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Acute ischemic stroke continues to devastate millions of individuals worldwide. Current treatments work to restore blood flow but not rescue affected tissue. Our goal was to develop a combination of neuroprotective agents administered intra‐arterially following recanalization to target ischemic tissue. Using C57Bl/6J male mice, we performed tandem transient ipsilateral middle cerebral/common carotid artery occlusion, followed by immediate intra‐arterial pharmacotherapy administration through a standardized protocol. Two pharmacotherapy agents, verapamil and lubeluzole, were selected based on their potential to modulate different aspects of the ischemic cascade; verapamil, a calcium channel blocker, works in an acute fashion blocking L‐type calcium channels, whereas lubeluzole, an N‐methyl‐D‐aspartate modulator, works in a delayed fashion blocking intracellular glutamate trafficking. We hypothesized that combination therapy would provide complimentary and potentially synergistic benefit treating brain tissue undergoing various stages of injury. Physiological measurements for heart rate and pulse distention (blood pressure) demonstrated no detrimental effects between groups, suggesting that the combination drug administration is safe. Tissue analysis demonstrated a significant difference between combination and control (saline) groups in infarct volume, neuronal health, and astrogliosis. Although a significant difference in functional outcome was not observed, we did note that the combination treatment group had a greater percent change from baseline in forced motor movement as compared with controls. This study demonstrates the safety and feasibility of intra‐arterial combination therapy following successful recanalization and warrants further study.

Background/aim We describe a pharmacological strategy for selectively targeting glioblastoma using a redox-active combination drug menadione/ascorbate (M/A), compared to the chemotherapeutic standard-of-care temozolomide (TMZ). Materials and methods Experiments were conducted on glioblastoma mice (GS9L cell transplants - intracranial model), treated with M/A or TMZ. Tumor growth was monitored by magnetic resonance imaging. Effects of M/A and TMZ on cell viability and overproduction of mitochondrial superoxide were also evaluated on isolated glioblastoma cells (GS9L) and normal microglial cells (EOC2). Results M/A treatment suppressed tumor growth and increased survival without adverse drug-related side effects that were characteristic of TMZ. Survival was comparable with that of TMZ at the doses we have tested so far, although the effect of M/A on tumor growth was less pronounced than that of TMZ. M/A induced highly specific cytotoxicity accompanied by dose-dependent overproduction of mitochondrial superoxide in glioblastoma cells, but not in normal microglial cells. Conclusion M/A differentiates glioblastoma cells from normal microglial cells, causing redox alterations and oxidative stress only in the tumor. This easier-to-tolerate treatment has a potential to support the surgery and conventional therapy of glioblastoma.

This article presents the mechanisms of stress-induced autonomic dysfunction and insomnia development. The possibility of using combination drug Silenta in these states is discussed. The pharmacodynamics of its components and data of evidence-based medicine regarding their application are considered in detail. The mechanisms of stress-limiting action of magnesium (glutamate receptor antagonism) and L-tryptophan (a source of nicotinamide coenzymes, serotonin and melatonin) were described. A combination of extracts of Matricaria chamomilla flowers, Melissa officinalis leaves, Tilia platyphyllos Scop. will harmonize the balance of excitatory and inhibitory processes in the central nervous system. This combination will reduce psycho-emotional stress, irritability, anxiety, fears, psycho-vegetative manifestations and insomnia.

Sulfamethoxazole and trimethoprim are synthetic bacteriostatic drugs. A potentiometric multisensory system for the analysis of sulfamethoxazole and trimethoprim combination drugs was developed. Perfluorosulfonic acid membranes containing functionalized CNTs were used as the sensor materials. The CNTs’ surface was modified by carboxyl, sulfonic acid, or (3-aminopropyl)trimethoxysilanol groups. The influence of the CNT concentration and the properties of their surface, as well as preliminary ultrasonic treatment of the polymer and CNT solution before the casting of hybrid membranes, on their ion-exchange capacity, water uptake, and transport properties was revealed. Cross-sensitivity of the sensors to the analytes was achieved due to ion exchange and hydrophobic interactions with hybrid membranes. An array of cross-sensitive sensors based on the membranes containing 1.0 wt% of CNTs with sulfonic acid or (3-aminopropyl)trimethoxysilanol groups enabled us to provide the simultaneous determination of sulfamethoxazole and trimethoprim in aqueous solutions with a concentration ranging from 1.0 × 10−5 to 1.0 × 10−3 M (pH 4.53–8.31). The detection limits of sulfamethoxazole and trimethoprim were 3.5 × 10−7 and 1.3 × 10−7 M. The relative errors of sulfamethoxazole and trimethoprim determination in the combination drug as compared with the content declared by the manufacturer were 4% (at 6% RSD) and 5% (at 7% RSD).

