Abdom Radiol (NY). 2021 Mar 5. doi: 10.1007/s00261-021-03006-x. Online ahead of print.

ABSTRACT

OBJECTIVES: To evaluate the relationship between abnormal findings on abdomino-pelvic CT and adverse events in oncologic patients treated with lenvatinib, and their relationship with treatment planning.

METHODS: This single institutional retrospective study included 58 patients with unresectable hepatocellular carcinoma or unresectable thyroid carcinoma (mean age ± standard deviation 69.6 ± 10.0 years; range 39-84 years; 48 men) who underwent CT between October 2016 and July 2020. Two radiologists who were blinded to clinical information including the presence or absence of diarrhea evaluated the imaging findings, including the presence/absence of enteritis in each intestinal segment. Gastrointestinal adverse events (diarrhea, decreased appetite, nausea, and vomiting) and other drug-induced adverse events requiring treatment or follow-up during lenvatinib treatment were also investigated. The frequency of these adverse events was compared between the patients with and without enteritis using Fisher's exact test or the Mann-Whitney U test.

RESULTS: Enteritis was found on CT in the majority (33/58 [56.9%]) of the patients, and most of them (25/33 [75.8%]) showed duodenojejunitis. The frequency of gastrointestinal adverse events (28/33 [84.8%] vs. 13/25 [56.0%], p = 0.009), diarrhea (20/33 [60.6%] vs. 3/25 [12.0%], p < 0.001), and drug interruptions (25/33 [75.8%] vs. 10/25 [40.0%], p = 0.008) and the number of other adverse events (3.9 ± 1.7 vs. 2.3 ± 1.3, p < 0.001) were significantly higher in the patients with enteritis on CT than in those without.

CONCLUSIONS: Lenvatinib-induced enteritis frequently involved the duodenum and jejunum and was related to a significantly higher frequency of treatment interruptions and gastrointestinal adverse events.

PMID:33674959 | DOI:10.1007/s00261-021-03006-x

J Clin Med. 2021 Feb 16;10(4):786. doi: 10.3390/jcm10040786.

ABSTRACT

Rituximab (RTX), a monoclonal antibody against the CD20 molecule, is used as an induction therapy in the treatment of small vessel vasculitis (SVV). The aim of the study was to evaluate the efficacy and safety of RTX induction therapy for refractory SVV. A retrospective analysis of 20 patients treated with RTX for active SVV (BVAS/WG ≥ 3) was performed to assess the remission rate and the drug-related severe adverse events 6 months after therapy. The mean age of the studied population was 49 ± 13 years (50% female), 90% of which were PR3-ANCA positive. Complete remission was achieved in 85% of patients, and partial remission was achieved in a further 10% within 6 months after RTX infusions. The remission rate was not influenced by kidney function. Adverse events such as infections (25%), a late onset of neutropenia (10%) and severe hypogammaglobulinemia (5%) were noted. The patients who developed adverse events were older (42 ± 11 vs. 57 ± 12 years; p = 0.014) and had a higher serum creatinine level (1.3 mg/dL vs. 3.35 mg/dL; p = 0.044). Patients with a glomerular filtration rate (eGFR) lower than 30 mL/min/1.73 m2 had a nine-fold higher risk of side effects (OR 9.0, 95%CI: 1.14-71.0). In conclusion, RTX was highly effective as an induction therapy in patients with SVV. Advanced kidney failure with an eGFR lower than 30 mL/min/1.73 m2 was one of the risk factors for the occurrence of side effects.

PMID:33669267 | DOI:10.3390/jcm10040786

J Psychiatry Neurosci. 2021 Mar 5;46(2):E210-E211. doi: 10.1503/jpn.210027.

NO ABSTRACT

PMID:33667055 | DOI:10.1503/jpn.210027

J Bone Miner Res. 2021 Mar 5. doi: 10.1002/jbmr.4274. Online ahead of print.

