Drug Saf. 2022 Nov;45(11):1423-1438. doi: 10.1007/s40264-022-01225-9. Epub 2022 Oct 6.

ABSTRACT

INTRODUCTION: Signal detection yields confirmed signals in only 2.1%, which imposes a heavy burden on the pharmacovigilance system in the European Union.

OBJECTIVES: We aimed to develop a network theoretical metric to increase the confirmed signal ratio of individual case safety report (ICSR) networks.

METHODS: ICSRs of five cardiovascular adverse events were requested from EudraVigilance. We developed Vigilace™, a web-based application to build network representation of ICSRs. Three network-based signal scores, which we termed NEWS (normalized edge weight for signals) scores, were calculated by normalizing the weight of each edge in the report-based weighted network by the weight of the same edge in topological weighted networks. Depending on the third node in topological network edges, we defined full-, adverse event-, and drug-type NEWS scores. Area under the receiver operating characteristic curves (AUROC) were analyzed to compare the reporting odds ratio (ROR) and NEWS scores.

RESULTS: Overall, 72,475 ICSRs were accessed from EudraVigilance. Drug-type NEWS (NEWSD) score performed better (DeLong test, p-value <0.05) compared with the ROR in case of four adverse events: acute myocardial infarction (AUROC: 0.856 vs. 0.720), arrhythmia (0.657 vs. 0.614), pulmonary hypertension (0.861 vs. 0.720), and QT prolongation (0.830 vs. 0.749). Postural orthostatic tachycardia syndrome was excluded due to the lack of reference data.

CONCLUSION: This is the first demonstration that report-based weighting normalized by topological weighting of co-reported drugs, which we termed as NEWSD score, can perform better compared with the ROR. An application was developed for ICSR network analysis that facilitates the calculation of this score.

PMID:36198930 | PMC:PMC9561003 | DOI:10.1007/s40264-022-01225-9

BMC Med Inform Decis Mak. 2022 Oct 5;22(1):260. doi: 10.1186/s12911-022-02005-2.

ABSTRACT

BACKGROUND: Statistical information (e.g., on long-term survival or side effects) may be valuable for healthcare providers to share with their patients to facilitate shared decision making on treatment options. In this pre-registered study, we assessed cancer survivors' need for generic (population-based) versus personalized (tailored towards patient/tumor characteristics) statistical information after their diagnosis. We examined how information coping style, subjective numeracy, and anxiety levels of survivors relate to these needs and identified statistical need profiles. Additionally, we qualitatively explored survivors' considerations for (not) wanting statistical information.

METHODS: Cancer survivors' need for statistics regarding incidence, survival, recurrence, side effects and quality of life were assessed with an online questionnaire. For each of these topics, survivors were asked to think back to their first cancer diagnosis and to indicate their need for generic and personalized statistics on a 4-point scale ('not at all'- 'very much'). Associations between information coping style, subjective numeracy, and anxiety with need for generic and personalized statistics were examined with Pearson's correlations. Statistical need profiles were identified using latent class analysis. Considerations for (not) wanting statistics were analyzed qualitatively.

RESULTS: Overall, cancer survivors (n = 174) had a higher need for personalized than for generic statistics (p < .001, d = 0.74). Need for personalized statistics was associated with higher subjective numeracy (r = .29) and an information-seeking coping style (r = .41). Three statistical need profiles were identified (1) a strong need for both generic and personalized statistics (34%), (2) a stronger need for personalized than for generic statistics (55%), and (3) a little need for both generic and personalized statistics (11%). Considerations for wanting personalized cancer statistics ranged from feelings of being in control to making better informed decisions about treatment. Considerations for not wanting statistics related to negative experience with statistics and to the unpredictability of future events for individual patients.

