Front Pharmacol. 2024 Jun 14;15:1412188. doi: 10.3389/fphar.2024.1412188. eCollection 2024.

ABSTRACT

The management of neurological disorders heavily relies on neurotherapeutic drugs, but notable concerns exist regarding their possible negative effects on reproductive health. Traditional preclinical models often fail to accurately predict reprotoxicity, highlighting the need for more physiologically relevant systems. Organoid models represent a promising approach for concurrently studying neurotoxicity and reprotoxicity, providing insights into the complex interplay between neurotherapeutic drugs and reproductive systems. Herein, we have examined the molecular mechanisms underlying neurotherapeutic drug-induced reprotoxicity and discussed experimental findings from case studies. Additionally, we explore the utility of organoid models in elucidating the reproductive complications of neurodrug exposure. Have discussed the principles of organoid models, highlighting their ability to recapitulate neurodevelopmental processes and simulate drug-induced toxicity in a controlled environment. Challenges and future perspectives in the field have been addressed with a focus on advancing organoid technologies to improve reprotoxicity assessment and enhance drug safety screening. This review underscores the importance of organoid models in unraveling the complex relationship between neurotherapeutic drugs and reproductive health.

PMID:38948466 | PMC:PMC11211546 | DOI:10.3389/fphar.2024.1412188

J Pediatr. 2024 Jun 28:114176. doi: 10.1016/j.jpeds.2024.114176. Online ahead of print.

ABSTRACT

OBJECTIVE: To describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers.

STUDY DESIGN: This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period.

RESULTS: Among 608 patients on ETI, 109 (17.9%) reported at least one AE. The majority (N=85, 77.9%) were temporary, with a median duration of 11 days (range 1-441 days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs. 12-18 years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA p-value 0·026).

CONCLUSIONS: This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted.

PMID:38945446 | DOI:10.1016/j.jpeds.2024.114176

Adv Gerontol. 2024;37(1-2):33-39.

ABSTRACT

In recent years, complications of drug therapy are an important medical problem. Data on adverse drug reactions (ADR) in patients of older age groups were analyzed. The object of the study was notification cards for unwanted reactions received from medical organizations of the Irkutsk region for period 2009-2020 years. The Narangio scale was used to assess the causality between ADR and medicines. Of the 1021 ADR notifications in patients over 65 years of age, 2/3 (668) are presented with ADR notifications in women, 353 (34,6%) in men. The presence of background diseases was registered in 915 notifications (89,6%). There were no gender differences except for a higher incidence of chronic obstructive pulmonary disease in men (7,2 and 3,5% respectively, p<0,05) and diabetes mellitus in women (14 and 3,5% respectively, p<0,05). ADRs for antibacterial agents amounted to 31,8%, drugs for the treatment of cardiovascular diseases - 10,5%, cases of therapeutic inefficiency - 5,1%. The ADR data statement was in line with the recommended form of 76%. The most common filling defect was incomplete patient information. The validity of the Narango causation was high. The deadlines for reporting data were observed in 89,1%. For effective interaction in the pharmacovigilance system, it is necessary in each medical organization to constantly inform about the procedure for pharmacovigilance, types of ADRs, the rules for their detection and the timing of data reporting. The work should be supervised by a trained specialist.

PMID:38944770

Clin Transl Sci. 2024 Jul;17(7):e13871. doi: 10.1111/cts.13871.

