Multidrug Combination Therapy Research Articles

Tuberculosis in kidney transplant candidates and recipients.

Tuberculosis (TB) is the leading cause of infectious mortality and morbidity in the world, second only to coronavirus disease 2019. Patients with chronic kidney disease and kidney transplant recipients are at a higher risk of developing TB than the general population. Active TB is difficult to diagnose in this population due to close mimics. All transplant candidates should be screened for latent TB infection and given TB prophylaxis. Patients who develop active TB pre- or post-transplantation should receive multidrug combination therapy of antitubercular therapy for the recommended duration with optimal dose modification as per glomerular filtration rate.

New advances in the role of JAK2 V617F mutation in myeloproliferative neoplasms.

The JAK2 V617F mutation is the most common driver gene in myeloproliferative neoplasm (MPN), which means that the JAK/STAT signaling pathway is persistently activated independent of cytokines, and plays an important part in the onset and development of MPN. The JAK inhibitors, although widely used in the clinical practice, are unable to eradicate MPN. Therefore, the unavoidable long-term treatment poses a serious burden for patients with MPN. It is established that the JAK2 V617F mutation, in addition its role in the JAK/STAT pathway, can promote cell proliferation, differentiation, anti-apoptosis, DNA damage accumulation, and other key biologic processes through multiple pathways. Other than that, the JAK2 V617F mutation affects the cardiovascular system through multiple mechanisms. Although JAK inhibitors cannot eradicate MPN cells, the combined use of JAK inhibitors and other drugs may have surprising effects. This requires an in-depth understanding of the mechanism of action of the JAK2 V617F mutation. In this review, the authors explored the role of the JAK2 V617F mutation in MPN from multiple aspects, including the mechanisms of non-JAK/STAT pathways, the regulation of cellular methylation, the induction of cellular DNA damage accumulation, and effects on the cardiovascular system, with the objective of providing valuable insights into multidrug combination therapy for MPN.

Indian Consensus on the Role and Position of Angiotensin Receptor-neprilysin Inhibitors in the Management of Heart Failure.

The incidence of heart failure (HF) in India is estimated to be 0.5-1.7 cases per 1,000 people per year, and approximately 4,92,000-1.8 million new cases are detected every year. Despite the high rate of mortality associated with HF, most patients do not receive maximal guideline-directed medical therapy (GDMT). Current guidelines advocate early multidrug combination therapy with four classes of drugs, namely, beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), angiotensin receptor-neprilysin inhibitors (ARNIs), and sodium-glucose transport protein 2 inhibitors (SGLT-2is), particularly in patients with heart failure with reduced ejection fraction (HFrEF). ARNIs reduce cardiac morbidity and mortality in patients with HFrEF. However, recent data indicated that only 4.8% of patients with HFrEF receive ARNI in India. Hence, at a national consensus on HF meeting, cardiology experts from India formulated a national consensus on the use of ARNI in HF based on current evidence and guidelines. The consensus states that ARNI should be used early in HF, particularly in de novo patients with HFrEF, and those with acute decompensated heart failure (ADHF), irrespective of the presence of low systolic blood pressure (SBP) or diabetes. Moreover, those with HFrEF on renin-angiotensin-aldosterone system (RAAS) inhibitors should be switched to ARNI to reduce the risk of repeated hospitalization for HF, worsening HF, and cardiac death, and to improve the quality of life (QoL). Starting ARNI during the first hospitalization is preferable, and it is safe and effective across all doses. ARNIs can also be used for secondary benefits in patients with preserved ejection fraction [heart failure with preserved ejection fraction (HFpEF)] and HF with mildly reduced EF [heart failure with mildly reduced ejection fraction (HFmrEF)].

Triple combination therapy comprising osimertinib, an AXL inhibitor, and an FGFR inhibitor improves the efficacy of EGFR-mutated non-small cell lung cancer

