Triple-drug Combination Research Articles

Potential Combination Drug Therapy to Prevent Redox Stress and Mitophagy Dysregulation in Retinal Müller Cells under High Glucose Conditions: Implications for Diabetic Retinopathy.

Chronic hyperglycemia-induced thioredoxin-interacting protein (TXNIP) expression, associated oxidative/nitrosative stress (ROS/RNS), and mitochondrial dysfunction play critical roles in the etiology of diabetic retinopathy (DR). However, there is no effective drug treatment to prevent or slow down the progression of DR. The purpose of this study is to examine if a combination drug treatment targeting TXNIP and the mitochondria-lysosome pathway prevents high glucose-induced mitochondrial stress and mitophagic flux in retinal Müller glial cells in culture, relevant to DR. We show that diabetes induces TXNIP expression, redox stress, and Müller glia activation (gliosis) in rat retinas when compared to non-diabetic rat retinas. Furthermore, high glucose (HG, 25 mM versus low glucose, LG 5.5 mM) also induces TXNIP expression and mitochondrial stress in a rat retinal Müller cell line, rMC1, in in vitro cultures. Additionally, we develop a mitochondria-targeted mCherry and EGFP probe tagged with two tandem COX8a mitochondrial target sequences (adenovirus-CMV-2×mt8a-CG) to examine mitophagic flux in rMC1. A triple drug combination treatment was applied using TXNIP-IN1 (which inhibits TXNIP interaction with thioredoxin), Mito-Tempo (mitochondrial anti-oxidant), and ML-SA1 (lysosome targeted activator of transient calcium channel MCOLN1/TRPML1 and of transcription factor TFEB) to study the mitochondrial–lysosomal axis dysregulation. We found that HG induces TXNIP expression, redox stress, and mitophagic flux in rMC1 versus LG. Treatment with the triple drug combination prevents mitophagic flux and restores transcription factor TFEB and PGC1α nuclear localization under HG, which is critical for lysosome biosynthesis and mitogenesis, respectively. Our results demonstrate that 2×mt8a-CG is a suitable probe for monitoring mitophagic flux, both in live and fixed cells in in vitro experiments, which may also be applicable to in vivo animal studies, and that the triple drug combination treatment has the potential for preventing retinal injury and disease progression in diabetes.

Effective Response to DPP-4 Inhibitors in Patients of COVID – 19 Triggered Uncontrolled Type 2 DM – A Case Report

Introduction: A bidirectional relationship exist between the COVID -19 diagnosed & recovered patient and Type 2 Diabetes Mellitus. As per the various article available in public domain it has been proved that entry of COVID – 19 virus can lead to a series of pathological changes into a patient’s body which may lead to the development of insulin resistance and damage to the pancreas.
 The patient in our case was a COVID – 19 survivor which was diagnosed with type 2 DM during the treatment. The patient was started with the Glargine insulin when she was undergoing her treatment in the hospital for COVID – 19 Symptoms. Her fasting and postprandial blood sugar level was controlled with the insulin. After her discharged she was started with the Metformin 500 mg twice a day but her blood sugar was not controlled with the Metformin monotherapy, so we started with the triple drug combination Metformin + Glimepiride + Pioglitazone. After 1 month of follow-up, it was seen that the blood sugar level was not controlled, so the Pioglitazone was replaced with the DPP-4 inhibitor drug Vildagliptin and again the patient was asked to come for follow-up after 15 days, it was seen in this follow-up that the patients’ blood sugar was dramatically controlled.
 Conclusion: COVID – 19 triggered Type 2 DM is the result of cytokine storm develop during the disease. Metformin and DPP – 4 inhibitors reduce the insulin resistance in type 2 diabetes patients and helps to achieve the euglycemic goal of the patient.

