Indian J Tuberc. 2024;71 Suppl 1:S97-S100. doi: 10.1016/j.ijtb.2024.06.001. Epub 2024 Jun 10.

ABSTRACT

BACKGROUND: It is estimated that drug-resistant (DR) Tuberculosis (TB) (DR-TB) patients in Indonesia are 2.40% of all new TB patients and 13% of previously treated TB patients with a total incidence of DR-TB cases of 24,000 people. The adverse drug reactions (ADRs) of DR-TB are still a problem that can certainly affect the success of therapy. The aim of this study was to determine the correlation between the length of therapy and regimen therapy of DR-TB with the severity of ADRs.

METHODS: Data collection was carried out retrospectively on the medical records of DR-TB patients in 2020-2021 and sampling used a purposive sampling technique that complied with the inclusion criteria.

RESULTS: Of the 86 patients, the majority of DR-TB patients in X Hospital were 26-45 years old 35 (40.7%), 52 (60.5%) male, the most common comorbid was type II DM, 19 (22.1%), and the most nutritional status was malnutrition as much as 39 (45.3%). The most common type of ADR was hyperuricemia in 31 (36.0%). The results of the correlation analysis showed that there was a relationship between the length of therapy and the severity of ADRs (ρ = 0.002) and there was no relationship between the type of therapy regimen and the severity of ADRs (ρ = 0.184).

CONCLUSION: The longer DR-TB therapy, the higher the severity of ADRs and there is no relationship between the type of therapy regimen and the severity of ADRs.

PMID:39067964 | DOI:10.1016/j.ijtb.2024.06.001

Indian J Tuberc. 2024;71 Suppl 1:S25-S28. doi: 10.1016/j.ijtb.2023.06.001. Epub 2023 Jun 7.

ABSTRACT

This study is conducted from year 2019-2022 in Gujarat Cancer Society medical college and research center, Ahmedabad. Out of total 275 patients on drug resistant TB regimen (all oral longer, shorter injectable and mono H) seen in opd, 55 patients presented with adverse drug reaction. Most commonly affected age group was 20-40 yr old. During the course of treatment 32.7% required hospitalization, of which 29% were admitted in ward, rest required ICU care. Maximum ADR occurred in first 30 days of starting ATT. Drug had to be withdrawn in 41.81% and in 32.7%, offending agent was withdrawn permanently. There was no mortality during the study.

PMID:39067950 | DOI:10.1016/j.ijtb.2023.06.001

Indian J Tuberc. 2024;71 Suppl 1:S136-S140. doi: 10.1016/j.ijtb.2024.03.002. Epub 2024 Mar 6.

ABSTRACT

BACKGROUND: Pharmacovigilance entails monitoring of patients for timely detection of ADR and reporting them so that more information about drug safety can be obtained. This may help in the future for dose modification or alteration of regimen. In NTEP, ADSm (Active Drug Safety monitoring) is part of pharmacovigilance. In this study we shall be studying ADRs to Anti TB drugs in DRTB.

METHODOLOGY: This study is observational, retrospective and record based, of patients admitted from 2021 to 2023 in the DOTS ward of Respiratory Medicine Department of a tertiary care hospital in Goa. Data such as age, sex, regimen, date of AKT initiation and adverse effects documented has been noted and compiled.

RESULTS: ADRs have been tabulated in the form of tables. Statistical analysis is done to find out the commonest ADR, time when they are likely to occur, which age and gender are most likely affected and if there are any other associated risk factors for ADRs.

CONCLUSION: This study will enable in future to better monitor patients with regard to particular adverse drug reaction, patient safety and if needed to alter the regimen as early as possible.

PMID:39067945 | DOI:10.1016/j.ijtb.2024.03.002

Indian J Tuberc. 2024;71 Suppl 1:S110-S116. doi: 10.1016/j.ijtb.2023.04.011. Epub 2023 Apr 11.