We previously reported that combined therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and AXL inhibitor ONO-7475 is effective in preventing the survival of drug-tolerant cells in high-AXL-expressing EGFR-mutated non-small cell lung cancer (NSCLC) cells. Nevertheless, certain residual cells are anticipated to eventually develop acquired resistance to this combination therapy. In this study, we attempted to establish a multidrug combination therapy from the first-line setting to overcome resistance to this combination therapy in high-AXL-expressing EGFR-mutated NSCLC. siRNA screening assay showed that fibroblast growth factor receptor 1 (FGFR1) knockdown induced pronounced inhibition of cell viability in the presence of the osimertinib–ONO-7475 combination, which activates FGFR1 by upregulating FGF2 via the c-Myc pathway. Cell-based assays showed that triple therapy with osimertinib, ONO-7475, and the FGFR inhibitor BGJ398 significantly increased apoptosis by increasing expression of proapoptotic factor Bim and reduced cell viability compared with that observed for the osimertinib–ONO-7475 therapy. Xenograft models showed that triple therapy considerably suppressed tumor regrowth. A novel therapeutic strategy of additional initial FGFR1 inhibition may be highly effective in suppressing the emergence of osimertinib- and ONO-7475-resistant cells.

Magnetic/Acoustic Dual-Controlled Microrobot Overcoming Oto-Biological Barrier for On-Demand Multidrug Delivery against Hearing Loss.

Multidrug combination therapy in the inner ear faces diverse challenges due to the distinct physicochemical properties of drugs and the difficulties of overcoming the oto-biologic barrier. Although nanomedicine platforms offer potential solutions to multidrug delivery, the access of drugs to the inner ear remains limited. Micro/nanomachines, capable of delivering cargo actively, are promising tools for overcoming bio-barriers. Herein, a novel microrobot-based strategy to penetrate the round window membrane (RWM) is presented and multidrug in on-demand manner is delivered. The tube-type microrobot (TTMR) is constructed using the template-assisted layer-by-layer (LbL) assembly of chitosan/ferroferric oxide/silicon dioxide (CS/Fe3O4/SiO2) and loaded with anti-ototoxic drugs (curcumin, CUR and tanshinone IIA, TSA) and perfluorohexane (PFH). Fe3O4 provides magnetic actuation, while PFH ensures acoustic propulsion. Upon ultrasound stimulation, the vaporization of PFH enables a microshotgun-like behavior, propelling the drugs through barriers and driving them into the inner ear. Notably, the proportion of drugs entering the inner ear can be precisely controlled by varying the feeding ratios. Furthermore, in vivo studies demonstrate that the drug-loaded microrobot exhibits superior protective effects and excellent biosafety toward cisplatin (CDDP)-induced hearing loss. Overall, the microrobot-based strategy provides a promising direction for on-demand multidrug delivery for ear diseases.

Injectable hybrid hydrogels enable enhanced combination chemotherapy and roused anti-tumor immunity in the synergistic treatment of pancreatic ductal adenocarcinoma

Chemotherapy and immunotherapy have shown no significant outcome for unresectable pancreatic ductal adenocarcinoma (PDAC). Multi-drug combination therapy has become a consensus in clinical trials to explore how to arouse anti-tumor immunity and meanwhile overcome the poorly tumoricidal effect and the stroma barrier that greatly hinders drug penetration. To address this challenge, a comprehensive strategy is proposed to fully utilize both the ferroptotic vulnerability of PDAC to potently irritate anti-tumor immunity and the desmoplasia-associated focal adhesion kinase (FAK) to wholly improve the immunosuppressive microenvironment via sustained release of drugs in an injectable hydrogel for increasing drug penetration in tumor location and averting systematic toxicity. The injectable hydrogel ED-M@CS/MC is hybridized with micelles loaded with erastin that exclusively induces ferroptosis and a FAK inhibitor defactinib for inhibiting stroma formation, and achieves sustained release of the drugs for up to 12 days. With only a single intratumoral injection, the combination treatment with erastin and defactinib produces further anti-tumor performance both in xenograft and KrasG12D-engineered primary PDAC mice and synergistically promotes the infiltration of CD8+ cytotoxic T cells and the reduction of type II macrophages. The findings may provide a novel promising strategy for the clinical treatment of PDAC.

Analysis of the Clinical Effect of Multi-Drug Combination Therapy on Patients with Gynecological Inflammation

Objective: To investigate the effect of multi-drug combination therapy for patients diagnosed with gynecological inflammation. Methods: A total of 100 patients diagnosed with gynecological inflammation between August 2023 and January 2024 were selected as the study subjects. The patients were separated into a control group and an observation group, with 50 patients in each group. The control group underwent conventional drug therapy while the observation group combined lactobacillus vaginal capsule treatment. The clinical effects of the treatments were compared. Results: The total efficacy of the treatment received in the observation was higher. The time taken for gynecological symptom relief was shorter, and the values of vaginal pH, interleukin-6 (IL-6), and C-reactive protein (CRP) were lower after treatment (P < 0.05) compared to the control group. Conclusion: The multi-drug combination therapy can achieve rapid symptomatic relief and improve the vaginal microenvironment in patients with gynecological inflammation, which can reduce their inflammatory response and improve their prognosis.

