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Sample records for antifungal combination therapy

  1. Combination Antifungal Therapy for Invasive Aspergillosis Revisited

    PubMed Central

    Panackal, Anil A.

    2016-01-01

    Invasive aspergillosis (IA) causes significant morbidity and mortality among immunocompromised hosts. Combination therapy with mold-active triazoles and echinocandins has been used with the hope of improving outcomes over monotherapy, especially in the setting of refractory disease. Herein, I update our prior systematic review and meta-analysis on combination therapy for salvage IA in the context of the recently published randomized clinical trial of combination therapy for primary IA. Clinicians should consider combination antifungals for IA in refractory disease despite immune reconstitution when there are concerns for resistance or pharmacokinetic variability. PMID:27441304

  2. Disseminated mucormycosis in a paediatric patient: Lichthemia corymbifera successfully treated with combination antifungal therapy

    PubMed Central

    Campbell, Anita; Cooper, Celia; Davis, Stephen

    2014-01-01

    Mucormycosis is a severe fungal infection that largely affects immunocompromised individuals. It carries a high morbidity and mortality rate and is characterised by extensive angioinvasion and necrosis of host tissue. This case report details success in treating disseminated mucormycosis in a paediatric patient with an underlying haematological malignancy. Treatment included institution of combination antifungal therapy with liposomal amphotericin B and caspofungin, aggressive surgical debridement of infected tissue and reversal of underlying immunosuppression. PMID:25379392

  3. Invasive aspergillosis successfully treated by combined antifungal therapy and immunosuppressive monotherapy two months following heart transplantation

    PubMed Central

    Żabicki, Bartłomiej; Baszyńska-Wachowiak, Hanna; Straburzyńska-Migaj, Ewa; Juszkat, Robert; Grajek, Stefan; Jemielity, Marek

    2016-01-01

    Invasive aspergillosis is becoming increasingly prevalent, especially following transplantation. Invasive aspergillosis is associated with mortality. Successful therapy is related to early diagnosis and proper therapy. We present the case of a 61-year-old man suffering from invasive aspergillosis 2 months following heart transplantation. He was suffering from hypertrophic cardiomyopathy and he underwent orthotropic heart transplantation. He was readmitted to the Department of Cardiology 69 days following transplantation due to symptoms of productive cough for 5 days. It was accompanied by chest pain, shortness of breath, and fever up to 39°C. He was slightly cyanotic and confused on physical examination. The patient's status deteriorated within the following 2 days. On bronchoscopic specimen examinations Aspergillus mould filaments were detected and the serum galactomannan index was 12.162. His blood saturation decreased to 85%. C-reactive protein serum level increased to 273 mg/l. The patient was admitted to the intensive care unit and intubated due to severe respiratory insufficiency. Computed tomography revealed massive, mostly homogeneous consolidation. The patient was treated with 200 mg of voriconazole and 50 mg of caspofungin daily. Caspofungin therapy was continued for 23 days and voriconazole was administered parenterally for 62 days. Voriconazole therapy was continued orally for 9 months. During combined antifungal therapy, the galactomannan serum index constantly decreased from 12.1 to 0.33 (end-point of caspofungin therapy) and to 0.23 (end-point of voriconazole parenteral administration). His immunosuppressive therapy was limited to calcineurin inhibitor (tacrolimus) monotherapy. Post-treatment imaging 9 months after diagnosis confirmed the efficacy of therapy as a lack of pulmonary infiltration associated with left apical peribronchial scarring as a result of treatment. The present case proved the efficiency of combined (voriconazole and caspofungin

  4. Antifungal therapy with an emphasis on biofilms

    PubMed Central

    Pierce, Christopher G.; Srinivasan, Anand; Uppuluri, Priya; Ramasubramanian, Anand K.; López-Ribot, José Luis

    2013-01-01

    Fungal infections are on the rise as advances in modern medicine prolong the lives of severely ill patients. Fungi are eukaryotic organisms and there are a limited number of targets for antifungal drug development; as a result the antifungal arsenal is exceedingly limited. Azoles, polyenes and echinocandins, constitute the mainstay of antifungal therapy for patients with life-threatening mycoses. One of the main factors complicating antifungal therapy is the formation of fungal biofilms, microbial communities displaying resistance to most antifungal agents. A better understanding of fungal biofilms provides for new opportunities for the development of urgently needed novel antifungal agents and strategies. PMID:24011516

  5. Evaluation of the Effects of Photodynamic Therapy Alone and Combined with Standard Antifungal Therapy on Planktonic Cells and Biofilms of Fusarium spp. and Exophiala spp.

    PubMed Central

    Gao, Lujuan; Jiang, Shaojie; Sun, Yi; Deng, Meiqi; Wu, Qingzhi; Li, Ming; Zeng, Tongxiang

    2016-01-01

    50 and SMIC80 compared to untreated groups for both species, except SMIC80 of itraconazole against Fusarium biofilms. In conclusion, in vitro photodynamic therapy was efficient in inactivation of Fusarium spp. and Exophiala spp., both planktonic cultures and biofilms. In addition, the combination of aPDT and antifungal drugs represents an attractive alternative to the current antifungal strategies. However, further investigations are warranted for the reliable and safe application in clinical practice. PMID:27199946

  6. Evaluation of the Effects of Photodynamic Therapy Alone and Combined with Standard Antifungal Therapy on Planktonic Cells and Biofilms of Fusarium spp. and Exophiala spp.

    PubMed

    Gao, Lujuan; Jiang, Shaojie; Sun, Yi; Deng, Meiqi; Wu, Qingzhi; Li, Ming; Zeng, Tongxiang

    2016-01-01

    SMIC50 and SMIC80 compared to untreated groups for both species, except SMIC80 of itraconazole against Fusarium biofilms. In conclusion, in vitro photodynamic therapy was efficient in inactivation of Fusarium spp. and Exophiala spp., both planktonic cultures and biofilms. In addition, the combination of aPDT and antifungal drugs represents an attractive alternative to the current antifungal strategies. However, further investigations are warranted for the reliable and safe application in clinical practice. PMID:27199946

  7. Topical antifungal-corticosteroid combination therapy for the treatment of superficial mycoses: conclusions of an expert panel meeting.

    PubMed

    Schaller, Martin; Friedrich, Markus; Papini, Manuela; Pujol, Ramon M; Veraldi, Stefano

    2016-06-01

    Superficial fungal infections affect 20-25% of people worldwide and can cause considerable morbidity, particularly if an inflammatory component is present. As superficial fungal infections can be diverse, the treatment should be tailored to the individual needs of the patient and several factors should be taken into account when deciding on the most appropriate treatment option. These include the type, location and surface area of the infection, patient age, degree of inflammation and underlying comorbidities. Although several meta-analyses have shown that there are no significant differences between the numerous available topical antifungal agents with regard to mycological cure, agents differ in their specific intrinsic properties, which can affect their clinical use. The addition of a corticosteroid to an antifungal agent at the initiation of treatment can attenuate the inflammatory symptoms of the infection and is thought to increase patient compliance, reduce the risk of bacterial superinfection and enhance the efficacy of the antifungal agent. However, incorrect use of antifungal-corticosteroid therapy may be associated with treatment failure and adverse effects. This review summarises available treatment options for superficial fungal infections and provides general treatment recommendations based on the consensus outcomes of an Expert Panel meeting on the topical treatment of superficial mycoses. PMID:26916648

  8. Scedosporium apiospermum and S. prolificans mixed disseminated infection in a lung transplant recipient: An unusual case of long-term survival with combined systemic and local antifungal therapy in intensive care unit

    PubMed Central

    Balandin, Bárbara; Aguilar, Miriam; Sánchez, Isabel; Monzón, Araceli; Rivera, Isabel; Salas, Clara; Valdivia, Miguel; Alcántara, Sara; Pérez, Aris; Ussetti, Piedad

    2016-01-01

    Infections due Scedosporium spp. in lung transplant recipients are associated with disseminated disease with high mortality rates. The adjunctive local antifungal therapy may be a useful option when systemic treatment is insufficient and/or surgery is not feasible. We present a case of mixed disseminated infection due Scedosporium apiospermum and S. prolificans in a lung transplant recipient. Combined local and systemic antifungal therapy provided an unusual long-term survival in the intensive care unit. PMID:27222774

  9. Scedosporium apiospermum and S. prolificans mixed disseminated infection in a lung transplant recipient: An unusual case of long-term survival with combined systemic and local antifungal therapy in intensive care unit.

    PubMed

    Balandin, Bárbara; Aguilar, Miriam; Sánchez, Isabel; Monzón, Araceli; Rivera, Isabel; Salas, Clara; Valdivia, Miguel; Alcántara, Sara; Pérez, Aris; Ussetti, Piedad

    2016-03-01

    Infections due Scedosporium spp. in lung transplant recipients are associated with disseminated disease with high mortality rates. The adjunctive local antifungal therapy may be a useful option when systemic treatment is insufficient and/or surgery is not feasible. We present a case of mixed disseminated infection due Scedosporium apiospermum and S. prolificans in a lung transplant recipient. Combined local and systemic antifungal therapy provided an unusual long-term survival in the intensive care unit. PMID:27222774

  10. Successful therapy of progressive rhino-orbital mucormycosis caused by Rhizopus arrhizus with combined and sequential antifungal therapy, surgery and hyperbaric therapy

    PubMed Central

    Imbernón, Adrián; Agud, José Luis; Cuétara, María Soledad; Casqueiro, José Carlos; Nuñez, Pilar; Domínguez, Alegría R.; Bullido, Eusebio; Stchigel, Alberto M.

    2014-01-01

    We present a case of rhino-orbitary mucormycosis which progressed despite liposomal amphotericin and early surgical debridement. Combined echinocandin and high dose liposomal amphotericin, repeated debridement, prolonged therapy with hyperbaric oxygen and continued therapy with posaconazole, along with strict diabetic control, allowed cure without disfigurement. PMID:25383316

  11. Oral fungi in HIV: challenges in antifungal therapies.

    PubMed

    Nittayananta, W

    2016-04-01

    Oral candidiasis (OC) caused by Candida species is a common fungal infection among HIV-infected individuals. Despite the wide use of antiretroviral therapy (ART) resulting in a declined prevalence, OC remains the most common oral lesions seen in those living with HIV/AIDS. Various topical and systemic antifungal drugs are available to treat OC. However, due to the patients' immunodeficiency and the nature of OC as biofilm-associated infection, relapse is frequently observed after cessation of antifungal therapy. In addition, long-term antifungal therapy may lead to drug resistance. This review article addressed three major challenges in the treatment of OC in HIV infection including antifungal drug resistance, biofilm-associated infection of OC, and the host underlying immunodeficiency. To reduce the risks of antifungal drug resistance, the author recommends that future studies should focus on herbal plant-derived compounds with antifungal activity that may be used in combination with the drugs. Also, it is recommended that more research should be carried out to explore how to enhance the host innate immunity against oral Candida. PMID:27109279

  12. Alternative approaches to antifungal therapies

    PubMed Central

    Mehra, T; Köberle, M; Braunsdorf, C; Mailänder-Sanchez, D; Borelli, C; Schaller, M

    2012-01-01

    The expansive use of immunosuppressive medications in fields such as transplantational medicine and oncology, the higher frequency of invasive procedures in an aging population and the HIV/AIDS pandemic have increased the frequency of systemic fungal infections. At the same time, increased resistance of pathogenic fungi to classical antifungal agents has led to sustained research efforts targeting alternative antifungal strategies. In this review, we focus on two promising approaches: cationic peptides and the targeting of fungal virulence factors. Cationic peptides are small, predominantly positively charged protein fragments which exert direct and indirect antifungal activities, one mechanism of action being the permeabilization of the fungal membrane. They include lysozyme, defensins, and cathelicidins, as well as novel synthetic peptides. Amongst fungal virulence factors, the targeting of candidal secreted aspartic proteinases seems to be a particularly promising approach. PMID:23078400

  13. Antifungal Lock Therapy with Liposomal Amphotericin B: A Prospective Trial.

    PubMed

    McGhee, William; Michaels, Marian G; Martin, Judith M; Mazariegos, George V; Green, Michael

    2016-03-01

    We conducted a prospective pilot study to evaluate the potential role of combined systemic antifungal and liposomal amphotericin B lock therapy in children with intestinal insufficiency with fungal catheter-related bloodstream infections whose central venous catheters had not been removed. Our results provide supportive evidence for the conduct of larger clinical trials to confirm the efficacy and safety of this approach. PMID:26908494

  14. The fungal resistome: a risk and an opportunity for the development of novel antifungal therapies.

    PubMed

    Reales-Calderón, Jose A; Molero, Gloria; Gil, Concha; Martínez, José L

    2016-08-01

    The risks for toxicity of novel antifungal compounds, together with the emergence of resistance, makes the use of inhibitors of resistance, in combination with antifungal compounds, a suitable strategy for developing novel antifungal formulations. Among them, inhibitors of efflux pumps are suitable candidates. Increasing drug influx or interfering with the stress response may also improve the efficacy of antifungals. Therapies as induction of fungal apoptosis or immunostimulation are also good strategies for reducing the risks for resistance and to improve antifungals' efficacy. Understanding the effect of the acquisition of resistance on the fungal physiology and determining the collateral sensitivity networks are useful for the development of novel strategies based on combination of antifungals for improving the efficacy of the therapy. PMID:27485839

  15. Photodynamic therapy as an antifungal treatment

    PubMed Central

    LIANG, YI; LU, LI-MING; CHEN, YONG; LIN, YOU-KUN

    2016-01-01

    Photodynamic therapy (PDT) involves the systemic or topical application of a photosensitizer (PS), alongside the selective illumination of the target lesion with light of an appropriate wavelength, in order to promote localized oxidative photodamage and subsequent cell death. Numerous studies have demonstrated that PDT is highly effective in the destruction of fungi in vitro. The mechanism underlying the effects of PDT results from the photons of visible light of an appropriate wavelength interacting with the intracellular molecules of the PS. Reactive species are produced as a result of the oxidative stress caused by the interaction between the visible light and the biological tissue. At present, no antifungal treatment based on PDT has been licensed. However, antifungal PDT is emerging as an area of interest for research. PMID:27347012

  16. Synergistic combinations of antifungals and anti-virulence agents to fight against Candida albicans

    PubMed Central

    Cui, Jinhui; Ren, Biao; Tong, Yaojun; Dai, Huanqin; Zhang, Lixin

    2015-01-01

    Candida albicans, one of the pathogenic Candida species, causes high mortality rate in immunocompromised and high-risk surgical patients. In the last decade, only one new class of antifungal drug echinocandin was applied. The increased therapy failures, such as the one caused by multi-drug resistance, demand innovative strategies for new effective antifungal drugs. Synergistic combinations of antifungals and anti-virulence agents highlight the pragmatic strategy to reduce the development of drug resistant and potentially repurpose known antifungals, which bypass the costly and time-consuming pipeline of new drug development. Anti-virulence and synergistic combination provide new options for antifungal drug discovery by counteracting the difficulty or failure of traditional therapy for fungal infections. PMID:26048362

  17. Novel, Synergistic Antifungal Combinations that Target Translation Fidelity

    PubMed Central

    Moreno-Martinez, Elena; Vallieres, Cindy; Holland, Sara L.; Avery, Simon V.

    2015-01-01

    There is an unmet need for new antifungal or fungicide treatments, as resistance to existing treatments grows. Combination treatments help to combat resistance. Here we develop a novel, effective target for combination antifungal therapy. Different aminoglycoside antibiotics combined with different sulphate-transport inhibitors produced strong, synergistic growth-inhibition of several fungi. Combinations decreased the respective MICs by ≥8-fold. Synergy was suppressed in yeast mutants resistant to effects of sulphate-mimetics (like chromate or molybdate) on sulphate transport. By different mechanisms, aminoglycosides and inhibition of sulphate transport cause errors in mRNA translation. The mistranslation rate was stimulated up to 10-fold when the agents were used in combination, consistent with this being the mode of synergistic action. A range of undesirable fungi were susceptible to synergistic inhibition by the combinations, including the human pathogens Candida albicans, C. glabrata and Cryptococcus neoformans, the food spoilage organism Zygosaccharomyces bailii and the phytopathogens Rhizoctonia solani and Zymoseptoria tritici. There was some specificity as certain fungi were unaffected. There was no synergy against bacterial or mammalian cells. The results indicate that translation fidelity is a promising new target for combinatorial treatment of undesirable fungi, the combinations requiring substantially decreased doses of active components compared to each agent alone. PMID:26573415

  18. Novel, Synergistic Antifungal Combinations that Target Translation Fidelity.

    PubMed

    Moreno-Martinez, Elena; Vallieres, Cindy; Holland, Sara L; Avery, Simon V

    2015-01-01

    There is an unmet need for new antifungal or fungicide treatments, as resistance to existing treatments grows. Combination treatments help to combat resistance. Here we develop a novel, effective target for combination antifungal therapy. Different aminoglycoside antibiotics combined with different sulphate-transport inhibitors produced strong, synergistic growth-inhibition of several fungi. Combinations decreased the respective MICs by ≥8-fold. Synergy was suppressed in yeast mutants resistant to effects of sulphate-mimetics (like chromate or molybdate) on sulphate transport. By different mechanisms, aminoglycosides and inhibition of sulphate transport cause errors in mRNA translation. The mistranslation rate was stimulated up to 10-fold when the agents were used in combination, consistent with this being the mode of synergistic action. A range of undesirable fungi were susceptible to synergistic inhibition by the combinations, including the human pathogens Candida albicans, C. glabrata and Cryptococcus neoformans, the food spoilage organism Zygosaccharomyces bailii and the phytopathogens Rhizoctonia solani and Zymoseptoria tritici. There was some specificity as certain fungi were unaffected. There was no synergy against bacterial or mammalian cells. The results indicate that translation fidelity is a promising new target for combinatorial treatment of undesirable fungi, the combinations requiring substantially decreased doses of active components compared to each agent alone. PMID:26573415

  19. Outcome of empirical or targeted antifungal therapy after antifungal prophylaxis in febrile neutropenia.

    PubMed

    Hahn-Ast, C; Felder, L; Mayer, K; Mückter, S; Ruhnke, M; Hein, R; Hellmich, M; Schwab, K; Rachow, T; Brossart, P; von Lilienfeld-Toal, M

    2016-05-01

    Azole prophylaxis has been shown to be effective in preventing invasive fungal infections (IFIs) and increasing survival in patients with prolonged neutropenia after myelosuppressive chemotherapy for haematological malignancies. Similarly, empirical antifungal therapy for persistent neutropenic fever has been shown to reduce IFI-related mortality. However, to date, there is little information with regard to the outcome of patients who receive both strategies. Here, we present our retrospective data on three cohorts of patients receiving empirical or targeted antifungal therapy after different antifungal prophylaxis regimens. All records from patients who received myelosuppressive induction chemotherapy for acute myelogenous leukemia (AML) in our centre from 2004-2010 were analysed. From 2004-2006, itraconazole was used as antifungal prophylaxis; for the first 6 months in 2007, local polyenes and from mid-2007 till 2010, posaconazole. Data of 315 courses of chemotherapy in 211 patients were analysed. Antifungal therapy (empirical or targeted, time point and antifungal agent at the physician's discretion) was initiated in 50/174 (29 %), 7/18 (39 %) and 34/123 courses (28 %, p = 0.615) in the itra cohort, the cohort without systemic prophylaxis and the posa cohort, respectively, and was effective in 24/50 (48 %), 5/7 (71 %) and 22/34 courses (65 %, p = 0.221), respectively. IFI occurred in 25/174 (14 %), 4/18 (22 %) and 16/123 (13 %) courses, respectively (p = 0.580). IFI-related survival was not different in the three cohorts. Antifungal treatment in patients with AML who received azole prophylaxis resulted in the expected efficacy-importantly, prior posaconazole prophylaxis did not render subsequent antifungal treatment less effective than prior itraconazole prophylaxis. PMID:27021301

  20. Scedosporium apiospermum infections and the role of combination antifungal therapy and GM-CSF: A case report and review of the literature

    PubMed Central

    Goldman, Chloe; Akiyama, Mathew J.; Torres, Julian; Louie, Eddie; Meehan, Shane A.

    2016-01-01

    Scedosporium apiospermum, a ubiquitous environmental mold, is increasingly reported as causing invasive fungal disease in immunocompromised hosts. It poses a therapeutic challenge due to its intrinsic resistance to traditional antifungals and ability to recur despite demonstrating susceptibility. We present an immunocompromised patient with a cutaneous S. apiospermum infection that disseminated despite treatment with voriconazole, the drug of choice. Adding echinocandins and GM-CSF provided partial recovery, indicating a potential synergistic role of dual-antifungal and immunotherapeutic agents. PMID:27182483

  1. Scedosporium apiospermum infections and the role of combination antifungal therapy and GM-CSF: A case report and review of the literature.

    PubMed

    Goldman, Chloe; Akiyama, Mathew J; Torres, Julian; Louie, Eddie; Meehan, Shane A

    2016-03-01

    Scedosporium apiospermum, a ubiquitous environmental mold, is increasingly reported as causing invasive fungal disease in immunocompromised hosts. It poses a therapeutic challenge due to its intrinsic resistance to traditional antifungals and ability to recur despite demonstrating susceptibility. We present an immunocompromised patient with a cutaneous S. apiospermum infection that disseminated despite treatment with voriconazole, the drug of choice. Adding echinocandins and GM-CSF provided partial recovery, indicating a potential synergistic role of dual-antifungal and immunotherapeutic agents. PMID:27182483

  2. Acquired Multidrug Antifungal Resistance in Candida lusitaniae during Therapy

    PubMed Central

    Asner, Sandra A.; Giulieri, Stefano; Diezi, Manuel; Marchetti, Oscar

    2015-01-01

    -flurocytosine. This clinical report describes resistance of C. lusitaniae to all common antifungals. While candins or azole resistance followed monotherapy, multidrug antifungal resistance emerged during combined therapy. PMID:26438490

  3. Combinations Therapies.

    PubMed

    Reinmuth, Niels; Reck, Martin

    2015-01-01

    Immunotherapy of cancer encompasses different strategies that elicit or enhance the immune response against tumors. The first results from clinical studies have provided promising data for the treatment of lung cancer patients with immunomodulating monotherapies. To improve the potential benefit of cancer immunotherapy, synergistic combinations of the various immunotherapy approaches or of different elements within each of the immunotherapy approaches are being explored. The rationale typically involves different but complementary mechanisms of action, eventually impinging on more than one immune system mechanism. As a prominent example, the simultaneous blockade of PD-1 and CTLA-4 is giving rise to therapeutic synergy, while still offering room for efficacy improvement. Moreover, combinations of immunomodulating agents with chemotherapy or targeted molecules are being tested. Animal models suggest that immunotherapies in combination with these various options offer evidence for synergistic effects and are likely to radically change cancer treatment paradigms. However, data obtained so far indicate that toxic side effects are also potentiated, which may even restrict the selection of patients that are suitable for these combinational approaches. Advancing the field of combinatorial immunotherapy will require changes in the way investigational agents are clinically developed as well as novel experimental end-points for efficacy evaluation. However, this combined therapeutic manipulation of both tumor and stromal cells may lead to a dramatic change in the therapeutic options of lung cancer patients in any disease stage that can only grossly be appreciated by the current studies. PMID:26384009

  4. Salvage therapy with topical antifungal for Aspergillus fumigatus empyema complicating extrapleural pneumonectomy

    PubMed Central

    Purohit, Manoj; Guleri, Achyut; Zacharias, Joseph

    2012-01-01

    We describe an unusual case of Aspergillus fumigatus empyema and bronchopleural fistulae after extrapleural pneumonectomy (EPP) and chemoradiotherapy (CRT), which was treated successfully under salvage conditions with debridement, an innovative topical antifungal application and supplemented systemic antifungal therapy and which went on for a definitive surgical procedure. Combinations of CRT and EPP have been recommended in a select group of patients with malignant mesothelioma. Irrespective of the combination, EPP is associated with mortality in the range of 4–15% and a complication rate as high as 62%. PMID:22617507

  5. Successful management of renal mucormycosis with antifungal therapy and drainage

    PubMed Central

    Devana, Sudheer K.; Bora, Girdhar S.; Mavuduru, Ravimohan S.; Panwar, Pankaj; Kakkar, Nandita; Mandal, Arup K.

    2016-01-01

    We report a case of isolated extensive renal mucormycosis in an immunocompetent adult, who was successfully managed conservatively without surgical debridement. To the best of our knowledge, this is the first case where antifungal therapy alone was sufficient even with such an extensive involvement. PMID:27127360

  6. Antifungal therapy and length of hospitalization in transplant patients with invasive aspergillosis.

    PubMed

    Baddley, John W; Andes, David R; Marr, Kieren A; Kauffman, Carol A; Kontoyiannis, Dimitrios P; Ito, James I; Schuster, Mindy G; Brizendine, Kyle D; Patterson, Thomas F; Lyon, G Marshall; Boeckh, Michael; Oster, Robert A; Chiller, Tom; Pappas, Peter G

    2013-02-01

    The impact of antifungal therapy on economic outcomes in patients with invasive aspergillosis (IA) needs further exploration. The purpose of this study was to describe antifungal therapy and factors associated with hospital length of stay (LOS) in transplant patients with IA. Patients were enrolled from March 2001 to October 2005 and IA cases identified through March 2006 from a sub-group of patients in the Transplant Associated Infection Surveillance Network (TRANSNET). Factors associated with hospital LOS were determined by logistic regression analysis. Of 361 patients, the mean age was 49 years, 60.7% were male, and 63% were hematopoietic stem cell transplantation (HSCT) recipients. Primary monotherapy was used in 233 (64.5%) patients, of which voriconazole (93/233, 39.9%) was most commonly used antifungal. Primary combination therapy was used in 128 (35.4%) of 361 patients, with voriconazole plus caspofungin (81/361, 22.4%) the most frequently employed. Mean duration of therapy was 115 days (HSCT 109.7; solid organ transplant [SOT] 125.3). Mean hospital LOS was 35.3 days (HSCT 38.7; SOT 29.7). Regression analysis identified disseminated IA, neutropenia, malnutrition and length of ICU stay as factors associated with increased hospital LOS. Initial voriconazole use was associated with decreased LOS. Further investigation on impact of antifungal therapy on economic outcomes is needed. PMID:22680976

  7. Atmospheric pressure cold plasma as an antifungal therapy

    NASA Astrophysics Data System (ADS)

    Sun, Peng; Sun, Yi; Wu, Haiyan; Zhu, Weidong; Lopez, Jose L.; Liu, Wei; Zhang, Jue; Li, Ruoyu; Fang, Jing

    2011-01-01

    A microhollow cathode based, direct-current, atmospheric pressure, He/O2 (2%) cold plasma microjet was used to inactive antifungal resistants Candida albicans, Candida krusei, and Candida glabrata in air and in water. Effective inactivation (>90%) was achieved in 10 min in air and 1 min in water. Antifungal susceptibility tests showed drastic reduction of the minimum inhibitory concentration after plasma treatment. The inactivation was attributed to the reactive oxygen species generated in plasma or in water. Hydroxyl and singlet molecular oxygen radicals were detected in plasma-water system by electron spin resonance spectroscopy. This approach proposed a promising clinical dermatology therapy.

  8. Atmospheric pressure cold plasma as an antifungal therapy

    SciTech Connect

    Sun Peng; Wu Haiyan; Sun Yi; Liu Wei; Li Ruoyu; Zhu Weidong; Lopez, Jose L.; Zhang Jue; Fang Jing

    2011-01-10

    A microhollow cathode based, direct-current, atmospheric pressure, He/O{sub 2} (2%) cold plasma microjet was used to inactive antifungal resistants Candida albicans, Candida krusei, and Candida glabrata in air and in water. Effective inactivation (>90%) was achieved in 10 min in air and 1 min in water. Antifungal susceptibility tests showed drastic reduction of the minimum inhibitory concentration after plasma treatment. The inactivation was attributed to the reactive oxygen species generated in plasma or in water. Hydroxyl and singlet molecular oxygen radicals were detected in plasma-water system by electron spin resonance spectroscopy. This approach proposed a promising clinical dermatology therapy.

  9. Peptide-based Antifungal Therapies against Emerging Infections

    PubMed Central

    Matejuk, A.; Leng, Q.; Begum, M.D.; Woodle, M.C.; Scaria, P.; Chou, S-T; Mixson, A.J.

    2010-01-01

    Acquired drug resistance to mycotic infections is rapidly emerging as a major medical problem. Opportunistic fungal infections create therapeutic challenges, particularly in high risk immunocompromised patients with AIDS, cancer, and those undergoing transplantation. Higher mortality and/or morbidity rates due to invasive mycosis have been increasing over the last 20 years, and in light of growing resistance to commonly used antibiotics, novel antifungal drugs and approaches are required. Currently there is considerable interest in antifungal peptides that are ubiquitous in plant and animal kingdoms. These small cationic peptides may have specific targets or may be multifunctional in their mechanism of action. On the basis of recent advances in protein engineering and solid phase syntheses, the utility and potential of selected peptides as efficient antifungal drugs with acceptable toxicity profiles are being realized. This review will discuss recent advances in peptide therapy for opportunistic fungal infections. PMID:20495663

  10. Antifungal effect of TONS504-photodynamic therapy on Malassezia furfur.

    PubMed

    Takahashi, Hidetoshi; Nakajima, Susumu; Sakata, Isao; Iizuka, Hajime

    2014-10-01

    Numerous reports indicate therapeutic efficacy of photodynamic therapy (PDT) against skin tumors, acne and for skin rejuvenation. However, few reports exist regarding its efficacy for fungal skin diseases. In order to determine the antifungal effect, PDT was applied on Malassezia furfur. M. furfur was cultured in the presence of a novel cationic photosensitizer, TONS504, and was irradiated with a 670-nm diode laser. TONS504-PDT showed a significant antifungal effect against M. furfur. The effect was irradiation dose- and TONS504 concentration-dependent and the maximal effect was observed at 100 J/cm2 and 1 μg/mL, respectively. In conclusion, TONS504-PDT showed antifungal effect against M. furfur in vitro, and may be a new therapeutic modality for M. furfur-related skin disorders. PMID:25226792

  11. In Search of the Holy Grail of Antifungal Therapy

    PubMed Central

    Chapman, Stanley W.; Sullivan, Donna C.; Cleary, John D.

    2008-01-01

    The ideal antifungal agent remains an elusive goal for treatment of life-threatening systemic fungal infections. Such an agent would have broad antifungal activity, low rates of resistance, flexible routes of administration, few associated adverse events, and limited drug-drug interactions. Only three of the seven classes of antifungal agents currently available are suitable for treatment of systemic infection: the polyenes, the azoles, and the echinocandins. None match all the characteristics of an ideal agent, the Holy Grail of antifungal therapy. Academia and industry need to collaborate in the search for new lead antifungal compounds using traditional screening methods as well as the new pharmacogenomics methods. Enhancing efficacy and reducing toxicity of the currently available therapeutic agents is also another important avenue of study. As an example, the Mycosis Research Center at the University of Mississippi Medical Center has identified pyogenic polyenes in commercial preparations of amphotericin B deoxycholate which correlate with infusion related toxicities. A highly purified formulation of amphotericin B appears promising, with a better therapeutic index compared to its parent compound as evidenced by results of in vitro and in vivo studies reviewed in this presentation. PMID:18596853

  12. Conventional and alternative antifungal therapies to oral candidiasis

    PubMed Central

    Anibal, Paula Cristina; de Cássia Orlandi Sardi, Janaina; Peixoto, Iza Teixeira Alves; de Carvalho Moraes, Julianna Joanna; Höfling, José Francisco

    2010-01-01

    Candida-associated denture stomatitis is the most common form of oral candidal infection, with Candida albicans being the principal etiological agent. Candida adheres directly or via an intermediary layer of plaque-forming bacteria to denture acrylic. Despite antifungal therapy to treat denture stomatitis, infection is reestablished soon after the treatment ceases. In addition, many predisposing factors have been identified as important in the development of oral candidiasis, including malnourishment, common endocrine disorders, such as diabetis mellitus, antibacterial drug therapy, corticosteroids, radiotherapy and other immunocompromised conditions, such as acquired immunodeficiency syndrome (AIDS). These often results in increased tolerance to the most commonly used antifungals. So this review suggests new therapies to oral candidiasis. PMID:24031562

  13. Virulence and Resistance to Antifungal Therapies of Scopulariopsis Species.

    PubMed

    Paredes, Katihuska; Capilla, Javier; Mayayo, Emilio; Guarro, Josep

    2016-04-01

    Scopulariopsisis an emerging opportunistic fungus characterized by its high resistance to antifungal therapies. We have developed a murine model of disseminated infection in immunosuppressed animals by intravenous inoculation ofScopulariopsis brevicaulisandScopulariopsis brumptii, the most clinically relevant species, in order to evaluate their virulence and their responses to conventional antifungal treatments. Survival and tissue burden studies showed thatS. brumptiiwas more virulent thanS. brevicaulis The three drugs tested, liposomal amphotericin B, posaconazole, and voriconazole, prolonged the survival of mice infected withS. brumptii, but none showed efficacy againstS. brevicaulis The different therapies were only able to modestly reduce the fungal burden of infected tissue; however, in general, despite the high serum levels reached, they showed poor efficacy in the treatment of the infection. Unfortunately, the most effective therapy forScopulariopsisinfections remains unresolved. PMID:26787688

  14. [Combination therapy for invasive aspergillosis].

    PubMed

    Ruiz-Camps, Isabel

    2011-03-01

    The frequency of invasive fungal infections, and specifically invasive aspergillosis, has increased in the last few decades. Despite the development of new antifungal agents, these infections are associated with high mortality, ranging from 40% to 80%, depending on the patient and the localization of the infection. To reduce these figures, several therapeutic strategies have been proposed, including combination therapy. Most of the available data on the efficacy of these combinations are from experimental models, in vitro data and retrospective observational studies or studies with a small number of patients that have included both patients in first-line treatment and those receiving rescue therapy; in addition there are many patients with possible forms of aspergillosis and few with demonstrated or probable forms. To date, there is no evidence that combination therapy has significantly higher efficacy than monotherapy; however, combination therapy could be indicated in severe forms of aspergillosis, or forms with central nervous involvement or extensive pulmonary involvement with respiratory insufficiency, etc. Among the combinations, the association of an echinocandin--the group that includes micafungin--with voriconazole or liposomal amphotericin B seems to show synergy. These combinations are those most extensively studied in clinical trials and therefore, although the grade of evidence is low, are recommended by the various scientific societies. PMID:21420576

  15. Persistence of histoplasma in adrenals 7 years after antifungal therapy

    PubMed Central

    Kothari, Deepak; Chopra, Shweta; Bhardwaj, Minakshi; Ajmani, Ajay K.; Kulshreshtha, Bindu

    2013-01-01

    Adrenal histoplasmosis is an uncommon cause for adrenal insufficiency. The duration of treatment for adrenal histoplasmosis is not clear. Existing treatment regimens advocate antifungals given for periods ranging from 6 months to 2 years. We report here a rare case who showed persistence of histoplasma in adrenal biopsy 7 years after being initially treated with itraconazole for 9 months. This calls for a prolonged therapy with regular review of adrenal morphology and histology in these patients. PMID:23869317

  16. [MIKAMINOM ANTIFUNGAL THERAPY IN NEWBORNS AND INFANTS WITH SURGICAL PATHOLOGY].

    PubMed

    Melnikova, N I; Strogonov, I A; Kartseva, E V; Haritonova, G D; Gliznutsin, O E; Gabulaev, S V; Pulikova, E M

    2016-01-01

    Prolonged empiric and etiotropic therapy of multidrug-resistant or pan-resistant bacterial flora in different gestation age newborns has led to the growth of resistant fungalflora in intencive care units (ICU). According to risk factors and rating scales every child of ICU undergoing the abdominal cavity surgery is threatened the development of a fungal infection and requires antifungal therapy appointment or causal prophylactic. In recent years, before the advent of medications of the group of echinocandins, therapy of invasive fungal infections has been a challenge. Currently alternative drug to diflucane in neonates and infants is micafungine (mycamine) in the dose of 2-8 mg/kg/day, depending on the signs of infestation and severity of the condition. PMID:27192854

  17. High-dose caspofungin as a component of combination antifungal therapy in 91 patients with neoplastic diseases and hematopoietic stem cell transplantation: a critical review of short-term and long-term adverse events.

    PubMed

    Safdar, Amar; Rodriguez, Gilhen; Zuniga, Jorge; Al Akhrass, Fadi; Pande, Anupam

    2015-04-01

    The antifungal activity of echinocandins is concentration dependent. Previously, we demonstrated that high-dose caspofungin (HD-CSP; 100 mg daily) was well tolerated in 34 immunosuppressed patients with cancer and may have favorably influenced outcomes. We retrospectively assessed all 91 patients in whom HD-CSP was given for the treatment of invasive fungal disease (IFD). The median number of doses was 18.5 ± 21.5, and in 8 (9%) patients more than 40 doses were given. Most (62%) of the patients had leukemia. A total of 45 (49%) patients had undergone stem cell transplantation; 80% received allogeneic grafts and 47% had graft-versus-host disease. High-dose corticosteroids were given during antifungal therapy in 26 (29%) patients. In all, 8 (9%) patients had new elevation in serum bilirubin during HD-CSP therapy; normalization occurred after voriconazole and HD-CSP were discontinued in 4 patients each. No other short-term or delayed adverse events were observed. In all, 40 (44%) patients died of IFD. High-dose corticosteroids during HD-CSP (odds ratio [OR] 8, 95% confidence interval [CI] 2.1-30.4; P < .002) and starting HD-CSP in the critical care unit (OR 67.5, 95% CI 5.25-868.9; P < .001) were associated with death from fungal disease. Prolonged HD-CSP therapy was well tolerated. Drug-induced hyperbilirubinemia may pose a potential limitation for continued HD-CSP use in highly susceptible patients with hematologic neoplasms and stem cell transplantation. PMID:24366977

  18. Canine gastrointestinal pythiosis treatment by combined antifungal and immunotherapy and review of published studies.

    PubMed

    Pereira, Daniela I B; Botton, Sônia A; Azevedo, Maria I; Motta, Marco A A; Lobo, Raulene R; Soares, Mauro P; Fonseca, Anelise O S; Jesus, Francielli P K; Alves, Sydney H; Santurio, Janio M

    2013-10-01

    Pythium insidiosum is an oomycete, a fungal like microorganism, which infects mammals, causing pythiosis in animals and humans, especially in tropical and subtropical regions around the world. The treatment for this infection is very difficult, and therapeutic options commonly comprise surgery, immunotherapy and antimicrobial drugs. The present report describes the clinical healing of a dog with gastrointestinal pythiosis by treatment with a combination of antifungals and immunotherapy, as well as reviews the cases reported in the literature that used some type of therapy for canine pythiosis. A 2.5-year-old male beagle initially showed sporadic vomiting episodes, and this symptom became more frequent 5 months after the onset of clinical signs. Celiotomy procedure found thickness of the stomach wall extending to the pylorus and duodenum. A biopsy was performed, and the diagnosis of pythiosis was made by mycological, histopathological analyses and molecular identification. Therapy was based on an association of terbinafine plus itraconazole during 12 months and immunotherapy for 2.5 months. The healing of the dog reported here allows us to propose the use of immunotherapy associated with antifungal therapy to treat canine gastrointestinal pythiosis. However, additional studies should be performed on a larger number of patients to establish a standard treatment protocol for canine pythiosis. PMID:23918089

  19. Concepts and Principles of Photodynamic Therapy as an Alternative Antifungal Discovery Platform

    PubMed Central

    Dai, Tianhong; Fuchs, Beth B.; Coleman, Jeffrey J.; Prates, Renato A.; Astrakas, Christos; St. Denis, Tyler G.; Ribeiro, Martha S.; Mylonakis, Eleftherios; Hamblin, Michael R.; Tegos, George P.

