week 4, 61 (90%) of 68 patients in the BI 695501 group and 68 (94%) of 72 in the adalimumab reference product group had a clinical response (adjusted RR 0·945 [90% CI 0·870-1·028]). In the safety analysis set, 45 (63%) of 72 patients in the BI 695501 group and 42 (56%) of 75 in the adalimumab reference product group had an adverse event during weeks 0-24; 31 (43%) and 34 (45%) had adverse events during weeks 24-56. The most common drug-related treatment-emergent adverse events during weeks 0-24 were weight increase (three [4%] patients in the BI 695501 group) and injection-site erythema and upper respiratory tract infection (three [4%] patients for each event) in the adalimumab reference product group. The only drug-related TEAEs reported in two or more patients during weeks 24-56 were weight increase and increased γ-glutamyltransferase, which occured in two (3%) patients each in the BI 695501 group. No drug-related TEAEs were reported in two or more patients during weeks 24-56 in the adalimumab reference product followed by BI 699501 group. Serious adverse events occurred in six (8%) patients in the BI 695501 group and eight (11%) in the adalimumab reference group between weeks 0-24, and two (3%) and nine (12%) patients between weeks 24-56. Adverse events of special interest occurred in two (3%) patients in each treatment group during weeks 0-24 (acute sinusitis and pulmonary tuberculosis in the BI 695501 group and anal abscess and postoperative wound infection in the adalimumab reference product group) and two (3%) patients in each group during weeks 24-56 (psoas abscess and hypersensitivity in the BI 695501 group and pulmonary tuberculosis and erythematous rash in the adalimumab reference product followed by BI 699501 group).

INTERPRETATION: Safety and efficacy were similar in patients with Crohn's disease treated with BI 695501 or adalimumab reference product. Treatment benefits were maintained in patients receiving adalimumab reference product who switched to BI 695501. These results further support the existing licensure of BI 695501 as an alternative to adalimumab reference product for patients with Crohn's disease, as well as the other indications for which BI 695501 is approved.

FUNDING: Boehringer Ingelheim.

PMID:34388360 | DOI:10.1016/S2468-1253(21)00252-1

Clin Ther. 2021 Aug 9:S0149-2918(21)00246-0. doi: 10.1016/j.clinthera.2021.07.002. Online ahead of print.

ABSTRACT

PURPOSE: Although the clinical effect of dienogest for endometriosis after conservative surgery has been proven, the cost-effectiveness of this new pharmacotherapy remains to be determined. We aimed to assess the health economic implications of dienogest versus a gonadotropin-releasing hormone agonist (GnRH-a; goserelin in the Chinese setting.

METHODS: A decision tree model was developed to evaluate the cost-effectiveness of dienogest compared with a GnRH-a (goserelin) after conservative surgery for endometriosis during a 2-year time horizon from the perspective of a health care system in China. The cost of drugs, use of outpatient care facilities, administration of medications, routine laboratory work and imaging studies, and treatment of drug-related adverse events were considered. We obtained clinical efficacy data from the peer-reviewed literature. Base case findings were further tested with 1-way and probabilistic sensitivity analyses.

FINDINGS: The model projects that treatment with dienogest would result in a modest incremental 0.02 quality-adjusted life-year gains compared with a GnRH-a (goserelin) (1.48 vs 1.46) at a cost saving of ¥7274 (¥22,809 vs ¥30,164). Probabilistic sensitivity analysis found that dienogest has a 100% probability of % being considered cost-effective compared with a GnRH-a (goserelin) at the willingness-to-pay threshold of 3 times the gross domestic product per capita (¥64,644 × 3) of China in 2018 (¥1 = US$0.1454 and €0.1248).

IMPLICATIONS: Dienogest is more effective and cost-saving compared with a GnRH-a (goserelin) in the treatment of patients with endometriosis after conservative surgery in China.

PMID:34384611 | DOI:10.1016/j.clinthera.2021.07.002

Eur J Med Res. 2021 Aug 12;26(1):92. doi: 10.1186/s40001-021-00565-z.

ABSTRACT

PURPOSE: Herpes zoster (HZ), or shingles, is a clinical syndrome resulting from the reactivation of latent varicella zoster virus (VZV) within the sensory ganglia. We evaluated the safety and tolerability of ES16001 (ethanol extract of Elaeocarpus sylvestris var. ellipticus), a novel inhibitor of varicella zoster virus reactivation in healthy adults.