ABSTRACT

Electronic health records (EHRs) contain a vast array of phenotypic data on large numbers of individuals, often collected over decades. Due to the wealth of information, EHR data have emerged as a powerful resource to make first discoveries and identify disparities in our healthcare system. While the number of EHR-based studies has exploded in recent years, most of these studies are directed at associations with disease rather than pharmacotherapeutic outcomes, such as drug response or adverse drug reactions. This is largely due to challenges specific to deriving drug-related phenotypes from the EHR. There is great potential for EHR-based discovery in clinical pharmacology research, and there is a critical need to address specific challenges related to accurate and reproducible derivation of drug-related phenotypes from the EHR. This review provides a detailed evaluation of challenges and considerations for deriving drug-related data from EHRs. We provide an examination of EHR-based computable phenotypes and discuss cutting-edge approaches to map medication information for clinical pharmacology research, including medication-based computable phenotypes and natural language processing. We also discuss additional considerations such as data structure, heterogeneity and missing data, rare phenotypes, and diversity within the EHR. By further understanding the complexities associated with conducting clinical pharmacology research using EHR-based data, investigators will be better equipped to design thoughtful studies with more reproducible results. Progress in utilizing EHRs for clinical pharmacology research should lead to significant advances in our ability to understand differential drug response and predict adverse drug reactions.

PMID:38943244 | DOI:10.1111/cts.13871

Rev Fac Cien Med Univ Nac Cordoba. 2024 Jun 28;81(2):254-269. doi: 10.31053/1853.0605.v81.n2.42261.

ABSTRACT

INTRODUCTION: The World Health Organization recommends prioritizing safe and effective drugs proven by clinical or epidemiological studies. However, in population groups with little research, a drug can be used for an indication or pharmaceutical form different from that approved by the regulatory agency (off-label), extrapolating data from studies in adults and exposing pediatric patients. to develop an Adverse Drug Reaction (ADR) due to safety considerations that have not been systematically studied. Intravenous immunoglobulin (IVIg), a high-cost drug, is used with scant evidence in some low-prevalence pathologies. This paper describes and analyzes the off-label use of IVIg at the J. P. Garrahan Pediatric Hospital.

METHODS: Observational, descriptive, prospective study on off-label indications of IVIg. The sampling technique was non-probabilistic and for convenience during 7 months.

RESULTS: 305 IVIg infusions were studied, corresponding to 111 patients. The indication classification showed that 22% (n=67) of the infusions were off-label. In neurology there was a higher percentage of off-label indications (46%) and within them 45% corresponded to the use in neurological disorders. 81% of the doses indicated off-label were in the range 0.8-1g/kg. The off-label infusions presented 61.5% (n=8) of the ADRs. Those from the Neurology service represented 87.5%; 75% being from the "Neurological disorders" group.

CONCLUSION: In some cases, IVIg was indicated in an off-label manner, finding a statistically significant relationship with the appearance of ADR. This finding motivates the proposition of new hypotheses to carry out more studies.

PMID:38941229 | DOI:10.31053/1853.0605.v81.n2.42261

J Immunol. 2024 Jun 28:ji2300893. doi: 10.4049/jimmunol.2300893. Online ahead of print.

ABSTRACT

Catecholamines binding to α- and β-adrenergic receptors on immune cells have recently been shown to play an important role in regulating immune responses. Although α2-adrenergic receptors are known to modulate the immune response in different ways, the therapeutic exploration of their utility has been limited by the lack of agonists selective for the three α2-adrenergic subtypes. We report in this study the identification of the agonist AGN-762, which activates α2B- and α2C-adrenergic subtypes, but not the α2A subtype. We show that AGN-762 reduced clinical disease in an experimental autoimmune encephalitis model of autoimmune disease via direct or indirect effects on T regulatory cells. The activity of AGN-762 was abrogated by depletion of T regulatory cells, which express the α2B-adrenergic receptor. Furthermore, a drug-induced shift to an anti-inflammatory phenotype was demonstrated in immune cells in the spleen of drug-treated experimental autoimmune encephalitis mice. AGN-762 does not display sedative and cardiovascular side effects associated with α2A subtype agonists. Immune modulation by selective α2-adrenergic agonists represents a novel, to our knowledge, approach for treating autoimmune disease.

PMID:38940628 | DOI:10.4049/jimmunol.2300893

JAAD Case Rep. 2024 May 15;49:85-87. doi: 10.1016/j.jdcr.2024.05.007. eCollection 2024 Jul.

NO ABSTRACT

PMID:38938698 | PMC:PMC11208765 | DOI:10.1016/j.jdcr.2024.05.007

Innov Clin Neurosci. 2024 Jun 1;21(4-6):27-30. eCollection 2024 Apr-Jun.

