Knee. 2022 Nov 18;40:63-70. doi: 10.1016/j.knee.2022.11.008. Online ahead of print.

ABSTRACT

BACKGROUND: Two-stage revision arthroplasty is a widely used treatment method for infected knee arthroplasty. Loading high doses of antibiotics to spacer during the first stage is standard practice. However, there are reported systemic side effects attributed to antibiotic-loaded spacers. The aim of our study is to investigate the success rate and systemic toxicity following the first stage revision knee arthroplasty with low-dose vancomycin-loaded spacers.

METHOD: We included patients with infected knee arthroplasty eligible for two-stage revision arthroplasty from 2001 to 2020. One gram of vancomycin is added per pack of bone cement. Spacers were handmade in the operating theatre. Following the first stage, pre-operative and postoperative culture results, infection parameters, kidney and liver function tests, and functional scores were analyzed. Kaplan-Meier survival analysis was done to determine the success rate.

RESULTS: Fifty patients with a mean follow-up of 48 months (24-108) were included in the study. A five-year survival analysis showed an 88.5% success rate. Fourteen percent of the patients had acute kidney injury with creatinine levels between 1.12-2.80 mg/dl, and 8% had a mild drug-induced liver injury with elevated serum ALT levels between 223-540 U/L and total bilirubin levels between 0.59-1.23 mg/dl. None of the patients required dialysis. All of the systemic side effects were reversible.

CONCLUSION: Our results have suggested that low dose antibiotic-loaded spacers are comparable to the studies with high dose antibiotic loaded spacers regarding infection eradication and survival rates. They are less likely to cause severe systemic side effects. Therefore we suggest low dose antibiotic-loaded spacers should be considered when treating patients with vancomycin sensitive Staphylococcal species and culture negative infected knee arthroplasty.

PMID:36410252 | DOI:10.1016/j.knee.2022.11.008

Respir Med Case Rep. 2022 Nov 8;40:101773. doi: 10.1016/j.rmcr.2022.101773. eCollection 2022.

ABSTRACT

In recent years, the combination of platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) has become the standard treatment for patients with lung cancer. Hepatitis is one of the common toxicities following ICI/chemotherapy. When drug-induced hepatitis occurs, the suspected drug must be discontinued. Since it may be difficult to determine the exact drug causing the hepatitis, liver biopsy may help identify this. We report the case of a patient diagnosed with immune-related adverse event hepatitis from liver biopsy and clinical course. A 45-year-old man with lung adenocarcinoma (stage IV, cT4N3M1c) negative for driver gene mutation was treated with carboplatin (CBDCA), pemetrexed (PEM), and pembrolizumab. Elevated blood aspartate aminotransferase and alanine aminotransferase levels after chemotherapy indicated hepatitis induced by cytotoxic anticancer agents and ICIs. As autoimmune hepatitis was also suspected, liver biopsy was performed and the findings suggested ICI-induced hepatitis. Pembrolizumab was discontinued and CBDCA/PEM was resumed, following which, the primary lesion shrank. When drug-induced hepatitis is suspected, clinicians should actively perform liver biopsy to confirm the diagnosis, so that appropriate therapeutic regimen can be administered.

PMID:36408484 | PMC:PMC9672405 | DOI:10.1016/j.rmcr.2022.101773

Indian J Occup Environ Med. 2022 Jul-Sep;26(3):140-150. doi: 10.4103/ijoem.ijoem_32_22. Epub 2022 Sep 26.

ABSTRACT

BACKGROUND: The COVID-19 pandemic has necessitated the use of personal protective equipment (PPE) among the frontline health care workers (HCWs). Even though PPE helps in preventing infection, it poses significant physical and psychological impacts at varying levels. Correspondingly, multiple independent studies have brought out the PPE-associated problems. However, there exists a lacuna on comprehensive information of global prevalence related to the same.

AIM: To estimate the prevalence and risk factors of PPE among HCWs during COVID-19 across the globe.

