JAMA Netw Open. 2023 Mar 1;6(3):e234732. doi: 10.1001/jamanetworkopen.2023.4732.

ABSTRACT

IMPORTANCE: Uptake of vaccination against COVID-19 is strongly affected by concerns about adverse effects. Research on nocebo effects suggests that these concerns can amplify symptom burden.

OBJECTIVE: To investigate whether positive and negative expectations prior to COVID-19 vaccination are associated with systemic adverse effects.

DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study analyzed the association of expected benefits and risks of vaccination, adverse effects at first vaccination, and observed adverse effects in close contacts with severity of systemic adverse effects among adults receiving a second dose of messenger RNA (mRNA)-based vaccines between August 16 and 28, 2021. A total of 7771 individuals receiving the second dose at a state vaccination center in Hamburg, Germany, were invited to participate; of these, 5370 did not respond, 535 provided incomplete information, and 188 were excluded retrospectively. The mobile application m-Path was used for data collection.

MAIN OUTCOMES AND MEASURES: Primary outcome was a composite severity index of systemic adverse effects in 12 symptom areas measured once daily with an electronic symptom diary over 7 consecutive days. Data were analyzed by mixed-effects multivariable ordered logistic regression adjusted for prevaccine symptom levels and observation times.

RESULTS: A total of 10 447 observations from 1678 individuals receiving vaccinations (BNT162b2 [Pfizer BioNTech] in 1297 [77.3%] and mRNA-1273 [Moderna] in 381 [22.7%]) were collected. The participants' median age was 34 (IQR, 27-44) years, and 862 (51.4%) were women. The risk for more severe adverse effects was higher for persons expecting a lower benefit of vaccination (odds ratio [OR] for higher expectations, 0.72 [95% CI, 0.63-0.83]; P < .001), expecting higher adverse effects of vaccination (OR, 1.39 [95% CI, 1.23-1.58]; P < .001), having experienced higher symptom burden at the first vaccination (OR, 1.60 [95% CI, 1.42-1.82]; P < .001), scoring higher on the Somatosensory Amplification Scale (OR, 1.21 [95% CI, 1.06-1.38]; P = .004), and if the vaccine mRNA-1273 was given rather than BNT162b2 (OR, 2.45 [95% CI, 2.01-2.99]; P < .001). No associations were seen for observed experiences.

CONCLUSIONS AND RELEVANCE: In this cohort study, several nocebo effects occurred in the first week after COVID-19 vaccination. The severity of systemic adverse effects was associated not only with vaccine-specific reactogenicity but also more negative prior experiences with adverse effects from the first COVID-19 vaccination, more negative expectations regarding vaccination, and tendency to catastrophize instead of normalize benign bodily sensations. Clinician-patient interactions and public vaccine campaigns may both benefit from these insights by optimizing and contextualizing information provided about COVID-19 vaccines.

PMID:36972051 | PMC:PMC10043751 | DOI:10.1001/jamanetworkopen.2023.4732

Support Care Cancer. 2023 Mar 27;31(4):235. doi: 10.1007/s00520-023-07688-5.

ABSTRACT

PURPOSE: Chemotherapy-related polyneuropathy (CIPN) is a very common, often dose-limiting side effect that affects the patients' quality of life. Treatment usually consists of a combination of medicinal, medical, and individualized treatment approaches, although the effectiveness of these therapies is insufficient for many patients. The aim of this article is to review and evaluate the impact of CIPN on patients' daily lives and possible effective treatment approaches.

METHODS: A standardized questionnaire was developed based on ten anonymous telephone interviews with CIPN patients. The content of the questionnaire was divided into 5 categories: demographics, clinical presentation, everyday symptoms, treatment of CIPN symptoms, and medical care. Mostly closed questions were used but multiple choice and individual additions by free text answers were possible.

RESULTS: CIPN limits patients' quality of life over a long period of time. In addition to diurnal and situational fluctuations, the emotional burden negatively affects patients' daily lives in many ways. From the patients' point of view, the individually implemented therapy measures were most effective in treating their complaints. But even the combination of different therapy methods insufficiently alleviates the symptoms of the patients.

CONCLUSION: It is important and necessary to comprehensively inform patients about CIPN as a possible side effect, to point out prevention strategies, and to critically examine and evaluate different therapy approaches. In this way, misunderstandings of the doctor-patient relationship can be avoided. In addition, patient satisfaction and quality of life can be increased in the long term.