ABSTRACT

INTRODUCTION: Well-known adverse events of antipsychotics are movement disorders, or extrapyramidal symptoms, such as drug-induced parkinsonism and tardive dyskinesia.

OBJECTIVE: With new evidence suggesting a link between low high-density lipoprotein cholesterol (HDL-C) and risk of Parkinson's disease, this study sought to investigate if that link also translated to patients taking antipsychotics with low HDL-C and an increased risk for developing a movement disorder.

DESIGN: Adult patients (n=89) at an inpatient state psychiatric facility taking at least one antipsychotic with at least one HDL-C level were assessed for signs of a movement disorder through their history and physical, progress notes, and Abnormal Involuntary Movement Scale (AIMS) score.

RESULTS: There was no statistical significance when comparing a patient's movement disorder, AIMS scores, and HDL-C levels to suggest that the HDL-C level influenced a patient's movement disorder.

CONCLUSION: This study did not show a correlation between HDL-C levels and a patient's risk of developing a movement disorder while taking an antipsychotic.

PMID:38938537 | PMC:PMC11208005

In Vivo. 2024 Jul-Aug;38(4):2090-2096. doi: 10.21873/invivo.13669.

ABSTRACT

BACKGROUND/AIM: A few case reports of central nervous system (CNS) symptoms caused by amantadine intoxication have been published, detailing various types of symptoms and differing times to onset. We encountered a patient who developed CNS symptoms with amantadine. This prompted us to investigate the types, time to onset, and outcome of CNS adverse reactions to amantadine by analyzing data from a pharmacovigilance database.

PATIENTS AND METHODS: The patient was evaluated at Chutoen General Hospital, Shizuoka, Japan. Analysis was performed using the Japanese Adverse Drug Event Report (JADER) database.

RESULTS: In our case, the amantadine blood concentration was 4,042 ng/ml, i.e., in the toxic range. The time to onset was 26 days for dyskinesia and 90 days for depressed level of consciousness. Symptoms resolved when amantadine was discontinued. The JADER database contained 974 cases of adverse reactions to amantadine. The most frequently reported CNS adverse reaction was hallucination, with a reporting odds ratio of 64.28 (95% confidence interval=52.67-78.46). Positive signals were detected for all CNS adverse reactions. For all CNS reactions, clinical outcomes were poor in a comparatively low percentage of cases. Most CNS reactions occurred soon after administration of amantadine, usually within approximately one month.

CONCLUSION: Because most CNS adverse reactions to amantadine usually occur within approximately one month of initiating treatment, healthcare providers should exercise heightened vigilance in monitoring patients for such reactions during this period.

PMID:38936887 | DOI:10.21873/invivo.13669

Ann Allergy Asthma Immunol. 2024 Jun 25:S1081-1206(24)00376-4. doi: 10.1016/j.anai.2024.06.024. Online ahead of print.

ABSTRACT

BACKGROUND: Limited data exist comparing inhaled corticosteroid (ICS) plus adjunctive therapy versus ICS alone in pediatric asthma patients.

OBJECTIVE: Evaluate the efficacy and safety of fluticasone furoate/vilanterol (FF/VI) versus FF in children and adolescents with asthma.

METHODS: This Phase 3, randomized, double-blind, multicenter study (NCT03248128) included participants aged 5-17 years with ≥6 months' asthma history uncontrolled on ICS monotherapy. Participants received 4 weeks' open-label fluticasone propionate (100 µg) twice daily before 1:1 randomization to 24 weeks' double-blind FF (50 µg:100 µg) or FF/VI (50/25 µg:100/25 µg) once daily. Two populations with different primary endpoints were analyzed to meet United States (Week 12 weighted mean forced expiratory volume in 1 second [FEV1; 0-4 hours]; participants aged 5-17 years) and European (change from baseline pre-dose morning peak expiratory flow [ΔAM PEF] averaged over Weeks 1-12; participants aged 5-11 years) regulator requirements.