ABSTRACT

World Health Organization (WHO) issued the latest recommendations regarding the management of drug-resistant Tuberculosis (TB) in 2022, allowing the replacement of ethambutol (6 months) with linezolid (2 months). This recommendation also introduced a new regimen, namely bedaquiline, pretomanide, linezolid, moxifloxacin (BPaLM) for fluoroquinolone-sensitive patients and bedaquiline, pretomanide, linezolid, (BPaL) for patients insensitive to fluoroquinolone (6-9 months). The latest TB regimen introduced by WHO provides a shorter-course treatment, however not much has been discussed about the impact of this new regimen on chronic kidney disease (CKD) patients, particularly on hemodialysis (HD). The condition of CKD can interfere with the pharmacokinetics of TB medication, thus could reduce effectiveness and increase toxicity. The drugs used on this new regimen are mostly safe for renal impairment patients due to the dominant metabolism in the liver. Particular precaution is given to the administration of linezolid due to increased hematology side effects and bedaquiline with the side effect of QTC interval lengthening and increased risk of arrhythmias. Although this regimen research has not been in many studies in renal failure patients, no significant side effects nor kidney damage evidence was found. This remains to be proven by more research on the patient population with renal failure.

PMID:39067942 | DOI:10.1016/j.ijtb.2023.04.011

Indian J Tuberc. 2024;71 Suppl 1:S101-S109. doi: 10.1016/j.ijtb.2023.04.006. Epub 2023 Apr 10.

ABSTRACT

BACKGROUND: Monitoring and managing adverse drug reactions (ADR) are critical for treating drug-resistant tuberculosis (TB).

OBJECTIVE: To study symptomatic, linezolid-attributable ADRs in TB patients initiated on all oral longer bedaquiline-based treatment regime for multidrug-resistant/rifampicin-resistant (MDR/RR)-TB under programmatic conditions.

METHODS: It was a multicenter, retrospective study of people with MDR/RR-TB in nine TB units in Nagpur, India, from March 2020 to April 2022.

RESULTS: The study consisted of a sample size of 106 individuals with multidrug-resistant and rifampicin-resistant tuberculosis out of a total of 110 individuals with the disease. Of these, 45 (42.45%) experienced linezolid ADRs, with an incidence of 11.37 cases per 1000 person-weeks. These patients were significantly younger (31.24 ± 11.13 years) and more likely to be female (27, 50%) than those without ADRs. ADR severity was mild in 20 (44.45%), moderate in 15 (33.33%), and severe in 10 (22.22%) patients. The most common ADR was peripheral neuropathy (42, 93.33%), followed by lactic acidosis (3, 6.67%), anemia (2, 4.44%), and optic neuritis (2, 4.44%). Dosing was reduced in 17 (37.78%) patients, and linezolid was withdrawn entirely in 19 (42.22%) patients. Only 9 (20%) patients continued linezolid unmodified. For mild to moderate linezolid-associated symptomatic peripheral neuropathy, symptom management with or without dose reduction is an effective strategy; however, immediate linezolid withdrawal is necessary in severe or life-threatening peripheral neuropathy cases. After a mean follow-up of 41 ± 21.33 weeks, ADR symptoms resolved completely in 4 (6.67%) patients and decreased in 42 (93.33%) patients.

CONCLUSION: Linezolid ADRs, often neuropathy, frequently occur in patients on an all-oral bedaquiline-based treatment regime for MDR/RR-TB. Women and younger patients are more likely to experience these ADRs, usually mild to moderate in severity. Management of symptomatic linezolid-associated peripheral neuropathy should be based on ADR severity. These ADRs often affect linezolid dosing, so it is important to identify and manage them early.

PMID:39067941 | DOI:10.1016/j.ijtb.2023.04.006

Medicina (Kaunas). 2024 Jul 12;60(7):1123. doi: 10.3390/medicina60071123.