PMID:36971861 | PMC:PMC10042917 | DOI:10.1007/s00520-023-07688-5

Pak J Pharm Sci. 2023 Jan;36(1):31-38.

ABSTRACT

The goal of this research was to determine whether the combination of baicalein (BL) and losartan (LT) would provide greater protection against DOX-induced nephrotoxicity. There were five groups of male rats in the experiment: the 1) control, 2) DOX, 3) DOX+LT, 4) DOX+BL and 5) DOX+LT+BL groups. A dose of DOX was administered following two weeks of LT and BL therapy. In the DOX-affected group, serum renal indicators, including creatinine and urea, rose considerably compared to those in the control groups (p<0.01). Further, there was a statistically significant increase (p<0.001) in the levels of the cytokines that promote inflammation in renal tissue, including tumor necrosis factor-α, interleukin (IL)-1 and IL-6. In addition, the level of the anti-inflammatory cytokine IL-10 decreased significantly (p<0.001) in the DOX-challenged group compared to the control groups. In addition, renal cell indicators of oxidative stress (p<0.001) and enzymatic activity (p<0.01) reduced dramatically in the DOX-challenged group, whereas renal cell thiobarbituric acid retroactive materials rose greatly (p<0.001). Finally, the DOX group had higher kidney protein expression and inflammatory activity than the control groups (p<0.001). The combination of BL and LT therapy protected DOX-challenged rats via antioxidant and anti-inflammatory activities.

PMID:36967494

Front Med (Lausanne). 2023 Mar 8;10:1027589. doi: 10.3389/fmed.2023.1027589. eCollection 2023.

ABSTRACT

Dupilumab was the first biological medication licensed to treat atopic dermatitis (AD), and it has shown remarkable effectiveness and safety in the treatment of moderate-to-severe atopic dermatitis. There are limited drug-related adverse events associated with dupilumab in atopic dermatitis (AD) treatment. Here, we present two cases of local Staphylococcus aureus infection during the treatment of atopic dermatitis with dupilumab.

PMID:36968828 | PMC:PMC10031056 | DOI:10.3389/fmed.2023.1027589

JHEP Rep. 2023 Feb 15;5(5):100699. doi: 10.1016/j.jhepr.2023.100699. eCollection 2023 May.

ABSTRACT

BACKGROUND & AIMS: The aim of the study was to evaluate the efficacy and safety of adjuvant sorafenib treatment compared with placebo in patients with hepatocellular carcinoma who underwent local ablation.

METHODS: The SORAMIC trial is a randomised controlled trial with diagnostic, local ablation, and palliative sub-study arms. After initial imaging within the diagnostic study, patients were assigned to local ablation or palliative arms. In the local ablation cohort, patients were randomised 1:1 to local ablation + sorafenib vs. local ablation + placebo. The primary endpoint was time-to-recurrence (TTR). Secondary endpoints were local control rate and safety in terms of adverse events and quality-of-life.

RESULTS: The recruitment was terminated prematurely after 104 patients owing to slow recruitment. One patient was excluded because of a technical failure. Fifty-four patients were randomised to local ablation + sorafenib and 49 to local ablation + placebo. Eighty-eight patients who underwent standardised follow-up imaging comprised the per-protocol population. The median TTR was 15.2 months in the sorafenib arm and 16.4 months in the placebo arm (hazard ratio 1.1; 95% CI 0.53-2.2; p = 0.82). Out of 136 lesions ablated within the trial, there was no difference in local recurrence rate between sorafenib (6/69, 8.6%) and placebo groups (5/67, 5.9%; p = 0.792).Overall (92.5% vs. 71.4%, p = 0.008) and drug-related (81.4% vs. 55.1%, p = 0.003) adverse events were more common in the sorafenib arm compared with the placebo arm. Dose reduction because of adverse events were common in the sorafenib arm (79.6% vs. 30.6%, p <0.001).

CONCLUSIONS: Adjuvant sorafenib did not improve in TTR or local control rate after local ablation in patients with hepatocellular carcinoma within the limitations of an early terminated trial.

IMPACT AND IMPLICATIONS: Local ablation is the standard of care treatment in patients with early stages of hepatocellular carcinoma, along with surgical therapies. However, there is a risk of disease recurrence during follow-up. Sorafenib, an oral medication, is a routinely used treatment for patients with advanced hepatocellular carcinoma. This study found that sorafenib treatment after local ablation in people with early hepatocellular carcinoma did not significantly improve the disease-free period compared with placebo.

