New Drug Combinations Research Articles

Blinatumomab + Ponatinib for Relapsed Ph1-Positive Acute Lymphoblastic Leukemia: The French Experience

Prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1+ ALL) has been considerably improved since the beginning of the BCR-ABL1 tyrosine kinase inhibitors (TKI) era 20 years ago. However, the prognosis of patients with a refractory/relapsed (including molecular relapse) disease is still very dismal. New drugs or combination of new drugs may improve outcomes of these patients. For example, ponatinib, a 3rd-generation oral TKI, known to have activity against BCR-ABL1 T315I mutations, has shown some efficacy in this context. Similarly, a recent study has reported very encouraging results of the bispecific anti-CD3/CD19 monoclonal antibody blinatumomab as single-agent in refractory/relapsed Ph1+ ALL. Data regarding the efficacy and tolerance of a combination of blinatumomab+ponatinib (blina/pona) are still scarce.This was a retrospective study with the aim to report outcomes of patients receiving a combination of blina/pona for refractory/relapsed Ph1+ ALL in France. Fifteen adults from 8 French centers were identified and data were collected by physicians of each centers, then gathered for the purpose of this study.There were 9 males and 6 females, with a median age of 53 years (range:17-72). All patients, but 2 with blast crisis of chronic myeloid leukemia, had de novo Ph1+ ALL. Four cases had BCR-ABL1 T315I mutation. Patients received the blina/pona combination, either after a first (n=8) or a second (n=7) cytologic relapse. There was no refractory patient in theses series. Previous allograft and autograft has been performed in 7 and 2 patients, respectively. The majority of patients (n=12) had previously received 2 or more lines of TKI. The median time between the first cycle of blina/pona and diagnosis was 14 months (range: 8-40). The median number of blinatumomab cycle (28 mg/day by continuous infusion for 28 days every 6 weeks) administered per patient was 3 (range: 1-6) while ponatinib was concomittantly administered continuously at an initial dose of 45 mg once daily in 11 pts (73%) and 30 mg in 4 pts (27%). Median duration of ponatinib administration was 4 months (range: 1.1-10.9) from first blinatumomab cycle. The toxicity profile was safe: all patients received a complete first cycle without grade 3-4 adverse events. After cycle 1, blinatumomab was stopped in 47% of cases because of neurologic events in 4 and infections in 3; ponatinib was stopped in 33% of cases because of neurologic events in 3, fluid retention in 1 and severe arteriopathy in 1 patient with other vascular disease risk factors. All neurologic events resolved after stopping blinatumomab or ponatinib.The majority of patients were evaluated after one cycle (n=11, after cycle 2 n=3, after cycle 3 n=1). All but one patients (93%) obtained a cytologic complete remission (CR), of whom 12/14 (86%) achieved a complete molecular response. However, 2 patients were documented with CNS relapse at the time of blina/pona evaluation although in bone marrow molecular remission. Both obtained clearance of leukemic blasts after intrathecal infusion of chemotherapy. Then, 5 patients underwent allogeneic transplant (including 2 patients already allotransplanted before blina/pona) and 1 patient received donor lymphocyte infusion. Seven cases pursued maintenance therapy with ponatinib as single agent after stopping blinatumomab. With a median follow-up of 8 months (range: 2.6-30.2) for alive patients, median overall and leukemia-free survivals from first cycle of blina/pona were 8.5 months (range: 1.7-30.2) and 8 months (range: 1.3-30.2), respectively.At last follow-up (July 2018), only 4 relapses had occurred at a median of 3.3 months (range: 1.3-8.3) from first blina/pona cycle and 6 patients had died (3 bacterial infections, 1 fungal infection, 1 secondary cancer and 1 ALL relapse). All alive patients (n=9) but one (cytologic CR but detectable minimal residual disease) are in complete molecular response. Four patients are still under ponatinib medication at last follow-up.The combination of blinatumomab+ponatinib appears effective and tolerable in relapsed Ph1+ALL patients and may replace chemotherapy salvage regimens. The combination should be tested in first-line therapy in the future. Our results have also to be confirmed prospectively on a larger cohort of patients. DisclosuresNo relevant conflicts of interest to declare.

