Drugs最新文献

Type 1 diabetes mellitus (T1DM) is characterized by the progressive, autoimmune-mediated destruction of β cells. As such, restoring immunoregulation early in the disease course is sought to retain endogenous insulin production. Nevertheless, in the more than 100 years since the discovery of insulin, treatment of T1DM has focused primarily on hormone replacement and glucose monitoring. That said, immunotherapies are widely used to interdict autoimmune and autoinflammatory diseases and are emerging as potential therapeutics seeking the preservation of β-cell function among those with T1DM. In the past 4 decades of diabetes research, several immunomodulatory therapies have been explored, culminating with the US Food and Drug Administration approval of teplizumab to delay stage 3 (clinical) onset of T1DM. Clinical trials seeking to prevent or reverse T1DM by repurposing immunotherapies approved for other autoimmune conditions and by exploring new therapeutics are ongoing. Collectively, these efforts have the potential to transform the future of diabetes care. We encapsulate the past 40 years of immunotherapy trials, take stock of our successes and failures, and chart paths forward in this new age of clinically available immune therapies for T1DM.

Acute pain, defined as short-term pain arising from injury or other noxious stimuli, affects patient outcomes, quality of life, and healthcare costs. Safe, effective treatment of acute pain is essential in preventing increased morbidity, mortality, and the transition to chronic pain. In this review, we explore some of the latest therapeutic agents, formulations, combinations, and administration routes of drugs emerging in clinical practice in the USA for the treatment of acute pain. These agents include VX-548 (Suzetrigine), Cebranopadol, AAT-076, Combogesic intravenous (IV), sublingual ketamine, XG004 (naproxen/pregabalin conjugate), and HTX-011 (Zynrelef). We analyze the pharmacodynamics, pharmacokinetics, development status, and clinical implications of these drugs, emphasizing the importance of finding an agent that provides both a strong safety profile and effective relief from acute pain. Our findings show promise but also highlight the need for further large-scale research to allow these drugs to be utilized in a clinical context for patients experiencing acute pain.

A small number of patients with chronic myeloid leukemia (CML) either present with or progress to the accelerated phase (AP) or blast phase (BP). This occurs in approximately 4-7% of patients with CML. Most patients who progress to BP-CML are of myeloid lineage, while approximately 30% are of lymphoid lineage. Due to the rarity of this condition, there are no large or randomized trials that can inform clinical decisions. Most data are from retrospective chart reviews or data from old studies when tyrosine kinase inhibitors (TKIs) were initially approved. In addition, the definition of these categories has been in continuous flux over the last 20 years, making applicability of data even more confusing. In some classifications, the cutoff is 30% blasts for the definition of BP-CML, while in others a cutoff of 20% is used. In addition, more recently the World Health Organization (WHO) classification omitted the accelerated phase and recognized only a two-phase disease, while the International Consensus Classification retained a three-phase definition and retained the accelerated phase. Therapy for patients with AP/BP-CML depends on several factors, including prior therapy, BCR::ABL1 mutation, co-morbidities, cell lineage, and eligibility for allogeneic stem cell transplantation (alloHCT). Patients with AP-CML at presentation have a relatively favorable prognosis and may not need alloHCT if they respond appropriately to therapy. For patients with AP-CML who progressed while on TKI therapy or those with BP-CML, alloHCT is considered the only curative therapy. Our goal is to review the available data on the therapy of patients with AP-CML and BP-CML.

The introduction of tumor necrosis factor inhibitors has led to a paradigm shift in the management of inflammatory bowel disease (IBD). The subsequent introduction of both anti-integrins and cytokine blockers has since expanded the biologic armamentarium. However, immunogenicity, defined as the production of anti-drug antibodies (ADAs) to the prescribed biopharmaceutical, means a significant fraction of patients exposed to biologic agents will experience a secondary loss of response to one or more of the drugs. In clinical settings, immunogenicity may be caused by several factors, both patient related (e.g., underlying chronic disease, systemic immune burden, including previous biologic therapy failure, and [epi]genetic background) and treatment related (e.g., dose and administration regimens, drug physical structure, photostability, temperature, and agitation). Here, we outline these elements in detail to enhance biopharmaceutical delivery and therapy for patients with IBD. Moreover, concurrent immunomodulator medication may reduce the risks of ADA generation, especially when using the chimeric drug infliximab. Summarizing the latest developments and knowledge in the field, this review aims to provide strategies to prevent ADA production and information on managing non-responsiveness or loss of response to biologics. Better understanding of the molecular mechanisms underlying the formation of ADAs and the critical factors influencing the immunogenicity of biopharmaceuticals may lead to improved health outcomes in the IBD community that may benefit both the individual patient and society through lower healthcare expenses.

Objectives: To investigate the safety profiles and clinical outcomes in a continuous cohort of tuberculosis (TB) patients from a clinical referral centre in Germany receiving self-administered outpatient parenteral antimicrobial therapy (sOPAT).

Methods: We conducted a retrospective observational cohort study of patients receiving sOPAT after discharge from the Research Center Borstel in Germany between January 2015 and December 2020. Data were extracted from medical records.

