Medicines (Basel, Switzerland)最新文献

Background: Alcohol Use Disorder (AUD) is a major contributor to global morbidity, mortality, and socioeconomic burden. Cravings, defined as intense urges to consume alcohol, play a central role in relapse and are recognized as a diagnostic criterion in DSM-5. Pharmacological strategies targeting cravings may offer immediate or short-term relief, complementing existing long-term approaches. However, evidence on short-term (up to approximately three months) anti-craving interventions remains fragmented.

Objective: To systematically review randomized, double-blind, placebo-controlled trials (RCTs) assessing the short-term effects of pharmacological treatments on cue-induced alcohol cravings.

Methods: A systematic search was conducted in PubMed and PsycINFO using terms related to alcohol, craving, and randomized controlled designs. Eligibility included clinical trials on alcohol-dependent participants that evaluated craving as an outcome. Exclusion criteria encompassed non-clinical studies, non-pharmacological interventions, animal studies, single-blind trials, and studies with psychiatric comorbidities. Study quality was appraised using Cochrane and Joanna Briggs Institute tools.

Results: From 442 studies screened, 26 RCTs fulfilled the inclusion criteria. In total, 1097 participants were enrolled across the trials (range = 16-125 per study; mean = 44), predominantly male outpatients aged 15-65 years. Craving was assessed primarily with the Visual Analog Scale and Alcohol Urge Questionnaire. Intervention duration ranged from 1 to 98 days. Naltrexone consistently reduced cue-induced craving across four trials, with additional benefit observed when combined with ondansetron. Varenicline and acamprosate also demonstrated reductions in craving and drinking. Memantine showed efficacy in craving reduction but was not assessed for abstinence. Topiramate was effective, whereas gabapentin showed limited short-term benefit. Other agents (e.g., citalopram, oxytocin, ondansetron, quetiapine) yielded mixed findings, often limited to single studies. Overall, 58% of trials reported positive anti-craving effects, 23% no difference, and 8% increased craving versus placebo. However, these findings should be interpreted in light of important methodological limitations, including small sample sizes and heterogeneous experimental paradigms.

Conclusions: This review suggests that naltrexone and varenicline appear to be the most consistently supported short-term pharmacotherapies for alcohol craving within the available evidence, with promising but less consistent findings for memantine, acamprosate, and topiramate. These results highlight potential candidates for immediate craving management in AUD, while underscoring the need for larger and longer-term trials to confirm their efficacy and safety.

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Acyclovir is an antiviral drug effective against infections caused by herpes simplex and varicella zoster viruses. It is given intravenously to treat serious infections such as herpes encephalitis. High acyclovir concentrations could cause toxicity, observed mainly as nephrotoxicity and, to a lesser extent, neurotoxicity. Acyclovir nephrotoxicity is primarily attributed to the crystallization of acyclovir within the renal tubules, although additional mechanisms may also contribute. However, the mechanism of acyclovir-induced neurotoxicity is unknown. Acyclovir is mainly eliminated from the body through renal excretion; however, around 15-20% of acyclovir is metabolized subsequently by alcohol and aldehyde dehydrogenase to the main metabolite 9-carboxymethoxymethylguanine (CMMG), and around 2% is metabolized by aldehyde oxidase to the minor metabolite, 8-hydroxyl acyclovir. It has been suggested that CMMG levels above 10 µmol/mL in the serum and 1 µmol/mL in the cerebrospinal fluid are highly associated with neurotoxicity. Studies have shown that there is a potential contribution of CMMG to acyclovir-induced neurotoxicity and of the acyclovir aldehyde to nephrotoxicity. In this narrative review, we approach the topic of acyclovir metabolites and their association with acyclovir toxicity. Moreover, we identify the research gap of the mechanisms by which these metabolites contribute to toxicity.