A Clinician’s guide to vitamin D supplementation for patients with cystic fibrosis

Vitamin D deficiency is common in the general population, and even more so in patients with cystic fibrosis. Deficiency is exacerbated in cystic fibrosis patients because of a myriad of causes including malabsorption, decreased fat mass, reduced 25-hydroxylation of vitamin D, reduced exposure to sunlight, decreased vitamin D binding protein, and exposure to drugs that increase catabolism. In turn, vitamin D deficiency can contribute to poor bone health. Additionally, it may contribute to pulmonary decline in the form of worsening pulmonary function, increased colonization with pathogens, and increased pulmonary exacerbation. Because vitamin D deficiency is correlated with negative clinical effects in multiple organ systems of patients with cystic fibrosis, it is important to screen for and treat deficiency in these patients. The Cystic Fibrosis Foundation has issued guidelines for the treatment of vitamin D deficiency, targeting serum levels of 25-hydroxyvitamin D of at least 30 ng/ml. The guidelines offer age-specific escalating dose regimens depending on serum vitamin D levels, with monitoring at 12- week intervals after changing therapy. They address the literature on alternative vitamin D sources, such as UV lamps, ideal formulations (cholecalciferol in preference to ergocalciferol), and optimal vehicles of administration. Despite these detailed recommendations, most centers are still unable to achieve in-target serum vitamin D levels for many of their patients. Future research examining ideal treatment regimens to achieve serum targets and maximize clinical effects are needed. Moreover, it is unknown whether vitamin D sufficiency will be easier to achieve on new triple therapy cystic fibrosis drug combinations, and how these drugs will contribute to vitamin D-related clinical outcomes.

Triple therapy in a single inhaler for chronic obstructive pulmonary disease: clinical studies and case report (real practice)

Algorithms for de-escalation of basic therapy, including the abolition of inhaled corticosteroids (ICS), in patients with chronic obstructive pulmonary disease (COPD), as well as the development of clear criteria for prescribing triple therapy in clinical practice remain the subject of numerous studies and discussions. The given case report of managing a patient with a long experience of smoking and severe COPD demonstrated an unsuccessful experience of de-escalation of therapy with the abolition of ICS due to concerns about the fact of pneumonia. The dual bronchodilator therapy prescribed in accordance with modern recommendations was insufficiently effective in preventing exacerbations, and the stabilization of the patient’s condition was observed after the appointment of a fixed triple combination of drugs in a single inhaler (VI/UMEC/FF), which contains vilanterol (VI), umeclidinium bromide (UMEC) and ICS fluticasone furoate (FF). An additional contribution to ensuring clinical success was made by such factors as strict compliance with medical prescriptions by the patient, smoking cessation and compliance with recommendations for maintaining physical activity, compliance with a strict self-isolation regime during the pandemic, which reduced the risks of respiratory viral infections. Additional clinical predictors of the effectiveness of ICS in COPD were the bronchitis type, the persistence of symptoms and the recurrence of exacerbations of the disease after discontinuation of the drug, the level of blood eosinophilia. When deciding whether to prescribe or cancel triple therapy, it is recommended to take into account the data on the effect of ICS on improving the functional parameters and clinical course of the disease with a decrease in symptoms, on reducing the risk of exacerbations, on increasing patient survival and a positive prognosis during COPD.

Synergism of Temozolomide, Metformin, and Epigallocatechin Gallate Promotes Oxidative Stress-Induced Apoptosis in Glioma Cells

Aim: This study aimed to study the synergistic anti-glioma efficacies of Temozolomide, Metformin, and Epigallocatechin Gallate in U87MG and C6 glioma cells. Background: Glioblastoma (GBM) is the most malignant and invasive tumor of the central nervous system. The current standard treatment comprises surgical resection, followed by adjuvant radiotherapy and chemotherapy employing temozolomide (TMZ). Yet the survival rates for GBM patients are very low. Hence there is a need for new treatment regimes. Objective: This study aimed to unravel the synergistic anti-tumor potential of a biguanide drug, Metformin (MET) and a polyphenol, Epigallocatechin gallate (EGCG) to enhance the anti-GBM efficacy of the standard drug. Methods: The anti-proliferative effect of TMZ, MET, and EGCG, individually and in combination was elucidated in U87MG (human) and C6 (rat) glioma cells using MTT assay, and combination index was used to determine synergism. Cytotoxicity of the drugs was carried out in HEK293T noncancerous cells. Apoptotic morphological changes in the cells were observed by AO/EtBr staining. Furthermore, the effects of drugs on antioxidant and apoptotic genes (SOD, CAT, Nrf-2, Caspase- 9, and Bcl-2) were evaluated using qRT-PCR, and the protein levels of Nrf-2 and Caspase-9 were evaluated using ELISA. Results: The triple-drug combination (TMZ+ MET+ EGCG) synergistically inhibited the proliferation of U87MG and C6 glioma cells in a dose-dependent manner and promoted the apoptosis of glioma cells. The triple-drug combination significantly up-regulated the expression of antioxidant and apoptotic genes and induced oxidative stress, suggesting a shift in equilibrium towards apoptosis. Conclusion: MET and EGCG in combination with TMZ synergistically promoted oxidative stressinduced apoptosis in glioma cells. Hence, the combination of TMZ, MET, and EGCG may be therapeutically exploited for improving the clinical outcomes of patients with GBM.