CLINICAL TRIAL NUMBER: EudraCT 2009-012576-27, NCT01126645.

PMID:36968218 | PMC:PMC10031000 | DOI:10.1016/j.jhepr.2023.100699

Oncology (Williston Park). 2023 Mar 21;37(3):130-141. doi: 10.46883/2023.25920987.

ABSTRACT

BACKGROUND: Mitogen-activated protein kinase (MEK) inhibitors, which integrate the important signaling chain of the RAS-RAF-MEK-ERK1/2 pathway, regulate cell functions such as division and proliferation for patients with solid tumors. However, various ocular adverse effects (AEs) affect patients during clinical treatment. This systematic review aimed to assess the occurrence of AEs during treatment with MEK inhibitors plus targeted therapy or chemotherapy.

METHODS: A scientific literature search was conducted in PubMed, the Cochrane Library, Embase, and several Chinese databases to identify randomized controlled trials. Overall, ocular AEs were assessed as the primary end point; blurred vision, chorioretinopathy, and retinal detachment were assessed as secondary end points.

RESULTS: Seventeen randomized controlled trials were included. Overall, the use of MEK inhibitors combined with other targeted inhibitors or chemotherapy was significantly associated with a nearly 7.3% increased risk of overall ocular toxicities vs therapy without MEK inhibitors (risk ratio [RR], 2.88; 95% CI, 1.42-5.85, P < .05). An increased risk of blurred vision (RR, 4.10; 95% CI, 2.55- 6.58; P < .05), chorioretinopathy (RR, 8.36; 95% CI, 3.42-20.47; P < .05), and retinal detachment (RR, 8.98; 95% CI, 3.92-20.57; P < .05) was demonstrated.

CONCLUSIONS: Treatment with MEK inhibitors combined with targeted drugs or chemotherapy seems to increase overall ocular AEs. A more practical algorithm for the screening of ocular AEs was suggested to be conducted whenever new or worsening ocular toxicities occur.

PMID:36961957 | DOI:10.46883/2023.25920987

Front Immunol. 2023 Mar 7;14:1117447. doi: 10.3389/fimmu.2023.1117447. eCollection 2023.

ABSTRACT

BACKGROUND: Cancer is concerning owing to its high mortality rate. Consequently, methods of prolonging the life of patients with cancer have become the primary focus of attention research. In recent years, immune checkpoint inhibitors (ICIs) have achieved good clinical efficacy as antitumor drugs; however, their severe adverse effects have made their use challenging. In order to clarify the predictors of adverse effects, scientists have conducted a series of studies. Blood counts can potentially monitor risk factors associated with the occurrence of immune-related adverse events (irAEs). Herein, a meta-analysis was performed to clarify further the guiding significance of blood counts in the clinical setting.

METHODS: Studies that satisfied the inclusion criteria were obtained by searching the database. Included studies were those in which irAEs had been observed, and evidence of an association between blood counts and irAEs was reported. The included ones were evaluated for quality. In addition to sensitivity analysis and subgroup analysis, a meta-analysis was performed using the odds ratio (OR) and 95% confidence interval (CI) for each study.

RESULTS: A total of 18 articles were included in our study. The analyses were performed separately according to different blood cell count indicators. The blood cell count metrics associated with irAEs were: absolute eosinophil count, neutrophil: lymphocyte ratio, and platelet: lymphocyte ratio.

CONCLUSION: Our review and meta-analysis of studies suggest that absolute eosinophil count, neutrophil: lymphocyte ratio, and platelet: lymphocyte ratio may serve as predictors of the emergence of irAEs. Given the small number of studies focusing on the relationship between patient blood cell counts and the risk of irAEs, future studies need to further explore the mechanisms of occurrence and potential associations.

PMID:36960068 | PMC:PMC10029759 | DOI:10.3389/fimmu.2023.1117447

Pharmacol Res Perspect. 2023 Apr;11(2):e01077. doi: 10.1002/prp2.1077.

