Combination Effects of Peramivir and Favipiravir against Oseltamivir-Resistant 2009 Pandemic Influenza A(H1N1) Infection in Mice

Antiviral drugs are being used for therapeutic purposes against influenza illness in humans. However, antiviral-resistant variants often nullify the effectiveness of antivirals. Combined medications, as seen in the treatment of cancers and other infectious diseases, have been suggested as an option for the control of antiviral-resistant influenza viruses. Here, we evaluated the therapeutic value of combination therapy against oseltamivir-resistant 2009 pandemic influenza H1N1 virus infection in DBA/2 mice. Mice were treated for five days with favipiravir and peramivir starting 4 hours after lethal challenge. Compared with either monotherapy, combination therapy saved more mice from viral lethality and resulted in increased antiviral efficacy in the lungs of infected mice. Furthermore, the synergism between the two antivirals, which was consistent with the survival outcomes of combination therapy, indicated that favipiravir could serve as a critical agent of combination therapy for the control of oseltamivir-resistant strains. Our results provide new insight into the feasibility of favipiravir in combination therapy against oseltamivir-resistant influenza virus infection.     

Combined antimalarial therapy using artemisinin

The existing armamentarium of drugs for the treatment and prevention of malaria is limited primarily by resistance (and cross-resistance between closely related drugs). However, most of these drugs still have a place and their life-span could be prolonged if better deployed and used, and also by rationally combining them based on pharmacodynamic and pharmacokinetic properties. Newer compounds are also being developed. The nature of malaria disease and its prevalence in the developing world call for innovative approaches to develop new affordable drugs and to safeguard the available ones. According to WHO, the concept of combination therapy is based on the synergistic or additive potential of two or more drugs, to improve therapeutic efficacy and also delay the development of resistance to the individual components of the combination. Combination therapy (CT) with antimalarial drugs is the simultaneous use of two or more blood schizontocidal drugs with independent modes of action and different biochemical targets in the parasite. In the context of this definition, multiple-drug therapies that include a nonantimalarial drug to enhance the antimalarial effect of a blood schizontocidal drug are not considered combination therapy. Similarly, certain antimalarial drugs that fit the criteria of synergistic fixed-dose combinations are operationally considered as single products in that neither of the individual components would be given alone for anti-malarial therapy. An example is sulfadoxine-pyrimethamine. Artemisinin-based combination therapies have been shown to improve treatment efficacy and also contain drug resistance in South-East Asia. However, major challenges exist in the deployment and use of antimalarial drug combination therapies, particularly in Africa. These include: 1) the choice of drug combinations best suited for the different epidemiological situations; 2) the cost of combination therapy; 3) the timing of the introduction of combination therapy; 4) the operational obstacles to implementation, especially compliance. As a response to increasing levels of antimalarial resistance, the World Health Organization (WHO) recommends that all countries experiencing resistance to conventional monotherapies, such as chloroquine, amodiaquine or sulfadoxine/pyrimethamine, should use combination therapies, preferably those containing artemisinin derivatives (ACTs--artemisinin-based combination therapies) for malaria caused by Plasmodium falciparum. There is a promising role of such compounds in replacing or complementing current options. Since 1979, several different formulations of artemisinin and its derivatives have been produced and studied in China in several thousand patients for either P. falciparum or P. vivax malaria. To date, there is no evidence of drug resistance to these compounds. The use of artemisinin, artemether, arteether and artesunate for either uncomplicated or severe malaria is now spreading through almost all malarious areas of the world, although some of they have no patent protection, their development (with few exceptions) has not followed yet full international standards. Both artesunate, artemether and arteether are rapidly and extensively converted to their common bioactive metabolite, dihydroarte-misinin. WHO currently recommends the following therapeutic options: 1) artemether/lumefantrine; 2) artesunate plus amodiaquine; 3) artesunate plus sulfadoxine/pyrimethamine (in areas where SP efficacy remains high); 4) artesunate plus mefloquine (in areas with low to moderate transmission); and 5) amodiaquine plus sulfadoxine/pyrimethamine, in areas where efficacy of both amodiaquine and sulfadoxine/pyrimethamine remains high (mainly limited to countries in West Africa). This non artemisinin-based combination therapy is reserved as an interim option for countries, which, for whatever reason, are unable immediately to move to ACTs.     