Compound Application of Thalidomide and Recombinant Human Interferon-α-1b, Interleukin-2 in Different Disease Status of Acute Myeloid Leukemia a Multi-Center Prospective Study of a New Combination of Old Drugs

Objectives: The aim of this study was to investigate the therapeutic effects of combinational application of thalidomide and recombinant human interferon-α-1b, interleukin-2 (the ITI scheme) in treating acute myeloid leukemia (AML) in different settings.Methods: AML patients with different disease states were categorized into three groups and received treatments following the ITI scheme. Group A consisted of relapsed or refractory AML patients (R/R-AML) and primary AML patients who were unable to receive chemotherapy. Group B included patients with morphologically complete remission (CR) and consistently positive minimal residual disease (MRD). Group C is composed of AML patients with initial complete remission and negative MRD. The CR rate, partial remission rate, MRD status, quality of life, and long-term survival were observed accordingly. ITI scheme is administrated as: IFNα-1b 60ug/d qod ih, IL-2 1001 million units/d qod ih, Thalidomide 200mg qn po. the Compound Salvia Tablets were recommended orally taken in order to prevent deep venous thrombosis.Results: a. With a total response rate of 30% in 60 AML patients of Group A, 4 CR, 6 CRi and 8 PR, who maintained good quality of life with no transfusion with red blood cells or platelet components any more (Table1).The MRD of 13 cases (72.2%) turned negative among 18 patients in Group B. MRD levels turned unmeasurable in seven patients receiving a conventional dose of ITI regimen, and MRD levels significantly decreased in three patients. MRD levels turned unmeasurable after receiving a higher dose of ITI regimen in two patients, and one patients MRD level decreased. Five patients failed to this regimen and suffered a hematologic recurrence. The efficacy is positively correlated with level of MRD level before ITI administration. 81.8% (9/11) patients responded to ITI regimen in whose MRD level ≤1.0%. However, only 57.1% (4/7) responded in whose MRD≥1.0%. 3 patients responded to a extra dose of ITI after no response to a normal dose. Indicated that the efficacy of this regimen is positively correlated with the dose of the regimen.(Table 2)In group C of 88 patients, 11 patients failed to maintain MRD negative, and the relapse rate was 12.5% (Table 3and figure 1).Conclusions: The ITI scheme can provide a new, effective, and affordable treatment option for AML patients that are intolerant to conventional chemotherapy, including R/R-AML patients, patients with CR status but MRD positive, and patients after initial CR. DisclosuresNo relevant conflicts of interest to declare.

Prescribing pattern of fixed dose combinations of antibiotics in a post-operative surgical ward of tertiary care teaching hospital

Background: Fixed dose drug combinations (FDCs), are combinations of two or more active drugs. It should be used when the combination has an established advantage over single drug in efficacy, safety and compliance. The World Health Organization (WHO) lists only 19 of such combinations. But Indian market is filled with hundreds of FDCs which were not approved leading to irrational use. This study was focused on finding out the fixed dose combination of antimicrobial agents used in the post-operative general surgery ward of a tertiary care teaching hospital.Methods: After getting approval from institutional human ethics committee the prescriptions of patients admitted during April 2013 to March 2014 were analyzed. Demographic data, FDC prescribed by surgeons, Dose, Frequency, Duration, Route, Formulation, Brand or generic drugs, Adverse events due to use of FDC were collected and SPSS version 17 was used for statistical analysis. Fixed dose combinations were used in 90 Patients. The most commonly used FDC were ampicillin with Cloxacillin (43) followed by amoxicillin with clavulanic acid (22), cefoperazone with sulbactam (19) and piperacillin with tazobactam (6). A common drug used in combination along with FDC was metronidazole and aminoglycoside. The irrational combination seen in this study was ampicillin with Cloxacillin (8.88%) of the total FDC which is not approved by DCGI or FDA.Results: In this study out of 145 drugs used, 41drugs were administered three times a day, 90 drugs were given two times a day and 14 drugs were given once a day dosing. 53 patients received FDCs for prophylaxis and 37 patients for treatment purpose. All FDCs were prescribed in brand names. No adverse drug reaction was observed in this study.Conclusions: Consultants should undergo continuing medical education (CME) on newer drug combinations and their adverse drug reactions which will be evidence-based rather than to rely on representatives.

Co-Administered Polymeric Nano-Antidotes for Improved Photo-Triggered Response in Glioblastoma.