    2012-01-01

    Opportunistic fungal pathogens may cause superficial or serious invasive infections, especially in immunocompromised and debilitated patients. Invasive mycoses represent an exponentially growing threat for human health due to a combination of slow diagnosis and the existence of relatively few classes of available and effective antifungal drugs. Therefore systemic fungal infections result in high attributable mortality. There is an urgent need to pursue and deploy novel and effective alternative antifungal countermeasures. Photodynamic therapy (PDT) was established as a successful modality for malignancies and age-related macular degeneration but photodynamic inactivation has only recently been intensively investigated as an alternative antimicrobial discovery and development platform. The concept of photodynamic inactivation requires microbial exposure to either exogenous or endogenous photosensitizer molecules, followed by visible light energy, typically wavelengths in the red/near infrared region that cause the excitation of the photosensitizers resulting in the production of singlet oxygen and other reactive oxygen species that react with intracellular components, and consequently produce cell inactivation and death. Antifungal PDT is an area of increasing interest, as research is advancing (i) to identify the photochemical and photophysical mechanisms involved in photoinactivation; (ii) to develop potent and clinically compatible photosensitizers; (iii) to understand how photoinactivation is affected by key microbial phenotypic elements multidrug resistance and efflux, virulence and pathogenesis determinants, and formation of biofilms; (iv) to explore novel photosensitizer delivery platforms; and (v) to identify photoinactivation applications beyond the clinical setting such as environmental disinfectants. PMID:22514547

  20. Review of antifungal therapy, part II: treatment rationale, including specific patient populations.

    PubMed

    Baran, Robert; Hay, Rod J; Garduno, Javier I

    2008-01-01

    This portion of the antifungal review focuses on treatment rationale and suggestions, including special populations such as the elderly, children, and pregnant and immunocompromised individuals. In elderly individuals, the pathogen may be associated with certain comorbidities; treatment should begin with local treatments such as debridement (mechanical or chemical) and a topical. In children, the pathogen most commonly isolated is Trichophyton rubrum. Children should be examined for concomitant tinea and treatment options can begin with a chemical debridement (non-painful) and a topical, with non-responders being treated with combination therapy as in adults. It is suggested that blood tests are monitored at baseline and every 4-8 weeks in children on systemic therapy. Terbinafine is the only systemic in category B and local therapies should be the primary treatment modalities in pregnancy. Prevalence of onychomycosis is high in immunocompromised patients with higher relapse rates after treatment. The same fungal infections that are seen in healthy populations are usually represented in the immunocompromised host. There is a stepwise approach that is suggested in the treatment of onychomycosis. Before treatment, several factors should be determined, which include risk for failure and compliance issues. Strategies for therapy include monotherapy, combination therapy, supplemental therapy, and intermittent therapy. Topical monotherapy is effective in early distal nail disease and for the prevention of reinfection of the cured nail. Combination therapy is an appropriate progression of therapy for patients who failed monotherapy or are at risk for failure. Combined therapies are shown to increase cure rates. Mechanical interventions are essential in reducing fungal burdens to allow other modalities to penetrate, especially in dermatophytomas and onycholysis. PMID:18569273

  1. Combination therapy with statins.

    PubMed

    Gylling, Helena; Miettinen, Tatu A

    2002-09-01

    Statins effectively inhibit cholesterol synthesis and are currently the most commonly used drugs for the treatment of hypercholesterolemia. However, patients with familial hypercholesterolemia and those unwilling to take, or who cannot tolerate statins, and patients with combined hyperlipidemia require a combination treatment. Statins combined with cholesterol malabsorption, caused, e.g., by plant stanol esters or ezetimibe (Schering-Plough Corp/Merck & Co Inc), or with bile acid malabsorption, caused by bile acid binding resins or guar gum, inhibit compensatory increases in cholesterol synthesis and effectively lower LDL cholesterol levels. Combination therapy of statins with fibrates should be controlled by lipidology experts. Recent information on indications and advantages of combining statins with n-3 fatty acids, hormone replacement therapy, or niacin, will also be discussed. PMID:12498007

  2. Review of antifungal therapy and the severity index for assessing onychomycosis: part I.

    PubMed

    Baran, Robert; Hay, Rod J; Garduno, Javier I

    2008-01-01

    This review outlines recent data on treatment modalities and outcomes with antifungal therapy in onychomycosis. Included are topical, mechanical, chemical and systemic treatments or a combination thereof. Topical treatments, or transungual drug delivery systems (TUDDS), including ciclopirox and amorolfine were shown to be effective if used alone for mild-moderate nail involvement. Specifically, superficial white onychomycosis (SWO) restricted to the dorsum of the nail plate and moderate distal lateral subungual onychomycosis (DLSO). Mechanical treatments were mostly effective as adjuncts to topical therapy which include nail avulsion and abrasion. In particular, partial nail avulsion aids topical therapy in DLSO and partial subungual onychomycosis for a more effective therapy. Chemical avulsion is a painless method of debridement which uses a keratinolysis formula that is effective only in limited and early disease. Systemic therapies have been shown to be effective with terbinafine and itraconazole is suggested as being the most cost-effective therapy. Systemic therapies require consideration of side effects and monitoring by both patient and physician prior to treatment application. An effective suggestion is the use of a topical with debridement for mild-moderate onychomycosis and systemic (terbinafine) plus topical for severe onychomycosis. Most treatment modalities will require long-term use from 3 to 9 months to be most effective, with strategies presented in Part II of this review. PMID:18484426

  3. [Treatment of dermatoses : Significance and use of glucocorticoids in fixed combination with antifungals].

    PubMed

    Mayser, P

    2016-09-01

    Treating eczema with fungal and/or bacterial superinfections or superficial mycoses are a common problem in daily practice. A fungal superinfection as a consequence of a diminished skin barrier might complicate the course of eczema. In addition, in an inflammatory superficial mycotic infection a delayed-type hypersensitivity reaction may result in healing of the lesion, but might also be responsible for irreversible damage of epidermal structures. An example is permanent hair loss by scarring alopecia in the context of inflammatory tinea capitis. In both cases, combination of an antifungal and a glucocorticoid is appropriate in therapy, preferentially in topical application. The use of azole antimycotics is especially helpful, as they are also effective against gram-positive bacteria. PMID:27411685

  4. Monotherapy versus combination therapy.

    PubMed

    Patel, Shilpa M; Saravolatz, Louis D

    2006-11-01

    The science of antibiotic therapy for infectious diseases continues to evolve. In many instances where empiric coverage is necessary, treatment with more than one agent is considered prudent. If an etiology is identified, antibiotics are modified based on culture and susceptibility data. Even when the organism is known, more than one antibiotic may be needed. Decisions about antibiotics should be made after assessments of pertinent clinical information, laboratory and microbiology information, ease of administration, patient compliance, potential adverse effects, cost, and available evidence supporting various treatment options. Clinicians also need to consider synergy and local resistance patterns in selecting therapeutic options. In this article, the authors outline monotherapy and combination therapy options for several common infectious diseases. PMID:17116443

  5. New combination therapies for asthma.

    PubMed

    Donohue, J F; Ohar, J A

    2001-03-01

    Combination products often have useful clinical benefits in asthma. The scientific rationale for combination therapy includes the fact that different agents have complimentary modes of action. Long-acting beta(2)-agonists have effects on airway smooth muscle, and inhaled corticosteroids have potent topical antiinflammatory effect. This combination has been shown to effectively reduce exacerbations and improve symptoms. Substantial clinical trial data provide a rationale for dual-control therapy supported by basic scientific data. Another combined therapy is inhaled steroids plus leukotriene-receptor antagonists, which provides the patient with two effective therapies. Leukotriene-receptor antagonist can also be combined with antihistamines for improved asthma control. Older therapies including theophylline and controlled release albuterol have been effectively added to inhaled corticosteroids, enabling a reduction in the dose of the inhaled steroids. Many other combination therapies are presently being tested. PMID:11224725

  6. Antifungal activities of diphenyl diselenide and ebselen alone and in combination with antifungal agents against Fusarium spp.

    PubMed

    Venturini, Tarcieli Pozzebon; Chassot, Francieli; Loreto, Érico Silva; Keller, Jéssica Tairine; Azevedo, Maria Izabel; Zeni, Gilson; Santurio, Janio Morais; Alves, Sydney Hartz

    2016-07-01

    Herein, we describe the in vitro activity of a combination of the organoselenium compounds diphenyl diselenide and ebselen alone and in combination with amphotericin B, caspofungin, itraconazole, and voriconazole against 25 clinical isolates of Fusarium spp. For this analysis, we used the broth microdilution method based on the M38-A2 technique and checkerboard microdilution method. Diphenyl diselenide (MIC range = 4-32 μg/ml) and ebselen (MIC range = 2-8 μg/ml) showed in vitro activity against the isolates tested. The most effective combinations were (synergism rates): ebselen + amphotericin B (88%), ebselen + voriconazole (80%), diphenyl diselenide + amphotericin B (72%), and diphenyl diselenide + voriconazole (64%). Combination with caspofungin resulted in low rates of synergism: ebselen + caspofungin, 36%, and diphenyl diselenide + caspofungin, 28%; combination with itraconazole demonstrated indifferent interactions. Antagonistic effects were not observed for any of the combinations tested. Our findings suggest that the antifungal potential of diphenyl diselenide and ebselen deserves further investigation in in vivo experimental models, especially in combination with amphotericin B and voriconazole. PMID:26773133

  7. In Vitro Triple Combination of Antifungal Drugs against Clinical Scopulariopsis and Microascus Species

    PubMed Central

    Yao, Limin; Wan, Zhe; Li, Ruoyu

    2015-01-01

    Broth microdilution checkerboard techniques based on the methodology of the Clinical and Laboratory Standards Institute (CLSI) were employed to study the triple antifungal combination of caspofungin, posaconazole, and terbinafine against 27 clinical isolates of Scopulariopsis and Microascus species. Synergy was observed for 26 isolates, whereas antagonism was observed for Scopulariopsis candida in this study. PMID:26014943

  8. INJECTABLE IN SITU CROSS-LINKING HYDROGELS FOR LOCAL ANTIFUNGAL THERAPY

    PubMed Central

    Hudson, Sarah; Langer, Robert; Fink, Gerald R.; Kohane, Daniel S.

    2009-01-01

    Invasive fungal infections can be devastating, particularly in immunocompromised patients, and difficult to treat with systemic drugs. Furthermore, systemic administration of those medications can have severe side effects. We have developed an injectable local antifungal treatment for direct administration into existing or potential sites of fungal infection. Amphotericin B (AmB), a hydrophobic, potent, and broad-spectrum antifungal agent, was rendered water-soluble by conjugation to a dextran-aldehyde polymer. The dextran-aldehyde-AmB conjugate retained antifungal efficacy against C. albicans. Mixing carboxymethylcellulose-hydrazide with dextran-aldehyde formed a gel that cross-linked in situ by formation of hydrazone bonds. The gel provided in vitro release of antifungal activity for 11 days, and contact with the gel killed Candida for three weeks. There was no apparent tissue toxicity in the murine peritoneum and the gel caused no adhesions. Gels produced by entrapment of a suspension of AmB in CMC-dextran without conjugation of drug to polymers did not release fungicidal activity, but did kill on contact. Injectable systems of these types, containing soluble or insoluble drug formulations, could be useful for treatment of local antifungal infections, with or without concurrent systemic therapy. PMID:19942285

  9. Targeted Therapies Combined With Immune Checkpoint Therapy.

    PubMed

    Prieto, Peter A; Reuben, Alexandre; Cooper, Zachary A; Wargo, Jennifer A

    2016-01-01

    The age of personalized medicine continues to evolve within clinical oncology with the arsenal available to clinicians in a variety of malignancies expanding at an exponential rate. The development and advancement of molecular treatment modalities, including targeted therapy and immune checkpoint blockade, continue to flourish. Treatment with targeted therapy (BRAF, MEK, and other small molecule inhibitors) can be associated with swift disease control and high response rates, but limited durability when used as monotherapy. Conversely, treatment with immune checkpoint blockade monotherapy regimens (anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed cell death protein 1/programmed cell death protein 1 ligand) tends to have lower response rates than that observed with BRAF-targeted therapy, although these treatments may offer long-term durable disease control. With the advent of these forms of therapy, there was interest early on in empirically combining targeted therapy with immune checkpoint blockade with the hopes of preserving high response rates and adding durability; however, there is now strong scientific rationale for combining these forms of therapy-and early evidence of synergy in preclinical models of melanoma. Clinical trials combining these strategies are ongoing, and mature data regarding response rates and durability are not yet available. Synergy may ultimately be apparent; however, it has also become clear that complexities exist regarding toxicity when combining these therapies. Nonetheless, this increased appreciation of the complex interplay between oncogenic mutations and antitumor immunity has opened up tremendous opportunities for studying targeted agents and immunotherapy in combination, which extends far beyond melanoma to other solid tumors and also to hematologic malignancies. PMID:27111910

  10. Aspergillus tanneri sp. nov, a new pathogenic Aspergillus that causes invasive disease refractory to antifungal therapy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This is the first report documenting fatal invasive aspergillosis caused by a new pathogenic Aspergillus species that is inherently resistant to antifungal drugs. Phenotypic characteristics of A. tanneri combined with the molecular approach enabled diagnosis of this new pathogen. This study undersco...

  11. An overview of topical antifungal therapy in dermatomycoses. A North American perspective.

    PubMed

    Gupta, A K; Einarson, T R; Summerbell, R C; Shear, N H

    1998-05-01

    Dermatophytes cause fungal infections of keratinised tissues, e.g. skin, hair and nails. The organisms belong to 3 genera, Trichophyton, Epidermophyton and Microsporum. Dermatophytes may be grouped into 3 categories based on host preference and natural habitat. Anthropophilic species predominantly infect humans, geophilic species are soil based and may infect both humans and animals, zoophilic species generally infect non-human mammals. It is important to confirm mycologically the clinical diagnosis of onychomycosis and other tinea infections prior to commencing therapy. The identity of the fungal organism may provide guidance about the appropriateness of a given topical antifungal agent. Special techniques may be required to obtain the best yield of fungal organisms from a given site, especially the scalp and nails. It is also important to realise the limitations of certain diagnostic aids e.g., Wood's light examination is positive in tinea capitis due to M. canis and M. audouinii (ectothrix organisms); however, Wood's light examination is negative in T. tonsurans (endothrix organism). Similarly, it is important to be aware that cicloheximide in culture medium will inhibit growth of non-dermatophytes. Appropriate media are therefore required to evaluate the growth of some significant non-dermatophyte moulds. For tinea infections other than tinea capitis and tinea unguium, topical antifungals may be considered. For effective therapy of tinea capitis an oral antifungal is generally necessary. Similarly, oral antifungals are the therapy of choice, especially if onychomycosis is moderate to severe. Furthermore, where the tinea infection involves a large area, in an immunocompromised host or if infection is recurrent with poor response to topical agents, then oral antifungal therapy may be necessary. Topical antifungal agents may be broadly divided into specific and nonspecific agents. The former group includes the polyenes, azoles, allylamines, amorolfine, ciclopirox

  12. Combining Clozapine and Talk Therapies.

    ERIC Educational Resources Information Center

    Mulroy, Kevin

    Clozapine is an antipsychotic medication used in the treatment of schizophrenia. This paper reviews articles concerning clozapine therapy. It considers its benefits and dangers in various situations, and how it can be successfully combined with talk therapies. Studies are reviewed concerning patients in outpatient clinics, partial hospitalization…

  13. Optimizing topical antifungal therapy for superficial cutaneous fungal infections: focus on topical naftifine for cutaneous dermatophytosis.

    PubMed

    Del Rosso, James Q; Kircik, Leon H

    2013-11-01

    Superficial cutaneous fungal infections (SCFIs) are commonly encountered in clinical practice in the United States, and comprise infections of the skin by dermatophytes and yeasts. The most common organisms causing SCFI are dermatophytes, especially Trichophyton spp. With the exception of onchomycosis and tinea capitis, most cases of SCFIs are amenable to properly selected topical antifungal therapy used over an adequate period of time.

    A variety of topical antifungal agents are available for the treatment of SCFIs, and they encompass a few major chemical classes: the polyenes (ie, nystatin), imidazoles (ie, ketoconazole, econazole, oxiconazole, etc), allylamines (ie, naftifine, terbinafine), benzylamines (ie, butenafine), and hydroxypyridones (ie, ciclopirox). The 2 major classes that represent the majority of available topical antifungal agents are the azoles and the allylamines. Overall, the allylamines are superior to the azoles in activity against dermatophytes, although both are clinically effective. The reverse is true against yeasts such as Candida spp and Malassezia spp, although topical allylamines have proven to be efficacious in some cases of tinea versicolor and cutaneous candidiasis.

    Naftifine, a topical allylamine, is fungicidal in vitro against a wide spectrum of dermatophyte fungi and has been shown to be highly effective against a variety of cutaneous dermatophyte infections. Rapid onset of clinical activity and favorable data on sustained clearance of infection have been documented with naftifine. The more recent addition of naftifine 2% cream has expanded the armamentarium, with data supporting a clinically relevant therapeutic reservoir effect after completion of therapy. PMID:24196340

  14. Recent advances in antifungal chemotherapy.

    PubMed

    Petrikkos, George; Skiada, Anna

    2007-08-01

    For over 50 years, amphotericin B deoxycholate (AmBD) has been the 'gold standard' in antifungal chemotherapy, despite its frequent toxicities. However, improved treatment options for invasive fungal infections (IFIs) have been developed during the last 15 years. Newer antifungal agents, including less toxic lipid preparations of AmBD, triazoles and the echinocandins, have been added to our armamentarium against IFIs. Some of these newer drugs can now replace AmBD as primary therapy (e.g. caspofungin for candidiasis, voriconazole for aspergillosis), whilst others offer new therapeutic options for difficult-to-treat IFIs (e.g. posaconazole for zygomycosis, fusariosis and chromoblastomycosis). It is interesting that extended use of newer antifungals such as fluconazole, despite decreasing the mortality attributed to candidiasis, resulted in selection of species resistant to several antifungals (Candida krusei, Candida glabrata); whilst several publications suggest that prolonged use of voriconazole may expose severely immunocompromised patients to the risk of zygomycosis (breakthrough). On the other hand, the differences in the mode of action of newer antifungals such as echinocandins raise the question whether combination antifungal therapy is more effective than monotherapy. Finally, the availability of an oral formulation with excellent biosafety of several newer antifungals (e.g. posaconazole) makes them candidates for prophylactic or prolonged maintenance therapy. PMID:17524625

  15. Mice with persistent gastrointestinal Candida albicans as a model for antifungal therapy.

    PubMed Central

    Herrera, C; Guentzel, M N

    1982-01-01

    Persistent infection of the gastrointestinal tract of CFW mice with Candida albicans was produced by the oral-intragastric inoculation of 6-day-old infants. Other intraabdominal organs (liver, kidneys, and spleen) were usually free of the organism in survivors at 20 days of age. However, all survivors retained high levels of the organism in the stomach and intestinal tract at 30 days of age. The possible utility of these persisting C. albicans infections of the gastrointestinal tract for the study of the efficacy of short-term antifungal therapy was studied. Drug treatment was initiated for a 2-week period when the survivors were 15 to 19 days old. Some representative antifungal agents in current use (i.e., amphotericin B, 5-fluorocytosine, and miconazole) effected significant reductions in the numbers of C. albicans in homogenates of gastrointestinal organs. PMID:7044301

  16. Antifungal activity of Rubus chingii extract combined with fluconazole against fluconazole-resistant Candida albicans.

    PubMed

    Han, Bing; Chen, Jia; Yu, Yi-qun; Cao, Yong-bing; Jiang, Yuan-ying

    2016-02-01

    This study aimed to investigate the antifungal activity of Rubus chingii extract in combination with fluconazole (FLC) against FLC-resistant Candida albicans 100 in vitro. A R. chingii extract and FLC-resistant C. albicans fungus suspension were prepared. The minimum inhibitory concentration and fractional inhibitory concentration index of R. chingii extract combined with FLC against C. albicans were determined, after which growth curves for C. albicans treated with R. chingii extract, FLC alone and a combination of these preparations were constructed. Additionally, the mechanisms of drug combination against C. albicans were explored by flow cytometry, gas chromatographic mass spectrometry and drug efflux pump function detection. R. chingii extract combined with FLC showed significant synergy. Flow cytometry suggested that C. albicans cells mainly arrest in G1 and S phases when they have been treated with the drug combination. The drug combination resulted in a marked decrease in the ergosterol content of the cell membrane. Additionally, efflux of Rhodamine 6G decreased with increasing concentrations of R. chingii extract. R. chingii extract combined with FLC has antifungal activity against FLC-resistant C. albicans. PMID:26891940

  17. In vitro susceptibility of Scedosporium isolates to N-acetyl-L-cysteine alone and in combination with conventional antifungal agents.

    PubMed

    Homa, Mónika; Galgóczy, László; Tóth, Eszter; Virágh, Máté; Chandrasekaran, Muthusamy; Vágvölgyi, Csaba; Papp, Tamás

    2016-10-01

    In recent years, Scedosporium species have been more commonly recognized from severe, difficult-to-treat human infections, such as upper respiratory tract and pulmonary infections. To select an appropriate therapeutic approach for these infections is challenging, because of the commonly observed resistance of the causative agents to several antifungal drugs. Therefore, to find a novel strategy for the treatment of pulmonary Scedosporium infections the in vitro antifungal effect of a mucolytic agent, N-acetyl-L-cysteine and its in vitro combinations with conventional antifungals were investigated. Synergistic and indifferent interactions were registered in 23 and 13 cases, respectively. Antagonism was not revealed between the compounds. PMID:27143635

  18. Experimental disseminated trichosporonosis in mice: tissue distribution and therapy with antifungal agents.

    PubMed

    Yamamoto, K; Makimura, K; Sudo, T; Shibuya, K; Uchida, K; Yamaguchi, H

    1997-01-01

    Mice treated with cyclophosphamide were infected intravenously with titrated doses of Trichosporon asahii TIMM3140 or TIMM3144. Mortality and survival time correlated with inoculum size and fungal growth was found in the lung, heart, liver, spleen, kidney and brain. Fluconazole and amphotericin B prolonged survival time and reduced the CFU in the kidney, with fluconazole being superior to amphotericin B. The serum level of (1-->3)-beta-D-glucan was reduced by antifungal therapy and correlated well with the CFU/organ in kidney, but not CFU/ml in blood. PMID:9467108

  19. In vitro activity of carvacrol and thymol combined with antifungals or antibacterials against Pythium insidiosum.

    PubMed

    Jesus, F P K; Ferreiro, L; Bizzi, K S; Loreto, É S; Pilotto, M B; Ludwig, A; Alves, S H; Zanette, R A; Santurio, J M

    2015-06-01

    We describe the in vitro activities of the combinations of carvacrol and thymol with antibiotics (azithromycin, clarithromycin, minocycline and tigecycline) and antifungal agents (amphotericin B, caspofungin, itraconazole and terbinafine) against 23 isolates of the oomycete Pythium insidiosum. The assays were based on the M38-A2 technique and checkerboard microdilution. Based on the mean FICI values, the main synergies observed were combinations of carvacrol+itraconazole and thymol+itraconazole (96%), thymol+clarithromycin (92%), carvacrol+clarithromycin (88%), thymol+minocycline (84%), carvacrol+minocycline (80%), carvacrol+azithromycin (76%), thymol+azithromycin (68%), carvacrol+tigecycline (64%) and thymol+tigecycline (60%). In conclusion, we found that combinations of carvacrol or thymol with these antimicrobial agents might provide effective alternative treatments for cutaneous pythiosis due to their synergistic interactions. Future in vivo experiments are needed to elucidate the safety and therapeutic potential of these combinations. PMID:25639921

  20. Treatment trial of clinically ill corroboree frogs with chytridiomycosis with two triazole antifungals and electrolyte therapy.

    PubMed

    Brannelly, Laura A; Skerratt, Lee F; Berger, Lee

    2015-09-01

    Chytridiomycosis caused by the pathogen Batrachochytrium dendrobatidis is an important cause of amphibian declines globally, and is the worst pathogen on record for causing biodiversity loss. The critically endangered southern corroboree frog, Pseudophryne corroboree, is functionally extinct in the wild and is surviving in captive assurance colonies. These captive colonies must remain disease free, and there is no known treatment for corroboree frogs with terminal chytridiomycosis. In this study we tested two triazole antifungals (itraconazole and voriconazole) coupled with aggressive electrolyte therapy on moribund corroboree frogs with severe chytridiomycosis. Six moribund frogs were given 20 mL baths of 0.5 μg/mL itraconazole for 5 min/day for 5 days coupled with electrolyte injections every 8 h for 3 days followed by every 12 h for 3 days. Six other moribund frogs were given 1 mL drops of 1.25 μg/mL voriconazole daily for 7 days coupled with the aggressive electrolyte therapy. While only one animal survived this treatment regime, time until death was extended for all animals by at least 3 days and infection load decreased by an average of 89.3%. Our results suggest there is potential for recovery of terminally ill P. corroboree, and we suggest further trials include antibiotics as well as exploring variations on the above treatment regime with other antifungals. PMID:26246159

  1. [Combination therapy of hypopharyngeal cancer].

    PubMed

    Miyahara, H

    1987-06-01

    Between 1978 and 1983, ninety-three patients with cancer of the hypopharynx were treated. They were evaluated as to sex, age, primary site, TNM classification, stage, habits of smoking and drinking, past history of irradiation, treatment modality and end results. Eighty-seven percent of the patients visited us at as late a stage as advanced stage III or IV, and were treated mainly by combined therapy involving irradiation and pharyngolaryngoesophagectomy. The 3-year and 5-year survival rates were 38.6% and 33.3%, respectively. After December 1983, 14 new patients with advanced disease including three with coervical esophageal cancer were treated with neo-adjuvant combination chemotherapy which included cisplatin, peplomycin, methotrexate, and bleomycin over two courses of therapy. The response rate (CR + PR) was high, being 82% for the primary tumor and 78% for the metastatic node. Histopathological effects of neo-adjuvant chemotherapy were studied in the resected specimens. The evaluation was based on the Ohboshi-Shimosato classification. The histological effects did not agree with the clinical effects. Grade II b change was evaluated mostly in CR cases and grade II a change was seen in PR cases. It thus seems that neo-adjuvant chemotherapy prior to surgery and/or radiation including cisplatin and other agents is very useful as a multidisciplinary treatment for cancer of the hypopharynx. PMID:3592715

  2. Impact of systemic antifungal therapy on the detection of Candida species in blood cultures in clinical cases of candidemia.

    PubMed

    Bailly, S; Garnaud, C; Cornet, M; Pavese, P; Hamidfar-Roy, R; Foroni, L; Boisset, S; Timsit, J-F; Maubon, D

    2016-06-01

    The diagnosis and follow-up of candidemia still rely on blood cultures (BCs). In vitro studies show that antifungals can significantly modify the result of blood culture not containing adsorbing agents. We aimed to evaluate, under clinical conditions, the impact on BC yeast detection of systemic antifungal therapy (SAT). Patients (n = 125) experiencing candidemia at Grenoble University Hospital (France) were included in a 4-year retrospective study. The Plus Aerobic/F (Aerobic) and Plus Anaerobic/F (Anaerobic) bottles, which both contain adsorbing resins and the non-resin selective Mycosis IC/F (Mycosis) bottles, were compared using multivariate hierarchical models adjusted for clinical characteristics. The positivity rate (PR) is decreased in patients with SAT (p < 0.01), abdominal surgery (p = 0.01), and hemodialysis (p = 0.02). In all bottles, SAT reduces PR by a factor of 0.16 (95 % CI: [0.08; 0.32]) and increases the time to positivity (TTP) by a factor of 1.76 ([1.30; 2.40]; p < 0.01). In the presence of SAT, TTP is higher in non-resin bottles (Mycosis) than in resin bottles (RR = 1.76, [1.30; 2.40]); however, the TTP in nonresin and resin bottles remains comparable. Although discordant results are observed with and without SAT (37 and 58 % respectively), we showed that the presence of SAT decreases significantly the agreement rate by a factor of 0.29 (CI: [0.12; 0.68]). The combination of Anaerobic and Mycosis bottles allowed a 100 % positivity rate for C. glabrata. SAT significantly affects BC results. Because they provide additional and complementary results, this study supports the concomitant use of resin and selective bottles, especially in patients receiving SAT. PMID:27039341

  3. [A retrospective analysis of neurotoxicity induced by vinca alkaloids combined with azole anti-fungal agents in hematological malignancies].

    PubMed

    Osato, Yoichi; Yokoyama, Tomohisa; Saito, Yumiko; Kani, Rinako; Hayabe, Hiroko; Miyamatsu, Hironobu; Ohyashiki, Kazuma

    2011-10-01

    Vinca alkaloids (VA) are some of the key anti-tumor agents for patients with hematological malignancies, and various adverse events such as paralytic ileus, peripheral neuropathy, and constipation were now recognized as adverse VA effects. Furthermore, azole anti-fungal agents are known to enhance VA toxicity because they delay the metabolism and excretion of VA by inhibiting CYP3A4. However, their clinical relationship has not been clearly described. Therefore, we studied neurotoxicity as a possible adverse event associated with VA in patients treated with azole anti-fungal agents, retrospectively. In our study, 100 patients (479 episodes) who received VA in our department from August 2008 to December 2010 were analyzed. Adverse events attributed to the combined administration of vincristine (VCR) and azole anti-fungal agents were grade 3 paralytic ileuses in 8 patients (8 episodes), grade 3 or 4 constipation in 16 patients (16 episodes), and grade 3 peripheral neuropathy in 10 patients (16 episodes). In addition, we investigated whether temporal discontinuation of azole anti-fungal agents during VA treatment decreases the frequency of these adverse events, and detected that it is likely to help avoid neurotoxicities enhanced by itraconazole, such as severe constipation (p=0. 0308) and paralytic ileus (p=0. 0967). Our findings indicated that we should pay much more attention to these adverse events, and must select patients carefully when we administer azole anti-fungal agents to them while they are being treated with VA. PMID:21996963

  4. Oral Antifungal Drugs in the Treatment of Dermatomycosis.

    PubMed

    Tsunemi, Yuichiro

    2016-01-01

    Oral antifungal drugs are used primarily to treat tinea unguium; however, they are also useful for other types of tinea. For example, a combination of topical and oral antifungal drugs is effective in hyperkeratotic tinea pedis that is unresponsive to topical monotherapy. In cases of tinea facialis adjacent to the eyes, ears, or mouth, or widespread tinea corporis, or tinea cruris involving the complex skin folds of the external genitalia, it is difficult to apply topical drugs to all the lesions; therefore, oral antifungal drugs are necessary. Oral antifungal drugs are also useful not only for tinea but for widespread pityriasis versicolor and Malassezia folliculitis, candidal onychomycosis, and candidal paronychia and onychia. Topical antifungal drugs are in fact unsuitable for some mycoses. In tinea capitis, for example, irritation by topical drugs is likely to enhance inflammation; therefore, oral antifungal drug monotherapy is preferable. In interdigital tinea pedis with erosion or contact dermatitis, topical drugs are difficult to use because they tend to cause irritant dermatitis, resulting in exacerbation of the condition. In such cases, treatment should begin with a combination of topical corticosteroid therapy and oral antifungal drugs active against dermatophytes. Topical antifungal drugs are used after the complications resolve. A combination of topical and oral antifungal drugs can shorten the treatment period, thus improving patient adherence to topical treatment. Oral antifungal drugs are useful because of their wide range of applications in the treatment of dermatomycosis. PMID:27251319

  5. Current trends in outwitting resistance development in Candida infections through photodynamic and short peptide therapies: a strategic-shift from conventional antifungal agents.

    PubMed

    Louis, Bengyella; Waikhom, Sayanika Devi; Atadja, Peter W

    2016-01-01

    Disequilibrium in the human debilitated immune system favors proliferation of invasive Candida species, a major therapeutic challenge due to development of resistance to several conventional antifungal agents (CAA) worldwide. Multiple mutations observed at specific loci that are targets for CAA are recognized as sources of drug resistance. This has prompted a shift from CAA, to diverse combination therapies, photodynamic and short peptide therapies capable of triggering specific apoptotic reactions within candidal cells. In this review, new designs and combination of short peptide (SP) with CAA as well as current application of photodynamic inactivation (PDI) against Candida species geared at generating reactive species of oxygen (ROS) and nitrogen (RNS) are discussed. It is observed that oxidative and nitrosative stresses provides a superior broad candidacidal effects for eradication of drug-resistant Candida species. The mechanism and limitations in these strategic approaches over CAA is also discussed. PMID:26822688

  6. Combining Individual Psychodynamics with Structural Family Therapy.

    ERIC Educational Resources Information Center

    Melito, Richard

    1988-01-01

    Presents integrative framework for combining central aspects of individual psychodynamics with structural family therapy in meaningful way. Explains how framework derives from developmental perspective. Presents case example to illustrate combined approach and demonstrate its utility. (Author/NB)

  7. Calcofluor White Combination Antifungal Treatments for Trichophyton rubrum and Candida albicans

    PubMed Central

    Kingsbury, Joanne M.; Heitman, Joseph; Pinnell, Sheldon R.

    2012-01-01

    Superficial mycoses caused by dermatophyte fungi are among the most common infections worldwide, yet treatment is restricted by limited effective drugs available, drug toxicity, and emergence of drug resistance. The stilbene fluorescent brightener calcofluor white (CFW) inhibits fungi by binding chitin in the cell wall, disrupting cell wall integrity, and thus entails a different mechanism of inhibition than currently available antifungal drugs. To identify novel therapeutic options for the treatment of skin infections, we compared the sensitivity of representative strains of the dermatophyte Trichophyton rubrum and Candida albicans to CFW and a panel of fluorescent brighteners and phytoalexin compounds. We identified the structurally related stilbene fluorescent brighteners 71, 85, 113 and 134 as fungicidal to both T. rubrum and C. albicans to a similar degree as CFW, and the stilbene phytoalexins pinosylvan monomethyl ether and pterostilbene inhibited to a lesser degree, allowing us to develop a structure-activity relationship for fungal inhibition. Given the abilities of CFW to absorb UV365 nm and bind specifically to fungal cell walls, we tested whether CFW combined with UV365 nm irradiation would be synergistic to fungi and provide a novel photodynamic treatment option. However, while both treatments individually were cytocidal, UV365 nm irradiation reduced sensitivity to CFW, which we attribute to CFW photoinactivation. We also tested combination treatments of CFW with other fungal inhibitors and identified synergistic interactions between CFW and some ergosterol biosynthesis inhibitors in C. albicans. Therefore, our studies identify novel fungal inhibitors and drug interactions, offering promise for combination topical treatment regimes for superficial mycoses. PMID:22792174

  8. Statin combination therapy and cardiovascular risk reduction.

    PubMed

    Toth, Peter P; Farnier, Michel; Tomassini, Joanne E; Foody, JoAnne M; Tershakovec, Andrew M

    2016-05-01

    In numerous clinical trials, lowering LDL-C with statin therapy has been demonstrated to reduce the risk of cardiovascular disease (CVD) in primary and secondary prevention settings. Guidelines recommend statins for first-line therapy in cholesterol-lowering management of patients with CVD risk. Despite increased statin monotherapy use over the last decade, a number of patients with high CVD risk do not achieve optimal LDL-C lowering. Guidelines recommend consideration of statin combination therapy with nonstatin agents for these patients. However, combination therapy approaches have been hampered by neutral findings. Recently, ezetimibe added to simvastatin therapy reduced cardiovascular events in acute coronary syndrome patients, more than simvastatin alone. This article provides an overview of various agents in combination with statin therapy on cardiovascular outcomes. Other lipid-lowering agents in development, including PCSK9 and CETP inhibitors in development, are also described. PMID:27079178

  9. In vitro susceptibility of dermatomycoses agents to six antifungal drugs and evaluation by fractional inhibitory concentration index of combined effects of amorolfine and itraconazole in dermatophytes.

    PubMed

    Tamura, Takashi; Asahara, Miwa; Yamamoto, Mikachi; Yamaura, Mariko; Matsumura, Mitsuru; Goto, Kazuo; Rezaei-Matehkolaei, Ali; Mirhendi, Hossein; Makimura, Miho; Makimura, Koichi

    2014-01-01

    To investigate the antifungal drug susceptibility of fungi responsible for dermatomycoses, minimum inhibition concentration (MIC) tests were performed in 44 strains of dermatophytes, including Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton tonsurans, Microsporum canis, Microsporum gypseum and Epidermophyton floccosum, with six antifungal drugs (amorolfine, terbinafine, butenafine, ketoconazole, itraconazole and bifonazole) by broth microdilution assay according to Clinical Laboratory Standard Institute protocols. Six possible dermatomycosis-causing non-dermatophytic fungi were also tested. The two major causes of tinea, T. rubrum and T. mentagrophytes, showed significantly different sensitivities to ketoconazole and bifonazole. Clinically derived dermatophytes were sensitive to the six antifungal drugs tested. However, non-dermatophytes, especially Fusarium spp., tended to be resistant to these antifungal drugs. In Trichophyton spp., the MICs of non-azole drugs had narrower distributions than those of azoles. To evaluate the effects of antifungal drug combinations, the fractional inhibitory concentration index was calculated for the combination of amorolfine and itraconazole as representative external and internal drugs for dermatophytes. It was found that this combination had synergistic or additive effects on most dermatophytes, and had no antagonistic effects. The variation in susceptibility of clinically derived fungal isolates indicates that identification of causative fungi is indispensable for appropriately choosing effective antifungal drugs in the early stages of infection. The results of combination assay suggest that multiple drugs with different antifungal mechanisms against growth of dermatophytes should be used to treat refractory dermatomycoses, especially onychomycosis. PMID:24215461

  10. Tandem combination of Trigonella foenum-graecum defensin (Tfgd2) and Raphanus sativus antifungal protein (RsAFP2) generates a more potent antifungal protein.

    PubMed

    Karri, Vasavirama; Bharadwaja, Kirti Pulugurtha

    2013-11-01

    Plant defensins are small (45 to 54 amino acids) positively charged antimicrobial peptides produced by the plant species, which can inhibit the growth of a broad range of fungi at micro-molar concentrations. These basic peptides share a common characteristic three-dimensional folding pattern with one α-helix and three β-sheets that are stabilized by eight disulfide-linked cysteine residues. Instead of using two single-gene constructs, it is beneficial when two effective genes are made into a single fusion gene with one promoter and terminator. In this approach, we have linked two plant defensins namely Trigonella foenum-graecum defensin 2 (Tfgd2) and Raphanus sativus antifungal protein 2 (RsAFP2) genes by a linker peptide sequence (occurring in the seeds of Impatiens balsamina) and made into a single-fusion gene construct. We used pET-32a+ vector system to express Tfgd2-RsAFP2 fusion gene with hexahistidine tag in Escherichia coli BL21 (DE3) pLysS cells. Induction of these cells with 1 mM IPTG achieved expression of the fusion protein. The solubilized His6-tagged recombinant fusion protein was purified by immobilized-metal (Ni2+) affinity column chromatography. The final yield of the fusion protein was 500 ng/μL. This method produced biologically active recombinant His6-tagged fusion protein, which exhibited potent antifungal action towards the plant pathogenic fungi (Botrytis cinerea, Fusarium moniliforme, Fusarium oxysporum, Phaeoisariopsis personata and Rhizoctonia solani along with an oomycete pathogen Phytophthora parasitica var nicotianae) at lower concentrations under in vitro conditions. This strategy of combining activity of two defensin genes into a single-fusion gene will definitely be a promising utility for biotechnological applications. PMID:24022215

  11. Voriconazole is a safe and effective anti-fungal prophylactic agent during induction therapy of acute myeloid leukemia

    PubMed Central

    Shah, Akash; Ganesan, Prasanth; Radhakrishnan, Venkatraman; Kannan, Krishnarathinam; Rajendranath, Rejiv; Mahajan, Vandana; Vijayakumar, Varalakshmi; Ganesan, Trivadi; Sagar, Tenali Gnana

    2016-01-01

    Background: Antifungal prophylaxis (AFP) reduces the incidence of invasive fungal infections (IFIs) during induction therapy of acute myeloid leukemia (AML). Posaconazole is considered the standard of care. Voriconazole, a generic cheaper alternative is a newer generation azole with broad anti-fungal activity. There is limited data on the use of voriconazole as a prophylactic drug. Materials and Methods: A single-center, prospective study was performed during which patients with AML undergoing induction chemotherapy received voriconazole as AFP (April 2012 to February 2014). Outcomes were compared with historical patients who received fluconazole as AFP (January 2011-March 2012, n = 66). Results: Seventy-five patients with AML (median age: 17 years [range: 1-75]; male:female 1.6:1) received voriconazole as AFP. The incidence of proven/probable/possible (ppp) IFI was 6.6% (5/75). Voriconazole and fluconazole cohorts were well-matched with respect to baseline characteristics. Voriconazole (when compared to fluconazole) reduced the incidence of pppIFI (5/75, 6.6% vs. 19/66, 29%; P < 0.001), need to start therapeutic (empiric + pppIFI) antifungals (26/75, 34% vs. 51/66, 48%; P < 0.001) and delayed the start of therapeutic antifungals in those who needed it (day 16 vs. day 10; P < 0.001). Mortality due to IFI was also reduced with the use of voriconazole (1/75, 1.3% vs. 6/66, 9%; P = 0.0507), but this was not significant. Three patients discontinued voriconazole due to side-effects. Conclusion: Voriconazole is an effective and safe oral agent for IFI prophylaxis during induction therapy of AML. Availability of generic equivalents makes this a more economical alternative to posaconazole. PMID:27051159

  12. Antigenemia in Patients with Paracoccidioidomycosis: Detection of the 87-Kilodalton Determinant during and after Antifungal Therapy

    PubMed Central

    Gómez, B. L.; Figueroa, J. I.; Hamilton, A. J.; Diez, S.; Rojas, M.; Tobón, A. M.; Hay, R. J.; Restrepo, A.

    1998-01-01

    Serological diagnosis and follow-up of paracoccidioidomycosis (PCM) patients have relied mainly on the detection of antibody responses by using techniques such as complement fixation (CF) and immunodiffusion. We recently described a novel inhibition enzyme-linked immunosorbent assay (inh-ELISA) which proved to be useful in the diagnosis of PCM via the detection of an 87-kDa determinant in patient sera (B. L. Gomez, J. I. Figueroa, A. J. Hamilton, B. Ortiz, M. A. Robledo, R. J. Hay, and A. Restrepo, J. Clin. Microbiol. 35:3278–3283, 1997). This test has now been assessed as a means of following up PCM patients. A total of 24 PCM patients, classified according to their clinical presentation (6 with the acute form of the disease, of whom two had AIDS, 12 with the multifocal form of the disease, and 6 with the unifocal form of the disease), were studied. The four human immunodeficiency virus-negative patients with acute PCM showed a statistically significant decrease in circulating antigen levels after the start of antifungal therapy. Antigen levels in this group became negative by our criteria (≤2.3 μg/ml) before week 20 and remained so in three of four of these patients. In contrast, the two AIDS patients who also presented with the acute form of PCM showed no statistically significant decrease in circulating antigen levels even after 68 weeks of therapy. Taken together as a group, the patients with the multifocal form showed a statistically significant decrease in antigenemia after 28 weeks of therapy. In addition, five of six patients with the unifocal form became antigen negative by week 40. Antigen level decrease mirrored clinical cure in the majority of patients in all clinical groups; in contrast, measurement of anti-PCM antibodies via the CF test showed wide fluctuations in titers during the follow-up period. The inh-ELISA for the detection of the 87-kDa Paracoccidioides brasiliensis determinant would appear to be a valuable additional tool in the follow

  13. Recent Advances in Combined Modality Therapy

    PubMed Central

    Nyati, Mukesh K.; Morgan, Meredith A.; Lawrence, Theodore S.

