Inter Molecular Level Interaction Studies of Combination Drug Crizotinib And Temozolomide in Glioblastoma Multiforme Targets: An In-silico Approach

Combination drug treatments are frequently used in many diseases, including cancers and AIDS. The main aims of these treatments are to reduce toxicity, decrease or delay drug resistance, and improve drug efficacy by inhibiting the activity of a specific target or groups of targets in a cell. The net effect of combination drug efficacy is mainly quantified and interpreted by various terminologies like synergy, additive, agonism, and antagonism based on drugs dose ratio. In single or combination drug treatment, drug action occurs on cells due to the intermolecular level interaction of drugs with protein/DNA/RNA/Enzyme. This type of inter molecular level interaction can be detected with the help of docking software. The current study aims to identify the inter-molecular level interaction of combination drug Crizotinib and Temozolomide with C-MET, C-ROS1, and ALK targets in Glioblastoma Multiforme(GBM). To identify this, we performed forward and reverse docking of drugs with these proteins, and the results were evaluated by drug properties and the complex energy. From the analysis study, we recognized that first, Crizotinib and then, after Temozolomide bounded docked complexes showed the least complex energy in all the docked complex structures, and the better complexes were identified from the result by MD simulation.

Advantages of “Soft Steroids” in the Treatment of Inflammatory Eye Diseases. Оverview

The purpose to assess the benefits of using soft steroids in the treatment of inflammatory eye disorders according to literature data.Methods. The literature review concerning the administration of the gluco-corticosteroids and combination drugs based on gluco-corticosteroid for the treatment of inflammatory eye disorders. Both Russian and foreign sources for the 1980–2021 period were analyzed.The results. The combination drugs containing anti-infective drugs and gluco-corticosteroids are actively applied for the treatment of inflammatory eye disorders. That exerts joint ethiopathogenetic effect on the disorder. However, gluco-corticosteroid being a part of such drugs (predominantly dexamethasone) as often as not leads to ocular hypertension. In order to deal with this problem the so-called soft steroids (also classified as gluco-corticosteroids) were introduced. They lessen the possibility of the ocular hypertension and are marked by high efficiency and increased safety profile. One of the representatives of soft steroids is fluorometholone. There is a large evidential base in the modern literature that confirms much lesser influence of fluorometholone on ocular pressure if compared to dexamethasone. At the same time, dexamethasone has a higher anti-inflammatory activity, while on the other hand, its systemic immunosuppressive activity is lower. What is more, in terms of influence on the ocular surfaces, dexamethasone has an additional advantage which is causing mucin expression in conjuctival and corneal epithelium. The above mentioned merits of dexamethasone served as basis for its inclusion into the combination drug called Floas-T which is essentially the combination of tobramycin 0.3 % and fluorometholone 0.1 %. It is used in the treatment of inflammatory eye diseases and diseases of eye appendages, as well as for profylaxis of the diseases in the postoperative period.Conclusion. Combination drugs containing anti-infective components and gluco-corticosteroids seem to be highly promising for the treatment of inflammatory eye diseases. One of them worth highlighting is Floas-T classified as soft steroids containing tobramycin and fluorometholone. It compares to dexamethasone favourably in terms of efficiency, while contributing less to ocular hypertension.

Long-Term Mortality and Morbidity Related to Congestive Heart Failure with Reduced Ejection Fraction (CHFrEF) in Palestinian Patients Maintained on Submaximal Sacubitril/Valsartan Doses: A Pilot Study