Polymer-based nanoparticles (NPs) are useful vehicles in treating glioblastoma because of their favorable characteristics such as small size and ability to cross the blood–brain barrier, as well as reduced immunogenicity and side effects. The use of a photosensitizer drug such as Verteporfin (BPD), in combination with a pan-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), Cediranib (CED), encapsulated in NPs will provide the medical field with new research on the possible ways to treat glioblastoma. Concomitant administration of BPD and CED NPs have the potential to induce dual photocytotoxic and cytostatic effects in U87 MG cells by (1) remotely triggering BPD through photodynamic therapy by irradiating laser at 690 nm and subsequent production of reactive oxygen species and (2) inhibiting cell proliferation by VEGFR interference and growth factor signaling mechanisms which may allow for longer progression free survival in patients and fewer systemic side effects. The specific aims of this research were to synthesize, characterize and assess cell viability and drug interactions for polyethylene-glycolated (PEGylated) polymeric based CED and BPD NPs which were less than 100 nm in size for enhanced permeation and retention effects. Synergistic effects were found using the co-administered therapies compared to the individual drugs. The major goal of this research was to investigate a new combination of photodynamic-chemotherapy drugs in nano-formulation for increased efficacy in glioblastoma treatment at reduced concentrations of therapeutics for enhanced drug delivery in vitro.

Challenges of TB and HIV co-treatment: updates and insights.

In the past few years, tuberculosis (TB) has overtaken HIV as the infectious disease with the highest global mortality. Successful management of this syndemic will require improved diagnostic tests, shorter preventive therapies, and more effective treatments, particularly in light of drug-resistant TB. Results from several major studies have been published or presented recently, including the development of a more sensitive rapid, molecular assay for TB; several new symptom-based screening tools; use of a 1-month regimen for TB prevention; the results of early vs. delayed TB preventive therapy for pregnant women; newer drugs and regimens for multidrug-resistant tuberculosis; and pharmacokinetic, safety, and efficacy studies of new HIV drugs in combination with TB treatment. We reviewed each of these topic areas and summarize relevant findings for the management of TB and HIV co-infection. Moving forward, as new treatment regimes for HIV or TB are developed, consideration of the HIV-TB co-infected patient must figure prominently, both when determining the diagnostic tests employed and to assess properly the drug-drug and drug-disease interactions that influence dosing, safety, and response.

Oncobox Bioinformatical Platform for Selecting Potentially Effective Combinations of Target Cancer Drugs Using High-Throughput Gene Expression Data.

Sequential courses of anticancer target therapy lead to selection of drug-resistant cells, which results in continuous decrease of clinical response. Here we present a new approach for predicting effective combinations of target drugs, which act in a synergistic manner. Synergistic combinations of drugs may prevent or postpone acquired resistance, thus increasing treatment efficiency. We cultured human ovarian carcinoma SKOV-3 and neuroblastoma NGP-127 cancer cell lines in the presence of Tyrosine Kinase Inhibitors (Pazopanib, Sorafenib, and Sunitinib) and Rapalogues (Temsirolimus and Everolimus) for four months and obtained cell lines demonstrating increased drug resistance. We investigated gene expression profiles of intact and resistant cells by microarrays and analyzed alterations in 378 cancer-related signaling pathways using the bioinformatical platform Oncobox. This revealed numerous pathways linked with development of drug resistant phenotypes. Our approach is based on targeting proteins involved in as many as possible signaling pathways upregulated in resistant cells. We tested 13 combinations of drugs and/or selective inhibitors predicted by Oncobox and 10 random combinations. Synergy scores for Oncobox predictions were significantly higher than for randomly selected drug combinations. Thus, the proposed approach significantly outperforms random selection of drugs and can be adopted to enhance discovery of new synergistic combinations of anticancer target drugs.