ABSTRACT

Spontaneous reporting is based on the experience of all healthcare professionals (HCPs) but also consumers/non-HCPs and therefore reveals a broad picture of a drug's adverse reactions. Recent studies found substantial differences between reports from these varying sources including the reports' completeness. Using the example of opioid-associated abuse, dependence, or withdrawal, this study analyzed the completeness and characteristics of spontaneous reports from Germany focusing on the reporter. Based on EudraVigilance data, we included all cases of abuse, dependence, or withdrawal associated with opioids indicated for pain therapy and filed from Germany until 2018. Completeness and characteristics were analyzed by a reporter (physician, pharmacist, other HCPs, consumers/non-HCPs) and also by time period to account for other influencing factors. In total, 1721 cases were included, mainly filed by physicians (38.5%) and pharmacists (30.7%). Completeness of demographics varied from 74.5% (other HCPs) to 42.7% (consumers/non-HCPs). Consumers/non-HCPs most often provided any indication/comorbidity (75.2%), whereas this was the case for only 20.2% of pharmacists. Large differences between the reporters were found for almost all characteristics. Other HCPs far more often coded a history of drug abuse, dependence, or withdrawal than other reporters (46.9% vs. 11.6%-24.2%, respectively), and fatal outcomes were also mainly filed by other HCPs (68.1% vs. 14.8%-20.4% by all other reporters). Differences in completeness and characteristics were also observed over time. Studies analyzing spontaneous data should consider potential differences between the various reporting groups in terms of completeness and characteristics. Further, the impact of other influencing factors has to be assessed.

PMID:36959713 | PMC:PMC10036728 | DOI:10.1002/prp2.1077

Diagn Interv Radiol. 2023 Jan 31;29(1):80-90. doi: 10.5152/dir.2022.21614. Epub 2022 Nov 29.

ABSTRACT

Pulmonary adverse events and drug-induced lung disease (DILD) can occur when treating many conditions. The incidence of DILDs in clinical practice and the variety of radiological findings have increased, mainly due to the increased use of novel therapeutic agents. It is crucial to determine whether the newly emerging clinical and imaging findings in these patients are due to the progression of the underlying disease, infection, pulmonary edema, or drug use, as this will change the patient management. Although the diagnosis of DILD is usually obtained by excluding other possible causes, radiologists should be aware of the imaging findings of DILD. This article reviews the essential radiological results of DILD and summarizes the critical clinical and imaging findings with an emphasis on novel therapeutic agents.

PMID:36960496 | DOI:10.5152/dir.2022.21614

Eye (Lond). 2023 Mar 23. doi: 10.1038/s41433-023-02505-z. Online ahead of print.

ABSTRACT

PURPOSE: Assess short-term real-world outcomes in neovascular aged-related macular degeneration (nAMD) treated with novel faricimab.

METHODS: Retrospective case series of nine patients with nAMD (11 eyes) treated with faricimab between May and November 2022. Treatment-naïve patients and non-naïve patients underwent logMAR best corrected visual acuity (BCVA), optical coherence tomography (OCT) DRI OCT-1 Triton (Topcon Corp, Tokyo, Japan), ultra-widefield (UWF) and fundus autofluorescence (FAF) (California Optomap, Optos plc, Dunfermline, Scotland, UK). Previous treatment intervals, number of intravitreal injections, sub/intra retinal fluid (SRF/IRF), central retinal thickness (CRT) and presence/changes in pigment epithelial detachments (PEDs) were recorded.

RESULTS: Mean baseline BCVA and CRT values of patients who switched from other agents were 0.612 ± 0.75 logMAR and 256.16 ± 12.98 µm respectively, with a mean 36-day previous treatment interval. The median number of other previous anti-VEGF intravitreal injections was 8. Mean BCVA at one month significantly improved to 0.387 ± 0.54 logMAR, as well as CRT values which decreased to 245.43 ± 15.34 µm. In the 3 naïve patients, mean baseline BVCA and CRT values were 0.33 ± 0.29 and 874.67 ± 510.86 µm, respectively. At one month follow-up, mean BCVA improved to 0.30 ± 0.29 logMAR and mean CRT was 536.04 ± 36.15 µm. Overall, a significant improvement in BCVA of 0.21 ± 41 logMAR and 238.44 ± 114.9 µm was achieved at one month after the first faricimab intravitreal injection. In addition, a complete resolution of SRF was observed in 6 out of 8 eyes (75%) and of IRF in 2 out of 3 eyes (66.67%), respectively. Drusenoid PED morphology changes were observed in all patients and no drug-related adverse events were observed.

CONCLUSION: Real-world outcomes showed improvement in BCVA and anatomic parameters at an early timepoint, demonstrating the efficacy and durability of faricimab in nAMD patients. Larger numbers of patients and longer follow-up are needed to determine whether the loading dose is required in all, what percentage of patients experience an improvement, and whether improvement it is maintained.