RESULTS: Overall, 902 participants were randomized and treated, including 673 children aged 5-11 years. In participants aged 5-17, Week 12 weighted mean FEV1 (0-4 hours) was greater with FF/VI versus FF (difference: 0.083 L; P < .001). In participants aged 5-11, ΔAM PEF over Weeks 1-12 showed numerical improvement with FF/VI versus FF but was not statistically significant (difference: 3.2 L/minute; P = .228). No drug-related serious adverse events or deaths were reported.

CONCLUSION: FF/VI significantly improved weighted mean FEV1 (0-4 hours; participants aged 5-17 years), but not ΔAM PEF (participants aged 5-11 years) versus FF. No new safety concerns were apparent.

PMID:38936466 | DOI:10.1016/j.anai.2024.06.024

Indian J Public Health. 2023 Oct 1;67(4):542-545. doi: 10.4103/ijph.ijph_865_22. Epub 2023 Dec 29.

ABSTRACT

The Saharia tribe of Madhya Pradesh has a very high tuberculosis (TB) burden. However, there is no report of adverse drug reaction (ADR) available in patients receiving anti-TB chemotherapy in the community. Reporting and monitoring of ADRs among TB patients is still rare in marginalized communities. An observational prospective study was performed from November 2019 to June 2020 to assess the patterns of ADRs in 250 Saharia TB patients, who were prescribed Category-I daily DOTS (HRZE) by the physician. Both male and female participants equally experienced ADR during the treatment, but relatively more females (92.6%) than males (88.6%) reported ADR during Phase I. Out of 250 patients, 224 patients (89.6%) experienced one or more ADRs in Phase I. The central nervous system-related (75.6%) ADR was mostly reported followed by any gastrointestinal (74.4%), cardiovascular (49.2%) and any dermatological related (44.4%) ADRs. It is paramount to timely monitor and proactively manages ADRs pertaining to anti-TB drug treatment with minimal alteration in the treatment course.

PMID:38934815 | DOI:10.4103/ijph.ijph_865_22

Am J Hematol. 2024 Jun 27. doi: 10.1002/ajh.27424. Online ahead of print.

ABSTRACT

Belumosudil mesylate is a selective Rho-associated coiled-coil kinase 2 inhibitor with immunomodulatory and antifibrosis effects. This multicenter, open-label, single-arm study evaluated belumosudil 200 mg once daily as second or subsequent line of therapy (LOT) in 21 Japanese patients ≥12 years of age with steroid-dependent/steroid-resistant chronic graft-versus-host disease (cGVHD). The primary endpoint of best overall response rate (ORR) at 24 weeks after enrollment of the last patient was 85.7% (95% confidence interval [CI]: 63.7-97.0), and the lower limit of the 95% CI exceeded the pre-defined threshold of 25%. The Kaplan-Meier estimate of duration of response rate at 24 weeks was 75% (95% CI: 46-90); 13/18 responders (72.2%) had a sustained response for ≥20 weeks. The median time to response was 4.1 weeks (range 3.90-8.10); ORR was 47.6% at 4 weeks and 75.0% at 24 weeks; best ORR was 80% for joints/fascia, 66.7% for the mouth, and 54.5% for skin. Overall, 57.1% of patients had clinically meaningful symptom improvement at least once; the median duration of symptom improvement was 22.2 weeks (range 4.0-51.3). Corticosteroid dose reductions were recorded for 57.1% of patients. Median failure-free and overall survival were not reached. Treatment-emergent adverse events occurred in 85.7% of patients (most commonly diarrhea, 19.0%), of which 38.1% were drug-related. There were no drug-related discontinuations or deaths. In summary, belumosudil 200 mg once daily as second or subsequent LOT in Japanese patients with steroid-dependent/steroid-resistant cGVHD was effective, with no new safety concerns.

PMID:38934629 | DOI:10.1002/ajh.27424

Pharmaceutics. 2024 May 31;16(6):745. doi: 10.3390/pharmaceutics16060745.