    2010-01-01

    Combined modality therapy emerged from preclinical data showing that carefully chosen drugs could enhance the sensitivity of tumor cells to radiation while having nonoverlapping toxicities. Recent advances in molecular biology involving the identification of cellular receptors, enzymes, and pathways involved in tumor growth and immortality have resulted in the development of biologically targeted drugs. This review highlights the recent clinical data in support of newer generation cytotoxic chemotherapies and systemic targeted agents in combination with radiation therapy. PMID:20413642

  14. Rifampin Combination Therapy for Nonmycobacterial Infections

    PubMed Central

    Forrest, Graeme N.; Tamura, Kimberly

    2010-01-01

    Summary: The increasing emergence of antimicrobial-resistant organisms, especially methicillin-resistant Staphylococcus aureus (MRSA), has resulted in the increased use of rifampin combination therapy. The data supporting rifampin combination therapy in nonmycobacterial infections are limited by a lack of significantly controlled clinical studies. Therefore, its current use is based upon in vitro or in vivo data or retrospective case series, all with major limitations. A prominent observation from this review is that rifampin combination therapy appears to have improved treatment outcomes in cases in which there is a low organism burden, such as biofilm infections, but is less effective when effective surgery to obtain source control is not performed. The clinical data support rifampin combination therapy for the treatment of prosthetic joint infections due to methicillin-sensitive S. aureus (MSSA) after extensive debridement and for the treatment of prosthetic heart valve infections due to coagulase-negative staphylococci. Importantly, rifampin-vancomycin combination therapy has not shown any benefit over vancomycin monotherapy against MRSA infections either clinically or experimentally. Rifampin combination therapy with daptomycin, fusidic acid, and linezolid needs further exploration for these severe MRSA infections. Lastly, an assessment of the risk-benefits is needed before the addition of rifampin to other antimicrobials is considered to avoid drug interactions or other drug toxicities. PMID:20065324

  15. Ibuprofen Potentiates the In Vivo Antifungal Activity of Fluconazole against Candida albicans Murine Infection

    PubMed Central

    Miranda, Isabel M.; Silva-Dias, Ana; Silva, Ana P.; Rodrigues, Acácio G.; Pina-Vaz, Cidália

    2015-01-01

    Candida albicans is the most prevalent cause of fungemia worldwide. Its ability to develop resistance in patients receiving azole antifungal therapy is well documented. In a murine model of systemic infection, we show that ibuprofen potentiates fluconazole antifungal activity against a fluconazole-resistant strain, drastically reducing the fungal burden and morbidity. The therapeutic combination of fluconazole with ibuprofen may constitute a new approach for the management of antifungal therapeutics to reverse the resistance conferred by efflux pump overexpression. PMID:25845879

  16. Pharmacological properties of combination therapies for hypertension.

    PubMed

    Abernethy, D R

    1997-03-01

    Single drug therapy for the treatment of hypertension has traditionally been a standard of practice. More recently combination therapy as first-line treatment has gained acceptance both by the medical practice community and the US Food and Drug Administration. The advantages of combinations may be a synergistic or additive antihypertensive effect, metabolic improvement, or both. The combination of a thiazide-type diuretic and a potassium-sparing diuretic has been quite useful in the past to prevent the need for potassium supplementation. The combination of beta-adrenoceptor blockade and a thiazide diuretic results in an additive antihypertensive effect that permits the effective use of very low thiazide doses. The mechanism of antihypertensive effects of each member of the combination are complimentary with increased sympathetic outflow and renin-angiotensin axis activation induced by the diuretic being blunted by beta1-adrenergic blockade. Combinations not used as first-line therapy, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockade and a thiazide diuretic, have complimentary antihypertensive mechanisms and have been useful in treating patient groups who do not respond well to converting enzyme inhibitor monotherapy. The combination of a calcium antagonist with diuretic therapy has an additive hypertensive effect as well; however, the complimentary mechanisms are less obvious. Finally, the combination of angiotensin converting enzyme inhibition and calcium antagonist therapy has been useful in selected patients, but again the complimentary mechanisms are less obvious. As first-line therapy, combinations for diuretics and beta1-receptor blockers have been useful for achieving increased antihypertensive effect with decreased adverse drug effect. PMID:9056702

  17. Antifungal polypeptides

    DOEpatents

    Altier, Daniel J.; Ellanskaya, Irina; Ellanskaya, legal representative, Natalia; Gilliam, Jacob T.; Hunter-Cevera, Jennie; Presnail, James K.; Schepers, Eric; Simmons, Carl R.; Torok, Tamas; Yalpani, Nasser

    2009-09-15

    The invention relates to antifungal compositions and methods for protecting a plant from a fungal pathogen. Compositions including antifungal polypeptides isolated from a fungal fermentation broth are provided.

  18. Promising combination therapies with gemcitabine.

    PubMed

    Robinson, Blaine W; Ostruszka, Leo; Im, Michael M; Shewach, Donna S

    2004-04-01

    Because treatment regimens for breast cancer commonly include gemcitabine, we evaluated two promising combinations in preclinical studies: gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) with either ionizing radiation or docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Parsippany, NJ). In breast cancer cell lines that expressed either wild-type p53 (MCF-7) or mutant p53 (MCF-7/Adr), sensitivity to the cytotoxic effects of gemcitabine during a 24-hour incubation was similar (IC(50) values 80 and 60 nmol/L in MCF-7 and MCF-7/Adr, respectively). Both cell lines were well radiosensitized by gemcitabine at the corresponding IC(50), with radiation enhancement ratios of 1.6 to 1.7. Although the MCF-7 cells accumulated nearly twice as much gemcitabine triphosphate compared with the MCF-7/Adr cells, a similar reduction in 2'-deoxyadenosine 5'-triphosphate pools was observed. While the number of dying cells, as measured by sub-G1 DNA content or S-phase cells unable to replicate DNA, differed between the wild-type p53 or mutant p53-expressing cell lines, neither parameter correlated with radiosensitization. Docetaxel was a more potent cytotoxic agent than gemcitabine in MCF-7 cells (IC(50) = 1 nmol/L). Strong synergistic cytotoxicity was observed in cells treated with gemcitabine (24 hours) followed by docetaxel (24 hours) or the reverse sequence. However, simultaneous addition of the two drugs was antagonistic. To determine whether synergy with radiation or docetaxel was mediated by increased DNA damage, DNA double-strand breaks (double-strand breaks) were measured by immunostaining for phosphorylated H2AX. Ionizing radiation produced more double-strand breaks than gemcitabine alone, while no significant double-strand breaks formed with docetaxel alone. The addition of docetaxel or ionizing radiation to gemcitabine-treated cells did not increase H2AX foci formation. These results show that the combination of gemcitabine with ionizing radiation or docetaxel

  19. Emerging Threats in Antifungal-Resistant Fungal Pathogens

    PubMed Central

    Sanglard, Dominique

    2016-01-01

    The use of antifungal drugs in the therapy of fungal diseases can lead to the development of antifungal resistance. Resistance has been described for virtually all antifungal agents in diverse pathogens, including Candida and Aspergillus species. The majority of resistance mechanisms have also been elucidated at the molecular level in these pathogens. Drug resistance genes and genome mutations have been identified. Therapeutic choices are limited for the control of fungal diseases, and it is tempting to combine several drugs to achieve better therapeutic efficacy. In the recent years, several novel resistance patterns have been observed, including antifungal resistance originating from environmental sources in Aspergillus fumigatus and the emergence of simultaneous resistance to different antifungal classes (multidrug resistance) in different Candida species. This review will summarize these current trends. PMID:27014694

  20. Combined therapy in the treatment of dyslipidemia.

    PubMed

    Reiner, Zeljko

    2010-02-01

    This systematic review analyses the efficacy, tolerability and safety of combinations of different medicines used to treat dyslipidemias in clinical practice. A PubMed search up to January 2009, was conducted to identify relevant studies. Criteria used to identify studies included (1) English language, (2) published studies with original data or meta-analyses in peer-reviewed journals. Although statin treatment is a mainstay of dyslipidemia management today, complementary effects of other lipid-lowering and/or HDL-cholesterol-raising therapies might substantially increase the clinical benefits not only in the small minority of patients with severe dyslipidemias but in others as well. These therapies include combinations with bile acid sequestrants (cholestyramine, colestipol, colesevelam), ezetimibe, niacin, plant sterols, fibrates (fenofibrate, bezafibrate, gemfibrozil), and prescription omega-3 fatty acids. Therapeutic approaches which incorporate the use of multiple drugs combinations for dyslipidemia treatment should be more widely adopted since combination therapy might offer a means to increase the number of patients able to meet their lipoprotein goals according to the guidelines. However, it has to be stated that for most of these combination therapies data on cardiovascular outcomes are still lacking. PMID:19682080

  1. Antifungal Treatment in Stem Cell Transplantation Centers in Turkey

    PubMed Central

    Akan, Hamdi; Atilla, Erden

    2016-01-01

    Despite the development of various guidelines, the approach to antifungal treatment in stem cell transplantation centers differs according to country or even between centers. This led to the development of another survey that aims to understand the antifungal treatment policies of Turkish stem cell transplantation centers. Although there has been an increasing trend towards the use of diagnostic-based treatments in Turkey in the last few years, empirical treatment is still the main approach. The practices of the stem cell transplantation centers reflect the general trends and controversies in this area, while there is a considerable use of antifungal combination therapy. PMID:25913124

  2. Combination stem cell therapy for heart failure

    PubMed Central

    2010-01-01

    Patients with congestive heart failure (CHF) that are not eligible for transplantation have limited therapeutic options. Stem cell therapy such as autologous bone marrow, mobilized peripheral blood, or purified cells thereof has been used clinically since 2001. To date over 1000 patients have received cellular therapy as part of randomized trials, with the general consensus being that a moderate but statistically significant benefit occurs. Therefore, one of the important next steps in the field is optimization. In this paper we discuss three ways to approach this issue: a) increasing stem cell migration to the heart; b) augmenting stem cell activity; and c) combining existing stem cell therapies to recapitulate a "therapeutic niche". We conclude by describing a case report of a heart failure patient treated with a combination stem cell protocol in an attempt to augment beneficial aspects of cord blood CD34 cells and mesenchymal-like stem cells. PMID:20398245

  3. Mixture dynamics: Combination therapy in oncology.

    PubMed

    Gabrielsson, Johan; Gibbons, Francis D; Peletier, Lambertus A

    2016-06-10

    In recent years combination therapies have become increasingly popular in most therapeutic areas. We present a qualitative and quantitative approach and elucidate some of the challenges and solutions to a more optimal therapy. For tumor growth this involves the study of semi-mechanistic cell-growth/kill models with multiple sites of action. We introduce such models and analyze their dynamic properties using simulations and mathematical analysis. This is done for two specific case studies, one involving a single compound and one a combination of two compounds. We generalize the notion of Tumor Static Concentration to cases when two compounds are involved and develop a graphical method for determining the optimal combination of the two compounds, using ideas akin to those used in studies employing isobolograms. In studying the dynamics of the second case study we focus, not only on the different concentrations, but also on the different dosing regimens and pharmacokinetics of the two compounds. PMID:27050307

  4. Combination therapy for the treatment of dyslipidemia.

    PubMed

    Streja, Dan

    2004-03-01

    Statins have been proven to reduce cardiovascular risk, and guidelines for cardiovascular prevention recommend statin therapy in a wide range of patients. However, in spite of the dramatic success in large randomized clinical trials, two thirds of patients administered statins are not protected against cardiovascular events. This has prompted a search for additional targets for therapy. The pandemic of metabolic syndrome and type 2 diabetes has led to a dramatic increase in the prevalence of dyslipidemia. This, in turn, has prompted a resurgence of the search for drugs and algorithms that favorably affect high-density lipoprotein (HDL) and very low-density lipoprotein (VLDL) metabolism and function. Fibrates are the best-studied class of agents to be used as an addition to statins since they have also been proven to reduce clinical events as a monotherapy. However, there is a need for large safety trials of statin-fibrate combination therapy. Statin-niacin combination therapy has proven to be safe and effective in altering lipoprotein pattern. Randomized clinical trials and more research on the mechanism of action of niacin are necessary. Inhibitors of cholesterol ester transfer protein and HDL therapy drugs are in early developmental stages, and are the most promising potential additions to the current arsenal. PMID:15083597

  5. Combination Therapy Accelerates Diabetic Wound Closure

    PubMed Central

    Allen Jr., Robert J.; Soares, Marc A.; Haberman, Ilyse D.; Szpalski, Caroline; Schachar, Jeffrey; Lin, Clarence D.; Nguyen, Phuong D.; Saadeh, Pierre B.; Warren, Stephen M.

    2014-01-01

    Background Non-healing foot ulcers are the most common cause of non-traumatic amputation and hospitalization amongst diabetics in the developed world. Impaired wound neovascularization perpetuates a cycle of dysfunctional tissue repair and regeneration. Evidence implicates defective mobilization of marrow-derived progenitor cells (PCs) as a fundamental cause of impaired diabetic neovascularization. Currently, there are no FDA-approved therapies to address this defect. Here we report an endogenous PC strategy to improve diabetic wound neovascularization and closure through a combination therapy of AMD3100, which mobilizes marrow-derived PCs by competitively binding to the cell surface CXCR4 receptor, and PDGF-BB, which is a protein known to enhance cell growth, progenitor cell migration and angiogenesis. Methods and Results Wounded mice were assigned to 1 of 5 experimental arms (n = 8/arm): saline treated wild-type, saline treated diabetic, AMD3100 treated diabetic, PDGF-BB treated diabetic, and AMD3100/PDGF-BB treated diabetic. Circulating PC number and wound vascularity were analyzed for each group (n = 8/group). Cellular function was assessed in the presence of AMD3100. Using a validated preclinical model of type II diabetic wound healing, we show that AMD3100 therapy (10 mg/kg; i.p. daily) alone can rescue diabetes-specific defects in PC mobilization, but cannot restore normal wound neovascularization. Through further investigation, we demonstrate an acquired trafficking-defect within AMD3100-treated diabetic PCs that can be rescued by PDGF-BB (2 μg; topical) supplementation within the wound environment. Finally, we determine that combination therapy restores diabetic wound neovascularization and accelerates time to wound closure by 40%. Conclusions Combination AMD3100 and PDGF-BB therapy synergistically improves BM PC mobilization and trafficking, resulting in significantly improved diabetic wound closure and neovascularization. The success of this

  6. The advantages of topical combination therapy in the treatment of inflammatory dermatomycoses.

    PubMed

    Havlickova, Blanka; Friedrich, Markus

    2008-09-01

    Dermatomycoses are contagious superficial fungal infections, which are highly prevalent in developed and developing countries. Caused by a range of Epidermophyton, Microsporum and Trichophyton species, dermatomycoses manifest on glabrous skin as 'ringworm', an annular scaly lesion with a variable inflammatory component. Itch is the chief subjective symptom, particularly in tinea cruris. Unless lesions are extensive or resistant to local therapy, dermatomycoses of glabrous skin are treated with topical antifungal agents, such as imidazoles and allylamines. Studies show, however, that the addition of a topical corticosteroid to imidazole therapy increases the bioavailability and prolongs the activity of the antimycotic, while rapidly reducing inflammatory symptoms. Travocort is a combination of 1% isoconazole nitrate (ISN), a broad-spectrum imidazole with established antimicrobial activity and antimycotic efficacy, and 0.1% diflucortolone valerate (DFV), a potent topical corticosteroid with low systemic absorption and therefore a low risk of systemic glucocorticoid side-effects. In randomised, double-blind controlled clinical trials, Travocort therapy showed a more rapid onset of action, faster relief of itch and other inflammatory symptoms, improved overall therapeutic benefits and better mycological cure rate during the first 2 weeks of treatment compared with ISN monotherapy. Travocort is well tolerated and, because of prolonged ISN retention in the skin, provides antifungal protection against reinfection for some weeks after therapy. PMID:18783560

  7. Emerging targets for combination therapy in melanomas.

    PubMed

    Saito, Renata de Freitas; Tortelli, Tharcísio Citrângulo; Jacomassi, Mayara D'Auria; Otake, Andréia Hanada; Chammas, Roger

    2015-11-14

    Cutaneous melanomas are often difficult to treat when diagnosed in advanced stages. Melanoma cells adapt to survive in extreme environmental conditions and are among the tumors with larger genomic instability. Here we discuss some intrinsic and extrinsic mechanisms of resistance of melanoma cells to both conventional and target therapies, such as autophagy, adaptation to endoplasmic reticulum stress, metabolic reprogramming, mechanisms of tumor repopulation and the role of extracellular vesicles in this later phenomenon. These biological processes are potentially targetable and thus provide a platform for research and discovery of new drugs for combination therapy to manage melanoma patient treatment. PMID:26450371

  8. Combined Therapy of Gastrointestinal Stromal Tumors.

    PubMed

    Rutkowski, Piotr; Hompes, Daphne

    2016-10-01

    Radical surgery is the mainstay of therapy for primary resectable, localized gastrointestinal stromal tumors (GIST). Nevertheless, approximately 40% to 50% of patients with potentially curative resections develop recurrent or metastatic disease. The introduction of imatinib mesylate has revolutionized the therapy of advanced (inoperable and/or metastatic) GIST and has become the standard of care in treatment of patients with advanced GIST. This article discusses the proper selection of candidates for adjuvant and neoadjuvant treatment in locally advanced GIST, exploring the available evidence behind the combination of preoperative imatinib and surgery. PMID:27591496

  9. Fixed-dose combination therapy for psoriasis.

    PubMed

    Guenther, Lyn C

    2004-01-01

    Fixed-dose combination therapy offers stable products containing two or more medications with different mechanisms of action and safety profiles. It is also convenient for patients since only one product rather than two or more needs to be applied. Topical corticosteroids are often the mainstay of therapy in psoriasis. Diprosalic and Nerisalic contain a topical corticosteroid (betamethasone dipropionate and diflucortolone, respectively) and salicylic acid. A left/right study showed that both products have comparable efficacy. It has also been shown that betamethasone dipropionate + salicylic acid ointment has similar efficacy to clobetasol and calcipotriene (calcipotriol) ointments. Betamethasone dipropionate + salicylic acid lotion has similar efficacy to clobetasol lotion. Faster improvement of scaling, itching, and redness was noted with betamethasone dipropionate + salicylic acid lotion compared with betamethasone dipropionate alone. Dovobet (Daivobet) ointment is a fixed-dose combination product containing betamethasone dipropionate and calcipotriene. Clinical studies have shown that it has greater efficacy and a faster speed of onset than the individual components or tacalcitol. Once daily and twice daily treatments have similar efficacy. Psoriasis Area and Severity Index reductions of approximately 40% after 1 week and 70% after 4 weeks of therapy were consistently noted in six large international studies involving >6000 patients. Betamethasone dipropionate + calcipotriene treatment is associated with approximately 75% less adverse cutaneous events as compared with tacalcitol, 50% less compared with calcipotriene, and a similar number as treatment with betamethasone dipropionate. PMID:15109271

  10. Combination therapy for metastatic renal cell carcinoma

    PubMed Central

    Buonerba, Carlo; Di Lorenzo, Giuseppe

    2016-01-01

    Current therapy for metastatic clear cell renal cell carcinoma (RCC) consists of the serial administration of single agents. Combinations of VEGF and mTOR inhibitors have been disappointing in previous randomized trials. However, the combination of lenvatinib, a multitargeted agent that inhibits VEGF as well as FGF receptors, and everolimus demonstrated promising results in a randomized phase II trial. Moreover, the emergence of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors has spawned the investigation of combinations of these agents with VEGF inhibitors and cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors. These ongoing phase III trials in conjunction with the development of predictive biomarkers and agents inhibiting novel therapeutic targets may provide much needed advances in this still largely incurable disease. PMID:27047959

  11. Empirical antifungal therapy with an echinocandin in critically-ill patients: prospective evaluation of a pragmatic Candida score-based strategy in one medical ICU

    PubMed Central

    2014-01-01

    Background Invasive candidiasis (IC) is a life-threatening ICU-acquired infection. A strong correlation between time to antifungal therapy (AFT) administration and outcome has been established. Empirical therapy benefit should be balanced with the risk of echinocandin overuse. We assessed therefore a decision rule that aimed at guiding empirical therapy. Methods A 45-month prospective cohort study in a teaching medical ICU. All of the patients with suspected IC (uncontrolled sepsis despite broad spectrum antibiotics without any bacterial proven infection in patients with Candida score ≥ 3 points including multifocal Candida sp. colonization) were eligible. The primary endpoint was proven IC diagnosis (i.e., candidemia) following treatment onset. Timing of AFT administration was also investigated in those latter patients. Antifungal therapy step-down and discontinuation was done according to international guidelines in patients with candidemia. Otherwise, echinocandin discontinuation was encouraged in patients without proven IC, excepting when a clinical improvement was achieved without any other explanation that antifungals initiation (i.e., probable IC). In addition, a survival multivariate analysis using a Cox model was conducted. Results Fifty-one patients were given an echinocandin with respect to our decision rule. Among them, candidemia was diagnosed thereafter in 9 patients. Over the same period, antifungal therapy was triggered by candidemia announcement (i.e., definite therapy) in 12 patients who did not fulfill criteria for empirical therapy before. Time elapsed from candidemia onset to echinocandin therapy initiation was shortened (0.4 [0.5] vs. 2.4 [2.8] hours; p = 0.04) when it was given empirically. In addition, 18 patients clinically improved under empirical antifungal therapy without any obvious other explanation, despite IC remained unproven. Moreover, echinocandin exposure duration was independently related to survival in those patients

  12. Antifungal agents.

    PubMed

    Ryder, N S

    1999-12-01

    At this year's ICAAC Meeting, new data on approximately 20 different antifungal agents were presented, while no new agents were disclosed. Drugs in late development include the triazoles, voriconazole (Pfizer Ltd) and Sch-56592 (Schering-Plough Corp), and the echinocandins, caspofungin (Merck & Co Inc) and FK-463 (Fujisawa Pharmaceutical Co Ltd). In contrast to previous years, presentations on these and earlier developmental compounds were relatively modest in scope, with few significant new data. Little new information appeared on the most recent novel class of agents, the sordarins (Glaxo Wellcome plc). Early clinical results were presented for FK-463, showing acceptable tolerability and dose-dependent efficacy in AIDS-associated esophageal candidiasis. A new liposomal formulation of nystatin (Nyotran; Aronex Pharmaceuticals Inc) was shown to be equivalent to conventional amphotericin B in empiric therapy of presumed fungal infection in neutropenic patients, but with reduced toxicity. Intravenous itraconazole (Janssen Pharmaceutica NV) was an effective prophylactic therapy in invasive pulmonary aspergillosis, while oral itraconazole was discussed as a treatment for fungal infection in heart and liver transplant patients. The allylamine compound, terbinafine (Novartis AG), showed good clinical efficacy against fungal mycetoma, a serious tropical infection. A major highlight was the first presentation of inhibitors of fungal efflux pumps as a strategy for overcoming resistance. MC-510027 (milbemycin alpha-9; Microcide Pharmaceuticals Inc) and its derivatives, potentiated the antifungal activity of triazoles and terbinafine in a number of Candida spp. Another pump inhibitor, MC-005172 (Microcide Pharmaceuticals Inc) showed in vivo potentiation of fluconazole in a mouse kidney infection model. Microcide Pharmaceuticals Inc also presented inhibitors of bacterial efflux pumps. PMID:16113946

  13. Combination Therapies in Ophthalmology: Implications for Intravitreal Delivery

    PubMed Central

    Peyman, Gholam A.; Hosseini, Kamran

    2011-01-01

    Most pathological processes involve complex molecular pathways that can only be modified or blocked by a combination of medications. Combination therapy has become a common practice in medicine. In ophthalmology, this approach has been used effectively to treat bacterial, fungal, proliferative/neoplastic, and inflammatory eye diseases and vascular proliferation. Combination therapy also encompasses the synergistic effect of electromagnetic radiation and medications. However, combination therapy can augment inherent complications of individual interventions, therefore vigilance is required. Complications of combination therapy include potential incompatibility among compounds and tissue toxicity. Understanding these effects will assist the ophthalmologist in his decision to maximize the benefits of combination therapy while avoiding an unfavorable outcome. PMID:22454705

  14. Management of symptomatic erosive-ulcerative lesions of oral lichen planus in an adult Egyptian population using Selenium-ACE combined with topical corticosteroids plus antifungal agent

    PubMed Central

    Belal, Mahmoud Helmy

    2015-01-01

    Aim: Oral lichen planus (OLP) is a chronic mucocutaneous disease with an immunological etiology. This study was conducted to evaluate the effect of selenium combined with Vitamins A, C & E (Selenium-ACE) in the treatment of erosive-ulcerative OLP as an adjunctive to topical corticosteroids plus antifungal agent. Subjects and Methods: Thirty patients with a confirmed clinical and histopathologic diagnosis of OLP participated in this clinical trial. Patients were randomly allocated into one of three groups and treated as follows: (I) Topical corticosteroids, (II) topical corticosteroids plus antifungal, and (III) SE-ACE combined with topical corticosteroids plus antifungal. The patients were followed for 6 weeks. The pain and severity of the lesions were recorded at the initial and follow-up visits. All recorded data were analyzed using paired t-test and ANOVA test. A P ≤ 0.05 was considered significant. Results: The experimental groups showed a marked reduction in pain sensation and size of lesions, particularly in the final follow-up period, but there was no significant difference between the first two Groups I and II. However, healing of lesions and improvement of pain sensation was effective in Group III since a significant difference was found favoring Group III over both Groups I and II. Conclusion: No significant difference was found in treating erosive-ulcerative lesions of OLP by topical corticosteroids alone or combined with antifungal. However, when using SE-ACE in combination with topical corticosteroids plus antifungal, this approach may be effective in managing ulcerative lesions of OLP; but more research with a larger sample size and a longer evaluation period may be recommended. PMID:26681847

  15. Combination immunotherapy and photodynamic therapy for cancer

    NASA Astrophysics Data System (ADS)

    Hamblin, Michael R.; Castano, Ana P.; Mroz, Pawel

    2006-02-01

    Cancer is a leading cause of death among modern people largely due to metastatic disease. The ideal cancer treatment should target both the primary tumor and the metastases with minimal toxicity towards normal tissue. This is best accomplished by priming the body's immune system to recognize the tumor antigens so that after the primary tumor is destroyed, distant metastases will also be eradicated. Photodynamic therapy (PDT) involves the IV administration of photosensitizers followed by illumination of the tumor with red light producing reactive oxygen species leading to vascular shutdown and tumor cell death. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, generation of tumor-specific antigens, and induction of heat-shock proteins. Combination regimens using PDT and immunostimulating treatments are likely to even further enhance post-PDT immunity. These immunostimulants are likely to include products derived from pathogenic microorganisms that are effectively recognized by Toll-like receptors and lead to upregulation of transcription factors for cytokines and inflammatory mediators. The following cascade of events causes activation of macrophages, dendritic and natural killer cells. Exogenous cytokine administration can be another way to increase PDT-induced immunity as well as treatment with a low dose of cyclophosphamide that selectively reduces T-regulatory cells. Although so far these combination therapies have only been used in animal models, their use in clinical trials should receive careful consideration.

  16. Systemic therapy and synergies by combination.

    PubMed

    Wörns, Marcus-Alexander

    2013-01-01

    After years of therapeutic nihilism due to the inefficacy of conventional cytotoxic chemotherapy, the multikinase inhibitor sorafenib was the first agent to demonstrate a significant improvement in the survival of patients with advanced hepatocellular carcinoma (HCC). However, survival benefits on sorafenib treatment remain modest in clinical practice and developing more effective systemic therapies is challenging. No other targeted agent or regimen has proven efficacy to improve survival in a phase III trial in the first- or second-line setting, and no standard treatment option currently exists outside of clinical trials for patients with acquired resistance or intolerance to sorafenib. In contrast to other malignancies, no oncogene addiction has been identified in hepatocarcinogenesis thus far, which may explain why currently tested agents do not achieve sustained partial or complete response in the majority of patients. Several agents with mainly antiangiogenic properties are currently in phase II and III development, including brivanib, ramucirumab, everolimus, tivantinib and resminostat. In addition, the role of molecularly targeted therapy (MTT) in earlier stages of the disease in combination with transcatheter arterial chemoembolization or in the adjuvant setting after potentially curative approaches is under investigation. The identification of the key driver mutations and the assessment of relevant targets for specific subpopulations of patients according to their biomarker-based profile will hopefully lead to a more personalized medicine. This article attempts to provide a concise overview on recent developments of MTT in the phase II-III setting in advanced HCC with an additional focus on synergistic combinations and combined treatment approaches. PMID:23797131

  17. Searching new antifungals: The use of in vitro and in vivo methods for evaluation of natural compounds.

    PubMed

    Scorzoni, Liliana; Sangalli-Leite, Fernanda; de Lacorte Singulani, Junya; de Paula E Silva, Ana Carolina Alves; Costa-Orlandi, Caroline Barcelos; Fusco-Almeida, Ana Marisa; Mendes-Giannini, Maria José Soares

    2016-04-01

    In the last decades, the increased number of immunocompromised patients has led to the emergence of many forms of fungal infections. Furthermore, there are a restricted arsenal of antifungals available and an increase in the development of resistance to antifungal drugs. Because of these disadvantages, the search for new antifungal agents in natural sources has increased. The development of these new antifungal drugs involves various steps and methodologies. The evaluation of the in vitro antifungal activity and cytotoxicity are the first steps in the screening. There is also the possibility of antifungal combinations to improve the therapy and reduce toxicity. Despite that, the application of the new antifungal candidate could be used in association with photodynamic therapy or using nanotechnology as an ally. In vivo tests can be performed to evaluate the efficacy and toxicity using conventional and alternative animal models. In this work, we review the methods available for the evaluation of the antifungal activity and safety of natural products, as well as the recent advances of new technology in the application of natural products for antifungal therapy. PMID:26853122

  18. Clinical experience of the use of voriconazole, caspofungin or the combination in primary and salvage therapy of invasive aspergillosis in haematological malignancies.

    PubMed

    Raad, Issam I; Zakhem, Aline El; Helou, Gilbert El; Jiang, Ying; Kontoyiannis, Dimitrios P; Hachem, Ray

    2015-03-01

    Invasive aspergillosis (IA) is a life-threatening infection in severely immunocompromised haematological malignancy patients. In this study, the efficacy and safety of caspofungin, voriconazole or the combination as primary and salvage therapy in patients with IA were compared. The study included 181 patients with haematological malignancies and IA who received primary or salvage therapy with caspofungin, voriconazole or the combination. In total, 138 patients who received treatment for ≥7 days were analysed; 86 underwent primary antifungal therapy (15 with caspofungin, 38 with voriconazole and 33 with both). Among the salvage therapy patients, 17 received caspofungin, 24 received voriconazole and 35 received both. In the primary therapy group, no difference in therapy response was found, but caspofungin was associated with higher IA mortality rates. A multivariate competing risk analysis of primary antifungal therapy revealed that voriconazole was independently associated with lower IA-associated mortality rates than caspofungin (hazard ratio=0.2, 95% confidence interval 0.06-0.96; P=0.04). In the salvage therapy group, the three treatment groups had similar responses and IA-associated mortality rates. The combination of voriconazole and caspofungin did not result in better outcomes compared with voriconazole alone, as primary or salvage therapy, in haematological malignancy patients. However, voriconazole was associated with a lower Aspergillus-associated mortality rate compared with caspofungin monotherapy. PMID:25455847

  19. New antifungal agents.

    PubMed

    Gupta, Aditya K; Tomas, Elizabeth

    2003-07-01

    Currently, use of standard antifungal therapies can be limited because of toxicity, low efficacy rates, and drug resistance. New formulations are being prepared to improve absorption and efficacy of some of these standard therapies. Various new antifungals have demonstrated therapeutic potential. These new agents may provide additional options for the treatment of superficial fungal infections and they may help to overcome the limitations of current treatments. Liposomal formulations of AmB have a broad spectrum of activity against invasive fungi, such as Candida spp., C. neoformans, and Aspergillus spp., but not dermatophyte fungi. The liposomal AmB is associated with significantly less toxicity and good rates of efficacy, which compare or exceed that of standard AmB. These factors may provide enough of an advantage to patients to overcome the increased costs of these formulations. Three new azole drugs have been developed, and may be of use in both systemic and superficial fungal infections. Voriconazole, ravuconazole, and posaconazole are triazoles, with broad-spectrum activity. Voriconazole has a high bioavailability, and has been used with success in immunocompromised patients with invasive fungal infections. Ravuconazole has shown efficacy in candidiasis in immunocompromised patients, and onychomycosis in healthy patients. Preliminary in vivo studies with posaconazole indicated potential use in a variety of invasive fungal infections including oropharyngeal candidiasis. Echinocandins and pneumocandins are a new class of antifungals, which act as fungal cell wall beta-(1,3)-D-glucan synthase enzyme complex inhibitors. Caspofungin (MK-0991) is the first of the echinocandins to receive Food and Drug Administration approval for patients with invasive aspergillosis not responding or intolerant to other antifungal therapies, and has been effective in patients with oropharyngeal and esophageal candidiasis. Standardization of MIC value determination has improved the

  20. Artemisinin combination therapy for vivax malaria?

    PubMed Central

    Douglas, Nicholas M.; Anstey, Nicholas M.; Angus, Brian J.; Nosten, Francois; Price, Ric N.

    2012-01-01

    Early parasitological diagnosis and treatment with artemisinin-based combination therapies (ACT) are seen as key components of global malaria elimination programmes. In general, use of ACTs has been limited to patients with falciparum malaria whereas blood-stage P. vivax infections are mostly still treated with chloroquine. We review the evidence for the relative benefits and disadvantages of the existing ‘separate’ treatment approach versus a ‘unified’ ACT-based strategy for treating P. falciparum and P. vivax infections in regions where both species are endemic (co-endemic). The ‘separate’ treatment scenario is justifiable where P. vivax remains sensitive to chloroquine and providing that diagnostic tests reliably distinguish P. vivax from P. falciparum. However, with the high frequency of misdiagnosis in routine practice and the rise and spread of chloroquine-resistant P. vivax, there may be a compelling rationale for a unified ACT-based strategy for vivax and falciparum malaria in all co-endemic areas. Analyses of the cost-effectiveness of ACTs for both Plasmodium species are required to assess the role of these drugs in vivax malaria control and elimination efforts. PMID:20510281

  1. Combined therapy for post-irradiation infection

    SciTech Connect

    Elliott, T.B.; Madonna, G.S.; Ledney, G.D.; Brook, I.

    1989-01-01

    Increased susceptibility to bacterial infection, probably by translocation from the intestinal flora, can be a lethal complication for 2-3 weeks after exposure to ionizing radiation. Antibiotics alone do not provide adequate therapy for induced infections in neutropenic mice. Because some substances that are derived from bacterial cell walls activate macrophages and stimulate nonspecific resistance to infection, such agents might be used to prevent or treat postirradiation infections. In this study, a cell-wall glycolipid, trehalose dimycolate (TDM), was evaluated together with a third-generation cephalosporin, ceftriaxone, for their separate and combined effects on survival of B6D2F1 female mice that were exposed to the sublethal dose of 7.0 Gy Co radiation and challenged s.c. with lethal doses of Klebsiella pneumoniae. A single injection of TDM inoculated i.p. 1 hr postirradiation increased 30-day survival to 80% after a lethal challenge by K. pneumoniae 4 days later. When the challenge dose of K. pneumoniae was increased to 5000 Ld 50/30 on Day 4, all mice died.

  2. Therapeutic monitoring of experimental invasive pulmonary aspergillosis by ultrafast computerized tomography, a novel, noninvasive method for measuring responses to antifungal therapy.

    PubMed Central

    Walsh, T J; Garrett, K; Feurerstein, E; Girton, M; Allende, M; Bacher, J; Francesconi, A; Schaufele, R; Pizzo, P A

    1995-01-01

    Pulmonary infiltrates in neutropenic hosts with invasive aspergillosis are due to vascular invasion and hemorrhagic infarction. In order to measure the effect of antifungal compounds on this organism-mediated tissue injury, we monitored the course of pulmonary infiltrates by serial ultrafast computerized tomography (UFCT) in persistently granulocytopenic rabbits with experimental invasive pulmonary aspergillosis. The course of pulmonary lesions measured by serial UFCT scans was compared with those measured by conventional chest radiography, histopathological resolution of lesions, and microbiological clearance of Aspergillus fumigatus. Treatment groups included either amphotericin B colloidal dispersion in dosages of 1, 5, and 10 mg/kg of body weight per day intravenously or conventional desoxycholate amphotericin B at 1 mg/kg/day intravenously. Therapeutic monitoring of pulmonary lesions by UFCT demonstrated a significant dose-response relationship. Lesions continued to progress in untreated controls, whereas lesions in treated rabbits initially increased and then decreased in response to antifungal therapy in a dosage-dependent manner (P < or = 0.05 to P < or = 0.005, depending upon the groups compared). This same trend of resolution of lesions in response to antifungal therapy was also demonstrated by postmortem examination and by microbiological clearance of the organism. These data indicated that amphotericin B colloidal dispersion at 5 and 10 mg/kg/day exerted a more rapid rate of clearance of lesions than conventional amphotericin B. UFCT was more sensitive than conventional chest radiography in detecting lesions due to invasive pulmonary aspergillosis (P < 0.05 to P < 0.005, depending upon the groups compared). These findings establish a correlation among UFCT-defined lesions, microbiological response, and resolution of pathologically defined lesions in experimental invasive pulmonary aspergillosis. Serial monitoring of UFCT-defined lesions of aspergillosis

  3. Chemosensitization as a Means to Augment Commercial Antifungal Agents

    PubMed Central

    Campbell, Bruce C.; Chan, Kathleen L.; Kim, Jong H.

    2012-01-01

    Antimycotic chemosensitization and its mode of action are of growing interest. Currently, use of antifungal agents in agriculture and medicine has a number of obstacles. Foremost of these is development of resistance or cross-resistance to one or more antifungal agents. The generally high expense and negative impact, or side effects, associated with antifungal agents are two further issues of concern. Collectively, these problems are exacerbated by efforts to control resistant strains, which can evolve into a treadmill of higher dosages for longer periods. This cycle in turn, inflates cost of treatment, dramatically. A further problem is stagnation in development of new and effective antifungal agents, especially for treatment of human mycoses. Efforts to overcome some of these issues have involved using combinations of available antimycotics (e.g., combination therapy for invasive mycoses). However, this approach has had inconsistent success and is often associated with a marked increase in negative side effects. Chemosensitization by natural compounds to increase effectiveness of commercial antimycotics is a somewhat new approach to dealing with the aforementioned problems. The potential for safe natural products to improve antifungal activity has been observed for over three decades. Chemosensitizing agents possess antifungal activity, but at insufficient levels to serve as antimycotics, alone. Their main function is to disrupt fungal stress response, destabilize the structural integrity of cellular and vacuolar membranes or stimulate production of reactive oxygen species, augmenting oxidative stress and apoptosis. Use of safe chemosensitizing agents has potential benefit to both agriculture and medicine. When co-applied with a commercial antifungal agent, an additive or synergistic interaction may occur, augmenting antifungal efficacy. This augmentation, in turn, lowers effective dosages, costs, negative side effects and, in some cases, countermands resistance

  4. Therapeutic usefulness of a corticosteroid, antibacterial and antifungal combination in skin diseases of various origins.

    PubMed

    Marras, F

    1985-01-01

    Forty-one patients with skin diseases of various origins were treated with an extempore combination of three creams containing clobetasone butyrate, sodium fusidate and ketoconazole. A mixture of the creams was applied once to 3-times daily for periods ranging from 5 to 15 days (mean 8.5 days). Assessments were made before, during and at the end of the treatment period using a symptom severity rating scale. The results showed that all symptoms regressed to a significant extent and by the end of the treatment period there had been complete disappearance or improvement with satisfactory remission in 97.6% of the patients. Local tolerance was excellent or good in all patients and there were no reports of any side-effects. PMID:4059294

  5. Aspergillus tanneri sp. nov., a new pathogen that causes invasive disease refractory to antifungal therapy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Two fatal IA cases and treatment regimens were reviewed. The fungus was characterized by mycological and molecular approaches. The combined sequence data of three loci, Mcm7, RPB2 and Tsr1, were used for phylogenetic analysis. Virulence of the new species was analyzed in corticosteroid treated BALB/...

  6. Clinical effects of topical antifungal therapy in chronic rhinosinusitis: a randomized, double-blind, placebo-controlled trial of intranasal fluconazole

    PubMed Central

    Hashemian, Farshad; Hashemian, Farnaz; Molaali, Najmeh; Rouini, Mohammadreza; Roohi, Elnaz; Torabian, Saadat

    2016-01-01

    Several studies have been in favor of fungi as a possible pathogenesis of chronic rhinosinusitis (CRS); however, to date, there is no scientific consensus about the use of antifungal agents in disease management. The aim of the present study was to investigate the efficacy of intranasal fluconazole in improving disease symptoms and objective outcomes of patients with CRS. A randomized, double-blind, placebo-controlled study was conducted on 54 patients who were diagnosed with CRS and had not been responsive to routine medical treatments. They were randomly assigned to receive either fluconazole nasal drop 0.2 % or placebo in addition to the standard regimen for a duration of 8 weeks. Patients' outcomes were evaluated according to Sino-Nasal Outcome Test 20 (SNOT-20), endoscopic scores, and Computed Tomography (CT) scores. No statistically significant difference was found in SNOT-20 (p = 0.201), endoscopic (p = 0.283), and CT scores (p = 0.212) of the patients at baseline and after 8-week course of treatment between drug and placebo group. Similar to many studies, the use of topical antifungal treatment for patients with CRS was not shown to be significantly effective. However, further studies are needed to obtain high levels of consistent evidence in order to arrive at a decision whether antifungal therapy is effective in management of CRS or not. PMID:27065776

  7. Chloroquine sensitizes biofilms of Candida albicans to antifungal azoles.

    PubMed

    Shinde, Ravikumar Bapurao; Raut, Jayant Shankar; Chauhan, Nitin Mahendra; Karuppayil, Sankunny Mohan

    2013-01-01

    Biofilms formed by Candida albicans, a human pathogen, are known to be resistant to different antifungal agents. Novel strategies to combat the biofilm associated Candida infections like multiple drug therapy are being explored. In this study, potential of chloroquine to be a partner drug in combination with four antifungal agents, namely fluconazole, voriconazole, amphotericin B, and caspofungin, was explored against biofilms of C. albicans. Activity of various concentrations of chloroquine in combination with a particular antifungal drug was analyzed in a checkerboard format. Growth of biofilm in presence of drugs was analyzed by XTT-assay, in terms of relative metabolic activity compared to that of drug free control. Results obtained by XTT-metabolic assay were confirmed by scanning electron microscopy. The interactions between chloroquine and four antifungal drugs were determined by calculating fractional inhibitory concentration indices. Azole resistance in biofilms was reverted significantly (p<0.05) in presence of 250μg/mL of chloroquine, which resulted in inhibition of biofilms at very low concentrations of antifungal drugs. No significant alteration in the sensitivity of biofilms to caspofungin and amphotericin B was evident in combination with chloroquine. This study for the first time indicates that chloroquine potentiates anti-biofilm activity of fluconazole and voriconazole. PMID:23602464

  8. Adjuvant antifungal therapy using tissue tolerable plasma on oral mucosa and removable dentures in oral candidiasis patients: a randomised double-blinded split-mouth pilot study.