ABSTRACT

The standard treatment of primary hypoparathyroidism (hypoPT) with oral calcium supplementation and calcitriol (or an analog), intended to control hypocalcemia and hyperphosphatemia and avoid hypercalciuria, remains challenging for both patients and clinicians. In 2015, human parathyroid hormone (hPTH) (1-84) administered as a daily subcutaneous injection was approved as an adjunctive treatment in patients who cannot be well controlled on the standard treatments alone. This open-label study aimed to assess the safety and efficacy of an oral hPTH(1-34) formulation as an adjunct to standard treatment in adult subjects with hypoparathyroidism. Oral hPTH(1-34) tablets (0.75 mg human hPTH(1-34) acetate) were administered four times daily for 16 consecutive weeks, and changes in calcium supplementation and alfacalcidol use, albumin-adjusted serum calcium (ACa), serum phosphate, urinary calcium excretion, and quality of life throughout the study were monitored. Of the 19 enrolled subjects, 15 completed the trial per protocol. A median 42% reduction from baseline in exogenous calcium dose was recorded (p = .001), whereas median serum ACa levels remained above the lower target ACa levels for hypoPT patients (>7.5 mg/dL) throughout the study. Median serum phosphate levels rapidly decreased (23%, p = .0003) 2 hours after the first dose and were maintained within the normal range for the duration of the study. A notable, but not statistically significant, median decrease (21%, p = .07) in 24-hour urine calcium excretion was observed between the first and last treatment days. Only four possible drug-related, non-serious adverse events were reported over the 16-week study, all by the same patient. A small but statistically significant increase from baseline quality of life (5%, p = .03) was reported by the end of the treatment period. Oral hPTH(1-34) treatment was generally safe and well tolerated and allowed for a reduction in exogenous calcium supplementation, while maintaining normocalcemia in adult patients with hypoparathyroidism. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

PMID:33666947 | DOI:10.1002/jbmr.4274

Aust Prescr. 2021 Feb;44(1):2-3. doi: 10.18773/austprescr.2020.077. Epub 2021 Feb 1.

NO ABSTRACT

PMID:33664539 | PMC:PMC7900275 | DOI:10.18773/austprescr.2020.077

Future Oncol. 2021 Mar 5. doi: 10.2217/fon-2020-1278. Online ahead of print.

ABSTRACT

The international PRECONNECT Phase IIIb study demonstrated safety and efficacy of trifluridine/tipiracil in the management of patients with metastatic colorectal cancer. Post-hoc analyses in a national context are important because of the differences in disease management across countries. Post-hoc safety and efficacy analyses in the PRECONNECT Italian patient subset were conducted. Patients' quality of life was assessed from baseline to end of treatment. In Italy, 161 patients were enrolled. The median age was 64 years, with a performance status of 0-1. The most common hematological drug-related adverse events ≥grade 3 were neutropenia (41.0%) and anemia (13.7%). The median progression-free survival was reached at 3.0 months, with a disease control rate of 28.6%. The Quality of Life Questionnaire Core 30 score improved in 25.4% of the patients. Safety, efficacy and quality of life results confirmed trifluridine/tipiracil as a feasible and favorable treatment option for metastatic colorectal cancer patients.

PMID:33663264 | DOI:10.2217/fon-2020-1278

J Diabetes. 2021 Mar 4. doi: 10.1111/1753-0407.13174. Online ahead of print.

ABSTRACT

BACKGROUND: Neutrophil-related chronic inflammation (NRCI) may contribute to the pathogenesis of diabetic kidney disease (DKD). We evaluated whether blocking NRCI with a low-dose colchicine prevents DKD.

METHODS: A double-blind, randomized, placebo-controlled study was conducted. A total of 160 Patients with type 2 diabetes (T2D) and microalbuminuria (urinary albumin creatinine ratio [UACR] 30 to 300 mg/g Cr) who received angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) for at least 3 months were included. Subjects were 1:1 randomized to a placebo or colchicine group (0.5 mg/day).

RESULTS: The primary endpoint was the incidence of overt nephropathy (UACR>300 mg/g Cr). During the 36 months, 38 patients (51.4%) in colchicine group and 39 (54.1%) in the control group developed overt nephropathy (HR = 1.066; 95%CI = 0.679 to 1.673; P = 0.78). Compared with placebo, colchicine modestly lowered levels of NRCI parameters (P values <0.05 for hs-CRP, WBCC, NC and NLR), while the changes of UACR and estimated glomerular filtration rate (eGFR) were similar between the two groups. There were no significant differences between two groups in drug-related adverse events, including infection, gastrointestinal symptoms and limb numbness.

CONCLUSIONS: In patients with T2D with microalbuminuria, low-dose colchicine effectively and safely lowered NRCI but did not prevent the incidence of overt nephropathy. This article is protected by copyright. All rights reserved.