DESIGN: Systematic review and meta-analysis.

METHOD: The review was undertaken as per the protocol registered in PROSPERO CRD42021272216 following Preferred Reporting Items for Systematic Reviews and Meta-Analysis(PRISMA) guidelines. Two independent reviewers have undertaken the search strategy, study selection, and methodological quality assessment. Discrepancies were addressed by the third reviewer. Heterogeneity was addressed through I2 statistics and forest plots generated by open meta-software.

RESULTS: A total of 16 articles conducted across 6 different countries among 10,182 HCWs were included in the review. The pooled prevalence of skin lesions, headache, sweating, breathing difficulty, vision difficulty, thirst/dry mouth, fatigue, and communication difficulty, anxiety, fear were 57 (47-66%), 51 (37-64%), 75 (56-90%), 44 (23-68%), 61 (21-94%), 54 (30-77%), 67 (58-76%), 74 (47-94%), 28 (24-33%), 14 (10-17%), respectively. Moreover, the various risk factors included are the use of PPE for >6 h and young females. In addition, the medical management of new-onset problems created an additional burden on the frontline health care personnel (HCP).

CONCLUSION: The frontline HCWs encountered physical and psychological problems at varying levels as a result of wearing PPE which needs to be addressed to prevent the inadequate use of PPE leading to infections.

PMID:36408432 | PMC:PMC9674076 | DOI:10.4103/ijoem.ijoem_32_22

Cureus. 2022 Oct 17;14(10):e30377. doi: 10.7759/cureus.30377. eCollection 2022 Oct.

ABSTRACT

The recreational use of a drug such as 3,4-methylenedioxymethamphetamine (MDMA), also known as "ecstasy," may be associated with significant side effects. Although liver failure with ecstasy is rare, the use of the drug should be investigated in all patients with severe hepatitis of unknown origin. Early diagnosis and intervention can prevent patients from ending up in liver transplantation. Here, we present a case of a 27-year-old female who developed acute liver injury secondary to recreational intoxication with ecstasy.

PMID:36407170 | PMC:PMC9671195 | DOI:10.7759/cureus.30377

J Clin Pharm Ther. 2022 Nov 20. doi: 10.1111/jcpt.13794. Online ahead of print.

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: The present study compared the efficacy and safety of low-dose febuxostat versus allopurinol in chronic kidney disease (CKD) patients complicated with hyperuricemia (HUA).

METHODS: In this double-centre, randomized, controlled study, 120 CKD patients complicated with HUA were recruited and randomly assigned to low-dose febuxostat group (20 mg/day) or allopurinol group (200 mg/day) at 1:1 ratio. The serum creatinine (Scr), serum uric acid (SUA), and estimated glomerular filtration rate (eGFR) were measured at baseline (M0), month (M) 1, M3, and M6. Besides, the drug-related adverse events (AEs) were recorded. The primary outcome was the proportion of patients showing a > 10% decline in eGFR from M0 to M6.

RESULTS: The eGFR level was increased at M6, but similar at M0, M1 and M3 in febuxostat group compared with allopurinol group. Notably, the proportion of patients with >10% decline in eGFR from M0 to M6 was decreased in febuxostat group compared with allopurinol group. However, there was no difference of Scr, SUA at M0, M1, M3 and M6 between febuxostat group and allopurinol group. Moreover, there was no difference of drug-related AEs between febuxostat group and allopurinol group. Further subgroup analysis exhibited that low-dose febuxostat presented superior effect on attenuating eGFR decline and lowering SUA level compared with allopurinol in CKD stage 3 subgroup, but not in CKD stage 2 subgroup.

CONCLUSION: Low-dose febuxostat may exhibit a superior renal-protective effect, non-inferior SUA lowering ability and safety profile compared with allopurinol in CKD patients complicated with HUA.