Background. The efficacy of sacubitril/valsartan, a newly introduced combination drug for heart failure with reduced ejection fraction (HFrEF), was demonstrated in the PARADIGM-HF trial conducted in Western countries. However, these findings need to be verified in the Middle Eastern context, where patients may exhibit a different response due to different environmental and racial factors. Objectives. The goal of this study was to evaluate the efficacy of submaximal sacubitril/valsartan doses in terms of improving the disease symptoms, as measured by the New York Heart Association (NYHA) classification and left ventricular ejection fraction (LVEF) percentage, as well as establish long-term morbidity and mortality associated with HFrEF among Palestinian patients administered target doses of an angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs). Material and Methods. This study involved a retrospective review of charts related to patients with HFrEF maintained on sacubitril/valsartan and was conducted in a referral cardiology clinic in Palestine. The inclusion criteria were age 18+, HFrEF diagnosis, sacubitril/valsartan usage for at least six months during the period between January 1, 2016, and June 30, 2019, and LVEF < 40 % . The exclusion criteria included LVEF ≥ 40 % and drug administration duration < 6 months. The collected data included NYHA class, as well as LVEF, serum sodium (Na), potassium (K), serum creatinine (Cr), and blood urea nitrogen (BUN) levels and the mortality rate before and after the minimum treatment duration. IBM SPSS STATISTICS for Windows, version 20.0, Armonk, NY: IBM Corp. IBM Corp., released 2012, was used for data analysis, whereby T score was calculated for comparisons between numerical groups, and p < 0.05 was considered statistically significant. Results. The initial study sample comprised of 205 consecutive patients with HFrEF maintained on sacubitril/valsartan for at least six months from January 1, 2016, to June 30, 2019. Three patients were excluded due to attrition, along with further 12 patients with LVEF ≥ 40 % (based on the PARADIGM-HF trial criteria). Throughout the treatment period, most patients showed escalating improvement in terms of the LVEF and NYHA classification, as LVEF = 29.8 % and NYHA = 3 were obtained on average before initiating sacubitril/valsartan, compared to 41% and 1.7, respectively, after 6-month treatment ( p = 0.0003 and 0.046, respectively). These improvements in LVEF and NYHA class were noted across all sacubitril/valsartan doses (50−400 mg). However, 23 patients (12%) died while undergoing sacubitril/valsartan treatment. Conclusion. A significant long-term reduction in the mortality and morbidity rates was observed in Palestinian patients with HFrEF maintained on submaximal doses of sacubitril/valsartan.

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.

Alternating anti-prion regimens reduce combination drug resistance but do not further extend survival in scrapie-infected mice

Prion diseases are fatal and infectious neurodegenerative diseases in humans and other mammals caused by templated misfolding of the endogenous prion protein (PrP). Although there is currently no vaccine or therapy against prion disease, several classes of small-molecule compounds have been shown to increase disease-free incubation time in prion-infected mice. An apparent obstacle to effective anti-prion therapy is the emergence of drug-resistant strains during static therapy with either single compounds or multi-drug combination regimens. Here, we treated scrapie-infected mice with dynamic regimens that alternate between different classes of anti-prion drugs. The results show that alternating regimens containing various combinations of Anle138b, IND24 and IND116135 reduce the incidence of combination drug resistance, but do not significantly increase long-term disease-free survival compared to monotherapy. Furthermore, the alternating regimens induced regional vacuolation profiles resembling those generated by a single component of the alternating regimen, suggesting the emergence of strain dominance.

Efficacy of Naproxen Plus Gabapentin Vs Naproxen Alone in Relieving Post-Extraction Pain of Impacted Mandibular 3rd Molar

Background: Evaluate the efficacy of using combination drug treatment to relieve post extraction pain of impacted mandibular third molar by using Naproxen plus Gabapentin versus Naproxen alone. Aim: To evaluate the efficacy of using combination drug treatment to relieve post extraction pain of impacted mandibular third molar by using Naproxen plus Gabapentin versus Naproxen alone. Methods: Randomized control study, outcome was evaluated by measuring Pre – Operative and 24-Hour Post – Operative Pain status on Visual Analogue Scale and Wong Baker’s Face Pain Rating Scale. Results: Combination therapy (Naproxen and Gabapentin) was effective in significant pain reduction at 12 Hour and 24-Hour Post Extraction period. With 26 patients out 31 presented with Pain Scale of 0 on combination therapy while only 3 out of 31 for naproxen alone after 24 hours. Conclusion: Enhanced effect of combination therapy of naproxen with gabapentin in reducing post extraction pain of impacted mandibular third molar with respect to naproxen alone. Keywords: Naproxen, Gabapentin, Combination Therapy, Post Extraction Pain, Post Extraction Analgesia, Efficacy.

Design principles to assemble drug combinations for effective tuberculosis therapy using interpretable pairwise drug response measurements

A challenge in designing treatment regimens for tuberculosis is the necessity to use three or more antibiotics in combination. The combination space is too large to be comprehensively assayed; therefore, only a small number of possible combinations are tested. We narrowed the prohibitively large search space of combination drug responses by breaking down high-order combinations into units of drug pairs. Using pairwise drug potency and drug interaction metrics from in vitro experiments across multiple growth environments, we trained machine learning models to predict outcomes associated with higher-order combinations in the BALB/c relapsing mouse model, an important preclinical model for drug development. We systematically predicted treatment outcomes of >500 combinations among twelve antibiotics. Our classifiers performed well on test data and predicted many novel combinations to be improved over bedaquiline + pretomanid + linezolid, an effective regimen for multidrug-resistant tuberculosis that also shortens treatment in BALB/c mice compared to the standard of care. To understand the design features of effective drug combinations, we reformulated classifiers as simple rulesets to reveal guiding principles of constructing combination therapies for both preclinical and clinical outcomes. One example ruleset is to include a drug pair that is synergistic in dormancy and another pair that is potent in a cholesterol-rich growth environment. These rulesets are predictive, intuitive, and practical, thus enabling rational construction of effective drug combinations based on in vitro pairwise drug synergies and potencies. As more preclinical and clinical drug combination data become available, we expect to improve predictions and combination design rules.

