Drug Combinations Research Articles

Leveraging artificial intelligence and machine learning to accelerate discovery of disease-modifying therapies in type 1 diabetes.

Progress in developing therapies for the maintenance of endogenous insulin secretion in, or the prevention of, type 1 diabetes has been hindered by limited animal models, the length and cost of clinical trials, difficulties in identifying individuals who will progress faster to a clinical diagnosis of type 1 diabetes, and heterogeneous clinical responses in intervention trials. Classic placebo-controlled intervention trials often include monotherapies, broad participant populations and extended follow-up periods focused on clinical endpoints. While this approach remains the 'gold standard' of clinical research, efforts are underway to implement new approaches harnessing the power of artificial intelligence and machine learning to accelerate drug discovery and efficacy testing. Here, we review emerging approaches for repurposing agents used to treat diseases that share pathogenic pathways with type 1 diabetes and selecting synergistic combinations of drugs to maximise therapeutic efficacy. We discuss how emerging multi-omics technologies, including analysis of antigen processing and presentation to adaptive immune cells, may lead to the discovery of novel biomarkers and subsequent translation into antigen-specific immunotherapies. We also discuss the potential for using artificial intelligence to create 'digital twin' models that enable rapid in silico testing of personalised agents as well as dose determination. To conclude, we discuss some limitations of artificial intelligence and machine learning, including issues pertaining to model interpretability and bias, as well as the continued need for validation studies via confirmatory intervention trials.

Evaluation of Adherence to European Society of Cardiology Guidelines for Heart Failure Patients in Shahid Modarres Hospital

Background: The prevalence of heart failure (HF) presents a significant burden on global healthcare systems, accounting for approximately 1.2% of the total healthcare budget. Adherence to the European Society of Cardiology (ESC) guidelines is associated with improved clinical outcomes, fewer cardiovascular hospitalizations, and delayed rehospitalization. Objectives: Given the lack of studies on compliance with ESC guidelines for HF patients in Iranian hospitals, this study aimed to evaluate the compliance of HF treatment at Shahid Modarres Hospital with the ESC guidelines. Methods: This descriptive cross-sectional study was conducted on 97 patients with HF who were referred to Shahid Modarres Hospital, Tehran, in 2023. Patients were diagnosed based on their medical records and clinical evaluations by a cardiologist. Medications were reviewed for compliance with the ESC guidelines regarding drug category, type, and dosage. Results: The results showed that 42.3% of patients received treatment in compliance with the ESC guidelines, while 57.7% had non-compliance. The most common non-adherence was observed in the use of ACE/ARB, mineralocorticoid receptor antagonists (MRAs), and Empa/Dapa drug combinations. The study found that 57% of patients were already being treated at Modarres Hospital, and treatment compliance was higher among these patients (60%), compared to those who referred to the hospital for the first time (30%). Conclusions: Although the HF treatment compliance rate at Shahid Modarres Hospital is high, it still requires improvement. A thorough examination of the underlying reasons for non-adherence to HF medication guidelines is needed, with the goal of identifying and addressing potential barriers to optimal treatment.

BABINE: An original and user-friendly scale for the simple and quick management of herb-drug interactions in clinical practice

BackgroundWhile more and more people tend to use herbal products thinking they are safer than conventional western medicine, the reality is other. If natural products are bio-active and possess potential therapeutic activities, then the benefit/risk balance should be considered like any other health product. Some herbs are known to have the potential to interact with patient’s treatment and to cause adverse drug reactions. While these are scarce, they are potentially harmful, and can lead to major sequels and even death in some cases. Despite these known facts, little guidelines about how to evaluate the risk of interaction and to handle them exist in literature. Notably, few scales allowing to assess the risk of a specific combination of herbs and drugs exist.MethodWe propose a new scoring method BABINE (Boosting Analysis of Bibliography for herb- drug INteraction Evaluation) and discuss a scale to evaluate this risk based on iterative rounds of experts’ discussion.ResultsAfter 6 rounds of case reports/clinical studies evaluation, we analyzed and synthesized criteria identified as important by the experts and developed a corresponding evaluation scale.ConclusionEven if our scale greatly simplifies pharmacological events, we believe it provides a robust and transparent way to rapidly assess the risk of adverse event.