    PubMed

    Preissner, Saskia; Kastner, Isabell; Schütte, Eyke; Hartwig, Stefan; Schmidt-Westhausen, Andrea Maria; Paris, Sebastian; Preissner, Robert; Hertel, Moritz

    2016-07-01

    Extended use of antimycotics in oral candidiasis therapy gives rise to problems related to fungal drug resistance. The aim of this pilot study was to investigate the efficacy of tissue tolerable plasma (TTP) in denture stomatitis patients. It was hypothesised that (I): erythema and (IIa): complaint remission would be accelerated and (IIb): colony forming unit (CFU) reduction would be improved. The halves of the upper jaws of eight patients were randomly assigned to control (nystatin, chlorhexidine and placebo treatment) and test sides (nystatin, chlorhexidine and TTP administered six times each 7 days). The patients and the investigators, who were different from the therapists, were both blinded. Compared to the control sides, the erythema surface was reduced significantly more extensively on the test sides between 2 and 6 weeks of antifungal therapy (P ≤ 0.05). Visual analogue scale values and the frequency of moderate or heavy growth of Candida post-treatment did not differ significantly between both sides (P > 0.05). The primary hypothesis was confirmed, which may be interpreted as an accelerated remission. As drug therapy is usually limited to the time in which signs of infection are present, TTP might help reducing antifungal use. Even though the secondary hypotheses were not confirmed, persistence of Candida might be only colonisation. PMID:26932256

  9. Combining Locoregional Therapies in the Treatment of Hepatocellular Carcinoma

    PubMed Central

    Higgins, Mikhail C. S. S.; Soulen, Michael C.

    2013-01-01

    In an effort to promote more durable local control of larger lesions, thermal ablation has been combined with chemical ablative techniques and with vaso-occlusive procedures such as chemoembolization and bland embolization in an effort to mitigate the limitations inherent in the use of any single treatment for hepatocellular carcinoma (HCC) >3 cm. The heat-sink effect is the underlying principle for combining vaso-occlusive therapies with ablative techniques. Combination therapies do present viable options for abrogating tumor progression and potentially downsizing tumors to facilitate transplant. We discuss the two most commonly used combination locoregional therapies by the interventionalist and the evidence defining the best techniques in practice. PMID:24436520

  10. Combination therapy for erectile dysfunction: an update review

    PubMed Central

    Dhir, Rohit R; Lin, Hao-Cheng; Canfield, Steven E; Wang, Run

    2011-01-01

    The introduction of oral phosphodiesterase-5 inhibitors (PDE5Is) in the late 1990s and early 2000s revolutionized the field of sexual medicine and PDE5Is are currently first-line monotherapy for erectile dysfunction (ED). However, a significant proportion of patients with complex ED will be therapeutic non-responders to PDE5I monotherapy. Combination therapy has recently been adopted for more refractory cases of ED, but a critical evaluation of current combination therapies is lacking. A thorough PubMed and Cochrane Library search was conducted focusing on the effectiveness of combination therapies for ED in therapeutic non-responders to PDE5I therapy. Journal articles spanning the time period between January 1990 and December 2010 were reviewed. Criteria included all pertinent review articles, randomized controlled trials, cohort studies and retrospective analyses. References from retrieved articles were also manually scanned for additional relevant publications. Published combination therapies include PDE5I plus vacuum erectile device (VED), intraurethral medication, intracavernosal injection (ICI), androgen supplement, α-blocker or miscellaneous combinations. Based on this review, some of these combination treatments appeared to be quite effective in preliminary testing. Caution must be advised, however, as the majority of combination therapy articles in the last decade have numerous limitations including study biases and small subject size. Regardless of limitations, present combination therapy research provides a solid foundation for future studies in complex ED management. PMID:21423198

  11. Pirfenidone enhances the efficacy of combined radiation and sunitinib therapy

    SciTech Connect

    Choi, Seo-Hyun; Nam, Jae-Kyung; Jang, Junho; Lee, Hae-June Lee, Yoon-Jin

    2015-06-26

    Radiotherapy is a widely used treatment for many tumors. Combination therapy using anti-angiogenic agents and radiation has shown promise; however, these combined therapies are reported to have many limitations in clinical trials. Here, we show that radiation transformed tumor endothelial cells (ECs) to fibroblasts, resulting in reduced vascular endothelial growth factor (VEGF) response and increased Snail1, Twist1, Type I collagen, and transforming growth factor (TGF)-β release. Irradiation of radioresistant Lewis lung carcinoma (LLC) tumors greater than 250 mm{sup 3} increased collagen levels, particularly in large tumor vessels. Furthermore, concomitant sunitinib therapy did not show a significant difference in tumor inhibition versus radiation alone. Thus, we evaluated multimodal therapy that combined pirfenidone, an inhibitor of TGF-induced collagen production, with radiation and sunitinib treatment. This trimodal therapy significantly reduced tumor growth, as compared to radiation alone. Immunohistochemical analysis revealed that radiation-induced collagen deposition and tumor microvessel density were significantly reduced with trimodal therapy, as compared to radiation alone. These data suggest that combined therapy using pirfenidone may modulate the radiation-altered tumor microenvironment, thereby enhancing the efficacy of radiation therapy and concurrent chemotherapy. - Highlights: • Radiation changes tumor endothelial cells to fibroblasts. • Radio-resistant tumors contain collagen deposits, especially in tumor vessels. • Pirfenidone enhances the efficacy of combined radiation and sunitinib therapy. • Pirfenidone reduces radiation-induced collagen deposits in tumors.

  12. Investigation of different combinations of estrogen therapy and radiation therapy on prostatic adenocarcinoma (R-3327)

    SciTech Connect

    Camuzzi, F.; Block, N.L.; Stover, B.; Gottlieb, C.; Charyulu, K.; Politano, V.A.

    1980-05-01

    The relative effectiveness of different combinations of estrogen therapy and radiation therapy against the R-3327 prostatic adenocarcinoma of the Copenhagen rat was studied. Because of similar actions of estrogens and radiation in the cell cycle, and possibly antagonistic effects reported in the clinical literature, we looked for an antagonism between these two therapeutic modalities. Radiation therapy consistently showed a greater tumor inhibitory effect than estrogen therapy alone at the dose tested. Combinations of radiation therapy with hormonal manipulation did not appear to show a greater inhibition of tumor growth than radiation therapy alone. There also did not appear to be an antagonistic effect between these two modalities in this system.

  13. Combination Therapy for Advanced Kaposi Sarcoma

    Cancer.gov

    In this clinical trial, adult patients with any form of advanced Kaposi sarcoma will be treated with liposomal doxorubicin and bevacizumab every 3 weeks for a maximum of six treatments.  Patients who respond to this therapy or have stable disease will rec

  14. Interlaboratory and Interstudy Reproducibility of a Novel Lateral-Flow Device and Influence of Antifungal Therapy on Detection of Invasive Pulmonary Aspergillosis

    PubMed Central

    Najvar, Laura K.; Bocanegra, Rosie; Kirkpatrick, William R.; Patterson, Thomas F.; Thornton, Christopher R.

    2013-01-01

    Interest in lateral-flow devices (LFDs) as potential point-of-care assays for the diagnosis of infectious diseases has increased. Our objective was to evaluate the interlaboratory and interstudy reproducibility and the effects of antifungal therapy on an LFD developed for invasive pulmonary aspergillosis (IPA) detection. An established neutropenic guinea pig model of IPA caused by Aspergillus fumigatus was used. At predetermined time points (1 h and 3, 5, and 7 days postinoculation), blood and bronchoalveolar lavage (BAL) fluid were collected from infected and uninfected animals. In a separate experiment, guinea pigs were treated with posaconazole (10 mg/kg of body weight orally [p.o.] twice a day [BID]), voriconazole (10 mg/kg p.o. BID), liposomal amphotericin B (10 mg/kg intraperitoneally [i.p.] once a day [QD]), or caspofungin (2 mg/kg i.p. QD), and samples were collected on days 7 and 11. Each laboratory independently evaluated the IgG monoclonal antibody-based LFD. Galactomannan and (1→3)-β-d-glucan were also measured using commercially available kits. Good interlaboratory agreement was observed with the LFD, as the results for 97% (32/33) of the serum and 78.8% (26/33) of the BAL fluid samples from infected animals were in agreement. Good interstudy agreement was also observed. The serum sensitivity of each surrogate-marker assay was reduced in animals treated with antifungals. In contrast, these markers remained elevated within the BAL fluids of treated animals, which was consistent with the fungal burden and histopathology results. These results demonstrate that the LFD assay is reproducible between different laboratories and studies. However, the sensitivity of this assay and other markers of IPA may be reduced with serum in the presence of antifungal therapy. PMID:23175252

  15. Diverse array-designed modes of combination therapies in Fangjiomics.

    PubMed

    Liu, Jun; Wang, Zhong

    2015-06-01

    In line with the complexity of disease networks, diverse combination therapies have been demonstrated potential in the treatment of different patients with complex diseases in a personal combination profile. However, the identification of rational, compatible and effective drug combinations remains an ongoing challenge. Based on a holistic theory integrated with reductionism, Fangjiomics systematically develops multiple modes of array-designed combination therapies. We define diverse "magic shotgun" vertical, horizontal, focusing, siege and dynamic arrays according to different spatiotemporal distributions of hits on targets, pathways and networks. Through these multiple adaptive modes for treating complex diseases, Fangjiomics may help to identify rational drug combinations with synergistic or additive efficacy but reduced adverse side effects that reverse complex diseases by reconstructing or rewiring multiple targets, pathways and networks. Such a novel paradigm for combination therapies may allow us to achieve more precise treatments by developing phenotype-driven quantitative multi-scale modeling for rational drug combinations. PMID:25864646

  16. Gene and Stem Cell Therapy: Alone or in Combination?

    PubMed Central

    Rafi, Mohammad A.

    2011-01-01

    Introduction Both gene and stem cell therapies hold great promise in the treatment of many genetic diseases and are currently focus of interest for many investigators. While both approaches are offering great and valuable treatment options for devastating and life-threatening diseases, they hold much greater promise in combination. Methods As there are multiple options in selecting gene transfer vehicles among the non-viral and viral vectors, there are also many options among the different transplantable cell types ranging from lineage-restricted progenitor cells to multipotent and pluripotent stem cells. Here, combination of the gene therapy and stem cell therapy is discussed. Results Several suc-cessful gene and stem cell therapies have been reported both in animal and human trials. Combination of the gene therapy and stem cell therapy can be carried out sequentially where the cell transplantation and the in vivo gene therapy are accomplished one after the other; or, as it is more commonly practiced, they can be carried out as ex vivo gene therapy where the transplantable cells are genetically modified outside the body before being transplanted into the body. Conclusion The combination of the stem-cell technology with gene therapy has the potential of providing both regenerative tissue and therapeutic material simultaneously; therefore, having the benefits of both technologies. PMID:23678430

  17. The effect of antifungal combination on transcripts of a subset of drug-resistance genes in clinical isolates of Candida species induced biofilms.

    PubMed

    Ibrahim, Nermin H; Melake, Nahla A; Somily, Ali M; Zakaria, Azza S; Baddour, Manal M; Mahmoud, Amany Z

    2015-01-01

    Biofilm formation is often associated with increased Candida resistance toward antifungal agents. Therefore, the current study aimed to assess the incidence of biofilm formation among Candida isolates and to investigate the effect of high doses of fluconazole {FLC}, voriconazole {VOC} and amphotericin B {AMB}, singly and in combination on mature biofilms. Moreover, it aimed to assess the expression of selected genes (CDR1, KRE1 and SKN1) responsible for Candida biofilm resistance. The study included 49 patients; samples were collected from the King Khalid Hospital, Riyadh, Saudi Arabia. Isolates were prepared for biofilm formation and quantification using 0.4% (w/v) crystal violet. Minimum Inhibitory concentration (MIC) and fractional inhibitory concentration (FIC) were conducted by the broth microdilution method. Biofilm eradication was evaluated using counting, XTT stain intensity and observed under the inverted microscope. Selected genes were evaluated in Candida biofilms under the effect of antifungal exposure using QPCR. The major isolates were Candida albicans (65.3%) followed by Candida tropicalis and Candida glabrata. 77.6% of the strains were biofilm formers. AMB showed susceptibility in 87.8% of isolates, followed by VOC (77.6%) and FLC (67.3%). MIC50 and MIC90 were (0.03, 0.125), (0.5, 8), (2, >128) μg/ml for AMB, VOC and FLC, respectively. 34.7% and 18.4% of the isolates were antagonistic to AMB/FLC and AMB/VOC, respectively. Mature biofilms of ten selected isolates were found resistant to FLC (1000 μg/ml). VOR and AMB concentration required to inhibit biofilm formation was 16-250 fold higher than the MIC for planktonic cells. Isolates showed significant reduction with antifungal combination when compared with the untreated controls (p value ⩽ 0.01), or using fluconazole alone (p value ⩽ 0.05). High doses of the antifungals were employed to assess the effect on the persisters' selected gene expression. Marked over expression of SKN1 and to a

  18. Hyperbilirubinemia without Transaminitis during Combined Therapy with Daclatasvir and Asunaprevir.

    PubMed

    Baba, Hayato; Tajiri, Kazuto; Nagata, Kohei; Kawai, Kengo; Minemura, Masami; Sugiyama, Toshiro

    2016-01-01

    Daclatasvir (DCV) and asunaprevir (ASV) are direct-acting antivirals (DAAs) used in the treatment of chronic hepatitis C virus (HCV) infection. Combined therapy with DCV and ASV shows high efficacy and safety even in patients with cirrhosis. We encountered a patient exhibiting severe hyperbilirubinemia during combined therapy, which is an unreported side effect of DCV and ASV. A 78-year-old woman with cirrhosis developed hyperbilirubinemia >10 mg/dl without transaminitis 3 weeks after starting combined therapy. We suspected DAAs-induced liver disorder and discontinued treatment, which resulted in the improvement of hyperbilirubinemia. Caution is required in the use of DAAs for patients with advanced cirrhosis. PMID:27504082

  19. Current concepts in combination antibiotic therapy for critically ill patients

    PubMed Central

    Ahmed, Armin; Azim, Afzal; Gurjar, Mohan; Baronia, Arvind Kumar

    2014-01-01

    Widespread emergence of multidrug resistant (MDR) bacterial pathogens is a problem of global dimension. MDR infections are difficult to treat and frequently associated with high mortality. More than one antibiotic is commonly used to treat such infections, but scientific evidence does not favor use of combination therapy in most cases. However, there are certain subgroups where combination therapy may be beneficial, e.g. sepsis due to carbapenem-resistant Enterobacteriaceae (CRE), bacteremic pneumococcal pneumonia, and patients with multiple organ failure. Well-designed prospective studies are needed to clearly define the role of combination therapy in these subgroups. PMID:24914260

  20. Hyperbilirubinemia without Transaminitis during Combined Therapy with Daclatasvir and Asunaprevir

    PubMed Central

    Baba, Hayato; Tajiri, Kazuto; Nagata, Kohei; Kawai, Kengo; Minemura, Masami; Sugiyama, Toshiro

    2016-01-01

    Daclatasvir (DCV) and asunaprevir (ASV) are direct-acting antivirals (DAAs) used in the treatment of chronic hepatitis C virus (HCV) infection. Combined therapy with DCV and ASV shows high efficacy and safety even in patients with cirrhosis. We encountered a patient exhibiting severe hyperbilirubinemia during combined therapy, which is an unreported side effect of DCV and ASV. A 78-year-old woman with cirrhosis developed hyperbilirubinemia >10 mg/dl without transaminitis 3 weeks after starting combined therapy. We suspected DAAs-induced liver disorder and discontinued treatment, which resulted in the improvement of hyperbilirubinemia. Caution is required in the use of DAAs for patients with advanced cirrhosis. PMID:27504082

  1. Synthesis, antifungal evaluation and optical properties of silver molybdate microcrystals in different solvents: a combined experimental and theoretical study.

    PubMed

    Fabbro, Maria T; Foggi, Camila C; Santos, Luis P S; Gracia, Lourdes; Perrin, André; Perrin, Christiane; Vergani, Carlos E; Machado, Ana L; Andrés, Juan; Cordoncillo, Eloisa; Longo, Elson

    2016-06-28

    In this study, we investigate the structure, antifungal activity, and optical properties of β-Ag2MoO4 using experimental and theoretical approaches. β-Ag2MoO4 samples were prepared by a co-precipitation method using different solvents (water, ethanol and ammonia), and their antifungal activity against Candida albicans was investigated. The samples were characterized by X-ray diffraction, micro-Raman spectroscopy, field emission scanning electron microscopy, and transmission electron microscopy with energy dispersive spectroscopy. The optical properties were investigated by UV-Vis spectroscopy and photoluminescence measurements at room temperature. The thermodynamic equilibrium shape of the β-Ag2MoO4 crystals was determined based on the surface energies calculated using Wulff construction. The (011) orientation was the predominant surface in the morphology. The experimental morphology was obtained by varying the surface energy ratio for each facet. A large decrease in surface energy for the (111) surface provided the experimental morphology for crystals synthesized using water and ethanol as solvents; when the surface energies for both (011) and (001) surfaces increased, the crystal morphology obtained using ammonia as a solvent was reproduced. A correlation between the exposed surfaces and antifungal activity was revealed, and an explanation to this behavior that arises from different morphologies and structural data was provided. Theoretical calculations confirm the rationality of the experimental scheme and elucidate the underlying reason for the fungistatic and fungicidal activity against Candida albicans. PMID:27283468

  2. Short-Term Therapy with Luliconazole, a Novel Topical Antifungal Imidazole, in Guinea Pig Models of Tinea Corporis and Tinea Pedis

    PubMed Central

    Nanjoh, Yasuko; Kaneda, Hideo; Yamaguchi, Hideyo; Tsuboi, Ryoji

    2012-01-01

    Luliconazole is a novel topical antifungal imidazole with broad-spectrum and potent antifungal activity. The drug is under clinical development in the United States for management of dermatophytosis with a short-term treatment regimen. The present study was undertaken to investigate the clinical benefit of short-term therapy with luliconazole cream in guinea pig models of tinea corporis and tinea pedis induced with Trichophyton mentagrophytes. The dose-dependent therapeutic efficacy of topical luliconazole cream (0.02 to 1%), measured by macroscopic improvement of skin lesions and by fungal eradication as determined by a culture assay, was demonstrated using a tinea corporis model. The improvement in skin lesions seen with luliconazole cream was observed even at a concentration of 0.02%, and its efficacy at 0.1% was equal to that of 1% bifonazole cream. The efficacy of short-term therapy with 1% luliconazole cream, which is used for clinical management, was investigated using the tinea corporis model (4- and 8-day treatment regimens) and the tinea pedis model (7- and 14-day treatment regimens). The 1% luliconazole cream completely eradicated the fungus in half or less of the treatment time required for 1% terbinafine cream and 1% bifonazole cream, as determined by a culture assay for both models. These results clearly indicate that 1% luliconazole cream is sufficiently potent for short-term treatment for dermatophytosis compared to existing drugs. Luliconazole is expected to be useful in the clinical management of dermatophytosis. PMID:22391525

  3. Antifungal hydrogels

    PubMed Central

    Zumbuehl, Andreas; Ferreira, Lino; Kuhn, Duncan; Astashkina, Anna; Long, Lisa; Yeo, Yoon; Iaconis, Tiffany; Ghannoum, Mahmoud; Fink, Gerald R.; Langer, Robert; Kohane, Daniel S.

    2007-01-01

    Fungi are increasingly identified as major pathogens in bloodstream infections, often involving indwelling devices. Materials with antifungal properties may provide an important deterrent to these infections. Here we describe amphogel, a dextran-based hydrogel into which amphotericin B is adsorbed. Amphogel kills fungi within 2 h of contact and can be reused for at least 53 days without losing its effectiveness against Candida albicans. The antifungal material is biocompatible in vivo and does not cause hemolysis in human blood. Amphogel inoculated with C. albicans and implanted in mice prevents fungal infection. Amphogel also mitigates fungal biofilm formation. An antifungal matrix with these properties could be used to coat a variety of medical devices such as catheters as well as industrial surfaces. PMID:17664427

  4. Use of the ES-D3 cell differentiation assay, combined with the BeWo transport model, to predict relative in vivo developmental toxicity of antifungal compounds.

    PubMed

    Li, Hequn; Rietjens, Ivonne M C M; Louisse, Jochem; Blok, Martine; Wang, Xinyi; Snijders, Linda; van Ravenzwaay, Bennard

    2015-03-01

    We investigated the applicability of the ES-D3 cell differentiation assay combined with the in vitro BeWo transport model to predict the relative in vivo developmental toxicity potencies. To this purpose, the in vitro developmental toxicity of five antifungal compounds was investigated by characterizing their inhibitory effect on the differentiation of ES-D3 cells into cardiomyocytes. The BeWo transport model, consisting of BeWo b30 cells grown on transwell inserts and mimicking the placental barrier, was used to determine the relative placental transport velocity. The ES-D3 cell differentiation data were first compared to benchmark doses (BMDs) for in vivo developmental toxicity as derived from data reported in the literature. Correlation between the benchmark concentration for 50% effect (BMCd50) values, obtained in the ES-D3 cell differentiation assay, with in vivo BMD10 values showed a reasonable correlation (R(2)=0.57). When the ES-D3 cell differentiation data were combined with the relative transport rates obtained from the BeWo model, the correlation with the in vivo data increased (R(2)=0.95). In conclusion, we show that the ES-D3 cell differentiation assay is able to better predict the in vivo developmental toxicity ranking of antifungal compounds when combined with the BeWo transport model, than as a stand-alone assay. PMID:25489799

  5. Antifungal therapy, 1978.

    PubMed Central

    Baum, G. L.

    1979-01-01

    The past 40 years have brought great advances in the knowledge of morphology, immunology and epidemiology of fungal infections in man. Each general advance in the science of medicine has had its counterpart in man's improved facility to deal with these infections therapeutically. Although satisfactory control of fungal infections of man is still lacking, productive paths of investigation seem to have been found and the continued application of rigorous discipline to research efforts should provide even more efficient treatment in the future. PMID:392475

  6. Combination Therapies for Traumatic Brain Injury: Prospective Considerations

    PubMed Central

    Hicks, Ramona

    2009-01-01

    Abstract Traumatic brain injury (TBI) initiates a cascade of numerous pathophysiological events that evolve over time. Despite the complexity of TBI, research aimed at therapy development has almost exclusively focused on single therapies, all of which have failed in multicenter clinical trials. Therefore, in February 2008 the National Institute of Neurological Disorders and Stroke, with support from the National Institute of Child Health and Development, the National Heart, Lung, and Blood Institute, and the Department of Veterans Affairs, convened a workshop to discuss the opportunities and challenges of testing combination therapies for TBI. Workshop participants included clinicians and scientists from a variety of disciplines, institutions, and agencies. The objectives of the workshop were to: (1) identify the most promising combinations of therapies for TBI; (2) identify challenges of testing combination therapies in clinical and pre-clinical studies; and (3) propose research methodologies and study designs to overcome these challenges. Several promising combination therapies were discussed, but no one combination was identified as being the most promising. Rather, the general recommendation was to combine agents with complementary targets and effects (e.g., mechanisms and time-points), rather than focusing on a single target with multiple agents. In addition, it was recommended that clinical management guidelines be carefully considered when designing pre-clinical studies for therapeutic development. To overcome the challenges of testing combination therapies it was recommended that statisticians and the U.S. Food and Drug Administration be included in early discussions of experimental design. Furthermore, it was agreed that an efficient and validated screening platform for candidate therapeutics, sensitive and clinically relevant biomarkers and outcome measures, and standardization and data sharing across centers would greatly facilitate the development of

  7. Fixed-combination and emerging glaucoma therapies.

    PubMed

    Woodward, David F; Chen, June

    2007-05-01

    Ocular hypotensive agents are the only approved pharmacotherapy for glaucoma. Despite significant advances during the past two decades, a large proportion of glaucoma patients require more than one drug. The most recent additions to the armamentarium of antiglaucoma drugs are fixed-combination products for the glaucoma patient who is insufficiently responsive to monotherapy. Fixed-combination products have the combined efficacy of two ocular hypotensive drugs, and the convenience of a two-drug treatment regimen in a single container, which may aid patient adherence to treatment. Available fixed-combination products consist of timolol 0.5% as an invariant with brimonidine 0.2%, dorzolamide 2%, travoprost 0.004%, latanoprost 0.005% or bimatoprost 0.03%. Research on more advanced antiglaucoma medications continues. Promising new directions appear to be the Rho-kinase inhibitors, microtubule-disrupting agents, serotonergics and cannabimimetics. Efforts continue to improve existing antiglaucoma drugs in an attempt to design second-generation cholinomimetics, adrenergics, prostaglandins and prostamides. PMID:17604504

  8. A combination therapy for cystic fibrosis.

    PubMed

    Brodsky, Jeffrey L; Frizzell, Raymond A

    2015-09-24

    The most prevalent form of cystic fibrosis arises from an amino acid deletion in the cystic fibrosis transmembrane conductance regulator, CFTR. A recently approved treatment for individuals homozygous for this mutation combines a chemical corrector, which helps CFTR fold, and a potentiator that increases CFTR channel activity. PMID:26406363

  9. Photodynamic therapy combined with terbinafine against chromoblastomycosis and the effect of PDT on Fonsecaea monophora in vitro.

    PubMed

    Hu, Yongxuan; Huang, Xiaowen; Lu, Sha; Hamblin, Michael R; Mylonakis, Eleftherios; Zhang, Junmin; Xi, Liyan

    2015-02-01

    Chromoblastomycosis, a chronic fungal infection of skin and subcutaneous tissue caused by dematiaceous fungi, is associated with low cure and high relapse rates. Among all factors affecting clinical outcome, etiological agents have an important position. In southern China, Fonsecaea pedrosoi and Fonsecaea monophora are main causative agents causing Chromoblastomycosis. We treated one case of chromoblastomycosis by photodynamic therapy (PDT) of 5-aminolevulinic acid (ALA) irradiation combined with terbinafine 250 mg a day. The lesions were improved after two sessions of ALA-PDT treatment, each including nine times, at an interval of 1 week, combined with terbinafine 250 mg/day oral, and clinical improvement could be observed. In the following study, based on the clinical treatment, the effect of PDT and antifungal drugs on this isolate was detected in vitro. It showed sensitivity to terbinafine, itraconazole or voriconazole, and PDT inhibited the growth. Both the clinic and experiments in vitro confirm the good outcome of ALA-PDT applied in the inhibition of F. monophora. It demonstrated that combination of antifungal drugs with ALA-PDT arises as a promising alternative method for the treatment of these refractory cases of chromoblastomycosis. PMID:25366276

  10. Photodynamic Therapy Combined with Terbinafine Against Chromoblastomycosis and the Effect of PDT on Fonsecaea monophora In Vitro

    PubMed Central

    Hu, Yongxuan; Huang, Xiaowen; Lu, Sha; Hamblin, Michael R.; Mylonakis, Eleftherios; Zhang, Junmin

    2014-01-01

    Chromoblastomycosis, a chronic fungal infection of skin and subcutaneous tissue caused by dematiaceous fungi, is associated with low cure and high relapse rates. Among all factors affecting clinical outcome, etiological agents have an important position. In southern China, Fonsecaea pedrosoi and Fonsecaea monophora are main causative agents causing Chromoblastomycosis. We treated one case of chromoblastomycosis by photodynamic therapy (PDT) of 5-aminolevulinic acid (ALA) irradiation combined with terbinafine 250 mg a day. The lesions were improved after two sessions of ALA-PDT treatment, each including nine times, at an interval of 1 week, combined with terbinafine 250 mg/day oral, and clinical improvement could be observed. In the following study, based on the clinical treatment, the effect of PDT and antifungal drugs on this isolate was detected in vitro. It showed sensitivity to terbinafine, itraconazole or voriconazole, and PDT inhibited the growth. Both the clinic and experiments in vitro confirm the good outcome of ALA-PDT applied in the inhibition of F. monophora. It demonstrated that combination of antifungal drugs with ALA-PDT arises as a promising alternative method for the treatment of these refractory cases of chromoblastomycosis. PMID:25366276

  11. HT update: spotlight on estradiol/norethindrone acetate combination therapy

    PubMed Central

    Casey, Colleen L; Murray, Christine A

    2008-01-01

    The goal of postmenopausal hormone therapy is to alleviate the symptoms that are associated with the loss of estrogen. Many formulations of estrogen and progestin are available, depending on the needs and circumstances of each individual woman. For postmenopausal women, the choice of whether or not to begin therapy requires knowledge of the risks and benefits of estrogen and/or progestin replacement. The purpose of this review is to describe the risks and benefits of hormonal therapy, focusing on estradiol/norethindrone acetate combination therapy. PMID:18488874

  12. Combination therapies for the endoscopic treatment of gastrointestinal bleeding.

    PubMed

    Hiele, M; Rutgeerts, P

    2000-06-01

    This review discusses the background and analysis of data in the literature regarding the effect of a combination of endoscopic therapies on the treatment of bleeding gastroduodenal ulcers. Although these techniques are commonly used, convincing data to support combinations of injection therapies are scarce, and various studies give somewhat conflicting results. In one study, a combination of the injection of adrenaline and a high dose of thrombin was superior to using adrenaline alone. The combination of injection therapy with a thermal method tends to give better results than injection therapy alone in several studies, but the difference is only statistically significant in one study (which uses the gold probe). The data regarding a combination of injection therapy with haemostatic clips are somewhat discordant regarding the effect of the haemoclip itself, but none of the studies found an advantage of combining the two modalities. Some studies suggest that subgroups may exist, such as ulcers with spurting haemorrhage, in which combined treatment might be more useful. PMID:10952808

  13. Tumorigenicity of a combination of psoriasis therapies.

    PubMed Central

    Phillips, D. H.; Alldrick, A. J.

    1994-01-01

    Coal tar, a tumour initiator, and dithranol, a tumour promoter, are used in the treatment of psoriasis. Topical treatment of mice with pharmaceutical formulations of these two agents, at therapeutic doses, induced skin papillomas in a classical two-stage carcinogenesis protocol, while treatment with either agent alone did not. This finding has implications for the use of both agents in combination in the treatment of psoriasis. Images Figure 1 PMID:8198968

  14. Combination of phytochemicals as adjuvants for cancer therapy.

    PubMed

    Ho, John W S; Cheung, Matt W M

    2014-01-01

    Newer treatments of advanced human cancer are based on combination of cancer drugs that have different mechanism of actions yet the combination strategy may potentiate the anti-cancer effects and cytotoxicity. Recent studies suggest that cancer growth can be inhibited more effectively by combination of phytochemicals that affect different pathways. The apoptotic activity can be modulated by intrinsic and extrinsic molecules. The combination of anti-tumor phytochemicals can be more effective in modulating different signaling pathways associated with tumor cell growth which is the common target for anti-tumor action. Combinations of cytotoxic anti-tumor agents and inhibitors from phytochemicals are believed to act together producing inhibitory mechanisms on cancer growth. This combination strategy shows promise on cancer therapy. However, the combination of phytochemicals in cancer therapy needs to be further investigated to develop a better treatment strategy. Recent patents on anti-tumor phytochemicals are reviewed in this article. PMID:24942759

  15. Combined photovacuum therapy of copulative dysfunction

    NASA Astrophysics Data System (ADS)

    Menyaev, Yulian A.; Zharov, Vladimir P.; Mishanin, Evgeniy A.; Kuzmich, Aleksandr P.; Bessonov, Sergey E.

    2006-02-01

    One of the important problems of modern medicine is treatment of urogenital diseases. 1-2 There is a set of the treatment methods for such problems, but any of them does not obey the modern physicians completely. 3-4 Our aim is to present the new combined therapeutic apparatus called "Yarovit" (produced in Russia, in collaboration between Bauman Moscow State University of Technology and Scientific Production Association and Medical Center "Yarovit") which successfully applied in clinics for cure the patients with copulative dysfunction diseases. 5-6 At this apparatus "Yarovit" (description model have abbreviation AMVL-0 1) there is a combination of vacuum decompression (0.1-0.4 kgs/cm2) and light emitting diodes matrix system (660 nm, 1-3 mW/cm2). In treatment procedure apparatus can be applied together with expanded module "Intratherm" (39 °C on average), which has rectal heating elements. The latest clinical studies were made together with volunteer participation of more then one hundred patients, and received results showed the good dynamic of healing. That let to conclude these combinations of physical therapeutic methods supplement each other and in conjunction provides a significant clinical effect. The further developments of such apparatuses are discussed.

  16. Combination therapy: New hope for alcoholic hepatitis?

    PubMed

    Gao, Bin; Shah, Vijay H

    2015-09-01

    Alcoholic hepatitis (AH) is a severe form of alcoholic liver disease with high mortality. The pathogenesis of AH is not fully understood, but it is generally believed that inflammation is a key factor leading to liver failure in AH. Steroids, which have broad immunosuppressive effects, have been used for the treatment of AH over the last forty years. Steroids elicit modest improvement in short-term survival rate in patients with severe AH, but also cause severe side effects. Several specific inflammatory targets (e.g., IL-1, LPS, and gut microbiota) are currently under investigation for the treatment of AH with the goal to obviate or reduce steroid administration. In addition to inflammation, impaired liver regeneration is another major cause of liver failure in AH, which deteriorates further after steroid treatment because inflammation plays a key role in promoting liver repair. Interleukin-22 (IL-22) is a promising drug for the treatment of AH because of its hepatoprotective and anti-fibrotic functions and relatively few known side effects. In addition, IL-22 treatment also ameliorates bacterial infection and kidney injury, two major complications associated with severe AH. IL-22 is currently under investigation in preclinical and clinical studies and may hold great promise for AH by providing more beneficial effects and fewer side effects than current therapies. PMID:26193867

  17. Drug combination therapy increases successful drug repositioning.

    PubMed

    Sun, Wei; Sanderson, Philip E; Zheng, Wei

    2016-07-01

    Repositioning of approved drugs has recently gained new momentum for rapid identification and development of new therapeutics for diseases that lack effective drug treatment. Reported repurposing screens have increased dramatically in number in the past five years. However, many newly identified compounds have low potency; this limits their immediate clinical applications because the known, tolerated plasma drug concentrations are lower than the required therapeutic drug concentrations. Drug combinations of two or more compounds with different mechanisms of action are an alternative approach to increase the success rate of drug repositioning. PMID:27240777

  18. Combined cannabinoid therapy via an oromucosal spray.

    PubMed

    Perez, Jordi

    2006-08-01

    Extensive basic science research has identified the potential therapeutic benefits of active compounds extracted from the Cannabis sativa L. plant (the cannabinoids). It is recognized that a significant proportion of patients suffering with the debilitating symptoms of pain and spasticity in multiple sclerosis or other conditions smoke cannabis despite the legal implications and stigma associated with this controlled substance. GW Pharmaceuticals have developed Sativex (GW- 1,000-02), a combined cannabinoid medicine that delivers and maintains therapeutic levels of two principal cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), via an oromucosal pump spray, that aims to minimize psychotropic side effects. Sativex has proved to be well tolerated and successfully self-administered and self-titrated in both healthy volunteers and patient cohorts. Clinical assessment of this combined cannabinoid medicine has demonstrated efficacy in patients with intractable pain (chronic neuropathic pain, pain due to brachial plexus nerve injury, allodynic peripheral neuropathic pain and advanced cancer pain), rheumatoid arthritis and multiple sclerosis (bladder problems, spasticity and central pain), with no significant intoxication-like symptoms, tolerance or withdrawal syndrome. PMID:16969427

  19. Comparison of echinocandin antifungals

    PubMed Central

    Eschenauer, Gregory; DePestel, Daryl D; Carver, Peggy L

    2007-01-01

    The incidence of invasive fungal infections, especially those due to Aspergillus spp. and Candida spp., continues to increase. Despite advances in medical practice, the associated mortality from these infections continues to be substantial. The echinocandin antifungals provide clinicians with another treatment option for serious fungal infections. These agents possess a completely novel mechanism of action, are relatively well-tolerated, and have a low potential for serious drug–drug interactions. At the present time, the echinocandins are an option for the treatment of infections due Candida spp (such as esophageal candidiasis, invasive candidiasis, and candidemia). In addition, caspofungin is a viable option for the treatment of refractory aspergillosis. Although micafungin is not Food and Drug Administration-approved for this indication, recent data suggests that it may also be effective. Finally, caspofungin- or micafungin-containing combination therapy should be a consideration for the treatment of severe infections due to Aspergillus spp. Although the echinocandins share many common properties, data regarding their differences are emerging at a rapid pace. Anidulafungin exhibits a unique pharmacokinetic profile, and limited cases have shown a potential far activity in isolates with increased minimum inhibitory concentrations to caspofungin and micafungin. Caspofungin appears to have a slightly higher incidence of side effects and potential for drug–drug interactions. This, combined with some evidence of decreasing susceptibility among some strains of Candida, may lessen its future utility. However, one must take these findings in the context of substantially more data and use with caspofungin compared with the other agents. Micafungin appears to be very similar to caspofungin, with very few obvious differences between the two agents. PMID:18360617

  20. Components of the calcium-calcineurin signaling pathway in fungal cells and their potential as antifungal targets.

    PubMed

    Liu, Shuyuan; Hou, Yinglong; Liu, Weiguo; Lu, Chunyan; Wang, Weixin; Sun, Shujuan

    2015-04-01

    In recent years, the emergence of fungal resistance has become frequent, partly due to the widespread clinical use of fluconazole, which is minimally toxic and effective in the prevention and treatment of Candida albicans infections. The limited selection of antifungal drugs for clinical fungal infection therapy has prompted us to search for new antifungal drug targets. Calcium, which acts as the second messenger in both mammals and fungi, plays a direct role in controlling the expression patterns of its signaling systems and has important roles in cell survival. In addition, calcium and some of the components, mainly calcineurin, in the fungal calcium signaling pathway mediate fungal resistance to antifungal drugs. Therefore, an overview of the components of the fungal calcium-calcineurin signaling network and their potential roles as antifungal targets is urgently needed. The calcium-calcineurin signaling pathway consists of various channels, transporters, pumps, and other proteins or enzymes. Many transcriptional profiles have indicated that mutant strains that lack some of these components are sensitized to fluconazole or other antifungal drugs. In addition, many researchers have identified efficient compounds that exhibit antifungal activity by themselves or in combination with antifungal drugs by targeting some of the components in the fungal calcium-calcineurin signaling pathway. This targeting disrupts Ca(2+) homeostasis, which suggests that this pathway contains potential targets for the development of new antifungal drugs. PMID:25636321

  1. Components of the Calcium-Calcineurin Signaling Pathway in Fungal Cells and Their Potential as Antifungal Targets

    PubMed Central

    Liu, Shuyuan; Hou, Yinglong; Liu, Weiguo; Lu, Chunyan; Wang, Weixin

    2015-01-01

    In recent years, the emergence of fungal resistance has become frequent, partly due to the widespread clinical use of fluconazole, which is minimally toxic and effective in the prevention and treatment of Candida albicans infections. The limited selection of antifungal drugs for clinical fungal infection therapy has prompted us to search for new antifungal drug targets. Calcium, which acts as the second messenger in both mammals and fungi, plays a direct role in controlling the expression patterns of its signaling systems and has important roles in cell survival. In addition, calcium and some of the components, mainly calcineurin, in the fungal calcium signaling pathway mediate fungal resistance to antifungal drugs. Therefore, an overview of the components of the fungal calcium-calcineurin signaling network and their potential roles as antifungal targets is urgently needed. The calcium-calcineurin signaling pathway consists of various channels, transporters, pumps, and other proteins or enzymes. Many transcriptional profiles have indicated that mutant strains that lack some of these components are sensitized to fluconazole or other antifungal drugs. In addition, many researchers have identified efficient compounds that exhibit antifungal activity by themselves or in combination with antifungal drugs by targeting some of the components in the fungal calcium-calcineurin signaling pathway. This targeting disrupts Ca2+ homeostasis, which suggests that this pathway contains potential targets for the development of new antifungal drugs. PMID:25636321

  2. Antifungal serum concentration monitoring: an update.

    PubMed

    Goodwin, Megan L; Drew, Richard H

    2008-01-01

    Invasive fungal infections (IFIs) are occurring with increasing incidence and are associated with significant morbidity and mortality. Understanding the relationship between the pharmacokinetic and pharmacodynamic properties of antifungals is essential to optimize the potential for favourable clinical and microbiological outcomes while minimizing risks of treatment-related toxicity. Antifungal serum concentrations may aid in the determination of appropriate dosing in select circumstances. The polyene and echinocandin classes of antifungals lack sufficient data to justify serum concentration monitoring in routine clinical practice. In contrast, serum concentration monitoring of flucytosine may help to reduce the risk of treatment-related haematological toxicity. Determination of itraconazole serum concentrations is advised in situations where the drug is used for prolonged periods to treat serious IFIs (such as invasive aspergillosis or histoplasmosis) because of variability in absorption following oral administration (most notable for the capsule formulation). The use of serum concentration monitoring during therapy with the extended-spectrum triazoles (i.e. voriconazole and posaconazole) is still evolving, due primarily to inter-patient variability in drug exposure combined with sparse data regarding relationships with efficacy (posaconazole) and both safety and efficacy (voriconazole). PMID:17999982

  3. Propensity Score Analysis of the Role of Initial Antifungal Therapy in the Outcome of Candida glabrata Bloodstream Infections.

    PubMed

    Puig-Asensio, M; Fernández-Ruiz, M; Aguado, J M; Merino, P; Lora-Pablos, D; Guinea, J; Martín-Dávila, P; Cuenca-Estrella, M; Almirante, B

    2016-06-01

    Candida glabrata isolates have reduced in vitro susceptibility to azoles, which raises concerns about the clinical effectiveness of fluconazole for treating bloodstream infection (BSI) by this Candida species. We aimed to evaluate whether the choice of initial antifungal treatment (fluconazole versus echinocandins or liposomal amphotericin B [L-AmB]-based regimens) has an impact on the outcome of C. glabrata BSI. We analyzed data from a prospective, multicenter, population-based surveillance program on candidemia conducted in 5 metropolitan areas of Spain (May 2010 to April 2011). Adult patients with an episode of C. glabrata BSI were included. The main outcomes were 14-day mortality and treatment failure (14-day mortality and/or persistent C. glabrata BSI for ≥48 h despite antifungal initiation). The impact of using fluconazole as initial antifungal treatment on the patients' prognosis was assessed by logistic regression analysis with the addition of a propensity score approach. A total of 94 patients with C. glabrata BSI were identified. Of these, 34 had received fluconazole and 35 had received an echinocandin/L-AmB-based regimen. Patients in the echinocandin/L-AmB group had poorer baseline clinical status than did those in the fluconazole group. Patients in the fluconazole group were more frequently (55.9% versus 28.6%) and much earlier (median time, 3 versus 7 days) switched to another antifungal regimen. Overall, 14-day mortality was 13% (9/69) and treatment failure 34.8% (24/69), with no significant differences between the groups. On multivariate analysis, after adjusting for baseline characteristics by propensity score, fluconazole use was not associated with an unfavorable evolution (adjusted odds ratio [OR] for 14-day mortality, 1.16, with 95% confidence interval [CI] of 0.22 to 6.17; adjusted OR for treatment failure, 0.83, with 95% CI of 0.27 to 2.61). In conclusion, initial fluconazole treatment was not associated with a poorer outcome than that

  4. Gastrointestinal Toxicities With Combined Antiangiogenic and Stereotactic Body Radiation Therapy

    PubMed Central

    Pollom, Erqi L.; Deng, Lei; Pai, Reetesh K.; Brown, J. Martin; Giaccia, Amato; Loo, Billy W.; Shultz, David B.; Le, Quynh Thu; Koong, Albert C.; Chang, Daniel T.