抗流感病毒小RNAs研究进展

流行性感冒是一类由流感病毒引起的呼吸道传染病, 通过季节性流行或全球性爆发严重威胁着人类健康。目前防治流感的主要方法是疫苗和药物, 但存在神经毒性、肠胃副作用、易耐药等诸多限制因素。新的技术特别是小RNAs介导的RNA干扰(RNAi)技术, 因其具有高效、特异、快速等特点, 已成为抗病毒治疗的候选方法之一。随着近年来流感病毒的流行, 应用小RNAs抗流感病毒的报导越来越多, 其中靶向PA、NP和M2的PA-2087, NP-1496和M-950是目前报道的抑制流感病毒效果最好的siRNA。靶向不同流感病毒基因保守区域的siRNA具有更广泛的病毒毒株抑制效果, 靶向不同基因的siRNAs联合使用可取得更好的病毒抑制效果。文章就目前siRNAs和miRNAs在抗流感病毒方面的研究进展及RNAi治疗的前景和问题进行了综述。     

抗流感病毒小RNAs研究进展

流行性感冒是一类由流感病毒引起的呼吸道传染病,通过季节性流行或全球性爆发严重威胁着人类健康。目前防治流感的主要方法是疫苗和药物,但存在神经毒性、肠胃副作用、易耐药等诸多限制因素。新的技术特别是小RNAs介导的RNA干扰(RNAi)技术,因其具有高效、特异、快速等特点,已成为抗病毒治疗的候选方法之一。随着近年来流感病毒的流行,应用小RNAs抗流感病毒的报导越来越多,其中靶向PA、NP和M2的PA-2087,NP-1496和M-950是目前报道的抑制流感病毒效果最好的siRNA。靶向不同流感病毒基因保守区域的siRNA具有更广泛的病毒毒株抑制效果,靶向不同基因的siRNAs联合使用可取得更好的病毒抑制效果。文章就目前siRNAs和miRNAs在抗流感病毒方面的研究进展及RNAi治疗的前景和问题进行了综述。     

Immunopharmacologic bases of immunotherapy

Secondary immune deficiency generally involves more profound defects in cellular than humoral immunity. This type of immune deficiency occurs in acquired immunodeficiency syndrome (AIDS), cancer, malnutrition, aging and following immunosuppressive therapy. Immunorestorative therapies were developed for use in the immunotherapy of cancer. Their experimental use in cancer and other diseases such as infections and autoimmunity has demonstrated their safety and their capacity to improve host responses to disease particularly when the host is immunocompromised. Biologicals such as the thymic hormones and interferon have been intensively studied and are briefly reviewed in this paper. Chemically defined drugs such as levamisole, isoprinosine, azimexon, and muramyl dipeptides have also been extensively analyzed and the action of certain purine-related compounds are discussed to exemplify their immunopharmacologic features. The combined uses of biologicals and drugs are suggested to improve the efficiency of immunotherapy.     

Photodynamic inactivation for controlling Candida albicans infections

Antimicrobial photodynamic therapy (APDT) combines a non-toxic dye, termed photosensitizer, which is activated by visible light of appropriate wavelength which will produce reactive oxygen species (ROS). These ROS will react with cellular components inducing oxidative processes, leading to cell death. A wide range of microorganisms, have already showed susceptibility to APDT. Therefore, this treatment might consist in an alternative for the management of fungal infections that is mainly caused by biofilms, since they respond poorly to conventional antibiotics and may play a role in persistent infections. Biofilms are the leading cause of microbial infections in humans, thus representing a serious problem in health care. Candida albicans is the main type of fungi able to form biofilms, which cause superficial skin and mucous membrane infections as well as deep-seated mycoses, particularly in immunocompromised patients. In these patients, invasive infections are often associated with high morbidity and mortality. Furthermore, the increase in antifungal resistance has decreased the efficacy of conventional therapies. Treatments are time-consuming and thus demanding on health care budgets. Additionally, current antifungal drugs only have a limited spectrum of action and toxicity. The use of APDT as an antimicrobial topical agent against superficial and cutaneous diseases represents an effective method for eliminating microorganisms.     