Peripheral keratitis (PK) is a group of destructive inflammatory diseases of the juxtalimbal corneal stroma that are associated with an epithelial defect, the presence of inflammatory cells in the stroma, and progressive destruction of the corneal stroma. The causes of PK may be as follows: pathology of the eyelids and skin diseases, systemic infectious diseases, as well as a number of non-infectious immune disorders and diffuse connective tissue diseases. The clinical picture of peripheral infectious keratitis (PIK) is characterized by the formation of infiltrates on the periphe­ry of the cornea and the formation of crescent-shaped ulcerations of the cornea. PIK are most common in inflammatory diseases of the conjunctiva, the edges of the eyelids (in seborrheic blepharitis, staphylococcal blepharitis, and rosacea). Differential diagnosis of PIK must be performed with keratitis in case of systemic connective tissue diseases, marginal keratitis in case of lagophthalmos, Mooren’s ulcer, autoimmune diseases of the body involving the mucous membranes and surface of the eye in the pathological process. The main principles of PIC treatment are finding out the cause, controlling the inflammatory process and stimulating corneal regeneration. In the comprehensive therapy for PIK, antibiotics, collagenase inhibitors, reparative drugs, artificial tears, mydriatics are used, as well as combination drugs, which include a bactericidal antibiotic and a corticosteroid. For the treatment of PK associated with the disease of the edges of the eyelids and skin, a combination of antibacterial and glucocorticoid drugs is necessary with control of the underlying disease., Периферические кератиты (ПК) — это группа деструктивных воспалительных заболеваний стромы юксталимбальной роговицы, которые ассоциируются с дефектом эпителия, присутствием клеток воспаления в строме и прогрессирующим расплавлением стромы роговицы. Причинами развития ПК могут быть патология век и заболевания кожи, системные инфекционные заболевания, а также ряд неинфекционных иммунных расстройств и диффузных болезней соединительной ткани. Клиническая картина периферических инфекционных кератитов (ПИК) характеризуется формированием инфильтратов на периферии роговицы и образованием серповидных изъязвлений роговицы. ПИК наиболее часто встречаются при воспалительных заболеваниях конъюнктивы, краев век (при себорейных блефаритах, стафилококковых блефаритах, а также розацеа). Дифференциальную диагностику ПИК необходимо проводить с кератитами при системных заболеваниях соединительной ткани, краевым кератитом при лагофтальме, язвой Мурена, аутоиммунными заболеваниями организма с вовлечением в патологический процесс слизистых оболочек и поверхности глаза. Главными принципами лечения ПИК являются выяснение причины, контроль над воспалительным процессом и стимуляция регенерации роговицы. В комплексной терапии ПИК используют антибиотики, ингибиторы коллагеназы, репаративные, слезозаместительные препараты, мидриатики, а также комбинированные препараты, в состав которых входит бактерицидный антибиотик и кортикостероид. Для лечения ПК, ассоциированных с заболеванием краев век и кожи, необходима комбинация антибактериальных и глюкокортикоидных препаратов с конт­ролем основного заболевания., Периферичні кератити (ПК) — це група деструктивних запальних захворювань строми юксталімбальної рогівки, що асоціюються з дефектом епітелію, присутністю клітин запалення у стромі і прогресуючим розплавленням строми рогівки. Причинами розвитку ПК можуть бути патологія повік і захворювання шкіри, системні інфекційні захворювання, а також низка неінфекційних імунних розладів і дифузних хвороб сполучної тканини. Клінічна картина периферичних інфекційних кератитів (ПІК) характеризується формуванням інфільтратів на периферії рогівки і утворенням серпоподібних виразок рогівки. ПІК найбільш часто зустрічаються при запальних захворюваннях кон’юнктиви, країв повік (при себорейних блефаритах, стафілококових блефаритах, а також розацеа). Диференційну діагностику ПІК необхідно проводити з кератитами при системних захворюваннях сполучної тканини, крайовим кератитом при лагофтальмі, виразкою Мурена, автоімунними захворюваннями організму з залученням до патологічного процесу слизових оболонок і поверхні ока. Головними принципами лікування ПІК є з’ясування причини, контроль над запальним процесом і стимуляція регенерації рогівки. У комплексній терапії ПІК використовують антибіотики, інгібітори колагенази, репаративні, сльозозамісні препарати, мідріатики, а також комбіновані препарати, до складу яких входить бактерицидний антибіотик і кортикостероїд. Для лікування ПК, асоційованих із захворюванням країв повік і шкіри, необхідна комбінація антибактеріальних і глюкокортикоїдних препаратів із контролем основного захворювання.