PMID:36403976 | DOI:10.1111/jcpt.13794

Medicine (Baltimore). 2022 Nov 18;101(46):e31700. doi: 10.1097/MD.0000000000031700.

ABSTRACT

BACKGROUND: Osteoarthritis (OA) is the leading cause of disability in the elderly. Prevention and treatment of OA have become an urgent global demand. The pharmacologic role of diacerein in the treatment of osteoarthritis is controversial. We systematically reviewed the efficacy, safety, and residual effectiveness of diacerein.

OBJECTIVES: To estimate the symptomatic efficacy, residual effect and safety of diacerein in the treatment of knee osteoarthritis, using a meta-analysis of published randomized controlled trials (RCTs).

METHODS: On December 1, 2021, we searched PubMed Medline, Web of Science, Cochrane Library databases, Wan Fang Medical Database, and National Knowledge Infrastructure. This study followed the inclusion criteria of the principle P(Population), I(Intervention), C(Comparison), O(Outcome), S (Study design) principle. All studies were randomized controlled trials of knee osteoarthritis. Cochrane bias risk assessment tool was used to assess the risk of bias. Meta-analyses were performed using a random-effects model. To explore sources of heterogeneity, subgroup analysis, sensitivity analysis, regression analysis and publication bias analysis were performed. Drug side effects with complete data were extracted from the included articles and then a combined analysis of these data was performed.

RESULTS: Eight studies were eligible and were included in our analysis (N = 1277 participants). All studies were randomized controlled trials of knee osteoarthritis. There was no significant difference in reduction of joint pain and improvement of function between diacerein and the control group. However, subgroup analysis suggested, compared with the placebo group, diacerein treatment yielded an improved mean reduction in visual analogue scale score of-0.44% (95% confidence interval [CI]-0.79 to 0.09), an improved the western Ontario and McMaster universities (physical function) score of -0.44% (95% CI-0.72 to -0.12). Follow-up analysis after discontinuation showed that diacerein treatment had a significant residual effect (95% CI-0.81 to- 0.24). Data on drug side effects described in the included articles were extracted for statistical analysis. There was an increased risk of diarrhea with diacerein (Risk Ratio [RR] = 1.95 [1.03 to 2.47]) and withdrawal event from therapy (RR = 0.93 [0.75 to 1.15]).

CONCLUSION: Diacerein might be considered an effective drug for the treatment of patients with KOA, showing short-term residual effectiveness. Although it is associated with an increased risk of diarrhea, the adverse event is mostly tolerable.

PMID:36401382 | DOI:10.1097/MD.0000000000031700

Medicine (Baltimore). 2022 Nov 18;101(46):e31770. doi: 10.1097/MD.0000000000031770.

ABSTRACT

The irrational use of tyrosine kinase inhibitors (TKIs) has attracted increasing attention, especially because of drug-drug interactions. The objective of this study was to analyze TKI prescriptions and evaluate the rationality of concomitant use of TKIs and acid-suppressants. TKI prescriptions from 2016 to 2018 were collected from hospitals in Beijing, Guangzhou, Hangzhou, and Zhengzhou for 40 d/yr. Focusing on the data in 2018, we analyzed the pharmacoeconomic indicators of TKIs and the number and proportion of different coprescriptions. The evaluation criteria for coprescriptions were based on clinical literature and package inserts. A total of 41,738 TKI prescriptions were assessed. The total dose and sales of imatinib were the highest, the medication days and defined daily doses of gefitinib were the highest, and the highest defined daily cost was sunitinib. Meanwhile, there were 17 TKIs with drug utilization indices of ≤ 1.0. The irrational combination rate of prescriptions of non-cancer-related departments was high in 3 cities, but not Hangzhou. The irrational combination rate of prescription of inpatient prescriptions was > 23% in the 4 cities. The combined use of TKIs and acid-suppressants is common in China and may have a clear or potential impact on the pharmacokinetics, pharmacodynamics, and adverse drug reactions of TKIs. Therefore, it is urgent to implement necessary interventions to stop such irrational use or if the combined use is necessary, to correct adverse consequences. The aims should be to achieve safe and effective use of TKIs and reduce unnecessary costs.