PMID:33660924 | DOI:10.1111/1753-0407.13174

J Pain Res. 2021 Feb 25;14:549-560. doi: 10.2147/JPR.S287571. eCollection 2021.

ABSTRACT

BACKGROUND: Nonsteroidal anti-inflammatory drugs are widely used for migraine, but gastrointestinal tolerability limits use. We previously reported results from the first treatment period of this 2-period, randomized, controlled study comparing DFN-15-an oral, ready-made liquid solution of a selective cyclo-oxygenase-2 inhibitor celecoxib-with placebo for the acute treatment of a moderate-severe migraine attack. Herein, we report the effects of treatment for the second treatment period.

METHODS: In the first treatment period of this trial, adults with migraine were randomized to double-blind trial treatment of attacks of moderate or severe pain with DFN-15,120 mg or placebo. For the second treatment period, reported herein, participants were re-randomized to treat an attack of any baseline pain intensity (mild, moderate, or severe). Co-primary efficacy endpoints specified for the first attack were not specified for the second attack.

RESULTS: Of the 531 patients who completed the first treatment period, 491 (n = 243 DFN-15; n = 248 placebo; 87% female, mean age 41 years) were re-randomized into the second double-blind treatment period. Baseline pain intensity was mild in 17.2% (85/493) of patients, moderate in 58.4% (288/493) of patients, and severe in 22.9% (113/493) of patients. At 2 hours post-dose, DFN-15 was superior to placebo for freedom from pain (46.2% [110/238] vs 31.1% [76/244], p ≤ 0.001) and the most bothersome symptom (63.4% [121/191] vs 50.0% [98/196], p = 0.010). Treatment-emergent adverse events (TEAEs) occurred in 7.1% (35/493) of patients (DFN-15: 6.1% [15/244]; placebo 8.0% [20/249]). Study drug-related TEAEs occurred in 5.1% (25/493) of patients (DFN-15: 4.5% [11/244]; placebo 5.6% [14/249]); nausea (1% [5/493]) and dysgeusia (0.8% [4/493]) were most common. No serious TEAEs, severe TEAEs, or TEAEs leading to study drug termination were reported.

CONCLUSIONS: DFN-15 was superior to placebo for pain freedom and freedom from the most bothersome symptom when patients treat a migraine attack of any baseline pain intensity. Rates of TEAEs did not differ between treatment groups.

PMID:33658842 | PMC:PMC7920610 | DOI:10.2147/JPR.S287571

Rheumatol Ther. 2021 Mar 3. doi: 10.1007/s40744-021-00280-5. Online ahead of print.

ABSTRACT

INTRODUCTION: This final analysis of a long-term extension (LTE) study assessed the safety, tolerability, and effectiveness of peficitinib (ASP015K), a pan-Janus kinase inhibitor, in Asian patients with rheumatoid arthritis (RA).

METHODS: Patients had previously completed the 12-week phase 2b (RAJ1), or 52-week phase 3 (RAJ3 and RAJ4) peficitinib studies in Japan, Korea, and Taiwan, and received oral peficitinib 50 or 100 mg/day. Dose increase to 150 mg/day or reduction to 50 mg/day was permitted. Efficacy endpoints included American College of Rheumatology (ACR)20/50/70 response rates, 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP), and ACR components. Safety endpoints included treatment-emergent adverse events (TEAEs), and incidence rates (IRs) of adverse events of special interest per 100 patient-years (PY).

RESULTS: Overall, 843 patients received peficitinib for a mean 32.0 months (maximum 85.2 months), and most (64.4%) received peficitinib 100 mg/day as a maximum dose. Respective ACR20/50/70 response rates were maintained from baseline (week 0 of LTE; 71.6, 52.1, and 34.7%) to end of treatment (78.7, 63.3, and 44.1%); continuous improvements in ACR components and DAS28-CRP were observed from the baselines of preceding studies and throughout the LTE. Overall, 796/843 (94.4%) patients experienced TEAEs; most were severity grade 1/2. Most common TEAEs were nasopharyngitis (47.0%) and herpes zoster (17.3%). Drug-related TEAEs leading to permanent discontinuation occurred in 140 (16.6%) patients, and IRs (95% confidence interval) per 100 PY of serious infections, herpes zoster-related disease, and malignancies were 2.7 (2.1, 3.4), 7.3 (6.2, 8.6), and 1.2 (0.9, 1.8), respectively. Two deaths occurred during the study; one each from diffuse large B cell lymphoma and pneumonia, which were, respectively considered probably and possibly related to study drug.

