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Esophageal cancer (EC) is one of the most common cancers with high morbidity and mortality rates. EC includes two histological subtypes, namely esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC primarily occurs in East Asia, whereas EAC occurs in Western countries. The currently available treatment strategies for EC include surgery, chemotherapy, radiation therapy, molecular targeted therapy, and combinations thereof. However, the prognosis remains poor, and the overall five-year survival rate is very low. Therefore, achieving the goal of effective treatment remains challenging. In this review, we discuss the latest developments in chemotherapy and molecular targeted therapy for EC, and comprehensively analyze the application prospects and existing problems of immunotherapy. Collectively, this review aims to provide a better understanding of the currently available drugs through in-depth analysis, promote the development of new therapeutic agents, and eventually improve the treatment outcomes of patients with EC., Graphical abstract Esophageal cancer (EC) is one of the most common cancers worldwide. This review summarizes the latest developments in chemotherapy, molecular targeted therapy, and immunotherapy for EC.Image 1

Background Breast cancer is the most common cause of the majority of cancer-related deaths in women, among which triple-negative breast cancer is the most aggressive type of breast cancer diagnosed with limited treatment options. Thymoquinone (TQ), the main bioactive constituent of Nigella sativa, has been extensively studied as a potent anticancer molecule against various types of cancers. Honeybee products such as the royal jelly (RJ), the nutritive secretion fed to honeybee queens, exhibit a variety of biological activities besides its anticancer effect. However, the anticancer activity of the combination of TQ and RJ against breast cancer is still unknown. Aim To investigate cytotoxicity of RJ in FHs 74 Int cells and the anticancer effects of TQ, RJ, and their combinations in the MDA-MB-231 cell line. Methods Cells were treated with TQ, RJ, and their combinations for 24 h. Using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, we determined the half-maximal inhibitory concentration of TQ. Trypan blue and 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays were then performed to assess the cell viability in response to different treatment conditions. Cell death and cycle regulation were investigated using propidium iodide deoxyribonucleic acid staining followed by flow cytometry in response to a single dose of TQ, RJ, and their combination. Immunostaining for cleaved caspase 3 and Ki67 expression was used to determine apoptosis induction and changes in cell proliferation. Results TQ alone inhibited cell viability in a dose-dependent manner at concentrations below and above the half-maximal inhibitory concentration. RJ exhibited relatively nontoxic effects against MDA-MB-231 cells and FHs 74 Int small intestinal cells at concentrations below 5 µg/mL. High doses of RJ (200 µg/mL) had greater toxicity against MDA-MB-231 cells. Interestingly, the inhibition of cell viability was most pronounced in response to 15 µmol/L TQ and 5 µg/mL RJ. A dose of 15 µmol/L TQ caused a significant increase in the PreG1 population, while a more pronounced effect on cell viability inhibition and PreG1 increase was observed in response to TQ and RJ combinations. TQ was the main inducer of caspase 3-dependent apoptosis when applied alone and in combination with RJ. In contrast, no significant regulation of Ki67 expression was observed, indicating that the decrease in cell viability was due to apoptosis induction rather than to inhibition of cell proliferation. Conclusion This study is the first to report enhanced anticancer effects of TQ and RJ combination against MDA-MB-231 breast cancer cells, which could confer an advantage for cancer therapy.

Chagas disease is a neglected tropical disease caused by the protozoan Trypanosoma cruzi. Currently, only nitroheterocyclic nifurtimox (NFX) and benznidazole (BNZ) are available for the treatment of Chagas disease, with limitations such as variable efficacy, long treatment regimens and toxicity. Different strategies have been used to discover new active molecules for the treatment of Chagas disease. Target-based and phenotypic screening led to thousands of compounds with anti-T. cruzi activity, notably the nitroheterocyclic compounds, fexinidazole and its metabolites. In addition, drug repurposing, drug combinations, re-dosing regimens and the development of new formulations have been evaluated. The CYP51 antifungal azoles, as posaconazole, ravuconazole and its prodrug fosravuconazole presented promising results in experimental Chagas disease. Drug combinations of nitroheterocyclic and azoles were able to induce cure in murine infection. New treatment schemes using BNZ showed efficacy in the experimental chronic stage, including against dormant forms of T. cruzi. And finally, sesquiterpene lactone formulated in nanocarriers displayed outstanding efficacy against different strains of T. cruzi, susceptible or resistant to BNZ, the reference drug. These pre-clinical results are encouraging and provide interesting evidence to improve the treatment of patients with Chagas disease.

Adiponectin (Acrp30) and leptin, adipokines produced and secreted mainly by the adipose tissue, are involved in human carcinogenesis. Thyroid carcinomas are frequent endocrine cancers, and several evidences suggest that they are correlated with obesity. In this study, we first analyzed the expression levels and prognostic values of Acrp30, leptin, and their receptors in thyroid cancer cells. Then, we investigated the role of Acrp30 and leptin in proliferation, migration, and invasion. We found that Acrp30 treatment alone inhibits cell proliferation and cell viability in a time and dose-dependent manner; leptin alone does not influence thyroid cancer cells (BCPAP and K1) proliferation, but the combined treatment reverts Acrp30-induced effects on cell proliferation. Additionally, through wound healing and Matrigel Matrix invasion assays, we unveiled that Acrp30 inhibits thyroid cancer cell motility, while leptin induces the opposite effect. Importantly, in the combined treatment, Acrp30 and leptin exert antagonizing effects on papillary thyroid cancer cells’ migration and invasion in both BCPAP and K1 cell lines. Highlights of these studies suggest that Acrp30 and leptin could represent therapeutic targets and biomarkers for the management of thyroid cancer. Supplementary Information The online version contains supplementary material available at 10.1007/s13105-021-00789-x.

Successful clinical drug development requires rational design of combination treatments based on preclinical data. Anti-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-hepatitis C virus (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.

Background: Post-surgical pain is a challenging problem. Different modifications of surgical procedures and use of different analgesics had been reported. However, no consensus had been reached for post-surgical pain control. Tonsillectomy is one of the most commonly performed surgical procedure and pain control still controversial. Aim of the work:To investigation safety and efficacy of intravenous paracetamol, ibuprofen, or both for post-tonsillectomy pain control. Patients and Methods:The study had been carried at Otorhinolaryngology and Eye, Al-Jabr hospital,Anesthesia and Intensive Care Department in collaboration with Otorhinolaryngology department and the day care surgery unit], Al-Ahasa directorate, Kingdom of Saudi Arabia [KSA]. It included children aged 2 to 10 years. Patients had been randomly allocated into 3 equal groups [each 30 patients]. Group A [intravenous paracetamol 15mg/kg], Group B [intravenous ibuprofen 10mg/kg], and Group C [intravenous paracetamol 7.5 mg/kg and ibuprofen 5mg/kg]. The examined drug had been administrated 20 minutes after induction of general anesthesia. The analgesic effects and hemodynamics had been assessed on regular postoperative intervals till patient discharge, and patient satisfaction had been addressed. Any side effects and need for postoperative analgesia had been documented. Results: Studied groups were comparable regarding patient demographics, recovery time, hospital stay duration and need for additional analgesia. However, pain was significantly variable between studied groups till 3 hours postoperatively. Pain was significantly reduced at groups B [IV ibuprofen] and C [IV paracetamol and Ibuprofen with reduced dose] when compared to group A [IV paracetamol] at all times. In addition, hemodynamic variability was observed for mean arterial pressure and heart rate. At five minutes, blood pressure was significantly higher in group B when compared to group C, and at 5 minutes to 2.5 hours, it was significantly increased among group A when compared to group C. Conclusion: Drug combination with reduced [half the dose] of both intravenous paracetamol and ibuprofen is more effective and safer than single drug with higher dose. The studied drugs avoid the well-known side effects of opioids.