METHOD: Single-center, randomized, double-blind, placebo-controlled, single and multiple ascending dose (SAD and MAD, respectively) studies were conducted in 20- to 45-year-old healthy adults without chronic disease. In the SAD study (n = 32), subjects randomly received a single oral dose of 240, 480, 960, or 1440 mg ES16001 or a placebo. In the MAD study (n = 16), subjects randomly received once daily doses of 480 or 960 mg ES16001 or a placebo for 5 days. The safety and tolerability of the drug were evaluated by monitoring participants' treatment emergent adverse events (TEAEs) and vital signs, electrocardiograms (ECGs), physical examinations, and clinical laboratory tests.

RESULTS: In the SAD study, 11 adverse reactions were seen in 5 subjects, and in the MAD study, 8 adverse reactions were seen in 6 subjects. All adverse reactions were mild, and no serious adverse reactions occurred. The most common adverse reaction was an increase in alanine aminotransferase (ALT), but all test values were in the clinically non-significant range, and their clinical significance was judged to be small considering the fact that most of the test values returned to normal immediately after the end of drug administration.

CONCLUSION: ES16001 has good safety and tolerability when administered both once and repeatedly to healthy subjects. Further research is needed to identify any possible drug-induced hepatotoxicity, which appears infrequently. Our findings provide a rationale for further clinical investigations of ES16001 for the prevention of HZ.

TRIAL REGISTRATION: CRIS, KCT0006066. Registered 7 April 2021-Retrospectively registered, https://cris.nih.go.kr/cris/search/detailSearch.do/19071 ).

PMID:34384499 | DOI:10.1186/s40001-021-00565-z

Front Pharmacol. 2021 Jul 26;12:692292. doi: 10.3389/fphar.2021.692292. eCollection 2021.

ABSTRACT

Drug-induced gastrointestinal obstruction (DIGO) and gastrointestinal perforation (DIGP) may be the result of gastrointestinal hypomotility and severe constipation, which may lead to potentially fatal complications of bowel ischemia, sepsis and perforation. We evaluated the onset profile of DIGs (DIGO and DIGP) associated with prescription drugs by analyzing data in the Japanese Adverse Drug Event Report (JADER) database. We selected 161 DIG-related drugs and categorized them into 19 classes based on the Anatomical Therapeutic Chemical (ATC) Classification System. Finally, we focused on 58 drugs and conducted subsequent analyses for the time-to-onset and outcomes. We extracted 79 preferred terms (PTs) with the strings "ileus," "stenosis," "obstruction," "obstructive," "impaction," "perforation," "perforated," "hypomotility," and "intussusception" from the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) of SMQ20000104: gastrointestinal perforation, ulcer, hemorrhage, obstruction non-specific findings/procedures; SMQ20000105: gastrointestinal obstruction; and SMQ20000107: gastrointestinal perforation. Among the 667, 729 reports in the JADER database submitted between April 2004 and November 2020, we identified 11,351 occurrences of DIGs. The reporting odds ratios (RORs) (95% confidence interval) of "barium sulfate containing X-ray media," "drugs for treatment of hyperkalemia and hyperphosphatemia," and "oral bowel cleanser" were 142.0 (127.1-158.6), 25.8 (23.1-28.8), and 29.7 (24.8-35.6), respectively. The median number of days (interquartile range) until the onset of an adverse event caused by each drug category was as follows: barium sulfate containing X-ray contrast media [2.0 (1.0-3.0)], diazepines, oxazepines, thiazepines, and oxepines [8.0 (8.0-18.5)], drugs for treatment of hyperkalemia and hyperphosphatemia [29.0 (8.0-55.0)], non-selective monoamine reuptake inhibitors [19.0 (7.0-47.5)], and oral bowel cleanser [0.0 (0.0-0.0)]. Depending on the drug, the time to onset of side effects ranged from days to several months. Our results highlighted the need to perform detailed monitoring of each drug for possible association with DIGs, which might otherwise have fatal consequences.

PMID:34381361 | PMC:PMC8350341 | DOI:10.3389/fphar.2021.692292

Reg Anesth Pain Med. 2021 Aug 11:rapm-2021-102933. doi: 10.1136/rapm-2021-102933. Online ahead of print.

ABSTRACT

BACKGROUND: Administration of the wrong drug via the epidural or intrathecal route can cause devastating consequences. Because of the commonality of potassium replacement therapy coupled to its potential neurotoxic profile, we suspected that injuries related to this drug error would be present in the literature.