CONCLUSIONS: In light of the increased possibilities for using personalized statistics in clinical practice and decision aids, it appears that most cancer survivors want personalized statistical information during treatment decision-making. Subjective numeracy and information coping style seem important factors influencing this need. We encourage further development and implementation of data-driven personalized decision support technologies in oncological care to support patients in treatment decision making.

PMID:36199092 | PMC:PMC9535944 | DOI:10.1186/s12911-022-02005-2

BMJ. 2022 Oct 5;379:e071752. doi: 10.1136/bmj-2022-071752.

ABSTRACT

OBJECTIVE: To characterize potential drug safety signals identified from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), from 2008 to 2019, to determine how often these signals resulted in regulatory action by the FDA and whether these actions were corroborated by published research findings or public assessments by the Sentinel Initiative.

DESIGN: Cross sectional study.

SETTING: USA.

POPULATION: Safety signals identified from the FAERS and publicly reported by the FDA between 2008 and 2019; and review of the relevant literature published before and after safety signals were reported in 2014-15. Literature searches were performed in November 2019, Sentinel Initiative assessments were searched in December 2021, and data analysis was finalized in December 2021.

MAIN OUTCOME MEASURES: Safety signals and resulting regulatory actions; number and characteristics of published studies, including corroboration of regulatory action as evidenced by significant associations (or no associations) between the drug related to the signal and the adverse event.

RESULTS: From 2008 to 2019, 603 potential safety signals identified from the FAERS were reported by the FDA (median 48 annually, interquartile range 41-61), of which 413 (68.5%) were resolved as of December 2021 (372 of 399 (93.2%) signals ≥3 years old were resolved). Among the resolved safety signals, 91 (22.0%) led to no regulatory action and 322 (78.0%) resulted in regulatory action, including 319 (77.2%) changes to drug labeling and 59 (14.3%) drug safety communications or other public communications from the FDA. For a subset of 82 potential safety signals reported in 2014-15, a literature search identified 1712 relevant publications; 1201 (70.2%) were case reports or case series. Among these 82 safety signals, 76 (92.7%) were resolved, of which relevant published research was identified for 57 (75.0%) signals and relevant Sentinel Initiative assessments for four (5.3%) signals. Regulatory actions by the FDA were corroborated by at least one relevant published research study for 17 of the 57 (29.8%) resolved safety signals; none of the relevant Sentinel Initiative assessments corroborated FDA regulatory action.

CONCLUSIONS: Most potential safety signals identified from the FAERS led to regulatory action by the FDA. Only a third of regulatory actions were corroborated by published research, however, and none by public assessments from the Sentinel Initiative. These findings suggest that either the FDA is taking regulatory actions based on evidence not made publicly available or more comprehensive safety evaluations might be needed when potential safety signals are identified.

PMID:36198428 | PMC:PMC9533298 | DOI:10.1136/bmj-2022-071752

BMJ. 2022 Oct 5;379:o2409. doi: 10.1136/bmj.o2409.

NO ABSTRACT

PMID:36198410 | DOI:10.1136/bmj.o2409

J Popul Ther Clin Pharmacol. 2022 Jul 8;29(3):e1-e10. doi: 10.47750/jptcp.2022.843. eCollection 2022.

ABSTRACT

India has a unique position with its vast population and rapidly increasing healthcare demand. Dental health is integral to a holistic health care need, and a robust dental education system is necessary. Dental education in India is mainly regulated by the Dental Councilof India, setting broad guidelines. Universities having dental colleges and institutes develop fine curriculum development and evaluation details. General and Dental Pharmacology and Therapeuticsis a crucial subject taught to undergraduate dental students during the second year of a 4-year duration course. A dental graduate should be well trained in general and systemic pharmacology and rational therapeutics principles. This has been set as an objective by the Dental Council of India. Sound knowledge of the drug action mechanisms, indications, adverse drug reactions, drug interactions and contraindications, evidence-based medicine, and rational use of adrug is core to the allopathic system. The practical exercises on human simulation or computer-assisted learning are critical for understanding pharmacology. The subject of pharmacology for dental graduates has been allotted 70 hours of theory and 20 hours of practicals with almost the same syllabus as medical graduates. This article highlights the areas of concern concerning the deficiency of teaching hours and needed improvement in the curriculum to make it competent to achieve its objective. The authors bring this much-needed topic for discussion among academicians and for the attention of regulatory authorities.