ABSTRACT

Acemetacin (ACM) is a new non-steroidal anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic effects. However, the poor water solubility and gastrointestinal side effects limit its use. Recently, the co-amorphous (CAM) strategy has attracted great interest to improve solubility for poorly water-soluble drugs, and basic amino acids have the potential to protect the gastrointestinal tract. In order to develop a highly efficient and low-toxic ACM formulation, we prepared ACM CAM systems, with basic amino acids (lysine, arginine, and histidine) as co-formers, using a cryo-milling method. The solid-state behaviors of the ACM CAM systems were characterized by polarizing light microscopy, differential scanning calorimetry, and powder X-ray diffraction. Fourier transform infrared spectroscopy and molecular docking were carried out to understand the formation mechanism. Moreover, the gastro-protective effects of ACM CAM systems were evaluated in a rat gastric ulcer model. The results demonstrated that the CAM systems improved the dissolution rates of ACM compared with the neat amorphous counterpart. Furthermore, ACM CAM systems are significantly effective in mitigating the ACM-induced gastric ulcer in rats, and the ulcer inhibition rates were almost 90%. More importantly, this study provided a useful method for mitigating drug-induced gastrointestinal damage and broadened the applications of drug-amino acid CAM systems.

PMID:38931867 | DOI:10.3390/pharmaceutics16060745

Pharmaceuticals (Basel). 2024 Jun 17;17(6):795. doi: 10.3390/ph17060795.

ABSTRACT

BACKGROUND: Drug safety relies on advanced methods for timely and accurate prediction of side effects. To tackle this requirement, this scoping review examines machine-learning approaches for predicting drug-related side effects with a particular focus on chemical, biological, and phenotypical features.

METHODS: This was a scoping review in which a comprehensive search was conducted in various databases from 1 January 2013 to 31 December 2023.

RESULTS: The results showed the widespread use of Random Forest, k-nearest neighbor, and support vector machine algorithms. Ensemble methods, particularly random forest, emphasized the significance of integrating chemical and biological features in predicting drug-related side effects.

CONCLUSIONS: This review article emphasized the significance of considering a variety of features, datasets, and machine learning algorithms for predicting drug-related side effects. Ensemble methods and Random Forest showed the best performance and combining chemical and biological features improved prediction. The results suggested that machine learning techniques have some potential to improve drug development and trials. Future work should focus on specific feature types, selection techniques, and graph-based methods for even better prediction.

PMID:38931462 | DOI:10.3390/ph17060795

Pharmaceuticals (Basel). 2024 May 28;17(6):698. doi: 10.3390/ph17060698.

ABSTRACT

Novel potassium-competitive acid blockers (P-CABs) have emerged as effective acid-suppressive drugs in recent years, replacing proton pump inhibitors (PPIs). We aim to compare the efficacy and safety of P-CABs versus PPIs in the treatment of peptic ulcers with or without Helicobacter pylori (H. pylori) infection. We searched in PubMed, Embase, WOS, Cochrane Library, ClinicalTrials.gov, CNKI, and Wanfang databases (all years up to January 2024). Efficacy and safety outcomes were evaluated using odds ratio (OR) and 95% confidence intervals (CI). The Surface Under the Cumulative Ranking (SUCRA) probabilities were used to rank each intervention. Among 14,056 studies screened, 56 studies involving 9792 participants were analyzed. Vonoprazan demonstrated the best efficacy in ulcer healing rate and H. pylori eradication rate (SUCRA = 86.4% and 90.7%, respectively). Keverprazan ranked second in ulcer healing rates (SUCRA = 76.0%) and was more effective in pain remission rates (SUCRA = 91.7%). The risk of adverse events was low for keverprazan (SUCRA = 11.8%) and tegoprazan (SUCRA = 12.9%), and moderate risk for vonoprazan (SUCRA = 44.3%) was demonstrated. Compared to lansoprazole, vonoprazan exhibited a higher risk of drug-related adverse events (OR: 2.15; 95% CI: 1.60-2.89) and serious adverse events (OR: 2.22; 95% CI: 1.11-4.42). Subgroup analysis on patients with H. pylori-positive peptic ulcers showed that vonoprazan was at the top of the SUCRA rankings, followed by keverprazan. Vonoprazan showed superior performance in peptic ulcers, especially for patients with H. pylori-positive peptic ulcers. However, the risk of adverse events associated with vonoprazan should be noted. Keverprazan has also shown good therapeutic outcomes and has performed better in terms of safety.