OBJECTIVES: We aimed to identify clinical characteristics associated with the inadvertent administration of potassium chloride (KCl) during neuraxial anesthesia. Our secondary objective was to identify human factors that may have been associated.

EVIDENCE REVIEW: Published reports of neuraxial administration of KCl in humans were searched using Medline and Google Scholar. Error reports in any language were included.

FINDINGS: 25 case reports/series reported administration of KCl via epidural (25 patients) or intrathecal routes (three patients). There were six cases during interventional pain procedures, five cases in operating rooms and 17 in wards or intensive care units. Neuraxial KCl caused paraplegia in 22 patients. Mechanical ventilation was instituted in 11 of 28 patients. Three patients died. Epidural (eight patients) and spinal (two patients) lavage were performed to minimize consequences. A correctly prepared KCl infusion was connected to the epidural catheter for nine patients on wards (32%; 95% upper confidence limit: 48%) due to epidural-intravenous line confusion. Among the other 19 errors, KCl was confused with normal saline for 13 patients or local anesthetic in three patients. A wide range of concentrations and doses of KCl were administered. Variable use of intravenous steroid (13 patients) and epidural saline (eight patients) was found among patients who received epidural KCl. Human factors identified included incorrect visual perception, inadequate monitoring of infusions and substandard practice related to neuraxial anesthesia or analgesia.

CONCLUSIONS: KCl administration via epidural or intrathecal route has been reported to cause catastrophic consequences.

PMID:34380745 | DOI:10.1136/rapm-2021-102933

Dermatol Ther (Heidelb). 2021 Aug 11. doi: 10.1007/s13555-021-00584-y. Online ahead of print.

ABSTRACT

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease often requiring long-term treatment. Crisaborole significantly improved global AD signs and symptoms in 28-day phase 3 studies of patients aged ≥ 2 years with mild-to-moderate AD (Investigator's Static Global Assessment [ISGA] 2 or 3). A post hoc analysis of a long-term, open-label extension study was conducted to assess efficacy and safety trends of crisaborole in patients stratified by the number of initial consecutive crisaborole treatment cycles, defined as the number of treatment cycles completed before achievement of ISGA 0 (clear)/1 (almost clear).

METHODS: Patients completing phase 3 studies without drug-related safety issues that precluded further crisaborole treatment were analyzed. Patients with ISGA 0/1 at baseline (the end of a 28-day cycle) did not receive crisaborole for the next 28-day cycle (off-treatment), whereas patients with ISGA ≥ 2 received crisaborole for the next 28-day cycle (on-treatment). Patients were stratified by number of initial consecutive crisaborole treatment cycles. Efficacy was assessed by achievement and maintenance of ISGA 0/1, and safety was assessed by incidence of treatment-emergent adverse events (TEAEs) and treatment-related AEs (TRAEs).

RESULTS: Overall, 418 patients were included in exclusive cohorts based on number of consecutive on-treatment cycles (1 on-treatment cycle, n = 133; 2 consecutive on-treatment cycles, n = 106; 3 consecutive on-treatment cycles, n = 106; 4 consecutive on-treatment cycles, n = 73). After one to four initial consecutive on-treatment cycles, 77.6, 76.3, 59.4, and 43.1% of patients, respectively, achieved ISGA 0/1. Of these patients, 49.5, 37.8, 44.4, and 45.2%, respectively, maintained ISGA 0/1 at the end of a 28-day cycle off-treatment. Incidence of TRAEs was 4.5, 4.7, 3.8, and 1.4% for patients receiving one to four consecutive on-treatment cycles, respectively. One patient discontinued because of AEs.

CONCLUSION: These results support the efficacious and safe continuous, long-term use of crisaborole for the management of mild-to-moderate AD.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT02118766, NCT02118792.

PMID:34379285 | DOI:10.1007/s13555-021-00584-y

Theranostics. 2021 Jul 13;11(17):8301-8321. doi: 10.7150/thno.61214. eCollection 2021.

