Int J Environ Res Public Health. 2023 Feb 17;20(4):3548. doi: 10.3390/ijerph20043548.

ABSTRACT

BACKGROUND: Pharmacovigilance (PV) is an essential activity to detect adverse drug reactions (ADRs) and ensure patient safety. Hence, we aimed to evaluate knowledge, attitudes, and practices (KAP) regarding PV among community pharmacists in Qassim, Saudi Arabia.

METHODS: A cross-sectional study was conducted by using a validated questionnaire after obtaining ethical approval from the Deanship of Scientific Research, Qassim University. The sample size was calculated based on the total number of pharmacists in the Qassim area by using Raosoft, Inc. Statistical Package for the Social Sciences version 20 was used for data entry and analysis. Ordinal logistic regression was performed to identify the predictors of KAP. A p-value of <0.05 was considered statistically significant.

RESULTS: A total of 209 community pharmacists participated in the study; 62.9% of them defined the PV correctly, and 59% of them defined ADRs correctly. However, only 17.2% knew where to report ADRs. Interestingly, the majority of participants (92.9%) reported that it is necessary to report ADRs, and 73.8% of them were willing to report ADRs. A total of 53.8% of the participants identified ADRs during their careers; however, only 21.9% reported ADRs. Barriers discourage ADR reporting; the majority of the participants (85.6%) do not know how to report ADRs.

CONCLUSION: Community pharmacists who participated in the study were knowledgeable about PV, and their attitude towards reporting ADRs was highly positive. However, the number of reported ADRs was low because of the lack of knowledge on how and where to report ADRs. Continuous education and motivation about ADRs reporting and PV are warranted among community pharmacists for the rational use of medications.

PMID:36834240 | PMC:PMC9958751 | DOI:10.3390/ijerph20043548

Int J Environ Res Public Health. 2023 Feb 16;20(4):3473. doi: 10.3390/ijerph20043473.

ABSTRACT

Physiologically Based Pharmacokinetic (PBPK) models are mechanistic tools generally employed in the pharmaceutical industry and environmental health risk assessment. These models are recognized by regulatory authorities for predicting organ concentration-time profiles, pharmacokinetics and daily intake dose of xenobiotics. The extension of PBPK models to capture sensitive populations such as pediatric, geriatric, pregnant females, fetus, etc., and diseased populations such as those with renal impairment, liver cirrhosis, etc., is a must. However, the current modelling practices and existing models are not mature enough to confidently predict the risk in these populations. A multidisciplinary collaboration between clinicians, experimental and modeler scientist is vital to improve the physiology and calculation of biochemical parameters for integrating knowledge and refining existing PBPK models. Specific PBPK covering compartments such as cerebrospinal fluid and the hippocampus are required to gain mechanistic understanding about xenobiotic disposition in these sub-parts. The PBPK model assists in building quantitative adverse outcome pathways (qAOPs) for several endpoints such as developmental neurotoxicity (DNT), hepatotoxicity and cardiotoxicity. Machine learning algorithms can predict physicochemical parameters required to develop in silico models where experimental data are unavailable. Integrating machine learning with PBPK carries the potential to revolutionize the field of drug discovery and development and environmental risk. Overall, this review tried to summarize the recent developments in the in-silico models, building of qAOPs and use of machine learning for improving existing models, along with a regulatory perspective. This review can act as a guide for toxicologists who wish to build their careers in kinetic modeling.

PMID:36834167 | PMC:PMC9966583 | DOI:10.3390/ijerph20043473

Int J Environ Res Public Health. 2023 Feb 15;20(4):3398. doi: 10.3390/ijerph20043398.