PMID:36196933 | DOI:10.47750/jptcp.2022.843

Int J Clin Pharmacol Ther. 2022 Oct 5. doi: 10.5414/CP204244. Online ahead of print.

ABSTRACT

OBJECTIVES: Clinical pharmacists play a pivotal role in ensuring medication safety due to their detailed understanding of the medication-use process. This study aimed to propose the concept of pharmaceutical care pathway (PCP) in surgical care and design the work pattern and workflow in the healthcare systems of China.

SETTING: Data were collected from patients in the Department of Hepatobiliary Surgery of the First People's Hospital of Lianyungang in China between January 2019 and December 2019.

MATERIALS AND METHODS: The study was conducted using 346 patients in the control group and 363 in the intervention group. The control group was managed only by the clinical pathway (CP), while the intervention group was managed by the CP and PCP.

MAIN OUTCOME MEASURE: Adverse drug reactions (ADRs), patient satisfaction, hospital expense, drug cost, length of stay, and prescription situations were documented.

RESULTS: Using PCP, the rational use of drugs increased from 56% in the control group to 94.2% in the intervention group. Further, 124 (35.8%) ADRs in the control group and 44 (12.1%) ADRs in the intervention group were assessed using the Karch and -Lasagna scale. The mean hospital expense was 21,949.12 ± 2,311.25 yuan in the control group and 17,566.25 ± 1,082.56 yuan in the intervention group. The mean drug cost was 6,250.69 ± 589.35 yuan and 4,894.22 ± 356.14 yuan (1 US$ = 6.37 yuan). The mean length of stay was 12.23 ± 2.51 days and 8.35 ± 1.32 days in the control and intervention groups, respectively. Patient satisfaction increased significantly.

CONCLUSION: PCP reduced the length of stay for patients and drug-related adverse events, increased the rational use of drugs, cost-effectiveness, patient satisfaction, and consequently, improved the quality of service in surgery medicine.

PMID:36197787 | DOI:10.5414/CP204244

Cancer. 2022 Oct 5. doi: 10.1002/cncr.34474. Online ahead of print.

ABSTRACT

BACKGROUND: Pruritus is one of the most common and challenging side effects of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and has impaired patients' quality of life and treatment compliance. Our study evaluated the efficacy and safety of aprepitant in managing EGFR-TKIs-related pruritus.

METHODS: This randomized, double-blind, placebo-controlled study was conducted between December 2016 and August 2020 in China. Patients were eligible if they were 18 years or older and had histologically confirmed locally advanced or metastatic non-small cell lung cancer (NSCLC) with first onset of moderate to severe pruritus during EGFR-TKI treatment.

RESULTS: A total of 130 eligible patients were randomly assigned to aprepitant (n = 65) or desloratadine (n = 65) groups. The median (interquartile range [Q1, Q3]) age was 63 (54, 70) years, and 79 (60.8%) were women. Mean visual analog scale scores at baseline were 6.35 (95% confidence interval [CI], 5.89-6.82) in the aprepitant group and 5.94 (95% CI, 5.56-6.32) in the desloratadine group. After 1 week of treatment, 33 (53.2%) patients responded to aprepitant, which was significantly higher than that of 14 (23.7%) patients responded to desloratadine (p = .001). Moreover, patients in the aprepitant group had a significantly shorter response time than patients in the desloratadine group (mean [days], 13.39 [95% CI, 11.08-15.70] vs. 16.67 [95% CI, 14.19-19.13], p = .04). The most frequent drug-related adverse events in aprepitant group and desloratadine were constipation and dry mouth, and all adverse events were grade 1-2.