OBJECTIVE: The aim of this study was to investigate the effects of neuromuscular electric stimulation applied to the erector spinae on balance, motor function and functional capacity in patients with stroke in a randomized controlled trial. METHODS: Sixty patients with stroke were recruited and randomly distributed into two groups: control group and neuromuscular electric stimulation group. All participants underwent conventional physical therapy five times a week for six weeks. The neuromuscular electric stimulation group received additional electrical stimulation. Outcome measures were evaluated with Brunnel Balance Assessment, Stroke Rehabilitation Movement Assessment, Functional Ambulation Classification, Adapted Patient Evaluation and Conference System, Postural Assesment Scale for Stroke patients, Short Form-36, and Minimental State Examination scales. RESULTS: Significant differences were observed in all scores at the end of the study in both groups. Postural Assesment Scale for Stroke patients and Stroke Rehabilitation Movement Assessment scores were higher in the neuromuscular electric stimulation group compared to the control group (p

Given the scale and rapid spread of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is an urgent need for medicines that can help before vaccines are available. In this study, we present a viral-associated disease-specific chemogenomics knowledgebase (Virus-CKB) and apply our computational systems pharmacology-target mapping to rapidly predict the FDA-approved drugs which can quickly progress into clinical trials to meet the urgent demand of the COVID-19 outbreak. Virus-CKB reuses the underlying platform of our DAKB-GPCRs but adds new features like multiple-compound support, multi-cavity protein support and customizable symbol display. Our one-stop computing platform describes the chemical molecules, genes and proteins involved in viral-associated diseases regulation. To date, Virus-CKB archived 65 antiviral drugs in the market, 107 viral-related targets with 189 available 3D crystal or cryo-EM structures and 2698 chemical agents reported for these target proteins. Moreover, Virus-CKB is implemented with web applications for the prediction of the relevant protein targets and analysis and visualization of the outputs, including HTDocking, TargetHunter, BBB predictor, NGL Viewer, Spider Plot, etc. The Virus-CKB server is accessible at https://www.cbligand.org/g/virus-ckb.

Context Naoxintong Capsule (NXT), a Chinese medicine, has been widely used for the treatment of coronary heart disease (CHD) in clinics. Objective This study evaluated the cardioprotective effects of NXT alone and in combination with ticagrelor (TIC) and atorvastatin (ATO). Materials and methods Qi deficiency and blood stasis rats were established by 8 weeks high fat diet feeding and 16 days exhaustive swimming and randomly divided into seven groups, that is, NXT (250, 500 and 1000 mg/kg/d), TIC (20 mg/kg/d), ATO (8 mg/kg/d), NXT (500 mg/kg/d)+TIC (20 mg/kg/d) and NXT (500 mg/kg/d)+ATO (8 mg/kg/d) group, with oral administration for 12 weeks. The contents of TC, TG, LDL-C, HDL-C, IL-1β, IL-6, IL-8, TNF-α, AST, ALT, SOD, MDA, CK-MB, LDH, TXA2, PGI2, IgA, IgG, IgM and C3 in serum were measured. Results NXT + TIC group was significantly superior to the TIC group in decreasing the levels of TC (4.34 vs. 5.54), TG (3.37 vs. 4.66), LDL-C (1.21 vs. 1.35), LDH (4919.71vs. 5367.19) and elevating SOD level (248.54 vs. 192.04). NXT + ATO group was significantly superior to the ATO group in decreasing the levels of AST (195.931 vs. 241.63), ALT (71.26 vs. 83.16), LDH (4690.05 vs. 5285.82), TXA2 (133.73 vs. 158.67), IgG (8.08 vs. 9.80), C3 (2.03 vs. 2.35) and elevating the levels of HDL-C (1.19 vs. 0.91), SOD (241.91vs. 209.49). Conclusions The present findings demonstrate that the combined use of NXT with TIC and ATO had better integrated regulating effects than TIC and ATO, respectively. The mechanism of action requires further research.

Metastatic Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (cSCC) are rare and both show impressive responses to immune checkpoint inhibitor treatment. However, at least 40% of patients do not respond to these expensive and potentially toxic drugs. Development of predictive biomarkers of response and rational, effective combination treatment strategies in these rare, often frail patient populations is challenging. This review discusses the pathophysiology and treatment of MCC and cSCC, with a particular focus on potential biomarkers of response to immunotherapy, and discusses how transfer learning using big data collected from patients with common tumours can be used in combination with deep phenotyping of rare tumours to develop predictive biomarkers and elucidate novel treatment targets.

The checkerboard broth method based on the Clinical and Laboratory Standards Institute M38-A3 document was used in this study to evaluate the in vitro activity of allicin alone and in combination with the antifungal drugs (griseofulvin, fluconazole, itraconazole and terbinafine) against Microsporum canis isolated from patients with tinea capitis. When allicin was used alone, only weak anti-M. canis effects were found. The MIC50, MIC90 and geometric mean (GM) of terbinafine were the lowest among the compounds tested. Synergism was observed for the combinations of allicin with itraconazole and terbinafine. Only indifference was observed for the combinations of allicin with griseofulvin and fluconazole. Our study illustrated the synergism of allicin in combination with itraconazole and terbinafine, which could be a reference for the treatment of tinea capitis due to M. canis.

Preclinical, clinical, and epidemiological studies indicate that vitamin D3 (VD) deficiency is a risk factor for the development of breast cancer. Underlying mechanisms include the ability of calcitriol to induce cell differentiation, inhibit oncogenes expression, and modify different signaling pathways involved in the control of cell proliferation. In addition, calcitriol combined with different kinds of antineoplastic drugs has been demonstrated to enhance their beneficial effects in an additive or synergistic fashion. However, a recognized adjuvant regimen based on calcitriol for treating patients with breast cancer has not yet been fully established. Accordingly, in the present work, we review and discuss the preclinical and clinical studies about the combination of calcitriol with different oncological drugs, aiming to emphasize its main therapeutic benefits and opportunities for the treatment of this pathology.

PurposeThis study aims to inform previous clinical assessments to better understand the total risk of hypertension with atezolizumab and bevacizumab (hereafter referred to as “A-B”) in cancer patients, and reduce future incidence of hypertension-related cardiovascular complications.MethodsDatabases, including PubMed, Embase, Cochrane, and Web of Science were searched to identify relevant studies, which were retrieved from inception to March 6, 2021. Studies focused on cancer patients treated with A-B that provided data on hypertension were included. Statistical analyses were conducted to calculate hypertension incidence and relative risk (RR) with a random-effects or fixed-effects model, hinging on heterogeneity status.ResultsTen studies including 2106 patients with renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), ovarian cancer, anal cancer, neuroendocrine tumors (NETs), and cervical cancer were selected for this meta-analysis. For patients treated with A-B, the all-grade and high-grade (grade 3) hypertension incidence were 31.1% (95% CI: 25.5-37.3) and 14.1% (95% CI: 10.9-18.1), respectively. No significant difference was observed in all-grade hypertension incidence between RCC and a non-RCC patients (32.9% [95% CI: 25.3-42.6] v.s. 29.2% [95% CI: 19.7-39.6)]). However, the number of high-grade hypertension incidence in RCC patients (9.4% [95% CI: 4.1-21.3]) was lower than that of non-RCC patients (15.6% [95% CI: 12.8-19.1]). RCC or HCC patients who received the A-B treatment were associated with significantly increased risk of all-grade hypertension with a RR of 7.22 (95% CI: 3.3-15.7; p = 0.6) compared with patients treated with atezolizumab.ConclusionsCancer Patients treated with atezolizumab and bevacizumab have a significantly increased risk of hypertension. Sufficient monitoring is highly recommended to prevent the consequences of treatment-induced hypertension and other cardiovascular complications.