Comprehensive Management of Helicobacter pylori Infection

Helicobacter pylori (Hp) infection is a chronic gram-negative bacterial infection, that infects the epithelium of the stomach. This prevalence is very high and varies depending on factors such as geographical location, ethnicity, age, and socioeconomic. The key management of Hp infection is accurate diagnosis and treatment. The H. pylori diagnostic examination consists of non-invasive and invasive tests, the most common non-invasive tests are serological tests, urea breath tests (UBT), and stool antigen tests, while invasive tests are rapid urease tests, histopathology, culture, and PCR. The goal of H. pylori eradication is to heal peptic ulcers and reduce the risk of gastric cancer. Eradication therapy that is recommended worldwide and used in Indonesia is the triple drug combination therapy consisting of a PPI, clarithromycin and amoxicillin or metronidazole for 14 days. The success of eradication therapy is highly dependent on the choice of therapeutic regimen, patient compliance in taking multi-drugs with possible drug side effects, and the sensitivity of H. pylori strains to the antibiotics consumed.

Cystic fibrosis: A changing landscape.

Cystic fibrosis is an autosomal recessive genetic disorder that causes a lifetime of debilitating and potentially fatal complications affecting the lungs and other organ systems. Over 1,700 gene mutations that cause this rare disorder have been identified. This article describes the current treatment landscape for adults with CF, including the 2019 FDA approval of a breakthrough triple-drug combination therapy that may significantly improve the quality of life for an estimated 90% of patients with CF.

Triple drug therapy to manage uncontrolled BP in hypertensive patients during Covid-19 lockdown: perspectives from India

Funding AcknowledgementsType of funding sources: None.BackgroundReportedly, hypertension (HTN) independently increases the risk of Covid-19 severity and doubles the risk of Covid-19 mortality. Also, individuals with untreated HTN remain at high risk of covid-19 complications in comparison to those managed with antihypertensive treatment.ObjectiveThe survey was carried out to seek the opinion of healthcare practitioners (HCPs) on the impact of Covid-19 lockdown on the blood pressure (BP) control, and the role of triple drug therapy in management of uncontrolled BP.MethodThis PAN India study was carried out through a structured web-based objective questionnaire survey involving 479 HCPs. The survey comprised questions related to the prevalence and causes of uncontrolled BP during the Covid-19 lockdown, and the use of triple drug therapy in the management of uncontrolled BP.ResultsThe respondent pool of 479 HCPs consisted of consulting physicians (51.5%), family physicians (19%), diabetologists (15%), cardiologists (14%) and nephrologists (0.5%). In this study a majority (40%) of HCPs agreed that stress was the most common reason behind uncontrolled BP during Covid-19 lockdown followed by non-compliance of treatment and sedentary lifestyle, each opined by 30% of HCPs. Almost 54% and 40% of the HCPs respectively, mentioned that 10-40% and 40-80% of their patients with hypertension have reported uncontrolled BP levels following the Covid-19 lockdown. 4% of the HCPs reported that all of their patients lost BP control, while 2% of HCPs mentioned that none of their patients reported uncontrolled BP after the Covid-19 lockdown. Of all the HCPs, 12% opined that they will choose a triple drug combination (TDC) for patients uncontrolled with high dose monotherapy, ∼75% opined that they will chose TDC for patients uncontrolled with dual therapy while 13% mentioned that they will chose TDC for patients at high risk. Regarding the TDC of choice, more than half (51%) of the HCPs opted for Telmisartan + Amlodipine + Hydrochlorothiazide as the preferred combination. Among other TDCs, Telmisartan + Amlodipine + Chlorthalidone, Telmisartan + Cilnidipine + Chlorthalidone, and Olmesartan + Amlodipine + Hydrochlorothiazide were ranked as the next three choices opted by 28%, 17.5% and 2.5% of HCPs for the management of uncontrolled BP. A majority of HCPs (58%) also agreed that they would adopt TDC early in the treatment, during the ongoing Covid-19 pandemic.ConclusionThis study underlined the negative impact of Covid-19 lockdown on the blood pressure control in patients with hypertension. It also highlighted the HCPs perspectives on the early use of TDC, and that Telmisartan + Amlodipine + Hydrochlorothiazide is the most commonly preferred TDC in patients with uncontrolled BP levels in Indian settings.