CONCLUSIONS: To the authors' knowledge, this is the first study to prospectively present that aprepitant elicited a better and faster response and mild toxicity for managing EGFR-TKI induced pruritus than desloratadine.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02646020.

PMID:36197287 | DOI:10.1002/cncr.34474

Rev Panam Salud Publica. 2022 Sep 30;46:e178. doi: 10.26633/RPSP.2022.178. eCollection 2022.

ABSTRACT

OBJECTIVE: Characterize and describe reports of suspected adverse reactions to a group of drugs used in Colombia, Costa Rica, Cuba, Chile, El Salvador, Mexico, and Peru to treat or prevent coronavirus disease (COVID-19) between 1 March and 31 August 2020.

METHODS: A list of the 13 drugs used to treat or prevent COVID-19 was prepared, based on official and unofficial sources. Drawing on the databases of the national pharmacovigilance programs of the participating countries, reports of suspected adverse reactions to these drugs were collected for the period from 1 March and 31 August 2020.

RESULTS: A total of 3 490 reports of suspected adverse reactions were received from the pharmacovigilance programs of Peru (n = 3 037), Cuba (n = 270), Colombia (n = 108), Chile (n = 72), and El Salvador (n = 3). The drugs with the highest number of reported adverse reactions were azithromycin, ivermectin, and hydroxychloroquine. Diarrhea was the most frequent event (15.0%). Of the total suspected adverse reactions, 11.9% were reported as serious. The most frequent was QT prolongation following use of hydroxychloroquine. Of these suspected serious adverse reactions, 54.5% occurred in people over 65 years of age.

CONCLUSIONS: While it is not possible to establish a causal relationship from the evaluation of spontaneous reports, the present study confirms the presence of adverse reactions-some of them serious-involving drugs used to treat or prevent COVID-19.

PMID:36196452 | PMC:PMC9524408 | DOI:10.26633/RPSP.2022.178

Br J Hosp Med (Lond). 2022 Sep 2;83(9):1-16. doi: 10.12968/hmed.2022.0313. Epub 2022 Sep 13.

ABSTRACT

Intentional and accidental drug overdose, recreational drug use and exposure to toxic substances are common reasons for people presenting to emergency departments. Although the mortality rate associated with these presentations is low in the UK, they can lead to significant morbidity and prolonged hospital admissions. This review discusses new developments in the management of paracetamol overdose. Several new protocols for the infusion of acetylcysteine, the antidote for paracetamol overdose, have been proposed in the past decade and evaluated in clinical studies. The 12-hour Scottish and Newcastle Acetylcysteine Protocol regimen and 20-hour Australian two-infusion bag protocol have been widely adopted into clinical practice and endorsed in national guidelines because of their shorter duration, reduction in adverse effects and efficacy in treating overdose. This article includes a care pathway that can facilitate the implementation of the Scottish and Newcastle Acetylcysteine Protocol. This article also discusses the emergency management of ingested button batteries, describes the emerging threat of novel psychoactive substances, and provides an update on new UK antidote guidelines. Further up-to-date guidance on management of clinical toxicology is available to healthcare professionals on the internet database TOXBASE.

PMID:36193928 | DOI:10.12968/hmed.2022.0313

Br J Hosp Med (Lond). 2022 Sep 2;83(9):1-8. doi: 10.12968/hmed.2022.0324. Epub 2022 Sep 22.

ABSTRACT

Almost all cancer therapies lead to a wide array of side effects, owing to the disruption of normal physiological processes and alteration of immunological responses. Of these, mucositis is one of the most commonly encountered side effects, presenting in about 20-40% of all patients receiving chemotherapy and 80% of those being treated with radiotherapy for head and neck malignancies. This article provides a brief introduction and comprehensive overview of the various treatment modalities used in managing this complication. The key to management is a multidisciplinary approach, revolving around pain control, oral hygiene, nutritional support and management of superimposed infection. The scarcity of therapeutic options for prevention or treatment of mucositis has resulted in clinical difficulty in controlling it, which, in turn, seriously affects the patient's quality of life and cancer management, contributing to patient morbidity and mortality.