CONCLUSIONS: Improvements in effectiveness variables were maintained during this long-term study of peficitinib in Asian patients with RA; peficitinib was generally well tolerated over a mean 32 months' duration.

TRIAL REGISTRATION: ClinicalTrials.gov. NCT01638013, retrospectively registered on 11 July 2012 https://clinicaltrials.gov/ct2/show/NCT01638013 .

PMID:33656739 | DOI:10.1007/s40744-021-00280-5

Cureus. 2021 Jan 25;13(1):e12903. doi: 10.7759/cureus.12903.

ABSTRACT

Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.

PMID:33654588 | PMC:PMC7904503 | DOI:10.7759/cureus.12903

Drug Ther Bull. 2021 Mar 2:dtb-2021-000007. doi: 10.1136/dtb.2021.000007. Online ahead of print.

ABSTRACT

Every month, DTB scans sources of information on treatments, disease management and other healthcare topics for key items to bring to our readers' attention and help them keep up to date. To do this, we produce succinct, contextualised summaries of the information concerned.

PMID:33653729 | DOI:10.1136/dtb.2021.000007

Transfusion. 2021 Mar 2. doi: 10.1111/trf.16341. Online ahead of print.

ABSTRACT

FcRn, a non-classical Fc gamma (γ) receptor (FcγR) with near ubiquitous expression, plays key roles in disease pathogenesis and progression though immunoglobulin G (IgG) transport, IgG recycling, and IgG-immune complex clearance. FcRn function can be inhibited using IgG-based and non-IgG-based antagonists, by exploiting the pH-dependent binding affinity of FcRn for the IgG Fc region. FcRn therapeutics have shown promise in murine models and human clinical trials for autoimmune diseases and maternal-fetal immune cytopenias; they appear safe, well-tolerated, and reduce circulating IgG levels. Compared to traditional therapeutics, inhibiting FcRn has fewer adverse side effects and represents a new approach that is less invasive, time-consuming, and costly.

PMID:33650699 | DOI:10.1111/trf.16341

Ann Nucl Med. 2021 Mar 1. doi: 10.1007/s12149-021-01601-y. Online ahead of print.

ABSTRACT

OBJECTIVES: NMB58 is a novel positron emission tomography (PET) tracer containing flurpiridaz as an active ingredient and available as a myocardial perfusion imaging tracer that targets mitochondrial complex 1. A phase I clinical study of NMB58 was conducted to evaluate its safety and pharmacokinetics in healthy volunteers.

METHODS: Ten healthy Japanese volunteers received bolus injection of NMB58 (111-167 MBq) intravenously and underwent imaging studies at rest on day 1. Of these subjects, 5 (day 2 cohort 1; exercise stress) and 5 (day 2 cohort 2; pharmacological stress) similarly underwent stress imaging studies on day 2. The safety of NMB58 was evaluated through monitoring of signs/symptoms, electrocardiography, vital signs, and laboratory examinations at baseline and several time points during 3 days. Sequential whole-body positron emission tomography-computed tomography (PET/CT) scan data were acquired for up to 5-h post-injection, with venous blood and urine samples collected for up to 8-h post-injection. Based on the results of the biodistribution study, the absorbed radiation dose (Rad) was estimated by the Medical Internal Radiation Dose method.

RESULTS: On day 1, the kidneys were shown to have the highest Rad, followed by the myocardium. On day 2, the myocardium was shown to have the highest Rad, followed by the kidneys. The mean effective doses (EDs) per unit activity administered were 0.021, 0.017 and 0.021 mSv/MBq for overall subjects (day 1), day 2 cohort 1 and day 2 cohort 2, respectively. The estimated exposure dose of NMB58 was similar to or lower than those of radiotracers currently approved for clinical use, including 18F-Fludeoxyglucose. Biodistribution results indicated that NMB58 distributed to the myocardium exhibited high and sustained retention after administration. The cumulative urinary radioactivity excretion rate was shown to be 6.9, 2.3%, and 8.0% of the injected dose in overall subjects (day 1), day 2 cohort 1 and day 2 cohort 2. There were no drug-related adverse events, and the tracer was well tolerated in all subjects.