Results of foreign and Russian studies indicate a higher mortality rate of patients with concomitant cardiovascular diseases (CVD) due to the new coronavirus infection COVID-19. It has been proven that arterial hypertension, as one of the significant risk factors for the development of concomitant cardiovascular diseases, is associated with a more severe prognosis of COVID-19. This article presents the results of modern studies and large meta-analyzes of necessity and safety of the use of blockers of the renin-angiotensin-aldosterone system in patients with arterial hypertension and COVID-19. The data of studies show that an angiotensin-converting enzyme inhibitor (ACE inhibitor) and a thiazide-like diuretic is a pathogenetically rational combination. It realizes various ways of lowering blood pressure by reducing the activity of the renin-angiotensin-aldosterone system, which is achieved by using an ACE inhibitor, and natriuresis due to diuretics. As an example, a highly effective fixed combination of drugs is considered, characterized by good tolerance, which consists of an ACE inhibitor lisinopril and a thiazide-like diuretic indapamide of prolonged action. The authors expressed the opinion that the appointment of the fixed combination drug Diroton Plus (Gedeon Richter) will contribute to effective control of blood pressure and organoprotection in conditions of increased thrombogenic and prooxidative potential, characteristic of COVID-19 both in the acute stage and within the post-COVID Syndrome.Данные зарубежных и российских исследований свидетельствуют о более высокой смертности пациентов с сопутствующими сердечно- сосудистыми заболеваниями вследствие новой коронавирусной инфекции COVID-19. Доказано, что артериальная гипертензия как один из значимых факторов риска развития сердечно-сосудистых заболеваний связана с более тяжелым прогнозом COVID-19. В статье представлены результаты современных исследований и крупных метаанализов о необходимости и безопасности применения блокаторов ренин-ангиотензин-альдостероновой системы у пациентов с артериальной гипертензией и COVID-19. Приведены данные, свидетельствующие о том, что патогенетически оправданной рациональной комбинацией является сочетание ингибитора ангиотензинпревращающего фермента (ИАПФ) и тиазидоподобного диуретика. Данная комбинация препаратов реализует различные пути снижения артериального давления посредством уменьшения активности ренин-ангиотензин-альдостероновой системы, которое достигается применением ИАПФ, и натриуреза за счет диуретиков. В качестве примера рассматривается высокоэффективная фиксированная комбинация препаратов, характеризующаяся хорошей переносимостью, которая состоит из ИАПФ лизиноприла и тиазидоподобного диуретика индапамида пролонгированного действия. Авторами высказано мнение, что назначение фиксированного комбинированного препарата Диротон Плюс (компания Гедеон Рихтер) будет способствовать эффективному контролю уровня артериального давления и органопротекции в условиях повышения тромбогенного и прооксидативного потенциала, свойственного COVID-19 как в острой стадии, так и в рамках постковидного синдрома.

In this paper a simple, accurate and precise RP-HPLC method for the simultaneous. Estimation of piracetam and citicoline in synthetic mixtures has been developed and validated. Separation of drugs was carried out using buffer and Acetonitryle with proportion of 60:40 %v/v as mobile phase at 5 min. run time and 265nm. The Rt value for piracetam and citicoline was found to be 3.158 and 5.196 min respectively. The developed method has been validated for linearity, accuracy and precision, LOD, LOQ, and system suitability according to ICH guidelines. The low values of LOD and LOQ illustrate that the developed method was sensitive, accurate, and precise as it can detected and quantify with very low concentration. The low % RSD values below 2 indicate that the method is precise. The above validation studies revealed the method is specific, rapid, reliable, and reproducible. The high recovery and low relative standard deviation confirm the suitability of the method for routine determination of piracetam and citicoline in combined dose products.

Conventional chemotherapy is still of great utility in oncology and rationally constructing combinations with it remains a top priority. Drug-induced mitochondrial apoptotic priming, measured by dynamic BH3 profiling (DBP), has been shown in multiple cancers to identify drugs that promote apoptosis in vivo. We therefore hypothesized that we could use DBP to identify drugs that would render cancers more sensitive to conventional chemotherapy. We found that targeted agents that increased priming of non-small cell lung cancer (NSCLC) tumor cells resulted in increased sensitivity to chemotherapy in vitro. To assess whether targeted agents that increase priming might enhance the efficacy of cytotoxic agents in vivo as well, we carried out an efficacy study in a PC9 xenograft mouse model. The BH3 mimetic navitoclax, which antagonizes BCL-xL, BCL-w, and BCL-2, consistently primed NSCLC tumors in vitro and in vivo. The BH3 mimetic venetoclax, which electively antagonizes BCL-2, did not. Combining navitoclax with etoposide significantly reduced tumor burden compared to either single agent, while adding venetoclax to etoposide had no effect on tumor burden. Next, we assessed priming of primary patient NSCLC tumor cells on drugs from a clinically relevant oncology combination screen (CROCS). Results confirmed for the first time the utility of BCL-xL inhibition by navitoclax in priming primary NSCLC tumor cells and identified combinations that primed further. This is a demonstration of the principle that DBP can be used as a functional precision medicine tool to rationally construct combination drug regimens that include BH3 mimetics in solid tumors like NSCLC.