54 Sacubitril–valsartan (LCZ 696) improves longitudinal strain and ejection fraction in preclinical models treated with doxorubicin through NLRP3, MyD88, and pro-fibrotic chemokines

Aims Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sacubitril–valsartan (LCZ 696) is a combination drug, made up of neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan, used for the treatment of heart failure in patients with a reduced ejection fraction. We hypothesized that LCZ 696, administered during doxorubicin, could improve cardiac function and cardiac inflammation in preclinical models. Methods Human Foetal cardiomyocytes (HFC cell line) were exposed to subclinical concentration of doxorubicin (200 nM) alone or in combination with LCZ-696 (100 mM) for 72 h. After the incubation period, we performed the following tests: cell viability, apoptosis and necrosis; expression of malondialdehyde and 4-hydroxynonenal and concentration of intracellular Ca2+. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; NF-κB). C57Bl/6 mice were untreated (Sham, n = 6) or treated for 10 days with doxorubicin i.p. at 2.17 mg/kg (DOXO, n = 6), LCZ-696 at 60 mg/kg (LCZ, n = 6) or doxorubicin combined to LCZ-696 (DOXO-LCZ, n = 6). Ejection fraction, radial and longitudinal strain were analysed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, NF-kB, and 13 chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified. Results LCZ-696 exerts cardioprotective effects, enhancing cell viability of 48–54.6% compared to only doxorubicin-treated cells (P &lt; 0.001 for all); LCZ 696 decreased NLRP3, MyD88 and NF-kB expression in cardiac cells. In preclinical study, LCZ 696 improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of NLRP3, MyD88 and NF-kB in cardiac tissues was seen in DOXO-LCZ group compared to DOXO mice (P &lt; 0.001). Cardiac expression of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with LCZ-696 indicating anti-inflammatory properties. Conclusions LCZ-696 exerts direct beneficial effects in cardiomyocytes exposed to doxorubicin. In preclinical models, LCZ-696 reduced inflammation and cytokine expression involved in doxorubicin-mediated cardiotoxicity.

Investigation of the effects of mTOR inhibitors rapamycin and everolimus in combination with carboplatin on canine malignant melanoma cells

Background Malignant melanoma in dogs is considered to be largely resistant to conventional chemotherapy, although responses to carboplatin have been documented. Invasion and early metastasis are common features of certain melanoma subtypes that contribute to tumour progression despite aggressive local and systemic therapy. Upregulation of the PI3K/AKT/mTOR pathway has been observed in canine malignant melanoma and may represent a potential target for therapy. Rapamycin (sirolimus) and everolimus are commercially available small molecule inhibitors that target mTOR and therefore may have anticancer activity in canine melanoma. It was hypothesized that there is synergism between rapamycin or everolimus and platinum chemotherapy, and that combination drug treatment would inhibit target/downstream proteins involved in cell viability/proliferation and increase cell death in canine melanoma cells. It was further hypothesized that rapamycin or everolimus would impact metabolism by reducing glycolysis in these cells. Four canine melanoma cell lines were treated in vitro with rapamycin and everolimus as sole treatment or combined with carboplatin. Cell viability, apoptosis, target modulation, and glycolytic metabolism were evaluated by crystal violet colourimetric assay, Annexin V/PI flow cytometry, western blotting, and Seahorse bioanalyzer, respectively. Results When combined with carboplatin chemotherapy, rapamycin or everolimus treatment was overall synergistic in reducing cell viability. Carboplatin-induced apoptosis was noted at 72 h after treatment compared to the vehicle control. Levels of phosphorylated mTOR were reduced by rapamycin and everolimus in all four cell lines, but activation of the downstream protein p70S6K was not consistently reduced by treatment in two of the cell lines. Both mTOR inhibitors decreased the extracellular acidification rate of canine melanoma cells, indicating reduced cancer cell glycolytic activity. Conclusions Inhibition of mTOR by rapalogs, such as rapamycin and everolimus combined with carboplatin chemotherapy may have activity in canine melanoma. Future mechanistic investigation is warranted, including in vivo assessment of this combination therapy.