PMID:36959312 | DOI:10.1038/s41433-023-02505-z

Clin Med (Lond). 2023 Mar;23(2):190. doi: 10.7861/clinmed.Let.23.2.1.

NO ABSTRACT

PMID:36958831 | DOI:10.7861/clinmed.Let.23.2.1

PLoS One. 2023 Mar 23;18(3):e0283538. doi: 10.1371/journal.pone.0283538. eCollection 2023.

ABSTRACT

OBJECTIVES: Previous studies suggested a higher rate of COVID-19 infection in patients with multiple sclerosis than in the general population, and limited studies addressed the impact of COVID-19 and its vaccination in patients with multiple sclerosis in Iran. We decided to investigate the factors associated with COVID-19 infection, the effects and side effects of the COVID-19 vaccination in patients with multiple sclerosis (MS).

METHODS: We used the data of the patients with multiple sclerosis registered in a referral clinic in Kerman, one of the large cities in Iran (a population of 537,000 inhabitants), to explore the association between demographic variables, the history of COVID-19 vaccination, and the clinical outcomes.

RESULTS: Of the 367 participants in this study, 88.3% received the COVID-19 vaccine, 35.4% were confirmed COVID-19 cases, and the incidence of COVID-19 was much higher before vaccination (24.5% before vaccination versus 10.1% after vaccination). The multivariable logistic regression model showed that male gender (OR = 2.64, 95% confidence interval: 1.21, 5.74) and current employment (OR = 3.04, 95% confidence interval: 1.59, 5.80) were associated with an increased risk of COVID-19. The only factor associated with the adverse effects of COVID-19 vaccination was the type of vaccine (AstraZeneca).

CONCLUSION: Our findings showed that the vaccination protected MS cases considerably against COVID-19. In addition, the side effects of the vaccines were not noticeably high in these cases as well. Among all COVID-19 vaccines, AstraZeneca had the most common side effects, so people must be aware of them before vaccination. The male gender and employment were the most important variables in the prevalence of COVID-19 in patients with multiple sclerosis in our study.

PMID:36952532 | PMC:PMC10035930 | DOI:10.1371/journal.pone.0283538

Front Immunol. 2023 Mar 6;14:1112409. doi: 10.3389/fimmu.2023.1112409. eCollection 2023.

ABSTRACT

OBJECTIVES: Immune checkpoint inhibitors (ICIs) alone or combined with other antitumor agents are largely used in lung cancer patients, which show both positive effects and side effects in particular subjects. Our study aims to identify biomarkers that can predict response to immunotherapy or risk of side effects, which may help us play a positive role and minimize the risk of adverse effects in clinical practice.

METHODS: We retrospectively collected data from patients with advanced non-small cell lung cancer (NSCLC) treated with ICIs at our center. Patients who received initial ICI therapy for >1 year without progression of disease were classified as long-term treatment (LT) group, while others were classified as the non-long-term treatment (NLT) group. Multivariate logistic analysis was performed to identify independent risk factors of progression-free survival (PFS) and immune-related adverse events (irAEs).

RESULTS: A total of 83 patients (55.7%) had irAEs. The median PFS for patients in grades 1-2 of irAEs vs. grades 3-4 vs non-irAEs groups was (undefined vs. 12 vs. 8 months; p = 0.0025). The 1-year PFS rate for multisystem vs. single vs. non-irAE groups was 63%, 56%, and 31%, respectively. Signal transduction of inflammatory cytokines improves clinical prognosis through immunomodulatory function, but the benefit is also limited by the resulting organ damage, making it a complex immune balance. Serum biomarkers including EOS% of ≥ 1.15 (HR: 8.30 (95% CI, 2.06 to 33.42); p = 0.003) and IFN-γ of ≥ 3.75 (HR: 5.10 (95% CI, 1.29 to 20.15), p = 0.02) were found to be predictive for irAEs.

CONCLUSION: EOS% of ≥1.15% and IFN-γ of ≥3.75 ng/L were considered peripheral-blood markers for irAEs and associated with improved clinical outcomes for immunotherapy in patients with advanced NSCLC.

PMID:36949952 | PMC:PMC10025375 | DOI:10.3389/fimmu.2023.1112409

Clin Med (Lond). 2023 Mar;23(2):173-174. doi: 10.7861/clinmed.2022-0431.

