Expert Review of Clinical Pharmacology最新文献

Introduction: Sickle cell disease is an inherited disorder characterized by hemoglobin S polymerization leading to vaso-occlusion and hemolytic anemia. These result in a variety of pathological events, causing both acute and chronic complications. Millions around the world are affected by sickle cell disease with predominance in sub-Saharan Africa. Hydroxyurea was the first drug approved for use in sickle cell disease to reduce the occurrence of painful crises and blood transfusions in patients with frequent, moderate to severe painful crises.

Areas covered: With the development of new therapeutics, the role of hydroxyurea is evolving. This narrative review aims to provide clinical data, safety information, and supplementary evidence for the role of hydroxyurea in the current era of sickle cell disease. A comprehensive literature search of databases, including PubMed and Cochrane Library, was conducted from 1963 to 2024.

Expert opinion: Even though new medications have been approved for sickle cell disease, hydroxyurea remains the gold standard. Hydroxyurea is not only a disease modifier but it has additional clinical benefits, it is affordable, and its longevity has prompted expanded research in areas such as underutilization and pharmacogenomics. As the treatment landscape evolves, hydroxyurea's long-standing record of efficacy and safety continues to support its role as a key agent in disease management.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive-fibrosing lung disease with a median survival of less than 5 years. Currently, two agents, pirfenidone and nintedanib are approved for this disease, and both have been shown to reduce the rate of decline in lung function in patients with IPF. However, both have significant adverse effects and neither completely arrest the decline in lung function.

Areas covered: Thirty experimental agents with unique mechanisms of action that are being evaluated for the treatment of IPF are discussed. These agents work through various mechanisms of action, these include inhibition of transcription nuclear factor k-B on fibroblasts, reduced expression of metalloproteinase 7, the generation of more lysophosphatidic acids, blocking the effects of transforming growth factor ß, and reducing reactive oxygen species as examples of some unique mechanisms of action of these agents.

Expert opinion: New drug development has the potential to expand the treatment options available in the treatment of IPF patients. It is expected that the adverse drug effect profiles will be more favorable than current agents. It is further anticipated that these new agents or combinations of agents will arrest the fibrosis, not just slow the fibrotic process.

Background: Older people (i.e. ≥40 years) with intellectual disability have unique medication needs and may experience high levels of potentially inappropriate prescribing. Despite the availability of tools to optimize older adults' prescriptions, there is no comprehensive tool specifically for use in older adults with intellectual disability. We aimed to develop a tool for this purpose: Optimizing Pharmaco-Therapy and Improving Medication for Ageing with Intellectual Disability (OPTIMA-ID).

Research design and methods: A draft tool was developed based on literature review and clinical expertise. Focus groups with healthcare professionals and people with intellectual disability were conducted to refine the tool. The tool was presented electronically to an expert panel for Delphi validation. Median level of agreement and 75^th percentile values were used to establish if consensus was reached. Criteria were accepted, rejected, revised or removed to develop the final tool.

Results: Following two Delphi rounds, consensus on the content of OPTIMA-ID was reached for 67 prescribing criteria, 63 of which were agreed upon after Round 1 and a further 4 criteria accepted after Round 2.

Conclusions: OPTIMA-ID contains 67 criteria that can optimize medications for older people with intellectual disability. Its effectiveness, feasibility and impact on patient outcomes need to be established.

Background: Cognitive dysfunction is a non-motor manifestation of Parkinson's disease (PD). We aimed to determine the frequency and patterns of cognitive dysfunction in treated patients with PD and their predictors.

Research design and methods: This study included 80 patients (male = 48; female = 32) and 30 healthy individuals. They underwent neuropsychiatric evaluations. Measurements included Beck's depression inventory - II (BDI-II), mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA).

Results: Patients had mean age of 55.56 ± 9.06 yrs, duration of PD of 4.86 ± 2.71 yrs and Hoehn and Yahr Scoring of 2.19 ± 0.89. They were on levodopa/carbidopa therapy and adjuvant therapy with benztropine mesylate, an anticholinergic drug, (n = 51) or amantadine sulfate, a dopaminergic drug, (n = 29). Sixteen (20%) had moderate depressive symptoms. Mild and moderate cognitive impairments were reported in 38.8% and 28.8% (by MMSE) and 46.3% and 31.3% (by MoCA). Patients had lower global cognitive scoring (p = 0.0001) and scorings of different cognitive functions (naming, attention, language, abstraction, memory and orientation) than controls. Patients treated with benztropine had lower cognition than with amantadine. Correlation analyses showed that lower cognition was only associated with chronic PD and its treatment (p = 0.0001).

Conclusions: Cognitive dysfunction is common with PD (77.5%) particularly with anticholinergic drugs. De-prescription of anticholinergics is recommended for patients with PD.

