Expert Opinion on Pharmacotherapy最新文献

Introduction: Musculoskeletal (MSK) pain remains a prevalent cause of disability and healthcare burden. Acetaminophen is widely used for its safety and accessibility, but its positioning within multimodal pain strategies varies across healthcare systems.

Areas covered: This expert-based position paper aims to offer practical reflections on the role of acetaminophen in managing acute MSK pain, based on the experience of a multidisciplinary panel of Italian clinicians. The manuscript addresses current prescribing practices, organizational barriers, and opportunities for optimizing acetaminophen use across clinical settings.

Expert opinion: Rather than presenting a systematic review, this paper synthesizes experiential knowledge and clinical reasoning drawn from routine practice. The insights may be particularly relevant for healthcare systems undergoing reform or seeking to strengthen pain management strategies for managing acute musculoskeletal pain across all age groups.

Background: Sickle cell disease (SCD) is a chronic hemoglobinopathy marked by hemolytic anemia, VOEs, and multiorgan complications. Mitapivat, an oral Pyruvate Kinase (PK) activator, has emerged as a potential disease-modifying therapy. This systematic review assessed the efficacy and safety of Mitapivat in individuals with SCD.

Methods: A systematic literature search was conducted from different search engines from inception. The review followed PRISMA 2020 guidelines, and the protocol was registered in PROSPERO [CRD420251000061]. RCTs and NRSIs evaluating Mitapivat monotherapy were included. ROB was assessed. A narrative synthesis was undertaken due to heterogeneity.

Results: One RCT and two NRSIs involving 156 participants were included. Reduced annualized Vaso-occlusive episodes (VOE) rates compared to placebo by 51.6% (50 mg) and 70.0% (100 mg). Statistically significant hemoglobin response was observed in 46.2%-56% of participants. Increased markers of hemolysis and reduced transfusion requirements in Mitapivat groups were reported. However, SAEs were low, in 8%-19% of Mitapivat recipients.

Conclusions: Preliminary evidence suggests Mitapivat demonstrates potential to reduce VOEs, improve hemoglobin levels, and decrease hemolysis with an acceptable safety profile. However, small sample sizes, lack of functional outcomes, and limited follow-up warrant cautious interpretation. Further large-scale RCTs are needed to validate these findings and establish a long-term benefit-risk balance.

Introduction: The process of diagnosing patients with epilepsy and selecting the optimal drug remains a significant challenge. Broad-spectrum antiseizure medications (ASMs) treat focal and generalized seizures without worsening other seizure types, making them the drug of choice when the exact seizure classification for patients is unknown. Cenobamate, an ASM approved for the treatment of adult focal seizures, has demonstrated strong efficacy, including high rates of seizure freedom. Evidence suggests that cenobamate has potential to be a broad-spectrum ASM.

Areas covered: Considerations for the selection of broad- versus narrow-spectrum ASMs are discussed and an overview of preclinical, clinical, and real-world evidence relating to cenobamate as a potential broad-spectrum ASM is presented.

Expert opinion: Combined evidence from preclinical data, clinical study data, and real-world evidence may indicate that cenobamate may be a broad-spectrum ASM. Evidence is accumulating regarding the utility of cenobamate in treating primary generalized tonic-clonic (PGTC) and seizures associated with developmental epileptic encephalopathies such as Lennox-Gastaut syndrome and Dravet syndrome. Results from the ongoing cenobamate trial in patients with idiopathic generalized epilepsy will determine the efficacy of cenobamate for the treatment of PGTC seizures.

Introduction: Over the past two decades, the global burden of multidrug-resistant organisms has grown steadily, representing a major concern in pediatric healthcare. Among these, hospital-acquired infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) are particularly challenging to manage in children, due to limited therapeutic options and the scarcity of pharmacokinetic data in the pediatric population. Although several new antibiotics - especially β-lactams combined with β-lactamase inhibitors - have become available, uncertainties remain regarding their optimal use in pediatric populations.

Areas covered: This review explores potential treatment strategies for MDR-GNB infections in children, with a focus on pathogens listed in the WHO priority list. It examines the pharmacological properties of both traditional and newly approved antibiotics, assessing their role and applicability in pediatric clinical practice.

Expert opinion: New β-lactam antibiotics, alone or in combination with β-lactamase inhibitors - such as ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol - have emerged as preferred options for treating carbapenem-resistant and difficult-to-treat Gram-negative infections. Therapy should be guided by pathogen identification and resistance mechanisms, as susceptibility profiles vary widely based on the resistance-mechanism. Older agents like colistin, fosfomycin, nitrofurantoin, and aminoglycosides remain important, particularly in resource-limited settings, despite concerns over toxicity and safety.

Introduction: Adult-type IDH-mutant diffuse gliomas grade 2 are rare tumors mainly affecting young patients, classified by WHO 2021 into IDH-mutant astrocytomas and IDH-mutant 1p/19q codeleted oligodendrogliomas. IDH-mutant grade 2 gliomas are slowly growing tumors; however, they grow continuously, and almost all patients will ultimately recur. Surgical resection is the first option, followed by observation with MRI in low-risk patients and radio-chemotherapy in high-risk patients. Early clinical trials and phase 3 INDIGO trial have demonstrated the efficacy of vorasidenib, a dual IDH1/2 inhibitor, in prolonging imaging-based progression-free survival and time-to-next-intervention.