Recent advances in the treatment of IBD: Targets,mechanisms and related therapies

Inflammatory bowel disease (IBD), as a representative inflammatory disease, currently has multiple effective treatment options available and new therapeutic strategies are being actively explored to further increase the treatment options for patients with IBD. Furthermore, biologic agents and small molecule drugs developed for ulcerative colitis (UC) and Crohn's disease (CD) have evolved toward fewer side effects and more accurate targeting. Novel inhibitors that target cytokines (such as IL-12/23 inhibitors, PDE4 inhibitors), integrins (such as integrin inhibitors), cytokine signaling pathways (such as JAK inhibitors, SMAD7 blocker) and cell signaling receptors (such as S1P receptor modulator) have become the preferred treatment choice for many IBD patients. Conventional therapies such as 5-aminosalicylic acid, corticosteroids, immunomodulators and anti-tumor necrosis factor agents continue to demonstrate therapeutic efficacy, particularly in combination with drug therapy. This review integrates research from chemical, biological and adjuvant therapies to evaluate current and future IBD therapies, highlighting the mechanism of action of each therapy and emphasizing the potential of development prospects.     

Yeast glucan of Pneumocystis carinii cyst wall: an excellent target for chemotherapy.

Pneumocystis pneumonia is the most serious opportunistic infection in immunocompromised patients, particularly those with AIDS. Approved therapy is limited to pentamidine and inhibitors of folic acid synthesis, but these drugs show a high rate of adverse reactions in AIDS patients emphasizing the urgent need for additional effective therapies. Progress has, however, been hindered by lack of knowledge about this parasite's cellular characteristics. Previously we reported that beta (1,3)glucan is a major component of the Pneumocystis carinii cyst wall. This study shows that administration of aculeacin A, an inhibitor of beta (1,3)glucan biosynthesis, affects cyst wall formation, inhibits cyst maturation, and prevents severe pneumonia in steroid-treated rats. Thus this study not only demonstrates that beta (1,3)glucan is indispensable for growth of the parasite in rats, but suggests a new therapeutic strategy for human pneumocystosis.     

Adjuvanted vaccines against influenza in the elderly

Influenza is an important public health issue,especially with the aging of the population,since the most serious consequences of the illness affect the elderly.Between 1979 and 2001,approximately 41000...     

An Empirical Approach towards the Efficient and Optimal Production of Influenza-Neutralizing Ovine Polyclonal Antibodies Demonstrates That the Novel Adjuvant CoVaccine HT? Is Functionally Superior to Freund's Adjuvant

Passive immunotherapies utilising polyclonal antibodies could have a valuable role in preventing and treating infectious diseases such as influenza, particularly in pandemic situations but also in immunocompromised populations such as the elderly, the chronically immunosuppressed, pregnant women, infants and those with chronic diseases. The aim of this study was to optimise current methods used to generate ovine polyclonal antibodies. Polyclonal antibodies to baculovirus-expressed recombinant influenza haemagglutinin from A/Puerto Rico/8/1934 H1N1 (PR8) were elicited in sheep using various immunisation regimens designed to investigate the priming immunisation route, adjuvant formulation, sheep age, and antigen dose, and to empirically ascertain which combination maximised antibody output. The novel adjuvant CoVaccine HT™ was compared to Freund’s adjuvant which is currently the adjuvant of choice for commercial production of ovine polyclonal Fab therapies. CoVaccine HT™ induced significantly higher titres of functional ovine anti-haemagglutinin IgG than Freund’s adjuvant but with fewer side effects, including reduced site reactions. Polyclonal hyperimmune sheep sera effectively neutralised influenza virus in vitro and, when given before or after influenza virus challenge, prevented the death of infected mice. Neither the age of the sheep nor the route of antigen administration appeared to influence antibody titre. Moreover, reducing the administrated dose of haemagglutinin antigen minimally affected antibody titre. Together, these results suggest a cost effective way of producing high and sustained yields of functional ovine polyclonal antibodies specifically for the prevention and treatment of globally significant diseases.     