Objective — to conduct an in-depth search of foreign and national literary sources, in particular, reports about the results of randomized controlled clinical trials regarding the use of local combination drugs for the treatment of psoriatic onychodystrophy. The focus is on both short-term and long-term therapeutic effects, as well as minimizing the side effects. Materials and methods. We conducted the analysis of the world experience of using the local combination drug Onychocid® Emtrix for the treatment of psoriatic onychodystrophy and minimization of side effects by searching for data (2010—2021) in the Cochrane Library controlled tests by keywords: psoriasis, onychodystrophy; in PubMed, High Wire Press, Google Scholar — by terms of the catalog and medical subjects: psoriasis + onychodystrophy + treatment; reports of randomized controlled clinical trials, meta-analyses and literature reviews. Results and discussion. The modern view on the problem of psoriatic onychodystrophy, methods and approaches to the treatment of this pathology are presented.According to the analysis of the results of foreign and national studies, Onychocid® Emtrix is proved to be clinically efficient and safe as complex treatment for various clinical forms of psoriatic onychodystrophy. It contains a combination of propylene glycol, urea and lactic acid. Active substances, which are part of the drug, are synergists, which provides triple action of ingredients — combining moisturizing and keratolytic effects with antifungal properties. Most patients showed an early (in the 2nd to 4th week of use of the drug) improvement in the appearance of the affected nails. In the future, they observed thinning of nail plates, color restoration, disappearance of excessively keratinized nail tissue, tendency to the restoration of the integrity of nails. The use of this topical medication provided high compliance due to an excellent profile of tolerance and the possibility of application once a day. Conclusions. It has been proven that the modern medication of local action Onychocid® Emtrix is currently the most optimal treatment for psoriatic onychodystrophy which allows achieving a therapeutic effect both in monotherapy and in the standard complex schemes. Treatment of psoriatic onychodystrophy with Onychocid® Emtrix is more effective in comparison with standard therapy, contributes to a rapid partial or full restoration of the integrity of nail plates. The high effectiveness and safety of Onychocid® Emtrix give reason to recommend it for inclusion in the schemes of complex treatment of patients with psoriatic onychodystophy.

Acute abdominal pain, a set of symptoms developing in patients having pathology of the gastrointestinal tract, abdominal cavity and retroperitoneal space, is known as one of the leading causes for surgical hospitalization both in Ukraine and abroad. The aim of this study was to evaluate the effects of a combination drug "Neospastil", which belongs to the group of antispasmodics in combination with analgesics, on the severity of symptoms of abdominal spastic pain in order to improve the treatment of patients. This clinical study included 90 patients with a clinical picture of abdominal pain syndrome, who were hospitalized to the surgical departments. The patients were divided into 3 groups, 30 patients in each. We used various options for antispasmodic and analgesic therapy and compared their effectiveness in terms of the time of the onset of the analgesic effect, the time period of relieving abdominal spasm, and the duration of the periods between repeated spastic pain attacks. The results of our study demonstrated the use of the combined drug "Neospastil" in the management of acute abdominal pain syndrome even in the first day enabled to reduce the severity of the pain syndrome by 38% compared with the drotaverine therapy and by 19% compared with analogues of the combined drugs. The period of the occurrence of subsequent spastic pains was prolonged with the study drug by 2.2 ± 0.5 hours compared with drotaverine and by 1.1 ± 0.1 hours compared with spasmalgon. When using “Neospastil”, a decrease in the duration of an attack of abdominal spasm was noted by 29% compared with drotaverine and by 22% compared with spasmalgon. Summarizing the obtained data, we can recommend the use of “Neospastil” for the primary therapy of abdominal spastic pain in surgical patients that will lead to an improvement in the clinical treatment outcomes.

Resistance to single-agent chemotherapy and molecularly targeted drugs prevents sustained efficacy of treatments. To address this challenge, combination drug treatments have been used to improve outcomes for patients. Potential toxicity of combination treatments is a major concern, however, and has led to the failure of several clinical trials in different cancers. The use of cell-based models of normal tissues in preclinical studies enables testing and identifying toxic effects of drug combinations and facilitates an informed decision-making process for advancing the treatments to animal models and clinical trials. Recently, we established that combinations of molecular inhibitors of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase-protein kinase B (PI3K/Akt) pathways effectively and synergistically inhibit growth of BRAFmut and KRASmut colorectal tumor spheroids by blocking feedback signaling of downstream kinase pathways. These pathways are important for cell proliferation, however, and their simultaneous inhibition may cause toxicity to normal cells. We used a cellular spheroid model to study toxicities of drug combinations to human bone marrow and colon. Our results indicated that MAPK and PI3K/Akt inhibitors used simultaneously were only moderately toxic to bone marrow cells but significantly more toxic to colon cells. Our molecular analysis of proliferative cell activities and housekeeping proteins further corroborated these results. Overall, our approach to identify toxic effects of combinations of cancer drugs to normal cells in three-dimensional cultures will facilitate more informed treatment selections for subsequent animal studies.