Simple Summary The repurposing and combination of drugs are important therapeutic strategies in cancer therapy, being important for combating drug resistance and improving therapeutical regimens. This paper outlines the use of candidate drugs that are to be repurposed, and combines clinically approved drugs in breast cancer, aiming to understand the response of feline mammary carcinoma cells to this therapeutic approach, previously applied in human breast cancer cells. By using cell viability assays, we revealed that feline mammary carcinoma cells were highly resistant to these tested approaches, contrasting with human breast cancer cells. Abstract Drug repurposing and drug combination are important therapeutic approaches in cancer therapy. Drug repurposing aims to give new indications to drugs, rather than the original indication, whereas drug combination presupposes that the effect that is obtained should be more beneficial than the effect obtained by the individual drugs. Previously, drug repurposing and the combination of different drugs was evaluated in our research group against human breast cancer cells (MCF-7 cells). Our results demonstrated that the response obtained through the combination of drugs, when compared with the single drugs, led to more synergic responses. Therefore, using potential drugs for repurposing, combined with a reference drug in breast cancer (5-Fluorouracil), was the major aim of this project, but for the first time using the feline mammary carcinoma cell line, FMCm. Surprisingly, the feline neoplastic cells demonstrated considerable resistance to the drugs tested in isolation, and the combination was not effective, which contrasted with the obtained MCF-7 cells’ response.

Simple Summary Breast cancer (BC) is a typical global cancer and the second leading cause of cancer-related deaths among women worldwide. BC is a heterogeneous disease with several subtypes, and it is a challenge to use multi-omic data effectively to find suitable drugs for patients. In this paper, we used the GeneRank algorithm and gene dependency network to propose a precision drug discovery strategy that can recommend drugs for individuals and screen existing drug combinations that could be used to treat different BC subtypes. Our results showed that this precision drug discovery strategy identified important disease-related genes in individuals and specific groups, supporting its efficiency, high reliability, and practical application value in drug discovery. Abstract Breast cancer (BC) is a common disease and one of the main causes of death in females worldwide. In the omics era, researchers have used various high-throughput sequencing technologies to accumulate massive amounts of biomedical data and reveal an increasing number of disease-related mutations/genes. It is a major challenge to use these data effectively to find drugs that may protect human health. In this study, we combined the GeneRank algorithm and gene dependency network to propose a precision drug discovery strategy that can recommend drugs for individuals and screen existing drugs that could be used to treat different BC subtypes. We used this strategy to screen four BC subtype-specific drug combinations and verified the potential activity of combining gefitinib and irinotecan in triple-negative breast cancer (TNBC) through in vivo and in vitro experiments. The results of cell and animal experiments demonstrated that the combination of gefitinib and irinotecan can significantly inhibit the growth of TNBC tumour cells. The results also demonstrated that this systems pharmacology-based precision drug discovery strategy effectively identified important disease-related genes in individuals and special groups, which supports its efficiency, high reliability, and practical application value in drug discovery.

Pharmacokinetic (PK) studies improve the design of dosing regimens in preclinical and clinical settings. In complex diseases like cancer, single-agent approaches are often insufficient for an effective treatment, and drug combination therapies can be implemented. In this work, in silico PK models were developed based on in vitro assays results, with the goal of predicting the in vivo performance of drug combinations in the context of cancer therapy. Combinations of reference drugs for cancer treatment, gemcitabine and 5-fluorouracil (5-FU), and repurposed drugs itraconazole, verapamil or tacrine, were evaluated in vitro. Then, two-compartment PK models were developed based on the previous in vitro studies and on the PK profile reported in the literature for human patients. Considering the quantification parameter area under the dose-response-time curve (AUCeffect) for the combinations effect, itraconazole was the most effective in combination with either reference anticancer drugs. In addition, cell growth inhibition was itraconazole-dose dependent and an increase in effect was predicted if itraconazole administration was continued (24-h dosing interval). This work demonstrates that in silico methods and AUCeffect are powerful tools to study relationships between tissue drug concentration and the percentage of cell growth inhibition over time.

Prostate cancer is the most prevalent tumor found in men worldwide. Despite the efficiency of primary endocrine prostate cancer therapies, more efficient drugs are needed to tackle the most advanced and resistant forms of this condition. The present study investigated the antitumor effects of low-dose bufalin combined with hydroxycamptothecin on castration-resistant prostate cancer (CRPC) in mice, as well as the possible mechanisms of apoptosis induction. CRPC xenograft tumors were generated in mice and, subsequently, mice received appropriate doses of bufalin, hydroxycamptothecin or a combination of the two drugs. Tumors from each treatment group were removed, and the tumor volume, weight and inhibition rate of each group was determined. Hematoxylin and eosin staining was performed for pathological analysis and TUNEL staining was used to assess the level of apoptosis in the xenografts. Immunohistochemistry was used for the analysis of proliferating cell nuclear antigen expression and the expression of Bax, Bcl-XL, p53, programmed cell death 4 (PDCD4), phosphorylated (p)-AKT and glycogen synthase kinase (GSK)-3β was determined by western blotting. Treatment with bufalin significantly (P

Hepatocellular carcinoma (HCC) is the second deadliest cancer worldwide, due to its high incidence and poor prognosis. Frequent initial presentation at advanced stages along with impaired liver function limit the use of a broad therapeutic arsenal in patients with HCC. Although main HCC oncogenic drivers have been deciphered in recent years (TERT, TP53, CTNNB1 mutations, miR122 and CDKN2A silencing), therapeutic applications derived from this molecular knowledge are still limited. Given its high vascularization and immunogenicity, antiangiogenics and immune checkpoint inhibitors (ICI), respectively, are two therapeutic approaches that have shown efficacy in HCC. Depending on HCC immune profile, combinations of these therapies aim to modify the protumoral/antitumoral immune balance, and to reactivate and favor the intratumoral trafficking of cytotoxic T cells. Combination therapies involving antiangiogenics and ICI may be synergistic, because vascular endothelial growth factor A inhibition increases intratumoral infiltration and survival of cytotoxic T lymphocytes and decreases regulatory T lymphocyte recruitment, resulting in a more favorable immune microenvironment for ICI antitumoral activity. First results from clinical trials evaluating combinations of these therapies are encouraging with response rates never observed before in patients with HCC. A better understanding of the balance and interactions between protumoral and antitumoral immune cells will help to ensure the success of future therapeutic trials. Here, we present an overview of the current state of clinical development of antitumoral therapies in HCC and the biological rationale for their use. Moreover, translational studies on tumor tissue and blood, prior to and during treatment, will help to identify biomarkers and immune signatures with predictive value for both clinical outcome and response to combination therapies.

Blood pressure (BP) control in patients with hypertension is variable worldwide, and in general, it results largely unsatisfactory. Factors responsible for this phenomenon include insufficient national cardiovascular healthcare policies for prevention, poor patient compliance with prescribed treatment schedules, and the reluctance of physicians to modify treatment strategies when BP is still elevated, that is, the so-called therapeutic inertia. A further important factor favoring poor BP control is the limited use of combination drug treatment, despite evidence of its superior ability to control BP in patients with difficult-to-treat hypertension. In addition, combination treatment allows to achieve BP control more easily (and more quickly) as compared with monotherapy. This article, after briefly examining the main features of BP control, will review the importance in the treatment of hypertension of the drug combination strategy, based on the recommendations of the 2018 European Society of Cardiology/European Society of Hypertension guidelines. Empahsis will be given to the drug combination treatment as first step of the antihypertensive therapeutic intervention. The potential drawbacks and barriers to combination drug treatment as initial therapeutic strategy will also be briefly discussed.