ABSTRACT

A relationship was found between the COVID-19 pandemic and depression among older adults and between depressed mood and increased use of antidepressant medication among older adults during the pandemic. With the aim of broadening the understanding of these relationships, the study examined whether COVID-19 perceived susceptibility mediates the relationship between psychosocial resources (optimism and perceived social support) and depressive symptoms and medication use. Participants included 383 older adults (M = 71.75, SD = 6.77) reporting on socio-demographics, health characteristics, depression, optimism, social support, and COVID-19 perceived susceptibility. Medication use was retrieved from participants medical files. Lower optimism, lower social support, and higher COVID-19 perceived susceptibility were associated with greater depression, related with higher medication use. The findings emphasize the buffering effect of psychosocial resources on the adverse effects of depression affecting older adults during the COVID-19 pandemic, and consequently, the increased use of medication in this population. Practitioners should focus interventions on enhancing optimism and expanding social support among older adults. Moreover, interventions focused on alleviating depression among older adults should aim at improving perceptions of perceived susceptibility in the older population.

PMID:36834090 | PMC:PMC9961318 | DOI:10.3390/ijerph20043398

Int J Environ Res Public Health. 2023 Feb 13;20(4):3289. doi: 10.3390/ijerph20043289.

ABSTRACT

Osteoporosis is a serious bone disease that affects many people worldwide. Various drugs have been used to treat osteoporosis. However, these drugs may cause severe adverse events in patients. Adverse drug events are harmful reactions caused by drug usage and remain one of the leading causes of death in many countries. Predicting serious adverse drug reactions in the early stages can help save patients' lives and reduce healthcare costs. Classification methods are commonly used to predict the severity of adverse events. These methods usually assume independence among attributes, which may not be practical in real-world applications. In this paper, a new attribute weighted logistic regression is proposed to predict the severity of adverse drug events. Our method relaxes the assumption of independence among the attributes. An evaluation was performed on osteoporosis data obtained from the United States Food and Drug Administration databases. The results showed that our method achieved a higher recognition performance and outperformed baseline methods in predicting the severity of adverse drug events.

PMID:36833984 | PMC:PMC9965583 | DOI:10.3390/ijerph20043289

Genes (Basel). 2023 Feb 10;14(2):456. doi: 10.3390/genes14020456.

ABSTRACT

Pharmacogenomic testing is a method to prevent adverse drug reactions. Pharmacogenomics could be relevant to optimize statin treatment, by identifying patients at high risk for adverse drug reactions. We aim to investigate the clinical validity and utility of pre-emptive pharmacogenomics screening in primary care, with SLCO1B1 c.521T>C as a risk factor for statin-induced adverse drug reactions. The focus was on changes in therapy as a proxy for adverse drug reactions observed in statin-users in a population-based Dutch cohort. In total, 1136 statin users were retrospectively genotyped for the SLCO1B1 c.521T>C polymorphism (rs4149056) and information on their statin dispensing was evaluated as cross-sectional research. Approximately half of the included participants discontinued or switched their statin treatment within three years. In our analyses, we could not confirm an association between the SLCO1B1 c.521T>C genotype and any change in statin therapy or arriving at a stable dose sooner in primary care. To be able to evaluate the predictive values of SLCO1B1 c.521T>C genotype on adverse drug reactions from statins, prospective data collection of actual adverse drug reactions and reasons to change statin treatment should be facilitated.

PMID:36833383 | PMC:PMC9957000 | DOI:10.3390/genes14020456

Trials. 2023 Feb 25;24(1):144. doi: 10.1186/s13063-023-07178-3.

ABSTRACT

BACKGROUND: Perioperative pain management is one of the most challenging issues for patients with spinal neoplasms. Inadequate postoperative analgesia usually leads to severe postsurgical pain, which could cause patients to suffer from many other related complications. Meanwhile, there is no appropriate analgesic strategy for patients with spinal neoplasms.