Combination drug therapies have become an integral part of precision oncology, and while evidence of clinical effectiveness continues to grow, the underlying mechanisms supporting synergy are poorly understood. Immortalized human lymphoblastoid cell lines (LCLs) have been proven as a particularly useful, scalable and low-cost model in pharmacogenetics research, and are suitable for elucidating the molecular mechanisms of synergistic combination therapies. In this review, we cover the advantages of LCLs in synergy pharmacogenomics and consider recent studies providing initial evidence of the utility of LCLs in synergy research. We also discuss several opportunities for LCL-based systems to address gaps in the research through the expansion of testing regimens, assessment of new drug classes and higher-order combinations, and utilization of integrated omics technologies.

Background Dirofilaria immitis, a globally distributed filarial parasite of dogs, is known to cause serious or fatal cardiopulmonary disease. Client-owned dogs were enrolled in a clinical field study in the USA to evaluate the clinical effectiveness and field safety of an orally administered combination investigational product (IP) containing milbemycin oxime and lotilaner (Credelio® Plus) as compared to a control product (CP) for the prevention of heartworm disease when administered monthly for 11 consecutive months. Methods In this 11-month field study, 319 dogs ≥ 8 weeks old confirmed to be heartworm-negative were enrolled from eight geographically distinct US veterinary clinics, including sites in the southern USA and Mississippi River Valley. The dogs were treated with either the IP combination product at 0.75–1.53 mg/kg milbemycin oxime and 20–41.5 mg/kg lotilaner (n = 159) or the CP (Sentinel® Flavor Tabs®; milbemycin oxime/lufenuron) at the label-recommended dose rate (n = 158.) On day 330, effectiveness was evaluated in each dog using antigen and microfilarial (modified Knott’s) testing to assess the establishment of any patent adult heartworm infections. Results All dogs treated with the IP combination product and the CP tested negative (100% prevention) for heartworm infection on day 330. The IP combination product tablets containing milbemycin oxime and lotilaner were well tolerated based on the safety assessments in all treated dogs. Conclusions This multi-site clinical study using client-owned dogs demonstrated that monthly use of flavored, chewable tablets containing a combination of milbemycin oxime and lotilaner administered orally under end use conditions is safe for dogs. None of the enrolled dogs developed heartworm infections. Eleven consecutive monthly treatments of the IP provided 100% prevention of heartworm disease caused by D. immitis. Graphical Abstract

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk ALL subtype with high rates of relapse and poor patient outcome. Activating mutations affecting components of the JAK-STAT signaling pathway occur in the majority of Ph-like ALL cases. The use of JAK inhibitors represents a potential treatment option for Ph-like ALL, although we and others have shown that CRLF2-rearranged Ph-like ALL responds poorly to single-agent JAK inhibitors in the preclinical setting. Therefore, the aim of this study was to identify effective combination treatments against CRLF2-rearranged Ph-like ALL, and to elucidate the underlying mechanisms of synergy. We carried out a series of high-throughput combination drug screenings and found that ruxolitinib exerted synergy with standard-of-care drugs used in the treatment of ALL. In addition, we investigated the molecular effects of ruxolitinib on Ph-like ALL by combining mass spectrometry phosphoproteomics with gene expression analysis. Based on these findings, we conducted preclinical in vivo drug testing and demonstrated that ruxolitinib enhanced the in vivo efficacy of an induction-type regimen consisting of vincristine, dexamethasone, and L-asparaginase in 2/3 CRLF2-rearranged Ph-like ALL xenografts. Overall, our findings support evaluating the addition of ruxolitinib to conventional induction regimens for the treatment of CRLF2-rearranged Ph-like ALL.

At a meeting held on 20 May 2021, reviewed the available literature on the use of the medicinal product Bijuva® for the relief of menopausal symptoms.

Introduction: Approximately 300,000 women worldwide are diagnosed each year with ovarian cancer. Frequently diagnosed in late stages with ambiguous symptomatology, ovarian cancer has a low survival rate.Areas covered: Niraparib, a PARP inhibitor, was approved in 2020 for use in the maintenance treatment of ovarian cancer regardless of biomarker status. Included in the review are PRIMA (NCT02655016), NOVA (NCT01847274), AVANOVA2 (NCT02354131), and QUADRA (NCT02354586) trials which herald the advent of using maintenance oral therapies in the treatment of ovarian cancer. Additionally, with new combination drug trials, exciting avenues for treatment are also discussed with the FIRST (NCT03016338) trial.Expert opinion: Maintenance niraparib treatment regardless of genetic profile offers a new modality for the treatment of ovarian cancer with a low side effect profile and importantly oral dosing. New combinations of synergistic immunotherapeutics, and antiangiogenesis therapies with niraparib also offer exciting new frontiers for patients with ovarian cancer.