CONCLUSIONS: Based on radiation dosimetry, biodistribution, and safety evaluations, NMB58 was found to be a suitable tracer for clinical use in PET myocardial perfusion imaging during exercise or pharmacological stress.

PMID:33649886 | DOI:10.1007/s12149-021-01601-y

Zhongguo Zhong Yao Za Zhi. 2021 Jan;46(2):306-311. doi: 10.19540/j.cnki.cjcmm.20200904.601.

ABSTRACT

Liver is the main place of drug metabolism. Mitochondria of hepatocytes are important targets of drug-induced liver injury. Mitochondrial autophagy could maintain the healthy operation of mitochondria in cells and the stable proliferation of cells. Therefore, the use of mitochondrial autophagy to remove damaged mitochondria is an important strategy of anti-drug-induced liver injury. Active ingredients that could enhance mitochondrial autophagy are contained in many traditional Chinese medicines, which could regulate the mitochondrial autophagy to alleviate relevant diseases. However, there are only a few reports on how to accurately and efficiently identify and evaluate such components targeting mitochondria from traditional Chinese medicine. Liquid chromatography-mass spectro-metry(LC-MS) combined with serum pharmacology in vivo can be used to accurately and efficiently find active ingredients of traditional Chinese medicine acting on mitochondrial targets. This paper reviewed the research ideas and methods of traditional Chinese medicine ingredients for increasing the hepatotoxicity of mitochondrial autophagy, in order to provide new ideas and methods for the study of active ingredients of traditional Chinese medicine targeting mitochondria.

PMID:33645116 | DOI:10.19540/j.cnki.cjcmm.20200904.601

Zhongguo Zhong Yao Za Zhi. 2021 Feb;46(3):712-721. doi: 10.19540/j.cnki.cjcmm.20201015.501.

ABSTRACT

This study aimed to comprehensively analyze and compare the differences of different clinical study types currently published in the safety evaluation of Xuebijing Injection. Six databases, namely the Cochrane Library, PubMed, EMbase, CNKI, VIP and Wanfang database, were electronically retrieved to collect all types of studies on the safety of Xuebijing Injection, including randomized controlled trials, case-controlled studies, cohort studies, systematic reviews, and centralized monitoring studies of clinical safety(hospital), in order to comprehensively and objectively evaluate the safety of Xuebijing Injection, and analyze the differences of different research results. A total of 211 literatures were included, involving a total of 46 384 patients treated with Xuebijing Injection, and 423 adverse reactions(ADRs) occurred. They included 191 randomized controlled trials, 3 cohort studies, 15 systematic reviews, and 2 centralized monitoring studies of clinical safety(hospital), and the incidence of adverse reactions was 2.54%(common), 2.31%(common), 0.95%(occasionally), and 0.50%(occasionally). More than half of the 423 cases of ADRs occurred in skin and adnexal system(151 cases) and gastrointestinal system(65 cases), including such manifestations as rash, skin itching, nausea and vomiting, diarrhea. The degree of ADRs was mild. Randomized controlled trials showed that the incidence of ADR was the highest when Xuebijing Injection was used for malignant tumor and multiple organ failure. And the systematic evaluation showed that the incidence of ADR was the highest when Xuebijing Injection was used for spontaneous peritonitis of liver cirrhosis. In conclusion, different study types could lead to significant differences in the results of drug safety evaluation. Sample size, study type, and quality control are the main factors for biased results. Due to large sample size and high-quality, centralized monitoring studies become the better clinical safety evaluation model of drugs at present, and full life cycle management could more objectively reflect drug safety and guide clinical rational drug use.

PMID:33645039 | DOI:10.19540/j.cnki.cjcmm.20201015.501

Nihon Yakurigaku Zasshi. 2021;156(2):107-113. doi: 10.1254/fpj.20097.

ABSTRACT

Predicting drug-induced side effects in central nervous system is important because they can lead to the discontinuation of new drugs/candidates or the withdrawal of marketed drugs. Although many efforts are made, evaluation system using animals have not been highly predictive in humans. In addition, animal experiments are time-consuming and costly. To address these issues, in vitro evaluation methods, such as the use of New Approach Methodologies (NAM) have been explored. Human iPS cell technology has already been applied to assess drug-induced cardiotoxicity. In addition, the use of human iPS cell technology and in silico has been promoted for neurotoxicity assessment during the developmental neurotoxicity in terms of chemical safety issues. Organization for Economic Cooperation and Development (OECD) guidance regarding developmental neurotoxicity is under preparation. In this review, we will review the current trends in safety assessment methods for the central nervous system in light of these international trends.

