Drugs最新文献

With rapid expansion of cannabis legalization worldwide, rates of cannabis use and cannabis use disorder (CUD) are increasing; the need for safe and effective medications to treat CUD is urgent. This narrative review evaluates evidence for promising pharmacotherapies to treat CUD from randomized, placebo-controlled trials. Pharmacotherapies for CUD are categorized based on compound targets (e.g., cannabinoid receptor 1 [CB1] agonists such as nabilone, serotonergic compounds such as bupropion, GABAergic compounds such as zolpidem) and outcomes are organized by predetermined withdrawal symptoms, cannabis craving, and cannabis relapse/use. Most promising pharmacotherapies for CUD are drugs that act on the endocannabinoid system and specifically at the CB1 receptor. Priority populations such as females, certain racial/ethnic groups, and age groups experience a different course of CUD progression, symptoms, and drug effects that are important to consider when evaluating outcomes related to CUD. Possible explanations for these disparities are explored, along with the clinical trials that explore these demographics in treating CUD with pharmacotherapies.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder with defining abnormalities in memory, and psychedelics may be promising candidates for the treatment of PTSD given their effects on multiple memory systems. Most PTSD and psychedelic research has investigated memory with fear conditioning and extinction. While fruitful, conditioning and extinction provide a limited model of the complexity of PTSD and phenomenology of psychedelics, thereby limiting the refinement of therapies. In this review, we discuss abnormalities in fear conditioning and extinction in PTSD and review 25 studies testing psychedelics on these forms of memory. Perhaps the most reliable effect is that the acute effects of psychedelics can enhance extinction learning, which is impaired in PTSD. However, the post-acute effects may also enhance extinction learning, and the acute effects can also enhance fear conditioning. We then discuss abnormalities in episodic and semantic memory in PTSD and review current knowledge on how psychedelics impact these memory systems. Although PTSD and psychedelics acutely impair the formation of hippocampal-dependent episodic memories, psychedelics may acutely enhance cortical-dependent learning of semantic memories that could facilitate the integration of trauma memories and disrupt maladaptive beliefs. More research is needed on the acute effects of psychedelics on episodic memory consolidation, retrieval, and reconsolidation and post-acute effects of psychedelics on all phases of episodic memory. We conclude by discussing how targeting multiple memory mechanisms could improve upon the current psychedelic therapy paradigm for PTSD, thereby necessitating a greater emphasis on assessing diverse measures of memory in translational PTSD and psychedelic research.

Axatilimab (NIKTIMVO™; axatilimab-csfr), an anti-colony-stimulating Factor 1 Receptor (CSF-1R) humanized IgG4 (κ light chain) monoclonal antibody, is being developed by Incyte Corporation and Syndax Pharmaceuticals for the treatment of chronic graft-versus-host disease (cGVHD) and other indications, including idiopathic pulmonary fibrosis (IPF). In August 2024, axatilimab was approved in the USA for the treatment of cGVHD after failure of at least two prior lines of systemic therapy in adult and paediatric patients weighing at least 40 kg. Axatilimab was added to the NCCN guidelines for cGVHD in August 2024. This article summarizes the development milestones leading to this first approval of axatilimab for the treatment of cGVHD.

Seladelpar (LIVDELZI^®) is an oral delpar [i.e. a selective peroxisome proliferator-activated receptor (PPAR)δ agonist] being developed by Gilead Sciences for the treatment of primary biliary cholangitis (PBC). On 14 August 2024, based on a reduction in alkaline phosphatase (ALP), it received accelerated approval in the USA for the treatment of PBC in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory studies. A regulatory assessment for seladelpar for the treatment of PBC is underway in the EU and the UK. This article summarizes the milestones in the development of seladelpar leading to this first approval.

Background: Although a range of renin-angiotensin-aldosterone system (RAAS) modulators are available for blood pressure lowering, the optimal choice within this class remains unclear. We aimed to compare the efficacy and safety of RAAS modulators in the adult hypertensive population.

Methods: A systematic literature search was performed in PubMed, CENTRAL, and Embase. The primary efficacy outcome was all-cause mortality and the secondary efficacy outcome was cardiovascular mortality. Tolerability outcome was discontinuation due to adverse events. Safety outcomes included the occurrence of cough, dizziness, edema, hyperkalemia, and hypotension. Network meta-analyses were performed utilizing a random-effects model within a frequentist framework.

Results: We finally identified 51 articles from 49 randomized controlled trials. When compared to placebo, mineralocorticoid receptor antagonists (MRAs) significantly reduced the risk of all-cause mortality (odds ratio (OR) 0.83; 95% confidence interval (CI) 0.74-0.92) and cardiovascular mortality (OR 0.79; 95% CI 0.68-0.93), while none of other RAAS modulators significantly lowered the risk of all-cause or cardiovascular mortality. Individual comparisons indicated that MRAs were associated with a significantly lower risk of all-cause mortality than the other RAAS modulators (reduction: 16% compared with angiotensin-converting enzyme inhibitors (ACEIs), 14% compared with angiotensin receptor blockers (ARBs), and 22% compared with direct renin inhibitors (DRIs)). No difference in discontinuation due to adverse events was found in a comparison of RAAS modulators with placebo. With regard to safety outcomes, ACEIs have a higher risk of cough (OR 4.68; 95% CI 1.61-13.60), ARBs have a higher risk of dizziness (OR 1.42; 95% CI 1.06-1.91), hypotension (OR 2.10; 95% CI 1.02-4.34), and hyperkalemia (OR 1.99; 95% CI 1.17-3.41), and MRAs had a higher risk of hyperkalemia (OR 2.68; 95% CI 1.99-3.62) when compared to placebo.