ABSTRACT

A 45-year-old woman presented to the hospital with bloody diarrhoea and significant weight loss over the past 1 month. On admission and evaluation, she was found to have acute ulcerative colitis. She was started on prednisolone and mesalamine therapy. Within 24 hours of initiation of this therapy, the patient complained of giddiness and chest discomfort and was found to have sinus bradycardia on ECG with no acute coronary event. After withdrawing mesalamine, her heart rate normalised within 24 hours and she remained symptom-free. This is a rare case report of severe symptomatic sinus bradycardia due to mesalamine therapy; to our knowledge, only four cases of mesalamine-induced bradycardia have been reported in the literature.

PMID:36958845 | DOI:10.7861/clinmed.2022-0431

Metabolism. 2023 Mar 21:155550. doi: 10.1016/j.metabol.2023.155550. Online ahead of print.

ABSTRACT

BACKGROUND: Obesity is a complex disease associated with multiple concurrent complications, and the coordinated targeting of multiple pathways in pharmacological treatment may improve weight loss outcomes. During synthesis, ghrelin is converted from the 'inactive' unacylated ghrelin (UAG) to the active acylated ghrelin (AG) by the enzyme ghrelin-O-acyltransferase (GOAT), stimulating appetite and food intake.

AIMS: To report the results of two Phase I studies investigating single rising doses (SRDs) or multiple rising doses (MRDs) of the novel oral GOAT inhibitor BI 1356225 versus placebo in male and postmenopausal/sterilised female subjects with overweight or obesity.

METHODS: The SRD study investigated single doses of BI 1356225 (0.1-20 mg) in healthy male subjects with BMI of 18.5-29.9 kg/m2 (SRD cohort) and assessed doses of 2.5 mg BI 1356225 under fed and fasted conditions (bioavailability [BA] cohort). The MRD study investigated multiple doses of BI 1356225 (0.2, 1, 2.5 or 10 mg) or 5 mg BI 1356225 with a single dose of midazolam and celecoxib (drug-drug interaction part) over 28 days in adults with a BMI of 27.0-39.9 kg/m2.

RESULTS: Sixty-five subjects were treated in the SRD study. Drug-related adverse events (AEs) were reported for five subjects (9.1 %) in the SRD cohort and two subjects (20.0 %) in the BA cohort, with the most frequent being headache (SRD: n = 4, 9.8 %; BA: n = 1, 10.0 %). In the MRD study, two (2.3 %) of the 87 subjects treated discontinued treatment because of AEs. Drug-related AEs were reported for 18 subjects (20.7 %), did not increase with dose and were most frequently reported as headache (n = 5, 5.7 %) and gastrointestinal disorders (n = 5, 5.7 %). In both studies, exposure parameters (area under the concentration-time curve [AUC] and maximum plasma concentration [Cmax]) of BI 1356225 increased across dose groups, although this was less than dose-proportional across the entire dose range. In the BA cohort of the SRD study, AUC0-∞ was slightly increased and Cmax slightly decreased in fed versus fasted conditions, with fed/fasted ratios (90 % CI) of 101.10 % (92.42, 110.60) and 91.67 % (78.50, 107.05), respectively. In both studies, AG concentrations and the AG/UAG ratio were dose-dependently decreased after BI 1356225 treatment from baseline versus placebo. In the MRD study, UAG concentrations were increased from baseline, but not dose-dependently. No differences were observed in bodyweight, appetite, food cravings, ad libitum food uptake or obesity-related biomarkers after 28 days of treatment with BI 1356225.

CONCLUSIONS: Treatment with SRDs and MRDs of BI 1356225 was well tolerated by healthy males and subjects with overweight/obesity. BI 1356225 treatment over 28 days reduced AG concentrations and the AG/UAG ratio by >80 %, but no effect was seen on bodyweight, hunger/satiety, control of eating or energy intake. Although, at 4 weeks, the MRD study was fairly short, a reduction in bodyweight would be expected to be evident by this time, suggesting that a reduction of AG via a GOAT inhibitor is not sufficient to induce clinically relevant bodyweight loss.

PMID:36958671 | DOI:10.1016/j.metabol.2023.155550

Cutis. 2023 Jan;111(1):18-21. doi: 10.12788/cutis.0681.