Benznidazole/Itraconazole Combination Treatment Enhances Anti-Trypanosoma cruzi Activity in Experimental Chagas Disease

The nitroheterocyclic drugs nifurtimox and benznidazole are first-line drugs available to treat Chagas disease; however, they have limitations, including long treatment courses and toxicity. Strategies to overcome these limitations include the identification of new drugs with specific target profiles, re-dosing regimens for the current drugs, drug repositioning and combination therapy. In this work, we evaluated combination therapy as an approach for optimization of the current therapeutic regimen for Chagas disease. The curative action of benznidazole/itraconazole combinations was explored in an established infection of the mice model with the T. cruzi Y strain. The activities of the benznidazole/itraconazole combinations were compared with the results from those receiving the same dosage of each individual drug. The administration of benznidazole/itraconazole in combination eliminated parasites from the blood more efficiently than each drug alone. Here, there was a significant reduction of the number of treatment days (number of doses) necessary to induce parasitemia suppression with the benznidazole/itraconazole combination, as compared to each compound administered alone. These results clearly indicate the enhanced effects of these drugs in combination, particularly at the dose of 75 mg/kg, as the effects observed with the drug combinations were four times more effective than those of each drug used alone. Moreover, benznidazole/itraconazole treatment was shown to prevent or decrease the typical lesions associated with chronic experimental Chagas disease, as illustrated by similar levels of inflammatory cells and fibrosis in the cardiac muscle tissue of healthy and treated mice. These results emphasize the importance of exploring the potential of combination treatments with currently available compounds to specifically treat Chagas disease.     

AACE/ACE Disease State Clinical Review: Medical Management of Cushing Disease

ObjectiveTo review available medical therapies for patients with Cushing disease and to provide a roadmap for their use in clinical practice.MethodsPubMed searches were performed to identify all of the available published data on medical management of Cushing disease.ResultsMedical therapy is usually not the firstline treatment for patients with Cushing disease but may be used to improve clinical manifestations of Cushing disease in patients who are not suitable candidates for surgery, following unsuccessful surgery or recurrence, or as a “bridge therapy” in those who have undergone radiotherapy. Medical therapy may also be used in preoperative preparation of patients with severe disease. Current available medical options for patients with Cushing disease include centrally acting agents, steroidogenesis inhibitors, and a glucocorticoid receptor antagonists. At present, there are no head-to-head studies comparing the efficacy, tolerability, and safety of different U.S. Food and Drug Administration (FDA)- and non-FDA-approved drugs in patients with Cushing disease. With the initiation of new studies and the completion of ongoing clinical trials, the number of FDA-approved drugs for medical treatment of Cushing disease is expected to increase.ConclusionMedical therapy has an important adjunctive role in the management of patients with Cushing disease. The decision to initiate medical treatment depends on many factors, including patient characteristics and preference. Long-term studies are needed to better define the clinical efficacy, safety, and tolerability of medical treatment of Cushing disease, including the role of combination therapies. (Endocr Pract. 2014;20:746-757)     

Drug failure during HIV-1 treatment. New perspectives in monitoring drug resistance

Since the discovery of 3'-azido-3'deoxthymidine (zidovudine) as an effective antiretroviral agent against human immunodeficiency virus type 1 (HIV-1), drug therapy has been widely used in the treatment of AIDS. To date, new combination therapies have significantly altered the longterm prognosis for HIV-infected patients showing a reduction of plasma viral load, associated with clinical and immunological recovery. Nevertheless, in various circumstances treatment can fail for several reasons, such as patient noncompliance with the therapeutic regimen, suboptimal antiviral drug concentrations, drug pharmacokinetics, and virus resistance to one or more drugs. Virus drug resistance is the most important factor contributing to the failure of antiretroviral therapy. Since some evidence indicates that viral resistance and treatment failure are closely linked, this brief review explores the routine determination of drug resistance and its importance to shed more light on the meaning of mutations correlated to drug resistance.     