ABSTRACT

Background and Objectives: Obstructive sleep apnea (OSA) is a prevalent sleep-disordered breathing pathology with significant clinical consequences, including increased cardiovascular risk and cognitive decline. Continuous positive airway pressure (CPAP) is the gold-standard treatment, but alternative strategies are sometimes needed for patients intolerant to CPAP. Drug-induced sleep endoscopy (DISE) is a key diagnostic tool for assessing upper airway obstruction in OSA patients and subsequently tailoring a surgical approach, with sedation protocols playing a crucial role in its efficacy and results accuracy. This study aimed to investigate the effect of adding remifentanil to a propofol target-controlled infusion (TCI) regimen on the sedation parameters and procedural outcomes of DISE. Materials and Methods: The study was conducted at the Central University and Emergency Military Hospital "Dr. Carol Davila" and Ria Clinic in Bucharest between July 2021 and October 2023. Thirty-one patients were enrolled and randomised into two groups: a propofol group (P group, n= 11) and a remifentanil-propofol group (R-P group, n = 20). DISE was performed using standardised protocols, sedative drugs were administered in TCI mode, and data on sedation levels, respiratory and cardiovascular parameters, and procedural incidents were collected. Results: The addition of remifentanil at 1 ng/mL effect-site concentration significantly reduced the effect-site concentration of propofol required for adequate sedation (3.4 ± 0.7 µg/mL in the P group vs. 2.8 ± 0.6 µg/mL in the R-P group, p = 0.035). The time to achieve adequate sedation was also shorter in the R-P group (7.1 ± 2.5 min vs. 9.5 ± 2.7 min, p = 0.017). The incidence of cough, hypoxemia, and cardiovascular events did not significantly differ between the two groups. Conclusions: Adding remifentanil to a propofol TCI regimen for DISE effectively reduces the required propofol effect-site concentration and shortens sedation time without increasing the risk of adverse events. This combination may enhance the safety and efficiency of DISE, offering a promising alternative for patients undergoing this procedure.

PMID:39064552 | DOI:10.3390/medicina60071123

Medicina (Kaunas). 2024 Jul 3;60(7):1092. doi: 10.3390/medicina60071092.

ABSTRACT

Triple-negative breast cancer (TNBC) represents a challenging malignancy with limited treatment options and a poor prognosis. Adjuvant therapies, including chemotherapy and immune checkpoint inhibitors (ICI), are commonly employed following breast conservation surgery. However, these treatments can lead to various adverse effects, including cutaneous complications and connective tissue disorders. Here, we present the case of a 54-year-old woman with TNBC who developed morphea, a form of localized scleroderma, following adjuvant chemotherapy and pembrolizumab administration. This case highlights the rarity of drug-induced morphea and emphasizes the importance of recognizing and managing such adverse events in breast cancer patients. We discuss the clinical characteristics, diagnostic challenges, and treatment considerations associated with drug-induced scleroderma-like lesions, as well as the potential mechanisms underlying their development. Furthermore, we review the literature on the incidence, clinical features, and outcomes of scleroderma-like lesions induced by chemotherapy and ICIs. This case underscores the need for increased awareness of immune-related adverse events in patients receiving immunotherapy, as well as the importance of individualized treatment approaches to optimize patient care and outcomes.

PMID:39064521 | DOI:10.3390/medicina60071092

Medicina (Kaunas). 2024 Jun 23;60(7):1028. doi: 10.3390/medicina60071028.

ABSTRACT

Background and Objectives: Despite high incidences of cognitive impairment with aging, evidence on the prevalence and the seriousness of drug-induced cognitive impairment is limited. This study aims to evaluate the prevalence and the severity of drug-induced cognitive impairment and to investigate the clinical predictors of increased hospitalization risk from serious drug-induced cognitive impairment. Materials and Methods: Adverse drug events (ADEs) regarding drug-induced cognitive impairment reported to the Korean Adverse Event Reporting System Database (KAERS DB) from January 2012 to December 2021 were included (KIDS KAERS DB 2212A0073). The association between the etiologic classes and the reporting serious adverse events (SAEs) was evaluated using disproportionality analysis, and the effect was estimated with reporting odds ratio (ROR). Clinical predictors associated with increased risk of hospitalization from SAEs were identified via multivariate logistic analysis, and the effect was estimated with odds ratio (OR). Results: The most etiologic medication class for drug-induced cognitive impairment ADEs was analgesics, followed by sedative-hypnotics. Anticancer (ROR 57.105, 95% CI 15.174-214.909) and anti-Parkinson agents (ROR 4.057, 95% CI 1.121-14.688) were more likely to report serious drug-induced cognitive impairments. Male sex (OR 19.540, 95% CI 2.440-156.647) and cancer diagnosis (OR 18.115, 95% CI 3.246-101.101) are the major clinical predictors for increased risk of hospitalizations due to serious drug-induced cognitive impairment. Conclusions: This study highlights the significant prevalence and severity of drug-induced cognitive impairment with cancer diagnosis and anticancer agents. However, further large-scaled studies are required because of the potential underreporting of drug-induced cognitive impairments in real practice settings, which is further contributed to by the complexity of multiple contributing factors such as comorbidities.