METHODS/DESIGN: This is a protocol for a randomized double-blind controlled trial to evaluate the effect of esketamine combined with pregabalin on postsurgical pain in spinal surgery. Patients aged 18 to 65 years scheduled for spinal neoplasm resection will be randomly allocated into the combined and control groups in a 1:1 ratio. In the combined group, esketamine will be given during the during the surgery procedure until 48-h postoperative period, and pregabalin will be taken from 2 h before the surgery to 2 weeks postoperatively. The control group will receive normal saline and placebo capsules at the same time points. Both groups received a background analgesic regimen by using patient-controlled intravenous analgesia (containing 100 μg sufentanil and 16 mg ondansetron) until 2 days after surgery. To ensure the accuracy and reliability of this trial, all the researchers and patients will be blinded until the completion of this study. The primary outcome will be the proportion of patients with acute moderate-to-severe postsurgical pain (visual analog scale, VAS ≥ 40, range: 0-100, with 0, no pain; 100, the worst pain) during the 48-h postoperative period. The secondary outcomes will include the maximal VAS scores (when the patients felt the most intense pain over the last 24 h before being interviewed) at 0-2 h, 2-24 h, 24-48 h, and 48-72 h after leaving the operating room and 24 h before discharge; the incidence of acute moderate-to-severe postsurgical pain at each other time point; chronic postsurgical pain assessment; neuropathic pain assessment; and the incidence of drug-related adverse events and other postoperative complications, such as postoperative delirium and postoperative nausea and vomiting (PONV).

DISCUSSION: The aim of this study was to evaluate the effect of esketamine combined with pregabalin on acute postsurgical pain in patients undergoing resection of spinal neoplasms. The safety of this perioperative pain management strategy will also be examined.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05096468. Registered on October 27, 2021.

PMID:36841794 | DOI:10.1186/s13063-023-07178-3

Molecules. 2023 Feb 20;28(4):1990. doi: 10.3390/molecules28041990.

ABSTRACT

The kidney is an important organ in the human body, with functions such as urine production, the excretion of metabolic waste, the regulation of water, electrolyte and acid-base balance and endocrine release. The morbidity and mortality of kidney diseases are increasing year by year worldwide, and they have become a serious public health problem. In recent years, natural products derived from fungi, plants and animals have become an important alternative source of treatment for kidney diseases because of their multiple pathways, multiple targets, safety, low toxicity and few side effects. Tanshinone IIA (Tan IIA) is a lipid-soluble diterpene quinone isolated from the Chinese herb Salvia miltiorrhiza, considered as a common drug for the treatment of cardiovascular diseases. As researchers around the world continue to explore its unknown biological activities, it has also been found to have a wide range of biological effects, such as anti-cancer, anti-oxidative stress, anti-inflammatory, anti-fibrotic, and hepatoprotective effects, among others. In recent years, many studies have elaborated on its renoprotective effects in various renal diseases, including diabetic nephropathy (DN), renal fibrosis (RF), uric acid nephropathy (UAN), renal cell carcinoma (RCC) and drug-induced kidney injury caused by cisplatin, vancomycin and acetaminophen (APAP). These effects imply that Tan IIA may be a promising drug to use against renal diseases. This article provides a comprehensive review of the pharmacological mechanisms of Tan IIA in the treatment of various renal diseases, and it provides some references for further research and clinical application of Tan IIA in renal diseases.

PMID:36838978 | DOI:10.3390/molecules28041990

Medicina (Kaunas). 2023 Feb 9;59(2):324. doi: 10.3390/medicina59020324.

ABSTRACT

Background and Objectives: The treatment of chronic lymphocytic leukemia (CLL) has acquired new targeted therapies. In clinical trials, ibrutinib improved outcomes safely. Real-world data called for a reappraisal of ibrutinib strategies. We report on a single center's experience with ibrutinib monotherapy, aiming to explore the outcomes, tolerability, and prognosis of CLL patients in routine clinical practice. Materials and Methods: Data were collected from all CLL patients treated with ibrutinib at Fundeni Clinical Institute, Bucharest, Romania, between January 2016 and June 2021. Results: A total of one hundred twenty-three CLL adult patients were treated with ibrutinib. Of the patients, 87% had relapsed/refractory CLL. The median age at ibrutinib initiation was 65 years; 44.7% of patients were staged Rai III/IV. At 32-month median follow-up, the median progression-free survival (PFS) was 50 months, the overall survival (OS) was not reached, and the overall response rate (ORR) was 86.2%. The age or number of previous therapies did not impact outcomes or tolerability. An Eastern Cooperative Oncology Group performance status (ECOG PS) score ≥ 2 and shorter time from initiation of last therapy (TILT) before ibrutinib predicted inferior PFS. Baseline characteristics had no impact on the OS except for TILT in R/R CLL patients. Drug-related adverse events (AEs) of any grade and grade ≥ 3 AEs were reported in 82.1% and 30.9% of the patients, respectively. Infections were the most common AEs (29.3%). Drug discontinuation was permanent in 43.9% of patients, mainly due to disease progression (17.1%) and toxicity (8.9%). Patients with a Cumulative Illness Rating Scale (CIRS) score ≥ 6 had a higher risk for toxicity-related discontinuation. An ECOG PS ≥ 2 predicted an increased rate of permanent discontinuation and grade ≥ 3 AEs. Conclusions: The outcomes of this study align with the results from ibrutinib clinical trials. Our study demonstrated that poor patient fitness, early relapse before ibrutinib, and permanent ibrutinib discontinuation are essential outcome determinants. Patient comorbidity burden and fitness were significant predictors for ibrutinib intolerance.