Artemisinin and multidrug-resistant Plasmodium falciparum - a threat for malaria control and elimination.

Purpose of reviewArtemisinin-based combination therapies (ACTs) are globally the first-line treatment for uncomplicated falciparum malaria and new compounds will not be available within the next few years. Artemisinin-resistant Plasmodium falciparum emerged over a decade ago in the Greater Mekong Subregion (GMS) and, compounded by ACT partner drug resistance, has caused significant ACT treatment failure. This review provides an update on the epidemiology, and mechanisms of artemisinin resistance and approaches to counter multidrug-resistant falciparum malaria.Recent findingsAn aggressive malaria elimination programme in the GMS has helped prevent the spread of drug resistance to neighbouring countries. However, parasites carrying artemisinin resistance-associated mutations in the P. falciparum Kelch13 gene (pfk13) have now emerged independently in multiple locations elsewhere in Asia, Africa and South America. Notably, artemisinin-resistant infections with parasites carrying the pfk13 R561H mutation have emerged and spread in Rwanda.SummaryEnhancing the geographic coverage of surveillance for resistance will be key to ensure prompt detection of emerging resistance in order to implement effective countermeasures without delay. Treatment strategies designed to prevent the emergence and spread of multidrug resistance must be considered, including deployment of triple drug combination therapies and multiple first-line therapies.

Cystic fibrosis: A changing landscape.

Cystic fibrosis (CF) is an autosomal recessive genetic disorder that causes a lifetime of debilitating and life-threatening complications affecting the lungs and other organ systems. Over 1,700 gene mutations that cause this rare disorder have been identified. This article describes the current treatment landscape for adults with CF, including the 2019 FDA approval of a breakthrough triple-drug combination therapy that may significantly improve the quality of life for an estimated 90% of patients with CF.

Effectiveness and tolerability of FOLFOXIRI regimen in the third- and subsequent lines of therapy in patients with metastatic colorectal cancer.