PMID:39064457 | DOI:10.3390/medicina60071028

Aging Clin Exp Res. 2024 Jul 26;36(1):151. doi: 10.1007/s40520-024-02799-3.

ABSTRACT

Drug-related problems (DRPs) are critical medical issues during transition from hospital to home with high prevalence. The application of a variety of interventional strategies as part of the transitional care has been studied for preventing DRPs. However, it remains challenging for minimizing DRPs in patients, especially in older adults and those with high risk of medication discrepancies after hospital discharge. In this narrative review, we demonstrated that age, specific medications and polypharmacy, as well as some patient-related and system-related factors all contribute to a higher prevalence of transitional DPRs, most of which could be largely prevented by enhancing nurse-led multidisciplinary medication reconciliation. Nurses' contributions during transitional period for preventing DRPs include information collection and evaluation, communication and education, enhancement of medication adherence, as well as coordination among healthcare professionals. We concluded that nurse-led strategies for medication management can be implemented to prevent or solve DRPs during the high-risk transitional period, and subsequently improve patients' satisfaction and health-related outcomes, prevent the unnecessary loss and waste of medical expenditure and resources, and increase the efficiency of the multidisciplinary teamwork during transitional care.

PMID:39060872 | PMC:PMC11282160 | DOI:10.1007/s40520-024-02799-3

Sci Rep. 2024 Jul 25;14(1):17138. doi: 10.1038/s41598-024-67627-0.

ABSTRACT

This study aims to collect and analyze adverse event (AE) reports related to Nusinersen from the FAERS database. The study employed a combination of signal quantification techniques, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS), to enhance the accuracy of signal detection and reduce the risk of false positives or negatives. Between the first quarter of 2017 and the third quarter of 2023, the FAERS database collected a total of 11,485,105 drug AE reports, of which 5772 were related to Nusinersen. Through signal mining analysis, 218 preferred term (PT) signals involving 27 system organ classes (SOCs) were identified. The study discovered AEs related to metabolism and nutrition disorders, psychiatric disorders, and cardiac disorders SOCs, which were not mentioned in the product information. Additionally, complications directly related to the intrathecal administration of Nusinersen, such as increased CSF pressure, positive CSF red blood cell count, and AEs related to the method of drug use, such as neuromuscular scoliosis and cerebrospinal fluid reservoir placement, were highlighted. Notably, AEs related to renal function abnormalities, such as abnormal Urine protein/creatinine ratio and protein urine presence, showed higher frequency and signal strength. The findings of this study emphasize the importance of comprehensive safety monitoring in the clinical application of Nusinersen. These results are significant for guiding future clinical practices, improving disease management strategies, and developing safer treatment protocols.

PMID:39060346 | PMC:PMC11282055 | DOI:10.1038/s41598-024-67627-0

Eur J Cancer. 2024 Jul 22;209:114235. doi: 10.1016/j.ejca.2024.114235. Online ahead of print.

ABSTRACT

The use of immune checkpoint inhibitors (ICI) in cancer treatment is expanding, offering promising outcomes but with an important risk of immune-related adverse events (irAEs). These events, stemming from an overstimulated immune system attacking healthy cells, can necessitate immunosuppressant treatment, disrupt treatment courses, and impact patients' quality of life. The analysis of ICI efficacy data has led to a better understanding of the characteristics of responders. Similarly, we are gaining clearer insights into the characteristics of patients who develop irAEs, prompting an increasing emphasis on modifiable factors associated with irAE risk. These factors include lifestyle choices and the composition of the gut microbiome. Despite comprehensive reviews exploring the microbiome's role in therapy efficacy, understanding its connection with immune-related toxicity remains incomplete. While endeavours to identify predictive biomarkers continue, lifestyle modifications emerge as a promising avenue for enhancing treatment outcomes. This review consolidates the current evidence regarding the impact of the gut microbiome on irAE occurrence. Furthermore, it focuses on actionable strategies for mitigating these adverse events, elucidating the evidence supporting dietary adjustments, supplementation, medication management, and physical activity. With the expanding range of indications for ICI therapy, a significant proportion of oncology patients, including those in early disease stages, are now exposed to these treatments. Acknowledging the importance of averting irAEs in this context, our review offers timely insights crucial for addressing the evolving challenges associated with immunotherapy across diverse oncological settings.