PMID:36193926 | DOI:10.12968/hmed.2022.0324

Dtsch Med Wochenschr. 2022 Oct;147(20):1342-1354. doi: 10.1055/a-1752-4440. Epub 2022 Oct 4.

ABSTRACT

The application of chemotherapy against malignant tumors might control the malignant disease but harbours many pitfalls. The chemotherapy type is chosen depending on the entity and stage of the tumor as well as on the patient's characteristics and fitness. Patients under therapy should be informed on the potential side effects and should be closely monitored by physicians, familiar with the common as well as the substance specific side effects of the drugs used. Preventive or timely application of supportive medication can prevent or diminish drug-induced toxicities. The attending physician has to be aware of the potential treatment-related emergency situations during application as well as several days after. One of the most common and dangerous emergencies that requires immediate medical attention is fever in neutropenia.The use of new medical drug classes, targeted molecular and immune therapies has changed and improved disease control in many tumor entities in a revolutionary manner. Overall, combination treatments including targeted drugs, immunotherapy and/or classical chemotherapy show improved efficacy in tumor control. These novel (combination) therapies may provoke different side effects that physicians need to be familiar with and take into account.

PMID:36195093 | DOI:10.1055/a-1752-4440

Sci Rep. 2022 Oct 3;12(1):16519. doi: 10.1038/s41598-022-20633-6.

ABSTRACT

Aceclofenac controlled-release (CR) is a once-a-day tablet with 200 mg of aceclofenac, and is bioequivalent to conventional aceclofenac. However, its safety in humans has not been well studied in Korea. Therefore, we aimed to evaluate the overall incidence and patterns of adverse events (AEs), the effectiveness of aceclofenac CR, and the differences in incidence rates of the AEs based on each patient's baseline charateristics. This study was conducted on patients receiving aceclofenac CR in clinical practice at each investigational institution to treat musculoskeletal pain and inflammation. The subjects were administered one tablet of aceclofenac CR (200 mg once-a-day) and were observed for 4 weeks post-administration. Factors affecting the occurrence of AEs were evaluated, and the Visual Analogue Scale (VAS) was used to measure the pain intensity. Among 14,543 subjects, the incidence rate of AEs was 0.86%, and that of adverse drug reactions was 0.74%. No serious AEs and unexpected adverse drug reactions were monitored. The incidence rates of AEs were significantly higher in females, inpatient treatment, individuals with concurrent disorders, and those receiving concomitant medications, respectively (all P < 0.05). Four weeks post-using aceclofenac CR, the mean changes in VAS was significantly decreased compared to prior administration. The overall clinical efficacy rate was 91.63%. This study confirmed that no severe adverse reactions were observed for aceclofenac CR exceeding those previously reported for safety results of conventional formulation of this drug in routine clinical practice settings. The use of aceclofenac CR might not violate the previously reported information on the safety and effectiveness of aceclofenac.

PMID:36192565 | DOI:10.1038/s41598-022-20633-6

Anticancer Res. 2022 Oct;42(10):5017-5020. doi: 10.21873/anticanres.16009.

ABSTRACT

BACKGROUND/AIM: Actinic keratoses (AKs) are precursors of squamous cell carcinomas and early intervention is important. Photodynamic therapy (PDT) is often first-choice treatment for widespread AKs. Classic PDT consists of: Superficial curettage, application of 5-aminolevulinic acid or methyl aminolevulinate, incubation and protoporphyrin IX (PpIX) accumulation under occlusion for 3 hours, followed by illumination with red light-emitting diode light (37 J/cm2). Classic PDT is effective in treating AKs, but side-effects include unpleasant pretreatment, severe pain during illumination, inflammation after treatment, and long waiting time in the clinic.