PMID:36401366 | DOI:10.1097/MD.0000000000031770

BMC Public Health. 2022 Nov 18;22(1):2121. doi: 10.1186/s12889-022-14586-8.

ABSTRACT

BACKGROUND: Illicit drug poisoning (overdose) continues to be an important public health problem with overdose-related deaths currently recorded at an unprecedented level. Understanding the geographic variations in fatal overdose mortality is necessary to avoid disproportionate risk resulting from service access inequity.

METHODS: We estimated the odds of fatal overdose per event from all cases captured by the overdose surveillance system in British Columbia (2015 - 2018), using both conventional logistic regression and Generalized Additive Models (GAM). The results of GAM were mapped to identify spatial-temporal trends in the risk of fatal overdose.

RESULTS: We found that the odds of fatal overdose were about 30% higher in rural areas than in large urban centers, with some regions reporting odds 50% higher than others. Temporal variations in fatal overdose revealed an increasing trend over the entire province. However, the increase occurred earlier and faster in the Interior and Northern regions.

CONCLUSION: Rural areas were disproportionately affected by fatal overdose; lack of access to harm reduction services may partly explain the elevated risk in these areas.

PMID:36401244 | PMC:PMC9675064 | DOI:10.1186/s12889-022-14586-8

BMC Health Serv Res. 2022 Nov 17;22(1):1363. doi: 10.1186/s12913-022-08696-7.

ABSTRACT

BACKGROUND: Drug overuse or drug underuse are the most common causes of adverse drug events and can lead to hospital admissions. Using clinical pharmacists in the emergency department may improve patient safety as they are specialised in recognising of adverse drug events and tackling drug overuse and drug underuse. This study tested the effect of an emergency department pharmacist on the number of medication changes for drug overuse and drug underuse taking place in patients with an adverse drug event-related hospitalisation following an emergency department visit.

METHODS: A multicenter prospective non-randomized controlled intervention study was conducted in a university hospital and a general teaching hospital. Trained emergency department pharmacists included patients in the intervention group with a hospital admission related to an adverse drug event. The interdisciplinary intervention consisted of a pharmacist-led medication review, patient counselling regarding medication, and information transmission to general practitioners and community pharmacies after discharge. The control patients were also admitted after an emergency department visit and received the usual care. The primary outcome was the number of medication changes for drug overuse and drug underuse that took place during hospital admission and persisted 6 months thereafter. Poisson regression analysis was used to estimate the difference in these medication changes between the intervention group and the control group.

RESULTS: A total of 216 patients were included (intervention group 104, control group 112). In the intervention group, 156 medication changes for drug overuse and drug underuse persisted 6 months after admission compared to 59 in the control group (adjusted rate ratio 1.22 [95%CI 1.01-1.49] p = 0.039).

CONCLUSION: Emergency department pharmacists do contribute to reduction of drug overuse and drug underuse of medication in patients with a hospitalisation related to adverse drug events after an emergency department visit.

PMID:36397102 | PMC:PMC9670389 | DOI:10.1186/s12913-022-08696-7

Indian J Tuberc. 2022;69 Suppl 2:S202-S204. doi: 10.1016/j.ijtb.2022.10.022. Epub 2022 Oct 26.

ABSTRACT

The article deals with challenges faced by the geriatric populations while on MDR treatment. Risk factors like tobacco use, low socio-economic status, previous disease, longer delays in seeking treatment and reduced mobility are some of the challenges while initiating MDR treatment. Other issues like drug-related adverse events and increased co-morbidity pose a major challenge while treating patients. Susceptibility among the geriatric age group includes various anatomical and physiological changes including nutritional deficiencies and co morbidities.