An antibiotic that mediates immune destruction of senescent cancer cells

Drugs that eliminate senescent cells, senolytics, can be powerful when combined with prosenescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation, and interferes with redox signaling, leading to death of senescent cells. These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a pyroptosis-apoptosis-necroptosis (PAN)optosis-like cell death in senescent cells, including apoptosis and two forms of immunogenic cell death: necroptosis and pyroptosis. Notably, we observed that salinomycin treatment or SLC25A23 suppression elevates reactive oxygen species, upregulating death receptor 5 via Jun N-terminal protein kinase (JNK) pathway activation. We show that a combination of a death receptor 5 (DR5) agonistic antibody and salinomycin is a robust senolytic cocktail. We provide evidence that this drug combination provokes a potent natural killer (NK) and CD8+ T cell-mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine interleukin 18 (IL18).

Cancer Cell’s Achilles Heels: Considerations for Design of Anti-Cancer Drug Combinations

Loss of function screens using shRNA (short hairpin RNA) and CRISPR (clustered regularly interspaced short palindromic repeats) are routinely used to identify genes that modulate responses of tumor cells to anti-cancer drugs. Here, by integrating GSEA (Gene Set Enrichment Analysis) and CMAP (Connectivity Map) analyses of multiple published shRNA screens, we identified a core set of pathways that affect responses to multiple drugs with diverse mechanisms of action. This suggests that these pathways represent “weak points” or “Achilles heels”, whose mild disturbance should make cancer cells vulnerable to a variety of treatments. These “weak points” include proteasome, protein synthesis, RNA splicing, RNA synthesis, cell cycle, Akt-mTOR, and tight junction-related pathways. Therefore, inhibitors of these pathways are expected to sensitize cancer cells to a variety of drugs. This hypothesis was tested by analyzing the diversity of drugs that synergize with FDA-approved inhibitors of the proteasome, RNA synthesis, and Akt-mTOR pathways. Indeed, the quantitative evaluation indicates that inhibitors of any of these signaling pathways can synergize with a more diverse set of pharmaceuticals, compared to compounds inhibiting targets distinct from the “weak points” pathways. Our findings described here imply that inhibitors of the “weak points” pathways should be considered as primary candidates in a search for synergistic drug combinations.

Effectiveness and Tolerability of DOR/3TC/TDF in Experienced People with HIV Switching from RPV/FTC/TDF: A Retrospective, Single Center Cohort Study

Background: With advances in antiretroviral therapy for HIV treatment, newer drug combinations provide improved efficacy, safety, and compliance. This study evaluates switching to a regimen of doravirine (DOR), tenofovir disoproxil fumarate (TDF), and lamivudine (3TC) in a cohort of people living with HIV (PLWH). Methods: this Italian retrospective study included 426 PLWH who switched from rilpivirine (RPV)/TDF/emtricitabine (FTC) to DOR/3TC/TDF. The analysis focused on treatment effectiveness, safety, and metabolic and renal markers. Results: this study reports a treatment failure (defined as virological failure or discontinuation of the regimen) rate of 2.34% (95% confidence interval, 1.28–4.50%), with significant improvement in CD4 counts (+49.93 cells/µL, p < 0.001). Notably, the switch to DOR/3TC/TDF did not result in adverse metabolic effects or significant changes in renal function. Analysis of lipid profiles showed stabilization in the majority of PLWH. Conclusions: this study indicates that switching to a DOR/3TC/TDF from RPV/TDF/FTC is an effective and well-tolerated option for PLWH, with benefits in terms of maintaining viral suppression, CD4 count recovery, and metabolic health, without evidence of renal impairment. These results support the continued use of DOR/3TC/TDF as part of HIV treatment strategies and highlight the need for ongoing research to refine ART regimens for different populations.