PMID:36837525 | DOI:10.3390/medicina59020324

J Clin Med. 2023 Feb 7;12(4):1320. doi: 10.3390/jcm12041320.

ABSTRACT

Adverse drug events (ADEs) and adverse drug reactions (ADRs) are leading causes of iatrogenic injury, which can result in emergency department (ED) visits or admissions to inpatient wards. The aim of this systematic review and meta-analysis was to provide up-to-date estimates of the prevalence of (preventable) drug-related ED visits and hospital admissions, as well as the type and prevalence of implicated ADRs/ADEs and drugs. A literature search of studies published between January 2012 and December 2021 was performed in PubMed, Medline, EMBASE, Cochrane Library, and Web of Science. Retrospective and prospective observational studies investigating acute admissions to EDs or inpatient wards due to ADRs or ADEs in the general population were included. Meta-analyses of prevalence rates were conducted using generalized linear mixed models (GLMM) with the random-effect method. Seventeen studies reporting ADRs and/or ADEs were eligible for inclusion. The prevalence rates of ADR- and ADE-related admissions to EDs or inpatient wards were estimated at 8.3% ([95% CI, 6.4-10.7%]) and 13.9% ([95% CI, 8.1-22.8%]), respectively, of which almost half (ADRs: 44.7% [95% CI: 28.1; 62.4]) and more than two thirds (ADEs: 71.0% [95% CI, 65.9-75.6%]) had been classified as at least possibly preventable. The ADR categories most frequently implicated in ADR-related admissions were gastrointestinal disorders, electrolyte disturbances, bleeding events, and renal and urinary disorders. Nervous system drugs were found to be the most commonly implicated drug groups, followed by cardiovascular and antithrombotic agents. Our findings demonstrate that ADR-related admissions to EDs and inpatient wards still represent a major and often preventable health care problem. In comparison to previous systematic reviews, cardiovascular and antithrombotic drugs remain common causes of drug-related admissions, while nervous system drugs appear to have become more commonly implicated. These developments may be considered in future efforts to improve medication safety in primary care.

PMID:36835854 | DOI:10.3390/jcm12041320

Int J Mol Sci. 2023 Feb 7;24(4):3345. doi: 10.3390/ijms24043345.

ABSTRACT

Duchenne Muscular Dystrophy (DMD) is a very severe X-linked dystrophinopathy. It is due to a mutation in the DMD gene and causes muscular degeneration in conjunction with several secondary co-morbidities, such cardiomyopathy and respiratory failure. DMD is characterized by a chronic inflammatory state, and corticosteroids represent the main therapy for these patients. To contradict drug-related side effects, there is need for novel and more safe therapeutic strategies. Macrophages are immune cells stringently involved in both physiological and pathological inflammatory processes. They express the CB2 receptor, one of the main elements of the endocannabinoid system, and have been proposed as an anti-inflammatory target in several inflammatory and immune diseases. We observed a lower expression of the CB2 receptor in DMD-associated macrophages, hypothesizing its involvement in the pathogenesis of this pathology. Therefore, we analyzed the effect of JWH-133, a CB2 receptor selective agonist, on DMD-associated primary macrophages. Our study describes the beneficial effect of JWH-133 in counteracting inflammation by inhibiting pro-inflammatory cytokines release and by directing macrophages' phenotype toward the M2 anti-inflammatory one.