Areas covered: This review covers the following areas: importance of surgical resection, traditional treatments after surgery, mechanisms of IDH mutations and IDH inhibitors in preclinical models, early clinical studies on ivosidenib and vorasidenib, INDIGO trial, the future role of vorasidenib, open issues beyond INDIGO trial, and novel IDH targeting strategies.

Expert opinion: IDH1/2 mutations are ideal targets of therapy and early clinical studies and INDIGO phase 3 trial confirmed the clinical efficacy of vorasidenib. Long-term follow-up is needed to better define the efficacy across different subgroups of patients. Overall, vorasidenib will replace observation with MRI for low-risk patients and allow to delay radiotherapy and chemotherapy and their adverse effects.

Background: Clinical trials have shown semaglutide effective in mitigating risks associated with type 2 diabetes and chronic kidney disease. However, semaglutide's real-world effectiveness and long-term outcomes are not fully established.

Research design & methods: Using 2019-2024 Kythera Labs data, an external control arm was created using criteria identified in the FLOW clinical trial. Primary outcomes were major kidney disease events (kidney failure onset and ≥ 50% reduction in estimated glomerular filtration rate from baseline). Propensity score matching and Cox regression were used to determine risk-adjusted outcomes.

Results: The control arm (n = 896,257) was compared with the clinical trial cohort (n = 1,766). After propensity score matching on age, sex, socioeconomic status, and comorbidities, semaglutide treatment was associated with a 26% reduction in primary event risk compared with the comparator group (702 vs 1,068 events; HR: 0.74; 95% CI, 0.67-0.81), consistent with the 24% risk reduction observed in the clinical trial.

Conclusion: Semaglutide treatment was linked to a significantly lower risk of clinically relevant renal outcomes. Our findings provide robust real-world evidence that supports the FLOW trial results regarding the renoprotective effects of semaglutide, highlighting its promise as an effective therapeutic option for managing renal complications.

Introduction: Hereditary angioedema (HAE) is a genetic rare condition characterized by recurrent attacks of swelling that might be potentially life-threatening. Recurrence and severity of attacks may impact psychological life, expectations and productivity. We aim to review the state-of-the-art of HAE preventive and on-demand treatment of non-biologic drugs, providing a perspective of their personalized use and development.

Areas covered: This literature analysis integrates international guidelines and clinical trial data on on-demand therapies and short-/long-term prophylaxis. Modern medications should be considered and personalized for HAE patients to provide benefits compatible with patients' lifestyles, preferences, and experiences. Accordingly, a new era toward oral formulations has begun starting from berotralstat, with a consistent number of drugs under development.

Expert opinion: All HAE patients should have an effective on-demand treatment available in case of attacks. Long-term prophylaxis (LTP) should be considered and individualized for all patients at every visit, following a shared decision-making approach to optimize disease control while limiting side effects. Parenteral administration of LTP is associated with treatment complexities and barriers. Oral treatment could address practical needs for HAE patients both in preventive and on-demand setting, avoiding injection-related side effects, reducing treatment burden, and improving quality of life. In the next future, significant advances in HAE therapeutics could result from gene therapy.

Introduction: Primary biliary cholangitis (PBC) is a chronic, cholestatic liver disease, is associated with fatigue and pruritus and can progress to cirrhosis if left untreated. Ursodeoxycholic acid (UDCA) has been the mainstay of therapy for over 40 years. However, 30-40% of PBC patients do not adequately respond to UDCA or have risk factors for disease progression and require second-line treatment.

Areas covered: Recent international cohort analyses have provided new insights that enable early identification of high-risk PBC patients and suggest that stricter treatment goals may lower mortality and reduce the need for liver transplantation. Alongside established second-line agents, several promising substances have progressed to phase 2 and 3 trials. Notably, seladelpar and elafibranor, two selective agonists of peroxisome proliferator-activated receptors, achieved high rates of biochemical response and good tolerability, leading to their recent approval for second-line treatment of PBC. Moreover, dedicated clinical trials addressed fatigue and pruritus, the two main symptoms of PBC.

Expert opinion: Personalized treatment approaches for PBC are both feasible and essential to improve biochemical response, extend transplant-free survival and alleviate symptom burden. Well-tolerated novel therapies are poised to reshape the treatment landscape in the near future.

Introduction: Lennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizures, cognitive impairments, and distinctive EEG patterns. Given its profound impact on patients' quality of life, developing effective pharmacotherapies remains a critical clinical challenge.

Areas covered: This review examines FDA-approved medications for LGS (clonazepam, felbamate, lamotrigine, topiramate, rufinamide, clobazam, cannabidiol, and fenfluramine), commonly used off-label antiseizure medications, emerging treatments in clinical trials, and precision therapeutics targeting etiology-specific mechanisms. The literature encompasses randomized controlled trials, observational studies, and expert consensus statements on treatment approaches and challenges.

Expert opinion: Despite therapeutic advances, most patients with LGS lack individualized treatment plans with regular adjustments. Current management requires a multimodal approach integrating pharmacotherapy with other interventions. Future progress depends on improved natural history studies, standardized data collection, advanced preclinical models, innovative trial designs, and addressing healthcare inequities. While emerging precision therapies targeting genetic causes show promise, the field urgently needs better strategies to optimize existing treatments while developing disease-modifying approaches that address both seizures and non-seizure outcomes.