PMID:36400509 | DOI:10.1016/j.ijtb.2022.10.022

Lancet Glob Health. 2022 Dec;10(12):e1845-e1854. doi: 10.1016/S2214-109X(22)00450-8.

ABSTRACT

BACKGROUND: HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis.

METHODS: The AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed.

FINDINGS: The AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US$1369 (95% CI 1314-1424) in the AmBisome group and $1237 (1181-1293) in the control group. The incremental cost-effectiveness ratio was $128 (59-257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to $80 (15-275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from $71 in Botswana to $121 in Uganda.

INTERPRETATION: The AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays.

FUNDING: European Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research.

TRANSLATIONS: For the Chichewa, Isixhosa, Luganda, Setswana and Shona translations of the abstract see Supplementary Materials section.

PMID:36400090 | DOI:10.1016/S2214-109X(22)00450-8

Stem Cell Res. 2022 Nov 14;65:102970. doi: 10.1016/j.scr.2022.102970. Online ahead of print.

ABSTRACT

Cytochrome P450 (CYP) reaction phenotyping has become crucial for predicting drug reactions and side effects. Single nucleotide polymorphisms (SNPs) in CYP genes alter drug metabolism capacity and cause unexpected drug-related reactions. Here, we established two human induced pluripotent stem cell (hiPSC) lines with pharmacologically important SNPs in CYP2D6 in conjunction with CYP2C19 or CYP3A5 genes. These hiPSC lines can serve as valuable resources for expanding our understanding of the relationships between genotypes and drug reactions.

PMID:36399926 | DOI:10.1016/j.scr.2022.102970

J Popul Ther Clin Pharmacol. 2022 Nov 12;29(4):e46-e54. doi: 10.15586/jptcp.2022.967. eCollection 2022.

ABSTRACT

Teratogenicity and hyperuricemia are considered as the major adverse effects of favipiravir, but less is known about other possible side effects which includes drug-induced liver damage and renal injury. In the current research, assessment of favipiravir-induced liver injury was performed by evaluating liver enzymes among patients with mild to moderate COVID-19 infection. A prospective cohort study was conducted on 66 patients diagnosed with mild to moderate COVID-19 infection who were treated with favipiravir for 5 days. During this period, a baseline assessment of liver enzymes (aspartate aminotransferase - AST, alanine transaminase - ALT and alkaline phosphatase - ALP) in addition to bilirubin before initiation of therapy and after 1 day of completion of therapy were carried out. The comparison of all measured parameters among all patients before and after receiving the treatment showed that non-significant differences were obtained in their levels. It was noticed that COVID-19 patients demonstrated high AST levels in which only 16 patients out of the all-subjected cases (66 patients) had AST levels of less than 45 U/L whereas the majority of patients showed normal ALT, ALP, and bilirubin levels. It was concluded that 5 days administration of favipiravir in mild to moderate COVID-19 patients who had no previous liver diseases did not affect the liver enzymes significantly and only transient elevations were occurred.

PMID:36398597 | DOI:10.15586/jptcp.2022.967

Drug Des Devel Ther. 2022 Nov 10;16:3915-3927. doi: 10.2147/DDDT.S236926. eCollection 2022.

ABSTRACT

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disorder of the central nervous system. Disease-modifying drugs (DMDs) and subsequent adherence are crucial for preventing reversible episodes of neurological dysfunction and delayed onset of progressive accumulation of irreversible deficits. Yet, side effects may limit their usage in clinical practice. Gastrointestinal (GI) side effects are a significant limitation of the use of dimethyl fumarate (DMF), the most frequently prescribed oral DMD in MS worldwide. Diroximel fumarate (DRF) is a second-generation oral fumaric acid ester (FAE) that was developed as a formulation with better GI tolerability. The improved tolerability is assumed to be related to a lower synthesis of gut-irritating methanol. Other explanations for DRF's lower extent of GI irritation include a more modest off-target activity due to its chemical structure. The superior GI tolerability of DRF compared to DMF could be proven in clinical trials and lead to approval of DRF for the treatment of relapsing forms of MS/relapsing-remitting MS (United States Food and Drug Administration and European Medicines Agency, respectively). Here, we summarize the mode of action of oral FAE and compare the chemical and physiological characteristics of DMF and DRF. Moreover, we discuss the adverse effects of FAE and introduce the emerging preclinical and trial data leading to the approval of DRF in MS. This article additionally reviews our current understanding of coronavirus disease 2019 (COVID-19) and the efficacy of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination in people treated with FAE.

