Expert Opinion on Pharmacotherapy最新文献

Introduction: Mutation-specific disease modifying drugs such as the triple combination Elexacaftor/Tezacaftor/Ivacaftor (ETI), are associated with significant improvements in physical health. Reproductive health and a pursuit of parenthood are of increased relevance; a dramatic increase in childbirth rates for females with CF has already been observed.

Areas covered: Fertility in males and females with CF, and any subsequent impact of CFTR modulator therapy, is reviewed. The potential impacts of maternal use of CFTR modulator drugs on offspring health are considered, as constituent components have been found in fetal circulation in animals and humans, and the implications for maternal continuation or cessation of treatment. Clinical data are reassuring, although cases of lens opacities, and missed CF diagnoses due to false negative newborn screening results have been reported.

Expert opinion: More research and high-quality evidence are needed to characterize maternal, fetal and long-term offspring outcomes following CFTR modulator therapy use during pregnancy and breastfeeding. There is a potential therapeutic impact of targeting CFTR-related organ dysfunction in CF-fetuses via maternal-administration of CFTR modulators. Additionally, any consequences of CFTR-modulation in heterozygote carrier infant warrants urgent and collective consensus regarding ethical and clinical research programs to evaluate this discrete population.

Introduction: Pharmacological and other treatments for binge eating disorder (BED) predate its inclusion as the third main eating disorder in the 2013 DSM-5. Currently, second in line to psychological therapy are psychotropics such as antidepressants, anticonvulsants and stimulants.

Areas covered: This review summarizes the evidence and emerging evidence on the pharmacotherapies for BED and their potential for wider use.

Expert opinion: Pharmacotherapy has utility as an alternative or adjunctive treatment for those exhibiting insufficient response to, or not preferencing, psychological interventions. Medications may also benefit individuals with BED and other co-occurring mental health conditions, such as depression and attention deficit hyperactivity disorder. In addition, there are several agents (e.g. glucagon like peptide-1 receptor agonists and the combination of naltrexone-bupropion) displaying promise for weight and binge eating reduction in people with BED and high BMI. Future research should extend the understanding of the role of medication in BED, focusing on their sustained effects over time, when and if they may be ceased, their effectiveness in people with adequate weight, and the risks associated with weight loss in those with BED and high weight.

Introduction: Despite a rising incidence, biliary tract cancers (BTCs) are still considered a rare tumor entity. The disease's subtle clinical presentation and lack of effective early detection strategies often lead to a diagnosis at an advanced or unresectable stage, where curative options are limited.

Areas covered: This review provides an overview of current systemic therapies and emerging novel approaches for BTC. For decades, the combination of gemcitabine with cisplatin (GemCis) has been the standard of care for palliative treatment. However, since 2020, the diagnostic and therapeutic landscape for BTC has evolved considerably, not only in the first-line setting but also beyond, driven by the development of clinical trials exploring immunotherapy and molecularly targeted agents. Due to the high frequency of targetable genetic alterations in BTC patients, there is a growing emphasis on obtaining tissue or liquid biopsy samples to identify markers like microsatellite instability and other actionable oncogenic driver genes.

Expert opinion: Early initiation of systemic therapies in combination with multimodal approaches is essential for maximizing survival outcomes in patients with BTC.

Introduction: Liposarcomas are malignancies of adipocytic lineage and represent one of the most common types of soft tissue sarcomas. They encompass multiple histologies, each with unique molecular profiles. Treatment for localized disease includes resection, potentially with perioperative radiation or systemic therapy. Treatment for unresectable or metastatic disease revolves around palliative systemic therapy, for which improved therapies are urgently needed.

Areas covered: We reviewed the literature on novel therapies in clinical development for liposarcomas within the past 5 years and discuss their potential impact on future treatment strategies.

Expert opinion: Understanding of the molecular characteristics of liposarcoma subtypes has led to testing of several targeted therapies, including inhibitors of amplified gene products (CDK4 and MDM2) and upregulated proteins (XPO1). Immuno-oncology has played an increasing role in the treatment of liposarcomas, with checkpoint inhibition showing promise in dedifferentiated liposarcomas, and immune therapies targeting cancer testis antigens NY-ESO-1 and MAGE family proteins poised to become an option for myxoid/round cell liposarcomas. The search for novel agents from existing classes (tyrosine kinase inhibitors) with efficacy in liposarcoma also continues. Combination therapies as well as biomarker identification for patient selection of therapies warrant ongoing exploration.

Introduction: Over a half century ago, a component of glucagon was found to have potent gastrointestinal effects. Shortly after proglucagon was sequenced, its component peptides were characterized, and glucagon-like polypeptide-2 (GLP-2) was noted to have the most potent intestinotrophic properties improving fluid and electrolyte balance in experimental animals and humans.

Areas covered: Glucagon-like polypeptide-1 (GLP-1) slows small intestinal motility more effectively, but its intestinotrophic properties are weaker. GLP-2's properties prompted study of its effects upon function of the surgically foreshortened small intestine, but its short half-life limited its usefulness, but the subsequent discovery that substitution of glycine for alanine at the second position of the molecule's N-terminus could lengthen its half-life to 2.5 hours, established efficacy in short bowel management with a single daily subcutaneous injection. Both adult and pediatric studies have shown reduced parenteral nutrition requirements and establishment of enteral autonomy for some patients. More recently, ultralong acting GLP-2 analogs with half-lives of 70-80 hours can improve gastrointestinal function in surgically foreshortened bowel with only one injection every three to seven days.

Expert opinion: Future research is likely to focus upon the potential complementary role of GLP-1 and GLP-2 in treating short bowel syndrome.