MATERIALS AND METHODS: This targeted mini review describes efforts to counteract side-effects and simplify the procedure considering the clinic capacity. Changes are only acceptable if treatment effect is maintained.

RESULTS: We introduce the following procedure changes: (i) reducing pre-treatment pain, bleeding, and oozing by omitting curettage; (ii) long-term illumination for 2 hours during PpIX formation (already in use as daylight PDT) and shortening of incubation time from 3 hours to 30 minutes to minimize pain and inflammation risk. In addition, options of timing, incubation, and illumination indoors and outdoors are discussed, focusing on advantages and disadvantages for patients and clinics.

CONCLUSION: We report several options to counteract side-effects of classic PDT.

PMID:36192011 | DOI:10.21873/anticanres.16009

Drug Ther Bull. 2022 Oct 3:dtb-2022-000053. doi: 10.1136/dtb.2022.000053. Online ahead of print.

ABSTRACT

Overview of: Williams DJ, Creech CB, Walter EB, et al Short- vs standard-course outpatient antibiotic therapy for community-acquired pneumonia in children: The SCOUT-CAP randomized clinical trial. JAMA Pediatr 2022;176:253-261.

PMID:36192126 | DOI:10.1136/dtb.2022.000053

Iran J Immunol. 2022 Sep;19(3):219-231. doi: 10.22034/iji.2022.92623.2161.

ABSTRACT

BACKGROUND: Impaired renal function is considered as a significant risk factor for cardiovascular events in chronic kidney disease patients. Several immunosuppressive drugs are used in these patients, which necessitates to minimize the drug-related side effects by employing alternative strategies.

OBJECTIVE: This study aimed to evaluate prospectively the influence of low dose ATG induction therapy with two different protocols (Sirolimus versus Mycophenolate mofetil) on the expression of functional markers (LAG-3, CD39, and intracellular CTLA-4) on conventional Tregs in renal recipients.

METHODS: Thirty-eight renal transplant recipients were enrolled in this study. The patients were randomly assigned into two groups, including TMP: Tacrolimus (Tac), Mycophenolate mofetil (MMF), and Prednisolone (n=23); and TSP: Tac, Sirolimus (SRL), and Prednisolone (n=15). The frequency of LAG-3, CD39, and intracellular CTLA-4 on circulating Tregs was analyzed by flow cytometry before and after transplantation.

RESULTS: Analysis of the flow cytometry data showed that the frequency of CD4+CD25+FOXP3+ Tregs increased 4 months post-transplantation compared to pre-transplantation in both groups, although this increase was only significant in TMP group. In TMP treated patients, the frequency of LAG-3+ Tregs and CD39+ Tregs increased, whereas the frequency of intracellular CTLA-4+ Tregs decreased 4 months post-transplantation. In TSP group, while the frequency of CD39+ Tregs increased, the frequency of CTLA-4+ Tregs decreased in post-transplantation compared to pre-transplantation.

CONCLUSIONS: it seems that both treatment regimen protocols with a low dose ATG induction therapy may be clinically applicable in kidney transplant recipients.

PMID:36190377 | DOI:10.22034/iji.2022.92623.2161

Front Immunol. 2022 Sep 15;13:998516. doi: 10.3389/fimmu.2022.998516. eCollection 2022.