A phase ib-II study of dabrafenib, trametinib, cetuximab plus irinotecan in patients with BRAF mutant metastatic colorectal cancer: Subgroup analysis and biomarker identification.

e15581 Background: About 5%-12% of patients with metastatic CRC (mCRC) have BRAF mutations in which BRAF V600E mutated was most common, accounts for approximately 90% of cases of BRAF mutation mCRC. Therefore, multi-drug combination therapy with BRAF inhibitor has been tried. The efficacy results of this study have been reported in 2023 ASCO GI (#156). The ORR was 30% (3/10), the DCR was 80% (8/10). After a median follow-up of 19.7 months, the median PFS was 7.5 months. Here, we reported the results of subsequent analyses. Methods: In this phase Ib-II trial, 15 patients with BRAF-mutant mCRC received Dabrafenib, trametinib, cetuximab plus irinotecan combination therapy. Whole exome sequencing was conducted in 8 proficient mismatch repair (pMMR) mCRC patients with BRAF V600E-mutant. Patients were followed up clinically and radiographically. Response was defined as Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) were defined according to the response definitions of the RECIST criteria. Results: 3 mCRC patients (CR or PR) were divided into response group, 5 mCRC patients (SD or PD) were divided into non-response group. Age (59.6±4.22 vs 39.0±9.93), Gender (male 66.67% vs 80%), ECOG score (0.67 vs 0.60), ALT flare rate (66.67% vs 60%) were similar in the two group. Patients in response group have better 2-year survival rate (66.7% vs 0%, P < 0.05). Furthermore, response-related Differential Expression Genes (DEGs) (log2fc > 1, P < 0.05) were analyzed. Meanwhile, GO and KEGG pathway analysis was conducted based on DEGs. Results showed that MAPK signaling pathway related genes were down-regulated in response group such as EGF, FGF18, HGF, IGF1, MAPK10, NGF. While Apoptosis related genes were up-regulated in response group such as BCL2L1, AIFM1, DAXX. Moreover, Antigen processing and presentation related genes such as CALR, CANX, HSPA8 were enriched in response group, which indicated a more active immune microenvironment. On the contrary, Hedgehog signaling pathway related genes such as GLI1, HHIP, BOC were enriched in non-response group. Next, we verified the clinical significance of DEGS in TCGA CRC cohort database using Cox-regression analysis. Results showed that expression of IGF1, NGF, CAMK2B, CCNA1 were associated with poor prognosis and CANX, HSPA8 were associated with better prognosis, which is in accordance with our sequencing results. Conclusions: Inhibition of MAPK signaling and promoted Apoptosis was found in BRAF V600E-mutant mCRC patients who were response to Dabrafenib, trametinib, cetuximab plus irinotecan. It's worth noticing that immune activation occurred in responsive patients, indicated a potential benefit from immunotherapy combination therapy. Moreover, Hedgehog signaling pathway may be target in rescue therapy in mCRC patients. Clinical trial information: ChiCTR2200063316.

A Multidrug Delivery Microrobot for the Synergistic Treatment of Cancer.

Multidrug combination therapy provides an effective strategy for malignant tumor treatment. This paper presents the development of a biodegradable microrobot for on-demand multidrug delivery. By combining magnetic targeting transportation with tumor therapy, it is hypothesized that loading multiple drugs on different regions of a single magnetic microrobot can enhance a synergistic effect for cancer treatment. The synergistic effect of using two drugs together is greater than that of using each drug separately. Here, a 3D-printed microrobot inspired by the fish structure with three hydrogel components: skeleton, head, and body structures is demonstrated. Made of iron oxide (Fe3 O4 ) nanoparticles embedded in poly(ethylene glycol) diacrylate (PEGDA), the skeleton can respond to magnetic fields for microrobot actuation and drug-targeted delivery. The drug storage structures, head, and body, made by biodegradable gelatin methacryloyl (GelMA) exhibit enzyme-responsive cargo release. The multidrug delivery microrobots carrying acetylsalicylic acid (ASA) and doxorubicin (DOX) in drug storage structures, respectively, exhibit the excellent synergistic effects of ASA and DOX by accelerating HeLa cell apoptosis and inhibiting HeLa cell metastasis. In vivo studies indicate that the microrobots improve the efficiency of tumor inhibition and induce a response to anti-angiogenesis. The versatile multidrug delivery microrobot conceptualized here provides a way for developing effective combination therapy for cancer.