PMID:39059186 | DOI:10.1016/j.ejca.2024.114235

Semin Arthritis Rheum. 2024 Jul 15;68:152516. doi: 10.1016/j.semarthrit.2024.152516. Online ahead of print.

ABSTRACT

OBJECTIVES: The pediatric Glucocorticoid Toxicity Index (pGTI) is a new, pediatric-specific tool to quantify glucocorticoid (GC)-related morbidity in children. We evaluated the feasibility and construct validity of retrospective pGTI scoring in patients with pediatric-onset systemic lupus erythematosus (pSLE) and identified risk factors for cumulative toxicity.

METHODS: We conducted a retrospective cohort study of patients with pSLE treated with GCs at two pediatric centers (1999-2023). GC exposure was estimated using interval-averaged oral prednisone-equivalent dose and cumulative prednisone-equivalent dose. We scored change in GC toxicity every 6 months (±2) using a modified pGTI including 7 of 10 domains. We calculated the Cumulative Worsening Score (CWS), a continuous summation of toxicity accrued. Mixed effects linear regression was used to identify factors associated with CWS.

RESULTS: There were 126 patients with pSLE, including 88 with nephritis, with a median of 6 visits/patient. Nearly half (47 %) experienced toxicity in the Blood Pressure domain. Other common toxicities were mood disturbance (25 %), followed by increased body mass index (BMI), striae, and sleep disturbance (21 % each). Decreased growth velocity was observed in 18 %. There was modest correlation between cumulative GC dose and CWS (rho 0.3; p < 0.01). Greater cumulative toxicity was associated with younger age, elevated BMI, and rituximab use at the time of GC initiation, albeit indications for the latter were not captured.

CONCLUSIONS: Patients with pSLE experience a high burden of GC toxicity, particularly related to blood pressure, BMI, sleep, and growth. Standardized, pediatric-specific GC toxicity assessment is feasible in real-world settings and can facilitate evaluation of strategies to reduce morbidity in children requiring chronic GC treatment.

PMID:39059156 | DOI:10.1016/j.semarthrit.2024.152516

Cells. 2024 Jul 19;13(14):1216. doi: 10.3390/cells13141216.

ABSTRACT

BACKGROUND: Solid organ transplantation is hindered by immune-mediated chronic graft dysfunction and the side effects of immunosuppressive therapy. Regulatory T cells (Tregs) are crucial for modulating immune responses post-transplantation; however, the transfer of polyspecific Tregs alone is insufficient to induce allotolerance in rodent models.

METHODS: To enhance the efficacy of adoptive Treg therapy, we investigated different immune interventions in the recipients. By utilizing an immunogenic skin transplant model and existing transplantation medicine reagents, we facilitated the clinical translation of our findings. Specifically, antigen-specific Tregs were used.

RESULTS: Our study demonstrated that combining the available induction therapies with drug-induced T-cell proliferation due to lymphopenia effectively increased the Treg/T effector ratios. This results in significant Treg accumulation within the graft, leading to long-term tolerance after the transfer of antigen-specific Tregs. Importantly, all the animals achieved operational tolerance, which boosted the presence of adoptively transferred Tregs within the graft.

CONCLUSIONS: This protocol offers a means to establish tolerance by utilizing antigen-specific Tregs. These results have promising implications for future trials involving adoptive Treg therapy in organ transplantation.

PMID:39056797 | DOI:10.3390/cells13141216

Digit Health. 2024 Jul 23;10:20552076241253090. doi: 10.1177/20552076241253090. eCollection 2024 Jan-Dec.

ABSTRACT

OBJECTIVE: This study aimed to analyze the effect of Smart Cancer Care program on the quality of life and ease of chemotherapy continuation in cancer patients and the effect of additional tele-management on frequency of use and satisfaction with the Smart Cancer Care program.