Background: Major cardiovascular events (MACEs) in people with HIV (PWH) may be partly related to antiretroviral therapy (ART) and persistent inflammation. The aim of the study was to evaluate the association between targeted variables and MACEs. Methods: Retrospective, single-center study conducted on PWH receiving ART between January 2010 and April 2024, classified according to HIV-RNA levels: virological suppression (<50 copies/mL), low-level viremia (50-200 or 200-1000 copies/mL), and non-suppression (≥1000 copies/mL). Viremia was considered as a time-dependent variable and by cumulative years in each category. A Cox proportional hazards model for multivariate time-to-event analysis assessed associations between virological status and MACEs. Results: We included 3349 PWH followed for a median time of 14 years (interquartile range, IQR 11.2-14.2). At baseline, 2794 (83.4%) were virologically suppressed, 189 (5.6%) and 90 (2.7%) presented 50-200 and 200-1000 copies/mL, respectively, and 276 (8.2%) were non-suppressed. During the follow-up, virological suppression was documented at least once in 3295 (98.4%), low-level viremia in 1579 (47.1%) with 50-200 copies/mL and 794 (23.7%) with 200-1000 copies/mL, and HIV-RNA > 1000 copies/mL in 844 (25.2%). Overall, 300 MACEs occurred, including 53 (17.7%) repeated events, with total incident rate of 0.00976 events per person-year. The risk of MACEs was significantly associated with previous MACEs (Hazard Ratio, HR 3.385, p-value < 0.001) and viremia > 1000 copies/mL at baseline (HR 2.209, p-value 0.039). Their onset was also significantly associated with greater age at baseline and years on ART, hypertension, diabetes, lower HDL, and higher triglycerides. Conclusions: PWH on ART with HIV-RNA > 1000 copies/mL at baseline and a previous MACE presented higher risk of developing MACEs.

Background/objectives: Trigeminal Neuralgia (TN) is a chronic neuropathic condition characterized by sudden, severe facial pain. Anticonvulsants are the cornerstone of pharmacological management, yet comparative evidence based on pharmacological class remains scarce. This systematic review aimed to evaluate the efficacy and safety of anticonvulsants in TN, stratified by their mechanism of action.

Methods: A systematic search in PubMed, Scopus and Web of Science was conducted following PRISMA 2020 guidelines. Studies employing a pharmacological approach including human patients with TN, published in English since 2000, were included. Risk of bias was assessed using the Cochrane RoB 2, the ROBINS-I and the ROBINS-E tools, according to the study design.

Results: Out of 922 initial records, 12 studies met the eligibility criteria. Sodium channel inhibitors showed high efficacy but frequent adverse effects, particularly hyponatremia and central nervous system symptoms. Calcium channel modulators offered a more favorable safety profile. Combination therapies showed benefits, levetiracetam and topiramate were moderately effective and well tolerated. Although the evidence has limitations, anticonvulsants continue to be the primary treatment for TN. Sodium-channel blockers demonstrate strong efficacy, whereas alternative agents generally provide superior tolerability.

Conclusions: These findings support selecting drugs according to their underlying mechanisms of action. Equally important is tailoring therapy to pain phenotype and patient characteristics, balancing mechanism with tolerability and efficacy.

Natural products have an invaluable therapeutic effect on human health. Natural antioxidants, including beta-carotene, turmeric, and polyphenols, are recognised for their health benefits but face significant barriers related to insufficient solubility, instability, volatility, and diminished bioavailability, which limit their therapeutic efficacy in drug delivery systems. Therefore, encapsulation of natural products in a carrier addresses the above concern. Drug delivery systems, such as solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), are promising carriers for effective release, consisting of solid and liquid lipids, which enhance efficiency, stability, and controlled release, thereby minimising bioavailability limitations. This review consolidates current studies on the formulation methodologies, mechanisms of action, and therapeutic applications of NLCs, emphasizing their use in the treatment of conditions such as cancer, neurological disorders, and cardiovascular diseases. The results demonstrate that NLCs substantially enhance the bioavailability and therapeutic efficacy of antioxidants, thereby improving their targeted administration and clinical effects. Nonetheless, difficulties in clinical translation remain, including drug loading capacity, regulatory authorisation, and the need for pervasive research on cytotoxicity. This article highlights important areas for future inquiry, specifically the optimisation of NLC formulations, the enhancement of targeting accuracy, and the resolution of safety issues to enhance their clinical application.

Symptomatic male hypogonadism, defined by low serum testosterone with associated clinical symptoms, is increasingly treated with testosterone replacement therapy. Traditional oral formulations were limited by hepatotoxicity and poor bioavailability, leading to reliance on injectable and transdermal routes. Recent advances in oral testosterone undecanoate formulations have introduced safer and more effective options. This review compares Jatenzo, Tlando, and Kyzatrex, highlighting their pharmacology, efficacy, safety, and clinical utility. Clinical trial data demonstrate restoration of eugonadal testosterone levels in most patients (80-88%), with shared risks including hypertension, polycythemia, and lipid changes. Differences in dosing regimens, titration requirements, and insurance coverage influence choice of therapy and patient adherence. Kyzatrex offers flexible titration and self-pay access, Tlando provides a fixed-dose regimen, and Jatenzo combines titratability with established clinical data. Collectively, these agents expand the therapeutic landscape of hypogonadism, offering effective, non-invasive alternatives that support individualized treatment strategies.