PMID:36834757 | DOI:10.3390/ijms24043345

PLoS One. 2023 Feb 24;18(2):e0282096. doi: 10.1371/journal.pone.0282096. eCollection 2023.

ABSTRACT

BACKGROUND: Adverse drug reactions (ADRs) have continued to be a public health challenge with significant clinical and healthcare costs. However, little is known regarding the incidence of ADR in Ethiopia, particularly in the study setting. Thus, this study aimed to assess the incidence and patterns of ADRs in patients admitted to the University of Gondar comprehensive specialized hospital (UoGCSH).

METHODS: A prospective observational follow-up study was conducted on admitted patients at the medical ward in the UoGCSH from May to August 2022. A multifaceted approach involving daily chart review and patient interviews was employed to collect the data. A standard Naranjo ADR Probability Scale measuring tool was used to characterize the probability of existing ADR. The data was analyzed using the Statistical Package for Social Sciences (SPSS) version 25. Logistic regression analysis was employed to determine the association between the occurrence of ADRs and other variables. A p-value at the 95% confidence interval was considered statistically significant.

RESULTS: This study included 237 participants in total. The average length of follow-up was 16.4 (±5.2) days. Overall, 65 ADRs were identified, resulting an incidence rate of 27.4 (95% CI: 19.8-30.4) per 100 admissions. The most common ADRs were hypokalemia (10.7%), followed by constipation, diarrhea, hypotension, and rash (9.2% each). The majority of these ADRs (73.8%) were classified as "definite" by the Naranjo ADR probability scale. Gastrointestinal tract (GIT) (41.5%) and metabolic (18.6%) were the most frequently exposed systems for ADR. Antibiotics (26.2%) and cardiovascular medications (24.7%) were the most frequently implicated medications in existing ADRs. ADRs were significantly associated with age (p = 0.035), the presence of comorbidities (p = 0.021) and complications (p = 0.008), and receiving a higher number of medications (p = 0.04).

CONCLUSION: In this study, ADR was identified in about one-fourth of the participants. Older patients, patients with comorbidities and complications, and patients who received a higher number of medications were more likely exposed for ADRs. Healthcare providers should strictly follow the admitted patients to minimize ADRs.

PMID:36827307 | PMC:PMC9955665 | DOI:10.1371/journal.pone.0282096

Healthc Q. 2023 Jan;25(4):6-9. doi: 10.12927/hcq.2023.27025.

ABSTRACT

Prescribing cascades occur when an adverse drug event is misinterpreted as a new medical condition, leading clinicians to prescribe an additional medication. Studies using ICES data have detected a number of common prescribing cascades, particularly among older adult populations. These findings have contributed to international initiatives aimed at optimizing prescribing practices in this population, with the goal of minimizing the risk of drug-related harms. Examining prescribing cascades through a sex and gender lens will better inform guidelines and recommendations tailored to older men and women.

PMID:36826233 | DOI:10.12927/hcq.2023.27025

Gen Dent. 2023 Mar-Apr;71(2):70-74.

ABSTRACT

Erythema multiforme (EM) is a rare immune-mediated reaction with mucocutaneous involvement. This case report describes the development of EM in a 9-year-old girl after treatment with imiquimod, a topical immunomodulator used in the management of some dermatologic conditions. Because imiquimod-related EM is rare, particularly in children, this article also reviews the potential adverse effects of this drug and the main characteristics of imiquimod-induced EM, especially in similar cases reported in the literature. Clinicians should be aware that topical imiquimod can induce EM, and this medication should be added to the extensive list of drugs that can trigger the condition.

PMID:36825977

Adv Respir Med. 2023 Feb 5;91(1):74-92. doi: 10.3390/arm91010008.