PMID:36388086 | PMC:PMC9663167 | DOI:10.2147/DDDT.S236926

Intern Med. 2022;61(22):3435-3438. doi: 10.2169/internalmedicine.9430-22. Epub 2022 Nov 15.

ABSTRACT

Miller Fisher syndrome (MFS) is a variant of Guillain-Barré syndrome. Delayed facial palsy (DFP) is a symptom that occurs after other neurological symptoms begin to recover within four weeks from the onset of MFS. As there have been few detailed reports about DFP in MFS cases treated with additional immunotherapy, we investigated three cases of DFP in MFS treated with additional steroid therapies. The duration of facial palsy in our cases was 12-24 days. No severe adverse effects were observed. Although adverse side effects should be carefully monitored, additional steroid therapy might be a treatment option for MFS-DFP.

PMID:36385049 | DOI:10.2169/internalmedicine.9430-22

Dtsch Arztebl Int. 2022 Aug 8;119(31-32):550. doi: 10.3238/arztebl.m2022.0098.

NO ABSTRACT

PMID:36384929 | DOI:10.3238/arztebl.m2022.0098

Am J Nurs. 2022 Dec 1;122(12):23. doi: 10.1097/01.NAJ.0000904084.55613.b6.

ABSTRACT

Ibrutinib (Imbruvica) has received a new indication for the treatment of graft-versus-host disease in pediatric patients at least one year of age when one or more systemic therapies have failed.The product's labeling warns of the risk of hemorrhage, infections, cardiac arrythmias, cardiac failure and sudden death, hypertension, cytopenia, secondary primary malignancies, tumor lysis syndrome, and embryo-fetal toxicity.The most common adverse effects include laboratory abnormalities, musculoskeletal pain, pyrexia, pneumonia, abdominal pain, stomatitis, diarrhea, and headache. Nurses should carefully assess for these adverse effects and provide appropriate education regarding their prevention.

PMID:36384792 | DOI:10.1097/01.NAJ.0000904084.55613.b6

Am J Nurs. 2022 Dec 1;122(12):22-23. doi: 10.1097/01.NAJ.0000904080.71037.14.

ABSTRACT

The Food and Drug Administration (FDA) has approved capmatinib (Tabrecta) for the treatment of metastatic non-small cell lung cancer in adults whose tumors have a mutation leading to mesenchymal-epithelial transition exon 14 skipping.Nurses should monitor patients for serious adverse effects such as interstitial lung disease/pneumonitis, hepatotoxicity, pancreatic toxicity, photosensitivity, and embryo-fetal toxicity.The FDA has granted accelerated approval to fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of unresectable or metastatic non-small cell lung cancer in adults whose tumors have activating human epidermal growth factor receptor 2 mutations and who have received a prior systemic therapy.Enhertu carries a boxed warning regarding the risk of interstitial lung disease and embryo-fetal toxicity.

PMID:36384791 | DOI:10.1097/01.NAJ.0000904080.71037.14

Front Pharmacol. 2022 Oct 28;13:1053356. doi: 10.3389/fphar.2022.1053356. eCollection 2022.