PMID:38931366 | DOI:10.3390/ph17060698

Expert Opin Drug Saf. 2024 Jul;23(7):793-796. doi: 10.1080/14740338.2024.2373905. Epub 2024 Jul 3.

NO ABSTRACT

PMID:38922349 | DOI:10.1080/14740338.2024.2373905

Commun Dis Intell (2018). 2024 Jun 24;48. doi: 10.33321/cdi.2024.48.2.

ABSTRACT

This report summarises Australia's spontaneous (passive) surveillance data for adverse events following immunisation (AEFI) for coronavirus disease 2019 (COVID-19) vaccines in 2021 reported to the Therapeutic Goods Administration (TGA). The TGA strongly promoted and facilitated adverse event reporting in preparation for, and during, the COVID-19 vaccine rollout as a core component of the most intensive vaccine safety monitoring ever conducted in Australia. There were 111,348 AEFI reports for COVID-19 vaccines administered in 2021, an annual AEFI reporting rate of 271.4 per 100,000 doses of COVID-19 vaccines administered to people aged ≥ 12 years. The annual AEFI reporting rate for non-COVID-19 vaccines in 2021 was 30.6 per 100,000 doses administered to people of all ages. Overall, the most frequently reported symptoms were headache, adverse events classified as 'gastrointestinal nonspecific symptoms and therapeutic procedures', myalgia, pyrexia and fatigue, which were consistent with common expected adverse events following COVID-19 vaccines used in Australia. The most commonly reported adverse events of special interest were myocarditis and/or pericarditis, followed by thrombosis and thromboembolism, and anaphylaxis. Of all COVID-19 vaccine AEFI reports, 762 (0.7%) included a fatal outcome, of which over 80% were in people aged ≥ 60 years. Thirteen deaths reported in 2021 were assessed as likely to be causally linked to vaccination. This report confirms the value of spontaneous post-marketing vaccine pharmacovigilance, especially in the context of new vaccines using novel vaccine technologies and near whole-of-population pandemic vaccination programs. The most frequently reported AEFI for COVID-19 vaccines were common, mild and temporary (lasting 1 or 2 days), and consistent with clinical trial and active surveillance data. Ongoing safety monitoring detected rare, unexpected conditions, such as myocarditis/pericarditis and thrombosis with thrombocytopenia syndrome (TTS), which were investigated and confirmed as safety signals, resulting in changes to vaccine recommendations and product information. The outcomes of TGA monitoring were published in weekly vaccine safety reports. Overall, COVID-19 vaccine safety monitoring provided critical information on the risks of vaccine related adverse events that enabled decisionmakers to undertake informed risk-benefit assessments.

PMID:38926650 | DOI:10.33321/cdi.2024.48.2

Commun Dis Intell (2018). 2024 Jun 24;48. doi: 10.33321/cdi.2024.48.1.

ABSTRACT

This report summarises Australia's spontaneous surveillance data for adverse events following immunisation (AEFI) for 2021 reported to the Therapeutic Goods Administration (TGA) and describes reporting trends over the 22-year period 1 January 2000 to 31 December 2021. This report excludes AEFI reports featuring pandemic coronavirus disease 2019 (COVID-19) vaccines, which are reported separately. There were 3,452 AEFI reports for non-COVID-19 vaccines administered in 2021, an annual AEFI reporting rate of 13.4 per 100,000 population compared with 14.9 per 100,000 population in 2020. This small decrease in the AEFI reporting rate in 2021 could potentially be related to an increased focus on COVID-19 vaccines and related AEFI, which are not included in this report. AEFI reporting rates for individual vaccines in 2021 were similar to 2020, as were the most commonly reported adverse events. Of the six deaths following vaccination in 2021 reported to the TGA, none were found to have a causal relationship with vaccination.