ABSTRACT

Immune-checkpoint inhibitors (ICI) targeting programmed cell death 1 (PD-1) and its ligand 1 (PD-L1) have quickly changed the treatment landscape in advanced non-small cell lung cancer. However, any patient treated with an immune checkpoint inhibitor is at risk for immune-related adverse events (irAEs). Checkpoint inhibitor pneumonitis (CIP) is a rare but potentially severe pulmonary toxicity of immunotherapy. Since the imaging features and symptoms are not specific, the diagnosis of CIP is challenging. In addition, CIP may mimic other lung diseases. Due to these characteristics, proper patient management may be delayed. So, a comprehensive understanding of imaging features is essential for a prompt detection and correct management of these drug-induced lung diseases. We presented a patient with lung squamous cell cancer who has clinical symptoms preceding imaging evidence of pneumonitis after immunotherapy and radiotherapy. We also discussed the safety of immunotherapy, the complexity and management of immune pneumonitis.

PMID:36189237 | PMC:PMC9520566 | DOI:10.3389/fimmu.2022.998516

ACS Omega. 2022 Sep 14;7(38):34341-34351. doi: 10.1021/acsomega.2c03948. eCollection 2022 Sep 27.

ABSTRACT

Glabridin is chemically an isoflavane class of natural phenols and is found mainly in the roots of Glycyrrhiza glabra. It has several beneficial pharmacological actions for the management of inflammatory disorders as well as can counteract drug-induced toxic effects. On the other hand, methotrexate (MTX) is the first-line disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis. However, its treatment is associated with major side effects like hepatotoxicity. In the quest to explore a suitable combination therapy that can improve the efficacy and reduce the hepatotoxicity of MTX, we hypothesized that glabridin might serve the purpose for which there is no literature precedent to date. We explored the antiarthritic efficacy of MTX in the presence or the absence of glabridin using Mycobacterium-induced arthritic model in rats. The results of reduction in paw swelling, inhibition of serum cytokines (TNF-α, IL-6, and IL-1β), and improvement in the bone joints from radiological and histopathological findings suggest that glabridin can substantially augment the antiarthritic efficacy of MTX. Further, results of concomitant glabridin treatment with MTX in the experimental time frame demonstrate that glabridin could considerably prevent the MTX-induced hepatic alteration in serum biochemical markers (SGPT and SGOT) and oxidative stress markers (malondialdehyde (MDA) and glutathione reduced (GSH)). Moreover, glabridin showed a marked effect in impeding the regulation of NF-κB/IκBα and Nrf2/Keap1 pathways in the hepatic tissues. The results of simultaneous administration of glabridin with MTX in the rat model indicate that glabridin had no pronounced effect of causing severe alteration in the pharmacokinetic behavior of MTX. In summary, glabridin can significantly potentiate the antiarthritic efficacy of MTX and can also minimize its hepatotoxicity via the inhibition of inflammation and oxidative stress. Further research should be performed to develop glabridin as a phytotherapeutics for the improved efficacy and better tolerability of MTX at the reduced dose level of MTX.

PMID:36188236 | PMC:PMC9520544 | DOI:10.1021/acsomega.2c03948

Pulm Circ. 2022 Jul 1;12(3):e12133. doi: 10.1002/pul2.12133. eCollection 2022 Jul.

ABSTRACT

Riociguat, a soluble guanylate cyclase stimulator, is approved for treatment of adults with pulmonary arterial hypertension (PAH). The safety, tolerability, and pharmacokinetics (PK) of oral riociguat in a pediatric population with PAH was assessed in PATENT-CHILD (NCT02562235), a multicenter, single-arm, 24-week, open-label, Phase 3 study. Patients aged 6-17 years in World Health Organization functional class (WHO-FC) I-III treated with stable endothelin receptor antagonists and/or prostacyclin analogs received riociguat equivalent to 0.5-2.5 mg three times daily in adults, as either oral pediatric suspension or tablets, based on bodyweight. Primary outcomes were safety, tolerability, and PK of riociguat. Twenty-four patients (mean age 12.8 years), 18 of whom were in WHO-FC II, were enrolled. Adverse events (AEs), mostly mild or moderate, were reported in 20 patients (83%). Four patients (17%) experienced a serious AE; all resolved by study end and two (8%) were considered study-drug related. Hypotension was reported in three patients and hemoptysis in one (all mild/moderate intensity). Riociguat plasma concentrations in pediatric patients were consistent with those published in adult patients. From baseline to Week 24, mean ± standard deviation increase in 6-minute walking distance was 23 ± 69 m (n = 19), and mean decrease in NT-proBNP was -66 ± 585 pg/ml (n = 14). There was no change in WHO-FC. Two patients experienced clinical worsening events of hospitalization for right heart failure. PK results confirmed a suitable riociguat dosing strategy for pediatric patients with PAH. The data suggest an acceptable safety profile with potential efficacy signals.