ABSTRACT

Background: Patients with respiratory disorders often have additional diseases and are usually treated with more than one medication to manage their respiratory conditions as well as additional comorbidities. Thus, they are frequently exposed to polypharmacy (≥5 drugs), which raises the risk for drug-drug interactions (DDIs) and adverse drug reactions (ADRs). In this work, we present the results regarding the prevalence of DDIs in hospitalized patients with respiratory disorders in Greece. Methods: A 6-month descriptive single-center retrospective observational study enrolled 102 patients with acute or chronic respiratory disorders. Clinical characteristics and medication regimens were recorded upon admission, hospitalization, and discharge. The prevalence of DDIs and their clinical significance was recorded and analyzed. Results: Unspecified acute lower respiratory tract infection (25%), exacerbations of chronic obstructive pulmonary disease (12%) and pneumonia (8%) were the most frequent reasons for admission. Cardiovascular disorders (46%), co-existing respiratory disorders (32%), and diabetes (25%) were the most prevalent comorbidities. Polypharmacy was noted in 61% of patients upon admission, 98% during hospitalization, and 63% upon discharge. Associated DDIs were estimated to be 55% upon admission, 96% throughout hospitalization, and 63% on discharge. Pharmacodynamic (PD) DDIs were the most prevalent cases (81%) and referred mostly to potential risk for QT-prolongation (31.4% of PD-DDIs) or modulation of coagulation process as expressed through the international normalized ratio (INR) (29.0% of DDIs). Pharmacokinetic (PK) DDIs (19% of DDIs) were due to inhibition of Cytochrome P450 mediated metabolism that could lead to elevated systemic drug concentrations. Clinically significant DDIs characterized as "serious-use alternative" related to 7% of cases while 59% of DDIs referred to combinations that could be characterized as "use with caution-monitor". Clinically significant DDIs mostly referred to medication regimens upon admission and discharge and were associated with outpatient prescriptions. Conclusions: Hospitalized patients with respiratory disorders often experience multimorbidity and polypharmacy that raise the risk of DDIs. Clinicians should be conscious especially if any occurring arrhythmias, INR modulations, and prolonged or increased drug action is associated with DDIs.

PMID:36825942 | PMC:PMC9952796 | DOI:10.3390/arm91010008

Crit Care Nurs Q. 2023 Apr-Jun 01;46(2):145-156. doi: 10.1097/CNQ.0000000000000447.

ABSTRACT

Depending on end-organ involvement, hypertensive crisis is classified as hypertensive urgency or hypertensive emergency. The recognition of a hypertensive crisis will lead to the adequate reduction of blood pressure to ameliorate the incidence of end-organ damage. Hypertensive crises result from dysfunction in the renin-angiotensin-aldosterone system and damage to the vascular bed. They occur commonly in the emergency department setting and can lead to increased mortality rates if not treated. Registered nurses play a vital role in assessing patients and administering medications during hypertensive crises. This article will outline the assessment strategies that registered nurses should implement in critical care units while patients are receiving antihypertensive drugs. We will also underscore the significance of monitoring specific laboratory values to mitigate the potential side effects of these drugs and exclude them when contraindicated.

PMID:36823741 | DOI:10.1097/CNQ.0000000000000447

Trop Med Infect Dis. 2023 Feb 16;8(2):123. doi: 10.3390/tropicalmed8020123.

ABSTRACT

BACKGROUND: The treatment of latent tuberculosis infection (LTBI) among high-risk populations is an essential component of Tuberculosis (TB) elimination. However, non-compliance with LTBI treatment remains a major obstacle hindering TB elimination efforts. We have previously reported high treatment compliance with nurse-managed, twice-weekly, directly observed Isoniazid treatment (DOT) for LTBI among hard-to-reach Ethiopian immigrants (EI's).

OBJECTIVES: to compare rate of completion of treatment, cost, and major adverse drug events with daily self-administered Isoniazid treatment (SAT) to nurse-managed Isoniazid DOT among hard-to-reach EIs.

MATERIALS AND METHODS: We conducted a retrospective study and compared self-administered LTBI treatment outcomes among EIs housed in reception centers during 2008-2012 to EIs treated with DOT.