MAPK (mitogen activated protein kinase) and PI3K/AKT (Phosphatidylinositol-3-Kinase and Protein Kinase B) pathways play a key role in melanoma progression and metastasis that are regulated by receptor tyrosine kinases (RTKs). Although RTKs are mutated in a small percentage of melanomas, several receptors were found up regulated/altered in various stages of melanoma initia-tion, progression, or metastasis. Targeting RTKs remains a significant challenge in melanoma, due to their variable expression across different melanoma stages of progression and among melanoma subtypes that consequently affect response to treatment and disease progression. In this review, we discuss in details the activation mechanism of several key RTKs: type III: c-KIT (mast/stem cell growth factor receptor); type I: EGFR (Epidermal growth factor receptor); type VIII: HGFR (hepato-cyte growth factor receptor); type V: VEGFR (Vascular endothelial growth factor), structure variants, the function of their structural domains, and their alteration and its association with melanoma initiation and progression. Furthermore, several RTK inhibitors targeting the same receptor were tested alone or in combination with other therapies, yielding variable responses among different melanoma groups. Here, we classified RTK inhibitors by families and summarized all tested drugs in melanoma indicating the rationale behind the use of these drugs in each melanoma subgroups from preclinical studies to clinical trials with a specific focus on their purpose of treatment, resulted effect, and outcomes., SCOPUS: re.j, info:eu-repo/semantics/published

Little is known about pharmacists' preferences for services to improve medication adherence in patients with diabetes in Indonesia. Identification of such preferences can provide valuable insights on suitable services from a pharmacist's perspective. This study elicits pharmacists' preferences for services to improve medication adherence among their patients. A discrete choice experiment (DCE) method was used to survey pharmacists in all community health centres and three hospitals in Surabaya, Indonesia. Four attributes of consultation, namely duration of consultation, place of consultation, access to a pharmacist and patient copayment, and two attributes on additional services (educational and behavioural-based services) were included. The 16 profiles generated for DCE were partially balanced and partially without overlap. A random-effect logistic regression was used in the analysis. In total, 99 pharmacists completed the questionnaire, but only 80 were included in the study based on a consistency check. All attributes were found to determine preferences for a pharmacist service package. Pharmacists preferred a consultation with a shorter duration accompanied by flexible access to the pharmacist as well as a private consultation room and a lower patient copayment. Providing the patient with a brochure/leaflet was the most preferred additional service to help improve medication adherence. Patient group discussion and medication review were also preferred in combination with a consultation. Pharmacists' socio-demographic background characteristics influence preferences. These findings can be considered in evaluating current practice and designing pharmacist services to help improve medication adherence among patients with diabetes.

Simple Summary A new era has emerged in oncology in the last ten years with the development of immune therapies. However, single-agent immune therapy such as immune checkpoint inhibitors seems to have a limited clinical activity in biliary tract cancers and are still largely investigational, except for the few patients with microsatellite-instable tumors. Here, we review: (i) the molecular and immune landscape of biliary tract cancers, (ii) the existing results of immune therapies in biliary tract cancers, and (iii) the future of immune therapies in biliary tract cancers, with the identification of predictive biomarkers for response to these therapies, and the ongoing therapeutic trials. Abstract Biliary tract cancers are rare tumors with a poor prognosis. Two-thirds of these primary liver malignancies are diagnosed at advanced stages where therapeutic options are limited. Whereas several molecular targeted therapies emerge in biliary tract cancers, immunotherapy is still investigational, the only approved immunotherapy to date being the immune checkpoint inhibitor pembrolizumab for the small fraction of patients with microsatellite-instable tumors. In microsatellite-stable, pre-treated biliary tract cancers, single-agent immune checkpoint blockade has a limited albeit often long-lasting clinical activity in a still ill-defined subgroup of patients. The identification of predictive biomarkers will allow a better selection of patients that may benefit from immunotherapy. Combinations of immunotherapies with each other, with chemotherapy or targeted molecular therapies are being investigated in early lines of therapy, including first-line.

Background Trypanosoma cruzi is the etiological agent of Chagas disease (CD) or American trypanosomiasis, an important public health problem in Latin America. Benznidazole (BZ), a drug available for its treatment, has limited efficacy and significant side effects. Essential oils (EOs) have demonstrated trypanocidal activity and may constitute a therapeutic alternative. Our aim was to evaluate the efficacy of the EOs of clove (CEO - Syzygium aromaticum) and ginger (GEO - Zingiber officinale), administered alone and in combination with BZ, in Swiss mice infected with T. cruzi. Methods The animals were inoculated with 10,000 blood trypomastigotes of the Y strain of T. cruzi II by gavage and divided into four groups (n = 12 to 15): 1) untreated control (NT); 2) treated with BZ; 3) treated with CEO or GEO; and 4) treated with BZ + CEO or GEO. The treatments consisted of oral administration of 100 mg/kg/day, from the 5th day after parasite inoculation, for 20 consecutive days. All groups were submitted to fresh blood examination (FBE), blood culture (BC), conventional PCR (cPCR) and real-time PCR (qPCR), before and after immunosuppression with cyclophosphamide. Results Clove and ginger EOs, administered alone and in combination with BZ, promoted suppression of parasitemia (p p p Conclusions Decreased parasite load, as detected by qPCR, was observed in all treatment groups (BZ, CEO, GEO and BZ + EOs), demonstrating benefits even in the absence of parasitological cure, thus opening perspectives for further studies.

The development of breast cancer is a complex process that involves the participation of different factors. Several authors have demonstrated the overexpression of muscarinic acetylcholine receptors (mAChRs) in different tumor tissues and their role in the modulation of tumor biology, positioning them as therapeutic targets in cancer. The conventional treatment for breast cancer involves surgery, radiotherapy, and/or chemotherapy. The latter presents disadvantages such as limited specificity, the appearance of resistance to treatment and other side effects. To prevent these side effects, several schedules of drug administration, like metronomic therapy, have been developed. Metronomic therapy is a type of chemotherapy in which one or more drugs are administered at low concentrations repetitively. Recently, two chemotherapeutic agents usually used to treat breast cancer have been considered able to activate mAChRs. The combination of low concentrations of these chemotherapeutic agents with muscarinic agonists could be a useful option to be applied in breast cancer treatment, since this combination not only reduces tumor cell survival without affecting normal cells, but also decreases pathological neo-angiogenesis, the expression of drug extrusion proteins and the cancer stem cell fraction. In this review, we focus on the previous evidences that have positioned mAChRs as relevant therapeutic targets in breast cancer and analyze the effects of administering muscarinic agonists in combination with conventional chemotherapeutic agents in a metronomic schedule.

To identify drugs that are potentially used for the treatment of COVID-19, the potency of 1403 FDA-approved drugs were evaluated using a robust pseudovirus assay and the candidates were further confirmed by authentic SARS-CoV-2 assay. Four compounds, Clomiphene (citrate), Vortioxetine, Vortioxetine (hydrobromide) and Asenapine (hydrochloride), showed potent inhibitory effects in both pseudovirus and authentic virus assay. The combination of Clomiphene (citrate), Vortioxetine and Asenapine (hydrochloride) is much more potent than used alone, with IC50 of 0.34 μM.

Clinical trials of single drugs intended to slow the progression of Alzheimer’s Disease (AD) have been notoriously unsuccessful. Combinations of repurposed drugs could provide effective treatments for AD. The challenge is to identify potentially effective combinations. To meet this challenge, machine learning (ML) was used to extract the knowledge from two leading AD databases, and then “the machine” predicted which combinations of the drugs in common between the two databases would be the most effective as treatments for AD. Specifically, three-layered artificial neural networks (ANNs) with compound, gated units in their internal layer were trained using ML to predict the cognitive scores of participants, separately in either database, given other data fields including age, demographic variables, comorbidities, and drugs taken. The predictions from the separately trained ANNs were statistically highly significantly correlated. The best drug combinations, jointly determined from both sets of predictions, were high in nonsteroidal anti-inflammatory drugs, anticoagulant, lipid-lowering, and antihypertensive drugs, and female hormones. The results suggest that the neurodegenerative processes that underlie AD and other dementias could be effectively treated using a combination of repurposed drugs. Predicted drug combinations could be evaluated in clinical trials.