To develop immunoliposomes modified with monoclonal cancer-specific antibody (mAb) 2C5 and co-loaded with a combination of two chemotherapeutics, in order to simultaneously target bulk cancer cells using paclitaxel and cancer stem cells (CSCs) using salinomycin to prevent cancer growth and metastases. Breast cancer cells (MDA-MB-231 and/or SK-BR-3) were chosen as models for all in vitro testing. Liposomes composed of natural phospholipids co-loaded with salinomycin and paclitaxel were prepared and physically characterized. Immunoliposomes modified with mAb 2C5 coupled to polymeric conjugate were prepared and characterized for specific targeting. Wound healing assay was performed using the combination of free drugs in vitro. In vitro studies on cellular interaction and uptake were followed by holographic imaging to study cell-killing, cell-division and proliferation inhibiting effects of the formulation. Ex-vivo study on hemolysis was investigated to check possible toxicity of the formulation. Physical characterization of the liposomes showed stable nanoparticles of consistent and desirable size range (170-220 nm), zeta potential (-13 mV to – 20 mV), polydispersity indices (

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in regulating cell growth, survival, and metastasis. STAT3 signaling is constitutively activated in various types of hematologic or solid malignancies. YHO-1701 has been developed as an orally available STAT3 inhibitor. Herein, YHO-1701 in combination with molecular-targeted agents was evaluated. Additive or synergistic effects were observed in a broad spectrum of “combination treatment + cell line” pairs. Of particular interest was the synergistic effect observed when YHO-1701 was combined with imatinib or dasatinib [breakpoint cluster region-abelson (BCR-ABL) inhibitors], osimertinib [epidermal growth factor receptor (EGFR) inhibitor], crizotinib, alectinib, or ceritinib [anaplastic lymphoma kinase (ALK) inhibitors]. The results further showed a close relationship between these synergistic effects and the cellular levels of the key molecules involved in the target pathways for YHO-1701 and each combination drug. The combination of YHO-1701 with alectinib resulted in a significantly greater antitumor activity without exhibiting body weight loss in an NCI-H2228 [echinoderm microtubule–associated protein-like 4 (EML4)-ALK fusion] xenograft mouse model. Our results strongly suggest that the logical strategy in combination with the novel STAT3 inhibitor YHO-1701 and other mechanistically different targeted agents could be a promising approach in the clinical setting.

Objectives The objective of this review was to compare the effectiveness of Colistin monotherapy and combination therapy for the treatment of multidrug-resistant gram-negative bacterial infections. Data sources PubMed, Cochrane Library. Study eligibility interventions and exclusions In this systematic review, we included all retrospective and prospective studies and randomized controlled trials (RCTs) that compared intravenous polymyxin monotherapy and combination therapy with any other antibiotic for treating multidrug-resistant infections. Studies using inhaled polymyxins with 5 or less than 5 patients were excluded. The primary outcome was 30-day all-cause mortality and if not reported at day 30 we extracted and documented the closest time point. Both crude outcome rates and adjusted effect estimates were extracted for mortality. Study appraisal data extraction and synthesis Search string used was "(Colistin OR polymyxin) AND (Enterobacteriaceae OR Klebsiella OR Acinetobacter OR Escherichia coli OR Pseudomonas) AND (random OR prospective OR retrospective OR cohort OR observational OR blind)." Thirty-nine studies were included in our analysis; out of which 6 RCTs were included and 9 studies used carbapenem as the adjunctive antibiotic. Each study was screened and reviewed for eligibility independently by two authors and data extrapolated on an Excel sheet. Results The meta-analysis of polymyxin monotherapy vs. combination therapy in multidrug-resistant infections yielded an odds ratio (OR) of 0.81 (95% confidence interval [CI]: 0.65-1.01) with minimal heterogeneity (I 2 = 40%), whereas pooled analysis of this comparison in studies that included carbapenem as combination therapy yielded an OR of 0.64 (CI: 0.40-1.03; I 2 = 62%). Likewise, the pooled analysis of the RCTs yielded an OR of 0.82 (95% CI: 0.58-1.16, I 2 = 22%). All these showed no statistical significance. However, it was seen that polymyxin combination therapy was more effective in multidrug-resistant infections compared to polymyxin monotherapy. The effectiveness was more glaring when carbapenems were used as the combination drug instead of any other antibiotic and more so in many in vitro studies that used polymyxin combination therapy. Conclusion Although statistically insignificant, it would be prudent to use polymyxin combination therapy to treat multidrug-resistant gram-negative bacilli (GNB) infection over monotherapy with preference to use carbapenem as the adjunct alongside polymyxins. How to cite this article Samal S, Mishra SB, Patra SK, Rath A, Dash A, Nayak B, et al. Polymyxin Monotherapy vs. Combination Therapy for the Treatment of Multidrug-resistant Infections: A Systematic Review and Meta-analysis. Indian J Crit Care Med 2021;25(2):199-206.