The Importance of Dental Screening Prior to Commencing Anti-Resorptive Therapy for Treatment of Cancer: A Case Report and Discussion

Osteonecrosis of the jaws (ONJ) can be a serious complication of radiation and anti-resorptive therapies. At present, patients due to undergo radiotherapy are required to have a dental assessment to treat current or anticipated dental disease prior to commencing treatment. However no agreed guidelines are in place for those due to start anti-resorptive therapy for cancer. More patients are now being treated with various drug therapies and new combinations of drugs with unknown long-term effects, with many patients now surviving their disease for longer periods of time. It is important to increase awareness among patients and dental professionals of the possibility of them developing medication-related osteonecrosis of the jaw (MRONJ) and to put in place effective preventative measures to help to stop such complications developing. CASE REPORT A 52-year-old patient with a complex medical history, including metastatic breast cancer, presented with generalised oral pain and tooth mobility (see Figure 1). The patient developed extensive stage III MRONJ following concurrent use of multiple anti-resorptive therapies for treatment of secondary bone disease. Dental treatment consisted of provision of antibiotics, hydrogen peroxide and chlorhexidine mouthwashes prior to the extraction of symptomatic teeth and the multiple bony sequestra. CONCLUSION Once established, stage III MRONJ can be challenging to manage for both the dental team and for the patient. This case demonstrates the importance of a comprehensive dental examination and need for preventative dental treatment prior to starting anti-resorptive therapy in order to prevent such instances.

A New Drug Combination Lowers Uric Acid Levels

You might have noted a recent advertising blitz for a gout drug called Duzallo on network television and in newspapers. Duzallo is a recently

The efficacy of Stereotactic body radiation therapy and the impact of systemic treatments in oligometastatic patients from prostate cancer.

BackgroundDiagnoses of oligometastatic prostate cancer (PC) increased in the recent years thanks to the advancement in imaging and more effective systemic therapies. Here we evaluate the efficacy of Stereotactic Body Radiation Therapy (SBRT) in oligorecurrent and oligoprogressive PC.MethodsWe included patients with a maximum of five metastases diagnosed in a maximum of two target organs. Concomitant treatment with hormonal therapies or chemotherapies was allowed. End points of the present study were the outcome in terms of Local control of treated metastases (LC), out‐field progression free survival, overall progression free survival (PFS), and overall survival.ResultsWe included in the analysis 64 patients treated on 90 metastases. Fifty (78.1%) patients were treated on lymph nodes, 2 (3.1%) patients simultaneously on lymph node and bone while 10 (15.7%) patients on bone only. Lung metastases were treated in 2 (3.1%) patients. Thirty‐seven (57.81%) were without androgen deprivation therapy when treated with SBRT. Median follow‐up was 15.2 months. Rates of LC at 6‐, 12‐, and 18‐ months were 94%, 88%, and 84%, respectively. Oligoprogressive patients compared to oligorecurrent (HR 9.10, P = 0.049) and prolongation of time from diagnosis of metastases to SBRT (HR 1.03, P = 0.047) were associated with worse LC. Median PFS was 6.6 months (range 1.1‐42.4). Castration resistant patients experienced worse PFS compared to castration sensitive group (HR 2.12, P = 0.021).ConclusionsStereotactic body radiation therapy seems to be an effective treatment for metastases from PC. Prospective trials are necessary to better define selection of patients and to evaluate combination of SBRT and new systemic drugs in castration resistant patients.

A review of the efficacy and safety of the finished fixed-ratio combination of insulin degludec and liraglutide in the treatment of type 2 diabetes mellitus

Due to the growing prevalence and progression of type 2 diabetes mellitus (DM), the researchers continue the search for the optimal drug not only to achieve the target level of glycaemic control, but also to reduce body weight and the risk of hypoglycaemic conditions. The new combinations of hypoglycaemic drugs are being developed in order to increase adherence to treatment. The studies showed that the addition of a single injection of a fixed combination of insulin degloudec/liraglutide is effective for glycaemic control and weight loss, generally well tolerated by patients and is preferred in individuals with poorly controlled type 2 diabetes on oral hypoglycaemic agents at adequate doses and/or glucagon-like peptide-1 receptor agonists and/or basal insulin to reduce the risk of hypoglycemia associated with insulin therapy.

Recent advances in developing therapeutics for cystic fibrosis.