e15584 Background: Options of therapy are limited for patients with colorectal cancer who developed disease progression during standard 5-FU-, oxaliplatin-, and irinotecan-contained regimens. There is straight information about synergy of irinotecan (SN-38) and oxaliplatin gained from fundamental and early clinical trials. We aimed to analyze effectiveness and safety of triple drug-combination of 5-FU, oxaliplatin and irinotecan (FOLFOXIRI) in heavily pretreated patients with metastatic colorectal cancer. Methods: Patients with a metastatic colorectal cancer who received more than 2 lines of standard 5-FU-, oxaliplatin- and irinotecan-based doublet regimens with or without targeted therapy were included. Reinduction of chemotherapy in previous lines was allowed. The retrospective analysis of medical histories was done. Eligible patients had to receive number of cycles that were sufficient for response rate estimation. Disease response was evaluated according to RECIST 1.1 criteria. Survival analysis was performed using the Kaplan-Meier method. Tolerability was estimated by CTCAE v. 5.0. Results: Forty-six patients were included in retrospective per protocol analysis. The median follow-up was 19 months. The median number of previous lines of chemotherapy was 2 (2-6). Primary resistance to oxaliplatin- and irinotecan-based chemo during previous lines was noted in 20 patients (43%) and 16 patients (35%), respectively, while seven patients (15%) developed the primary resistance to both agents given in a sequential order. All patients were treated with targeted therapy during previous treatment lines. The median of FOLFOXIRI cycles was 8 (range, 2-19). Two patients (4%) were treated with FOLFOXIRI without any targeted agents. The objective response rate was 33% (n = 15). The disease stabilization was reached in 43% (n = 20). The disease control rate was 76% (n = 35). Eleven patients (24%) had the progression of disease at the first follow-up. The median progression free survival and median overall survival were 6 months and 11 months, respectively. Toxicity was evaluated in 35 patients. The most common severe adverse events (grade 3 and 4) were neutropenia (46%) and fatigue (26%). Treatment was delayed in 20 patients (57%), and 13 patients (37%) required dose reduction. One patient had to discontinue treatment due to unacceptable toxicity. Conclusions: According to our study FOLFOXIRI provides the objective response and increased life expectancy in heavily pretreated patients. The further assessment of FOLFOXIRI regimen for refractory colorectal cancer in the prospective trials is needed.

Treatment of Resistant Hypertension in Real Clinical Settings

Background. Current guidelines describe in detail the approaches to the management of patients with resistant hypertension, however, in real clinical settings the number of non-rational and ineffective combinations of antihypertensive drugs used remains high.Aim. To analyze the distribution of different combinations of antihypertensive drugs for the treatment of resistant hypertension and to estimate the proportion of non-rational combinations.Methods. The retrospective analysis includes 117 outpatients with resistant hypertension. Resistant hypertension was defined as blood pressure that remains above goal despite concurrent use of three antihypertensive agents of different classes. Exclusion criteria was secondary hypertension. We defined rational combination as the standard combination (renin-angiotensin system [RAS] blocker + calcium-channel blocker [CCB] + diuretic) plus one of the group of reserve drugs (mineralocorticoid receptors antagonist [MRA], beta-blocker, alpha-blocker, agonist of imidazoline receptors [AIR]). Non-rational were considered combinations in which reserve drugs were used before the appointment of a triple combination of first-line drugs. Moreover, in a subgroup of non-rational therapy, situations were identified where such a combination was justified.Results. The proportion of rational combinations was 58.9%, reasonably non-rational - 15.5%, unreasonably non-rational - 25.6%. Unreasonably non-rational combinations are distributed as follows: non-appointment of CCB - 12%, non-appointment of RAS-blockers - 8%, non-appointment of diuretics - 6%, use of RAS-blockers for hyperkalemia - 6%, administration of MRA without non-potassium-sparing diuretics - 5%, double blockade of RAS - 3%, other combinations - 7%. In addition to first-line drugs, beta-blockers (93.2%), loop diuretics (22.2%), AIR (21.4) were the most prescribable, while the proportion of MRA is only 15.4% of the entire sample.Limitation: some patient's characteristics could be missed in case histories and some of the combinations could be falsely recognized as malpractice since the analysis was conducted retrospectively.Conclusion. The proportion of the non-rational combinations for the treatment of resistant hypertension is high. Among the drugs of the reserve, the frequent use of beta-blockers and moxonidine and the inadequate administration of spironolactone are noteworthy. The problem of treatment strategy choice remains relevant in real clinical practice.