Comparison of radiofrequency thermocoagulation of ganglion Impar with block using a combination of local anaesthetic and steroid in chronic perineal pain

Abstract Background and Aims: Chronic perineal pain (CPP) is the anorectal and perineal pain without underlying organic disease. The prevalence of CPP is 6–18%. The etiology for CPP may be idiopathic, benign, or malignant. We compared radiofrequency thermocoagulation of ganglion Impar with block using a combination of local anaesthetic and steroid for management of chronic perineal pain, with respect to pain relief, patients’ self-reported belief about the efficacy of treatment, and side effects or complications, if any. Material and Methods: Forty patients attending the Pain Management Centre of either sex in the age group of 20–70 years with history, physical examination, and pain patterns consistent with chronic perineal pain, who had been investigated to rule out malignancy and failed to respond to 6 weeks of conservative treatment with a combination of analgesics, anti-inflammatory drugs, neuromodulators, and physiotherapy, were enrolled in the study. The patients were randomly divided into two groups of 20 each using a computer-generated randomization number table. Group-I (n = 20): Patients were administered ganglion Impar block using a drug mixture comprising of 8 ml of 0.25% bupivacaine plus 80 mg of triamcinolone acetate under fluoroscopic guidance. Group II (n = 20): Patients received conventional radiofrequency thermocoagulation of ganglion Impar at 80 degree Celsius for 90 seconds under fluoroscopic guidance. Outcome assessment was done after minimally invasive pain and spine intervention (MIPSI) with evaluation of pain using the Numeric Rating Scale (0–10), patients’ self-reported belief about the efficacy of treatment using Patient Global Impression of Change (PGI-C), and side effects or complications, if any. Results: The majority of the patients in our study were in the age group of 40–50 years, and 80% of the patients were females and weighed 60–70 kg. The majority of the patients in our study had history of trauma, which led to coccygodynia. There was statistically and clinically significant improvement in pain score after ganglion Impar block in both the groups at all time intervals during the study period (P < 0.05). Patients’ self-reported belief about efficacy as per PGI-C was clinically and statistically better in group II as compared to group I at all time intervals throughout the study period (P < 0.005). Four patients in group I required second ganglion Impar block during the 12 months study period. The most common side effect was temporary pain on injection. Conclusions: Both the techniques of MIPSI, that is, fluoroscope-guided ganglion Impar block using corticosteroid and local anaesthetic and radiofrequency thermocoagulation, are effective and provide good pain relief to the symptomatic patients. With respect to improvement in pain relief and patients’ self-reported belief about the efficacy of treatment and side effects or complications, fluoroscope-guided ganglion Impar radiofrequency thermocoagulation is better as compared to fluoroscope-guided ganglion Impar block using corticosteroids and local anesthetics.

Choice of therapy for HER2-positive metastatic breast cancer in real clinical practice: analysis of physician preferences in Russian Federation

Metastatic breast cancer still remains an incurable disease, requiring lifelong treatment. Introduction of targeted therapy into clinical practice has radically changed treatment approaches of HER2-positive breast cancer, making it possible to significantly increase the life expectancy. The treatment algorithm for HER2-positive metastatic breast cancer appears to be quite clear and is reflected in both international and Russian recommendations. To assess actual clinical practice in the Russian Federation, a survey study “Therapy of Her2-positive breast cancer” was conducted. This publication presents results dedicated to the treatment of metastatic HER2-positive breast cancer. 50 specialists from 43 cities took part in the survey. Only heads of departments or their deputies who were personally involved in determining the treatment for patients were allowed to participate. Expertise of this level allows us to reliably assess the actual clinical practice that has developed in the Russian Federation and determine directions for optimizing therapeutic approaches. Despite ongoing questions about the availability of drugs, doctors primarily focus on the effectiveness of treatment. The main first-line therapy in the Russian Federation is the combination of trastuzumab with pertuzumab. However, experts noted that in conditions of unlimited access to drugs, the number of prescriptions for this regimen in the first line would increase by 13%. Doctors also agree that the use of a subcutaneous form of this combination of drugs would optimize the treatment process. Trastuzumab emtansine remains the standard of second-line therapy and, according to the survey results, almost all patients for whom it is indicated receive this type of therapy. Experts predict more frequent use of trastuzumab emtansine in first-line therapy, given the widespread use of neoadjuvant regimens with pertuzumab. The most significant changes are expected in the third line of therapy with the introduction of the new conjugate – trastuzumab deruxtecan. The survey results demonstrate high awareness and commitment of physicians to modern principles of treatment of HER2-positive mBC.