ABSTRACT

Drug-induced hepatitis (DIH), which seriously interferes with disease treatment, is one of the most common reasons for termination of new drugs during preclinical studies or post-marketing surveillance. Although antioxidants and anti-inflammatory agents are promising, their nonspecific distribution and insolubility limit their application. Therefore, precise drug release at the disease site is an important way to alleviate DIH and avoid side effects. Methods: A gripper-like hydrophilic cyclic phenylboronic acid (cPBA) was synthesized and a nanoprodrug (cPBA-BE) was established by coupling cPBA with hydrophobic baicalein (BE). The stimuli-responsive release properties and therapeutic effect of cPBA-BE on drug-injured hepatocyte were investigated. The biodistribution and therapeutic effect of cPBA-BE both in acetaminophen-induced acute hepatitis model and rifampicin-induced chronic hepatitis model were further evaluated. Results: cPBA-BE conjugate could self-assemble into nanoprodrug with cPBA as the hydrophilic external layer and BE as the hydrophobic core. In HepaRG cells, cPBA-BE showed stronger cellular uptake. Due to the H2O2- and acid-sensitivity, cPBA-BE could achieve adequate BE release, significantly resist the depletion of GSH, mitochondrial dysfunction, downregulation of inflammation and cell apoptosis in the acetaminophen injured HepaRG cells. Biodistribution showed that cPBA-BE specifically increased the concentration of BE in the liver of DIH mice. cPBA-BE could alleviate acetaminophen-induced acute hepatitis or rifampicin-induced chronic hepatitis more effectively through relieving the oxidative stress, inflammation and block the neutrophil infiltration in liver. Conclusions: cPBA is expected to be a good platform for constructing injectable nanoprodrug with both H2O2 and pH-responsive properties by coupling a wide range of drugs containing o-diol. In this study, the nanoprodrug cPBA-BE was determined to be effective for alleviating the DIH.

PMID:34373743 | PMC:PMC8344015 | DOI:10.7150/thno.61214

Pain Manag. 2021 Aug 10. doi: 10.2217/pmt-2021-0022. Online ahead of print.

ABSTRACT

Aim: To provide real-world evidence for the effectiveness and tolerability of lidocaine 700 mg medicated plaster (LMP) compared with oral systemic first-line medications (OSM) in postherpetic neuralgia treatment. Patients & methods: Retrospective cohort study in patients refractory to at least one recommended OSM (single drug or a combination of drugs) using anonymized routine medical care data from the German Pain e-Registry. A matched pair approach using propensity score matching was employed. Results: A total of 1711 data sets of postherpetic neuralgia patients were identified per treatment group. The majority (>60%) had experienced pain for more than a year and reported a high burden of pain and reduced quality of life. Six months of LMP treatment provided significantly greater pain reductions, improvements in pain-related impairments and quality of life than OSM treatment (p < 0.001 for all parameters). Drug-related adverse events and treatment discontinuation due to drug-related adverse events also occurred less frequently under LMP treatment (p < 0.001). Conclusion: These real-world data confirm the effectiveness and good tolerability of LMP under routine medical care. The treatment was significantly more effective when compared with first-line oral systemic medications.

PMID:34372662 | DOI:10.2217/pmt-2021-0022

East Mediterr Health J. 2021 Jul 29;27(7):693-697. doi: 10.26719/2021.27.7.693.

ABSTRACT

BACKGROUND: The concept of pharmacovigilance is not well known in Libya and its practice is still in the early stages.

AIMS: This study aimed to determine the knowledge, attitudes and practices of pharmacists in Tripoli, Libya about pharmacovigilance and the reporting of adverse drug reactions.

METHODS: A cross-sectional study was conducted from October 2019 to February 2020 of working pharmacists randomly selected from pharmacies in Tripoli. Participants were eligible for inclusion if they had a degree or diploma in pharmacy from a recognized university or institute. Data were collected using a validated self-administered questionnaire.

RESULTS: Of 500 pharmacists selected, 408 completed the questionnaire. The pharmacists' knowledge of pharmacovigilance and reporting of adverse drug reactions was poor overall: only 28.9% correctly defined pharmacovigilance and 14.7% knew about the existence of a centre for pharmacovigilance in Libya. The attitudes of the pharmacists to pharmacovigilance was positive: 77.2% believed that pharmacovigilance needed to be included in the pharmacy curriculum and 73.0% said that they would practice pharmacovigilance if trained. Pharmacists depended mostly on drug information leaflets to update their knowledge on adverse drug reactions.

CONCLUSION: Given the pharmacists' low level of knowledge about pharmacovigilance but their readiness to become involved if trained, training programmes should be introduced for practising pharmacists to improve their knowledge and encourage their active participation in pharmacovigilance. Regulators need to reinforce the importance of reporting adverse drug reactions and implement pharmacovigilance policies in the Libyan health care system.