METHODS: 'Smart Cancer Care' is a mobile program that allows cancer patients undergoing chemotherapy to report symptoms of adverse events and receive remote management. In this study, patients were randomly assigned to three groups: Group A, who received only classical face-to-face management; Group B, who used the Smart Cancer Care program as addition; and Group C, who used the Smart Cancer Care program and received telephone management. After 12 weeks of follow-up, the effectiveness of using the Smart Cancer Care program was analyzed by examining the quality of life, ease of maintaining chemotherapy, and unplanned hospital visits in each group. The frequency of use and satisfaction with the Smart Cancer Care program were also analyzed.

RESULTS: Cancer patients who used the Smart Cancer Care program had 1.93-fold (1.15-3.25) higher overall quality of life than those who did not. This became 2.33-fold (1.34-4.04) higher when phone care was added. Patients with tele-management were significantly more likely to use the Smart Cancer Care program (odds ratio (OR) = 25.80; 95% confidence interval (CI), 11.28-58.97).

CONCLUSIONS: A mobile self-reported management program has a positive effect on the quality of life of cancer patients undergoing chemotherapy. Tele-management is conducive to active and effective use of this program.

PMID:39055783 | PMC:PMC11271138 | DOI:10.1177/20552076241253090

BMC Cancer. 2024 Jul 25;23(Suppl 1):1256. doi: 10.1186/s12885-023-11213-6.

ABSTRACT

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) levels correlate with poor outcomes in urothelial carcinoma (UC). IDO1 and programmed death-ligand 1 (PD-L1) are often co-expressed. Epacadostat is a potent and highly selective inhibitor of IDO1. In a subgroup analysis of patients with advanced UC participating in a phase I/II study, epacadostat-pembrolizumab treatment produced an objective response rate (ORR) of 35%.

METHODS: ECHO-303/KEYNOTE-698 was a double-blinded, randomized phase III study of adults with metastatic or unresectable locally advanced UC with recurrence or progression following first-line platinum-based chemotherapy. Participants were randomized to epacadostat 100 mg twice daily (BID) plus pembrolizumab or placebo plus pembrolizumab until completion of 35 pembrolizumab infusions, disease progression, or unacceptable toxicity. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors version 1.1.

RESULTS: Target enrollment was 648 patients; enrollment was halted early based on efficacy results from the phase III ECHO-301/KEYNOTE-252 study in metastatic melanoma. Forty-two patients were randomized to each treatment arm. Median duration of follow-up was 62 days in each arm. The investigator-assessed ORR (unconfirmed) was 26.2% (95% CI 16.35-48.11) for epacadostat plus pembrolizumab and 11.9% (95% CI 4.67-29.50) for placebo plus pembrolizumab. Two complete responses were reported, both in the placebo-plus-pembrolizumab arm. Circulating kynurenine levels increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and numerically decreased in the epacadostat-plus-pembrolizumab arm. The safety profile of epacadostat plus pembrolizumab was similar to that of pembrolizumab monotherapy, although a numerically greater proportion of patients in the combination vs. control arm experienced treatment-related grade ≥ 3 adverse events (16.7% vs. 7.3%). One patient in each arm died due to cardiovascular events, which were not deemed drug-related. No new safety concerns were identified for either agent.

CONCLUSIONS: Epacadostat plus pembrolizumab demonstrated anti-tumor activity and was generally tolerable as second-line treatment of patients with unresectable locally advanced or recurrent/progressive metastatic UC. Epacadostat 100 mg BID, when administered with pembrolizumab, did not normalize circulating kynurenine in most patients. Further study of combined IDO1/PD-L1 inhibition in this patient population, particularly with epacadostat doses that result in durable normalization of circulating kynurenine, may be warranted.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT03374488. Registered 12/15/2017.

PMID:39054485 | DOI:10.1186/s12885-023-11213-6

BMC Cancer. 2024 Jul 25;23(Suppl 1):1251. doi: 10.1186/s12885-023-11203-8.

ABSTRACT

BACKGROUND: Pembrolizumab is a first-line therapy for certain patients with advanced/metastatic non-small cell lung cancer (NSCLC). Combining pembrolizumab with other immunotherapies may enhance tumor cell killing and clinical outcomes. Epacadostat is a selective inhibitor of indoleamine 2,3-dioxygenase 1, an immuno-regulatory enzyme involved in tryptophan to kynurenine metabolism that inhibits T cell-mediated immune responses.