Drug Interaction Studies of Cabamiquine:Ganaplacide Combination against Hepatic Plasmodium berghei.

New antimalarial combination therapies with novel modes of action are required to counter the emergence and spread of Plasmodium drug resistance against existing therapeutics. Here, we present a study to evaluate the preventive activity of a combination of clinical antimalarial drug candidates, cabamiquine and ganaplacide, that have multistage activity against the liver and blood stages of Plasmodium infection. Cabamiquine (DDD107498, M5717) inhibits parasite protein synthesis, and ganaplacide (KAF156) inhibits protein trafficking, blocks the establishment of new permeation pathways, and causes endoplasmic reticulum expansion. The pharmacodynamic parameters of a combination of the two compounds were assessed employing a pharmacometrics approach in conjunction with in vitro-in silico checkerboard analysis. The in vitro study was performed on a previously established 3D infection platform based on human hepatic cell lines that sustain infection by rodent P. berghei parasites. The in vivo efficacy of this drug combination was assessed against the liver stage of the P. berghei. Our results show that the combination of both drugs at the tested concentrations does not interfere with the drugs respective mode of action or affect hepatocyte cell viability. The drug combination was fully effective in preventing the appearance of blood stage parasites when a systemic plasma Cav0-24/EC50 ratio >2 for ganaplacide and >5 for cabamiquine was achieved. These findings demonstrate that chemoprevention using a combination of cabamiquine and ganaplacide has the potential to target the asymptomatic liver stage of Plasmodium infection and prevent the development of parasitemia.

Synergistic combinations of Angelica sinensis for myocardial infarction treatment: network pharmacology and quadratic optimization approach

Background and aimAngelica sinensis (Oliv.) Diels (Danggui, DG), exhibits potential in myocardial infarction (MI) treatment. However, research on its synergistic combinations for cardioprotective effects has been limited owing to inadequate approaches.Experimental procedureWe identified certain phenolic acids and phthalein compounds in DG. Network pharmacology analysis and experimental validation revealed the components that protected H9c2 cells and reduced lactate dehydrogenase levels. Subsequently, a combination of computational experimental strategies and a secondary phenotypic optimization platform was employed to identify effective component combinations with synergistic interactions. The Chou-Talalay and Zero Interaction Potency (ZIP) models were utilized to quantify the synergistic relationships. The optimal combination identified, Z-Ligustide and Chlorogenic acid (Z-LIG/CGA), was evaluated for its protective effects on cardiac function and cardiomyocytes apoptosis induced by inflammatory in a mouse model of induced by left anterior descending coronary artery ligation. Flow cytometry was further utilized to detect the polarization ratio of M1/M2 macrophages and the expression of inflammatory cytokines in serum was measured, assessing the inhibition of inflammatory responses and pro-inflammatory signaling factors by Z-LIG/CGA.Key resultsQuadratic surface analysis revealed that the Z-LIG/CGA combination displayed synergistic cardioprotective effects (combination index value <1; ZIP value >10). In vivo, Z-LIG/CGA significantly improved cardiac function and reduced the fibrotic area in mice post-MI, surpassing the results in groups treated with Z-LIG or CGA alone. Compared to the MI group, the Z-LIG/CGA group exhibited decreased ratios of the myocardial cell apoptosis-related proteins BAX/Bcl-2 and Cleaved Caspase-3/Caspase-3 in mice. Further research revealed that Z-LIG/CGA treatment significantly increased IL-1R2 levels, significantly decreased IL-17RA levels, and inhibited the activation of p-STAT1, thereby alleviating cell apoptosis after MI. Additionally, the Z-LIG/CGA combination significantly inhibited the ratio of M1/M2 macrophages and suppressed the expression levels of pro-inflammatory cytokines IL-1β, IL-6, IL-17, and TNF-α in the serum.Conclusion and implicationsWe successfully identified a synergistic drug combination, Z-LIG/CGA, which improves MI outcomes by inhibiting cardiomyocyte apoptosis and inflammatory damage through modulating macrophage polarization and regulating the IL-1R2/IL-17RA/STAT1 signaling pathway. This study provides a charming paradigm to explore effective drug combinations in traditional Chinese medicine and a promising treatment for MI.