Triple Chemotherapy Combination Improves Metastatic Colorectal Cancer Outcomes

A triple drug combination of irinotecan, cetuximab, and vemurafenib appears to be more successful at combating metastatic colorectal cancer for longer periods than irinotecan and cetuximab, according to a Journal of Clinical Oncology (JCO) study.1 Results from the SWOG Cancer Research Network are expected to change the standard of care for patients with metastatic colorectal cancer that includes a mutation in the BRAF gene called V600E. Found in approximately 10% of these cancers, the mutation rarely responds to treatment and leads to a poor prognosis. The study was led by Edmund Scott Kopetz, MD, PhD, FACP, a professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, and an expert in BRAF-mutated colorectal cancer. He has previously tested a variety of combination therapies and led the phase 3 BEACON trial, which found that 2 targeted drugs—cetuximab and encorafenib—significantly shrank tumors and extended patients' lives in comparison with patients who had received standard treatment. These findings were published in 2019 in The New England Journal of Medicine.2 Irinotecan is a traditional chemotherapy drug that kills cancer cells, and cetuximab is a monoclonal antibody–targeted drug that blocks the epidermal growth factor protein. Vemurafenib is a targeted BRAF inhibitor. The combination shuts down a major growth pathway in these aggressive cancers, according to Dr. Kopetz. For the JCO study,1 Dr. Kopetz and his colleagues investigated combination therapies in 106 patients whose metastatic colorectal cancer included the V600E mutation. All had undergone previous chemotherapy and did not respond to treatment. Patients were randomly assigned to 1 of 2 treatment groups: those who received irinotecan and cetuximab and those who received that combination along with the third drug, vemurafenib. Findings showed that patients receiving the triple combination responded better to the drugs at a rate of 17% versus a rate of 4% in the 2-drug combination group. The triple combination group also stayed cancer-free longer. The researchers also found an 87% decline in circulating tumor DNA of the BRAF V600E variant allele frequency in patients who received all 3 drugs and no such decline in circulating tumor DNA in patients on the 2-drug combination. Measuring the presence of circulating tumor DNA through liquid biopsy may be an effective way to measure short-term treatment response, Dr. Kopetz adds.

FIXED HIGH-DOSE TRIPLE COMBINATION ANTIHYPERTENSIVE MEDICATION IN PATIENTS WITH UNCONTROLLED HYPERTENSION

Objective: to evaluate efficacy and safety use of 3 antihypertensive medications including a calcium channel blocker, a blocker of the renin-angiotensin system and a thiazide diuretic with a maximal dose for 3 months in patients with long uncontrolled hypertension. Design and method: We studied 117 patients with uncontrolled hypertension which was confirmed by the office and 24-h ambulatory blood pressure monitoring (ABPM). All patients used 3.6 ± 0.1 antihypertensive drugs in free combinations. The adherence was moderate or low in 80 % of patients by the Morisky-Green test. After baseline examination patients have started treatment with the 3-component fixed-dose combination (FDC) of valsartan 320 mg/ hydrochlorothiazide 25 mg/ amlodipine 10 mg daily. The mean baseline systolic/diastolic BP was 170.2 ± 1.6/98.8 ± 1.2 mmHg and 24-h ambulatory BP was 160.3 ± 1.3/93.3 ± 1.1 mmHg. Results: After 3 months of treatment with triple combination pill, BP target was achieved in 57.3 % of patients according to the results of office and ABPM. In controlled hypertension (HTN) patients there was attenuated prevalence of non-dipping at the final evaluation (37 % vs 19 %, P < 0.01). The other 50 patients were classified as patients with resistant hypertension (RH). Patients with RH had a longer duration of hypertension, higher plasma aldosterone and 24-h urinary metanephrines, higher 24–h urinary sodium and were included more subjects with obesity, diabetes mellitus, chronic kidney disease (CKD), coronary artery disease than HTN patients (all P < 0.05). During the study, there were no adverse events such as dizziness, presyncope, or syncope, and headache. At the end of treatment, in HTN patients without initial CKD, creatinine level increased by 12.8% (P = 0.003), and GFR decreased by 10.0% (P = 0.004). Conclusions: The use of the fixed high-dose triple combination of antihypertensive drugs normalizes office and 24-hour BP in 57 % patients and differentiates the patients with true RH among the patients with low adherence to treatment and ineffective previous multicomponent therapy. BP lowering in patients without CKD has shown an increase in creatinine level and possibly refers to hemodynamic changes rather than renal damage; it requires observation.

The Combination of Amygdalin with Some Anticancer, Antiparasitic, and Antigout Drugs Against MG63, Saos2, SW1353, and FL Cells In Vitro.