Simple Summary Chemotherapy is a key modality in today’s practice of clinical oncology. The potential for systemic treatment of cancer patients with cytotoxic agents was discovered in the mid 20th century and its major shortcomings namely, off target toxicity and resistance to treatment, were apparent from the very beginning. These limitations pushed the scientific and medical communities to search for improvements, which as a final result, shaping modern research and clinical practice in the field. For minimizing off target toxic effects, drug discovery efforts became more focused on targeted therapies and on combinations of anti-cancer drugs in order to overcome the resistance problem. Here we outline the evolution of chemotherapy from its beginning as a single-agent based therapy to poly-drug treatment that involves targeted drugs, and discuss the concept of drug-conjugation based treatment as a strategy for further optimization of treatment regimes. Abstract It is well recognized today that anticancer drugs often are most effective when used in combination. However, the establishment of chemotherapy as key modality in clinical oncology began with sporadic discoveries of chemicals that showed antiproliferative properties and which as a first attempt were used as single agents. In this review we describe the development of chemotherapy from its origins as a single drug treatment with cytotoxic agents to polydrug therapy that includes targeted drugs. We discuss the limitations of the first chemotherapeutic drugs as a motivation for the establishment of combined drug treatment as standard practice in spite of concerns about frequent severe, dose limiting toxicities. Next, we introduce the development of targeted treatment as a concept for advancement within the broader field of small-molecule drug combination therapy in cancer and its accelerating progress that was boosted by recent scientific and technological progresses. Finally, we describe an alternative strategy of drug combinations using drug-conjugates for selective delivery of cytotoxic drugs to tumor cells that potentiates future improvement of drug combinations in cancer treatment. Overall, in this review we outline the development of chemotherapy from a pharmacological perspective, from its early stages to modern concepts of using targeted therapies for combinational treatment.

Despite Alzheimer’s disease (AD) incidence being projected to increase worldwide, the drugs currently on the market can only mitigate symptoms. Considering the failures of the classical paradigm “one target-one drug-one disease” in delivering effective medications for AD, polypharmacology appears to be a most viable therapeutic strategy. Polypharmacology can involve combinations of multiple drugs and/or single chemical entities modulating multiple targets. Taking inspiration from an ongoing clinical trial, this work aims to convert a promising cromolyn–ibuprofen drug combination into single-molecule “codrugs.” Such codrugs should be able to similarly modulate neuroinflammatory and amyloid pathways, while showing peculiar pros and cons. By exploiting a linking strategy, we designed and synthesized a small set of cromolyn–ibuprofen conjugates (4–6). Preliminary plasma stability and neurotoxicity assays allowed us to select diamide 5 and ethanolamide 6 as promising compounds for further studies. We investigated their immunomodulatory profile in immortalized microglia cells, in vitro anti-aggregating activity towards Aβ42-amyloid self-aggregation, and their cellular neuroprotective effect against Aβ42-induced neurotoxicity. The fact that 6 effectively reduced Aβ-induced neuronal death, prompted its investigation into an in vivo model. Notably, 6 was demonstrated to significantly increase the longevity of Aβ42-expressing Drosophila and to improve fly locomotor performance.

The purpose of this work was to reach the consensus of a multidisciplinary and multistakeholder Italian panel on the value of polypill in cardiovascular disease, with respect to the clinical, technological, economic and organizational dimension. A three-step modified Delphi method was used to establish consensus. Eleven experts in the area of cardiology, pharmaceutical technology, general practice, hospital pharmacy, pharmacology, and health economics participated in the expert panel. To identify existing evidence concerning the value of polypill in the prevention of patients with cardiovascular disease, a systematic literature review was carried out according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement guidelines. In the first round, 22 statements were distributed to the panel. Panel members were asked to mark 'agree' or 'disagree' for each statement and provide any comments. The same voting method was again used for the second round. In the first round nine statements met consensus. In the second round, 10 statements reached consensus. Overall, consensus was reached for 19 statements representing five value polypill domains: clinical, technological, economic and organizational. During a final web meeting with all panel members consensus document open points were discussed. Panel members agreed to recognize polypill as effective in reducing cardiovascular events, blood pressure and lipids, cardiovascular risk and the weight of therapy, in therapeutic adherence improvement, in the absence of differences in bioavailability between drugs administered in fixed or free combinations and the better cost-effectiveness profile compared with standard care. This document represents a knowledge framework to inform decision makers of the value of polypill in cardiovascular prevention.

Background and Aims The MARS post-marketing, observational study evaluates glecaprevir/pibrentasvir in a large population of Italian patients who are infected with HCV. Patients and Methods Achievement of SVR12 was the primary endpoint in the overall population and by subpopulations of interest (treatment-naive and treatment-experienced patients, subjects infected with different HCV genotype/sub-genotype, cirrhotic and non-cirrhotic patients, patients with different severity of fibrosis, patients with an APRI score ≥1, subjects with comorbidities, HIV-coinfected patients, elderly patients and people who use drugs). Safety and quality of life (assessed by SF-36 and Work Productivity and Activity Impairment) were also evaluated. Results The SVR12 rate was 99.4% (319/321; 95% CI: 97.8–99.8%) in the core population with sufficient follow-up (n = 321), 99.7% (289/290) in 8-week treated patients, and high (>96%) across subgroups. Only three patients (0.9%) had treatment-related adverse events that led to treatment discontinuation. In total, 30.1% of patients showed an improvement of ≥2.5 points in the Physical Component Summary of the SF-36 from baseline to the end of treatment, and this figure raised to 37.5% with the achievement of SVR12. Corresponding values for MCS were 42.2% and 42.8%, respectively. Conclusion Glecaprevir/pibrentasvir is safe and effective across subpopulations who are underserved in clinical trials.

Cancer is a set of extremely complex diseases, which are increasingly prominent today, as it affects and kills millions of people worldwide, being the subject of intense study both in its pathophysiology and therapy. Especially in women, breast cancer is still a cancer with a high incidence and mortality. Even though mortality rates for this type of cancer have declined in recent years, it remains challenging at the treatment level, especially the metastatic type. Due to all the impact on health, cancer therapy is the subject of costly and intense research. To enrich this therapy, as well as decrease its underlying high associated costs, drug repurposing and drug combinations are strategies that have been increasingly studied and addressed. As the name implies, drug repurposing presupposes giving new purposes to agents which, in this case, are approved for the therapy of other diseases (for example, cardiovascular or metabolic diseases), but are not approved for cancer therapy. Therefore, a better knowledge of these therapeutic modalities for breast cancer therapy is crucial for improved therapy. In this particular review, we will discuss some relevant aspects of cancer and, particularly, breast cancer and its therapy. Also, drug combination and repurposing will be highlighted, together with relevant examples. Despite some limitations that need to be overcome, these methodologies are extremely important and advantageous in combating several current problems of cancer therapy, namely in terms of costs and resistance to current therapeutic modalities. These approaches will be explored with a special focus on breast cancer., Cancer, Breast cancer, Drug repurposing, Drug combination.

Simple Summary In this study, drug combination screening was used to design a multidrug combination consisting of repurposed drugs to treat sunitinib-resistant clear cell renal cell carcinoma. In the frame of this project, the multidrug combination has been optimized and validated and an insight into the mechanism of action is given. The multidrug combinations significantly altered the transcription of genes related to apoptosis and metabolic pathways. Further analysis of the metabolism revealed strong upregulation of the presence of sphingolipids after multidrug combination treatment. Final evaluation for translation of the multidrug combination in ex vivo organoid-like cultures demonstrated significant anti-cancer efficacy. Abstract Repurposed drugs have been evaluated for the management of clear cell renal cell carcinoma (ccRCC), but only a few have influenced the overall survival of patients with advanced disease. To combine repurposed non-oncology with oncological drugs, we applied our validated phenotypic method, which consisted of a reduced experimental part and data modeling. A synergistic optimized multidrug combination (ODC) was identified to significantly reduce the energy levels in cancer remaining inactive in non-cancerous cells. The ODC consisted of Rapta-C, erlotinib, metformin and parthenolide and low doses. Molecular and functional analysis of ODC revealed a loss of adhesiveness and induction of apoptosis. Gene-expression network analysis displayed significant alterations in the cellular metabolism, confirmed by LC-MS based metabolomic analysis, highlighting significant changes in the lipid classes. We used heterotypic in vitro 3D co-cultures and ex vivo organoids to validate the activity of the ODC, maintaining an efficacy of over 70%. Our results show that repurposed drugs can be combined to target cancer cells selectively with prominent activity. The strong impact on cell adherence and metabolism indicates a favorable mechanism of action of the ODC to treat ccRCC.