Ecstasy use is commonly combined with ethanol consumption. While combination drug use in general is correlated with a higher risk for toxicity, the risk of the specific combination of ecstasy (3,4-methylenedioxymethamphetamine (MDMA)) and ethanol is largely unknown. Therefore, we have reviewed the literature on changes in MDMA pharmacokinetics and pharmacodynamics due to concurrent ethanol exposure in human, animal and

Chronic Obstructive Pulmonary Disease (COPD) is a chronic airway inflammation with resulting progressive airflow limitation that has a high incidence, morbidity, and mortality. Roflumilast is an oral phosphodiesterase-4 inhibitor as a therapy to decrease the risk of COPD exacerbations in patients with moderate-severe COPD with a history of chronic bronchitis. Roflumilast can be given orally once daily as a single or combination drug. It can be used as COPD moderate-severe but also more beneficial as COPD mild treatment. The efficacy of Roflumilast can prevent exacerbations of repetition and can fixed lung function both in terms of FEV1 and vital capacity to force. The incidence of side effects, which are diarrhea and digestive disorders. The cost-effectiveness showed that Quality of life patient with Roflumilast is better than the group without additional. This paper aimed to review systematically Roflumilast as COPD treatment for the clinical application.Keywords : COPD, Roflumilast, phosphodiesterase-4 inhibitorCorrespondence : fauna@staff.ubaya.ac.id

Summary Objectives The pharmaceutical industry and the National Regulatory Authorities (NRAs) are now focusing on the dissolution of multi-component drugs for quality control testing and predicting in vivo results to further consolidation of the biowaiver concept. The mixed formulation of Ciprofloxacin hydrochloride (CIP) and Metronidazole (MET) have been used as a model for simultaneous determination and obtaining in vitro dissolution profiles by using green analysis method namely (UV-CWT(Db4, a=490)). Material and methods The proposed method (UV-CWT(Db4, a=490)) includes UV detection combined with Continuous Wavelet Transform (CWT) with Daubechies family and the order of fourth at the scaling factor (a = 490) has been used and validated for analyzing and obtaining the dissolution profiles of the fixed-dose combination (CIP-MET). Results The proposed method (UV-CWT(Db4, a=490)) has been validated effectively in accordance with ICH rules, regarding linearity, specificity, rigor, and preciseness of the working range (3.0–16.0 μg/mL) for both (CIP) and (MET), respectively. As well as figures of merit were concluded. The dissolution profiles of CIP-MET tablets were acquired by the proposed (UV-CWT (Db4, a=490)) and HPLC reported methods were conveniently compared using the indicators f1 and f2 (“difference” and “similarity”) the results ensured that there were no statistically differences between the methods. In addition, the green assessment tool, namely analytical eco-scale, evaluated and compared the greenness of the suggested method (UV-CWT(Db4, a=490)) and HPLC reported one. Conclusion The suggested process (UV-CWT(Db4, a=490)) was considered as an excellent green, rapid, accurate, economical and minimum-steps method for simultaneously resolve and construct the dissolution curves of a fixed-dose combination drug (CIP-MET) in a short time and without the use of organic solvents, enabling significant labor and resource savings.

Background In spite of advances in the modern allopathic medicines, there is no satisfactory treatment of kidney stones, so formation and growth of calculi continues to trouble mankind. In India, many herbal formulations are in use for the treatment of urolithiasis. The purpose of the present study was to investigate the antiurolithiatic efficacy of combined extract of plants Dolichos biflorus (D.b) (hydroalcoholic seed extract) and Crataeva nurvala (C.n) (aqueous bark extract) in ethylene glycol-induced urolithiasis in Wistar rats. Rats were divided into 4 groups. Ethylene glycol (0.75% v/v, p.o.) was administered for 35 days. Different drug treatments were given from the 21st to 35th day of the study. On the last day, rats were sacrificed, and different samples were taken for further analysis. Results Both the combination drug treatments were found to be effective in treating urolithiasis. More significant protection was observed on treatment with the fraction ratio of D.b + C.n (3:1). Histopathology analysis showed degenerated glomeruli and inflammatory cells in urolithiasis control. The same were regenerated on treatment with combined extract of the two plants. Conclusion Administration of the combined plant extracts in a ratio of D.b + C.n (3:1) possesses better efficacy against ethylene glycol-induced urolithiasis in rats which may be evaluated further for mechanistic pathway elucidation in vivo.

Chemotherapy with combination drugs has become one of the most commonly used cancer prevention treatments, with positive clinical results. The goal of this study was to develop compostable polymeric nanomaterials (NMs) for the delivery of puerarin (PRN) and 5-fluorouracil (5FU), as well as to investigate the anticancer activity of the drug delivery system (PRN-5FU NMs) against in vitro and in vivo lung cancer cells. Since double antitumor drugs PRN and 5FU are insufficiently compressed in polymer-based bio-degradable nanoparticles, encapsulation of PRN and 5FU antitumor drugs were co-encapsulated with polyethylene glycol and polylactidecoglycolide nanoparticles (NMs) is efficient. The arrangement of PRN NMs, 5FU NMs, and PRN-5FU NMs, as well as the nanoparticles shape and scale, were studied using transmission electron microscopy (TEM). 5FU-PRN NMs triggered apoptosis in lung carcinoma cell lines such as HEL-299 and A549 in vitro. Acridine orange/ethidium bromide (AO/EB) and nuclear damaging staining techniques were used to observe morphologies and cell death. The mechanistic analysis of apoptosis was also confirmed by flow cytometry analysis using dual staining. When compared to free anticancer products, the hemolysis analysis findings of the 5FU-PRN NMs showed excellent biocompatibility. Taken together the advantages, this combination drug conveyance strategy exposed that 5FU-PRN NMs could have a significant promising to improve the effectiveness of lung cancer cells.