Osteosarcoma has a poor prognosis and survival rate due to inadequate chemotherapy, high recurrence ability, high metastasis potential, and almost no radiotherapy being applied. One of the strategies to solve these problems is to develop the pharmacologically active plant metabolite, amygdalin, in combination therapeutic systems. In this project, the antiproliferative effects of amygdalin alone and in binary or ternary combinations with some anticancer drugs (cisplatin, 5-fluorouracil, oxaliplatin, and camptothecin), antiparasitic drugs (metronidazole and miltefosine), and an antigout drug (colchicine) were examined using human bone osteosarcoma cell lines (MG-63 and Saos2), the chondrosarcoma cell line (SW1353), and the normal human cell line (FL). Known half-maximal inhibitory concentration values of the drugs were taken into consideration, and the recommended combination ratios were used in the Chou-Talalay method. The strong synergistic effect commonly seen in the combination of amygdalin with miltefosine, metronidazole, camptothecin, colchicine, oxaliplatin, 5-fluorouracil, and cisplatin dual drug indicates that these combinations can be used in cancer treatment. The synergistic effect caused by amygdalin decreases toxicity by increasing drug yield. However, amygdalin antagonism seen in several combinations may prevent these pairs from being used together. In combination with antagonistic effects, it may be preferable to use amygdalin alone as it generally causes strong antiproliferative effects. Besides, there is a more potent synergism between amygdalin and triple drug combinations. Overall, these results emphasize that amygdalin combinations in treatment of bone cancer are significant.

Dolutegravir-Based Regimen for Maintenance of Viral Suppression in People Living with HIV: 48-Week Results in Real-Life Setting.

To evaluate the efficacy, safety, and tolerability of switching to a dolutegravir (DTG)-based regimen in a cohort of virological suppressed HIV-infected patients who have previously been treated with different antiretroviral combination. The dynamics of total HIV-DNA and levels of high-sensitivity c-reactive protein, interleukin-6, soluble-CD14, and D-Dimer were also analyzed. Ninety-six individuals who switched to a DTG-containing regimen were followed up for 48 weeks. HIV RNA, CD4+ T cell count, weight, and levels of laboratory parameters were recorded at baseline, after 24 and 48 weeks of treatment for all study participants. In a subgroup of patients, HIV DNA and inflammation/coagulation marker levels were also analyzed until week 24. Ninety-three out of 96 patients maintained virological suppression, including patients who switched to dual-therapy from triple-drug combination. Eighteen out of 96 patients had residual viremia at baseline, of which 13 reached the maximal viral suppression at W48. Serum creatinine levels showed a significant increase at weeks 24 and 48. A progressive reduction of total cholesterol was observed from week 24 and up to week 48. No variation in body mass index was detected. HIV DNA, inflammation, and coagulation marker levels did not significantly change during follow-up. Switching to a DTG-based regimen may be a key option for achieving and maintaining maximal virological suppression, even in patients showing residual viremia at baseline. Furthermore, the improvement in blood lipid profile and the overall tolerability observed in this study strongly support the use of these regimens in the aging HIV population.

Negative Regulation of ULK1 by microRNA-106a in Autophagy Induced by a Triple Drug Combination in Colorectal Cancer Cells In Vitro

Colorectal cancer (CRC) is among the top three most deadly cancers worldwide. The survival rate for this disease has not been reduced despite the treatments, the reason why the search for therapeutic alternatives continues to be a priority issue in oncology. In this research work, we tested our successful pharmacological combination of three drugs, metformin, doxorubicin, and sodium oxamate (triple therapy, or TT), as an autophagy inducer. Firstly, we employed western blot (WB) assays, where we observed that after 8 h of stimulation with TT, the proteins Unc-51 like autophagy activating kinase 1(ULK1), becline-1, autophagy related 1 protein (Atg4), and LC3 increased in the CRC cell lines HCT116 and SW480 in contrast to monotherapy with doxorubicin. The overexpression of these proteins indicated the beginning of autophagy flow through the activation of ULK1 and the hyperlipidation of LC3 at the beginning of this process. Moreover, we confirm that ULK1 is a bona fide target of hsa-miR-106a-5p (referred to from here on as miR-106a) in HCT116. We also observed through the GFP-LC3 fusion protein that in the presence of miR-106a, the accumulation of autophagy vesicles in cells stimulated with TT is inhibited. These results show that the TT triggered autophagy to modulate miR-106a/ULK1 expression, probably affecting different cellular pathways involved in cellular proliferation, survivance, metabolic maintenance, and cell death. Therefore, considering the importance of autophagy in cancer biology, the study of miRNAs that regulate autophagy in cancer will allow a better understanding of malignant tumors and lead to the development of new disease markers and therapeutic strategies.