PMID:34369584 | DOI:10.26719/2021.27.7.693

ACG Case Rep J. 2021 Jan 7;8(1):e00518. doi: 10.14309/crj.0000000000000518. eCollection 2021 Jan.

ABSTRACT

Anabolic steroids are well-known to cause liver injury, which may manifest with jaundice and elevated liver enzymes. Selective androgen receptor modulators (SARMs) have been developed to enhance muscle bulk without the side effects associated with exogenous androgen steroids. We report a case of significant cholestatic liver injury associated with a SARM, ostarine (enobosarm), similar to that associated with anabolic steroids. Liver injury from SARMs has not been reported frequently, and we speculate that this may be seen more often as the consumption of SARMs increases in the athletic market.

PMID:34368386 | PMC:PMC8337042 | DOI:10.14309/crj.0000000000000518

World J Hepatol. 2021 Jul 27;13(7):747-762. doi: 10.4254/wjh.v13.i7.747.

ABSTRACT

Drug use during pregnancy is not common. Drug-induced liver injury (DILI) is a potential complication that is rare but can adversely affect both the mother and the fetus. Although many drugs can directly cause hepatotoxicity, idiosyncratic liver injury is common in pregnancy. Underreporting of adverse drug reactions, lack of adequate literature regarding drug safety in pregnancy, and the inherent difficulty in diagnosing DILI during pregnancy make the management of this condition challenging. This review attempts to describe the existing literature regarding DILI in pregnancy, which is mainly in the form of case reports; several studies have looked at the safety of antithyroid drugs, antiretroviral drugs, and paracetamol, which have an indication for use in pregnancy; the relevant data from these studies with regard to DILI has been presented. In addition, the review describes the diagnosis of DILI, grading the disease severity, assessment of causality linking the drug to the adverse event, regulatory guidelines for evaluating the potential of drugs to cause liver injury, efforts to ensure better participation of women in clinical trials and studies in pregnant women population in particular, and the challenges involved in generating adequate research evidence. The establishment of DILI registries in various countries is an encouraging development; however, there is a need for promoting active, spontaneous reporting of adverse events during pregnancy to ensure rapid generation of evidence regarding the safety of a drug in pregnant women.

PMID:34367496 | PMC:PMC8326163 | DOI:10.4254/wjh.v13.i7.747

Front Pharmacol. 2021 Jul 21;12:603068. doi: 10.3389/fphar.2021.603068. eCollection 2021.

ABSTRACT

Introduction: The extensive utilisation of antiretroviral therapy has greatly improved the survival rates of those infected with human immunodeficiency virus (HIV). The objective of this study was to compare 3-drug regimens containing non-nucleoside reverse transcriptase inhibitor with 3-drug regimens containing integrase inhibitor (INI) regarding efficacy and safety in treatment-naive HIV-1-infected adults at 48 and 96 weeks, respectively. Methods: This study was a network meta-analysis using a Bayesian methodology. On January 8, 2020, we searched databases and other sources for randomized controlled trials conducted in treatment-naive HIV-1 adults and compared multiple 3-drug antiretroviral regimens containing INI, efavirenz (EFV), or rilpivirine (RPV). We extracted data on the following outcomes: virologic suppression, CD4+ cell recovery, discontinuations, deaths, adverse events, serious adverse events, deaths related to study drugs, and drug-related adverse events. We conducted calculations within a Bayesian framework using R software. Results: The network contained 15 randomized controlled trials including 9,745 patients. For efficacy outcomes, regimens containing INI, especially dolutegravir (DTG), were generally superior to other regimens. For virologic suppression at 48 weeks, odds ratios (95% credible intervals) were 0.6 (0.43, 0.82) for EFV+ tenofovir disoproxil fumarate (TDF)+emtricitabine (FTC) versus DTG+ abacavir+ lamivudine (3TC) and 0.52 (0.36, 0.75) for EFV+TDF+FTC vs. DTG+TDF+FTC/3TC. For safety outcomes, regimens containing INI tended to be safer relative to regimens without INI. Outcomes associated with death were unsuitable for network meta-analysis due to low event rates. Conclusion: 3-drug regimens containing INI demonstrate better efficacy and safety than those containing RPV or EFV.