PMID:38926649 | DOI:10.33321/cdi.2024.48.1

Rheumatol Ther. 2024 Jun 26. doi: 10.1007/s40744-024-00692-z. Online ahead of print.

ABSTRACT

INTRODUCTION: Glucocorticoids (GCs) play a crucial role in the treatment of many rheumatic diseases regarding their anti-inflammatory and immunosuppressive effects. Inappropriate use of GCs can exacerbate GC-related problems besides complex treatment regimens and miscellaneous well-established adverse events. Although several guidelines exist for managing these problems, there is lack of real-life studies evaluating the problems at the patient level. This study aims to identify GC-related problems among patients with rheumatic diseases and address how they have been solved.

METHODS: This prospective follow-up study was conducted between January 2021 and June 2022 at a university rheumatology outpatient clinic and included patients using GCs. A clinical pharmacist assessed patients for possible GC-related problems at baseline, 3 months, and 6 months. Identified problems, their causes, interventions to address these problems, and their outcomes were categorized using the Pharmaceutical Care Network Europe (PCNE v9.1) classification system. The resolution of the problems was evaluated at the patient's next follow-up visit.

RESULTS: A total of 156 patients were included, and 236 GC-related problems were identified in 66% of the patients. Adverse drug events (possible) accounted for the highest proportion of GC-related problems (94.1%), and the most common causes were lack of laboratory monitoring of GC-related adverse events (41.5%) and lack of drug treatment despite existing indications (39.8%). The median cumulative prednisolone dose was higher in patients with GC-related problems (3115 vs. 5455 mg, p = 0.007). The clinical pharmacist suggested 381 interventions: 47.7% (n = 182) at the 'prescriber level', 31.8% (n = 121) at the 'patient level', and 20.5% (n = 78) at the 'drug level'. Of those interventions, 98% were accepted, and 80.1% of the problems were solved.

CONCLUSIONS: This study showed that the prevalence of GC-related problems is high in patients with rheumatic diseases. Integrating clinical pharmacists into the multidisciplinary rheumatology team provides an advantage in effectively identifying and managing GC-related problems at an early stage.

PMID:38926304 | DOI:10.1007/s40744-024-00692-z

Clin Pharmacol Ther. 2024 Jun 25. doi: 10.1002/cpt.3342. Online ahead of print.

ABSTRACT

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia in chronic kidney disease (CKD). Single ascending dose (SAD) and multiple ascending dose (MAD) studies assessed pharmacokinetics (PK), pharmacodynamics (PD), and safety of vadadustat in healthy volunteers. A single-dose, open-label study was conducted in patients with CKD stages 3 and 4 not on dialysis. In the SAD study, 48 healthy adult men (n = 8/cohort) received single doses of vadadustat (80-1,200 mg) or placebo. In the MAD study, 34 healthy adult men (n = 8-9/cohort) received daily vadadustat (500-900 mg) or placebo for 10 days. In the single-dose CKD study, 22 male and female patients with CKD (stage 3: n = 10; stage 4: n = 12) received single doses of vadadustat (500 mg). PK parameters included plasma vadadustat; PD biomarkers were measured, including erythropoietin (EPO) levels, reticulocytes, and others. Plasma vadadustat peaked 3-4 hours after single or multiple dosing in healthy volunteers, with a mean t1/2 of approximately 4.5 hours. In patients with CKD, plasma vadadustat peaked at 5-6 hours, with a mean t1/2 of 7.2 (stage 3) and 8.5 (stage 4) hours. Vadadustat AUC∞ and Cmax increased dose proportionally in SAD and MAD trials. In all trials, EPO concentrations increased in a dose-related manner and returned approximately to baseline by 24 hours. Adverse events were mild and considered not study drug related. The PK and PD results of these studies were utilized for further clinical development of vadadustat for treatment of anemia in CKD patients.

PMID:38924087 | DOI:10.1002/cpt.3342