Acid/GSH Dual-Responsive Endosome Escape Dual Pro-drug Micelles Targeted Synergistic Treatment for A549/ADR.

The resistance of cancer cells to anticancer drugs has been recognized as one of the main reasons for chemotherapy failure. Multidrug combination therapy is one of the most effective ways to solve this problem. Therefore, in this article, we designed and synthesized a pH/GSH dual-responsive camptothecin/doxorubicin (CPT/DOX) dual pro-drug synergistic treatment system with the aim of overcoming the resistance of non-small cell lung cancer A549/ADR cells to DOX. The pro-drug cRGD-PEOz-S-S-CPT (cPzT) was obtained by linking CPT to poly(2-ethyl-2-oxazoline) (PEOz) with endosomal escape properties through a GSH-responsive disulfide bond and modifying it with the targeted peptide cRGD. The pro-drug mPEG-NH-N=C-DOX (mPX) was synthesized by attaching DOX to polyethylene glycol (PEG) through acid-sensitive hydrazone bonds. The dual pro-drug micelles cPzT/mPX configured according to the CPT/DOX mass ratio of 3:1 showed a strong synergistic therapeutic effect at IC50 with a combined therapy index CI = 0.49, far less than 1. Moreover, with the further improvement of the inhibition rate, the 3:1 ratio showed a stronger synergistic therapeutic effect than other ratios. The cPzT/mPX micelles not only had better targeted uptake ability but also showed a better therapeutic effect in both 2D and 3D tumor suppression assays relative to free CPT/DOX and significantly enhanced the penetration ability into solid tumors. In addition, the results of confocal laser scanning microscopy (CLSM) showed that cPzT/mPX could effectively overcome the resistance of A549/ADR cells to DOX by delivering DOX into the nucleus to exert its effect. Thus, this dual pro-drug synergistic therapy system combining targeting and endosomal escape ability provides a possible strategy to overcome tumor drug resistance.

Liver fibrosis and MAFLD: the exploration of multi-drug combination therapy strategies.

In recent years, the prevalence of metabolic-associated fatty liver disease (MAFLD) has reached pandemic proportions as a leading cause of liver fibrosis worldwide. However, the stage of liver fibrosis is associated with an increased risk of severe liver-related and cardiovascular events and is the strongest predictor of mortality in MAFLD patients. More and more people believe that MAFLD is a multifactorial disease with multiple pathways are involved in promoting the progression of liver fibrosis. Numerous drug targets and drugs have been explored for various anti-fibrosis pathways. The treatment of single medicines is brutal to obtain satisfactory results, so the strategies of multi-drug combination therapies have attracted increasing attention. In this review, we discuss the mechanism of MAFLD-related liver fibrosis and its regression, summarize the current intervention and treatment methods for this disease, and focus on the analysis of drug combination strategies for MAFLD and its subsequent liver fibrosis in recent years to explore safer and more effective multi-drug combination therapy strategies.

Phase Ib study of dabrafenib, trametinib, irinotecan and cetuximab in BRAF V600E-mutated metastatic colorectal cancer.