PMID:33642528 | DOI:10.1254/fpj.20097

Iran J Allergy Asthma Immunol. 2021 Feb 11;20(1):11-23. doi: 10.18502/ijaai.v20i1.5409.

ABSTRACT

The Coronavirus disease 2019 (COVID-19) virus spread from Wuhan, China, in 2019 and is spreading rapidly around the world. COVID-19 victims are almost associated with cardiovascular disease, high blood pressure, diabetes, and other underlying diseases. Concerning the high prevalence of these disorders, widespread mortality threatens global society, and its fatality rate may increase with increasing COVID-19 prevalence in countries with older populations. Therefore, evaluating patients' clinical status with severe COVID-19 infection and their medical history can help manage treatment. Currently, one of the considered treatments is angiotensin-converting enzyme 2 (ACE2) inhibition. This study investigated virus entry mechanisms through membrane receptors, their role in the pathogenesis of COVID-19 and underlying diseases, and treatment methods based on the viral entrance inhibition. According to existing studies, inhibition of ACE2 can increase oxidative stress, inflammation, fibrosis and ultimately exacerbate underlying diseases such as cardiovascular disease, kidney disease, diabetes, and hypertension in individuals with COVID-19. The ACE2 inhibition is not suitable for patients with COVID-19 with underlying diseases, but it seems that the recombinant ACE2 solution is more appropriate for inhibiting the virus in these patients if hypotension would be monitored.

PMID:33639626 | DOI:10.18502/ijaai.v20i1.5409

BMC Infect Dis. 2021 Feb 26;21(1):222. doi: 10.1186/s12879-021-05850-0.

ABSTRACT

BACKGROUND: The objective of this study was to assess the durability of response of dolutegravir (DTG) as an antiretroviral core agent by comparing its efficacy and safety with other recommended or commonly used core agents up to 96-weeks (W96).

METHODS: A previously published systematic review was updated to identify phase 3/4 randomised controlled trials (RCTs) of core agents in treatment-naïve HIV-1 patients. Efficacy [virologic suppression (VS), CD4+ cell change from baseline] and safety [adverse events [AEs], discontinuations, drug-related AEs [DRAEs]] were analysed at W96 using Bayesian network meta-analysis (NMA) adjusting for nucleoside/nucleotide reverse transcriptase inhibitors' (NRTIs') backbone. Subgroups of patients with VL > 100,000 copies/mL or CD4+ ≤ 200 cells/μL at baseline were analysed separately.

RESULTS: The NMA included 20 studies reporting data at W96. A higher proportion of patients receiving DTG achieved VS compared to those on protease inhibitors [PI:Range:8.7%(CrI:3.1,16.0)-19.9%(10.8,30.5)], efavirenz [EFV:6.9%(1.3,10.8)] and cobicistat-boosted elvitegravir [EVG/c:8.2%(0.2,17.4)], and similar but numerically higher compared to rilpivirine [RPV:5.0%(- 2.8,12.5)], raltegravir [RAL:2.9%(- 1.6,7.7)] and bictegravir [BIC:2.7%(- 2.7,10.6)]. The probability that more patients on DTG would achieve VS at W96 compared to any other core agent was greater than 80%. A higher proportion of patients on DTG achieved VS compared to PI/rs [Range:33.1%(13.6,50.4)-45.3%(24.1,61.6)] and RAL [16.7%(3.3,31.2)] in patients with VL > 100,000 copies/mL at baseline, and similar VS was achieved in patients with CD4+ ≤ 200 cells/μL at baseline. DTG also achieved greater increase in CD4+ cells from baseline compared to EFV [32.6(10.7,54.7)], ritonavir-boosted darunavir [DRV/r:25.7(3.6,48.1)] and BIC [24.7(1.5,47.7)]. Patients receiving DTG had lower odds of discontinuing therapy by W96 compared to PI/rs, EFV, RAL and EVG/c. Patients on DTG had lower odds of experiencing an adverse event (AE) compared to patients on EFV [odds ratio:0.6(0.3,0.9)], ATV/r [0.4(0.3,0.6)] and LPV/r [0.3(0.2,0.5)]. For patients on DTG, the odds of experiencing a drug-related AE were lower than the odds for patients on EFV [0.3(0.2,0.4)], comparable to patients on RAL [1.1(0.8,1.4)] and higher than those on BIC [1.5(1.1,2.0)].