METHODS: In this randomized phase II study, patients with metastatic NSCLC expressing high (≥ 50%) programmed death-ligand 1 (PD-L1) levels received pembrolizumab 200 mg every 21 days plus oral epacadostat 100 mg twice daily (combination) or matching placebo (control). The primary objective was objective response rate (ORR); secondary objectives were progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety/tolerability.

RESULTS: 154 patients were randomized (77 per group). Median (range) follow-up was 6.8 months (0.1-11.4) and 7.0 months (0.2-11.9) in the combination and control groups, respectively Confirmed ORR was similar between groups (combination: 32.5%, 95% CI 22.2-44.1; control: 39.0%, 95% CI 28.0-50.8; difference: - 6.5, 95% CI - 21.5 to 8.7; 1-sided P = 0.8000). Median (range) DOR was 6.2 months (1.9 + to 6.5 +) and not reached (1.9 + to 8.6 +) in the combination and control groups, respectively. Although not formally tested, median PFS was 6.7 and 6.2 months for the combination and control groups, respectively, and median OS was not reached in either group. Circulating kynurenine levels increased from C1D1 to C2D1 (P < 0.01) in the control group and decreased from C1D1 to C2D1 (P < 0.01) in the combination group but were not normalized in most patients. The most frequent serious adverse events (AEs) (≥ 2%) were pneumonia (4.0%), anemia (2.7%), atelectasis (2.7%) and pneumonitis (2.7%) in the combination group and pneumonia (3.9%), pneumonitis (2.6%) and hypotension (2.6%) in the control group. Two deaths due to drug-related AEs were reported, both in the control group.

CONCLUSIONS: Addition of epacadostat to pembrolizumab therapy for PD-L1-high metastatic NSCLC was generally well tolerated but did not demonstrate an improved therapeutic effect. Evaluating higher doses of epacadostat that normalize kynurenine levels when given in combination with checkpoint inhibitors may be warranted.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT03322540. Registered 10/26/2017.

PMID:39054476 | DOI:10.1186/s12885-023-11203-8

Mol Genet Metab Rep. 2024 Jul 1;40:101115. doi: 10.1016/j.ymgmr.2024.101115. eCollection 2024 Sep.

ABSTRACT

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism, resulting from the deficient activity of phenylalanine hydroxylase that converts Phe to tyrosine in the liver, leading to elevated levels of Phe. Pegvaliase is an innovative and effective enzyme replacement therapy for reducing Phe concentration, but it has been associated with severe drug-induced hypersensitivity adverse events (HAEs). Limited data is available on the management of these HAEs, thus, we aimed to present a case report of a successful management strategy. The patient was a 28-year-old Caucasian male with classical PKU, who was otherwise healthy. Due to poor metabolic control, the pegvaliase treatment was initiated. The titration phase was uneventful, with transient and mild side effects, localized to the injection site. After the patient was on a maintenance dose of pegvaliase and had no reactions to the drug, we discontinued the H1-antihistamine. In the following days, within minutes after receiving the pegvaliase injection, an acute hypersensitivity reaction occurred that required emergency treatment. H1-antihistamine treatment was reintroduced. Four days after the incident he received pegvaliase under medical supervision and did not experience any symptoms. In conclusion, cautious reintroduction of pegvaliase in a hospital setting can be safely performed after HAE due to the discontinuation of H1-antihistamines. HAEs could be successfully mitigated by scheduling daily antihistamines administration closer to the pegvaliase injection. This approach can enable PKU patients to maintain their access to an effective and quality-of-life-improving therapy.

PMID:39049877 | PMC:PMC11267064 | DOI:10.1016/j.ymgmr.2024.101115

Pharmacol Res Perspect. 2024 Aug;12(4):e1236. doi: 10.1002/prp2.1236.