156 Background: The low efficacy of single-agent BRAF inhibitor in metastatic colorectal cancer (mCRC) is usually due to EGFR feedback upregulation caused by BRAF blockade. Therefore, multi-drug combination therapy with BRAF inhibitor has been tried. Here, we reported the preliminary results of quadruple therapy with dabrafenib, a selective BRAF inhibitor, trametinib, a selective MEK inhibitor, irinotecan and cetuximab in patients with BRAF V600E-mutated mCRC. Methods: This was an ongoing phase Ib study, patients with mCRC who relapse or refractory to standard treatments were enrolled. Patients were treated with dabrafenib (150mg/150mg doses orally twice daily), trametinib (2mg orally once daily), irinotecan (80mg/m2 weekly) and cetuximab (400mg/m2 in first dose and 250mg/m2 weekly). Treatment was continued until disease progression, development of unacceptable toxicity, or drawal of consent. The primary end-point was disease control rate (DCR), and the secondary end-points included progression-free survival (PFS) and duration of disease remission (DOR). This trial is registered with Chinese ClinicalTrials.gov, number ChiCTR2200063316. Results: From July 2018 to January 2021, 10 patients were enrolled. The median age was 53.5 (age 25-65), nine with colon cancer and one with rectal cancer. The most common adverse events (AEs) (50% or more) were fatigue, fever, rash, vomit, leukopenia, anemia, ALT elevation, and AST elevation. Four patients suffered rash which was the most common severe AE (SAE). Two patients presented with grade 3/4 anemia. Only one patient suffered grade 3/4 AEs with nausea and vomit. The DCR was 90% (9/10). After a median follow-up of 19.7 months, the median PFS was 7.5 months (range 1.8-32.4 months). The median DOR was 5.2 months (range 0-27.7 months). Conclusions: Dabrafenib, trametinib, irinotecan and cetuximab has tolerable toxicity and promising antitumor activity in BRAF V600E-mutated mCRC. This regimen warrants a further phase II clinical trial. Clinical trial information: ChiCTR2200063316 . [Table: see text]

Relapse After Drug Withdrawal in Patients with Epilepsy After Two Years of Seizure-Free: A Cohort Study.

Antiepileptic drugs are the first choice of treatment for patients with epilepsy. However, the withdrawal of antiepileptic drugs after seizure-free remains a significant focus for the majority of patients with epilepsy and their families. In this study, we evaluated the risk factors associated with relapse after drug withdrawal in patients with seizure free for 2 years. We aimed to guide patients in seizure-free to assess the risk of drug withdrawal. Through screening, 452 patients with epilepsy were included in the study.Patients were followed up for at least 2 years or more. Analyzed their clinical data by applying the χ2-test, Kaplan-Meier survival analysis and multivariate Cox regression analysis. 423 patients completed follow-up, of which 304 cases recurred (71.9%).Related recurrence factors include age of onset, type of seizure, number of AEDs, seizure-free time before withdrawal, and electroencephalogram (EEG) results before drug withdrawal (P<0.05). The results of correlation analysis showed that age of onset, seizure frequency, seizure type, number of AEDs, the period from AEDs treatment to a seizure-free status, EEG results before drug withdrawal, and pre-medication course, were all significantly related to the recurrence of seizures after drug reduction and withdrawal (P<0.05). We identified a range of independent risk factors, including onset age, seizure frequency, Multiple AEDs and the period from AEDs treatment to a seizure-free status. The overall recurrence rate of epilepsy in our patient cohort was high, and the peak recurrence period was within one-year of drug withdrawal. Patients with partial seizures, a short seizure-free time before withdrawal, severe EEG abnormalities before drug reduction, and a long course of the disease, are prone to relapse. Patients with an older age at onset and a high frequency of attack, those taking multi-drug combination therapy, and those that take a long time to gain control, should be managed carefully to AEDs withdrawal.

Smart composite hydrogel with magnetocaloric anisotropy for controllable multi-drug release

Controllable multi-drug release has been achieved by constructing a unique composite hydrogel structure comprising two layers of agar hydrogel, each incorporated with magnetically aligned anisotropic Fe3O4 nanorods. With the orthogonal alignment of the Fe3O4 nanorods chains in the two layers, controllable multi-drug release can be triggered by the magnetocaloric anisotropy in different layers of the composite hydrogel, depending on the direction of the external alternating magnetic field. The thermal-triggered release of methylene blue (MB) increases up to 1.4 folds by switching magnetic field direction from 0° to 90°. The physical origin of magnetocaloric anisotropy is magnetic anisotropy. The as-designed composite hydrogel displays an obvious opposite drug release trend by switching the magnetic field direction from 0° to 90°. This opposite drug release trend maintains significantly after more than 4 times of magnetic field direction switching. This work opens a promising avenue for realizing the combination of magnetic hyperthermia and remotely controllable multi-drug combination therapy.

Advances in the Preparation of Nanofiber Dressings by Electrospinning for Promoting Diabetic Wound Healing.