Results: In the observation period, 150 patients received parenteral antibiotics at the Research Center Borstel. Of these, 89 received sOPAT via a port catheter and were further analysed. The majority were male (n = 59, 66.3%), with a median age of 33.6 years (interquartile range-IQR 26.2-42.8). Most patients had multidrug-resistant (MDR)-TB (n = 56, 62.9%) or pre-extensively drug resistant (pre-XDR)-TB (n = 21; 23.6%). Fifty-eight (65.2%) patients received one and 24 patients (27.0%) received two parenteral drugs, most commonly capreomycin (n = 53, 59.6%) and meropenem (n = 44, 49.4%). The median duration of sOPAT was 7.4 months (IQR 5.2-17.2). In total, 71,128 intravenous drug administrations were recorded. One patient died of TB while another patient was lost to follow-up. Sixty-two (69.7%) patients completed the sOPAT regimen, the most common reason for premature discontinuation was adverse drug events (n = 12, 13.5%). There were eight (9.0%) port-related complications requiring port explantation (bloodstream infections: n = 6, local infection: n = 1, port thrombosis: n = 1).

Conclusions: In selected patients requiring long-term intravenous anti-TB therapy, sOPAT is a feasible treatment option with a low risk of complications when adequate infrastructure and training are in place.

Arimoclomol (MIPLYFFA™), an oral small molecule that crosses the blood brain barrier and is thought to upregulate CLEAR (Coordinated Lysosomal Expression and Regulation) network genes and improve lysosomal function, is being developed by Zevra Therapeutics Inc., for the treatment of neurological manifestations of Niemann-Pick disease type C (NPC). In September 2024, arimoclomol was approved for use in combination with miglustat for the treatment of neurological manifestations of NPC in adult and pediatric patients 2 years of age and older in the USA. This article summarizes the milestones in the development of arimoclomol leading to this first approval for use in combination with miglustat for the treatment of neurological manifestations of NPC in adult and pediatric patients aged ≥ 2 years.

Xeligekimab (Jinlixi^®) is a recombinant human interleukin (IL)-17A-neutralizing immunoglobulin (Ig)G4 monoclonal antibody being developed by Genrix (Shanghai) Biopharmaceutical for the treatment of plaque psoriasis, axial spondyloarthritis and lupus nephritis. Xeligekimab binds to IL-17A and blocks its interaction with the IL-17A receptor, thereby inhibiting the release of C-X-C motif chemokine ligand 1 and IL-6. On 27 August 2024, xeligekimab received approval in China for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Xeligekimab is under regulatory review in China for the treatment of axial spondyloarthritis and is undergoing phase II development for the treatment of lupus nephritis. This article summarizes the milestones in the development of xeligekimab leading to this first approval for plaque psoriasis.

Carbapenem-resistant Acinetobacter baumannii has been associated with over three hundred thousand annual deaths globally. It is resistant to most available antibiotics and associated with high morbidity and mortality. No global consensus currently exists for treatment strategies that balance safety and efficacy because of heterogeneity of treatment regimens in current clinical practice and scarcity of large-scale controlled studies arising from difficulties in establishing robust clinical outcomes. This review outlines the epidemiology and resistance mechanisms of carbapenem-resistant A. baumannii, then summarizes available clinical data on each approved agent with activity against this pathogen. Emerging treatment options such as cefiderocol and sulbactam-durlobactam show promise, but their success hinges on comprehensive clinical validation and access in regions most impacted by this pathogen. New therapeutic modalities that are in various stages of clinical development are also discussed.

Achievement of low-density lipoprotein cholesterol (LDL-C) targets is crucial for the prevention of cardiovascular disease (CVD) in individuals with dyslipidaemia who are at high risk. Current guidelines recommend high-intensity statins at the highest tolerated dose as initial treatment to achieve LDL-C goals. However, the real-world situation is dismal: high-intensity statins are underused and achievement of LDL-C goals is suboptimal. Various challenges exist in the implementation of the recommended initial treatment strategy, including hesitancy to use high-intensity statins, non-adherence, and side effects, and the response to high-intensity statins varies across individuals. Emerging studies have shown another line of lipid-lowering, moderate-intensity statins in combination with ezetimibe, presenting considerable efficacy/effectiveness, along with better safety and adherence compared to statin intensification alone. Here we review the clinical evidence, treatment guidelines and challenges associated with high-intensity statins, and summarise the evidence on the combination therapy, moderate-intensity statin plus ezetimibe, which is the core strategy recommended by the 2023 Chinese Guideline for Lipid Management, as a possible primary treatment to achieve the LDL-C targets across several populations. The upfront use of a moderate-intensity statin plus ezetimibe may improve LDL-C control and lead to the prevention of CVD in real-world settings.

Xanomeline/trospium chloride (COBENFY™), formerly KarXT, is a first-in-class, oral, fixed-dose muscarinic agonist/antagonist combination being developed for use in schizophrenia and Alzheimer's disease psychosis. Xanomeline is thought to confer efficacy by acting as an agonist at M₁ and M₄ muscarinic acetylcholine receptors in the brain, and trospium chloride reduces the peripheral cholinergic adverse events associated with xanomeline. Xanomeline/trospium chloride received its first approval on 26 September 2024 in the USA for the treatment of schizophrenia in adults. This article summarizes the milestones in the development of xanomeline/trospium chloride leading to this first approval for schizophrenia.