PMID:36186721 | PMC:PMC9485817 | DOI:10.1002/pul2.12133

Front Genet. 2022 Sep 14;13:982955. doi: 10.3389/fgene.2022.982955. eCollection 2022.

ABSTRACT

Apixaban is a direct oral anticoagulant, a factor Xa inhibitor, used for the prevention of ischemic stroke in patients with atrial fibrillation. Despite using recommended dosing a few patients might still experience bleeding or lack of efficacy that might be related to inappropriate drug exposure. We conducted a genome-wide association study using data from 1,325 participants in the pivotal phase three trial of apixaban with the aim to identify genetic factors affecting the pharmacokinetics of apixaban. A candidate gene analysis was also performed for pre-specified variants in ABCB1, ABCG2, CYP3A4, CYP3A5, and SULT1A1, with a subsequent analysis of all available polymorphisms within the candidate genes. Significant findings were further evaluated to assess a potential association with clinical outcome such as bleeding or thromboembolic events. No variant was consistently associated with an altered apixaban exposure on a genome-wide level. The candidate gene analyses showed a statistically significant association with a well-known variant in the drug transporter gene ABCG2 (c.421G > T, rs2231142). Patients carrying this variant had a higher exposure to apixaban [area under the curve (AUC), beta = 151 (95% CI 59-243), p = 0.001]. On average, heterozygotes displayed a 5% increase of AUC and homozygotes a 17% increase of AUC, compared with homozygotes for the wild-type allele. Bleeding or thromboembolic events were not significantly associated with ABCG2 rs2231142. This large genome-wide study demonstrates that genetic variation in the drug transporter gene ABCG2 is associated with the pharmacokinetics of apixaban. However, the influence of this finding on drug exposure was small, and further studies are needed to better understand whether it is of relevance for ischemic and bleeding events.

PMID:36186466 | PMC:PMC9515473 | DOI:10.3389/fgene.2022.982955

Farm Hosp. 2022 Apr 26;46(3):146-151.

ABSTRACT

OBJECTIVE: To estimate the incidence of potential in-hospital adverse reactions with the use of alert drugs in a general hospital in southern Brazil. Method: Cross-sectional study, carried out in a hospital in southern Brazil. The electronic medical records (TASY®) of patients hospitalized between January and August 2020, who were prescribed one of the drugs earmarked for tracking adverse drug reactions, were evaluated: the drugs included flumazenil, fexofenadine hydrochloride, naloxone, promethazine, diphenhydramine and loperamide.

RESULTS: A total of 13,476 medical records were reviewed and 204 (1.5%) were included in the study in which tracker use was indicated in the management of adverse drug reactions. In this study a total of 18 different signs or symptoms were found in medical records, with pruritus/hyperemia/urticaria being the most reported symptoms (n = 76). Among the drug classes that caused most adverse drug reactions, opioids were the most mentioned (n = 44). It should be noted that in 49 medical records the information on which drug caused the adverse events was not reported. Regarding the cause of hospitalization of patients who used creening drugs, cancer was the most frequent (n = 37).

CONCLUSIONS: This study indicates that the use of trackers can be a tool to estimate the occurrence of adverse drug reactions and to establish adverse events related to the use of medications, which should be reported to the pharmacovigilance service, with a view to patient safety.

PMID:36183207