The place of fixed antihypertensive drugs in modern therapy of arterial hypertension

The article provides information on modern approaches to the treatment of arterial hypertension. The historical information about therapy with combined antihypertensive drugs is given. Based on data from multicenter clinical trials, the article provides evidence of the benefits of dual and triple fixed drug combinations. Combinations of 1-adrenoreceptor antagonist bisoprolol and the dihydropyridine-type calcium channel blocker amlodipine are considered. The article highlights the advantages of each of the drugs, as well as their combination. It shows the benefits of a fixed combination of low and medium doses compared to high-dose monotherapy, such as efficacy in achieving target blood pressure, preventing cardiovascular events, increasing adherence to treatment, safety and development of side effects. It provides the evidence base for the effectiveness of a triple fixed combination of renin-angiotensin-aldosterone system blockers with calcium channel blockers and diuretics in achieving target blood pressure compared to a double fixed combination of members of these drug classes, which is due to additive effects. The safety and tolerability profiles were found to be more effective with triple therapy compared with dual therapy, which is also supported by studies.

The coArtHA trial\u2014identifying the most effective treatment strategies to control arterial hypertension in sub-Saharan Africa: study protocol for a randomized controlled trial

BackgroundArterial hypertension is the most prevalent risk factor for cardiovascular disease in sub-Saharan Africa. Only a few and mostly small randomized trials have studied antihypertensive treatments in people of African descent living in sub-Saharan Africa.MethodsIn this open-label, three-arm, parallel randomized controlled trial conducted at two rural hospitals in Lesotho and Tanzania, we compare the efficacy and cost-effectiveness of three antihypertensive treatment strategies among participants aged ≥ 18 years. The study includes patients with untreated uncomplicated arterial hypertension diagnosed by a standardized office blood pressure ≥ 140/90 mmHg. The trial encompasses a superiority comparison between a triple low-dose antihypertensive drug combination versus the current standard of care (monotherapy followed by dual treatment), as well as a non-inferiority comparison for a dual drug combination versus standard of care with optional dose titration after 4 and 8 weeks for participants not reaching the target blood pressure. The sample size is 1268 participants with parallel allocation and a randomization ratio of 2:1:2 for the dual, triple and control arms, respectively. The primary endpoint is the proportion of participants reaching a target blood pressure at 12 weeks of ≤ 130/80 mmHg and ≤ 140/90 mmHg among those aged < 65 years and ≥ 65 years, respectively. Clinical manifestations of end-organ damage and cost-effectiveness at 6 months are secondary endpoints.DiscussionThis trial will help to identify the most effective and cost-effective treatment strategies for uncomplicated arterial hypertension among people of African descent living in rural sub-Saharan Africa and inform future clinical guidelines on antihypertensive management in the region.Trial registrationClinicaltrials.govNCT04129840. Registered on 17 October 2019 (https://www.clinicaltrials.gov/).

Required concentration index quantifies effective drug combinations against hepatitis C virus infection

Successful clinical drug development requires rational design of combination treatments based on preclinical data. Anti-hepatitis C virus (HCV) drugs exhibit significant diversity in antiviral effect. Dose-response assessments can be used to determine parameters profiling the diverse antiviral effect during combination treatment. In the current study, a combined experimental and mathematical approaches were used to compare and score different combinations of anti-HCV treatments. A “required concentration index” was generated and used to rank the antiviral profile of possible double- and triple-drug combinations against HCV genotype 1b and 2a. Rankings varied based on target HCV genotype. Interestingly, multidrug (double and triple) treatment not only augmented antiviral activity, but also reduced genotype-specific efficacy, suggesting another advantage of multidrug treatment. The current study provides a quantitative method for profiling drug combinations against viral genotypes, to better inform clinical drug development.