Despite hope that a cure was imminent when the causative gene was cloned nearly 30 years ago, cystic fibrosis (CF [MIM: 219700]) remains a life-shortening disease affecting more than 70000 individuals worldwide. However, within the last 6 years the Food and Drug Administration's approval of Ivacaftor, the first drug that corrects the defective cystic fibrosis transmembrane conductance regulator protein [CFTR (MIM: 602421)] in patients with the G551D mutation, marks a watershed in the development of novel therapeutics for this devastating disease. Here we review recent progress in diverse research areas, which all focus on curing CF at the genetic, biochemical or physiological level. In the near future it seems probable that development of mutation-specific therapies will be the focus, since it is unlikely that any one approach will be efficient in correcting the more than 2000 disease-associated variants. We discuss the new drugs and combinations of drugs that either enhance delivery of misfolded CFTR protein to the cell membrane, where it functions as an ion channel, or that activate channel opening. Next we consider approaches to correct the causative genetic lesion at the DNA or RNA level, through repressing stop mutations and nonsense-mediated decay, modulating splice mutations, fixing errors by gene editing or using novel routes to gene replacement. Finally, we explore how modifier genes, loci elsewhere in the genome that modify CF disease severity, may be used to restore a normal phenotype. Progress in all of these areas has been dramatic, generating enthusiasm that CF may soon become a broadly treatable disease.

Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy

BackgroundThe intractability of castration-resistant prostate cancer (CRPC) is exacerbated by tumour heterogeneity, including diverse alterations to the androgen receptor (AR) axis and AR-independent phenotypes. The availability of additional models encompassing this heterogeneity would facilitate the identification of more effective therapies for CRPC. ObjectiveTo discover therapeutic strategies by exploiting patient-derived models that exemplify the heterogeneity of CRPC. Design, setting, and participantsFour new patient-derived xenografts (PDXs) were established from independent metastases of two patients and characterised using integrative genomics. A panel of rationally selected drugs was tested using an innovative ex vivo PDX culture system. InterventionThe following drugs were evaluated: AR signalling inhibitors (enzalutamide and galeterone), a PARP inhibitor (talazoparib), a chemotherapeutic (cisplatin), a CDK4/6 inhibitor (ribociclib), bromodomain and extraterminal (BET) protein inhibitors (iBET151 and JQ1), and inhibitors of ribosome biogenesis/function (RNA polymerase I inhibitor CX-5461 and pan-PIM kinase inhibitor CX-6258). Outcome measurements and statistical analysisDrug efficacy in ex vivo cultures of PDX tissues was evaluated using immunohistochemistry for Ki67 and cleaved caspase-3 levels. Candidate drugs were also tested for antitumour efficacy in vivo, with tumour volume being the primary endpoint. Two-tailed t tests were used to compare drug and control treatments. Results and limitationsIntegrative genomics revealed that the new PDXs exhibited heterogeneous mechanisms of resistance, including known and novel AR mutations, genomic structural rearrangements of the AR gene, and a neuroendocrine-like AR-null phenotype. Despite their heterogeneity, all models were sensitive to the combination of ribosome-targeting agents CX-5461 and CX-6258. ConclusionsThis study demonstrates that ribosome-targeting drugs may be effective against diverse CRPC subtypes including AR-null disease, and highlights the potential of contemporary patient-derived models to prioritise treatment strategies for clinical translation. Patient summaryDiverse types of therapy-resistant prostate cancers are sensitive to a new combination of drugs that inhibit protein synthesis pathways in cancer cells.

Abstract 2366: The tyrosine phosphatase, SHP-2, participates in regulating PD-L1 expression in non-small cell lung cancer