Conclusions: MRAs were the only RAAS modulators with a survival benefit in adults with hypertension, although they carried a higher risk of hyperkalemia. Our data challenge current hypertension guidelines which recommend MRAs as fourth-line therapy, and suggest that MRAs should be prescribed earlier and more widely.

Registration: PROSPERO identifier number CRD42023405714.

Efgartigimod (Vyvgart^®; Vyvgart^® Hytrulo) is a neonatal fragment crystallizable receptor (FcRn) antagonist indicated for the treatment of generalised myasthenia gravis (gMG) in adults who are acetylcholine receptor (AChR) antibody positive (Ab+). Efgartigimod is approved for both intravenous (IV) and subcutaneous (SC) use. In a pivotal phase III trial, IV efgartigimod was associated with significant and clinically meaningful improvements in myasthenia gravis symptoms and reductions in disease burden. The beneficial effects of IV efgartigimod were reproducible, durable and maintained over the long term. IV efgartigimod also improved health-related quality of life (HRQOL). In another phase III trial, SC efgartigimod PH20 was noninferior to IV efgartigimod in reducing total immunoglobulin G levels. Clinical improvement with SC efgartigimod PH20 was consistent with that of IV efgartigimod and was reproducible over the long term. Efgartigimod was generally well tolerated; the most common adverse events were headache and infections (with IV efgartigimod) and injection-site reactions (with SC efgartigimod PH20). Although further long-term data are required, IV and SC formulations of efgartigimod provide effective, generally well-tolerated and flexible treatment options for adults with AChR Ab+ gMG.

Orexins/hypocretins are neuropeptides produced by the hypothalamic neurons, binding two G-protein coupled receptors (orexin 1 and orexin 2 receptors) and playing a critical role in regulating arousal, wakefulness, and various physiological functions. Given the high prevalence of sleep disturbances in Alzheimer's disease (AD) and their reported involvement in AD pathophysiology, the orexin system is hypothesized to contribute to the disease pathogenesis. Specifically, recent evidence suggests that orexin's influence may extend beyond sleep regulation, potentially affecting amyloid-β and tau pathologies. Dual orexin receptor antagonists (DORAs), namely suvorexant, lemborexant, and daridorexant, demonstrated efficacy in treating chronic insomnia disorder across diverse clinical populations. Considering their stabilizing effects on sleep parameters and emerging evidence of a possible neuroprotective role, these agents represent a promising strategy for AD management. This leading article reviews the potential use of orexin receptor antagonists in AD, particularly focusing on their effect in modulating disease-associated sleep disturbances and clinical outcomes. Overall, clinical studies support the use of DORAs to enhance sleep quality in patients with AD with comorbid sleep and circadian sleep-wake rhythm disorders. Preliminary results also suggest that these compounds might influence AD pathology, potentially affecting disease progression. Conversely, research on selective orexin receptor antagonists in AD is currently limited. Further investigation is needed to explore orexin antagonism not only as a symptomatic treatment for sleep disturbances, but also for its broader implications in modifying AD neurodegeneration, emphasizing mechanisms of action and long-term outcomes.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have proven efficacy and safety in randomized clinical trials and observational real-life studies. Besides improving glucose control, reducing body weight, and lowering arterial blood pressure (surrogate endpoints), the breakthroughs were the demonstration of a significant reduction in cardiovascular and renal events in patients with type 2 diabetes at high risk. GLP-1RAs reduce events linked to atherogenic cardiovascular disease (especially ischemic stroke) and also renal outcomes (FLOW trial with semaglutide), with a limited effect on heart failure. The most striking protective effects of SGLT2is were a marked reduction in hospitalization for heart failure and a remarkable reduced progression of chronic kidney disease. These benefits have been attributed to numerous pleiotropic effects beyond glucose-lowering action. Underlying mechanisms contributing to cardiovascular and renal protection are at least partially different between GLP-1RAs (mainly anti-atherogenic and vascular effects) and SGLT2is (mainly systemic and intrarenal hemodynamic changes). Thus, patients at high risk may benefit from complementary actions when being treated with a GLP-1RA/SGLT2i combination. Such combination has proven its efficacy on surrogate endpoints. Furthermore, post hoc subgroup analyses of cardiovascular outcome trials have suggested a greater cardiorenal protection in patients treated with a combination versus either monotherapy. The benefits of a combined therapy have been confirmed in a few retrospective cohort studies. A dedicated prospective trial comparing a combined therapy versus either monotherapy is ongoing (PRECIDENTD); however, several challenges still remain, especially the higher cost of a combined therapy and the worldwide underuse of either GLP-1RAs or SGLT2is in clinical practice, even in patients at high cardiorenal risk.

Vunakizumab (^®) is a subcutaneous (SC) recombinant anti-interleukin (IL)-17A humanized monoclonal IgG1/κ antibody being developed by Suzhou Suncadia Biopharmaceutical Co., Ltd (a subsidiary of Jiangsu Hengrui Pharmaceuticals Co., Ltd) for the systemic treatment of autoimmune diseases related to the IL-17 pathway, including psoriasis, ankylosing spondylitis and psoriatic arthritis. In August 2024, vunakizumab was approved in China for the treatment of adult patients with moderate-to-severe plaque psoriasis who are suitable for systemic treatment or phototherapy. This article summarizes the milestones in the development of vunakizumab leading to this first approval for the systemic treatment of moderate-to-severe plaque psoriasis.