Psoriasis vulgaris is a chronic, immune-mediated disorder, which has a substantial impact on all aspects of patients’ quality of life. In most patients, the disease is mild to moderate and is successfully treated with topical agents. The most common therapy involves a vitamin D3 analogue (calcipotriene) in combination with a synthetic corticosteroid (betamethasone dipropionate). The aerosol vehicle (foam) with softening properties is another formulation of this combination drug, apart from ointment and gel, expanding the therapeutic options available to patients with psoriasis. The article describes the pharmacokinetic and pharmacodynamic properties of calcipotriene/betamethasone dipropionate foam. The results of the key randomised clinical studies investigating the efficacy, including patients’ quality of life and safety of the foam versus ointment, gel and either active ingredient in foam vehicle are presented. In addition, the results of a study on maintenance treatment with calcipotriene/betamethasone dipropionate foam as well as reports on real-world use of this medicine in patients with psoriasis, are discussed.

The development and review of combination drug regimens in oncology may present unique challenges to investigators and regulators. For regulatory approval of combination regimens, it is necessary to demonstrate the contribution of effect of each monotherapy to the overall combination. Alternative approaches to traditional designs may be needed to accelerate oncology drug development, for example, when combinations are substantially superior to available therapy, to reduce exposure to less effective therapies, and for drugs that are inactive as single agents and that in combination potentiate activity of another drug. These approaches include demonstration of activity in smaller randomized trials and/or monotherapy trials conducted in a similar disease setting. This article will discuss alternative approaches used in the development of approved drugs in combination, based on examples of recent approvals of combination regimens in renal cell carcinoma.

Aim: Traditional Japanese (Kampo) medicine has been used to treat viral infectious diseases In particular, saikatsugekito (a combination drug of kakkonto, shosaikoto, Platicodon glandiflorum root, and gypsum) has been reported to be useful during the past influenza pandemic The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide, causing the novel coronavirus disease (COVID-19) to emerge as a pandemic In this article, we conducted a literature review on the pharmacological activities of the components present in saikatsugekito against viral infection and respiratory inflammation Methods: We searched PubMed and the Cochrane Library for English articles, as well as Ichushi and J-stage for Japanese articles Articles published until January 1, 2000 were retrieved using the keywords ‘kakkonto’, ‘shosaikoto’, ‘Platycodon’, and ‘gypsum’ We then extracted articles on basic research investigating viral infections, inflammation, cytokine, the immune response, and lung tissue damage Results: We extracted 28 eligible articles Kampo medicines have antiviral activities by interfering with the attachment, internalization, replication, progeny virion release, and cell-to-cell spreading of single-strand RNA viruses They also enhance the immunomodulating activities of the host, including cytokine production, regulation of multiple immune cells, and protection from lung tissue injury Furthermore, Kampo medicine has been found to regulate body temperature and airway mucin release Conclusion: The results demonstrated that Kampo medicine has therapeutic activities against single-strand RNA virus infections and respiratory inflammation, and may also have activities against SARS-CoV-2 Further research is required to investigate the activity of Kampo medicines, such as saikatsugekito, against SARS-CoV-2

The article presents the results of analysis of works published over 25 years on the effectiveness and safety of interferon alpha-2b in combination with vitamins C and E for the treatment and prevention of congenital pneumonia. The purpose of the work is to summarize and evaluate the results of studies on the effectiveness and safety of the drug based on interferon alpha-2b in combination with ascorbic acid and alpha-tocopherol acetate in complex therapy and for the prevention of congenital pneumonia. Materials and methods . The analysis of available publications was carried out in accordance with the purpose. Selected studies that present the characteristics of the compared groups that received different therapies, conducted a qualitative analysis of the results and statistical processing of data. Results . We selected four researches out of more than a hundred publications, which provided data on the formation and characteristics of the compared groups, and a detailed analysis of the results obtained using statistical methods was carried. The efficacy and safety of interferon-based alpha-2b in combination with vitamins C and E were studied for the treatment of congenital pneumonia in 3 studies. The drug was evaluated of preventive effect in one study. Conclusions . The addition of a combination drug based on interferon alpha-2b in combination with vitamins C and E (Viferon ® ) leads to a significant reduction in the duration of symptoms, the period of hospitalization, the need for a ventilator, and the duration of isolation of pathogens to the treatment regimen for congenital pneumonia. Interferon therapy provides prevention of complications and repeated episodes of infectious diseases. The use of Viferon ® in pregnant women helps to reduce the risk of congenital pneumonia and improve the health indicators of newborns.