Abstract Immune checkpoint inhibitors, specifically those which target T cell surface receptor Programmed Cell Death-1 (PD-1) and its ligand, Programmed cell death ligand-1 (PD-L1), have demonstrated clinical benefit in patients with non-small cell lung cancer (NSCLC). Currently, tumor expression of PD-L1 serves as the FDA-approved companion diagnostic for response to anti-PD-1/PD-L1 therapy. However, a fraction of patients who express PD-L1 exhibit a response to treatment, and in some cases, patient tumors that do not express PD-L1 demonstrate response to therapy, making this a poor predictive biomarker. Further, the mechanism by which PD-L1 expression is controlled remains under-studied. In this study, we seek to determine the impact of the protein tyrosine phosphatase, SHP-2, on PD-L1 expression through Jak/STAT- mediated signaling in NSCLC cell lines. SHP-2 can harbor activating mutations which prevent auto-inhibition of the catalytic phosphatase domain, and that may be pro-tumorigenic in some tumors. To understand the impact of SHP-2 activity on PD-L1 expression, we first assessed activation of STAT3 in NSCLC tumor cells after treatment with IFNγ and other mitogens. We then transfected NSCLC cells with wildtype and hyperactive SHP-2 mutants or ablated SHP-2 with siRNA specific for SHP-2 and measured both STAT3 and PD-L1 expression. Cell lines A549 and H661 exhibit low endogenous expression of both SHP-2 and PD-L1, and thus were chosen for transfection with hyperactive SHP-2 mutants (E76K and G503V), which also altered PD-L1 expression by western blot analysis. Quantitative real-time PCR (qPCR) and western blot analysis revealed that siRNA ablation of SHP-2 led to increased PD-L1 expression in the H460 cell line. Cells transfected with the SHP-2 activating mutants will also be assessed alteration of cell proliferation. Finally, using data obtained from The Cancer Genome Atlas project, STAT3 and PD-L1 expression levels are being evaluated in NSCLC tumor samples in which SHP-2 is mutated (E76K or G503V). With these data, we expect to gain a more complete understanding of the role of SHP-2 within the tumor microenvironment and the extent to which it controls PD-L1 expression, leading to new drug targets or combinations of drugs and better predictive biomarkers of response to PD-1 and PD-L1 inhibitors. Citation Format: Keller Toral, Brent Harris, Jarrod Creameans, Penni Black. The tyrosine phosphatase, SHP-2, participates in regulating PD-L1 expression in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2366.

Recent Advances in the Treatment of Peripheral T-Cell Lymphoma.

Recent progress in understanding of the biology and pathogenesis of peripheral T-cell lymphoma has led to the emergence of new drugs. Unfortunately, this has not been met with similar advances in outcome improvement. Anthracycline-containing regimens, mostly cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), are considered the standard of care, although the best first-line approach remains to be defined. In the relapsed and refractory settings, several new agents achieved response rates between 10% and 30%, although these drugs do not significantly affect survival rates. Therapeutic options based on better molecular characterization of various histological types and combinations with the CHOP regimen or synergic combinations of new drugs may lead to better outcomes.

Promiscuous, Multi-Target Lupane-Type Triterpenoids Inhibits Wild Type and Drug Resistant HIV-1 Replication Through the Interference With Several Targets.

Current research on antiretroviral therapy is mainly focused in the development of new formulations or combinations of drugs belonging to already known targets. However, HIV-1 infection is not cured by current therapy and thus, new approaches are needed. Bevirimat was developed by chemical modification of betulinic acid, a lupane-type pentacyclic triterpenoid (LPT), as a first-in-class HIV-1 maturation inhibitor. However, in clinical trials, bevirimat showed less activity than expected because of the presence of a natural mutation in Gag protein that conferred resistance to a high proportion of HIV-1 strains. In this work, three HIV-1 inhibitors selected from a set of previously screened LPTs were investigated for their targets in the HIV-1 replication cycle, including their maturation inhibitor effect. LPTs were found to inhibit HIV-1 infection acting as promiscuous compounds with several targets in the HIV-1 replication cycle. LPT12 inhibited HIV-1 infection mainly through reverse transcription, integration, viral transcription, viral proteins (Gag) production and maturation inhibition. LPT38 did it through integration, viral transcription or Gag production inhibition and finally, LPT42 inhibited reverse transcription, viral transcription or Gag production. The three LPTs inhibited HIV-1 infection of human primary lymphocytes and infections with protease inhibitors and bevirimat resistant HIV-1 variants with similar values of IC50. Therefore, we show that the LPTs tested inhibited HIV-1 infection through acting on different targets depending on their chemical structure and the activities of the different LPTs vary with slight structural alterations. For example, of the three LPTs under study, we found that only LPT12 inhibited infectivity of newly-formed viral particles, suggesting a direct action on the maturation process. Thus, the multi-target behavior gives a potential advantage to these compounds since HIV-1 resistance can be overcome by modulating more than one target.

Drug Repurposing for Schistosomiasis: Combinations of Drugs or Biomolecules.