CONCLUSION: Un-boosted integrase inhibitors had better efficacy and similar safety compared to PI/rs at W96 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious core agent, particularly in patients with baseline VL > 100,000 copies/mL or ≤ 200 CD4+ cells/μL, who can be difficult to treat.

PMID:33637050 | DOI:10.1186/s12879-021-05850-0

Ecotoxicol Environ Saf. 2021 Apr 15;213:112063. doi: 10.1016/j.ecoenv.2021.112063. Epub 2021 Feb 24.

ABSTRACT

Evidence is still limited for the role of long-term PM2.5 exposure in cerebrovascular diseases among residents in high pollution regions. The study is aimed to investigate the long-term effects of PM2.5 exposure on stroke mortality, and further explore the effect modification of temperature variation on the PM2.5-mortality association in northern China. Based on a cohort data with an average follow-up of 9.8 years among 38,435 urban adults, high-resolution estimates of PM2.5 derived from a satellite-based model were assigned to each participant. A Cox regression model with time-varying exposures and strata of geographic regions was employed to assess the risks of stroke mortality associated with PM2.5, after adjusting for individual risk factors. The cross-product term of PM2.5 exposure and annual temperature range was further added into the regression model to test whether the long-term temperature variation would modify the association of PM2.5 with stroke mortality. Among the study participants, the annual mean level of PM2.5 concentration was 66.3 μg/m3 ranging from 39.0 μg/m3 to 100.6 μg/m3. For each 10 μg/m3 increment in PM2.5, the hazard ratio (HR) was 1.31 (95% CI: 1.04-1.65) for stroke mortality after multivariable adjustment. In addition, the HRs of PM2.5 decreased gradually as the increase of annual temperature range with the HRs of 1.95 (95% CI: 1.36-2.81), 1.53 (95% CI: 1.06-2.22), and 1.11 (95% CI: 0.75-1.63) in the low, middle, and high group of annual temperature range, respectively. The findings provided further evidence of long-term PM2.5 exposure on stroke mortality in high-exposure settings such as northern China, and also highlighted the view that assessing the adverse health effects of air pollution might not ignore the role of temperature variations in the context of climate change.

PMID:33636465 | DOI:10.1016/j.ecoenv.2021.112063

J Womens Health (Larchmt). 2021 Feb 24. doi: 10.1089/jwh.2020.8380. Online ahead of print.

ABSTRACT

A 2001 US Government Accountability Office (GAO) report indicated 8 of 10 drugs withdrawn from the US market between 1997 and 2000 posed greater risk to women than men. We examined drugs withdrawn from the market for safety-related reasons from January 1, 2001, to January 1, 2018. To be included, drugs must be listed as discontinued on Drugs@FDA and either listed in the Federal Register or cited in literature as being withdrawn for safety-related reasons. Biologics, over-the-counter products, and medical devices were excluded. During the 17-year time span, 19 drugs were withdrawn from the market for safety-related reasons, fewer drugs per year compared to the 3-year period examined in the GAO report. Food and Drug Administration (FDA) has not recommended the market removal of any drug approved since 2005 due to the time from the start of the Q wave to the end of the T wave (QT) interval prolongation resulting in torsades de pointes (TdP) or other abnormal heart rhythms. Furthermore, no drugs approved after the implementation of FDA's 2009 guidance on drug-induced liver injury (DILI) have been withdrawn because of hepatoxicity. All, but one of the drugs discontinued from the market for safety-related reasons during the period examined were approved between 1957 and 2002. TdP and DILI are two relevant examples of drug-induced adverse events posing greater risk to women than men. FDA has made measurable progress incorporating consideration of sex and gender differences into drug trial development and FDA review of these data, supporting inclusion of women in clinical trials, providing a comprehensive drug safety review, and advancing postmarket surveillance and risk assessment, thus strengthening FDA's ability to protect public health.

PMID:33635140 | DOI:10.1089/jwh.2020.8380