    2016-01-01

    Combining the latest targeted biologic agents with the most advanced radiation technologies has been an exciting development in the treatment of cancer patients. Stereotactic body radiation therapy (SBRT) is an ablative radiation approach that has become established for the treatment of a variety of malignancies, and it has been increasingly used in combination with biologic agents, including those targeting angiogenesis-specific pathways. Multiple reports have emerged describing unanticipated toxicities arising from the combination of SBRT and angiogenesis-targeting agents, particularly of late luminal gastrointestinal toxicities. In this review, we summarize the literature describing these toxicities, explore the biological mechanism of action of toxicity with the combined use of antiangiogenic therapies, and discuss areas of future research, so that this combination of treatment modalities can continue to be used in broader clinical contexts. PMID:26068491

  5. Gastrointestinal Toxicities With Combined Antiangiogenic and Stereotactic Body Radiation Therapy

    SciTech Connect

    Pollom, Erqi L.; Deng, Lei; Pai, Reetesh K.; Brown, J. Martin; Giaccia, Amato; Loo, Billy W.; Shultz, David B.; Le, Quynh Thu; Koong, Albert C.; Chang, Daniel T.

    2015-07-01

    Combining the latest targeted biologic agents with the most advanced radiation technologies has been an exciting development in the treatment of cancer patients. Stereotactic body radiation therapy (SBRT) is an ablative radiation approach that has become established for the treatment of a variety of malignancies, and it has been increasingly used in combination with biologic agents, including those targeting angiogenesis-specific pathways. Multiple reports have emerged describing unanticipated toxicities arising from the combination of SBRT and angiogenesis-targeting agents, particularly of late luminal gastrointestinal toxicities. In this review, we summarize the literature describing these toxicities, explore the biological mechanism of action of toxicity with the combined use of antiangiogenic therapies, and discuss areas of future research, so that this combination of treatment modalities can continue to be used in broader clinical contexts.

  6. Challenges, solutions, and recommendations for Alzheimer's disease combination therapy.

    PubMed

    Hendrix, James A; Bateman, Randall J; Brashear, H Robert; Duggan, Cynthia; Carrillo, Maria C; Bain, Lisa J; DeMattos, Ronald; Katz, Russell G; Ostrowitzki, Susanne; Siemers, Eric; Sperling, Reisa; Vitolo, Ottavio V

    2016-05-01

    Given the complex neuropathology Alzheimer's disease (AD), combination therapy may be necessary for effective treatment. However, scientific, pragmatic, regulatory, and business challenges need to be addressed before combination therapy for AD can become a reality. Leaders from academia and industry, along with a former member of the Food and Drug Administration and the Alzheimer's Association, have explored these challenges and here propose a strategy to facilitate proof-of-concept combination therapy trials in the near future. First, a more integrated understanding of the complex pathophysiology and progression of AD is needed to identify the appropriate pathways and the disease stage to target. Once drug candidates are identified, novel clinical trial designs and selection of appropriate outcome assessments will be needed to enable definition and evaluation of the appropriate dose and dosing regimen and determination of efficacy. Success in addressing this urgent problem will only be achieved through collaboration among multiple stakeholders. PMID:27017906

  7. Combination Therapy with Budesonide and Salmeterol in Experimental Allergic Inflammation.

    PubMed

    Pappová, L; Jošková, M; Kazimierová, I; Šutovská, M; Fraňová, S

    2016-01-01

    The aim of this study was to determinate bronchodilator, antitussive, and ciliomodulatory activity of inhaled combination therapy with budesonide and salmeterol, and to correlate the results with the anti-inflammatory effect. The experiments were performed using two models of allergic inflammation (21 and 28 days long sensitization with ovalbumine) in guinea pigs. The animals were treated daily by aerosols of budesonide (1 mM), salmeterol (0.17 mM), and a half-dose combination of the two drugs. Antitussive and bronchodilator activities were evaluated in vivo. The ciliary beat frequency (CBF) was assessed in vitro in tracheal brushed samples, and inflammatory cytokines (IL-4, IL-5, IL-13, GM-CSF, and TNF-α) were determined in bronchoalveolar lavage fluid (BALF). We found that the combination therapy significantly decreased the number of cough efforts, airway reactivity, and the level of inflammatory cytokines in both models of allergic asthma. Three weeks long sensitization led to an increase in CBF and all three therapeutic approaches have shown a ciliostimulatory effect in order: salmeterol < budesonid < combination therapy. Four weeks long ovalbumine sensitization, on the other hand, decreased the CBF, increased IL-5, and decreased IL-13. In this case, only the combination therapy was able to stimulate the CBF. We conclude that a half-dose combination therapy of budesonide and salmeterol shows comparable antitussive, bronchodilator, and the anti-inflammatory effect to a full dose therapy with budesonide alone, but had a more pronounced stimulatory effect on the CBF. PMID:27329088

  8. Drug Delivery Systems and Combination Therapy by Using Vinca Alkaloids

    PubMed Central

    Lee, Chun-Ting; Huang, Yen-Wei; Yang, Chih-Hui; Huang, Keng-Shiang

    2015-01-01

    Developing new methods for chemotherapy drug delivery has become a topic of great concern. Vinca alkaloids are among the most widely used chemotherapy reagents for tumor therapy; however, their side effects are particularly problematic for many medical doctors. To reduce the toxicity and enhance the therapeutic efficiency of vinca alkaloids, many researchers have developed strategies such as using liposome-entrapped drugs, chemical- or peptide-modified drugs, polymeric packaging drugs, and chemotherapy drug combinations. This review mainly focuses on the development of a vinca alkaloid drug delivery system and the combination therapy. Five vinca alkaloids (eg, vincristine, vinblastine, vinorelbine, vindesine, and vinflunine) are reviewed. PMID:25877096

  9. Drug delivery systems and combination therapy by using vinca alkaloids.

    PubMed

    Lee, Chun-Ting; Huang, Yen-Wei; Yang, Chih-Hui; Huang, Keng-Shiang

    2015-01-01

    Developing new methods for chemotherapy drug delivery has become a topic of great concern. Vinca alkaloids are among the most widely used chemotherapy reagents for tumor therapy; however, their side effects are particularly problematic for many medical doctors. To reduce the toxicity and enhance the therapeutic efficiency of vinca alkaloids, many researchers have developed strategies such as using liposome-entrapped drugs, chemical- or peptide-modified drugs, polymeric packaging drugs, and chemotherapy drug combinations. This review mainly focuses on the development of a vinca alkaloid drug delivery system and the combination therapy. Five vinca alkaloids (eg, vincristine, vinblastine, vinorelbine, vindesine, and vinflunine) are reviewed. PMID:25877096

  10. Optimal combination of antiangiogenic therapy for hepatocellular carcinoma

    PubMed Central

    Ch’ang, Hui-Ju

    2015-01-01

    The success of sorafenib in prolonging survival of patients with hepatocellular carcinoma (HCC) makes therapeutic inhibition of angiogenesis a component of treatment for HCC. To enhance therapeutic efficacy, overcome drug resistance and reduce toxicity, combination of antiangiogenic agents with chemotherapy, radiotherapy or other targeted agents were evaluated. Nevertheless, the use of antiangiogenic therapy remains suboptimal regarding dosage, schedule and duration of therapy. The issue is further complicated by combination antiangiogenesis to other cytotoxic or biologic agents. There is no way to determine which patients are most likely respond to a given form of antiangiogenic therapy. Activation of alternative pathways associated with disease progression in patients undergoing antiangiogenic therapy has also been recognized. There is increasing importance in identifying, validating and standardizing potential response biomarkers for antiangiogenesis therapy for HCC patients. In this review, biomarkers for antiangiogenesis therapy including systemic, circulating, tissue and imaging ones are summarized. The strength and deficit of circulating and imaging biomarkers were further demonstrated by a series of studies in HCC patients receiving radiotherapy with or without thalidomide. PMID:26261692

  11. Combination therapy: the propitious rationale for drug development.

    PubMed

    Phougat, Neetu; Khatri, Savita; Singh, Anu; Dangi, Mrridula; Kumar, Manish; Dabur, Rajesh; Chhillar, Anil Kumar

    2014-01-01

    Therapeutic options for many infections are extremely limited and at crisis point. We run the risk of entering a second pre-antibiotic era. There had been no miracle drug for the patients infected by resistant microbial pathogens. Most of the very few new drugs under development have problems with their toxicity, or pharmacokinetics and pharmacodynamics. We are already decades behind in the discovery, characterization and development of new antimicrobials. In that scenario, we could not imagine surviving without newer and effective antimicrobial agents. Bacteria have been the champions of evolution and are still evolving continuously, where they pose serious challenges for humans. Along with the crisis of evolving resistance, the condition is made worst by the meager drug pipeline for new antimicrobials. Despite ongoing efforts only 2 new antibiotics (Telavancin in 2009 and Ceftaroline fosamil in 2010) have been approved since 2009 pipeline status report of Infectious Disease Society of America (IDSA). Recent approval of new combination based antiviral drugs such as Stribild (combination of four drugs for HIV treatment) and Menhibrix (combination vaccine to prevent meningococcal disease and Haemophilus influenzae type b in children) proves that combination therapy is still the most promising approach to combat the ever evolving pathogens. Combination therapy involves the drug repurposing and regrouping of the existing antimicrobial agents to provide a synergistic approach for management of infectious diseases. This review article is an effort to highlight the challenges in new drug development and potential of combination drug therapy to deal with them. PMID:24138510

  12. Synergistic nanomedicine by combined gene and photothermal therapy.

    PubMed

    Kim, Jinhwan; Kim, Jihoon; Jeong, Cherlhyun; Kim, Won Jong

    2016-03-01

    To date, various nanomaterials with the ability for gene delivery or photothermal effect have been developed in the field of biomedicine. The therapeutic potential of these nanomaterials has raised considerable interests in their use in potential next-generation strategies for effective anticancer therapy. In particular, the advancement of novel nanomedicines utilizing both therapeutic strategies of gene delivery and photothermal effect has generated much optimism regarding the imminent development of effective and successful cancer treatments. In this review, we discuss current research progress with regard to combined gene and photothermal therapy. This review focuses on synergistic therapeutic systems combining gene regulation and photothermal ablation as well as logically designed nano-carriers aimed at enhancing the delivery efficiency of therapeutic genes using the photothermal effect. The examples detailed in this review provide insight to further our understanding of combinatorial gene and photothermal therapy, thus paving the way for the design of promising nanomedicines. PMID:26748259

  13. Combination therapy for malaria in Africa: hype or hope?

    PubMed Central

    Bloland, P. B.; Ettling, M.; Meek, S.

    2000-01-01

    The development of resistance to drugs poses one of the greatest threats to malaria control. In Africa, the efficacy of readily affordable antimalarial drugs is declining rapidly, while highly efficacious drugs tend to be too expensive. Cost-effective strategies are needed to extend the useful life spans of antimalarial drugs. Observations in South-East Asia on combination therapy with artemisinin derivatives and mefloquine indicate that the development of resistance to both components is slowed down. This suggests the possibility of a solution to the problem of drug resistance in Africa, where, however, there are major obstacles in the way of deploying combination therapy effectively. The rates of transmission are relatively high, a large proportion of asymptomatic infection occurs in semi-immune persons, the use of drugs is frequently inappropriate and ill-informed, there is a general lack of laboratory diagnoses, and public health systems in sub-Saharan Africa are generally weak. Furthermore, the cost of combination therapy is comparatively high. We review combination therapy as used in South-East Asia and outline the problems that have to be overcome in order to adopt it successfully in sub-Saharan Africa. PMID:11196485

  14. [Panzytopenia from combination therapy with azathioprin and allopurinol].

    PubMed

    Seidel, W

    2004-10-01

    Azathioprine has been used in rheumatology for more than twenty years. Indications are collagen diseases with multiorgan involvement, where co-medications are frequently necessary. We describe a patient suffering from pancytopenia following a combination therapy of azathioprine and allopurinol because of lupus erythematodes and diabetic nephropathy with hyperuricemia. PMID:15517303

  15. Building a roadmap for developing combination therapies for Alzheimer's disease.

    PubMed

    Perry, Daniel; Sperling, Reisa; Katz, Russell; Berry, Donald; Dilts, David; Hanna, Debra; Salloway, Stephen; Trojanowski, John Q; Bountra, Chas; Krams, Michael; Luthman, Johan; Potkin, Steven; Gribkoff, Val; Temple, Robert; Wang, Yaning; Carrillo, Maria C; Stephenson, Diane; Snyder, Heather; Liu, Enchi; Ware, Tony; McKew, John; Fields, F Owen; Bain, Lisa J; Bens, Cynthia

    2015-03-01

    Combination therapy has proven to be an effective strategy for treating many of the world's most intractable diseases. A growing number of investigators in academia, industry, regulatory agencies, foundations and advocacy organizations are interested in pursuing a combination approach to treating Alzheimer's disease. A meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer's Disease Coalition, the Critical Path Institute and the Alzheimer's Association addressed challenges in designing clinical trials to test multiple treatments in combination and outlined a roadmap for making such trials a reality. PMID:25708309

  16. Synergistic combination dry powders for inhaled antimicrobial therapy

    NASA Astrophysics Data System (ADS)

    Heng, Desmond; Lee, Sie Huey; Teo, Jeanette; Ng, Wai Kiong; Chan, Hak-Kim; Tan, Reginald B. H.

    2013-06-01

    Combination products play an important role in medicine as they offer improved clinical effectiveness, enhanced patient adherence, and reduced administrative costs. In combination antimicrobial therapy, the desired outcome is to extend the antimicrobial spectrum and to achieve a possible synergistic effect. However, adverse antagonistic species may sometimes emerge from such combinations, leading to treatment failure. Therefore, it is crucial to screen the drug candidates for compatibility and possible antagonistic interactions. This work aims to develop a novel synergistic dry powder inhaler (DPI) formulation for antimicrobial combination therapy via the pulmonary route. Binary and ternary combinations were prepared via spray drying on a BUCHI® Nano Spray Dryer B-90. All powders were within the respirable size range, and were consisted of spherical particles that were slightly corrugated. The powers yielded fine particle fractions (of the loaded dose) of over 40% when dispersed using an Aerolizer® DPI at 60 L/min. Time-kill studies carried out against common respiratory tract pathogenic bacteria Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumonia and Acinetobacter baumannii at 1x the minimum inhibitory concentration (MIC) over 24 hours revealed no antagonistic behavior for both combinations. While the interactions were generally found to be indifferent, a favorable synergistic effect was detected in the binary combination when it was tested against Pseudomonas aeruginosa bacteria.

  17. The role of combination medical therapy in benign prostatic hyperplasia.

    PubMed

    Greco, K A; McVary, K T

    2008-12-01

    To review key trials of monotherapy and combination therapy of alpha(1)-adrenergic receptor antagonists (alpha(1)-ARAs), 5alpha-reductase inhibitors (5alphaRIs) and anti-muscarinic agents in the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). To assess the safety and efficacy of combination therapies for LUTS associated with BPH, a search of the MEDLINE and Cochrane databases (1976-2008) was conducted for relevant trials and reviews using the terms benign prostatic hyperplasia, lower urinary tract symptoms, alpha(1)-adrenergic receptor antagonists, 5alpha-reductase inhibitors, anti-muscarinics, anticholinergics, combination therapy, alfuzosin, doxazosin, tamsulosin, terazosin, dutasteride, finasteride, tolterodine, flavoxate, propiverine, oxybutynin, erectile dysfunction, sildenafil, vardenafil and tadalafil. Data from the Medical Therapy of Prostatic Symptoms (MTOPS) study indicated a role for long-term use of alpha(1)-ARAs and 5alphaRIs in combination. In the MTOPS study, combination therapy with the alpha(1)-ARA doxazosin and the 5alphaRI finasteride was significantly more effective than either component alone in reducing symptoms (P=0.006 vs doxazosin monotherapy; P<0.001 vs finasteride monotherapy) and in lowering the rate of clinical progression (P<0.001 vs either monotherapy). These findings were confirmed by the 2-year preliminary results of the Combination of Avodart and Tamsulosin study. In this study, combination therapy of the alpha(1)-ARA tamsulosin and the 5alphaRI dutasteride resulted in a significantly greater decrease in International Prostate Symptom Score (IPSS) when compared with either monotherapy. Several recent trials have studied the efficacy of combining alpha(1)-ARAs and anti-muscarinic agents in the treatment of BPH. These studies have found this combination to result in statistically significant benefits in quality of life scores, patient satisfaction, urinary frequency, storage

  18. Current perspectives on combination therapy in the management of hypertension

    PubMed Central

    Mallat, Samir G; Itani, Houssam S; Tanios, Bassem Y

    2013-01-01

    Hypertension (HTN) is a worldwide health problem and a major preventable risk factor for cardiovascular (CV) events. Achieving an optimal blood pressure (BP) target for patients with HTN will often require more than one BP-lowering drug. Combination therapy is not only needed, but also confers many advantages such as better efficacy and a better tolerability. A better compliance and simplicity of treatment is noted with the single-pill combination (SPC). In addition, for those patients who do not achieve BP target when receiving dual combinations, triple SPCs are now available, and their efficacy and safety have been tested in large clinical trials. BP-lowering drugs used in combination therapy should have complementary mechanisms of action, leading to an additive BP-lowering effect and improvement in overall tolerability, achieved by decreasing the incidence of adverse effects. On the basis of large, outcome-driven trials, preferred dual combinations include an angiotensin receptor antagonist (ARB) or an angiotensin converting enzyme inhibitor (ACEI) combined with a calcium channel blocker (CCB), or an ARB or ACEI combined with a diuretic. Acceptable dual combinations include a direct rennin inhibitor (DRI) and a CCB, a DRI and a diuretic, a beta-blocker and a diuretic, a CCB and a diuretic, a CCB and a beta-blocker, a dihydropyridine CCB and a non-dihydropyridine CCB, and a thiazide diuretic combined with a potassium-sparing diuretic. Some combinations are not recommended and may even be harmful, such as dual renin angiotensin aldosterone system inhibition. Currently available triple SPCs combine a renin angiotensin aldosterone system inhibitor with a CCB and a diuretic. Combination therapy as an initial approach is advocated in patients with a systolic BP more than 20 mmHg and/or a diastolic BP more than 10 mmHg above target and in patients with high CV risk. In addition, using SPCs has been stressed and favored in recent international guidelines. Recently

  19. The efficacy of tenofovir-based therapy in patients showing suboptimal response to entecavir-adefovir combination therapy

    PubMed Central

    Kim, Jeong Han; Ahn, Sung Hyun; Ko, Soon Young; Choe, Won Hyeok; Kim, Kyun-Hwan; Kwon, So Young

    2016-01-01

    Background/Aims: Before tenofovir (TDF) become available in South Korea, combination therapy with entecavir (ETV) and adefovir (ADV) was the most potent regimen for chronic hepatitis B (CHB) patients who fail to respond to rescue therapy for drug resistance. We analyzed the efficacy of ETV-ADV combination therapy and investigated the clinical and clonal results of TDF-based rescue therapy in CHB patients refractory to this combination. Methods: We retrospectively reviewed the medical records of CHB patients treated for up to 3 years with ETV-ADV combination therapy as a rescue therapy for drug resistance. In cases refractory to this combination, clinical and clonal analyses were performed for TDF-based rescue therapy. Results: The analysis was performed on 48 patients. Twelve patients achieved a virological response (VR) within 3 years. A VR was subsequently achieved in nine of the ten patients without a VR who switched to TDF monotherapy. A VR was also achieved in six of the seven patients who switched to lamivudine-TDF combination therapy, and in two of the two patients who switched to ETV-TDF combination therapy. In an in vitro susceptibility test, viral replication was detected with TDF monotherapy but not with ETV-TDF combination therapy. Conclusions: The efficacy of ETV-ADV combination therapy was insufficient in CHB patients who were refractory to rescue therapy. A more potent regimen such as ETV-TDF combination therapy may be considered in such refractory cases. PMID:27304549

  20. Multifunctional nanoparticle systems for combined chemoand photothermal cancer therapy

    NASA Astrophysics Data System (ADS)

    Wang, Hai; Zhao, Yu-Liang; Nie, Guang-Jun

    2013-06-01

    Hyperthermia has long been considered as an adjuvant therapy for treating various diseases. Cancer treatment exploiting hyperthermia shows great clinical potential for a wide range of tumors. Importantly, the efficacy of hyperthermal therapy has recently been enhanced by the development of functional nanomaterials. The unique physicochemical properties of nanomaterials afford the specific localization of hyperthermia to primary tumors and early-stage cancers. In particular, due to their high rate of light-to-heat conversion and their capacity to be activated by tissue-penetrating electromagnetic radiation, near-infrared (NIR) light-absorbing plasmonic nanomaterials have attracted considerable attention as candidates for noninvasive photothermal therapy. The purpose of this article is to provide a overview on the current development in multifunctional nanomaterials capable of combined hyperthermia-chemotherapy delivery.

  1. [Combined modality therapy for a patient with primary adrenal lymphoma].

    PubMed

    Matsuno, Teppei; Kuroda, Hiroyuki; Jomen, Wataru; Yoshida, Masahiro; Yamada, Michiko; Sato, Masanori; Abe, Tomoyuki; Sakurai, Tamaki; Fujii, Shigeyuki; Maeda, Masahiro; Fujita, Miri; Nagashima, Kazuo; Nojiri, Shuichi; Arihara, Yohei; Kato, Junji

    2014-04-01

    A 71-year-old man with malaise, anorexia, and weight loss was referred to our hospital from a clinic. Abdominal computed tomography(CT)revealed bilateral adrenal masses. An ultrasound-guided percutaneous needle biopsy of the adrenal grand indicated diffuse large B-cell lymphoma. A rapid adrenocorticotropic hormone(ACTH)test revealed primary adrenal failure. Rituximab-cyclophosphamide/doxorubicin/vincristine/prednisolone(common name, R-CHOP)therapy accompanied by intrathecal treatment was initiated along with steroid replacement therapy. After the fourth courses, a CT scan showed a reduction of the adrenal masses, and there was no[18F]-fluorodeoxyglucose(FDG)uptake in the adrenal masses. The patient has remained in metabolic complete remission. Subsequently, both adrenal lymphomas were irradiated. The patient has been disease-free for 6 months after the diagnosis of primary adrenal lymphoma. The combined modality of chemoradiation therapy plus intrathecal treatment could be effective for primary adrenal lymphoma with a poor prognosis. PMID:24743371

  2. Prediction of antifungal activity of gemini imidazolium compounds.

    PubMed

    Pałkowski, Łukasz; Błaszczyński, Jerzy; Skrzypczak, Andrzej; Błaszczak, Jan; Nowaczyk, Alicja; Wróblewska, Joanna; Kożuszko, Sylwia; Gospodarek, Eugenia; Słowiński, Roman; Krysiński, Jerzy

    2015-01-01

    The progress of antimicrobial therapy contributes to the development of strains of fungi resistant to antimicrobial drugs. Since cationic surfactants have been described as good antifungals, we present a SAR study of a novel homologous series of 140 bis-quaternary imidazolium chlorides and analyze them with respect to their biological activity against Candida albicans as one of the major opportunistic pathogens causing a wide spectrum of diseases in human beings. We characterize a set of features of these compounds, concerning their structure, molecular descriptors, and surface active properties. SAR study was conducted with the help of the Dominance-Based Rough Set Approach (DRSA), which involves identification of relevant features and relevant combinations of features being in strong relationship with a high antifungal activity of the compounds. The SAR study shows, moreover, that the antifungal activity is dependent on the type of substituents and their position at the chloride moiety, as well as on the surface active properties of the compounds. We also show that molecular descriptors MlogP, HOMO-LUMO gap, total structure connectivity index, and Wiener index may be useful in prediction of antifungal activity of new chemical compounds. PMID:25961015

  3. Prediction of Antifungal Activity of Gemini Imidazolium Compounds

    PubMed Central

    Pałkowski, Łukasz; Błaszczyński, Jerzy; Skrzypczak, Andrzej; Błaszczak, Jan; Nowaczyk, Alicja; Wróblewska, Joanna; Kożuszko, Sylwia; Gospodarek, Eugenia; Słowiński, Roman; Krysiński, Jerzy

    2015-01-01

    The progress of antimicrobial therapy contributes to the development of strains of fungi resistant to antimicrobial drugs. Since cationic surfactants have been described as good antifungals, we present a SAR study of a novel homologous series of 140 bis-quaternary imidazolium chlorides and analyze them with respect to their biological activity against Candida albicans as one of the major opportunistic pathogens causing a wide spectrum of diseases in human beings. We characterize a set of features of these compounds, concerning their structure, molecular descriptors, and surface active properties. SAR study was conducted with the help of the Dominance-Based Rough Set Approach (DRSA), which involves identification of relevant features and relevant combinations of features being in strong relationship with a high antifungal activity of the compounds. The SAR study shows, moreover, that the antifungal activity is dependent on the type of substituents and their position at the chloride moiety, as well as on the surface active properties of the compounds. We also show that molecular descriptors MlogP, HOMO-LUMO gap, total structure connectivity index, and Wiener index may be useful in prediction of antifungal activity of new chemical compounds. PMID:25961015

  4. Combinational chelation therapy abrogates lead-induced neurodegeneration in rats.

    PubMed

    Pachauri, Vidhu; Saxena, Geetu; Mehta, Ashish; Mishra, Deepshikha; Flora, Swaran J S

    2009-10-15

    Lead, a ubiquitous and potent neurotoxicant causes oxidative stress which leads to numerous neurobehavioral and physiological alterations. The ability of lead to bind sulfhydryl groups or compete with calcium could be one of the reasons for its debilitating effects. In the present study, we addressed: i) if chelation therapy could circumvent the altered oxidative stress and prevent neuronal apoptosis in chronic lead-intoxicated rats, ii) whether chelation therapy could reverse biochemical and behavioral changes, and iii) if mono or combinational therapy with captopril (an antioxidant) and thiol chelating agents (DMSA/MiADMSA) is more effective than individual thiol chelator in lead-exposed rats. Results indicated that lead caused a significant increase in reactive oxygen species, nitric oxide, and intracellular free calcium levels along with altered behavioral abnormalities in locomotor activity, exploratory behavior, learning, and memory that were supported by changes in neurotransmitter levels. A fall in membrane potential, release of cytochrome c, and DNA damage indicated mitochondrial-dependent apoptosis. Most of these alterations showed significant recovery following combined therapy with captopril with MiADMSA and to a smaller extend with captopril+DMSA over monotherapy with these chelators. It could be concluded from our present results that co-administration of a potent antioxidant (like captopril) might be a better treatment protocol than monotherapy to counter lead-induced oxidative stress. The major highlight of the work is an interesting experimental evidence of the efficacy of combinational therapy using an antioxidant with a thiol chelator in reversing neurological dystrophy caused due to chronic lead exposure in rats. PMID:19595699

  5. Combinational chelation therapy abrogates lead-induced neurodegeneration in rats

    SciTech Connect

    Pachauri, Vidhu; Saxena, Geetu; Mehta, Ashish; Mishra, Deepshikha; Flora, Swaran J.S.

    2009-10-15

    Lead, a ubiquitous and potent neurotoxicant causes oxidative stress which leads to numerous neurobehavioral and physiological alterations. The ability of lead to bind sulfhydryl groups or compete with calcium could be one of the reasons for its debilitating effects. In the present study, we addressed: i) if chelation therapy could circumvent the altered oxidative stress and prevent neuronal apoptosis in chronic lead-intoxicated rats, ii) whether chelation therapy could reverse biochemical and behavioral changes, and iii) if mono or combinational therapy with captopril (an antioxidant) and thiol chelating agents (DMSA/MiADMSA) is more effective than individual thiol chelator in lead-exposed rats. Results indicated that lead caused a significant increase in reactive oxygen species, nitric oxide, and intracellular free calcium levels along with altered behavioral abnormalities in locomotor activity, exploratory behavior, learning, and memory that were supported by changes in neurotransmitter levels. A fall in membrane potential, release of cytochrome c, and DNA damage indicated mitochondrial-dependent apoptosis. Most of these alterations showed significant recovery following combined therapy with captopril with MiADMSA and to a smaller extend with captopril + DMSA over monotherapy with these chelators. It could be concluded from our present results that co-administration of a potent antioxidant (like captopril) might be a better treatment protocol than monotherapy to counter lead-induced oxidative stress. The major highlight of the work is an interesting experimental evidence of the efficacy of combinational therapy using an antioxidant with a thiol chelator in reversing neurological dystrophy caused due to chronic lead exposure in rats.

  6. Precision medicine and personalized breast cancer: combination pertuzumab therapy

    PubMed Central

    Reynolds, Kerry; Sarangi, Sasmit; Bardia, Aditya; Dizon, Don S

    2014-01-01

    Trastuzumab (Herceptin), a monoclonal antibody directed against the human epidermal growth-factor receptor 2 (HER2), is the poster child for antibody-based targeted therapy in breast cancer. Pertuzumab, another humanized monoclonal antibody, binds to a different domain of HER2 and prevents the formation of HER2:HER3 dimers, which is the most potent heterodimer in the HER family. The combination of trastuzumab and pertuzumab has synergistic activity, and is associated with improved clinical outcomes. The US Food and Drug Administration (FDA) approved pertuzumab in combination with trastuzumab-based chemotherapy originally as first-line therapy for metastatic HER2-positive breast cancer in 2012, and more recently as neoadjuvant therapy for localized disease in 2013. Pertuzumab is the first neoadjuvant drug to receive accelerated approval by the FDA based on pathological complete response as the primary end point. In this article, we review the mechanism of action, pharmacokinetics, clinical efficacy, safety, and current role of pertuzumab in the management of breast cancer, as well as ongoing clinical trials and future directions regarding the utility of pertuzumab as a personalized therapeutic option for HER2-positive breast cancer. In the coming years, we anticipate increased utilization of neoadjuvant trials for drug development, biomarker discovery, and validation, and envision conduct of personalized breast cancer clinics in which therapies will be routinely selected based on genetic alterations in the tumor. Regardless of the targeted therapy combinations employed based on tumor genomic profile, trastuzumab and pertuzumab will likely continue to form the backbone of the personalized regimen for HER2-positive breast cancer. PMID:24715764

  7. Optimal therapy for chronic hepatitis B: hepatitis B virus combination therapy?

    PubMed

    Petersen, Jorg; Dandri, Maura

    2015-01-01

    Currently available antiviral treatment for chronic hepatitis B can be divided into two classes of therapeutic agents: pegylated interferon alpha (PEG-IFN) and nucleos(t)ide analogues (NAs). The major advantages of NAs are good tolerance and potent antiviral activity associated with high rates of on-treatment response to therapy. The advantages of PEG-IFN include a finite course of treatment, the absence of drug resistance, and an opportunity to obtain a durable post-treatment response to therapy. The use of these two antiviral agents with different mechanisms of action in combination is theoretically an attractive approach for treatment, either simultaneously, as sequential combination therapy (add-on), or even as an immediate switch from one agent to the other. Different NAs have also been combined in certain clinical situations. At present, several studies have confirmed certain virological advantages to combination therapies, but pivotal prospective studies demonstrating long-term clinical benefit to patients are still missing. Therefore, combination treatment, especially with PEG-IFN plus NAs, is not indicated and was not recommended by the European Association for the Study of the Liver Clinical Practice Guidelines written in 2012, while the guidelines for the use of combination NAs is limited to very few clinical situations. PMID:25529096

  8. [Combination biological therapy for fistular Crohn's disease: clinical demonstration].

    PubMed

    Knyazev, O V; Parfenov, A I; Shcherbakov, P L; Konoplyannikov, A G; Ruchkina, I N; Lischchinskaya, A A

    2014-01-01

    Perianal fistulas are the most common and frequently encountered types of fistulas in Crohn's disease (CD). They are incurable, may worsen quality of life in a patient and increase the risk of total bowel resection. Despite the significant impact of biological (anticytokine) therapy for fistular CD, treatment in this category of patients remains a difficult task with the high risk of recurrent CD. Mesenchymal stromal cells (MSCs) having immunomodulatory properties and a great regenerative potential are currently also used to treat fistulas in CD and perianal fistulas of another etiology. The given clinical case demonstrates that complete fistula healing could be achieved only after a few local administrations of MSCs in combination with infliximab and azathioprine. World and our experiences indicate that there is a need for randomized controlled trials with a sufficient number of patients to prove the efficacy of MSCs in the combination therapy of fistulas in CD. PMID:24772517

  9. Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy

    PubMed Central

    Hoobler, Eric K.; Rai, Ganesha; Warrilow, Andrew G. S.; Perry, Steven C.; Smyrniotis, Christopher J.; Jadhav, Ajit; Simeonov, Anton; Parker, Josie E.; Kelly, Diane E.; Maloney, David J.; Kelly, S. L.; Holman, Theodore R.

    2013-01-01

    We report the discovery of a novel dual inhibitor targeting fungal sterol 14α-demethylase (CYP51 or Erg11) and human 5-lipoxygenase (5-LOX) with improved potency against 5-LOX due to its reduction of the iron center by its phenylenediamine core. A series of potent 5-LOX inhibitors containing a phenylenediamine core, were synthesized that exhibit nanomolar potency and >30-fold selectivity against the LOX paralogs, platelet-type 12-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, and epithelial 15-human lipoxygenase type-2, and >100-fold selectivity against ovine cyclooxygenase-1 and human cyclooxygnease-2. The phenylenediamine core was then translated into the structure of ketoconazole, a highly effective anti-fungal medication for seborrheic dermatitis, to generate a novel compound, ketaminazole. Ketaminazole was found to be a potent dual inhibitor against human 5-LOX (IC50 = 700 nM) and CYP51 (IC50 = 43 nM) in vitro. It was tested in whole blood and found to down-regulate LTB4 synthesis, displaying 45% inhibition at 10 µM. In addition, ketaminazole selectively inhibited yeast CYP51 relative to human CYP51 by 17-fold, which is greater selectivity than that of ketoconazole and could confer a therapeutic advantage. This novel dual anti-fungal/anti-inflammatory inhibitor could potentially have therapeutic uses against fungal infections that have an anti-inflammatory component. PMID:23826084

  10. The contribution of Aspergillus fumigatus stress responses to virulence and antifungal resistance.

    PubMed

    Brown, Neil A; Goldman, Gustavo H

    2016-03-01

    Invasive aspergillosis has emerged as one of the most common life-threatening fungal disease of humans. The emergence of antifungal resistant pathogens represents a current and increasing threat to society. In turn, new strategies to combat fungal infection are urgently required. Fungal adaptations to stresses experienced within the human host are a prerequisite for the survival and virulence strategies of the pathogen. Here, we review the latest information on the signalling pathways in Aspergillus fumigatus that contribute to stress adaptations and virulence, while highlighting their potential as targets for the development of novel combinational antifungal therapies. PMID:26920884

  11. Clinically relevant drug-drug interactions between antiretrovirals and antifungals

    PubMed Central

    Vadlapatla, Ramya Krishna; Patel, Mitesh; Paturi, Durga K; Pal, Dhananjay; Mitra, Ashim K

    2015-01-01

    Introduction Complete delineation of the HIV-1 life cycle has resulted in the development of several antiretroviral drugs. Twenty-five therapeutic agents belonging to five different classes are currently available for the treatment of HIV-1 infections. Advent of triple combination antiretroviral therapy has significantly lowered the mortality rate in HIV patients. However, fungal infections still represent major opportunistic diseases in immunocompromised patients worldwide. Areas covered Antiretroviral drugs that target enzymes and/or proteins indispensable for viral replication are discussed in this article. Fungal infections, causative organisms, epidemiology and preferred treatment modalities are also outlined. Finally, observed/predicted drug-drug interactions between antiretrovirals and antifungals are summarized along with clinical recommendations. Expert opinion Concomitant use of amphotericin B and tenofovir must be closely monitored for renal functioning. Due to relatively weak interactive potential with the CYP450 system, fluconazole is the preferred antifungal drug. High itraconazole doses (> 200 mg/day) are not advised in patients receiving booster protease inhibitor (PI) regimen. Posaconazole is contraindicated in combination with either efavirenz or fosamprenavir. Moreover, voriconazole is contraindicated with high-dose ritonavir-boosted PI. Echino-candins may aid in overcoming the limitations of existing antifungal therapy. An increasing number of documented or predicted drug-drug interactions and therapeutic drug monitoring may aid in the management of HIV-associated opportunistic fungal infections. PMID:24521092

  12. More is better: combination therapies for myelodysplastic syndromes.

    PubMed

    Ornstein, Moshe C; Mukherjee, Sudipto; Sekeres, Mikkael A

    2015-03-01

    The myelodysplastic syndromes (MDS) are a heterogenous collection of clonal hematopoietic malignancies that exist as a subgroup of the myeloid neoplasms as classified by the World Health Organization (WHO). They are characterized by ineffective hematopoiesis, subsequent cytopenias, transformation to acute myeloid leukemia (AML), and poor overall survival. There are currently three FDA-approved medications for MDS; lenalidomide, azacitidine, and decitabine. The role of these agents is to diminish the clinical impact of MDS and delay its progression to AML. However, despite known results with these monotherapies, recent clinical trials with a variety of combinations for MDS have demonstrated promising results. These trials include combinations of hypomethylating agents, histone deacetylase inhibitors, growth factors, and chemotherapy among others. In this paper we review the current literature on combination therapies in MDS, analyze on-going and concluded trials, and suggest future possibilities for combination strategies in MDS. PMID:25659727

  13. Intraocular pressure-lowering combination therapies with prostaglandin analogues.

    PubMed

    Aptel, Florent; Chiquet, Christophe; Romanet, Jean-Paul

    2012-07-01

    Intraocular pressure (IOP) reduction is currently the only therapeutic approach demonstrated to preserve visual function in patients with glaucoma. The first line of glaucoma treatment consists of topical IOP-lowering medications, usually initiated as monotherapy. A significant proportion of patients require more than one medication to reach a target IOP at which optic nerve damage will not progress. As prostaglandin analogues (PGAs) are the most effective class for reducing IOP, one of the other commonly used classes (β-adrenoceptor antagonist [β-blocker], carbonic anhydrase inhibitor or α(2)-adrenoceptor agonist) is frequently combined with a PGA. In the last decade, the use of fixed combinations containing two medications in a single bottle has steadily increased. Fixed combinations have the potential to simplify the dosing regimen, increase patient adherence, avoid the washout effect of the second drop on the first medication instilled, decrease exposure to preservatives and, sometimes, reduce the cost of treatment. Clinical trials have evaluated PGA-based fixed combinations versus unfixed combinations (individual components administered concomitantly) or versus individual monotherapies; however, any advantage that the fixed combinations may have in terms of IOP-lowering efficacy is still debated. For these reasons, the PGA-based fixed combinations are not approved by regulatory authorities in some countries, such as the US. We review the published studies evaluating the efficacy and tolerability of the IOP-lowering unfixed and fixed combination therapies with PGAs. Regarding unfixed combinations, the review shows that α(2)-adrenergic agonists-PGA and carbonic anhydrase inhibitor-PGA combinations seem to be at least as effective at reducing IOP as the β-blocker-PGA combinations. As for the fixed combinations, the review shows that the three PGA-timolol fixed combinations are more effective than their component medications used separately as monotherapy and

  14. Initial dual oral combination therapy in pulmonary arterial hypertension.

    PubMed

    Sitbon, Olivier; Sattler, Caroline; Bertoletti, Laurent; Savale, Laurent; Cottin, Vincent; Jaïs, Xavier; De Groote, Pascal; Chaouat, Ari; Chabannes, Céline; Bergot, Emmanuel; Bouvaist, Hélène; Dauphin, Claire; Bourdin, Arnaud; Bauer, Fabrice; Montani, David; Humbert, Marc; Simonneau, Gérald

    2016-06-01

    Treatment for pulmonary arterial hypertension (PAH) has been underpinned by single-agent therapy to which concomitant drugs are added sequentially when pre-defined treatment goals are not met.This retrospective analysis of real-world clinical data in 97 patients with newly diagnosed PAH (86% in New York Heart Association functional class III-IV) explored initial dual oral combination treatment with bosentan plus sildenafil (n=61), bosentan plus tadalafil (n=17), ambrisentan plus tadalafil (n=11) or ambrisentan plus sildenafil (n=8).All regimens were associated with significant improvements in functional class, exercise capacity, dyspnoea and haemodynamic indices after 4 months of therapy. Over a median follow-up period of 30 months, 75 (82%) patients were still alive, 53 (71%) of whom received only dual oral combination therapy. Overall survival rates were 97%, 94% and 83% at 1, 2 and 3 years, respectively, and 96%, 94% and 84%, respectively, for the patients with idiopathic PAH, heritable PAH and anorexigen-induced PAH. Expected survival rates calculated from the French equation for the latter were 86%, 75% and 66% at 1, 2 and 3 years, respectively.Initial combination of oral PAH-targeted medications may offer clinical benefits, especially in PAH patients with severe haemodynamic impairment. PMID:26989105

  15. Combination pharmacological therapies for the management of benign prostatic hyperplasia.

    PubMed

    Cohen, Seth A; Parsons, J Kellogg

    2012-04-01

    Benign prostatic hyperplasia (BPH) is a highly prevalent condition of older men caused by unregulated growth of the prostate gland. Clinical trials of medical therapy for BPH have consistently demonstrated that combined therapy with an α(1)-adrenergic receptor (AR) antagonist and a 5α-reductase inhibitor is superior to either agent alone. The addition of anticholinergic therapy to a treatment regimen could effectively improve symptoms in men with persistent storage lower urinary tract symptoms (LUTS) who have not seen a benefit with an α(1)-AR antagonist or 5α-reductase inhibitor. Among α(1)-AR antagonists, doxazosin, terazosin, tamsulosin, and alfuzosin, although with slight differences in adverse event profiles, are equivalent in effectiveness and efficacy. No data in the form of direct comparator trials exist to suggest a difference in clinical efficacy of finasteride and dutasteride, the two 5α-reductase inhibitors currently available. Current American Urological Association guidelines do not recommend phytotherapy or dietary supplements in any combination for the medical management of BPH. The current literature supports the safety and efficacy of the combination of an α(1)-AR antagonist and a 5α-reductase inhibitor in the treatment of symptomatic BPH and, in select patients, the use of an α(1)-AR antagonist and anticholinergic medication in the treatment of LUTS suggestive of BPH. PMID:22428659

  16. Characterization of Tamoxifen as an Antifungal Agent Using the Yeast Schizosaccharomyces Pombe Model Organism.

    PubMed

    Zhang, Xibo; Fang, Yue; Jaiseng, Wurentuya; Hu, Lingling; Lu, Yabin; Ma, Yan; Furuyashiki, Tomoyuki

    2015-01-01

    Tamoxifen, a selective estrogen receptor modulator used for managing breast cancer, is known to have antifungal activity. However, its molecular mechanism remains unknown. Using the fission yeast Schizosaccharomyces pombe as a model organism, we have explored the mechanism involved in antifungal action of tamoxifen. Since tamoxifen was shown to inhibit the binding of calmodulin to calcineurin in fungi, we first examined involvement of these molecules and found that overexpression of a catalytic subunit of calcineurin and its constitutively active mutant as well as calmodulin increases tamoxifen sensitivity. Since terbinafine and azoles inhibit enzymes for ergosterol biosynthesis, Erg1 and Erg11, for their antifungal actions, we also examined involvement of these molecules. Overexpression of Erg1 and Erg11 reduced the sensitivity to terbinafine and azoles, respectively, but increased tamoxifen sensitivity, suggesting that ergosterol biosynthesis is differently related to the action of tamoxifen and those of terbinafine and azoles. To elucidate molecules involved in tamoxifen action, we performed a genome-wide screen for altered sensitivity to tamoxifen using a fission yeast gene deletion library, and identified various hypersensitive and resistant mutants to this drug. Notably, these mutants are rarely overlapped with those identified in similar genetic screens with currently used antifungals, suggesting a novel mode of antifungal action. Furthermore, tamoxifen augmented antifungal actions of terbinafine and azoles, suggesting synergetic actions between these drugs. Therefore, our findings suggest that calmodulin-calcineurin pathway and ergosterol biosynthesis are related to antifungal action of tamoxifen, and propose novel targets for antifungal development as well as combined therapy with tamoxifen for fungal diseases. PMID:26628015

  17. Winter depression recurrence one year after cognitive-behavioral therapy, light therapy, or combination treatment.

    PubMed

    Rohan, Kelly J; Roecklein, Kathryn A; Lacy, Timothy J; Vacek, Pamela M

    2009-09-01

    The central public health challenge in the management of seasonal affective disorder (SAD) is prevention of depression recurrence each fall/winter season. The need for time-limited treatments with enduring effects is underscored by questionable long-term compliance with clinical practice guidelines recommending daily light therapy during the symptomatic months each year. We previously developed a SAD-tailored group cognitive-behavioral therapy (CBT) and tested its acute efficacy in 2 pilot studies. Here, we report an intent-to-treat (ITT) analysis of outcomes during the subsequent winter season (i.e., approximately 1 year after acute treatment) using participants randomized to CBT, light therapy, and combination treatment across our pilot studies (N=69). We used multiple imputation to estimate next winter outcomes for the 17 individuals who dropped out during treatment, were withdrawn from protocol, or were lost to follow-up. The CBT (7.0%) and combination treatment (5.5%) groups had significantly smaller proportions of winter depression recurrences than the light therapy group (36.7%). CBT alone, but not combination treatment, was also associated with significantly lower interviewer- and patient-rated depression severity at 1 year as compared to light therapy alone. Among completers who provided 1-year data, all statistically significant differences between the CBT and light therapy groups persisted after adjustment for ongoing treatment with light therapy, antidepressants, and psychotherapy. If these findings are replicated, CBT could represent a more effective, practical, and palatable approach to long-term SAD management than light therapy. PMID:19647524

  18. Combined immunomodulator and antimicrobial therapy eliminates polymicrobial sepsis and modulates cytokine production in combined injured mice

    PubMed Central

    Elliott, Thomas B.; Bolduc, David L.; Ledney, G. David; Kiang, Juliann G.; Fatanmi, Oluseyi O.; Wise, Stephen Y.; Romaine, Patricia L. P.; Newman, Victoria L.; Singh, Vijay K.