Abstract IA007: Preclinical Approaches to Discovery and Development of Novel Combination Therapies

Drug combinations provide an important tool to address the complexity of tumor biology, and the ability to drive deeper and more durable responses has led to many successful combination regimens in clinical use today. There are more possible novel combination regimens than can be feasibly explored clinically, and preclinical studies have become a common tool to identify and prioritize combinations partners for clinical investigation. Historically, these approaches have focused heavily on identification of synergy, however, a growing body of research is beginning to indicate that synergy may not be a key predictor of clinical utility. To better understand the role of synergy in combinations, we experimentally explored acquired resistance to combination therapies in preclinical models, and counterintuitively, find that combinations which derive activity through synergy rather than additivity can lead to less undesirable outcomes. Specifically, we find that the combinations which rely on synergy are more likely to develop resistance as well as demonstrate greater loss of combination activity upon acquisition of resistance than an equally active additive combination. We propose that instead of relying on synergy for combinations discovery, that a framework based on the 5Rs can be employed which emphasizes a more holistic view of combination rationale, development, and proposed clinical utility. We demonstrate the application of these principles to discovery of novel therapeutic agents in analysis of a large-scale pan-tumor screen, and how these factors can be used to identify novel rational combination partners linked to specific disease segments which drive activity in vivo. As more agents with novel mechanisms enter clinical development, preclinical studies will play an increasingly important role in designing combination regimens which can attack the tumor from multiple angles, leading to better activity, and present a more favorable therapeutic index. Citation Format: Jerome T. Mettetal Preclinical Approaches to Discovery and Development of Novel Combination Therapies. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA007

Integrating AI and Deep Learning for Efficient Drug Discovery and Target Identification

Artificial intelligence (AI) shows great potential in medical diagnosis and drug analysis. Through deep learning technology, AI can automatically extract features from large amounts of complex medical data, significantly improving diagnostic accuracy and drug development efficiency. Especially in drug target discovery and antiviral peptide classification, AI technology can accelerate data processing and prediction, helping researchers identify potential therapeutic molecules more quickly and optimize the drug development process. This study proposes and validates a Deep learn-based model, deep-Avpiden, to improve the classification and discovery efficiency of antiviral peptides (AVPs). By using sequential convolutional networks (TCNs), the model outperforms traditional recurrent neural networks (RNNs) and long short-term memory networks (LSTMs) in capturing long-term dependencies and parallel computing capabilities. In terms of dataset, we used AVPs and non-AVPS samples from multiple databases, totaling 5,414 cleaned and de-weighted peptide sequences for model training after data preprocessing and embedding. The Deep-AVPiden model has been shown to outperform existing advanced classifiers in experiments, and its effectiveness has been verified by accuracy, precision, recall rate, and area under the ROC curve (OC-ROC). In addition, to accommodate computing resource constraints, we propose an optimized version of Deep-AvPIDen (DS), which utilizes Deep separation convolution technology to significantly reduce computing resource consumption. Through the online application platform, researchers can efficiently classify antiviral proteins and discover new AVPs. Future research could further optimize the model's computational efficiency, handle larger data sets, and expand its potential for biomedical problems such as drug combination prediction and new drug discovery.