Topical treatment is the mainstay for mild or moderate psoriasis, but patients are generally little satisfied. Calcipotriol/betamethasone dipropionate (Cal/BD) cutaneous foam has shown to improve signs and symptoms in plaque psoriasis patients. This study assessed patient's satisfaction with Cal/BD foam in a real-life Italian dermatological clinical practice. A multicenter, 4-week observational prospective cohort study enrolled, in 17 Italian dermatology clinics, adult patients with plaque psoriasis on the body and/or scalp. Treatment satisfaction was assessed by 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9), preference over previous treatments by Patient Preference Questionnaire (PPQ), and change in disease state by Psoriasis Area Severity Index (PASI). Overall 256 patients were eligible, with a mean (SD) age of 55.6 (15.4) years, 59.4% were males. Psoriasis severity was mild in 52.0% of patients, moderate in 43.3%, and severe in 4.7%. Scalp involvement was present in 36.7% of patients. Previous antipsoriatic treatments had been received by 80.5% of patients. TSQM-9 median (25th-75th percentile) scores were 83.3 (66.7-88.9) for effectiveness, 77.8 (66.7-88.9) for convenience, and 78.6 (64.3-92.9) for global satisfaction. Mean (SD) PASI value decreased from 7.3 (4.8) to 2.1 (2.7) after 4 weeks. More than 90% of patients previously treated for psoriasis evaluated the Cal/BD foam more effective, easier to use and better tolerated compared to previous topical treatments at PPQ. This observational study provides real-life evidence of a high level of satisfaction with effectiveness and convenience of the Cal/BD foam in a cohort of plaque psoriasis patients, with an objective improvement in PASI.

Background Spasticity in people with Multiple Sclerosis (pwMS) is one of the most disabling symptoms on walking ability and balance. Among the systemic antispastic drugs, Nabiximols showed a good tolerability, safety profile and relevant efficacy. A few studies assessed long-term effects of this drug through clinical scales and instrumental tools, but no study investigated short-term effects. The aim of our study is to quantitatively evaluate the immediate effects of Nabiximols on walking and balance and their maintenance after 4 weeks in pwMS and spasticity. Methods pwMS were enrolled and randomized in 2 treatment groups: Sativex (SG) and control (CG) group. All patients were assessed at T0 (before the first Sativex puff), T1(after 45 minutes) and T2 (after 4 weeks of treatment) using clinical scales and 3d-Gait Analysis . Then, the patients treated with Sativex, were divided into 5 subgroups according to Numeric Rating Scale for spasticity (NRSs) and Berg Balance Score (BBS) response: NRSs responder[1] and non-[2]; BBS responders[3] and non-[4]; NRSs-BBS responders[5]. Results 32 pwMS (22 SG, 10 CG) were recruited. Significant improvements were found between T0 and T1 in SG compared to CG in a few clinical and kinematic parameters. Larger significant differences were found for NRSs and BBS responders’ groups versus CG. Eventually, no significant differences were found comparing the results between T1 and T2, suggesting the persistence of the improvements emerged at T1. Conclusion These results quantitatively demonstrated a short time effect of Nabiximols on balance and walking of pwMS, which is mantained after 4 weeks. Patients identified as responder by combination of NRSs and BBS showed the best efficacy. These findings may suggest how to early select the real responders in order to improve the adherence and cost-effectiveness of the therapy.

Introduction: Diabetes mellitus is a potentially morbid condition with high prevalence worldwide. Restoration of euglycemia in type 2 diabetes mellitus is difficult to achieve due to its multifactorial pathogenesis and frequently requires multiple anti-diabetic medications with different mechanism of action. This study is based on the possible synergistic effect of Sitagliptin and Bromocriptine in reducing blood sugar in diabetic animal models. Aim: To evaluate the effect of Sitagliptin and Bromocriptine monotherapy and their combination in three different doses on blood sugar, Lipid profile, Liver and renal parameters in diabetic albino Wistar rats. Materials and Methods: An experimental animal study was conducted on 48 adult male albino wistar rats for a period of one month (August 2014). Streptozotocin induced (40 mg/kg IP) diabetic rats were divided into six groups of eight animals each weighing 150-200 gms. Group I- Vehicle (distilled water), Group II- Sitagliptin (100 mg/kg), Group III- Bromocriptine (10 mg/kg), Group IV- Sitagliptin (75 mg/kg) + Bromocriptine (7.5 mg/kg), Group V- Sitagliptin (100 mg/kg) + Bromocriptine (10 mg/kg), Group VI- Sitagliptin (125 mg/kg) + Bromocriptine (12.5 mg/kg). All drugs were given once daily (per oral) for four weeks. Body weight, fasting blood sugar, fasting lipid profile, liver parameters and renal parameters were estimated before and after administration of the drugs. Results were analyzed with Statistical Package for the Social Science (SPSS) software version 16.0 using one-way ANOVA followed by post-hoc Dunnett t test, p-value

Background A growing body of observational evidence supports the value of ceftazidime-avibactam (CAZ-AVI) in managing infections caused by carbapenem-resistant Enterobacteriaceae. Methods We retrospectively analyzed observational data on use and outcomes of CAZ-AVI therapy for infections caused by Klebsiella pneumoniae carbapenemase–producing K. pneumoniae (KPC-Kp) strains. Multivariate regression analysis was used to identify variables independently associated with 30-day mortality. Results were adjusted for propensity score for receipt of CAZ-AVI combination regimens versus CAZ-AVI monotherapy. Results The cohort comprised 577 adults with bloodstream infections (n = 391) or nonbacteremic infections involving mainly the urinary tract, lower respiratory tract, and intra-abdominal structures. All received treatment with CAZ-AVI alone (n = 165) or with ≥1 other active antimicrobials (n = 412). The all-cause mortality rate 30 days after infection onset was 25% (146/577). There was no significant difference in mortality between patients managed with CAZ-AVI alone and those treated with combination regimens (26.1% vs 25.0%, P = .79). In multivariate analysis, mortality was positively associated with presence at infection onset of septic shock (P = .002), neutropenia (P < .001), or an INCREMENT score ≥8 (P = .01); with lower respiratory tract infection (LRTI) (P = .04); and with CAZ-AVI dose adjustment for renal function (P = .01). Mortality was negatively associated with CAZ-AVI administration by prolonged infusion (P = .006). All associations remained significant after propensity score adjustment. Conclusions CAZ-AVI is an important option for treating serious KPC-Kp infections, even when used alone. Further study is needed to explore the drug’s seemingly more limited efficacy in LRTIs and potential survival benefits of prolonging CAZ-AVI infusions to ≥3 hours.

Antibiotic resistance is a growing public health concern, though the constant development of new antibiotics. The combination of high-throughput screening and drug repurposing is an effective way to develop new therapeutic uses of drugs. In this study, we screened a drug library consisting of 1,573 drugs already approved by the Food and Drug Administration and 903 drugs from the natural product library, to identify antimicrobials against Pseudomonas aeruginosa. A high-throughput screening assay based on microtiter plate was used to screen 39 drugs that inhibit the planktonic or biofilm formation of P. aeruginosa while most of them are antibiotics. The antimicrobial activities of these drugs were evaluated by phenotypic analysis. Further studies showed the combined therapy of tetracycline antibiotics demeclocycline hydrochloride (DMCT) and the novel antimicrobial peptide SAAP-148 has an effective synergistic antibacterial effect on P. aeruginosa PAO1 and P. aeruginosa ATCC27853. Moreover, the time-kill curve assay and murine model of cutaneous abscesses further confirmed the synergistic effect. In addition, the combination of DMCT and SAAP-148 has the potential to combat clinically isolated multidrug-resistant (MDR) P. aeruginosa strains. Our results clearly indicate that DMCT and SAAP-148 combined therapy could be an effective method to combat MDR P. aeruginosa-related infections.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger “cytokine storm” leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on “multi-targeted” therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. NEP activity is elevated in acute respiratory distress syndrome and it is conceivable that it is also high in COVID-19. NEP is implicated in the degradation of natriuretic peptides, bradykinin, substance P, adrenomedullin, and apelin that account for prevention of organ injury. Thus, NEP/angiotensin receptor type 1 (AT1R) inhibitor sacubitril/valsartan (SAC/VAL) may increase levels of these molecules and block AT1Rs required for ACE2 endocytosis in SARS-CoV-2 infection. Moreover, SAC/VAL has a positive impact on acute heart failure that is very frequently observed in deceased COVID-19 patients. The current review aims to summarize actual therapeutic strategies for COVID-19 and to examine the data supporting the potential benefits of SAC/VAL in COVID-19 treatment.