    2015-01-01

    Purpose: A combination therapy for combined injury (CI) using a non-specific immunomodulator, synthetic trehalose dicorynomycolate and monophosphoryl lipid A (STDCM-MPL), was evaluated to augment oral antimicrobial agents, levofloxacin (LVX) and amoxicillin (AMX), to eliminate endogenous sepsis and modulate cytokine production. Materials and methods: Female B6D2F1/J mice received 9.75 Gy cobalt-60 gamma-radiation and wound. Bacteria were isolated and identified in three tissues. Incidence of bacteria and cytokines were compared between treatment groups. Results: Results demonstrated that the lethal dose for 50% at 30 days (LD50/30) of B6D2F1/J mice was 9.42 Gy. Antimicrobial therapy increased survival in radiation-injured (RI) mice. Combination therapy increased survival after RI and extended survival time but did not increase survival after CI. Sepsis began five days earlier in CI mice than RI mice with Gram-negative species predominating early and Gram-positive species increasing later. LVX plus AMX eliminated sepsis in CI and RI mice. STDCM-MPL eliminated Gram-positive bacteria in CI and most RI mice but not Gram-negative. Treatments significantly modulated 12 cytokines tested, which pertain to wound healing or elimination of infection. Conclusions: Combination therapy eliminates infection and prolongs survival time but does not assure CI mouse survival, suggesting that additional treatment for proliferative-cell recovery is required. PMID:25994812

  19. Azilsartan/chlorthalidone combination therapy for blood pressure control

    PubMed Central

    Cheng, Judy WM

    2013-01-01

    Background Edarbyclor® is a combined angiotensin receptor blocker (ARB) and thiazide-like diuretic (azilsartan and chlorthalidone), and was approved on December 20, 2011 by the US Food and Drug Administration (FDA) for hypertension management. Objective To review the pharmacology, pharmacokinetics, efficacy, safety, tolerability, and role of azilsartan plus chlorthalidone for hypertension management. Methods Peer-reviewed clinical trials, review articles, and relevant treatment guidelines, were identified from the databases MEDLINE and Current Contents (both 1966 to February 15, 2013, inclusive) using search terms “azilsartan”, “chlorthalidone”, “pharmacology”, “pharmacokinetics”, “pharmacodynamics”, “pharmacoeconomics”, and “cost-effectiveness”. The FDA website, as well as manufacturer prescribing information, was also reviewed to identify other relevant information. Results Azilsartan is a new ARB with high affinity for the angiotensin 1 receptor, approved by the FDA for hypertension management. Unlike other ARBs, azilsartan has no clinical data supporting improvement in cardiovascular outcomes, and is not approved for indications other than hypertension, which a select few other ARBs may be used for (eg, diabetic nephropathy and heart failure). Chlorthalidone is a longer acting thiazide-like diuretic that has been demonstrated to improve cardiovascular outcomes. Combination treatment with azilsartan/chlorthalidone is effective for reducing blood pressure. Compared to olmesartan/hydrochlorothiazide and azilsartan/hydrochlorothiazide combinations, azilsartan/chlorthalidone appears to be more efficacious for reducing blood pressure. Conclusions Azilsartan/chlorthalidone can be considered an antihypertensive therapy option in patients for whom combination therapy is required (blood pressure >20 mmHg systolic or >10 mmHg diastolic above goal). Cost to patients and insurance coverage will probably determine whether azilsartan

  20. Potentiation of Azole Antifungals by 2-Adamantanamine

    PubMed Central

    Sun, Lingmei; Lister, Ida; Keating, John; Nantel, Andre; Long, Lisa; Ghannoum, Mahmoud; North, Jeffrey; Lee, Richard E.; Coleman, Ken; Dahl, Thomas; Lewis, Kim

    2013-01-01

    Azoles are among the most successful classes of antifungals. They act by inhibiting α-14 lanosterol demethylase in the ergosterol biosynthesis pathway. Oropharyngeal candidiasis (OPC) occurs in about 90% of HIV-infected individuals, and 4 to 5% are refractory to current therapies, including azoles, due to the formation of resistant biofilms produced in the course of OPC. We reasoned that compounds affecting a different target may potentiate azoles to produce increased killing and an antibiofilm therapeutic. 2-Adamantanamine (AC17) was identified in a screen for compounds potentiating the action of miconazole against biofilms of Candida albicans. AC17, a close structural analog to the antiviral amantadine, did not affect the viability of C. albicans but caused the normally fungistatic azoles to become fungicidal. Transcriptome analysis of cells treated with AC17 revealed that the ergosterol and filamentation pathways were affected. Indeed, cells exposed to AC17 had decreased ergosterol contents and were unable to invade agar. In vivo, the combination of AC17 and fluconazole produced a significant reduction in fungal tissue burden in a guinea pig model of cutaneous candidiasis, while each treatment alone did not have a significant effect. The combination of fluconazole and AC17 also showed improved efficacy (P value of 0.018) compared to fluconazole alone when fungal lesions were evaluated. AC17 is a promising lead in the search for more effective antifungal therapeutics. PMID:23689724

  1. Chemogenomics and orthology-based design of antibiotic combination therapies.

    PubMed

    Chandrasekaran, Sriram; Cokol-Cakmak, Melike; Sahin, Nil; Yilancioglu, Kaan; Kazan, Hilal; Collins, James J; Cokol, Murat

    2016-01-01

    Combination antibiotic therapies are being increasingly used in the clinic to enhance potency and counter drug resistance. However, the large search space of candidate drugs and dosage regimes makes the identification of effective combinations highly challenging. Here, we present a computational approach called INDIGO, which uses chemogenomics data to predict antibiotic combinations that interact synergistically or antagonistically in inhibiting bacterial growth. INDIGO quantifies the influence of individual chemical-genetic interactions on synergy and antagonism and significantly outperforms existing approaches based on experimental evaluation of novel predictions in Escherichia coli Our analysis revealed a core set of genes and pathways (e.g. central metabolism) that are predictive of antibiotic interactions. By identifying the interactions that are associated with orthologous genes, we successfully estimated drug-interaction outcomes in the bacterial pathogens Mycobacterium tuberculosis and Staphylococcus aureus, using the E. coli INDIGO model. INDIGO thus enables the discovery of effective combination therapies in less-studied pathogens by leveraging chemogenomics data in model organisms. PMID:27222539

  2. Combination therapies improve the anticancer activities of retinoids in neuroblastoma

    PubMed Central

    Cheung, Belamy B

    2015-01-01

    Most therapeutic protocols for child cancers use cytotoxic agents which have a narrow therapeutic index, and resulting in severe acute and chronic toxicities to normal tissues. Despite the fact that most child cancer patients achieve complete remission after chemotherapy, death still occurs due to relapse of persistent minimal residual disease (MRD) which remaining after initial cytotoxic chemotherapy. Advanced neuroblastoma (NB) is a leading cause of cancer deaths in young children. Retinoids are an important component of advanced NB therapy at the stage of MRD, yet half of all patients treated with 13-cis-retinoic acid still relapse and die. More effective combination therapies, with a lower side-effect profile, are required to improve outcomes for NB. Fenretinide or N-4-hydroxyphenyl retinamide is a synthetic derivative of retinoic acid which works on cancer cells through nuclear receptor-dependent and -independent signalling mechanisms. Moreover, several histone deacetylase inhibitors have entered early phase trials, and, suberoylanilide hydroxamic acid has been approved for use in adult cutaneous T cell lymphoma. A number of studies suggest that retinoid signal activation is necessary for histone deacetylase inhibitor activity. A better understanding of their mechanism of actions will lead to more evidence-based retinoid combination therapies. PMID:26677433

  3. Optical Imaging, Photodynamic Therapy and Optically-Triggered Combination Treatments

    PubMed Central

    Hasan, Tayyaba

    2015-01-01

    Optical imaging is becoming increasingly promising for real-time image-guided resections and combined with photodynamic therapy (PDT), a photochemistry-based treatment modality, optical approaches can be intrinsically “theranostic”. Challenges in PDT include precise light delivery, dosimetry and photosensitizer tumor localization to establish tumor selectivity, and like all other modalities, incomplete treatment and subsequent activation of molecular escape pathways are often attributable to tumor heterogeneity. Key advances in molecular imaging, target-activatable photosensitizers and optically active nanoparticles that provide both cytotoxicity and a drug release mechanism, have opened exciting avenues to meet these challenges. The focus of the review is optical imaging in the context of PDT but the general principles presented are applicable to many of the conventional approaches to cancer management. We highlight the role of optical imaging in providing structural, functional and molecular information regarding photodynamic mechanisms of action, thereby advancing PDT and PDT-based combination therapies of cancer. These advances represent a PDT renaissance with increasing applications of clinical PDT as a frontline cancer therapy working in concert with fluorescence-guided surgery, chemotherapy and radiation. PMID:26049699

  4. 5-Alpha-Reductase Inhibitors and Combination Therapy.

    PubMed

    Füllhase, Claudius; Schneider, Marc P

    2016-08-01

    By inhibiting the conversion from testosterone to dihydrotestosterone 5-Alpha reductase inhibitors (5ARIs) are able to hinder prostatic growth, shrink prostate volumes, and improve BPH-related LUTS. 5ARIs are particularly beneficial for patients with larger prostates (>30-40ml). Generally the side effects of 5ARI treatment are mild, and according to the FORTA classification 5ARIs are suitable for frail elderly. 5ARI / alpha-blocker (AB) combination therapy showed the best symptomatic outcome and risk reduction for clinical progression. Combining Phosphodieseterase type 5 inhbibitors (PDE5Is) with 5ARIs counteracts the negative androgenic sexual side effects of 5ARIs, and simultaneously combines their synergistic effects on LUTS. PMID:27476125

  5. Synergistic combination of direct plasma membrane damage and oxidative stress as a cause of antifungal activity of polyol macrolide antibiotic niphimycin.

    PubMed

    Nakayama, Keiji; Yamaguchi, Takafumi; Doi, Takeshi; Usuki, Yoshinosuke; Taniguchi, Makoto; Tanaka, Toshio

    2002-01-01

    The polyol macrolide niphimycin (NM) exhibited fungicidal activity against Saccharomyces cerevisiae cells accompanying the leakage of cytoplasmic components including nucleotide-like materials in addition to K+ at 10 microM or above. Such a dynamic change in the plasma membrane was observed upon treatment of cells with H2O2 but not with the polyene macrolide antibiotic amphotericin B (AmB). The NM-induced cell death could be prevented by the exogenous addition of phosphatidylcholine (PC) whereas such a protective effect was only weakly observed with ergosterol, the molecular target of AmB. NM-treated cells were further characterized with a dramatic loss of glutathione even at a dose of 5 microM or less, representing NM-triggered metabolic conversion of the antioxidant molecule. NM-treatment indeed accelerated the cellular production of reactive oxygen species (ROS) such as H2O2 detectable with a specific fluorescent probe in a dose-dependent manner. These results suggested a synergistic combination of direct plasma membrane damage and oxidative stress as a cause of antifungal activity of NM against S. cerevisiae. PMID:16233293

  6. Combination chemotherapy and radiation therapy for small cell carcinoma.

    PubMed

    Holoye, P Y; Samuels, M L; Lanzotti, V J; Smith, T; Barkley, H T

    1977-03-21

    A three-drug combination of the chemotherapeutic agents cyclophosphamide, vincristine sulfate, and doxorubicin hydrochloride was given to 45 patients with small cell bronchogenic carcinoma. In addition, patients with limited disease received radiation therapy to the primary tumor. The complete response rate was 44%, with a median survival of 50 weeks. The partial response rate was 29%, with a median survival of 35 weeks. Patients who did not respond to therapy showed a median survival of only 12 weeks. Twenty percent of the patients had their first recurrence in the brain, and the median survival from the time of disease recurrence was ten weeks. Bone marrow metastasis was encountered in 24% of the patient population, but this did not adversely affect survival. PMID:190427

  7. A novel temperature-responsive micelle for enhancing combination therapy

    PubMed Central

    Peng, Cheng-Liang; Chen, Yuan-I; Liu, Hung-Jen; Lee, Pei-Chi; Luo, Tsai-Yueh; Shieh, Ming-Jium

    2016-01-01

    A novel thermosensitive polymer p(N-isopropylacrylamide-co-poly[ethylene glycol] methyl ether acrylate)-block-poly(epsilon-caprolactone), p(NIPAAM-co-PEGMEA)-b-PCL, was synthesized and developed as nanomicelles. The hydrophobic heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin and the photosensitizer cyanine dye infrared-780 were loaded into the core of the micelles to achieve both chemotherapy and photothermal therapy simultaneously at the tumor site. The release of the drug could be controlled by varying the temperature due to the thermosensitive nature of the micelles. The micelles were less than 200 nm in size, and the drug encapsulation efficiency was >50%. The critical micelle concentrations were small enough to allow micelle stability upon dilution. Data from cell viability and animal experiments indicate that this combination treatment using photothermal therapy with chemotherapy had synergistic effects while decreasing side effects. PMID:27524894

  8. Cancer Nanomedicine: From Targeted Delivery to Combination Therapy

    PubMed Central

    Xu, Xiaoyang; Ho, William; Zhang, Xueqing; Bertrand, Nicolas; Farokhzad, Omid

    2015-01-01

    The advent of nanomedicine marks an unparalleled opportunity to advance the treatment of a variety of diseases, including cancer. The unique properties of nanoparticles, such as large surface-to volume ratio, small size, the ability to encapsulate a variety of drugs, and tunable surface chemistry, gives them many advantages over their bulk counterparts. This includes multivalent surface modification with targeting ligands, efficient navigation of the complex in vivo environment, increased intracellular trafficking, and sustained release of drug payload. These advantages make nanoparticles a mode of treatment potentially superior to conventional cancer therapies. This article highlights the most recent developments in cancer treatment using nanoparticles as drug-delivery vehicles, including promising opportunities in targeted and combination therapy. PMID:25656384

  9. Metastatic melanoma treatment: Combining old and new therapies.

    PubMed

    Davey, Ryan J; van der Westhuizen, Andre; Bowden, Nikola A

    2016-02-01

    Metastatic melanoma is an aggressive form of cancer characterised by poor prognosis and a complex etiology. Until 2010, the treatment options for metastatic melanoma were very limited. Largely ineffective dacarbazine, temozolamide or fotemustine were the only agents in use for 35 years. In recent years, the development of molecularly targeted inhibitors in parallel with the development of checkpoint inhibition immunotherapies has rapidly improved the outcomes for metastatic melanoma patients. Despite these new therapies showing initial promise; resistance and poor duration of response have limited their effectiveness as monotherapies. Here we provide an overview of the history of melanoma treatment, as well as the current treatments in development. We also discuss the future of melanoma treatment as we go beyond monotherapies to a combinatorial approach. Combining older therapies with the new molecular and immunotherapies will be the most promising way forward for treatment of metastatic melanoma. PMID:26616525

  10. A novel temperature-responsive micelle for enhancing combination therapy.

    PubMed

    Peng, Cheng-Liang; Chen, Yuan-I; Liu, Hung-Jen; Lee, Pei-Chi; Luo, Tsai-Yueh; Shieh, Ming-Jium

    2016-01-01

    A novel thermosensitive polymer p(N-isopropylacrylamide-co-poly[ethylene glycol] methyl ether acrylate)-block-poly(epsilon-caprolactone), p(NIPAAM-co-PEGMEA)-b-PCL, was synthesized and developed as nanomicelles. The hydrophobic heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin and the photosensitizer cyanine dye infrared-780 were loaded into the core of the micelles to achieve both chemotherapy and photothermal therapy simultaneously at the tumor site. The release of the drug could be controlled by varying the temperature due to the thermosensitive nature of the micelles. The micelles were less than 200 nm in size, and the drug encapsulation efficiency was >50%. The critical micelle concentrations were small enough to allow micelle stability upon dilution. Data from cell viability and animal experiments indicate that this combination treatment using photothermal therapy with chemotherapy had synergistic effects while decreasing side effects. PMID:27524894

  11. Complete reversal of hypertensive cardiomyopathy after initiating combined antihypertensive therapy.

    PubMed

    Holl, Marijn J; van de Poll, Sweder W; Michels, Michelle

    2016-01-01

    Hypertensive cardiomyopathy is a common complication of hypertension, with a prevalence ranging from 12% to 26%. It is associated with an increased cardiac mortality and morbidity. Lifestyle changes and antihypertensive therapy usually have a significant, but relatively small effect on left ventricular hypertrophy (LVH), which is associated with a reduction in cardiovascular risk. In this paper, we describe a 39-year-old woman with severe LVH. On transthoracic echocardiogram there was concentric LVH, systolic function was a mildly reduced and there was diastolic dysfunction grade III. After only 6 months of therapy with a combination of antihypertensive agents, the left ventricular mass index was reduced by 29%, systolic function was normal and the diastolic dysfunction improved to grade I. This paper shows that in hypertensive cardiomyopathy, even severe LVH can be completely reversible. PMID:27060071

  12. Reappraisal of trimodal combination therapy for maxillary sinus carcinoma

    SciTech Connect

    Shibuya, H.; Suzuki, S.; Horiuchi, J.; Takagi, M.; Okuyama, T.; Suzuki, H.; Takeda, M.

    1982-12-15

    The introduction of trimodal combination therapy (surgery + radiation + intraarterial infusion) for maxillary carcinoma resulted in a change in the sites of recurrence and no satisfactory improvement in the local control rate. To examine the cause of these phenomena, external carotid angiography was performed on 51 patients prior to the start of the therapy and the results of the treatment were studied. Angiographic findings indicated that maxillary carcinoma is fed not only by the maxillary artery, but also by the internal carotid, facial, transverse facial and other arteries from the external carotid artery. The multiplicity of feeders causes irregular distribution of the intraarterially infused antimetabolites. Irregular and local low distribution of antimetabolites may well bring about the high rate of recurrence. The results of intraarterial transcatheter Tc-99m-MAA injection were also in accord with the angiographic findings.

  13. Calcific Uremic Arteriolopathy on Multimodal Combination Therapy: Still Unmet Goal

    PubMed Central

    Malabu, Usman Hammawa; Manickam, Valli; Kan, George; Doherty, Susan Lynette; Sangla, Kunwarjit Singh

    2012-01-01

    Background. Calcific uremic arteriolopathy (CUA) or calciphylaxis though generally noted for its high mortality, recent case reports have shown promising results using single agent therapies. However, it is not clear whether combination therapeutic agents will improve course of the disease. Objective. To determine clinical outcome in subjects with CUA on multimodal treatment. Methods. All patients with end-stage renal failure (ESRF) at The Townsville Hospital, Australia, from April 1, 2006, to March 31, 2011, with diagnosis of CUA were retrospectively studied. Results. Six subjects with CUA (4 females and 2 males) were on various combination therapeutic agents comprising sodium thiosulphate, hyperbaric oxygen, prednisolone, cinacalcet, and parathyroidectomy in addition to intensified haemodialysis, specialist local wound care, and antibiotics. The wounds failed to heal in 3 patients while 5 of the 6 subjects died; cause of death being sepsis in 3 and myocardial infarction in 2. Conclusion. Prognosis of CUA remains poor in spite of multimodal combination therapy. Further prospective studies on a larger population are needed to verify our findings. PMID:22518312

  14. Combination of photodynamic therapy and immunotherapy - evolving role in dermatology

    NASA Astrophysics Data System (ADS)

    Wang, Xiu-Li; Wang, Hong-Wei; Huang, Zheng

    2008-02-01

    Photodynamic therapy (PDT) is a promising treatment modality. It offers alternative options in the treatment of cancer and vascular diseases. In cancer treatment, PDT has been used primarily for localized superficial or endoluminal malignant and premalignant conditions. More recently, its application has also been expanded to solid tumors. However, its antitumor efficacy remains debatable and its acceptance still variable. Pre-clinical studies demonstrate that, in addition to the primary local cytotoxicity, PDT might induce secondary host immune responses, which may further enhance PDT's therapeutic effects on primary tumor as well as metastasis. Therefore, PDT-induced local and systemic antitumor immune response might play an important role in successful control of malignant diseases. Furthermore, PDT's antitumor efficacy might also be enhanced through an effective immunoadjuvant or immunomodulator. Our recent clinical data also indicate that improved clinical outcomes can be obtained by a combination of PDT and immunomodulation therapy for the treatment of pre-malignant skin diseases. For instance, the combination of topical ALA-PDT and Imiquimod is effective for the treatment of genital bowenoid papulosis. This presentation will also report our preliminary data in developing combination approaches of PDT and immunotherapy for actinic keratosis (AK), basal cell carcinomas (BCCs) and Bowen's disease.

  15. Evaluating cost benefits of combination therapies for advanced melanoma

    PubMed Central

    Jensen, Ivar S.; Zacherle, Emily; Blanchette, Christopher M.; Zhang, Jie; Yin, Wes

    2016-01-01

    Background: Although a number of monoimmunotherapies and targeted therapies are available to treat BRAF+ advanced melanoma, response rates remain relatively low in the range of 22–53% with progression-free survival (PFS) in the range of 4.8–8.8 months. Recently, combination targeted therapies have improved response rates to about 66–69%, PFS to 11.0–12.6 months and overall survival (OS) to 25.1–25.6 months. While combination immunotherapies have improved response rates of 67 compared with 19–29% with monotherapies and improved PFS of 11.7 compared with 4.4–5.8 months with monotherapies, the OS benefit is yet to be established in phase 3 trials. As healthcare costs continue to rise, US payers have a predominant interest in assessing the value of available treatments. Therefore, a cost-benefit model was developed to evaluate the value of treating BRAF+ advanced melanoma with two combination therapies: nivolumab + ipilimumab (N+I) and dabrafenib + trametinib (D+T). Scope: The model was used to estimate total costs, total costs by expenditure category, cost per month of PFS and cost per responder for the payer, and societal perspectives of treating advanced melanoma patients with the BRAF V600 mutation using combination targeted therapy (D+T) or combination immunotherapy (N+I). The model followed patients from initiation of treatment to the point of progression or death. Deterministic and probabilistic sensitivity analyses were conducted to evaluate the robustness of the results and to understand the dispersion of simulated results. Findings: Based on a hypothetical payer with one million covered lives, it was expected that fourteen metastatic melanoma patients with the BRAF V600 mutation would be treated each year. Cost-benefit with N+I and D+T was simulated from the payer perspective. The cost per month of PFS for N+I was $22,162, while that for D+T was $17,716 (−$4,446 cost difference); the cost per responder for N+I was $388,746 and that for D+T was

  16. Efficacy of Olanzapine Combined Therapy for Patients Receiving Highly Emetogenic Chemotherapy Resistant to Standard Antiemetic Therapy

    PubMed Central

    Abe, Masakazu; Kasamatsu, Yuka; Kado, Nobuhiro; Kuji, Shiho; Tanaka, Aki; Takahashi, Nobutaka; Takekuma, Munetaka; Hirashima, Yasuyuki

    2015-01-01

    Objective. Olanzapine is proved to be effective for chemotherapy induced nausea and vomiting (CINV). But its efficacy in combination with standard antiemetic therapy is unknown. The purpose of this study is to prove the preventive effect of olanzapine for the prevention of CINV caused by highly emetogenic chemotherapy when used with standard antiemetic therapy. Method. Gynecologic cancer patients receiving cisplatin-based chemotherapy who had grade 2 or 3 nausea in overall phase (0–120 h after chemotherapy) despite standard therapy were assigned to this study. From the next cycles to cycles in which patients developed grade 2 or 3 nausea, they received olanzapine with standard therapy. 5 mg oral olanzapine was administered for 7 days from the day before chemotherapy. The effectiveness of preventive administration of olanzapine was evaluated retrospectively. The primary endpoint was nausea control rate (grade 0 or 1) with olanzapine. Results. Fifty patients were evaluable. The nausea control rate with olanzapine was improved from 58% to 98% in acute phase (0–24 h after chemotherapy) and 2% to 94% in delayed phase (24–120 h after chemotherapy). In overall phase, the nausea control rate improved from 0% to 92%, and it was statistically significant (P < 0.001). Conclusion. Preventive use of olanzapine combined with standard antiemetic therapy showed improvement in control of refractory nausea. PMID:26425564

  17. Enhancing Photodynamyc Therapy Efficacy by Combination Therapy: Dated, Current and Oncoming Strategies

    PubMed Central

    Postiglione, Ilaria; Chiaviello, Angela; Palumbo, Giuseppe

    2011-01-01

    Combination therapy is a common practice in many medical disciplines. It is defined as the use of more than one drug to treat the same disease. Sometimes this expression describes the simultaneous use of therapeutic approaches that target different cellular/molecular pathways, increasing the chances of killing the diseased cell. This short review is concerned with therapeutic combinations in which PDT (Photodynamyc Therapy) is the core therapeutic partner. Besides the description of the principal methods used to assess the efficacy attained by combinations in respect to monotherapy, this review describes experimental results in which PDT was combined with conventional drugs in different experimental conditions. This inventory is far from exhaustive, as the number of photosensitizers used in combination with different drugs is very large. Reports cited in this work have been selected because considered representative. The combinations we have reviewed include the association of PDT with anti-oxidants, chemotherapeutics, drugs targeting topoisomerases I and II, antimetabolites and others. Some paragraphs are dedicated to PDT and immuno-modulation, others to associations of PDT with angiogenesis inhibitors, receptor inhibitors, radiotherapy and more. Finally, a look is dedicated to combinations involving the use of natural compounds and, as new entries, drugs that act as proteasome inhibitors. PMID:24212824

  18. The Role of Antifungals against Candida Biofilm in Catheter-Related Candidemia

    PubMed Central

    Bouza, Emilio; Guinea, Jesús; Guembe, María

    2014-01-01

    Catheter-related bloodstream infection (C-RBSI) is one of the most frequent nosocomial infections. It is associated with high rates of morbidity and mortality. Candida spp. is the third most common cause of C-RBSI after coagulase-negative staphylococci and Staphylococcus aureus and is responsible for approximately 8% of episodes. The main cause of catheter-related candidemia is the ability of some Candida strains—mainly C. albicans and C. parapsilosis—to produce biofilms. Many in vitro and in vivo models have been designed to assess the activity of antifungal drugs against Candida biofilms. Echinocandins have proven to be the most active antifungal drugs. Potential options in situations where the catheter cannot be removed include the combination of systemic and lock antifungal therapy. However, well-designed and -executed clinical trials must be performed before firm recommendations can be issued. PMID:27025612

  19. Antifungal and antiviral products of marine organisms.

    PubMed

    Cheung, Randy Chi Fai; Wong, Jack Ho; Pan, Wen Liang; Chan, Yau Sang; Yin, Cui Ming; Dan, Xiu Li; Wang, He Xiang; Fang, Evandro Fei; Lam, Sze Kwan; Ngai, Patrick Hung Kui; Xia, Li Xin; Liu, Fang; Ye, Xiu Yun; Zhang, Guo Qing; Liu, Qing Hong; Sha, Ou; Lin, Peng; Ki, Chan; Bekhit, Adnan A; Bekhit, Alaa El-Din; Wan, David Chi Cheong; Ye, Xiu Juan; Xia, Jiang; Ng, Tzi Bun

    2014-04-01

    Marine organisms including bacteria, fungi, algae, sponges, echinoderms, mollusks, and cephalochordates produce a variety of products with antifungal activity including bacterial chitinases, lipopeptides, and lactones; fungal (-)-sclerotiorin and peptaibols, purpurides B and C, berkedrimane B and purpuride; algal gambieric acids A and B, phlorotannins; 3,5-dibromo-2-(3,5-dibromo-2-methoxyphenoxy)phenol, spongistatin 1, eurysterols A and B, nortetillapyrone, bromotyrosine alkaloids, bis-indole alkaloid, ageloxime B and (-)-ageloxime D, haliscosamine, hamigeran G, hippolachnin A from sponges; echinoderm triterpene glycosides and alkene sulfates; molluscan kahalalide F and a 1485-Da peptide with a sequence SRSELIVHQR; and cepalochordate chitotriosidase and a 5026.9-Da antifungal peptide. The antiviral compounds from marine organisms include bacterial polysaccharide and furan-2-yl acetate; fungal macrolide, purpurester A, purpurquinone B, isoindolone derivatives, alterporriol Q, tetrahydroaltersolanol C and asperterrestide A, algal diterpenes, xylogalactofucan, alginic acid, glycolipid sulfoquinovosyldiacylglycerol, sulfated polysaccharide p-KG03, meroditerpenoids, methyl ester derivative of vatomaric acid, lectins, polysaccharides, tannins, cnidarian zoanthoxanthin alkaloids, norditerpenoid and capilloquinol; crustacean antilipopolysaccharide factors, molluscan hemocyanin; echinoderm triterpenoid glycosides; tunicate didemnin B, tamandarins A and B and; tilapia hepcidin 1-5 (TH 1-5), seabream SauMx1, SauMx2, and SauMx3, and orange-spotted grouper β-defensin. Although the mechanisms of antifungal and antiviral activities of only some of the aforementioned compounds have been elucidated, the possibility to use those known to have distinctly different mechanisms, good bioavailability, and minimal toxicity in combination therapy remains to be investigated. It is also worthwhile to test the marine antimicrobials for possible synergism with existing drugs. The prospects of

  20. Identification of Synergistic, Clinically Achievable, Combination Therapies for Osteosarcoma

    PubMed Central

    Yu, Diana; Kahen, Elliot; Cubitt, Christopher L.; McGuire, Jeremy; Kreahling, Jenny; Lee, Jae; Altiok, Soner; Lynch, Conor C.; Sullivan, Daniel M.; Reed, Damon R.

    2015-01-01

    Systemic therapy has improved osteosarcoma event-free and overall survival, but 30–50% of patients originally diagnosed will have progressive or recurrent disease, which is difficult to cure. Osteosarcoma has a complex karyotype, with loss of p53 in the vast majority of cases and an absence of recurrent, targetable pathways. In this study, we explored 54 agents that are clinically approved for other oncologic indications, agents in active clinical development, and others with promising preclinical data in osteosarcoma at clinically achievable concentrations in 5 osteosarcoma cell lines. We found significant single-agent activity of multiple agents and tested 10 drugs in all permutations of two-drug combinations to define synergistic combinations by Chou and Talalay analysis. We then evaluated order of addition to choose the combinations that may be best to translate to the clinic. We conclude that the repurposing of chemotherapeutics in osteosarcoma by using an in vitro system may define novel drug combinations with significant in vivo activity. In particular, combinations of proteasome inhibitors with histone deacetylase inhibitors and ixabepilone and MK1775 demonstrated excellent activity in our assays. PMID:26601688

  1. Use of a combination of an anti-inflammatory steroid, an antibacterial agent and an antifungal in dermatological practice.

    PubMed

    Pellerano, S

    1985-04-01

    Forty patients with skin diseases of various origins were treated with a combination of three creams, the respective bases of which were clobetasone butyrate, sodium fusidate and ketoconazole. Satisfactory results were obtained in 97.5% of cases, with remission of symptoms and good healing of lesions. Tolerance was excellent in 97.5% of cases, with only one patient complaining of burning sensations after the applications. PMID:3888858

  2. Treatment of dermatological conditions with a combination of an antibacterial agent, an antifungal agent and an antiinflammatory steroid.

    PubMed

    Franchi, G

    1985-09-01

    Thirty-eight patients suffering from dermatological conditions of various natures were treated by means of the simultaneous application of a combination of three creams, the bases of which were sodium fusidate, ketoconazole and clobetasone butyrate respectively. Positive results, in the form of remission of symptoms, were obtained in 86.7% of the cases. Local tolerance was excellent in all cases and no adverse reactions were observed. PMID:4055161

  3. Comparative evaluation of three antifungal susceptibility test methods for Candida albicans isolates and correlation with response to fluconazole therapy.

    PubMed Central

    Ruhnke, M; Schmidt-Westhausen, A; Engelmann, E; Trautmann, M

    1996-01-01

    In vitro susceptibilities were determined for 56 Candida albicans isolates obtained from the oral cavities of 41 patients with human immunodeficiency virus infection. The agents tested included fluconazole, itraconazole, ketoconazole, flucytosine, and amphotericin B. MICs were determined by the broth microdilution technique following National Committee for Clinical Laboratory Standards document M27-P (M27-P micro), a broth microdilution technique using high-resolution medium (HR micro), and the Etest with solidified yeast-nitrogen base agar. The in vitro findings were correlated with in vivo response to fluconazole therapy for oropharyngeal candidiasis. For all C. albicans isolates from patients with oropharyngeal candidiasis not responding to fluconazole MICs were found to be > or = 6.25 micrograms/ml by the M27-P micro method and > or = 25 micrograms/ml by the HR micro method as well as the Etest. However, for several C. albicans isolates from patients who responded to fluconazole therapy MICs found to be above the suggested breakpoints of resistance. The appropriate rank order of best agreement between the M27-P micro method and HR micro method was amphotericin B > fluconazole > flucytosine > ketoconazole > itraconazole. The appropriate rank order with best agreement between the M27-P micro method and the Etest was flucytosine > amphotericin B > fluconazole > ketoconazole > or = itraconazole. It could be concluded that a good correlation between in vitro resistance and clinical failure was found with all methods. However, the test methods used in this study did not necessarily predict clinical response to therapy with fluconazole. PMID:8940474

  4. Combination topical therapy in the treatment of acne.

    PubMed

    Del Rosso, James Q

    2006-08-01

    Many medications are available for the management of acne. The armamentarium includes topical retinoids (ie, adapalene, tazarotene, tretinoin), antimicrobial and antibacterial agents (ie, benzoyl peroxide, clindamycin, erythromycin, sulfacetamide with or without sulfur), oral antibiotics (ie, doxycycline, minocycline, tetracycline), hormonal agents (ie, oral contraceptives, spironolactone), and systemic retinoids (ie, isotretinoin). Acne usually is treated with combination therapy to address its multifactorial pathophysiology. The combination of clindamycin 1%-benzoyl peroxide 5% gel, available as a stable formulation in a single tube, is efficacious and well-tolerated. The product's excipients, glycerin and dimethicone, minimize treatment-related irritation, thereby increasing patient compliance. Clindamycin-benzoyl peroxide may be well-tolerated when applied with topical retinoids, creating a more targeted and complete treatment strategy. PMID:17966494

  5. Bioengineered lysozyme in combination therapies for Pseudomonas aeruginosa lung infections.

    PubMed

    Griswold, Karl E; Bement, Jenna L; Teneback, Charlotte C; Scanlon, Thomas C; Wargo, Matthew J; Leclair, Laurie W

    2014-01-01

    There is increasing urgency in the battle against drug-resistant bacterial pathogens, and this public health crisis has created a desperate need for novel antimicrobial agents. Recombinant human lysozyme represents one interesting candidate for treating pulmonary infections, but the wild type enzyme is subject to electrostatic mediated inhibition by anionic biopolymers that accumulate in the infected lung. We have redesigned lysozyme's electrostatic potential field, creating a genetically engineered variant that is less susceptible to polyanion inhibition, yet retains potent bactericidal activity. A recent publication demonstrated that the engineered enzyme outperforms wild type lysozyme in a murine model of Pseudomonas aeruginosa lung infection. Here, we expand upon our initial studies and consider dual therapies that combine lysozymes with an antimicrobial peptide. Consistent with our earlier results, the charge modified lysozyme combination outperformed its wild type counterpart, yielding more than an order-of-magnitude reduction in bacterial burden following treatment with a single dose. PMID:24637705

  6. Efficacy of combined photothermal therapy and chemotherapeutic drugs

    NASA Astrophysics Data System (ADS)

    Madsen, Steen J.; Shih, En-Chung; Hirschberg, Henry

    2015-03-01

    Hyperthermia has been shown to enhance the effects of chemotherapeutic agents in a wide variety of cancers. The purpose of this study was to investigate the combined effects of a number of commonly used chemotherapeutic drugs (bleomycin, doxorubicin and cisplatin) with photothermal therapy (PTT)-induced hyperthermia in an in vitro system consisting of human head and neck squamous carcinoma cells and murine lymphocytic monocytes which were used as delivery vehicles for gold-silica nanoshells (AuNS). PTT was accomplished via near infra-red (NIR) irradiation of AuNS. The results showed that PTT combined with cisplatin resulted in only a mild degree of synergism while additive effects were observed for concurrent treatments of PTT and doxorubicin and PTT and bleomycin.

  7. Pharmacokinetic drug interactions with clopidogrel: updated review and risk management in combination therapy

    PubMed Central

    Wang, Zhi-Yu; Chen, Meng; Zhu, Ling-Ling; Yu, Lu-Shan; Zeng, Su; Xiang, Mei-Xiang; Zhou, Quan

    2015-01-01

    Background Coprescribing of clopidogrel and other drugs is common. Available reviews have addressed the drug–drug interactions (DDIs) when clopidogrel is as an object drug, or focused on combination use of clopidogrel and a special class of drugs. Clinicians may still be ignorant of those DDIs when clopidogrel is a precipitant drug, the factors determining the degree of DDIs, and corresponding risk management. Methods A literature search was performed using PubMed, MEDLINE, Web of Science, and the Cochrane Library to analyze the pharmacokinetic DDIs of clopidogrel and new P2Y12 receptor inhibitors. Results Clopidogrel affects the pharmacokinetics of cerivastatin, repaglinide, ferulic acid, sibutramine, efavirenz, and omeprazole. Low efficacy of clopidogrel is anticipated in the presence of omeprazole, esomeprazole, morphine, grapefruit juice, scutellarin, fluoxetine, azole antifungals, calcium channel blockers, sulfonylureas, and ritonavir. Augmented antiplatelet effects are anticipated when clopidogrel is coprescribed with aspirin, curcumin, cyclosporin, St John’s wort, rifampicin, and angiotensin-converting enzyme inhibitors. The factors determining the degree of DDIs with clopidogrel include genetic status (eg, cytochrome P540 [CYP]2B6*6, CYP2C19 polymorphism, CYP3A5*3, CYP3A4*1G, and CYP1A2-163C.A), species differences, and dose strength. The DDI risk does not exhibit a class effect, eg, the effects of clopidogrel on cerivastatin versus other statins, the effects of proton pump inhibitors on clopidogrel (omeprazole, esomeprazole versus pantoprazole, rabeprazole), the effects of rifampicin on clopidogrel versus ticagrelor and prasugrel, and the effects of calcium channel blockers on clopidogrel (amlodipine versus P-glycoprotein-inhibiting calcium channel blockers). The mechanism of the DDIs with clopidogrel involves modulating CYP enzymes (eg, CYP2B6, CYP2C8, CYP2C19, and CYP3A4), paraoxonase-1, hepatic carboxylesterase 1, P-glycoprotein, and organic anion

  8. Successful Treatment of Primary Cutaneous Mucormycosis Complicating Anti-TNF Therapy with a Combination of Surgical Debridement and Oral Posaconazole.