Health Promoting Properties of Vitamins C and D Against HIV Disease Progression, a Narrative Review

Human immunodeficiency virus (HIV) has troubled humankind for many years. The rate of new HIV cases is decreasing steadily, mostly because of safer sexual practices and scientific advances in medicine. However, the number of HIV-related trials has significantly increased, as the search for a definite cure for HIV is still fruitless. Our current treatment options involve antiretroviral therapy (ART) with various drug combinations that lower the patients’ viral load in order for the immune system to reconstitute itself. This way, adherent patients achieve a life expectancy similar to the general population. Besides the established treatment protocols, the focus has currently shifted towards secondary pharmaceutical regimen programs that enhance a patient’s immune system and response to opportunistic infections. Vitamins C and D are easily obtainable even in the developing world and are known to improve an individual’s daily life, with vitamin D enhancing the human immune response and vitamin C having an assisting role in both the immune response and as an important antioxidant. Recently, many studies assessing the effect of these vitamins on the progression of HIV have been performed. We aimed to collect and review these studies in order to determine the necessity of the supplementation of these vitamins in HIV-infected patients, which might complement the existing ART. To this day, the scientific community is conflicted, and more studies must be conducted before a definite conclusion about these vitamins’ effects on HIV patients can be reached.

Comparative analysis of the therapeutic effect of traditional chinese medicine and western medicine on ROU

The prevalence of recurrent oral ulcer is as high as 50%. It is generally more prevalent in women than in men, and it typically occurs between the ages of 10 and 30. Surveys indicate that at least 10% to 25% of people have experienced this disease. This disease is characterized by cyclical, recurrent, self-limited symptoms of burning pain. Currently, there is no specific drug treatment available for recurrent oral ulcers, making it a major challenge in the academic field. This paper examines the efficacy of different medications in treating recurrent oral ulcers through literature review, data extraction, and quality evaluation. The study concludes that the most effective treatment approach is a combination of Chinese and Western medicine. The combination of Chinese and western medicine drugs has shown significant effects in reducing the recurrence rate of the disease, as well as improving oral flora and other aspects. Furthermore, the therapeutic effect of integrated Chinese and western medicine is considered to be superior.

Effects of combined immunosuppressant and hepatitis B virus antiviral use on COVID-19 vaccination in recipients of living donor liver transplantation.

The global pandemic caused by the highly contagious SARS-CoV-2 virus led to the emergency approval of COVID-19 vaccines to reduce rising morbidity and mortality. However, limited research exists on evaluating the impact of these vaccines on immunocompromised individuals, such as recipients of living donor liver transplantation, highlighting the need for further studies to better understand their effectiveness in this specific population. From June 2021, we followed up on the effectiveness of the vaccine for patients taking immunosuppressive drugs after living-donor liver transplantation (LDLT). A total of 105 immunocompromised individuals participated, of which 50 patients with hepatitis B were taking antiviral drugs. Patients were assessed to analyze how the combination of immunosuppressive and antiviral drugs affected the efficacy of the BNT162b2, mRNA-1273, and ChAdOx1 nCoV-19 COVID-19 vaccines. Before and after the vaccinations, patients were monitored to establish differences between immunosuppressed patients and those additionally taking antiviral drugs. In immunocompromised patients taking antiviral drugs for hepatitis B, we confirmed that the effect of the COVID-19 vaccine was reduced when compared to immunocompromised patients. Interestingly, 23 patients (11 without and 12 additionally with hepatitis B drug administration) encountered breakthrough infections, and although there was a minor discrepancy in vaccine efficacy among the patients taking antiviral drugs for hepatitis B, it did not reach statistical significance. Additional COVID-19 vaccination is recommended for patients taking immunosuppressive drugs and hepatitis B antiviral drugs after LDLT.