ABSTRACT

Detailed data on safety associated with drug-drug interactions (DDIs) between Linezolid (LZD) and other antibiotics are limited. The aim of this study was to investigate the safety signals related to these DDIs and to provide a reference for clinically related adverse drug event monitoring. Adverse event (AE) information from 1 January 2004 to 16 June 2022 of the target antibiotics including LZD using alone or in combination with LZD was extracted from the OpenVigil FDA data platform for safety signal analysis. The combined risk ratio model, reporting ratio method, Ω shrinkage measure model, and chi-square statistics model were used to analyze the safety signals related to DDIs. Meanwhile, we evaluated the correlation and the influence of sex and age between the drug(s) and the target AE detected. There were 18991 AEs related to LZD. There were 2293, 1726, 4449, 821, 2431, 1053, and 463 AE reports when LZD was combined with amikacin, voriconazole, meropenem, clarithromycin, levofloxacin, piperacillin-tazobactam, and azithromycin, respectively. Except for azithromycin, there were positive safety signals related to DDIs between LZD and these antibiotics. These DDIs might influence the incidence of 13, 16, 7, 7, 6, and 15 types of AEs, respectively, and is associated with higher reporting rates of AEs compared with use alone. Moreover, sex and age might influence the occurrence of AEs. We found that the combinations of LZD and other antibiotics are related to multiple AEs, such as hepatotoxicity, drug resistance and electrocardiogram QT prolonged, but further research is still required to investigate their underlying mechanisms. This study can provide a new reference for the safety monitoring of LZD combined with other antibiotics in clinical practice.

PMID:39049495 | DOI:10.1002/prp2.1236

Stud Health Technol Inform. 2024 Jul 24;315:398-403. doi: 10.3233/SHTI240177.

ABSTRACT

Frequent transitions of care among patients with cancer increase their risks for medication safety events (MSEs). Patients and families need to become "vigilant partners" in MSE self-reporting when transitioning back home. However, limited evidence is available to guide patient and family engagement in preventing and managing MSEs. This study explored patients' perceptions of using technology for MSE self-reporting by interviewing 41 patients with breast, prostate, lung, or colorectal cancer. The findings revealed that patients with cancer perceived technology as convenient and easy to use to address urgent MSE concerns. However, the lack of access to technology and being unconfident in using technology can be barriers to using technology for MSE reporting. Personalized support is needed to facilitate patients' engagement in MSE self-reporting. Factors identified in the study will further support the user-centered design and development of technology systems that can support patients' needs and expectations for medication safety.

PMID:39049290 | DOI:10.3233/SHTI240177

BMC Psychiatry. 2024 Jul 25;24(1):532. doi: 10.1186/s12888-024-05950-6.

ABSTRACT

BACKGROUND: Adverse events (AEs) are commonly reported in clinical studies using the Medical Dictionary for Regulatory Activities (MedDRA), an international standard for drug safety monitoring. However, the technical language of MedDRA makes it challenging for patients and clinicians to share understanding and therefore to make shared decisions about medical interventions. In this project, people with lived experience of depression and antidepressant treatment worked with clinicians and researchers to co-design an online dictionary of AEs associated with antidepressants, taking into account its ease of use and applicability to real-world settings.

METHODS: Through a pre-defined literature search, we identified MedDRA-coded AEs from randomised controlled trials of antidepressants used in the treatment of depression. In collaboration with the McPin Foundation, four co-design workshops with a lived experience advisory panel (LEAP) and one independent focus group (FG) were conducted to produce user-friendly translations of AE terms. Guiding principles for translation were co-designed with McPin/LEAP members and defined before the finalisation of Clinical Codes (CCs, or non-technical terms to represent specific AE concepts). FG results were thematically analysed using the Framework Method.

RESULTS: Starting from 522 trials identified by the search, 736 MedDRA-coded AE terms were translated into 187 CCs, which balanced key factors identified as important to the LEAP and FG (namely, breadth, specificity, generalisability, patient-understandability and acceptability). Work with the LEAP showed that a user-friendly language of AEs should aim to mitigate stigma, acknowledge the multiple levels of comprehension in 'lay' language and balance the need for semantic accuracy with user-friendliness. Guided by these principles, an online dictionary of AEs was co-designed and made freely available ( https://thesymptomglossary.com ). The digital tool was perceived by the LEAP and FG as a resource which could feasibly improve antidepressant treatment by facilitating the accurate, meaningful expression of preferences about potential harms through a shared decision-making process.

CONCLUSIONS: This dictionary was developed in English around AEs from antidepressants in depression but it can be adapted to different languages and cultural contexts, and can also become a model for other interventions and disorders (i.e., antipsychotics in schizophrenia). Co-designed digital resources may improve the patient experience by helping to deliver personalised information on potential benefits and harms in an evidence-based, preference-sensitive way.

PMID:39049079 | DOI:10.1186/s12888-024-05950-6