Schistosomiasis is a major neglected tropical disease. Control of schistosomiasis currently relies on a single drug, praziquantel, and despite its efficacy against the all schistosome species that parasitize humans, it displays some problematic drawbacks and alone is ineffective in counteracting adverse pathologies associated with infection. Moreover, due to the development of the potential emergence of PZQ-resistant strains, the search for additional or alternative antischistosomal drugs have become a public health priority. The current drug discovery for schistosomiasis has been slow and uninspiring. By contrast, repurposing of existing approved drugs may offer a safe, rapid and cost-effective alternative. Combined treatment with PZQ and other drugs with different mode of action, i.e., antimalarials, shows promise results. In addition, a combination of anthelminthic drugs with antioxidant might be advantageous for modulating oxidative processes associated with schistosomiasis. Herein, we review studies dealing with combination therapies that involve PZQ and other anthelminthic drugs and/or antioxidant agents in treatment of schistosomiasis. Whereas PZQ combined with antioxidant agents might or might not interfere with anthelminthic efficacy, combinations may nonetheless ameliorate tissue damage and infection-associated complications. In fact, alone or combine with other drugs, antioxidants might be a valuable adjuvant to reduce morbidity and mortality of schistosomiasis. Therefore, attempting new combinations of anthelmintic drugs with other biomolecules such as antioxidants provides new avenues for discovery of alternatives to PZQ.

Chagas Disease Recommendations for Solid-Organ Transplant Recipients and Donors.

Chagas Disease Recommendations for Solid-Organ Transplant Recipients and Donors.

Natural Products And Traditional Medicines For The Treatment Of Multidrug Resistant Bacteria

Multidrug resistant microorganisms (MDROs) have been responsible for numerous outbreaks of infectious epidemics, and pose a serious threat to global health. The lack of effective therapies for these MDROs, coupled with a reduced number of antimicrobial drugs in the pharmaceutical pipeline to treat these infections indicates an urgent need for research in this area. Of the resistant Gram-positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Pseudomonas aeruginosa and multidrug-resistant tuberculosis (MDR-TB) continue to be the most problematic, but more recently there has been increasing reports of vancomycin-resistant Staphylococcus aureus (VRSA) infections. For highly-resistant Gram-negative bacteria, Vancomycin-resistant Enterococci (VRE), multidrug-resistant carbapenemase-producing Klebsiella pneumoniae and MDR-Acinetobacter baumannii are important as these bacteria are often only susceptible to older antimicrobial agents, such as the polymyxins that have a higher adverse event profile. Thus, there is an urgent need for new antibiotics and combinations of drugs to treat these emerging MDR bacteria. The lack of interest by pharmaceutical companies in the research and development of new antibiotics has increased research in the field of natural products. An increasing body of scientific evidence suggests that specific marine, fungal and medicinal plant extracts, as well as traditional medicine formulas and purified natural products are active against specific MDR-bacteria, and thus could be further investigated and possibly developed as clinical agents. This review focuses on recently published data for natural products active against MDR bacteria and evaluates some of the recent published in vitro data.

Target therapy: new drugs or new combinations of drugs in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a disease with a poor prognosis due to its aggressive nature. The management of patients with MPM is controversial. Considering that the contribution of surgery and radiation therapy in the management of this disease is not yet established, systemic treatments are predominantly considered during the course of MPM. Unfortunately, the currently therapeutic armamentarium is scarce and its outcomes still appear modest. New treatment strategies are needed. In preclinical setting, cell cycle regulation, apoptosis, growth factor pathways, and angiogenesis pathways involved in the development of MPM have been identified. However, in clinical setting, several drugs targeting these pathways resulted without a significant activity. A deeper knowledge of the biology and pathogenesis of this disease is required to develop more effective tools for diagnosis, therapy and prevention. This paper reviews therapeutic advances in MPM, with a particular focus on new drugs and new association of drugs of target therapy.

Controversy between Obesity and Complications in Thromboembolic Disease, Series of Cases of Fuenlabrada University Hospital in Tinzaparine Treatment

Thromboembolic disease is the second leading cause of death in cancer patients (mostly, in the first year from diagnosis). The needing for anticoagulation with low molecular weight heparin (LMWH) in patients who are at high risk for complications (risk of bleeding in digestive tumors, brain tumors ...) require us to be more aware of their evolution. In addition, presenting venous thromboembolic disease (VTE) is usually an exclusion criterion in clinical trials so we do not know what happens with the combination of new drugs. Our objective is to study in a sample of 31 patients diagnosed with VTE, whether incidence of complications such as re-thrombosis or bleeding is higher in patients treated with tinzaparin (LMWH) depending on BMI.