PMID:34366835 | PMC:PMC8334007 | DOI:10.3389/fphar.2021.603068

J Hepatol. 2021 Aug 5:S0168-8278(21)01963-2. doi: 10.1016/j.jhep.2021.07.033. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a syndrome that develops in patients with decompensated liver cirrhosis and which is characterized by organ failure and poor short-term prognosis. Based on positive results from small single center studies, Granulocyte-Colony Stimulating Factor (G-CSF) is being widely used in the treatment of ACLF patients. The aim of that study was to evaluate the safety and efficacy of G-CSF in patients with ACLF.

METHODS: In this multicenter, prospective, controlled, open-label phase 2 study, 176 patients with ACLF defined by the EASL-CLIF criteria were randomized to receive G-CSF (at a dose 5 μg/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n=88) or SMT alone. The primary efficacy endpoint was the 90-day transplant free survival analysed by Cox regression modeling. The key secondary endpoints were the overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores (model of end-stage liver disease score (MELD) and CLIF-C OF score) during the entire observation period.

RESULTS: Patients treated with G-CSF had a 90-day transplant free survival of 34.1% compared to 37.5% in the SMT group with a hazard ratio (HR) of 1.05 (95%CI 0.711; 1.551) (p=0.805). The 360-day transplant free survival with a HR of 0.998 [95%CI 0.697; 1.430 (p=0.992)] and overall survival with a HR of 1.058 [95%CI 0.727; 1.548 (p=0.768)] also did not differ between groups. G-CSF did not improve the CLIF-C OF score (p=0.757), MELD score (p=0.884) or the occurrence of infections (p=0.251). In subgroups of patients without infections [p=0.883], with alcohol related ACLF [p=0.875], or with ACLF defined by the APASL criteria [p=0.405] G-CSF also failed to improve survival. Sixty-one serious adverse events (SAE) were reported in the G-CSF+SMT group and 57 SAEs in the SMT group. In total, seven drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation.

CONCLUSIONS: In contrast to previous findings, this first multicenter, controlled trial failed to show a significant beneficial effect of G-CSF in treating patients with ACLF, and therefore, suggests G-CSF should not be used as a standard treatment for ACLF.

LAY SUMMARY: G-CSF was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled trial phase 2 trial which showed that G-CSF in not improving survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies. CLINICALTRAILS.

GOV NUMBER: NCT02669680.

PMID:34364917 | DOI:10.1016/j.jhep.2021.07.033

Int J Mol Sci. 2021 Jul 23;22(15):7900. doi: 10.3390/ijms22157900.

ABSTRACT

The role of the microbiome in immunology is a rapidly burgeoning topic of study. Given the increasing use of immune checkpoint inhibitor (ICI) therapy in cancers, along with the recognition that carcinogenesis has been linked to dysregulations of the immune system, much attention is now directed at potentiation of ICI efficacy, as well as minimizing the incidence of treatment-associated immune-related adverse events (irAEs). We provide an overview of the major research establishing links between the microbiome to tumorigenesis, chemotherapy and radiation potentiation, and ICI efficacy and irAE development.

PMID:34360663 | PMC:PMC8347117 | DOI:10.3390/ijms22157900

Trials. 2021 Aug 6;22(1):521. doi: 10.1186/s13063-021-05501-4.

ABSTRACT

BACKGROUND: Adverse drug events (ADE) represent one of the main causes of admission to emergency department (ED). Their detection, documentation, and reporting are essential to avoid readmission. We hypothesize that a pharmacist-initiated multidisciplinary transition of care program combining ED pharmacist contribution and medications' data transfer between inpatient and outpatient caregivers will reduce emergency visits related to ADE METHOD/DESIGN: This is a prospective, open-label, randomized controlled trial. The primary aim of the study is 6-month ED readmission related to the same ADE. Three hundred forty-six adult patients with an ADE detected by a binomial pharmacist-physician will be recruited from the ED of an University Hospital and will be randomized in two groups: [1] experimental group (multidisciplinary transition of care program and medications' data transfer between inpatient and outpatient caregivers) and [2] control group (usual care). Patients will be followed up over a period of 6 months. Endpoints will be carried out blindly of the randomization arm. The primary endpoint is the rate of patients who had at least one readmission in the ED for the same reason at 6 months (data collected during a phone call with the patient and the general practitioner). Trials registered NCT03725046.

DISCUSSION: The trial results will have implications for the role of the clinical pharmacist in an emergency department. If successful, the intervention could be considered for implementation across other hospitals.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03725046 . Registered on 30 October 2018.

PMID:34362410 | PMC:PMC8349018 | DOI:10.1186/s13063-021-05501-4