ABSTRACT

Epidermal growth factor receptor (EGFR) inhibitors cause numerous cutaneous adverse events (AEs), including papulopustular eruptions, paronychia, acral fissures, xerosis, alopecia, and trichomegaly. Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a cutaneous reaction that has been uncommonly reported in association with EGFR inhibitors, though the optimal management strategy for this condition is unknown. We present 2 cases of SDRIFE secondary to EGFR inhibitor therapy in which the EGFR inhibitor was successfully continued while topical therapy was administered for effective control of symptoms. We also review the literature on EGFR inhibitor-related SDRIFE to assess the range of approaches to treating this condition. Our analysis suggests that the dermatologist is critical in diagnosing and treating this cutaneous AE, which may be supported with skin-directed therapy and may not require discontinuation of cancer treatment.

PMID:36947773 | DOI:10.12788/cutis.0681

Cureus. 2023 Feb 17;15(2):e35094. doi: 10.7759/cureus.35094. eCollection 2023 Feb.

ABSTRACT

Drug-induced liver injury (DILI) is one of the leading causes of death from acute liver failure (ALF) in the United States, accounting for approximately 13% of ALF cases in the United States. Selective androgen receptor modulators (SARMs) were first developed to increase muscle mass while avoiding the side effects of conventional androgenic steroids. Although not Food and Drug Administration (FDA) approved, they are widely available online and are consumed to enhance athletic performance. We report a 22-year-old, previously healthy male, who presented with a two-week history of worsening jaundice, nausea, fatigue, pruritus, dark urine, and light stools. He reported taking the SARM, RAD-140, for 16 weeks. Examination showed scleral icterus. The liver panel showed alkaline phosphatase (ALP) 5.3 µkat/L, alanine transaminase (ALT) 1.66 µkat/L, aspartate transaminase (AST) 1.18 µkat/L, direct bilirubin 294 µmol/L, total bilirubin 427.5 µmol/L, and international normalized ratio (INR) 0.9. Viral hepatitis and autoimmune panel were unremarkable. Alpha-1 antitrypsin and ceruloplasmin levels were within normal limits. Bile sludge was seen on ultrasound. Magnetic resonance cholangiopancreatography (MRCP) abdomen showed segmental narrowing of the intrahepatic ducts. Endoscopic retrograde cholangiopancreatography (ERCP) was unremarkable. Liver biopsy showed mixed portal hepatitis, cholestasis, and biliary reactive changes with ceroid-loaded macrophages; a picture consistent with DILI. The patient was treated supportively and discharged with scheduled hepatology follow-up. At the one-month follow-up, his total bilirubin had fallen from a peak of 530 mol/L to 188 mol/L. The diagnosis of DILI can be made based on the timing of exposure and the exclusion of other etiologies. Liver enzymes normalized three to 12 months after product discontinuation. We hope this report will remind primary care physicians of the potential hepatotoxic side effects of muscle-building compounds and encourage them to report suspected DILI to the FDA using the MedWatch system.

PMID:36945289 | PMC:PMC10024817 | DOI:10.7759/cureus.35094

J Pharm Pharm Sci. 2023 Feb 15;26:11235. doi: 10.3389/jpps.2023.11235. eCollection 2023.

ABSTRACT

Purpose: Gastrointestinal perforation (GIP) is a fatal adverse event (AE). The AE of GIP induced by novel antineoplastic agents has attracted attention recently. We aimed to explore the AE signals of GIP related to novel antineoplastic agents comprehensively based on the FDA Adverse Event Reporting System (FAERS). Methods: The FAERS database containing 71 quarters of records was used for analysis. Reporting odds ratio (ROR), information component (IC), and empirical Bayesian geometric mean (EBGM) were utilized to evaluate the signals of GIP associated with novel antineoplastic drugs. Standardization of drug names was by employing MedEx-UIMA software and Python. Data analysis and visualization were performed using MySQL Workbench and R software. Results: After cleaning and handling the data, 5226 GIP cases were identified that were associated with new antineoplastic medications, where these agents were the main suspected contributors. A total of 37 novel antineoplastic drugs were detected with signals of GIP for ROR and IC. Only 22 drugs showed statistically significant signals for EBGM. We found the GIP signals of 22 novel antineoplastic drugs overlapped for the 3 indicators, including anti-vascular endothelial growth factor/vascular endothelial growth factor receptor, anti-endothelial growth factor receptor, immune checkpoint inhibitors, and so on. Conclusion: The potential risk of GIP associated with several novel antineoplastic agents was identified through data mining, which provided valuable information on the safety risks associated with GIP among these drugs. The potential threat of GIP should be recognized and managed properly when using these novel antineoplastic agents.