RESULTS: Overall, 455 EIs were included (231 DOT, 224 SAT) in the study. We found no significant difference in treatment completion rates between the two groups (93.0% DOT vs. 87.9% SAT, p = 0.08). However, cases of grade III, drug-induced hepatitis were significantly fewer and treatment costs were significantly lower with the nurse-managed DOT compared with SAT (0% vs. 2.2%, p = 0.028, 363 vs. 521 United States Dollars, p < 0.001, respectively).

CONCLUSIONS: Nurse-managed, twice-weekly DOT among hard-to-reach EIs housed in reception centers had less severe drug-related adverse events and reduced treatment cost compared with daily isoniazid SAT, yet we found no significant difference in treatment completion between the two strategies in this population.

PMID:36828539 | DOI:10.3390/tropicalmed8020123

Front Oncol. 2023 Feb 7;13:1044327. doi: 10.3389/fonc.2023.1044327. eCollection 2023.

ABSTRACT

BACKGROUND: Several randomized controlled trials (RCTs) have confirmed the favorable clinical benefit of pembrolizumab in advanced non-small cell lung cancer (NSCLC). However, considering the strict inclusion and exclusion criteria in clinical research, there are certain differences between patients in the real-world, it is unclear whether the findings of clinical trials are fully representative of the treatment efficacy in patients who will eventually use it. Therefore, to further comprehensively assess the efficacy and safety of pembrolizumab in NSCLC, we conducted a systematic review and meta-analysis based on the latest RCTs and real-world studies (RWSs).

METHODS: We systematically searched PubMed, Embase, The Cochrane Library, The Web of Science, and clinical trials.gov as of December 2021. RCTs and RWSs of patients receiving pembrolizumab monotherapy or in combination with chemotherapy for advanced NSCLC were included.

RESULTS: The meta-analysis ultimately included 11 RCTs and 26 RWSs with a total of 10,695 patients. The primary outcomes of this study were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), serious adverse events (SAEs), the incidence of severe pneumonia reactions, and drug-related mortality. Direct meta-analysis results showed that in RCTs, pembrolizumab in combination with chemotherapy was superior to chemotherapy in terms of OS (HR=0.60, 95%CI:0.50-0.73), PFS (HR=0.47, 95%CI:0.38-0.58) and ORR (OR=3.22, 95%CI:2.57-4.03); pembrolizumab monotherapy was superior to chemotherapy in terms of OS (HR=0.73, 95%CI:0.66-0.80) and ORR (OR=1.90, 95%CI:1.17-3.09), but comparable to chemotherapy in terms of PFS (HR=0.83, 95%CI:0.66-1.04). The ORR values in retrospective single-arm studies were 45% (40%-51%).

CONCLUSION: In RCTs, pembrolizumab monotherapy or in combination with chemotherapy is more effective and safer than chemotherapy for advanced NSCLC. In RWSs, ECOG PS 0-1 was shown to correlate with PFS and OS for patients with NSCLC.

PMID:36824127 | PMC:PMC9942927 | DOI:10.3389/fonc.2023.1044327

J Int AIDS Soc. 2023 Feb;26(2):e26037. doi: 10.1002/jia2.26037.

ABSTRACT

INTRODUCTION: Tenofovir alafenamide (TAF) is approved for paediatric use in fixed-dose combination tablets, but efficacy and safety data in children are limited. We conducted a systematic review on the efficacy/effectiveness and safety of TAF in infants, children and adolescents living with HIV.

METHODS: We searched MEDLINE, Embase, the Cochrane Library, clinical trial registries, reference lists and relevant conferences to identify literature published January 2009-March 2021. We included clinical trials and observational studies assessing the efficacy/effectiveness or safety of TAF through ≥6 months of treatment in participants aged 0-19 years.