Discovery and development of SQ109: a new antitubercular drug with a novel mechanism of action

Existing drugs have limited efficacy against the rising threat of drug-resistant TB, have significant side effects, and must be given in combinations of four to six drugs for at least 6 months for drug-sensitive TB and up to 24 months for drug-resistant TB. The long treatment duration has led to increased patient noncompliance with therapy. This, in turn, drives the development of additional drug resistance in a spiral that has resulted in some forms of TB being currently untreatable by existing drugs. New antitubercular drugs in development, particularly those with mechanisms of action that are different from existing first- and second-line TB drugs, are anticipated to be effective against both drug-sensitive and drug-resistant TB. SQ109 is a new TB drug candidate with a novel mechanism of action that was safe and well tolerated in Phase I and early Phase II clinical trials. We describe herein the identification, development and characterization of SQ109 as a promising new antitubercular drug.     

Isavuconazole and Liposomal Amphotericin B as Successful Combination Therapy of Refractory Invasive Candidiasis in a Liver Transplant Recipient: A Case Report and Literature Review

Invasive fungal infections in liver transplant recipients are associated with elevated morbidity and mortality and pose a challenge to the treating physicians. Despite of lacking clinical data, the use of antifungal combination therapy is often considered to improve response rates in an immunocompromised patient population. We herein report a case of refractory invasive candidiasis in a liver transplant recipient treated successfully with a combination of isavuconazole und high-dose liposomal amphotericin B. The antimycotic combination treatment was able to clear a bloodstream infection with C. glabrata and led to regression of bilomas among tolerable side effects. The use of the above-mentioned antifungal combination therapy in a liver transplant recipient has not been reported previously. This case highlights the efficacy and safety of antifungal combination therapy in immunocompromised patients with refractory invasive candidiasis.

     

Synthetic antimicrobial β‐peptide in dual‐treatment with fluconazole or ketoconazole enhances the in vitro inhibition of planktonic and biofilm Candida albicans

Fungal infections are a pressing concern for human health worldwide, particularly for immunocompromised individuals. Current challenges such as the elevated toxicity of common antifungal drugs and the emerging resistance towards these could be overcome by multidrug therapy. Natural antimicrobial peptides, AMPs, in combination with other antifungal agents are a promising avenue to address the prevailing challenges. However, they possess limited biostability and susceptibility to proteases, which has significantly hampered their development as antifungal therapies. β‐peptides are synthetic materials designed to mimic AMPs while allowing high tunability and increased biostability. In this work, we report for the first time the inhibition achieved in Candida albicans when treated with a mixture of a β‐peptide model and fluconazole or ketoconazole. This combination treatment enhanced the biological activity of these azoles in planktonic and biofilm Candida, and also in a fluconazole‐resistant strain. Furthermore, the in vitro cytotoxicity of the dual treatment was evaluated towards the human hepatoma cell line, HepG2, a widely used model derived from liver tissue, which is primarily affected by azoles. Analyses based on the LA‐based method and the mass‐action law principle, using a microtiter checkerboard approach, revealed synergism of the combination treatment in the inhibition of planktonic C. albicans. The dual treatment proved to be fungicidal at 48 and 72 h. Interestingly, it was also found that the viability of HepG2 was not significantly affected by the dual treatments. Finally, a remarkable enhancement in the inhibition of the highly azole‐resistant biofilms and fluconazole resistant C. albicans strain was obtained. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.     