The purpose of this study is to characterize adverse events (AEs) of clinical interest reported with ceftolozane-tazobactam and ceftazidime-avibactam, as an aid in monitoring patients affected by severe multidrug-resistant Gram-negative infections. We queried the worldwide FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis, selecting only designated medical events (DMEs) where ceftolozane-tazobactam and ceftazidime-avibactam were reported as suspect. Serious neurological AEs were further investigated. The reporting odds ratios were calculated, deemed significant by the lower limit of the 95% confidence interval (LL95% CI) > 1. All other drugs/events recorded in FAERS and cephalosporins showing clinical evidence of neurological AEs were respectively selected as comparator for analysis of DMEs and neurotoxicity. Qualitative analysis including case-by-case assessment and deduplication was also performed. Overall, 654 and 506 reports mentioning respectively ceftolozane-tazobactam and ceftazidime-avibactam were found, with DMEs accounting respectively for 13.1% and 10.9% of cases. Agranulocytosis (N = 12; LL95% CI = 12.40) and pancytopenia (14; 6.18) emerged as unexpected AEs with ceftolozane-tazobactam, while acute pancreatitis (7; 8.63) was an over-reported unexpected DME with ceftazidime-avibactam. After deduplication, four unequivocally different cases of agranulocytosis with ceftolozane-tazobactam were retained, occurring on average after 8.8 days. Causality was probable and possible respectively in three and one case. Among neurological AEs exhibiting significant disproportionality, encephalopathy with both antibiotics and mental status changes with ceftazidime-avibactam were retained in at least three cases after deduplication. Although rare, clinicians should monitor high-risk patients (i.e. individuals affected by haematological malignances, HIV infection, or treated with concomitant myelotoxic agents) for early unexpected occurrence of agranulocytosis with ceftolozane-tazobactam.

Given the scale and rapid spread of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, or 2019-nCoV), there is an urgent need to identify therapeutics that are effective against COVID-19 before vaccines are available. Since the current rate of SARS-CoV-2 knowledge acquisition via traditional research methods is not sufficient to match the rapid spread of the virus, novel strategies of drug discovery for SARS-CoV-2 infection are required. Structure-based virtual screening for example relies primarily on docking scores and does not take the importance of key residues into consideration, which may lead to a significantly higher incidence rate of false-positive results. Our novel in silico approach, which overcomes these limitations, can be utilized to quickly evaluate FDA-approved drugs for repurposing and combination, as well as designing new chemical agents with therapeutic potential for COVID-19. As a result, anti-HIV or antiviral drugs (lopinavir, tenofovir disoproxil, fosamprenavir and ganciclovir), antiflu drugs (peramivir and zanamivir) and an anti-HCV drug (sofosbuvir) are predicted to bind to 3CLPro in SARS-CoV-2 with therapeutic potential for COVID-19 infection by our new protocol. In addition, we also propose three antidiabetic drugs (acarbose, glyburide and tolazamide) for the potential treatment of COVID-19. Finally, we apply our new virus chemogenomics knowledgebase platform with the integrated machine-learning computing algorithms to identify the potential drug combinations (e.g. remdesivir+chloroquine), which are congruent with ongoing clinical trials. In addition, another 10 compounds from CAS COVID-19 antiviral candidate compounds dataset are also suggested by Molecular Complex Characterizing System with potential treatment for COVID-19. Our work provides a novel strategy for the repurposing and combinations of drugs in the market and for prediction of chemical candidates with anti-COVID-19 potential.

Background Acute Kidney Injury (AKI) is a shared complication among Intensive Care Unit (ICU), marked by high cost, high morbidity and high mortality. As the early prediction of AKI is critical for patients’ outcomes and data mining is such a powerful prediction tool, many AKI prediction models based on machine learning methods have been proposed. Our motivation is inspired by the fact that the incidence of AKI is a changing temporal sequence affected by the joint action of patients’ daily drug combinations and their physiological indexes. However, most existing models have not considered such a temporal correlation. Besides, due to great challenges caused by sparse, high-dimensional and highly imbalanced clinical data, it is hard to achieve ideal performance. Methods We develop a fast, simple and less-costly model based on an ensemble learning algorithm, named Ensemble Time Series Model (ETSM). Besides benefiting from vital signs and laboratory results as explicit indicators, ETSM explores the effect of drug combinations as possible implicit indicators for the AKI prediction. The model transforms temporal medication information into a multidimensional vector to consider and measure drug cumulative effects that may cause AKI. Results We compare ETSM with state-of-the-art models on ICUC and MIMIC III datasets. On the basis of the experimental results, our model obtains satisfactory performance (ICUC: AUC 24 hours ahead: 0.81, 48 hours ahead: 0.78; MIMIC III: AUC 24 hours ahead: 0.95, 48 hours ahead: 0.95). Meanwhile, we compare the effects of different sampling and feature generation methods on the model performance. In the ablation study, we validate that medication information improves model performance (24 hours ahead: AUC increased from 0.74 to 0.81). We also find that the model’s performance is closely related to the balanced level of the derivation dataset. The optimal ratio of major class size to minor class size for the model is found for AKI prediction. Conclusions ETSM is an effective method for the early prediction of AKI. The model verifies that AKI incidence is related to the clinical medication. In comparison with other prediction methods, ETSM provides comparable performance results and better interpretability.

Helicobacter pylori is a Gram-negative bacterium responsible for the development of gastric diseases. The issue of spreading antibiotic resistance of H. pylori and its limited therapeutic options is an important topic in modern gastroenterology. This phenomenon is greatly associated with a very narrow range of antibiotics used in standard therapies and, as a consequence, an alarmingly high detection of multidrug-resistant H. pylori strains. For this reason, scientists are increasingly focused on the search for new substances that will not only exhibit antibacterial effect against H. pylori, but also potentiate the activity of antibiotics. The aim of the current review is to present scientific reports showing newly discovered or repurposed compounds with an ability to enhance the antimicrobial activity of classically used antibiotics against H. pylori. To gain a broader context in their future application in therapies of H. pylori infections, their antimicrobial properties, such as minimal inhibitory concentrations and minimal bactericidal concentrations, dose- and time-dependent mode of action, and, if characterized, anti-biofilm and/or in vivo activity are further described. The authors of this review hope that this article will encourage the scientific community to expand research on the important issue of synergistic therapies in the context of combating H. pylori infections.

Alzheimer’s disease (AD) is a multifactorial disease characterized by the presence of amyloid plaques, neurofibrillary tangles, and nerve cell death that affects, mainly, older people. After decades of investigation, the search for an efficacious treatment for AD remains and several strategies can be and are being employed in this journey. In this review, four of the most promising strategies, alongside with its most promising agents under investigation or development are highlighted. Marine natural products (MNP) are a source of unique chemical structures with useful biological activities for AD treatment. One of the most promising compounds, a marine-derived acidic oligosaccharide (GV-971) just passed phase III clinical trials with a unique mechanism of action. Combination therapy and multitargeted-directed ligand therapy (MTDL) are also two important strategies, with several examples in clinical trials, based on the belief that the best approach for AD is a therapy capable of modulating multiple target pathways. Drug repurposing, a strategy that requires a smaller investment and is less time consuming, is emerging as a strong contender with a variety of pharmacological agents resurfacing in an attempt to identify a therapeutic candidate capable of modifying the course of this disease.