Bispecific antibodies targeting BCMA or GPRC5D are highly effective in relapsed myeloma after CAR T-cell therapy

Despite the astonishing outcomes after chimeric antigen receptor (CAR) T-cell therapy for relapsed refractory multiple myeloma (RRMM), most patients eventually relapse. There are only limited data available on salvage therapies following relapse after BCMA-directed CAR T-cell therapy. Here, we analyzed outcomes of post-CAR T-cell therapy relapse and impact of different salvage strategies in an international cohort of 139 patients (n = 130 ide-cel, n = 9 cilta-cel), receiving talquetamab (n = 28), teclistamab (n = 37), combinations of immunomodulating drugs (IMiDs), proteasome inhibitors (PIs) or CD38 monoclonal antibodies (n = 43), and others (n = 31). The median time to relapse after CAR T-cell therapy was 5 months, 53% had the extramedullary disease (EMD) at relapse, associated with dismal post-relapse outcome (P = 0.005). Overall response and complete response upon salvage therapies were 79% and 39% for talquetamab, 64% and 32% for teclistamab, 30% and 0% for IMiDs/PIs/CD38, and 26% and 3% for others (P < 0.001). Duration of response, as well as median survival, was significantly improved with bispecific antibodies (P < 0.001, respectively). Bispecific antibodies seemed to overcome the poor prognosis associated with early relapse and EMD, and were independent predictors for improved survival in multivariable analysis. In summary, these results suggest bispecific antibodies as the standard of care for relapse after CAR T-cell therapy for RRMM.

Effect of single-pill versus free equivalent combinations on persistence and major adverse cardiovascular events in hypertension: a real-world analysis.

Hypertension guidelines recommend the use of single-pill combinations (SPCs) of antihypertensive drugs to improve treatment persistence and blood pressure control. This study aimed to investigate the long-term effects of ramipril/amlodipine (R/A) SPC versus free equivalent dose combinations (FEC) on cardiovascular outcomes and treatment persistence. This retrospective, observational study analysed the database of the Hungarian National Health Insurance Fund. The study included patients with hypertension aged at least 18 years who were initiated on R/A SPC or FEC of different dose combinations (R/A 5/5, 5/10, 10/5 and 10/10 mg) between 2012 and 2018, with follow-up for up to 60 months. Imbalances in baseline characteristics were reduced with propensity score-based sub-classification. All analyses were performed with Cox proportional hazard model and propensity score sub-classification to adjust the imbalances in baseline characteristics. Drug persistence and MACEs were the primary and secondary endpoints, respectively. Overall, 104 882 patients with SPC and 68 324 patients with FEC-treated hypertension were included. The R/A 5/5 mg combination represented the largest proportion (62%). The nonpersistence rate was significantly lower with SPC than with FEC from month 1 to month 24 in the R/A 5/5 mg combination (P < 0.001) and during the entire observation period in the remaining combinations. The MACE rate was significantly reduced with all R/A SPCs versus FECs. No effects on age and sex on both endpoints were noted. This study further supports the beneficial effects of the use of SPC on 60-month persistence and MACEs in hypertension.

Injectable Hierarchical Bioactive Hydrogels with Fibroblast Growth Factor 21/Edaravone/Caffeic Acid Asynchronous Delivery for Treating Parkinson's Disease.