Chronic diabetic wounds are one of the main complications of diabetes, manifested by persistent inflammation, decreased epithelialization motility, and impaired wound healing. This will not only lead to the repeated hospitalization of patients, but also bear expensive hospitalization costs. In severe cases, it can lead to amputation, sepsis or death. Electrospun nanofibers membranes have the characteristics of high porosity, high specific surface area, and easy functionalization of structure, so they can be used as a safe and effective platform in the treatment of diabetic wounds and have great application potential. This article briefly reviewed the pathogenesis of chronic diabetic wounds and the types of dressings commonly used, and then reviewed the development of electrospinning technology in recent years and the advantages of electrospun nanofibers in the treatment of diabetic wounds. Finally, the reports of different types of nanofiber dressings on diabetic wounds are summarized, and the method of using multi-drug combination therapy in diabetic wounds is emphasized, which provides new ideas for the effective treatment of diabetic wounds.

Effects of the POMC System on Glucose Homeostasis and Potential Therapeutic Targets for Obesity and Diabetes.

The hypothalamus is indispensable in energy regulation and glucose homeostasis. Previous studies have shown that pro-opiomelanocortin neurons receive both central neuronal signals, such as α-melanocyte-stimulating hormone, β-endorphin, and adrenocorticotropic hormone, as well as sense peripheral signals such as leptin, insulin, adiponectin, glucagon-like peptide-1, and glucagon-like peptide-2, affecting glucose metabolism through their corresponding receptors and related signaling pathways. Abnormalities in these processes can lead to obesity, type 2 diabetes, and other metabolic diseases. However, the mechanisms by which these signal molecules fulfill their role remain unclear. Consequently, in this review, we explored the mechanisms of these hormones and signals on obesity and diabetes to suggest potential therapeutic targets for obesity-related metabolic diseases. Multi-drug combination therapy for obesity and diabetes is becoming a trend and requires further research to help patients to better control their blood glucose and improve their prognosis.

P488: THZ1, A COVALENT CDK7 INHIBITOR, INDUCES APOPTOSIS IN ACUTE MYELOID LEUKEMIA CELLS AND EXERTS SYNERGISTIC ANTILEUKEMIA ACTIVITY WITH AZACITIDINE

Background: Acute myeloid leukemia (AML) is a malignant blood cancer that develops mainly in elderly adults and has dismal clinical outcomes. Azacitidine (AZA) is still the preferred treatment for elderly patients unfit for intensive chemotherapy. However, the remission rate of azacitidine monotherapy is dismal, which necessitates the multidrug combination therapy. THZ1, a CDK7 inhibitor, has been proven to be effective in various cancers by regulating transcription and the cell cycle and inducing cell death. Here, we investigated the antitumor effect of THZ1 monotherapy and its combination treatment with AZA. Aims: To investigate the antitumor activity of the CDK7 inhibitor - THZ1 in acute myeloid leukemia (AML). Methods: We first examined the cell viability of THZ1 against THP-1, MOLM-13, OCI-AML3 cell lines using CCK-8 assays. We used flow cytometry to detect apoptosis after cells were stained with Annexin V-FITC/Propidium Iodide (PI), and western blot to detect the expression levels of proteins. We detect cell cycle by flow cytometry after cells were stained with 50 µg/ml PI and then analyzed with ModFit LT 5.0. RNA-sequencing analysis was performed to explore the potential mechanism of THZ1 in AML cells. In the double-drug combination experiment, we used CCK-8 assays to detect the effect of drugs on the viability of the three cell lines, used CompuSyn software to calculate the combination index (CI), which indicates additive effects (CI = 1.0), synergism (CI < 1.0), and antagonism (CI > 1.0). Results: THZ1 decreased viability and induced apoptosis in THP1, MOLM-13, and OCI-AML3 cells in a dose- and time-dependent manner. Besides, THZ1 inhibited phosphorylation of Ser2, Ser5, and Ser7 residues of RNA Pol II CTD and induced cell cycle arrest at G0/G1 phase in AML cells. RNA-sequencing analysis revealed that THZ1 induced changes in the expression of genes involved in apoptosis, the cell cycle, and DNA repair. Combined treatment with AZA and THZ1 showed a synergetic effect (CI < 1.0). Western blot analysis of apoptosis markers, including cleaved caspase3 and PARP1, demonstrated that THZ1 increased the expression of these markers and potentiated AZA-related apoptosis. Compared with monotherapy, combined treatment with AZA and THZ1 resulted in more Annexin V positive cells detected by flow cytometry, which further verified the synergistic effect of the two drugs. Western blot results indicate that combined treatment with AZA and THZ1 downregulates MCL1 at the protein level without an apparent decrease in BCL2 protein expression. Image:Summary/Conclusion: Our data demonstrate that the CDK7 inhibitor THZ1 induces the apoptosis of AML cells and exerts synergistic antileukemia activity with azacytidine, which provide the rationale for combination treatment with AZA and THZ1 for AML.