Introduction: Endometriosis affects 5% to 10% of reproductive age women and may be associated with severely painful and debilitating symptoms as well as infertility. Endometriosis involves hormonal fluctuations, angiogenesis, neurogenesis, vascular changes and neuroinflammatory processes. The neuroinflammatory component of endometriosis makes it a systemic disorder, similar to other chronic epithelial inflammatory conditions.

Areas covered: Inflammatory mediators, mast cells, macrophages, and glial cells play a role in endometriosis which can result in peripheral sensitization and central sensitization. There is overlap between chronic pelvic pain and endometriosis, but the two conditions are distinct. Effective treatment is based on a personalized approach using a variety of pharmacologic and other treatment options.

Expert opinion: Hormonal therapies are a first-line approach, but endometriosis is a challenging condition to manage. 'Add-back' hormonal therapy has been effective. Painful symptoms are likely caused by the interplay of multiple factors and there may be a neuropathic component. Analgesics and anticonvulsants may be appropriate. A holistic approach and multimodal treatments are likely to be most effective. In addition to pharmacologic treatment, there are surgical and alternative medicine options. Endometriosis may also have a psychological component.

Introduction: The concept that children are therapeutic orphans emerged in the 1960s, triggering eventually worldwide legislation to facilitate pediatric studies, called 'Pediatric Drug Development (PDD).' However, PDD's true aim is not better medicines for children but labels in minors; minors are not another species.

Areas covered: Absorption, distribution, metabolism, and excretion (ADME) differ in preterm newborns, but babies mature. With the exception of neonatology, the justifications for clinical, pharmacokinetic, and safety studies were and are exaggerated.

Expert opinion: PDD reflects an artificial regulatory challenge, reflecting mankind's transition into a world of effective new drugs compared to previous millennia when only materials taken from nature were available. Minors need dose assessment and proof of safety; there is a tendency to exaggerate the scope of pharmacokinetic and safety studies before and after the eighteenth birthday, potentially motivated not by industry's greed, but by researchers' desire for funding and regulatory authorities' desire for recognition, specifically as since 2007 the European Medicines Agency (EMA) augmented and expanded PDD: a new type of conflict of interest in medicines' administration and mainstream medical science.

Introduction: Pneumonia remains a significant global health challenge due to its high prevalence and mortality rate, and challenging treatment. This review explores the best strategies to optimize the antibiotic therapy for pneumonia in critically ill patients, focusing on pharmacokinetics, pharmacodynamics, and therapeutic data.

Areas covered: A review of scientific publications on severe pneumonia highlights the challenges of optimizing antibiotic use to improve lung diffusion, bacterial killing, and achieving PK/PD targets, emphasizing the need to understand microbiological epidemiology and MIC breakpoints. Key strategies like nebulization, therapeutic drug monitoring, and emerging technologies such as ELF TDM and nanomaterial-based drug delivery systems are essential for optimizing PK/PD outcomes and addressing antimicrobial resistance.

Expert opinion: Improving our understanding of pulmonary pharmacokinetics and optimizing their tissue diffusion are instrumental for achieving precision antibiotic therapy for severe pneumonia. By addressing current limitations and embracing interdisciplinary collaboration, we can pave the way for more efficient personalized approaches in infectious disease management.

Introduction: Androgen deprivation therapy consists of the cornerstone of prostate cancer medical treatment. Until recently, castration of hypothalamus-hypophysis-gonadal axial was based on injectable medical agents. A few years ago, a novel per os administered GnRH antagonist was approved leading testosterone to castration level. Relugolix was approved by FDA in 2020, and it is the first per os administered GnRH antagonist. The present study is a literature review of the efficacy, safety and clinical perspectives of relugolix.

Areas covered: A literature narrative review was conducted using PubMed/MEDLINE, Scopus, and the Cochrane library. Studies written in English language, considering efficacy, safety and cost-effectiveness of relugolix compared with other androgen deprivation therapies were included in the review.

Expert opinion: Recent studies have examined efficacy of relugolix revealing a testosterone suppression percentage of 78.4% after 48 weeks from treatment initiation. Moreover, relugolix has been associated with less major cardiovascular events as well as better rate of testosterone recovery after treatment completion compared with the GnRH agonists. However, there is no head-to-head trial comparing relugolix with injectable GnRH antagonists, so far. As a result, a trial comparing the methods of antagonists' administration should be performed in the future.

Introduction: Gastroesophageal reflux disease (GERD) is a common debilitating chronic disease presenting in two main forms based on esophageal mucosal appearance, the erosive reflux disease (ERD) and the non-erosive reflux disease (NERD). Acid secretion is a key factor in the disease pathogenesis and management. Potent acid-suppressant drugs have been manufactured since the mid of 1970s, initially with histamine-H₂-receptors antagonists, and later, inhibitors of the proton pump (H⁺-K⁺-ATPase).More recently, potassium-competitive acid blockers (p-CABs), particularlyVonoprazan, have been introduced. Vonoprazan has shown high efficacy and safety profiles and exhibits several advantages that allow to overcome shortcomings of proton pump inhibitors (PPIs).

Areas covered: In this review, we provide an updated summary of Vonoprazan pharmacodynamics and its role in clinical practice for the management of erosive esophagitis and GERD-related heartburn. Moreover, we discuss characteristics of Vonoprazan that allow to bypass some limitations of the older PPIs.

Expert opinion: Long-term safety and efficacy of Vonoprazan have already been demonstrated for the induction and maintenance of ERD, preventing nocturnal acid breakthrough, reducing reflux symptoms in non-responder to standard therapy. Ongoing and future studies are expected to further elucidate its long-term benefits and potential applications in other acid-related disorders.