Background/objectives: Though ototoxic, cisplatin is a mainstay of chemotherapy for a variety of cancers. One suggested mechanism of cisplatin ototoxicity involves damage to the spiral ganglion afferent neurons in the inner ear. There is a need for a high-throughput model to screen medications for efficacy against cisplatin and to develop a local therapeutic to mitigate cisplatin's debilitating side effects. Microparticles encapsulating a therapeutic medication are an injectable and tunable method of sustained drug delivery, and thus a promising treatment.

Methods: SH-SY5y human neuroblastoma cells were used as a cell line model for the spiral ganglion neurons. The cells were dosed with cisplatin and four potential therapeutics (melatonin, metformin, cyclosporine, and N-acetylcysteine), with cell viability measured by CCK-8 assay. The most promising therapeutic, N-acetylcysteine (NAC), was then encapsulated into multiple poly(lactic-co-glycolic acid) (PLGA) microparticle subtypes of varied lactide-glycolide (L:G) ratios and NAC amounts. The elution profile of each microparticle subtype was determined over two months.

Results: Of the therapeutics screened, only cells dosed with 1 or 10 mM NAC prior to cisplatin injury demonstrated an improvement in cell viability (73.8%, p < 1 × 10^-8) when compared to cells dosed with cisplatin alone. The 75:25 L:G microparticles demonstrated an increase in the amount of NAC released compared to the 50:50 L:G microparticles.

Conclusions: NAC is a potential therapeutic agent for cisplatin toxicity when tested in a neuronal cell line model. NAC was encapsulated into PLGA microparticles and eluted detectable concentrations of NAC for 6 days, which is a first step towards otoprotection for the weeks long duration of chemotherapy treatment. This work describes a method of screening potential therapeutics and a strategy to develop local drug eluting treatments to protect against cisplatin ototoxicity.

Background: Glycation, a non-enzymatic reaction between sugars and biomolecules, leads to the formation of advanced glycation end-products (AGEs), which are implicated in the progression of chronic diseases. Connarus ruber (Poepp.) Planch (C. ruber), a traditional medicinal plant used for diabetes, has shown anti-glycation activity. This study aimed to identify the active components in C. ruber extract and elucidate their anti-glycation mechanisms.

Methods: Using NMR and LC-MS analyses, we identified epicatechin and procyanidin A2 as major polyphenolic constituents. Collagen glycation assays were performed to evaluate the inhibitory effects of these compounds on fructose- and glyceraldehyde (GA)-induced glycation. Additionally, their cytoprotective effects were assessed using GA-induced cytotoxicity assays in dental pulp stem cells (DPSCs).

Results: Both epicatechin and procyanidin A2 inhibited fructose- and GA-induced glycation in a dose-dependent manner, showing greater efficacy than aminoguanidine. Furthermore, these compounds significantly alleviated GA-induced cytotoxicity in DPSCs.

Conclusions: These findings suggest that epicatechin and procyanidin A2 are candidate contributors to the anti-glycation and cytoprotective effects of C. ruber. The results support the potential of C. ruber extract as a source of therapeutic agents for glycation-related diseases and for enhancing stem cell viability.

Drug repurposing is the process of discovering new therapeutic indications for already existing drugs. By using already approved molecules with known safety profiles, this approach reduces the time, costs, and failure rates associated with traditional drug development, accelerating the availability of new treatments to patients. Artificial Intelligence (AI) plays a crucial role in drug repurposing by exploiting various computational techniques to analyze and process big datasets of biological and medical information, predict similarities between biomolecules, and identify disease mechanisms. The purpose of this review is to explore the role of AI tools in drug repurposing and underline their applications across various medical domains, mainly in oncology, neurodegenerative disorders, and rare diseases. However, several challenges remain to be addressed. These include the need for a deeper understanding of molecular mechanisms, ethical concerns, regulatory requirements, and issues related to data quality and interpretability. Overall, AI-driven drug repurposing is an innovative and promising field that can transform medical research and drug development, covering unmet medical needs efficiently and cost-effectively.