Drug combination is now a hot research topic in the pharmaceutical industry, but experiment-based methodologies are extremely costly in time and money. Many computational methods have been proposed to address these problems by starting from existing drug combinations. However, in most cases, only molecular structure information is included, which covers too limited a set of drug characteristics to efficiently screen drug combinations. Here, we integrated similarity-based multifeature drug data to improve the prediction accuracy by using the neighbor recommender method combined with ensemble learning algorithms. By conducting feature assessment analysis, we selected the most useful drug features and achieved 0.964 AUC in the ensemble models. The comparison results showed that the ensemble models outperform traditional machine learning algorithms such as support vector machine (SVM), naïve Bayes (NB), and logistic regression (GLM). Furthermore, we predicted 7 candidate drug combinations for a specific drug, paclitaxel, and successfully verified that the two of the predicted combinations have promising effects.

We report the case of a man affected by cystic fibrosis who developed a severe SARS-CoV-2 related pneumonia in March 2020. In addition to lopinavir/ritonavir and hydroxychloroquine, he was treated with two doses of tocilizumab, displaying a significant clinical improvement. This is the first case described in the literature of an adult patient affected by cystic fibrosis who received tocilizumab for COVID-19, with documented total recovery, also assessed by a spirometry. was first described in December 2019 in Wuhan, China, and was declared pandemic by the World Health Organization (WHO) on March 11th, 2020. The clinical spectrum varies widely, from asymptomatic infection or mild influenza-like disease to potentially fatal pneumonia with respiratory failure. Hypertension, diabetes and coronary heart disease have already been described as common comorbidities and are linked, with various degrees of importance, with a worse evolution and outcome of the infection, both in preliminary papers and in most recent evaluations. With respect to respiratory tract pathological conditions, chronic obstructive pulmonary disease (COPD) and active smoking have been reported as factors linked to more severe outcomes [1]. Spread of Covid-19 among patients with cystic fibrosis (CF) might have a severe impact on their clinical conditions. To date, few data are available on the association of these two diseases.

Objectives: Up to 32% of women experience anatomic recurrence after conservative surgery for endometriomas, while pain recurs in 10–40% of cases. Long-term postoperative hormonal therapy is recommended to prevent disease recurrence. We evaluated the efficacy of long-term therapy with estroprogestins (EPs) or progestins (Ps) in preventing endometrioma recurrence, as identifiable cysts and subjective symptoms, after laparoscopic excision. Design: This retrospective cohort study included 375 women submitted to laparoscopic endometrioma excision. Women were followed up at 6 and 12 months and then yearly after surgery. Based on postoperative medical therapy, women were divided into 4 groups: nonusers, cyclic EP users, continuous EP users, and progestogen users. Materials, Setting, Methods: Anamnestic and anthropometric characteristics were collected as well as clinical and surgical data. Gynecological examination, and transvaginal and transabdominal ultrasound scans were performed. Pain (numerical rating score >5) and endometrioma recurrence at ultrasound (ovarian cyst with typical sonographic features ≥10 mm in mean diameter) were recorded at each examination. The reoperation rate in women with recurrence was investigated. Results: The median follow-up was 3.7 years with a maximum of 16.7 years. Most patients used EPs (119 cyclic and 61 continuous users), 95 used P, and 100 were nonusers. In 135 women (36%), endometriotic cyst recurrence was diagnosed, with a mean diameter of 18.7 ± 10.8 mm (range 10–55 mm). The median recurrent cyst-free time was 7.9 years (95% CI 5.8–10.8). Dysmenorrhea was the first symptom to reappear, affecting 162 patients (43.2%). Upon multivariable regression analysis, continuous users had a lower risk of relapse (OR 0.56, 95% CI 0.32–0.99), in terms of both cysts and symptom recurrence, than patients who received no medications. The reoperation rate was 16.2%. Limitations: The main limitation of this study is its retrospective design. Also, women switching therapies throughout the follow-up period were sorted into one of the study groups based on the longest treatment taken, without considering the discontinuation rates. Conclusions: Long-term EPs, administered in a continuous regimen and starting immediately after conservative surgery for endometriomas, seem to reduce the disease recurrence risk.

Laryngeal squamous cell carcinoma (LSCC), is characterized by an aggressive clinical behavior and lack of specific targeted therapies. Thus, novel therapeutic approaches that take advantage of the combination of anticancer natural compounds and chemotherapeutic molecules currently used for LSCC are strongly necessary. S-adenosyl-L-methionine (AdoMet), the main biological methyl donor, is well known for its antiproliferative, proapoptotic and antimetastatic effect in several type of human cancer. In the current study we investigated the antitumor activity of AdoMet in combination with cisplatin (cDDP), an agent usually used in cancer therapy of LSCC, in JHU-SCC-011 cells and we explored the underlying mechanisms. We found that the combination of 200μM AdoMet/0.18μM cDDP synergistically enhanced apoptosis via intrinsic mechanism as confirmed by Western blot analysis of the main proteins involved in this process. Because escape from apoptosis and decreased activation of JNK and ERK are mechanisms of resistance to cDPP, the activation of ERK-1/2 and JNK and the downregulation of the antiapoptotic Bcl-2 protein induced by combined treatments could represent the strategy utilized by AdoMet to potentiate the therapeutic effectiveness of cDDP. The overall data highlighted AdoMet and cisplatin combination as a potential therapy for LSCC in order to improve therapeutic efficacy by reducing side effects and drug resistance mechanisms.

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiere, y los autores pertenecientes a la UAM, Background: There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation. Objective: To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy. Methods: Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line. Results: Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases. Conclusions: Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile, The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacterand Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas

Approximately 50% of patients with type 2 diabetes mellitus (T2DM) do not achieve glycemic targets and require treatment intensification. A fixed-ratio combination of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with basal insulin, such as lixisenatide with insulin glargine (iGlarLixi), exploits the complementary mechanisms of action of each component to address hyperglycemia while mitigating potential adverse events (AEs). The iGlarLixi dose is titrated considering the effect of basal insulin on fasting plasma glucose, and the fixed-ratio combination ensures that the lixisenatide dose never exceeds 20 μg/day. We describe the characteristics of iGlarLixi therapy, based on the LixiLan clinical program, and provide guidance on the characteristics of patients likely to benefit from such treatment in routine clinical practice. In the phase III LixiLan trials, iGlarLixi resulted in significantly greater reductions in glycated hemoglobin (HbA1c), better achievement of HbA1c targets, less glycemic variability versus insulin glargine, lixisenatide or GLP-1 RA alone, and was associated with weight control, less hypoglycemia versus insulin glargine, and fewer GI AEs versus lixisenatide. Findings were consistent regardless of age, diabetes duration, and baseline HbA1c. The efficacy, safety, and convenient once-daily administration schedule of iGlarLixi make it a valuable treatment option for patients with T2DM requiring treatment intensification.

Malignant mesothelioma (MM) is a deadly tumor mainly caused by exposure to asbestos. Unfortunately, no current treatment is able to change significantly the natural history of the disease, which has a poor prognosis in the majority of patients. The non-receptor tyrosine kinase SRC and other SRC family kinase (SFK) members are frequently hyperactivated in many cancer types, including MM. Several works have indeed suggested that SFKs underlie MM cell proliferation, survival, motility, and invasion, overall affecting multiple oncogenic pathways. Consistently, SFK inhibitors effectively counteracted MM cancerous features at the preclinical level. Dasatinib, a multi-kinase inhibitor targeting SFKs, was also assessed in clinical trials either as second-line treatment for patients with unresectable MM or, more recently, as a neoadjuvant agent in patients with resectable MM. Here, we provide an overview of the molecular mechanisms implicating SFKs in MM progression and discuss possible strategies for a more successful clinical application of SFK inhibitors. Our aim is to stimulate discussion and further consideration of these agents in better designed preclinical and clinical studies to make the most of another class of powerful antitumoral drugs, which too often are lost in translation when applied to MM.