    PubMed

    Camargo, Jose F; Yakoub, Danny; Cho-Vega, Jeong Hee

    2015-10-01

    Lipid formulations of amphotericin B remain the first-line antifungal therapy for invasive mucormycosis. Posaconazole is an alternative for salvage therapy, but its use as primary therapy is not recommended due to the paucity of clinical data. Here we describe the case of a 57-year-old diabetic woman receiving etanercept and prednisone for the treatment of psoriatic arthritis who developed primary cutaneous mucormycosis after a minor gardening injury. Infection was successfully treated with aggressive surgical debridement followed by a 6-week course of the new delayed-release tablet formulation of posaconazole and temporary withholding of anti-TNF treatment. Primary antifungal therapy with posaconazole can be considered in selected cases of cutaneous mucormycosis. PMID:26112998

  9. Results Obtained with Various Antifungal Susceptibility Testing Methods Do Not Predict Early Clinical Outcome in Patients with Cryptococcosis

    PubMed Central

    Dannaoui, E.; Abdul, M.; Arpin, M.; Michel-Nguyen, A.; Piens, M. A.; Favel, A.; Lortholary, O.; Dromer, F.

    2006-01-01

    The in vitro susceptibilities of Cryptococcus neoformans isolates from consecutive human immunodeficiency virus-positive and -negative patients to the antifungal agents fluconazole, amphotericin B, and flucytosine were determined by different techniques, including the CLSI method, Etest, and broth microdilution in yeast nitrogen base (YNB) medium, during a multicenter prospective study in France. The relationship between the in vitro data and the clinical outcome 2 weeks after the initiation of antifungal therapy was assessed. In addition, the correlation between the strain serotype and the in vitro activities of the antifungals was determined, and the susceptibility results obtained with the different techniques were also compared. Thirty-seven patients received a combination of amphotericin B with flucytosine as first-line therapy, 22 were treated with amphotericin B alone, and 15 received fluconazole alone. Whatever the antifungal tested, there was no trend toward higher MICs for strains isolated from patients who failed to respond to a given therapy compared to those from patients who did not with either the CLSI method, Etest, or broth microdilution in YNB medium. The MICs obtained by the CLSI or Etest method were significantly lower for serotype D strains than for serotype A strains for both fluconazole and amphotericin B, while flucytosine MICs were not different according to serotype. These findings suggest that the in vitro antifungal susceptibility of C. neoformans, as determined with the techniques used, is not able to predict the early clinical outcome in patients with cryptococcosis. PMID:16801427

  10. Solid Tumor Therapy Using a Cannon and Pawn Combination Strategy.

    PubMed

    Song, Wantong; Tang, Zhaohui; Zhang, Dawei; Wen, Xue; Lv, Shixian; Liu, Zhilin; Deng, Mingxiao; Chen, Xuesi

    2016-01-01

    Nanocarrier-based anti-tumor drugs hold great promise for reducing side effects and improving tumor-site drug retention in the treatment of solid tumors. However, therapeutic outcomes are still limited, primarily due to a lack of drug penetration within most tumor tissues. Herein, we propose a strategy using a nanocarrier-based combination of vascular disrupting agents (VDAs) and cytotoxic drugs for solid tumor therapy. Specifically, combretastatin A-4 (CA4) serves as a "cannon" by eradicating tumor cells at a distance from blood vessels; concomitantly, doxorubicin (DOX) serves as a "pawn" by killing tumor cells in close proximity to blood vessels. This "cannon and pawn" combination strategy acts without a need to penetrate every tumor cell and is expected to eliminate all tumor cells in a solid tumor. In a murine C26 colon tumor model, this strategy proved effective in eradicating greater than 94% of tumor cells and efficiently inhibited tumor growth with a weekly injection. In large solid tumor models (C26 and 4T1 tumors with volumes of approximately 250 mm(3)), this strategy also proved effective for inhibiting tumor growth. These results showing remarkable inhibition of tumor growth provide a valuable therapeutic choice for solid tumor therapy. PMID:27217835

  11. Solid Tumor Therapy Using a Cannon and Pawn Combination Strategy

    PubMed Central

    Song, Wantong; Tang, Zhaohui; Zhang, Dawei; Wen, Xue; Lv, Shixian; Liu, Zhilin; Deng, Mingxiao; Chen, Xuesi

    2016-01-01

    Nanocarrier-based anti-tumor drugs hold great promise for reducing side effects and improving tumor-site drug retention in the treatment of solid tumors. However, therapeutic outcomes are still limited, primarily due to a lack of drug penetration within most tumor tissues. Herein, we propose a strategy using a nanocarrier-based combination of vascular disrupting agents (VDAs) and cytotoxic drugs for solid tumor therapy. Specifically, combretastatin A-4 (CA4) serves as a “cannon” by eradicating tumor cells at a distance from blood vessels; concomitantly, doxorubicin (DOX) serves as a “pawn” by killing tumor cells in close proximity to blood vessels. This “cannon and pawn” combination strategy acts without a need to penetrate every tumor cell and is expected to eliminate all tumor cells in a solid tumor. In a murine C26 colon tumor model, this strategy proved effective in eradicating greater than 94% of tumor cells and efficiently inhibited tumor growth with a weekly injection. In large solid tumor models (C26 and 4T1 tumors with volumes of approximately 250 mm3), this strategy also proved effective for inhibiting tumor growth. These results showing remarkable inhibition of tumor growth provide a valuable therapeutic choice for solid tumor therapy. PMID:27217835

  12. Innovative approaches of clinical photodynamic therapy combined with immunotherapy

    NASA Astrophysics Data System (ADS)

    Huang, Zheng

    2006-02-01

    Photodynamic therapy (PDT) is a clinically approved new treatment modality. It has been used for treatment of non-malignant and malignant diseases. Over the last decade its clinical application has gained increasing acceptance around the world after regulatory approvals. PDT offers various treatment options in cancer management and has been used primarily for localized superficial or endoluminal malignant and premalignant conditions. Recently, its application has also been expanded to solid tumors. However, its efficacy for the treatment of malignant tumors remains debatable and its acceptance still variable. Pre-clinical studies demonstrate that, in addition to the direct local cytotoxicity, PDT can induce host immune responses, which may further enhance the therapeutic effects on primary tumor as well as metastasis. Therefore, PDT-induced antitumor immune response might play an important role in successful control of malignant diseases. Furthermore, the antitumor efficacy of PDT might also be enhanced through an effective immunoadjuvant to further expand its usefulness for a possible control of distant metastases. Recent clinical data also indicate that improved clinical outcomes are seen in the combination of PDT and immunomodulation therapy for non-malignant disease. This review will summarize recent progress in developing innovative approaches of PDT combined with immunotherapy for non-malignant and malignant diseases.

  13. Epigenetic therapy in gastrointestinal cancer: the right combination.

    PubMed

    Abdelfatah, Eihab; Kerner, Zachary; Nanda, Nainika; Ahuja, Nita

    2016-07-01

    Epigenetics is a relatively recent field of molecular biology that has arisen over the past 25 years. Cancer is now understood to be a disease of widespread epigenetic dysregulation that interacts extensively with underlying genetic mutations. The development of drugs targeting these processes has rapidly progressed; with several drugs already FDA approved as first-line therapy in hematological malignancies. Gastrointestinal (GI) cancers possess high degrees of epigenetic dysregulation, exemplified by subtypes such as CpG island methylator phenotype (CIMP), and the potential benefit of epigenetic therapy in these cancers is evident. The application of epigenetic drugs in solid tumors, including GI cancers, is just emerging, with increased understanding of the cancer epigenome. In this review, we provide a brief overview of cancer epigenetics and the epigenetic targets of therapy including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. We discuss the epigenetic drugs currently in use, with a focus on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and explain the pharmacokinetic and mechanistic challenges in their application. We present the strategies employed in incorporating these drugs into the treatment of GI cancers, and explain the concept of the cancer stem cell in epigenetic reprogramming and reversal of chemo resistance. We discuss the most promising combination strategies in GI cancers including: (1) epigenetic sensitization to radiotherapy, (2) epigenetic sensitization to cytotoxic chemotherapy, and (3) epigenetic immune modulation and priming for immune therapy. Finally, we present preclinical and clinical trial data employing these strategies thus far in various GI cancers including colorectal, esophageal, gastric, and pancreatic cancer. PMID:27366224

  14. Epigenetic therapy in gastrointestinal cancer: the right combination

    PubMed Central

    Abdelfatah, Eihab; Kerner, Zachary; Nanda, Nainika; Ahuja, Nita

    2016-01-01

    Epigenetics is a relatively recent field of molecular biology that has arisen over the past 25 years. Cancer is now understood to be a disease of widespread epigenetic dysregulation that interacts extensively with underlying genetic mutations. The development of drugs targeting these processes has rapidly progressed; with several drugs already FDA approved as first-line therapy in hematological malignancies. Gastrointestinal (GI) cancers possess high degrees of epigenetic dysregulation, exemplified by subtypes such as CpG island methylator phenotype (CIMP), and the potential benefit of epigenetic therapy in these cancers is evident. The application of epigenetic drugs in solid tumors, including GI cancers, is just emerging, with increased understanding of the cancer epigenome. In this review, we provide a brief overview of cancer epigenetics and the epigenetic targets of therapy including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. We discuss the epigenetic drugs currently in use, with a focus on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and explain the pharmacokinetic and mechanistic challenges in their application. We present the strategies employed in incorporating these drugs into the treatment of GI cancers, and explain the concept of the cancer stem cell in epigenetic reprogramming and reversal of chemo resistance. We discuss the most promising combination strategies in GI cancers including: (1) epigenetic sensitization to radiotherapy, (2) epigenetic sensitization to cytotoxic chemotherapy, and (3) epigenetic immune modulation and priming for immune therapy. Finally, we present preclinical and clinical trial data employing these strategies thus far in various GI cancers including colorectal, esophageal, gastric, and pancreatic cancer. PMID:27366224

  15. Rapid screening of novel agents for combination therapy in sarcomas.

    PubMed

    Cubitt, Christopher L; Menth, Jiliana; Dawson, Jana; Martinez, Gary V; Foroutan, Parastou; Morse, David L; Bui, Marilyn M; Letson, G Douglas; Sullivan, Daniel M; Reed, Damon R

    2013-01-01

    For patients with sarcoma, metastatic disease remains very difficult to cure, and outcomes remain less than optimal. Treatment options have not largely changed, although some promising gains have been made with single agents in specific subtypes with the use of targeted agents. Here, we developed a system to investigate synergy of combinations of targeted and cytotoxic agents in a panel of sarcoma cell lines. Agents were investigated alone and in combination with varying dose ratios. Dose-response curves were analyzed for synergy using methods derived from Chou and Talalay (1984). A promising combination, dasatinib and triciribine, was explored in a murine model using the A673 cell line, and tumors were evaluated by MRI and histology for therapy effect. We found that histone deacetylase inhibitors were synergistic with etoposide, dasatinib, and Akt inhibitors across cell lines. Sorafenib and topotecan demonstrated a mixed response. Our systematic drug screening method allowed us to screen a large number of combinations of sarcoma agents. This method can be easily modified to accommodate other cell line models, and confirmatory assays, such as animal experiments, can provide excellent preclinical data to inform clinical trials for these rare malignancies. PMID:24282374

  16. Rapid Screening of Novel Agents for Combination Therapy in Sarcomas

    PubMed Central

    Cubitt, Christopher L.; Menth, Jiliana; Martinez, Gary V.; Foroutan, Parastou; Morse, David L.; Bui, Marilyn M.; Letson, G. Douglas; Sullivan, Daniel M.; Reed, Damon R.

    2013-01-01

    For patients with sarcoma, metastatic disease remains very difficult to cure, and outcomes remain less than optimal. Treatment options have not largely changed, although some promising gains have been made with single agents in specific subtypes with the use of targeted agents. Here, we developed a system to investigate synergy of combinations of targeted and cytotoxic agents in a panel of sarcoma cell lines. Agents were investigated alone and in combination with varying dose ratios. Dose-response curves were analyzed for synergy using methods derived from Chou and Talalay (1984). A promising combination, dasatinib and triciribine, was explored in a murine model using the A673 cell line, and tumors were evaluated by MRI and histology for therapy effect. We found that histone deacetylase inhibitors were synergistic with etoposide, dasatinib, and Akt inhibitors across cell lines. Sorafenib and topotecan demonstrated a mixed response. Our systematic drug screening method allowed us to screen a large number of combinations of sarcoma agents. This method can be easily modified to accommodate other cell line models, and confirmatory assays, such as animal experiments, can provide excellent preclinical data to inform clinical trials for these rare malignancies. PMID:24282374

  17. Combination Drug Therapy for Pain following Chronic Spinal Cord Injury

    PubMed Central

    Hama, Aldric; Sagen, Jacqueline

    2012-01-01

    A number of mechanisms have been elucidated that maintain neuropathic pain due to spinal cord injury (SCI). While target-based therapeutics are being developed based on elucidation of these mechanisms, treatment for neuropathic SCI pain has not been entirely satisfactory due in part to the significant convergence of neurological and inflammatory processes that maintain the neuropathic pain state. Thus, a combination drug treatment strategy, wherein several pain-related mechanism are simultaneously engaged, could be more efficacious than treatment against individual mechanisms alone. Also, by engaging several targets at once, it may be possible to reduce the doses of the individual drugs, thereby minimizing the potential for adverse side effects. Positive preclinical and clinical studies have demonstrated improved efficacy of combination drug treatment over single drug treatment in neuropathic pain of peripheral origin, and perhaps such combinations could be utilized for neuropathic SCI pain. At the same time, there are mechanisms that distinguish SCI from peripheral neuropathic pain, so novel combination therapies will be needed. PMID:22550581

  18. Gene Therapy for Brain Cancer: Combination Therapies Provide Enhanced Efficacy and Safety

    PubMed Central

    Candolfi, Marianela; Kroeger, Kurt M.; Muhammad, A.K.M.G.; Yagiz, Kader; Farrokhi, Catherine; Pechnick, Robert N.; Lowenstein, Pedro R.; Castro, Maria G.

    2009-01-01

    Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Despite significant advances in treatment and intensive research, the prognosis for patients with GBM remains poor. Therapeutic challenges for GBM include its invasive nature, the proximity of the tumor to vital brain structures often preventing total resection, and the resistance of recurrent GBM to conventional radiotherapy and chemotherapy. Gene therapy has been proposed as a useful adjuvant for GBM, to be used in conjunction with current treatment. Work from our laboratory has shown that combination of conditional cytotoxic with immunotherapeutic approaches for the treatment of GBM elicits regression of large intracranial tumor masses and anti-tumor immunological memory in syngeneic rodent models of GBM. In this review we examined the currently available animal models for GBM, including rodent transplantable models, endogenous rodent tumor models and spontaneous GBM in dogs. We discuss non-invasive surrogate end points to assess tumor progression and therapeutic efficacy, such as behavioral tests and circulating biomarkers. Growing preclinical and clinical data contradict the old dogma that cytotoxic anti-cancer therapy would lead to an immune-suppression that would impair the ability of the immune system to mount an anti-tumor response. The implications of the findings reviewed indicate that combination of cytotoxic therapy with immunotherapy will lead to synergistic antitumor efficacy with reduced neurotoxicity and supports the clinical implementation of combined cytotoxic-immunotherapeutic strategies for the treatment of patients with GBM. PMID:19860655

  19. Optimization of Polyene-Azole Combination Therapy against Aspergillosis Using an In Vitro Pharmacokinetic-Pharmacodynamic Model

    PubMed Central

    Siopi, Maria; Siafakas, Nikolaos; Vourli, Sophia; Zerva, Loukia

    2015-01-01

    be employed to optimize antifungal combination therapy with low-dose (≤0.6 mg/kg) amphotericin B-based combination regimens against resistant isolates for minimal toxicity. PMID:25896699

  20. In vitro antifungal susceptibility testing of Scopulariopsis brevicaulis strains using agar diffusion method.

    PubMed

    Skóra, Magdalena; Macura, Anna B

    2011-01-01

    The genus Scopulariopsis is a common soil saprotroph and has been isolated from air, organic waste and also from plant, animal and human tissues. Scopulariopsis has mainly been associated in humans with superficial mycoses, but it has also been described as the cause of subcutaneous and invasive infections. The most common aetiological agent of infections in humans is Scopulariopsis brevicaulis. This species has been reported to be resistant in vitro to broad-spectrum antifungal agents available today. The aim of the study was to establish in vitro antifungal susceptibility of 35 S. brevicaulis strains against amphotericin B (AMB), flucytosine (FC), caspofungin (CAS), terbinafine (TER), ciclopirox (CIC), voriconazole (VOR), clotrimazole (CTR), miconazole (MCZ), econazole (ECO), ketoconazole (KET), itraconazole (ITR), and fluconazole (FLU). Antifungal susceptibility tests were evaluated by an agar diffusion method (Neo-Sensitabs, Rosco, Denmark). AMB, FC, CAS, ITR and FLU showed no antifungal activity against S. brevicaulis. TER, CIC, CTR, KET, VOR, ECO, and MCZ revealed inhibitory activity for S. brevicaulis, but it varied for each of the drugs. The best antifungal effect was observed for TER and CIC. All isolates had large inhibition zones for TER and CIC. CTR was also inhibitory for all tested S. brevicaulis isolates, but the diameters of inhibition zones were smaller than for TER and CIC. Nearly 89% isolates showed inhibition zones for KET and the mean diameter of the inhibition zone was comparable to CTR. The least antifungal activity exhibited VQR, ECO and MCZ. Because of the multiresistance of S. brevicaulis, infections due to this species may not respond to particular antifungal treatment and other therapeutic approaches should be considered, e.g., combined therapy and/or surgery. PMID:21682097

  1. Niacin extended-release/lovastatin: combination therapy for lipid disorders.

    PubMed

    Moon, Yong S K; Kashyap, Moti L

    2002-12-01

    The new combination of niacin extended-release (ER) and lovastatin (Advicor, Kos pharmaceuticals), is a powerful lipid modifying agent and takes advantage of the different mechanisms of action of its two components. Niacin decreases hepatic atherogenic apolipoprotein (apo) B production whereas lovastatin increases apoB removal. Whereas niacin potently increases high density lipoprotein (HDL) levels by decreasing hepatic removal of antiatherogenic apoA-I particles, 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors ('statins') appear to increase production of apoA-I. Although there is no outcome data with this combination product, each component has been independently associated with a reduction of cardiovascular event risk by approximately 25 - 35%. The results of a long-term trial in 814 patients, where > 600 had been treated for 6 months and > 200 for 1 year, found reductions of 45 and 42% in low density lipoprotein cholesterol and triglycerides, respectively, at the maximum dose (niacin ER 2000 mg/ lovastatin 40 mg). HDL cholesterol increased by 41%. In addition, the combination decreased lipoprotein (a) by 25% and C-reactive protein by 24%. The niacin ER/lovastatin combination was generally well-tolerated. Flushing was the most common side effect, with approximately 10% of patients intolerant to niacin ER/lovastatin. Hepatotoxicity in this study was 0.5% and myopathy did not occur. Recent studies indicate that niacin can be used safely in diabetic patients who have good glucose control (HbA(1c) < 9%). Once-daily niacin ER/lovastatin exhibits potent synergistic actions on multiple lipid risk factors and represents an effective new agent in the clinical management of dyslipidaemia. Outcome studies are needed to evaluate if combination therapy would result in additive effects on morbidity and mortality. PMID:12472373

  2. Combined anticancer therapies: an overview of the latest applications.

    PubMed

    Piccolo, Maria Teresa; Menale, Ciro; Crispi, Stefania

    2015-01-01

    Tumor resistance and low drug efficacy prompt to investigate new therapeutic strategies that have high efficacy and low toxicity, especially for cancers with poor prognosis. This goal has been recently achieved using particular pharmaceutical combination or nanotechnologies to specifically deliver drugs at the tumor site. Novel combined treatments employ either naturally active ingredients or drugs already intended for other uses, with the aim to increase cell sensitivity to therapy and reduce drug toxicity. Combined treatments usually improve the overall therapeutic efficacy of the single drug. Drug-drug interactions allow synergistic effects. Several evidences indicate that synergy can be affected by drug-drug ratio and drug administration order. Therapeutic efficacy can be enhanced through drug entrapment in nanocarriers that allow a site-specific targeting, resulting in a build-up of the drug in the tumor with a significant toxicity reduction. Several studies investigated combined entrapment of two or more drugs each one characterized by different mechanisms of action. These nanosystems improve synergistic efficacy and could be a device to resolve toxicity and multi-drug resistance. Nano-encapsulation of anticancer agents by targeting specific tumor tissues significantly optimizes drug bioavailability, biocompatibility and therapeutic efficacy. The efficacy of these formulations results from receptor-mediated endocytosis and prolonged circulation time. Drug encapsulation also allows using limited final concentration while avoiding its activity within the blood circulation. In this review we report recent findings about novel combined treatment focusing on synergistic effects and mechanisms of action. We will also overview the latest drug delivery system and their therapeutic benefits in cancer treatment. PMID:25584691

  3. Hydrotherapy combined with Snoezelen multi-sensory therapy.

    PubMed

    Lavie, Efrat; Shapiro, Michele; Julius, Mona

    2005-01-01

    The aim of this article is to present a new and challenging model of treatment that combines two therapeutic interventions: hydrotherapy and Snoezelen or controlled multisensory stimulation. The combination of the two therapeutic approaches enhances the treatment effect by utilizing the unique characteristics of each approach. We believe that this combined model will further enhance each media to the benefit of the clients and create a new intervention approach. This article relates to a hydrotherapy swimming pool facility that has been established at the Williams Island Therapeutic Swimming and Recreation Center, Beit Issie Shapiro, Raanana in Israel, after acquiring many years of experience and gaining substantial knowledge both in the field of hydrotherapy and Snoezelen intervention. Beit Issie Shapiro is a non-profit community organization providing a range of services for children with developmental disabilities and their families. The organization provides direct services for nearly 6,000 children and adults each year. This article provides an overview of hydrotherapy and Snoezelen and presents a case study, which will demonstrate the new model of treatment and show how this new and innovative form of therapy can be used as a successful intervention. We believe it will open a path to enriching the repertoire of therapists helping people with special needs. This article is also addressed to researchers to provide ideas for further studies in this area. PMID:15900815

  4. Combination and triple therapy in patients with stable angina pectoris not adequately controlled by optimal β-blocker therapy

    PubMed Central

    Kok, W.E.M.; Visser, F.C.; Visser, C.A.

    2002-01-01

    In 60 to 80% of patients with stable angina pectoris at low risk for future coronary events, monotherapy with a β-blocker is an effective treatment. When patients with stable angina pectoris and low risk for events do not respond adequately to optimal β-blocker monotherapy, combination therapy or even triple therapy is may be recommended, but little is known of the actual benefit of such a strategy. We reviewed the evidence from the literature on the effectiveness of combination and triple therapy. Combination therapy with a calcium antagonist or nitrate was found to be more effective than β-blocker monotherapy in the majority of studies, but only an estimated 30% of patients objectively benefit from these combination therapies. Direct comparison shows that combination therapy of a β-blocker with a calcium antagonist is more effective than the combination of a β-blocker with a nitrate. An inadequate response to β-blocker monotherapy is more effectively improved by addition of a calcium antagonist than by alternative use of a calcium antagonist. The use of triple therapy is controversial and not recommended in patients with mild angina pectoris, while for patients with severe angina pectoris not responding to combination therapy of a β-blocker with a nitrate, triple therapy may be of advantage, although the number of patients studied has been small. PMID:25696045

  5. Sequences and Combinations of Multifaceted Therapy In Advanced Prostate Cancer

    PubMed Central

    Vaishampayan, Ulka

    2015-01-01

    Purpose of Review Multiple agents with very distinct mechanisms of actions and unique toxicities and efficacies have become available for use in advanced prostate cancer. The next wave of investigations is focused on development of combinations and optimal sequences of the currently available agents. The focus of this review paper is to provide an update on clinical developments in advanced prostate cancer occurring within the past year, and to highlight the ongoing investigations of promising novel targets and compounds. Recent Findings The clinical use of enzalutamide prior to chemotherapy, demonstrated improvement in progression free survival (PFS) and overall survival (OS) as compared to placebo in metastatic castrate resistant prostate cancer (CRPC). This report of the PREVAIL trial led to the FDA approval of this agent. Novel agents such as cabozantinib and custirsen that had shown promising results in phase II trials, revealed disappointing results in the phase III setting. The breakthrough report, of the ability of the ARV-7 mutation, detected in circulating tumor cells, to predict lack of response to abiraterone or enzalutamide, and the remarkable responses of poly ADP ribose polymerase (PARP) inhibitors in prostate cancer with BRCA1/2 mutations, have elevated hopes of a bright future in the biomarker driven therapeutic arena. Summary As the clinical application of the recently approved multifaceted therapies widens, trials addressing optimal sequences and combinations are gaining importance. In addition, exploring the utility of therapies in the hormone naïve or non-metastatic settings is an area of active investigation. Early use of available agents, optimal sequencing and aid of biomarkers to guide therapeutic choices will make the achievement of lifetime remissions in advanced prostate cancer a reachable goal. PMID:25811344

  6. Light parameters influence cell viability in antifungal photodynamic therapy in a fluence and rate fluence-dependent manner

    NASA Astrophysics Data System (ADS)

    Prates, Renato A.; da Silva, Eriques G.; Yamada, Aécio M.; Suzuki, Luis C.; Paula, Claudete R.; Ribeiro, Martha S.

    2009-05-01

    The aim of this study was to investigate the influence of light parameters on yeast cells. It has been proposed for many years that photodynamic therapy (PDT) can inactivate microbial cells. A number of photosensitizer and light sources were reported in different light parameters and in a range of dye concentrations. However, much more knowledge concerning the importance of fluence, fluence rate and exposure time are required for a better understanding of the photodynamic efficiency. Suspensions (106 CFU/mL) of Candida albicans, Candida krusei, and Cryptococcus neoformans var. grubii were used. Two fluence rates, 100 and 300 mW/cm2 were compared at 3, 6, and 9 min of irradiation, resulting fluences from 18 to 162 J/cm2. The light source was a laser emitting at λ = 660 nm with output power adjusted at 30 and 90 mW. As photosensitizer, one hundred-μM methylene blue was used. Temperature was monitored to verify possible heat effect and reactive oxygen species (ROS) formation was evaluated. The same fluence in different fluence rates showed dissimilar levels of inactivation on yeast cells as well as in ROS formation. In addition, the increase of the fluence rate showed an improvement on cell photoinactivation. PDT was efficient against yeast cells (6 log reduction), and no significant temperature increase was observed. Fluence per se should not be used as an isolate parameter to compare photoinactivation effects on yeast cells. The higher fluence rate was more effective than the lower one. Furthermore, an adequate duration of light exposure cannot be discarded.

  7. A combination approach to treating fungal infections

    PubMed Central

    Shrestha, Sanjib K.; Fosso, Marina Y.; Garneau-Tsodikova, Sylvie

    2015-01-01

    Azoles are antifungal drugs used to treat fungal infections such as candidiasis in humans. Their extensive use has led to the emergence of drug resistance, complicating antifungal therapy for yeast infections in critically ill patients. Combination therapy has become popular in clinical practice as a potential strategy to fight resistant fungal isolates. Recently, amphiphilic tobramycin analogues, C12 and C14, were shown to display antifungal activities. Herein, the antifungal synergy of C12 and C14 with four azoles, fluconazole (FLC), itraconazole (ITC), posaconazole (POS), and voriconazole (VOR), was examined against seven Candida albicans strains. All tested strains were synergistically inhibited by C12 when combined with azoles, with the exception of C. albicans 64124 and MYA-2876 by FLC and VOR. Likewise, when combined with POS and ITC, C14 exhibited synergistic growth inhibition of all C. albicans strains, except C. albicans MYA-2876 by ITC. The combinations of FLC-C14 and VOR-C14 showed synergistic antifungal effect against three C. albicans and four C. albicans strains, respectively. Finally, synergism between C12/C14 and POS were confirmed by time-kill and disk diffusion assays. These results suggest the possibility of combining C12 or C14 with azoles to treat invasive fungal infections at lower administration doses or with a higher efficiency. PMID:26594050

  8. A combination approach to treating fungal infections.

    PubMed

    Shrestha, Sanjib K; Fosso, Marina Y; Garneau-Tsodikova, Sylvie

    2015-01-01

    Azoles are antifungal drugs used to treat fungal infections such as candidiasis in humans. Their extensive use has led to the emergence of drug resistance, complicating antifungal therapy for yeast infections in critically ill patients. Combination therapy has become popular in clinical practice as a potential strategy to fight resistant fungal isolates. Recently, amphiphilic tobramycin analogues, C12 and C14, were shown to display antifungal activities. Herein, the antifungal synergy of C12 and C14 with four azoles, fluconazole (FLC), itraconazole (ITC), posaconazole (POS), and voriconazole (VOR), was examined against seven Candida albicans strains. All tested strains were synergistically inhibited by C12 when combined with azoles, with the exception of C. albicans 64124 and MYA-2876 by FLC and VOR. Likewise, when combined with POS and ITC, C14 exhibited synergistic growth inhibition of all C. albicans strains, except C. albicans MYA-2876 by ITC. The combinations of FLC-C14 and VOR-C14 showed synergistic antifungal effect against three C. albicans and four C. albicans strains, respectively. Finally, synergism between C12/C14 and POS were confirmed by time-kill and disk diffusion assays. These results suggest the possibility of combining C12 or C14 with azoles to treat invasive fungal infections at lower administration doses or with a higher efficiency. PMID:26594050

  9. Artemisinin-based combination therapies for uncomplicated malaria.

    PubMed

    Davis, Timothy M E; Karunajeewa, Harin A; Ilett, Kenneth F

    2005-02-21

    There has been a relentless increase in resistance of malaria parasites to conventional antimalarial drugs, including chloroquine, sulfadoxine-pyrimethamine and mefloquine. In response to this situation, short-course artemisinin-based combination therapies (ACTs) have been developed. The World Health Organization has endorsed ACT as first-line treatment where the potentially life-threatening parasite Plasmodium falciparum is the predominant infecting species. ACTs combine the rapid schizontocidal activity of an artemisinin derivative (artesunate, artemether or dihydroartemisinin) with a longer-half-life partner drug. Although the use of chloroquine and sulfadoxine-pyrimethamine as partners in ACT improves their efficacy, this may only have value as a short-term measure in patients with a degree of immunity to malaria. Alternative currently available partner drugs include mefloquine, lumefantrine and piperaquine. Artesunate-mefloquine is highly effective but is expensive and side effects (mainly neurotoxicity) can be problematic. Artemether-lumefantrine, the only ACT available in Australia, appears less effective than artesunate-mefloquine and needs to be administered with food to ensure adequate bioavailability. Dihydroartemisinin-piperaquine is highly effective, well tolerated and relatively inexpensive. The goal of potent, safe, easy-to-administer and inexpensive ACTs may see trioxolanes in place of artemisinin derivatives, as well as novel partner drugs such as pyronaridine or naphthoquine, in the future. PMID:15720175

  10. Quantifying the pharmacology of antimalarial drug combination therapy.

    PubMed

    Hastings, Ian M; Hodel, Eva Maria; Kay, Katherine

    2016-01-01

    Most current antimalarial drugs are combinations of an artemisinin plus a 'partner' drug from another class, and are known as artemisinin-based combination therapies (ACTs). They are the frontline drugs in treating human malaria infections. They also have a public-health role as an essential component of recent, comprehensive scale-ups of malaria interventions and containment efforts conceived as part of longer term malaria elimination efforts. Recent reports that resistance has arisen to artemisinins has caused considerable concern. We investigate the likely impact of artemisinin resistance by quantifying the contribution artemisinins make to the overall therapeutic capacity of ACTs. We achieve this using a simple, easily understood, algebraic approach and by more sophisticated pharmacokinetic/pharmacodynamic analyses of drug action; the two approaches gave consistent results. Surprisingly, the artemisinin component typically makes a negligible contribution (≪0.0001%) to the therapeutic capacity of the most widely used ACTs and only starts to make a significant contribution to therapeutic outcome once resistance has started to evolve to the partner drugs. The main threat to antimalarial drug effectiveness and control comes from resistance evolving to the partner drugs. We therefore argue that public health policies be re-focussed to maximise the likely long-term effectiveness of the partner drugs. PMID:27604175

  11. Treatment of porcine Pseudomonas ARDS with combination drug therapy.

    PubMed

    Sielaff, T D; Sugerman, H J; Tatum, J L; Kellum, J M; Blocher, C R

    1987-12-01

    A combination drug therapy (Poly-5: ibuprofen 12.5 mg/kg, methylprednisolone 30 mg/kg, cimetidine 150 mg, diphenhydramine 10 mg/kg, and ketanserin 0.2 mg/kg) given at 20 and 120 minutes after starting continuous intravenous Pseudomonas (Ps, 5 X 10(8) CFU/20 kg/min) was studied in three groups of swine: saline control (C, n = 9), Ps alone (Ps, n = 8), and Ps plus Poly-5 (n = 5). PaO2, systemic (SAP) and pulmonary arterial (PAP) pressures, cardiac index (CI), thermal-cardiogreen extravascular lung water (EVLW), pulmonary albumin flux (slope index, SI), and arterial blood serotonin levels (5-HT) were measured. Ps produced significant (p less than 0.05) increases in PAP, EVLW, and SI with decreases in PaO2, CI, and SAP. 5-HT fell significantly compared to baseline. Poly-5 prevented (p less than 0.05) the rise in EVLW and SI and the fall in PaO2 and CI compared to Ps. PAP and SI were maintained at C until 90 and 150 minutes, respectively. SAP fell significantly from C at 30, 60, and 180 minutes. 5-HT was significantly lower than Ps throughout, and significantly lower than baseline at 180 minutes. Combined blockade of arachidonic acid metabolites, histamine, and serotonin receptors prevented hypoxemia, increased pulmonary capillary permeability, and cardiovascular deterioration in this porcine septic ARDS model. PMID:3694722

  12. Combination Therapy in the Management of Atrophic Acne Scars

    PubMed Central

    Garg, Shilpa; Baveja, Sukriti

    2014-01-01

    Background: Atrophic acne scars are difficult to treat. The demand for less invasive but highly effective treatment for scars is growing. Objective: To assess the efficacy of combination therapy using subcision, microneedling and 15% trichloroacetic acid (TCA) peel in the management of atrophic scars. Materials and Methods: Fifty patients with atrophic acne scars were graded using Goodman and Baron Qualitative grading. After subcision, dermaroller and 15% TCA peel were performed alternatively at 2-weeks interval for a total of 6 sessions of each. Grading of acne scar photographs was done pretreatment and 1 month after last procedure. Patients own evaluation of improvement was assessed. Results: Out of 16 patients with Grade 4 scars, 10 (62.5%) patients improved to Grade 2 and 6 (37.5%) patients improved to Grade 3 scars. Out of 22 patients with Grade 3 scars, 5 (22.7%) patients were left with no scars, 2 (9.1%) patients improved to Grade 1and 15 (68.2%) patients improved to Grade 2. All 11 (100%) patients with Grade 2 scars were left with no scars. There was high level of patient satisfaction. Conclusion: This combination has shown good results in treating not only Grade 2 but also severe Grade 4 and 3 scars. PMID:24761094

  13. Antifungal Resistance and New Strategies to Control Fungal Infections

    PubMed Central

    Vandeputte, Patrick; Ferrari, Selene; Coste, Alix T.

    2012-01-01

    Despite improvement of antifungal therapies over the last 30 years, the phenomenon of antifungal resistance is still of major concern in clinical practice. In the last 10 years the molecular mechanisms underlying this phenomenon were extensively unraveled. In this paper, after a brief overview of currently available antifungals, molecular mechanisms of antifungal resistance will be detailed. It appears that major mechanisms of resistance are essential due to the deregulation of antifungal resistance effector genes. This deregulation is a consequence of point mutations occurring in transcriptional regulators of these effector genes. Resistance can also follow the emergence of point mutations directly in the genes coding antifungal targets. In addition we further describe new strategies currently undertaken to discover alternative therapy targets and antifungals. Identification of new antifungals is essentially achieved by the screening of natural or synthetic chemical compound collections. Discovery of new putative antifungal targets is performed through genome-wide approaches for a better understanding of the human pathogenic fungi biology. PMID:22187560

  14. Pediatric Antifungal Agents

    PubMed Central

    Cohen-Wolkowiez, Michael; Moran, Cassandra; Benjamin, Daniel K.; Smith, P Brian

    2009-01-01

    Purpose of review In immunocompromised hosts, invasive fungal infections are common and fatal. In the past decade, the antifungal armamentarium against invasive mycoses has expanded greatly. The purpose of this report is to review the most recent literature addressing the use of antifungal agents in children. Recent findings Most studies evaluating the safety and efficacy of antifungal agents are limited to adults. However, important progress has been made in describing the pharmacokinetics and safety of newer antifungal agents in children, including the echinocandins. Summary Dosage guidelines for newer antifungal agents are currently based on adult and limited pediatric data. Because important developmental pharmacology changes occur throughout childhood impacting the pharmacokinetics of these agents, antifungal studies specifically designed for children are necessary. PMID:19741525

  15. A Treatment Planning Method for Sequentially Combining Radiopharmaceutical Therapy and External Radiation Therapy;External beam therapy; Radiopharmaceutical therapy; Three-dimensional dosimetry; Treatment planning

    SciTech Connect

    Hobbs, Robert F.; McNutt, Todd; Baechler, Sebastien; He Bin; Esaias, Caroline E.; Frey, Eric C.; Loeb, David M.; Wahl, Richard L.; Shokek, Ori; Sgouros, George

    2011-07-15

    Purpose: Effective cancer treatment generally requires combination therapy. The combination of external beam therapy (XRT) with radiopharmaceutical therapy (RPT) requires accurate three-dimensional dose calculations to avoid toxicity and evaluate efficacy. We have developed and tested a treatment planning method, using the patient-specific three-dimensional dosimetry package 3D-RD, for sequentially combined RPT/XRT therapy designed to limit toxicity to organs at risk. Methods and Materials: The biologic effective dose (BED) was used to translate voxelized RPT absorbed dose (D{sub RPT}) values into a normalized total dose (or equivalent 2-Gy-fraction XRT absorbed dose), NTD{sub RPT} map. The BED was calculated numerically using an algorithmic approach, which enabled a more accurate calculation of BED and NTD{sub RPT}. A treatment plan from the combined Samarium-153 and external beam was designed that would deliver a tumoricidal dose while delivering no more than 50 Gy of NTD{sub sum} to the spinal cord of a patient with a paraspinal tumor. Results: The average voxel NTD{sub RPT} to tumor from RPT was 22.6 Gy (range, 1-85 Gy); the maximum spinal cord voxel NTD{sub RPT} from RPT was 6.8 Gy. The combined therapy NTD{sub sum} to tumor was 71.5 Gy (range, 40-135 Gy) for a maximum voxel spinal cord NTD{sub sum} equal to the maximum tolerated dose of 50 Gy. Conclusions: A method that enables real-time treatment planning of combined RPT-XRT has been developed. By implementing a more generalized conversion between the dose values from the two modalities and an activity-based treatment of partial volume effects, the reliability of combination therapy treatment planning has been expanded.

  16. [Therapy of nail mycoses].

    PubMed

    Büchner, S A

    1998-08-01

    Onchomycosis is the most common nail disease, accounting for approximately 30% of all cutaneous fungal infections. The treatment approach needs to take into account the location and extent of onychomycosis, sensitivity of drug to fungal organism, adverse-effects profile, dosage schedule, duration of therapy, concomitant medical conditions, and concurrent medications. To confirm the diagnosis, it is important to correctly select the appropriate site for specimen collection used for both direct microscopy and fungal culture. Topical antifungal agents may be considered for the treatment of early onychomycosis, in the absence of nail matrix involvement. The newer generation of oral antifungal agents for the treatment of onychomycosis are terbinafine, itraconazole and fluconazole. These drugs used alone, or in combination with topical antifungals, are providing the basis for effective treatment of onychomycosis in a large proportion of patients. PMID:9757817

  17. Breakthrough Scedosporium apiospermum (Pseudallescheria boydii) brain abscess during therapy for invasive pulmonary aspergillosis following high-risk allogeneic hematopoietic stem cell transplantation. Scedosporiasis and recent advances in antifungal therapy.