Triple Combination of Amantadine,Ribavirin, and Oseltamivir Is Highly Active and Synergistic against Drug Resistant Influenza Virus Strains In Vitro

The rapid emergence and subsequent spread of the novel 2009 Influenza A/H1N1 virus (2009 H1N1) has prompted the World Health Organization to declare the first pandemic of the 21^st century, highlighting the threat of influenza to public health and healthcare systems. Widespread resistance to both classes of influenza antivirals (adamantanes and neuraminidase inhibitors) occurs in both pandemic and seasonal viruses, rendering these drugs to be of marginal utility in the treatment modality. Worldwide, virtually all 2009 H1N1 and seasonal H3N2 strains are resistant to the adamantanes (rimantadine and amantadine), and the majority of seasonal H1N1 strains are resistant to oseltamivir, the most widely prescribed neuraminidase inhibitor (NAI). To address the need for more effective therapy, we evaluated the in vitro activity of a triple combination antiviral drug (TCAD) regimen composed of drugs with different mechanisms of action against drug-resistant seasonal and 2009 H1N1 influenza viruses. Amantadine, ribavirin, and oseltamivir, alone and in combination, were tested against amantadine- and oseltamivir-resistant influenza A viruses using an in vitro infection model in MDCK cells. Our data show that the triple combination was highly synergistic against drug-resistant viruses, and the synergy of the triple combination was significantly greater than the synergy of any double combination tested (P<0.05), including the combination of two NAIs. Surprisingly, amantadine and oseltamivir contributed to the antiviral activity of the TCAD regimen against amantadine- and oseltamivir-resistant viruses, respectively, at concentrations where they had no activity as single agents, and at concentrations that were clinically achievable. Our data demonstrate that the TCAD regimen composed of amantadine, ribavirin, and oseltamivir is highly synergistic against resistant viruses, including 2009 H1N1. The TCAD regimen overcomes baseline drug resistance to both classes of approved influenza antivirals, and thus may represent a highly active antiviral therapy for seasonal and pandemic influenza.     

Estrogen,Progesterone and Epithelial Ovarian Cancer

Ovarian carcinoma (OCa) continues to be the leading cause of death due to gynecologic malignancies and the vast majority of OCa is derived from the ovarian surface epithelium (OSE) and its cystic derivatives. Epidemiological evidence strongly suggests that steroid hormones, primarily estrogens and progesterone, are implicated in ovarian carcinogenesis. However, it has proved difficult to fully understand their mechanisms of action on the tumorigenic process. New convincing data have indicated that estrogens favor neoplastic transformation of the OSE while progesterone offers protection against OCa development. Specifically, estrogens, particularly those present in ovulatory follicles, are both genotoxic and mitogenic to OSE cells. In contrast, pregnancy-equivalent levels progesterone are highly effective as apoptosis inducers for OSE and OCa cells. In this regard, high-dose progestin may exert an exfoliation effect and rid an aged OSE of pre-malignant cells. A limited number of clinical studies has demonstrated efficacies of antiestrogens, aromatase inhibitors, and progestins alone or in combination with chemotherapeutic drugs in the treatment of OCa. As a result of increased life expectancy in most countries, the number of women taking hormone replacement therapies (HRT) continues to grow. Thus, knowledge of the mechanism of action of steroid hormones on the OSE and OCa is of paramount significance to HRT risk assessment and to the development of novel therapies for the prevention and treatment of OCa.     

Medical and Adjunctive Treatment of Mucormycosis in Children: Scientific Rationale and Analysis of Cases Reported in the Literature

Mucormycosis is associated with significant morbidity and mortality in both children and adults. Studies have shown an increase in the incidence of mucormycosis, particularly among hematopoietic stem cell transplant (HSCT) recipients, patients with hematologic malignancies, and those with diabetic ketoacidosis. The infection typically presents as soft tissue, rhinoorbitocerebral, pulmonary, or disseminated disease and is characterized by rapid clinical progression and high mortality rates. Treatment with amphotericin B lipid formulations in combination with surgery offers the best option for treatment and survival; posaconazole, a relatively new antifungal triazole, is increasingly used for consolidation or salvage therapy. Because of the poor prognosis of zygomycosis, particularly in immunocompromised cancer patients, adjunctive treatments such as hyperbaric oxygen therapy, use of immunomodulatory cytokines, and in vivo iron chelation continue to be explored. Thus far, it is unclear how these adjunctive treatments can be harnessed to impact outcomes and which patients may benefit from them.