Introduction: Standard treatment for patients with locally advanced rectal cancer (LARC) includes neoadjuvant chemoradiotherapy (nCRT) with fluoropyrimidines, followed by surgical excision. The newly introduced therapeutic strategies propose intensified regimens or more conservative approaches based on risk stratification algorithms that currently include clinicoradiological criteria but not molecular variables. How to better stratify patients is a burning clinical question, and pharmacogenomics may prove useful in identifying new genetic markers that could be incorporated into clinical algorithms to personalize nCRT. An emerging area could be the evaluation of somatic mutations as potential genetic markers that correlate with patient prognosis. Tumor mutations in the RAS/BRAF genes, as well as microsatellite instability (MSI) status, are currently used in treatment selection for colorectal cancer (CRC); however, their clinical value in LARC is still unclear.

Area covered: This literature review discusses the relevant findings on the prognostic role of mutations in the key oncogenes RAS, KRAS, BRAF, PIK3CA, SMAD4 and TP53, including MSI status in LARC patients treated with nCRT.

Expert opinion: KRAS proved to be the most promising marker, consistently associated with poorer disease-free survival and overall survival. Therefore, KRAS could be a good candidate for integration into the risk stratification algorithm to develop a personalized treatment.

Background: The US Food and Drug Administration (USFDA) communicates new drug safety concerns through drug safety communications (DSCs) and medication guides (MGs), which often challenge patients with average reading abilities due to their complexity. This study assesses whether large language models (LLMs) can enhance the readability of these materials.

Methods: We analyzed the latest DSCs and MGs, using ChatGPT 4.0© and Gemini© to simplify them to a sixth-grade reading level. Outputs were evaluated for readability, technical accuracy, and content inclusiveness.

Results: Original materials were difficult to read (DSCs grade level 13, MGs 22). LLMs significantly improved readability, reducing the grade levels to more accessible readings (Single prompt - DSCs: ChatGPT 4.0© 10.1, Gemini© 8; MGs: ChatGPT 4.0© 7.1, Gemini© 6.5. Multiple prompts - DSCs: ChatGPT 4.0© 10.3, Gemini© 7.5; MGs: ChatGPT 4.0© 8, Gemini© 6.8). LLM outputs retained technical accuracy and key messages.

Conclusion: LLMs can significantly simplify complex health-related information, making it more accessible to patients. Future research should extend these findings to other languages and patient groups in real-world settings.

Introduction: Despite the availability of several treatments for psoriasis (PsO), factors influencing the persistence of secukinumab (SEC) therapy remain inadequately understood. This study aimed to identify predictors of SEC persistence in PsO.

Methods: A retrospective analysis was conducted on 109 PsO patients who received SEC treatment at least 1 year. Patients were categorized based on continued or discontinued SEC therapy.

Results: Among the 109 patients, 64 continued SEC treatment while 45 discontinued. Univariate analysis demonstrated that PsA presence and previous biologic therapy use increased the risk of SEC discontinuation 3.56- and 2.33-fold (p = 0.001, %95 CI: 1.66-7.65 and p = 0.032, %95 CI: 1.08-5.04, respectively). Additionally, the risk of SEC discontinuation is 57% higher in patients with a body mass index (BMI) above 26.5 compared to those with a BMI below 26.5 (p = 0.016, %95 CI: 0.22-0.85). Additionally, patients with PsO onset age below 26.5 years were found to have a 2.93-times higher risk of discontinuing SEC compared to those with PsO onset age above 26.5 years (p = 0.004, %95 CI: 1.40-6.13).

Conclusion: PsA presence, previous biologic therapy experience, BMI, and PsO onset age were identified as independent predictors of SEC discontinuation. These findings underscore the importance of personalized treatment strategies for PsO patients receiving SEC therapy.

Introduction: Epilepsy is a disorder of recurrent, unprovoked seizures affecting approximately 15 million individuals of childbearing potential worldwide. Patients with epilepsy rely on regular daily therapy with antiseizure medications (ASMs). Furthermore, ASMs are also prescribed for other neuropsychiatric indications (e.g. bipolar disorder, pain, migraines) with over 2% of the pregnancies in the United States involving prenatal exposure to ASMs.

Areas covered: ASM concentrations are affected by hormonal and physiological changes in pregnancy, including increases in renal and hepatic blood flow, decreased protein binding, and changes in enzyme activity. Clearance changes typically reverse within a few weeks after delivery. During pregnancy, many ASMs, such as lamotrigine, levetiracetam, and oxcarbazepine, should have serum concentrations monitored and doses increased to maintain the individualized target range for seizure control. ASMs metabolized via glucuronidation, primarily lamotrigine, undergo marked increases in clearance throughout pregnancy, requiring about 3-fold the pre-pregnancy daily dose by delivery. Postpartum, ASM doses are usually decreased over several weeks to prevent drug toxicity.

Expert opinion: In the future, the development of a physiologically-based pharmacokinetic model for various ASMs may enable empiric dose adjustments in pregnancy without the difficulties of frequent therapeutic drug monitoring.