Novel therapeutics and drug-delivery approaches in the modulation of glioblastoma stem cell resistance.

Glioblastoma (GBM) is a deadlymalignancy with a poor prognosis. An important factor contributing to GBM recurrence is high resistance of GBM cancer stem cells (GSCs). While temozolomide (TMZ), has been shown to consistently extend survival, GSCs grow resistant to TMZ through upregulation of DNA damage repair mechanisms and avoidance of apoptosis. Since a single-drug approach has failed to significantly alter prognosis in the past 15 years, unique approaches such as multidrug combination therapy together with distinctive targeted drug-delivery approaches against cancer stem cells are needed. In this review, a rationale for multidrug therapy using a targeted nanotechnology approach that preferentially target GSCs is proposed with discussion and examples of drugs, nanomedicine delivery systems, and targeting moieties.

Four aces of heart failure therapy: systematic review of established and emerging therapies for heart failure with reduced ejection fraction

Abstract Heart failure with reduced ejection fraction (HFrEF) is a common disease requiring multi-drug therapy. Moreover, it is associated with a poor prognosis, with increasing prevalence in the community. In the last decade, two major drug classes were introduced to the heart failure (HF) specialist's arsenal: angiotensin receptor neprilysin inhibitors (ARNIs) and sodium-glucose-cotransporter 2 inhibitors (SGLT2is). The current paradigm of sequential drug therapy is changing, favoring a multi-drug combination therapy upfront, including four “pillar” classes: beta-blockers, mineralcorticoid receptor antagonists (MRAs), ARNIs, and SGLT-2is. Recent putative placebo analyses of large-scale randomized clinical trials compared a combination of all four drug classes with a standard of care and was in favor of the multi-drug combination revealing a hazard ratio for cardiovascular (CV) death and HF hospitalization of 0.5 and 0.32, respectively. We reviewed the approval landmark trials for the four drug classes and have subincluded a short comment about the implications and impact of each study in clinical practice. Moreover, we present more detailed trials concerning the use of these drugs in different settings (eg, acute phase, in-hospital, and outpatient) and more data about the clinical, biochemical, functional, and echographic remodeling effects of the molecules. The results of the meta-analyses and putative placebo analyses in the literature we reviewed suggest the benefit of offering all the best therapy available upfront. This approach ensures maximal life expectancy gain, especially in younger patients, and cuts the costs of rehospitalizations. Thus, this review underlines the importance of the four-drug approach to HFrEF therapy, as recently stated in the ESC guidelines.

Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria

The addition of a third anti-malarial drug matching the pharmacokinetic characteristics of the slowly eliminated partner drug in artemisinin-based combination therapy (ACT) has been proposed as new therapeutic paradigm for the treatment of uncomplicated falciparum malaria. These triple artemisinin-based combination therapy (TACT) should in theory more effectively prevent the development and spread of multidrug resistance than current ACT. Several clinical trials evaluating TACT—or other multidrug anti-malarial combination therapy (MDACT)—have been reported and more are underway. From a regulatory perspective, these clinical development programmes face a strategic dilemma: pivotal clinical trials evaluating TACT are designed to test for non-inferiority of efficacy compared to standard ACT as primary endpoint. While meeting the endpoint of non-inferior efficacy, TACT are consistently associated with a slightly higher frequency of adverse drug reactions than currently used ACT. Moreover, the prevention of the selection of specific drug resistance—one of the main reasons for TACT development—is beyond the scope of even large-scale clinical trials. This raises important questions: if equal efficacy is combined with poorer tolerability, how can then the actual benefit of these drug combinations be demonstrated? How should clinical development plans be conceived to provide objective evidence for or against an improved management of patients and effective prevention of anti-malarial drug resistance by TACT? What are the objective criteria to ultimately convince regulators to approve these new products? In this Opinion paper, the authors discuss the challenges for the clinical development of triple and multidrug anti-malarial combination therapies and the hard choices that need to be taken in the further clinical evaluation and future implementation of this new treatment paradigm.