Parkinson's disease (PD) is one of the most common long-term neurodegenerative disorders, with multiple comorbid psychiatric and behavioral abnormalities. The combination of clinical drugs targeting different symptoms with smart hydrogels to achieve asynchronous releases is highly translational and challenging. Here, a hierarchical bioactive hydrogel (OACDP) is designed with asynchronous release based on PD pathology. The hydrogel with caffeic acid-grafted polymer main chain is crosslinked using a micellar nanocrosslinker, with sufficient modulus (≈167Pa), antioxidant activity (>50%), injectability (30-gauge syringe needle), and shape-adaptability. Each of the three drugs (caffeic acid, fibroblast growth factor 21, and Edaravone) is separately engaged in different micro- or nanostructures of the hydrogel and released with asynchronous kinetics of first-order release, zero-order release, or matching Korsmeyer-Peppas model. The triple-loaded hydrogel is injected into the brains of PD rats, showing behavioral improvement. Histological analysis revealed that the triple-loaded OACDP hydrogels are effective in achieving immediate neuroprotection, i.e., reduction the loss of tyrosine hydroxylase in substantia nigra compacta and striatum (retained ≈10-fold versus control), decreasing oxidative stress, reducing astrocyte and microglia activation, and stimulating the AMPK/PGC-1α axis to regulate the mitochondrial function, providing a multi-dimensional PD therapy. The asynchronous release of OACDP hydrogel provides a new conception for PD treatment and other neurodegenerative diseases.

Model-informed precision dosing of quetiapine in bipolar affective disorder patients: initial dose recommendation.

Bipolar affective disorder (BAD) is a mood disorder with high morbidity and mortality. Quetiapine can be used in the treatment of patients with BAD; however, the precise administration regimen of quetiapine in these patients is still unknown. In this study, a population pharmacokinetic (PPK) model of quetiapine in patients with BAD was constructed based on model-informed precision dosing (MIPD) and real-world clinical data and an optimal initial dose of quetiapine in these patients was recommended. A total of 99 patients with BAD treated with quetiapine were included. At the same time, the quetiapine concentrations, the physical and chemical indices of the patients, and the drug combination information were collected. A quetiapine PPK model for patients with BAD was then constructed and an initial dose based on Monte Carlo simulation was recommended. In the final model of quetiapine for patients with BAD, the apparent oral clearance (CL/F) and the apparent volume of distribution (V/F) were 76.1 L/h and 530 L, respectively. For patients with BAD weighing 40-66 kg, the initial dose recommendation was 16 mg kg-1 day-1, the probability of reaching the therapeutic window was 78.8%-82.2%, and the probability of exceeding the upper limit of the therapeutic window was 5.2%-10.3%. For patients with BAD weighing 66-120 kg, the initial dose recommendation was 12 mg kg-1 day-1, the probability of reaching the therapeutic window was 81.5%-85.5%, and the probability of exceeding the upper limit of the therapeutic window was 3.6%-8.1%. The present study, for the first time, recommended an initial dose of quetiapine in patients with BAD based on MIPD and real-world data, providing an individualized reference for the administration of quetiapine in these patients.

A review on recent advances in the stability study of anti-mycobacterial drugs.

Several factors, including characteristic polymer composition of the cell wall, based on peptidoglycans cross-linked with arabinogalactans, together with the lipid layer contribute to the high resistance of Mycobacterium tuberculosis to antibiotics and other anti-tuberculosis drugs, leading to the development of new treatment methods. Implementation of therapeutic drug monitoring for anti-mycobacterial drugs in routine clinical practice requires understanding of the limited stability of these drugs. Rifampicin and isoniazid are the main anti-tuberculosis drugs that generate degradation products during sample handling and storage. Therefore, analytical methods used for analysis of clinical samples collected from tuberculosis patients treated with a combination of different drugs should enable the separation of the studied analytes from their metabolites and degradation products. Moreover, the samples require strictly regulated collection and storage conditions to prevent degradation processes. The purpose of this review was to present recent data on the stability studies of anti-mycobacterial drugs, specifically used as first-line treatment in patients with tuberculosis. Detailed degradation pathway of rifampicin was described, including conditions influencing the formation of specific rifampicin related substances. Moreover, the results of the stability studies of anti-mycobacterial drugs were presented in various matrices in conditions determined by international guidance such as U.S. Food and Drug Administration (FDA) or International Council for Harmonisation (ICH) guidelines. Particular attention was given to analytical methods designed for analysis of anti-mycobacterial drugs in the presence of their degradation products. Finally, recommendations proposed by different authors for collection, processing and storage of clinical samples to increase stability of anti-mycobacterial drugs were summarized.