PMID:36942297 | PMC:PMC9990630 | DOI:10.3389/jpps.2023.11235

BMJ Evid Based Med. 2023 Mar 21:bmjebm-2022-112005. doi: 10.1136/bmjebm-2022-112005. Online ahead of print.

ABSTRACT

OBJECTIVES: To examine the association between regulatory reviewer disagreements and postmarket safety actions among novel therapeutics approved by the US Food and Drug Administration (FDA) between 2011 and 2015. Disagreements among FDA reviewers regarding the recommendation for a novel therapeutic's approval, its safety, the indicated patient population and/or other parameters of the drug's approval are common. However, the implications of such disagreements-particularly with respect to postmarket safety actions-are poorly understood.

DESIGN: Cross-sectional study.

SETTING: All novel therapeutics approved by the FDA between January 2011 and December 2015.

PARTICIPANTS: None.

MAIN OUTCOME MEASURES: Postmarket safety actions defined as new label warnings/increased warning severity, FDA safety communications and safety-related therapeutic withdrawals after the original regulatory approval.

RESULTS: Among 174 novel therapeutics approved by the FDA between 2011 and 2015, 42 (24%) had at least one regulatory reviewer disagreement. Altogether, 156 instances of disagreement were observed. Following market approval, a total of 253 postmarket safety actions were taken by the FDA among all new therapeutics, with at least one postmarket safety action identified for 98 (56.3%) of the 174 novel therapeutic approvals. Overall, therapeutics that were the subject of disagreement during the FDA's review had fewer safety actions following approval compared with therapeutics in which no disagreement was observed (38.1% vs 62.1%; RR 0.61, 95% CI 0.41 to 0.92; p=0.006). Therapeutic approvals containing at least one reviewer disagreement also more often carried a black box warning at the point of approval (47.7% vs 31.1%; RR 1.53, 95% CI 1.02 to 2.30; p=0.05).

CONCLUSIONS: This investigation of regulatory reviewer disagreements and postmarket safety actions among new therapeutics suggests that disagreements among regulatory reviewers may lead to important pre-emptive actions, potentially mitigating the need for postmarket safety actions to be taken.

PMID:36944478 | DOI:10.1136/bmjebm-2022-112005

PeerJ. 2023 Mar 14;11:e14727. doi: 10.7717/peerj.14727. eCollection 2023.

ABSTRACT

BACKGROUND: Globally, there is an increased risk of COVID-19 infection among front-line health workers (FHW). This study aimed to evaluate the knowledge, attitude, and practices of FHW of Pakistan after receiving the COVID-19 vaccine.

METHODS: A population web-based survey on COVID-19 vaccine was conducted on 635 FHW in Pakistan between April 15, 2021, and July 15, 2021. The survey focused on four main sections consisting of socio-demographic data, knowledge, attitude, and practices after receiving the COVID-19 vaccine. The data was analyzed on SPSS. p < 0.05 was considered significant.

RESULTS: Overall, 60% of FHW were nervous before getting vaccinated, with the leading reason to get vaccinated being their concern to protect themselves and their community (53.4%). A majority of FHW had fear about the unseen side effects of the COVID-19 vaccine (59.7%) used in Pakistan, with the most common side effect reported as soreness at the injection site (39%). It has been noted that almost all of the FHW observed preventive practices after getting vaccinated. The results showed that married respondents had favorable practices towards COVID-19 vaccines (B = 0.53, p < 0.01) (B, unstandardized regression coefficient). It was also found that more informational sources (B = 0.19, p < 0.01), higher knowledge of vaccination (B = 0.15, p < 0.001), and favorable attitude toward vaccine (B = 0.12, p < 0.001) significantly predicted favorable practices toward COVID-19 vaccination.

CONCLUSION: The findings reflect that FHW, though they were worried about its side effects, have good knowledge and a positive attitude after getting the COVID-19 vaccine. This study is significant as the FHWs are a symbol for guidance, a reliable source of information, and an encouraging means of receiving COVID-19 vaccine for the general public. This study also reported that post-vaccination side effects were mild which will aid in reducing the vaccine hesitancy among the general Pakistani population.

PMID:36935914 | PMC:PMC10022508 | DOI:10.7717/peerj.14727