ABSTRACT

Background and objective: Idiopathic pulmonary fibrosis (IPF) is a critical disease, with limited treatments available. Clinical practices show that traditional Chinese medicine (TCM) has certain efficacy. This study was preliminarily to evaluate the efficacy and safety of TCM treatment based on syndrome differentiation in IPF. Methods: A study design of exploratory, multi-centers, randomized, double-blinded, placebo controlled trial has been adopted. A total of 80 IPF patients from four sub-centers were enrolled. All the patients were randomly assigned into TCM group (TCMG) or control group (CG) in 1:1. Patients in TCMG were given CM granules, as patients in CG given with the placebo of CM granule. All the patients received a 26-week treatment. The efficacy was assessed by acute exacerbations (AEs) of IPF, pulmonary function, clinical symptoms, dyspnea scores (mMRC), health-related quality of life (HRQoL), 6-min walk test (6MWT) and all-cause mortality. Safety has also been assessed. Results: A total of 67 patients completed the trial with 35 in TCM group and 32 in control group. Meaningful differences have been observed in mean changes in AEs (-1.56 times; 95% CI, -2.69 to -0.43, p = 0.01), DLco% (5.29; 95% CI, 0.76 to 9.81, p = 0.02), cough scores (-0.38 points; 95% CI, -0.73 to -0.04, p = 0.03), and 6MWT (30.43 m; 95% CI, 2.85 to 58.00, p = 0.03), with no statistical differences in FEV1, FVC, expectoration, chest tightness, Shortness of breath, Fatigue, Cyanosis, mMRC, CAT, SF-36, and SGRQ total scores in 26 weeks after treatment than before treatment. At of the end of follow-up, a total of 10 patients died, including three and seven in the TCM and control group respectively. And the HR (Hazard ratio) for CM granules in all-cause mortality was 0.39 (95% CI, 0.10-1.52). The drug-related adverse events were not observed. Conclusion: CM granules, as compared with placebo, could reduce frequencies of AEs, improve pulmonary function, HRQoL, exercise capacity and symptoms and signs for IPF to some extent with acceptable side-effect.

PMID:36386223 | PMC:PMC9649819 | DOI:10.3389/fphar.2022.1053356

Front Pharmacol. 2022 Oct 25;13:1043828. doi: 10.3389/fphar.2022.1043828. eCollection 2022.

ABSTRACT

GPR40 is a class A G-protein coupled receptor (GPCR) mainly expressed in pancreas, intestine, and brain. Its endogenous ligand is long-chain fatty acids, which activate GPR40 after meal ingestion to induce secretion of incretins in the gut, including GLP-1, GIP, and PYY, the latter control appetite and glucose metabolism. For its involvement in satiety regulation and metabolic homeostasis, partial and AgoPAM (Positive Allosteric Modulation agonist) GPR40 agonists had been developed for type 2 diabetes (T2D) by many pharmaceutical companies. The proof-of-concept of GPR40 for control of hyperglycemia was achieved by clinical trials of partial GPR40 agonist, TAK-875, demonstrating a robust decrease in HbA1c (-1.12%) after chronic treatment in T2D. The development of TAK-875, however, was terminated due to liver toxicity in 2.7% patients with more than 3-fold increase of ALT in phase II and III clinical trials. Different mechanisms had since been proposed to explain the drug-induced liver injury, including acyl glucuronidation, inhibition of mitochondrial respiration and hepatobiliary transporters, ROS generation, etc. In addition, activation of GPR40 by AgoPAM agonists in pancreas was also linked to β-cell damage in rats. Notwithstanding the multiple safety concerns on the development of small-molecule GPR40 agonists for T2D, some partial and AgoPAM GPR40 agonists are still under clinical development. Here we review the most recent progress of GPR40 agonists development and the possible mechanisms of the side effects in different organs, and discuss the possibility of developing novel strategies that retain the robust efficacy of GPR40 agonists for metabolic disorders while avoid toxicities caused by off-target and on-target mechanisms.

PMID:36386134 | PMC:PMC9640913 | DOI:10.3389/fphar.2022.1043828