RESULTS AND DISCUSSION: Overall 3626 abstracts and 371 full papers were screened. Four single-arm, innovator-funded trials (341 participants) and a pooled analysis of those trials were identified. All four trials included treatment-experienced and virally suppressed children or adolescents. One trial also included treatment-naïve adolescents with baseline viral load >1000 copies/ml. The risk of bias was rated as low in one study and unclear in the other three owing to missing data on study design (all conference presentations). At 48 weeks, 92% (46/50) of treatment-naïve participants were virally suppressed (one trial). Among treatment-experienced participants with viral load at 48 weeks, 214 of 224 participants were virally suppressed. Across the studies, one grade 3/4 adverse event was considered drug-related (intermediate uveitis). There were three discontinuations for adverse events (grade 2 anxiety and insomnia, grade 1 iridocyclitis [drug-related] and grade 1 pulmonary tuberculosis [unrelated to treatment]). One accidental death occurred across the four studies. In the pooled analysis of 223 participants, the median change in bone mineral density z-score (height- and age-adjusted) from baseline to 48 weeks was -0.12 (interquartile range [IQR] -0.46, 0.17) to 0.05 (IQR not reported) for spine, and -0.09 (IQR -0.33, 0.07) to 0.09 (IQR not reported) for total body less head. Weight-for-age z-scores increased by 0.25 from baseline to 48 weeks.

CONCLUSIONS: Four single-arm trials were identified in this systematic review, with initial evidence suggesting good viral suppression and no obvious safety concerns in children and adolescents on TAF-containing regimens over 24-48 weeks. However, further comparative and longer-term safety data are needed in children and adolescents, including on weight and metabolic changes.

PMID:36823283 | DOI:10.1002/jia2.26037

Crit Rev Toxicol. 2022 Oct;52(9):757-778. doi: 10.1080/10408444.2023.2168178. Epub 2023 Feb 23.

ABSTRACT

Herbal medicines (HMs) have long been considered safe and effective without serious toxic and side effects. With the continuous use of HMs, more and more attention has been paid to adverse reactions and toxic events, especially the nephrotoxicity caused by natural compounds in HMs. The composition of HMs is complex and various, especially the mechanism of toxic components has been a difficult and hot topic. This review comprehensively summarizes the kidney toxicity characterization and mechanism of nephrotoxic natural compounds (organic acids, alkaloids, glycosides, terpenoids, phenylpropanoids, flavonoids, anthraquinones, cytotoxic proteins, and minerals) from different sources. Recommendations for the prevention and treatment of HMs-induced kidney injury were provided. In vitro and in vivo models for evaluating nephrotoxicity and the latest biomarkers are also included in this investigation. More broadly, this review may provide theoretical basis for safety evaluation and further comprehensive development and utilization of HMs in the future.

PMID:36815678 | DOI:10.1080/10408444.2023.2168178

Nat Commun. 2023 Feb 23;14(1):1025. doi: 10.1038/s41467-023-36541-w.

ABSTRACT

Glucocorticoids prescribed to limit inflammation, have significant adverse effects. As 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoid, we investigated whether 11β-HSD1 inhibition with AZD4017 could mitigate adverse glucocorticoid effects without compromising their anti-inflammatory actions. We conducted a proof-of-concept, randomized, double-blind, placebo-controlled study at Research Unit, Churchill Hospital, Oxford, UK (NCT03111810). 32 healthy male volunteers were randomized to AZD4017 or placebo, alongside prednisolone treatment. Although the primary endpoint of the study (change in glucose disposal during a two-step hyperinsulinemic, normoglycemic clamp) wasn't met, hepatic insulin sensitivity worsened in the placebo-treated but not in the AZD4017-treated group. Protective effects of AZD4017 on markers of lipid metabolism and bone turnover were observed. Night-time blood pressure was higher in the placebo-treated but not in the AZD4017-treated group. Urinary (5aTHF+THF)/THE ratio was lower in the AZD4017-treated but remained the same in the placebo-treated group. Most anti-inflammatory actions of prednisolone persisted with AZD4017 co-treatment. Four adverse events were reported with AZD4017 and no serious adverse events. Here we show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects.

PMID:36823106 | PMC:PMC9950480 | DOI:10.1038/s41467-023-36541-w