    PubMed

    Safdar, A; Papadopoulos, E B; Young, J W

    2002-12-01

    Systemic scedosporiasis due to the anamorph or asexual form Scedosporium apiospermum (Pseudallescheria boydii) has become an important cause of opportunistic mycosis, especially in patients undergoing high-risk hematopoietic stem cell transplantation. We report a case of rapidly progressive cerebellar hyalohyphomycosis due to Scedosporium apiospermum in an allogeneic marrow graft recipient receiving treatment for severe graft-versus-host disease. This fatal breakthrough intracranial abscess, due to amphotericin B-resistant (minimum inhibitory concentration > 16 micro g/ml) mold, developed during the course of systemic antifungal therapy given for multicentric pulmonary aspergillosis. Despite treatment with high-dose Abelcet (10 mg/kg daily), free amphotericin B was not detected in postmortem cerebellar tissue. A broad-spectrum triazole-based agent (voriconazole/UK-109, 496--Vfend), and a novel fungal cell wall inhibitor, an echinocandin/pneumocandin analog (caspofungin/MK-0991--Cancidas), which exhibit excellent in vitro activity against most clinical Pseudallescheria boydii-Scedosporium apiospermum isolates, have recently become available in the United States and may provide much needed treatment options for patients at risk. PMID:12535265

  18. Advances in synthetic approach to and antifungal activity of triazoles

    PubMed Central

    Kumar, Nitin; Drabu, Sushma; Sharma, Pramod Kumar

    2011-01-01

    Summary Several five membered ring systems, e.g., triazole, oxadiazole dithiazole and thiadiazole with three heteroatoms at symmetrical or asymmetrical positions have been studied because of their interesting pharmacological properties. In this article our emphasis is on synthetic development and pharmacological activity of the triazole moiety which exhibit a broad spectrum of pharmacological activity such as antifungal, antibacterial, anti-inflammatory and anticancer etc. Triazoles have increased our ability to treat many fungal infections, for example, candidiasis, cryptococcal meningitis, aspergillosis etc. However, mortality due to these infections even with antifungal therapy is still unacceptably high. Therefore, the development of new antifungal agents targeting specific fungal structures or functions is being actively pursued. Rapid developments in molecular mycology have led to a concentrated search for more target antifungals. Although we are entering a new era of antifungal therapy in which we will continue to be challenged by systemic fungal diseases, the options for treatment will have greatly expanded. PMID:21804864

  19. The application of prodrug-based nano-drug delivery strategy in cancer combination therapy.

    PubMed

    Ge, Yanxiu; Ma, Yakun; Li, Lingbing

    2016-10-01

    Single drug therapy that leads to the multidrug resistance of cancer cells and severe side-effect is a thing of the past. Combination therapies that affect multiple signaling pathways have been the focus of recent active research. Due to the successful development of prodrug-based nano-drug delivery systems (P-N-DDSs), their use has been extended to combination therapy as drug delivery platforms. In this review, we focus specifically on the P-N-DDSs in the field of combination therapy including the combinations of prodrugs with different chemotherapeutic agents, other therapeutic agents, nucleic acid or the combination of different types of therapy (e.g. chemotherapy and phototherapy). The relevant examples of prodrug-based nanoparticulate drug delivery strategy in combination cancer therapy from the recent literature are discussed to demonstrate the feasibilities of relevant technology. PMID:27400243

  20. Degradation of Artemisinin-Based Combination Therapies under Tropical Conditions

    PubMed Central

    Hall, Zoe; Allan, Elizabeth Louise; van Schalkwyk, Donelly Andrew; van Wyk, Albert; Kaur, Harparkash

    2016-01-01

    Poor quality antimalarials, including falsified, substandard, and degraded drugs, are a serious health concern in malaria-endemic countries. Guidelines are lacking on how to distinguish between substandard and degraded drugs. “Forced degradation” in an oven was carried out on three common artemisinin-based combination therapy (ACT) brands to detect products of degradation using liquid chromatography mass spectrometry and help facilitate classification of degraded drugs. “Natural aging” of 2,880 tablets each of ACTs artemether/lumefantrine and artesunate/amodiaquine was undertaken to evaluate their long-term stability in tropical climates. Samples were aged in the presence and absence of light on-site in Ghana and in a stability chamber (London), removed at regular intervals, and analyzed to determine loss of the active pharmaceutical ingredients (APIs) over time and detect products of degradation. Loss of APIs in naturally aged tablets (both in Ghana and the pharmaceutical stability chamber) was 0–7% over 3 years (∼12 months beyond expiry) with low levels of degradation products detected. Using this developed methodology, it was found that a quarter of ACTs purchased in Enugu, Nigeria (concurrent study), that would have been classified as substandard, were in fact degraded. Presence of degradation products together with evidence of insufficient APIs can be used to classify drugs as degraded. PMID:26951346

  1. Polymeric-gold nanohybrids for combined imaging and cancer therapy.

    PubMed

    Topete, Antonio; Alatorre-Meda, Manuel; Villar-Alvarez, Eva M; Carregal-Romero, Susana; Barbosa, Silvia; Parak, Wolfgang J; Taboada, Pablo; Mosquera, Víctor

    2014-08-01

    Here, the use of folic acid (FA)-functionalized, doxorubicin (DOXO)/superparamagnetic iron oxide nanoparticles (SPION)-loaded poly(lactic-co-glycolic acid) (PLGA)-Au porous shell nanoparticles (NPs) as potential nanoplatforms is reported for targeted multimodal chemo- and photothermal therapy combined with optical and magnetic resonance imaging in cancer. These polymeric-gold nanohybrids (PGNH) are produced by a seeded-growth method using chitosan as an electrostatic "glue" to attach Au seeds to DOXO/SPION-PLGA NPs. In order to determine their potential as theranostic nanoplatforms, their physicochemical properties, cellular uptake, and photothermal and chemotherapeutic efficiencies are tested in vitro using a human cervical cancer (HeLa) cell line. The present NPs show a near-infrared (NIR)-light-triggered release of cargo molecules under illumination and a great capacity to induce localized cell death in a well-focused region. The functionalization of the PGNH NPs with the targeting ligand FA improves their internalization efficiency and specificity. Furthermore, the possibility to guide the PGNH NPs to cancer cells by an external magnetic field is also proven in vitro, which additionally increases the cellular uptake and therapeutic efficiency. PMID:24764284

  2. Degradation of Artemisinin-Based Combination Therapies Under Tropical Conditions.

    PubMed

    Hall, Zoe; Allan, Elizabeth Louise; van Schalkwyk, Donelly Andrew; van Wyk, Albert; Kaur, Harparkash

    2016-05-01

    Poor quality antimalarials, including falsified, substandard, and degraded drugs, are a serious health concern in malaria-endemic countries. Guidelines are lacking on how to distinguish between substandard and degraded drugs. "Forced degradation" in an oven was carried out on three common artemisinin-based combination therapy (ACT) brands to detect products of degradation using liquid chromatography mass spectrometry and help facilitate classification of degraded drugs. "Natural aging" of 2,880 tablets each of ACTs artemether/lumefantrine and artesunate/amodiaquine was undertaken to evaluate their long-term stability in tropical climates. Samples were aged in the presence and absence of light on-site in Ghana and in a stability chamber (London), removed at regular intervals, and analyzed to determine loss of the active pharmaceutical ingredients (APIs) over time and detect products of degradation. Loss of APIs in naturally aged tablets (both in Ghana and the pharmaceutical stability chamber) was 0-7% over 3 years (∼12 months beyond expiry) with low levels of degradation products detected. Using this developed methodology, it was found that a quarter of ACTs purchased in Enugu, Nigeria (concurrent study), that would have been classified as substandard, were in fact degraded. Presence of degradation products together with evidence of insufficient APIs can be used to classify drugs as degraded. PMID:26951346

  3. Antifungal polypeptides

    DOEpatents

    Altier, Daniel J.; Dahlbacka, Glen; Elleskaya, Irina; Ellanskaya, legal representative, Natalia; Herrmann, Rafael; Hunter-Cevera, Jennie; McCutchen, Billy F.; Presnail, James K.; Rice, Janet A.; Schepers, Eric; Simmons, Carl R.; Torok, Tamas; Yalpani, Nasser

    2011-04-12

    Compositions and methods for protecting a plant from a pathogen, particularly a fungal pathogen, are provided. Compositions include novel amino acid sequences, and variants and fragments thereof, for antipathogenic polypeptides that were isolated from microbial fermentation broths. Nucleic acid molecules comprising nucleotide sequences that encode the antipathogenic polypeptides of the invention are also provided. A method for inducing pathogen resistance in a plant using the nucleotide sequences disclosed herein is further provided. The method comprises introducing into a plant an expression cassette comprising a promoter operably linked to a nucleotide sequence that encodes an antipathogenic polypeptide of the invention. Compositions comprising an antipathogenic polypeptide or a transformed microorganism comprising a nucleic acid of the invention in combination with a carrier and methods of using these compositions to protect a plant from a pathogen are further provided. Transformed plants, plant cells, seeds, and microorganisms comprising a nucleotide sequence that encodes an antipathogenic polypeptide of the invention, or variant or fragment thereof, are also disclosed.

  4. Antifungal polypeptides

    DOEpatents

    Altier, Daniel J.; Dahlbacka, Glen; Ellanskaya, legal representative, Natalia; Herrmann, Rafael; Hunter-Cevera, Jennie; McCutchen, Billy F.; Presnail, James K.; Rice, Janet A.; Schepers, Eric; Simmons, Carl R.; Torok, Tamas; Yalpani, Nasser; Ellanskaya, deceased, Irina

    2007-12-11

    Compositions and methods for protecting a plant from a pathogen, particularly a fungal pathogen, are provided. Compositions include novel amino acid sequences, and variants and fragments thereof, for antipathogenic polypeptides that were isolated from microbial fermentation broths. Nucleic acid molecules comprising nucleotide sequences that encode the antipathogenic polypeptides of the invention are also provided. A method for inducing pathogen resistance in a plant using the nucleotide sequences disclosed herein is further provided. The method comprises introducing into a plant an expression cassette comprising a promoter operably linked to a nucleotide sequence that encodes an antipathogenic polypeptide of the invention. Compositions comprising an antipathogenic polypeptide or a transformed microorganism comprising a nucleic acid of the invention in combination with a carrier and methods of using these compositions to protect a plant from a pathogen are further provided. Transformed plants, plant cells, seeds, and microorganisms comprising a nucleotide sequence that encodes an antipathogenic polypeptide of the invention, or variant or fragment thereof, are also disclosed.

  5. Antifungal polypeptides

    DOEpatents

    Altier, Daniel J.; Dahlbacka, Glen; Ellanskaya, Irina; Ellanskaya, legal representative, Natalia; Herrmann, Rafael; Hunter-Cevera, Jennie; McCutchen, Billy F.; Presnail, James K.; Rice, Janet A.; Schepers, Eric; Simmons, Carl R.; Torok, Tamas; Yalpani, Nasser

    2012-04-03

    Compositions and methods for protecting a plant from a pathogen, particularly a fungal pathogen, are provided. Compositions include novel amino acid sequences, and variants and fragments thereof, for antipathogenic polypeptides that were isolated from microbial fermentation broths. Nucleic acid molecules comprising nucleotide sequences that encode the antipathogenic polypeptides of the invention are also provided. A method for inducing pathogen resistance in a plant using the nucleotide sequences disclosed herein is further provided. The method comprises introducing into a plant an expression cassette comprising a promoter operably linked to a nucleotide sequence that encodes an antipathogenic polypeptide of the invention. Compositions comprising an antipathogenic polypeptide or a transformed microorganism comprising a nucleic acid of the invention in combination with a carrier and methods of using these compositions to protect a plant from a pathogen are further provided. Transformed plants, plant cells, seeds, and microorganisms comprising a nucleotide sequence that encodes an antipathogenic polypeptide of the invention, or variant or fragment thereof, are also disclosed.

  6. Antifungal polypeptides

    DOEpatents

    Altier, Daniel J.; Dahlbacka, Glen; Elleskaya, Irina; Ellanskaya, legal representative; Natalia; Herrmann, Rafael; Hunter-Cevera, Jennie; McCutchen, Billy F.; Presnail, James K.; Rice, Janet A.; Schepers, Eric; Simmons, Carl R.; Torok, Tamas; Yalpani, Nasser

    2010-08-10

    Compositions and methods for protecting a plant from a pathogen, particularly a fungal pathogen, are provided. Compositions include novel amino acid sequences, and variants and fragments thereof, for antipathogenic polypeptides that were isolated from microbial fermentation broths. Nucleic acid molecules comprising nucleotide sequences that encode the antipathogenic polypeptides of the invention are also provided. A method for inducing pathogen resistance in a plant using the nucleotide sequences disclosed herein is further provided. The method comprises introducing into a plant an expression cassette comprising a promoter operably linked to a nucleotide sequence that encodes an antipathogenic polypeptide of the invention. Compositions comprising an antipathogenic polypeptide or a transformed microorganism comprising a nucleic acid of the invention in combination with a carrier and methods of using these compositions to protect a plant from a pathogen are further provided. Transformed plants, plant cells, seeds, and microorganisms comprising a nucleotide sequence that encodes an antipathogenic polypeptide of the invention, or variant or fragment thereof, are also disclosed.

  7. Defensins: antifungal lessons from eukaryotes

    PubMed Central

    Silva, Patrícia M.; Gonçalves, Sónia; Santos, Nuno C.

    2014-01-01

    Over the last years, antimicrobial peptides (AMPs) have been the focus of intense research toward the finding of a viable alternative to current antifungal drugs. Defensins are one of the major families of AMPs and the most represented among all eukaryotic groups, providing an important first line of host defense against pathogenic microorganisms. Several of these cysteine-stabilized peptides present a relevant effect against fungi. Defensins are the AMPs with the broader distribution across all eukaryotic kingdoms, namely, Fungi, Plantae, and Animalia, and were recently shown to have an ancestor in a bacterial organism. As a part of the host defense, defensins act as an important vehicle of information between innate and adaptive immune system and have a role in immunomodulation. This multidimensionality represents a powerful host shield, hard for microorganisms to overcome using single approach resistance strategies. Pathogenic fungi resistance to conventional antimycotic drugs is becoming a major problem. Defensins, as other AMPs, have shown to be an effective alternative to the current antimycotic therapies, demonstrating potential as novel therapeutic agents or drug leads. In this review, we summarize the current knowledge on some eukaryotic defensins with antifungal action. An overview of the main targets in the fungal cell and the mechanism of action of these AMPs (namely, the selectivity for some fungal membrane components) are presented. Additionally, recent works on antifungal defensins structure, activity, and cytotoxicity are also reviewed. PMID:24688483

  8. Combination Therapy for Treatment of Infections with Gram-Negative Bacteria

    PubMed Central

    Cosgrove, Sara E.; Maragakis, Lisa L.

    2012-01-01

    Summary: Combination antibiotic therapy for invasive infections with Gram-negative bacteria is employed in many health care facilities, especially for certain subgroups of patients, including those with neutropenia, those with infections caused by Pseudomonas aeruginosa, those with ventilator-associated pneumonia, and the severely ill. An argument can be made for empiric combination therapy, as we are witnessing a rise in infections caused by multidrug-resistant Gram-negative organisms. The wisdom of continued combination therapy after an organism is isolated and antimicrobial susceptibility data are known, however, is more controversial. The available evidence suggests that the greatest benefit of combination antibiotic therapy stems from the increased likelihood of choosing an effective agent during empiric therapy, rather than exploitation of in vitro synergy or the prevention of resistance during definitive treatment. In this review, we summarize the available data comparing monotherapy versus combination antimicrobial therapy for the treatment of infections with Gram-negative bacteria. PMID:22763634

  9. Triazole antifungals: a review.

    PubMed

    Peyton, L R; Gallagher, S; Hashemzadeh, M

    2015-12-01

    Invasive fungal infections and systemic mycosis, whether from nosocomial infection or immunodeficiency, have been on an upward trend for numerous years. Despite advancements in antifungal medication, treatment in certain patients can still be difficult for reasons such as impaired organ function, limited administration routes or poor safety profiles of the available antifungal medications. The growing number of invasive fungal species becoming resistant to current antifungal medications is of appreciable concern. Triazole compounds containing one or more 1,2,4-triazole rings have been shown to contain some of the most potent antifungal properties. Itracon-azole and fluconazole were some of the first triazoles synthesized, but had limitations associated with their use. Second-generation triazoles such as voriconazole, posa-conazole, albaconazole, efinaconazole, ravuconazole and isavuconazole are all derivatives of either itraconazole or fluconazole, and designed to overcome the deficiencies of their parent drugs. The goal of this manuscript is to review antifungal agents derived from triazole. PMID:26798851

  10. Naphthoquine: An Emerging Candidate for Artemisinin Combination Therapy.

    PubMed

    Moore, Brioni R; Laman, Moses; Salman, Sam; Batty, Kevin T; Page-Sharp, Madhu; Hombhanje, Francis; Manning, Laurens; Davis, Timothy M E

    2016-05-01

    Naphthoquine is a 4-aminoquinoline antimalarial drug first synthesised in China in 1986 but which was not developed for clinical use until the late 1990s. Early in vitro parasite sensitivity and in vivo efficacy data, together with a long terminal elimination half-life (up to 23 days), suggested that it could be used as monotherapy for uncomplicated falciparum and vivax malaria, but is now marketed as a single-dose, fixed co-formulation with artemisinin in a milligram per kilogram ratio of 1:2.5. This form of artemisinin combination therapy (ACT) has also shown high cure rates, especially in two randomised trials in which, consistent with World Health Organization recommendations for all ACTs, it was administered daily for 3 days rather than as single dose for Plasmodium falciparum and P. vivax infections (28-day adequate clinical and parasitological response ≥98.4 %). Although detailed safety monitoring has been performed in a minority of subjects, >4000 healthy volunteers and patients with malaria have been exposed to naphthoquine without any documented significant toxicity. As with other 4-aminoquinolines, naphthoquine is associated with prolongation of the electrocardiographic QT interval but not with cardiac or neurological events. It has been administered to children as young as 4 months of age but, due to a lack of pharmacokinetic, efficacy and toxicity data in young infants and in pregnant/lactating women, it should not be used in these vulnerable patient groups.With the emergence of parasite resistance to other ACTs, naphthoquine partnered with a potent artemisinin derivative may prove a viable alternative treatment for uncomplicated malaria. PMID:27075024

  11. Predicting virological decay in patients starting combination antiretroviral therapy

    PubMed Central

    2016-01-01

    Objective: Model trajectories of viral load measurements from time of starting combination antiretroviral therapy (cART), and use the model to predict whether patients will achieve suppressed viral load (≤200 copies/ml) within 6-months of starting cART. Design: Prospective cohort study including HIV-positive adults (UK Collaborative HIV Cohort Study). Methods: Eligible patients were antiretroviral naive and started cART after 1997. Random effects models were used to estimate viral load trends. Patients were randomly selected to form a validation dataset with those remaining used to fit the model. We evaluated predictions of suppression using indices of diagnostic test performance. Results: Of 9562 eligible patients 6435 were used to fit the model and 3127 for validation. Mean log10 viral load trajectories declined rapidly during the first 2 weeks post-cART, moderately between 2 weeks and 3 months, and more slowly thereafter. Higher pretreatment viral load predicted steeper declines, whereas older age, white ethnicity, and boosted protease inhibitor/non-nucleoside reverse transcriptase inhibitors based cART-regimen predicted a steeper decline from 3 months onwards. Specificity of predictions and the diagnostic odds ratio substantially improved when predictions were based on viral load measurements up to the 4-month visit compared with the 2 or 3-month visits. Diagnostic performance improved when suppression was defined by two consecutive suppressed viral loads compared with one. Conclusions: Viral load measurements can be used to predict if a patient will be suppressed by 6-month post-cART. Graphical presentations of this information could help clinicians decide the optimum time to switch treatment regimen during the first months of cART. PMID:27124894

  12. Colonic exclusion and combined therapy for refractory constipation

    PubMed Central

    Peng, Hong-Yun; Xu, Ai-Zhong

    2006-01-01

    AIM: To investigate the therapeutic effectiveness of colonic exclusion and combined therapy for refractory constipation. METHODS: Thirty-two patients with refractory constipation were randomly divided into treatment group (n = 14) and control group (n = 18). Fourteen patients in treatment group underwent colonic exclusion and end-to-side colorectal anastomosis. Eighteen patients in control group received subtotal colectomy and end-to-end colorectal anastomosis. The therapeutic effects of the operations were assessed by comparing the surgical time, incision length, volume of blood losses, hospital stay, recovery rate and complication incidence. All patients received long-term follow-up. RESULTS: All operations were successful and patients recovered fully after the operations. In comparison of treatment group and control group, the surgical time (h), incision length (cm), volume of blood losses (mL), hospital stay (d) were 87 ± 16 min vs 194 ± 23 min (t = 9.85), 10.4 ± 0.5 cm vs 21.2 ± 1.8 cm (t = 14.26), 79.5 ± 31.3 mL vs 286.3 ± 49.2 mL (t = 17.24), and 11.8 ± 2.4 d vs 18.6 ± 2.6 d (t = 6.91), respectively (P < 0.001 for all). The recovery rate and complication incidence were 85.7% vs 88.9% (P = 0.14 > 0.05), 21.4% vs 33.3% (P = 0.73 > 0.05), respectively. CONCLUSION: Colonic exclusion has better therapeutic efficacy on refractory constipation. It has many advantages such as shorter surgical time, smaller incision, fewer blood losses and shorter hospital stay. PMID:17203535

  13. Artemisinin-based combination therapies and their introduction in Japan.

    PubMed

    Kano, Shigeyuki

    2014-05-01

    Artemisinin was discovered in 1971 from a herb, Artemisia annua, which had been used for more than 2,000 years in China against intermittent fever. Now, the artemisinin and its derivatives have become essential components of artemisinin-based combination therapies (ACTs). The ACTs are the recommended first-line treatments of malaria because they are effective against all four human malarias, produce rapid parasite/fever clearance, and show fewer adverse effects. Some ACTs are particularly important in cases of severe and complicated falciparum malaria, including cerebral malaria. However, neither the artemisinin and its derivatives nor any ACTs are registered in Japan. Indeed, the only licensed drugs for the treatment of malaria in Japan are quinine, mefloquine, and sulfadoxine/pyrimethamine. Although indigenous malaria has been eradicated in Japan since 1959, 60-100 imported malaria cases have been reported annually for the past decade. Some of the patients were, in fact, dying of the severe complications. Thus, the introduction of the ACTs and their application to imported malaria patients in Japan are urgently needed. A few clinical studies using the ACTs have been reported in Japan. The first application of an ACT, intramuscular artemether plus mefloquine, was reported in 1988 to be very effective against cerebral malaria with coma. Five cases with intravenous artesunate plus mefloquine were reported through 2001-2007, for severe or drug-resistant falciparum cases, resulting in successful treatment with some side effects such as hemolytic anemia or postmalaria neurological syndrome. Currently, a fixed-dose ACT, artemether-lumefantrine, is prescribed successfully for uncomplicated falciparum cases, with a limited number of recrudescences. PMID:24979951

  14. Cancer therapy improvement with mesoporous silica nanoparticles combining photodynamic and photothermal therapy.

    PubMed

    Zhao, Z X; Huang, Y Z; Shi, S G; Tang, S H; Li, D H; Chen, X L

    2014-07-18

    In this work, we develop novel mesoporous silica composite nanoparticles (hm-SiO2(AlC4Pc)@Pd) for the co-delivery of photosensitizer (PS) tetra-substituted carboxyl aluminum phthalocyanine (AlC4Pc) and small Pd nanosheets as a potential dual carrier system to combine photodynamic therapy (PDT) with photothermal therapy (PTT). In the nanocomposite, PS AlC4Pc was covalently conjugated to a mesoporous silica network, and small Pd nanosheets were coated onto the surface of mesoporous silica by both coordination and electrostatic interaction. Since small Pd nanosheets and AlC4Pc display matched maximum absorptions in the 600-800 nm near-infrared (NIR) region, the fabricated hm-SiO2(AlC4Pc)@Pd nanocomposites can generate both singlet oxygen and heat upon 660 nm single continuous wavelength (CW) laser irradiation. In vitro results indicated that the cell-killing efficacy by simultaneous PDT/PTT treatment using hm-SiO2(AlC4Pc)@Pd was higher than PDT or PTT treatment alone after exposure to a 660 nm CW-NIR laser. PMID:24971525

  15. Cancer therapy improvement with mesoporous silica nanoparticles combining photodynamic and photothermal therapy

    NASA Astrophysics Data System (ADS)

    Zhao, Z. X.; Huang, Y. Z.; Shi, S. G.; Tang, S. H.; Li, D. H.; Chen, X. L.

    2014-07-01

    In this work, we develop novel mesoporous silica composite nanoparticles (hm-SiO2(AlC4Pc)@Pd) for the co-delivery of photosensitizer (PS) tetra-substituted carboxyl aluminum phthalocyanine (AlC4Pc) and small Pd nanosheets as a potential dual carrier system to combine photodynamic therapy (PDT) with photothermal therapy (PTT). In the nanocomposite, PS AlC4Pc was covalently conjugated to a mesoporous silica network, and small Pd nanosheets were coated onto the surface of mesoporous silica by both coordination and electrostatic interaction. Since small Pd nanosheets and AlC4Pc display matched maximum absorptions in the 600-800 nm near-infrared (NIR) region, the fabricated hm-SiO2(AlC4Pc)@Pd nanocomposites can generate both singlet oxygen and heat upon 660 nm single continuous wavelength (CW) laser irradiation. In vitro results indicated that the cell-killing efficacy by simultaneous PDT/PTT treatment using hm-SiO2(AlC4Pc)@Pd was higher than PDT or PTT treatment alone after exposure to a 660 nm CW-NIR laser.

  16. Effectiveness of cognitive behavioral therapy integrated with systematic desensitization, cognitive behavioral therapy combined with eye movement desensitization and reprocessing therapy, and cognitive behavioral therapy combined with virtual reality exposure therapy methods in the treatment of flight anxiety: a randomized trial

    PubMed Central

    Triscari, Maria Teresa; Faraci, Palmira; Catalisano, Dario; D’Angelo, Valerio; Urso, Viviana

    2015-01-01

    The purpose of the research was to compare the effectiveness of the following treatment methods for fear of flying: cognitive behavioral therapy (CBT) integrated with systematic desensitization, CBT combined with eye movement desensitization and reprocessing therapy, and CBT combined with virtual reality exposure therapy. Overall, our findings have proven the efficacy of all interventions in reducing fear of flying in a pre- to post-treatment comparison. All groups showed a decrease in flight anxiety, suggesting the efficiency of all three treatments in reducing self-report measures of fear of flying. In particular, our results indicated significant improvements for the treated patients using all the treatment programs, as shown not only by test scores but also by participation in the post-treatment flight. Nevertheless, outcome measures maintained a significant effect at a 1-year follow-up. In conclusion, combining CBT with both the application of eye movement desensitization and reprocessing treatment and the virtual stimuli used to expose patients with aerophobia seemed as efficient as traditional cognitive behavioral treatments integrated with systematic desensitization. PMID:26504391

  17. Effectiveness of cognitive behavioral therapy integrated with systematic desensitization, cognitive behavioral therapy combined with eye movement desensitization and reprocessing therapy, and cognitive behavioral therapy combined with virtual reality exposure therapy methods in the treatment of flight anxiety: a randomized trial.

    PubMed

    Triscari, Maria Teresa; Faraci, Palmira; Catalisano, Dario; D'Angelo, Valerio; Urso, Viviana

    2015-01-01

    The purpose of the research was to compare the effectiveness of the following treatment methods for fear of flying: cognitive behavioral therapy (CBT) integrated with systematic desensitization, CBT combined with eye movement desensitization and reprocessing therapy, and CBT combined with virtual reality exposure therapy. Overall, our findings have proven the efficacy of all interventions in reducing fear of flying in a pre- to post-treatment comparison. All groups showed a decrease in flight anxiety, suggesting the efficiency of all three treatments in reducing self-report measures of fear of flying. In particular, our results indicated significant improvements for the treated patients using all the treatment programs, as shown not only by test scores but also by participation in the post-treatment flight. Nevertheless, outcome measures maintained a significant effect at a 1-year follow-up. In conclusion, combining CBT with both the application of eye movement desensitization and reprocessing treatment and the virtual stimuli used to expose patients with aerophobia seemed as efficient as traditional cognitive behavioral treatments integrated with systematic desensitization. PMID:26504391

  18. Combination Therapy Shows Promise for Treating Advanced Breast Cancer

    Cancer.gov

    Adding the drug everolimus (Afinitor®) to exemestane helped postmenopausal women whose advanced breast cancer had stopped responding to hormonal therapy live about 4 months longer without the disease progressing than women who received exemestane alone.

  19. 5-Aminolevulinic Acid Photodynamic Therapy combined with CO2 laser therapy in treatment of laryngeal papilloma: Case report.

    PubMed

    Zhang, Yunjie; Yang, Yuguang; Zou, Xianbiao; Huang, Zheng

    2016-06-01

    This article describes the case of 5-Aminolevulinic Acid Photodynamic Therapy (ALA-PDT) via self-retaining laryngoscope under general anesthesia combined with CO2 Laser Therapy in the treatment of three patients with juvenile laryngeal papilloma. Laryngeal papilloma Clinically, it features rapid growth, multi-focus, frequent recurrence and possibility of spreading to the lower respiratory tract. ALA-PDT via self-retaining laryngoscope under general anesthesia combined with CO2 Laser Therapy is safe and effective for clearing laryngeal papilloma, laryngeal papilloma was fully removed from the three patients, with no recurrence during the 6-24 months of follow-up medical examination. 5-Aminolevulinic Acid Photodynamic Therapy (ALA-PDT) via self-retaining laryngoscope under general anesthesia combined with CO2 Laser can be used for treating laryngeal papilloma. PMID:27045601

  20. Current concepts in combination therapy for the treatment of hypertension: combined calcium channel blockers and RAAS inhibitors

    PubMed Central

    Rubio-Guerra, Alberto F; Castro-Serna, David; Barrera, Cesar I Elizalde; Ramos-Brizuela, Luz M

    2009-01-01

    Recent guidelines for the management of hypertension recommend target blood pressures <140/90 mmHg in hypertensive patients, or <130/80 mmHg in subjects with diabetes, chronic kidney disease, or coronary artery disease. Despite the availability and efficacy of antihypertensive drugs, most hypertensive patients do not reach the recommended treatment targets with monotherapy, making combination therapy necessary to achieve the therapeutic goal. Combination therapy with 2 or more agents is the most effective method for achieving strict blood pressure goals. Fixed-dose combination simplifies treatment, reduces costs, and improves adherence. There are many drug choices for combination therapy, but few data are available about the efficacy and safety of some specific combinations. Combination therapy of calcium antagonists and inhibitors of the renin-angiotensin-aldosterone system (RAAS) are efficacious and safe, and have been considered rational by both the JNC 7 and the 2007 European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension. The aim of this review is to discuss some relevant issues about the use of combinations with calcium channel blockers and RAAS inhibitors in the treatment of hypertension. PMID:21949615

  1. Delivery confirmation of bolus electron conformal therapy combined with intensity modulated x-ray therapy

    SciTech Connect

    Kavanaugh, James A.; Hogstrom, Kenneth R.; Fontenot, Jonas P.; Henkelmann, Gregory; Chu, Connel; Carver, Robert A.

    2013-02-15

    Purpose: The purpose of this study was to demonstrate that a bolus electron conformal therapy (ECT) dose plan and a mixed beam plan, composed of an intensity modulated x-ray therapy (IMXT) dose plan optimized on top of the bolus ECT plan, can be accurately delivered. Methods: Calculated dose distributions were compared with measured dose distributions for parotid and chest wall (CW) bolus ECT and mixed beam plans, each simulated in a cylindrical polystyrene phantom that allowed film dose measurements. Bolus ECT plans were created for both parotid and CW PTVs (planning target volumes) using 20 and 16 MeV beams, respectively, whose 90% dose surface conformed to the PTV. Mixed beam plans consisted of an IMXT dose plan optimized on top of the bolus ECT dose plan. The bolus ECT, IMXT, and mixed beam dose distributions were measured using radiographic films in five transverse and one sagittal planes for a total of 36 measurement conditions. Corrections for film dose response, effects of edge-on photon irradiation, and effects of irregular phantom optical properties on the Cerenkov component of the film signal resulted in high precision measurements. Data set consistency was verified by agreement of depth dose at the intersections of the sagittal plane with the five measured transverse planes. For these same depth doses, results for the mixed beam plan agreed with the sum of the individual depth doses for the bolus ECT and IMXT plans. The six mean measured planar dose distributions were compared with those calculated by the treatment planning system for all modalities. Dose agreement was assessed using the 4% dose difference and 0.2 cm distance to agreement. Results: For the combined high-dose region and low-dose region, pass rates for the parotid and CW plans were 98.7% and 96.2%, respectively, for the bolus ECT plans and 97.9% and 97.4%, respectively, for the mixed beam plans. For the high-dose gradient region, pass rates for the parotid and CW plans were 93.1% and 94

  2. Combination therapy with daclatasvir and asunaprevir for dialysis patients infected with hepatitis C virus.

    PubMed

    Sato, Ken; Yamazaki, Yuichi; Ohyama, Tatsuya; Kobayashi, Takeshi; Horiguchi, Norio; Kakizaki, Satoru; Kusano, Motoyasu; Yamada, Masanobu

    2016-03-16

    The standard antiviral therapy for dialysis patients infected with hepatitis C virus (HCV) is (pegylated) interferon monotherapy, but its efficacy is insufficient. Oral direct-acting antiviral agents (DAAs) have recently been developed for chronic hepatitis C patients. However, some DAAs have contraindications for chronic renal failure (CRF). Daclatasvir and asunaprevir are metabolized largely in the liver and are not contraindicated in CRF. Combination therapy with daclatasvir and asunaprevir was used for 4 dialysis patients infected with genotype 1b HCV. One patient had viral breakthrough, and the 3 others had sustained virological response 12. One patient was admitted for heart failure and percutaneous coronary intervention due to concomitant ischemic disease. Heart failure was unlikely to be caused by the combination therapy, as it was probably due to water overload. The patient continued to receive the combination therapy after the remission of the heart failure. The combination therapy was well tolerated in the other patients. PMID:26989674

  3. Treatment considerations for inflammatory acne: clinical evidence for adapalene 0.1% in combination therapies.

    PubMed

    Thiboutot, Diane M; Gollnick, Harald P

    2006-09-01

    Acne vulgaris is an exceptionally common, chronic, and recurring disease. It involves multiple etiological factors including follicular hyperkeratinization, increased sebum production, Propionibacterium acnes proliferation, and inflammation. Presently, oral isotretinoin is the only single agent that is effective against all 4 major pathophysiologic features. However, this drug is also responsible for several serious side effects, including teratogenicity. Therefore, it should be used in only the most severe cases and alternative treatment approaches for inflammatory acne, such as initial combination therapy, should be considered first. Combination therapy in inflammatory acne simultaneously targets multiple pathogenic factors. Current guidelines recommend early initiation of combination therapy with a topical retinoid and antimicrobials for mild to moderate inflammatory acne and topical retinoids with oral antibiotics (with or without the use of benzoyl peroxide) for moderate to severe cases of acne, followed by maintenance therapy with topical retinoids. This review evaluates the rationale and clinical evidence for the use of adapalene in combination therapy for inflammatory acne. PMID:16989194

  4. Combination therapy with daclatasvir and asunaprevir for dialysis patients infected with hepatitis C virus

    PubMed Central

    Sato, Ken; Yamazaki, Yuichi; Ohyama, Tatsuya; Kobayashi, Takeshi; Horiguchi, Norio; Kakizaki, Satoru; Kusano, Motoyasu; Yamada, Masanobu

    2016-01-01

    The standard antiviral therapy for dialysis patients infected with hepatitis C virus (HCV) is (pegylated) interferon monotherapy, but its efficacy is insufficient. Oral direct-acting antiviral agents (DAAs) have recently been developed for chronic hepatitis C patients. However, some DAAs have contraindications for chronic renal failure (CRF). Daclatasvir and asunaprevir are metabolized largely in the liver and are not contraindicated in CRF. Combination therapy with daclatasvir and asunaprevir was used for 4 dialysis patients infected with genotype 1b HCV. One patient had viral breakthrough, and the 3 others had sustained virological response 12. One patient was admitted for heart failure and percutaneous coronary intervention due to concomitant ischemic disease. Heart failure was unlikely to be caused by the combination therapy, as it was probably due to water overload. The patient continued to receive the combination therapy after the remission of the heart failure. The combination therapy was well tolerated in the other patients. PMID:26989674

  5. Universes Collide: Combining Immunotherapy with Targeted Therapy for Cancer

    PubMed Central

    Wargo, Jennifer A.; Cooper, Zachary A.; Flaherty, Keith T.

    2014-01-01

    There have been significant advances in the past several years with regard to targeted therapy and immunotherapy for cancer. This is highlighted in melanoma, where treatment with targeted therapy (against the BRAF oncogene) results in responses in the majority of patients, though duration of response is limited. In contrast, treatment with immunotherapy results in a lower response rate, but ones that tend to be more durable. Insights regarding mechanisms of response and potential synergy between these treatment strategies for melanoma are a focus of this review, with opportunities to extend these insights to the treatment of other cancers. PMID:25395294

  6. Endoscopic Combination Therapy Of Nd:YAG Laser In Conjunction With Conventional Treatments

    NASA Astrophysics Data System (ADS)

    Suzuki, Sohtaro; Aoki, Jun; Shiina, Yasubimi; Miwa, Takeshi; Daikuzono, Norio; Joffe, Stephen N.

    1988-06-01

    In this paper, we discuss the possibilities of the clinical application of the contact method with various endoprobes, either alone or combination with other conventional treat ment such as endoscopic polypectomy, local injection therapy, intubation of prosthesis, radiation therapy and general chemotherapy. According to the type of lesions and the severity of the complicated diseases, endoscopic techniques were chosen and combined. It was generally recognized that all of the endoscopic treatments were not curative therapies but applied as local therapeutics. Therefore, during the management of high risk patients with GI cancer within the mucosa, contact endoscopic Nd:YAG laser therapy should be preferred to general surgery.

  7. [Combination therapy in the medical treatment of glaucoma].

    PubMed

    Hommer, A

    2013-02-01

    A combination of antiglaucoma medications is indicated if monotherapy is not sufficient to achieve the predefined target pressure and/or in case of a progression of glaucomatous damage or conversion from ocular hypertension to glaucomatous optic neuropathy. Most recently many fixed combinations with two active compounds have become available for the medical treatment of glaucoma. Compared to non-fixed combinations, these drugs offer a much easier use for the patients. Fixed combinations have to be applied less frequently which may improve adherence. Furthermore, they most likely contain a lower amount of toxic preservatives compared to non-fixed combinations. And finally, fixed combinations may eliminate the risk of a "washout" of the first medication by using the second product of a non-fixed combination too soon after the first drop has been installed. This review aims to examine the most important aspects of IOP-lowering fixed and non-fixed combinations in glaucoma management with a clear focus on the results obtained with fixed combinations. In Germany, fixed combinations with the compositions dorzolamide/timolol (FCDT), brinzolamide/timolol (FCBRINT), latanoprost/timolol (FCLT), travoprost/timolol (FCTT), bimatoprost/timolol (FCBIMT), brimonidine/timolol (FCBT), pilocarpine/timolol (FCPT) and metipranolol/timolol (FCMT) are approved for the medical management of glaucoma and ocular hypertension. The results of clinical studies comparing fixed combinations with their active ingredients and with the corresponding non-fixed combinations will be discussed. Furthermore - if available - the results of direct comparisons of the efficacy and safety of different IOP-lowering fixed combinations are summarised. PMID:23335083

  8. Antifungal Compounds from Cyanobacteria

    PubMed Central

    Shishido, Tânia K.; Humisto, Anu; Jokela, Jouni; Liu, Liwei; Wahlsten, Matti; Tamrakar, Anisha; Fewer, David P.; Permi, Perttu; Andreote, Ana P. D.; Fiore, Marli F.; Sivonen, Kaarina

    2015-01-01

    Cyanobacteria are photosynthetic prokaryotes found in a range of environments. They are infamous for the production of toxins, as well as bioactive compounds, which exhibit anticancer, antimicrobial and protease inhibition activities. Cyanobacteria produce a broad range of antifungals belonging to structural classes, such as peptides, polyketides and alkaloids. Here, we tested cyanobacteria from a wide variety of environments for antifungal activity. The potent antifungal macrolide scytophycin was detected in Anabaena sp. HAN21/1, Anabaena cf. cylindrica PH133, Nostoc sp. HAN11/1 and Scytonema sp. HAN3/2. To our knowledge, this is the first description of Anabaena strains that produce scytophycins. We detected antifungal glycolipopeptide hassallidin production in Anabaena spp. BIR JV1 and HAN7/1 and in Nostoc spp. 6sf Calc and CENA 219. These strains were isolated from brackish and freshwater samples collected in Brazil, the Czech Republic and Finland. In addition, three cyanobacterial strains, Fischerella sp. CENA 298, Scytonema hofmanni PCC 7110 and Nostoc sp. N107.3, produced unidentified antifungal compounds that warrant further characterization. Interestingly, all of the strains shown to produce antifungal compounds in this study belong to Nostocales or Stigonematales cyanobacterial orders. PMID:25871291

  9. Eliminating Cancer Stem Cells in CML with Combination Transcriptional Therapy.

    PubMed

    Carvajal, Luis A; Steidl, Ulrich

    2016-07-01

    Leukemia stem cells (LSCs) are resistant to current therapies used to treat chronic myeloid leukemia (CML). Abraham et al. (2016) have identified a molecular network critical for CML LSC survival and propose that simultaneously targeting two of their major transcriptional regulators, p53 and c-Myc, may facilitate their eradication. PMID:27392220

  10. Combinations of Radiation Therapy and Immunotherapy for Melanoma: A Review of Clinical Outcomes

    SciTech Connect

    Barker, Christopher A.; Postow, Michael A.

    2014-04-01

    Radiation therapy has long played a role in the management of melanoma. Recent advances have also demonstrated the efficacy of immunotherapy in the treatment of melanoma. Preclinical data suggest a biologic interaction between radiation therapy and immunotherapy. Several clinical studies corroborate these findings. This review will summarize the outcomes of studies reporting on patients with melanoma treated with a combination of radiation therapy and immunotherapy. Vaccine therapies often use irradiated melanoma cells, and may be enhanced by radiation therapy. The cytokines interferon-α and interleukin-2 have been combined with radiation therapy in several small studies, with some evidence suggesting increased toxicity and/or efficacy. Ipilimumab, a monoclonal antibody which blocks cytotoxic T-lymphocyte antigen-4, has been combined with radiation therapy in several notable case studies and series. Finally, pilot studies of adoptive cell transfer have suggested that radiation therapy may improve the efficacy of treatment. The review will demonstrate that the combination of radiation therapy and immunotherapy has been reported in several notable case studies, series and clinical trials. These clinical results suggest interaction and the need for further study.

  11. Disseminated Mucormycosis With Cerebral Involvement Owing to Rhizopus Microsporus in a Kidney Recipient Treated With Combined Liposomal Amphotericin B and Posaconazole Therapy.

    PubMed

    Ville, Simon; Talarmin, Jean Philippe; Gaultier-Lintia, Alina; Bouquié, Régis; Sagan, Christine; Le Pape, Patrice; Giral, Magali; Morio, Florent

    2016-02-01

    Three months after a kidney transplant, a man experienced an internuclear ophthalmoplegia. Magnetic resonance imaging found a punctuate hyperintensity of the brainstem. Afterwards, the patient presented with peripheral facial paralysis. A complete morphologic assessment showed an increase of the brainstem lesion, together with an excavated pulmonary nodule. Combination therapy with high-dose liposomal amphotericin B and voriconazole was begun for the putative aspergillosis. Owing to its atypical clinical presentation and negative detection of Aspergillus galactomannan antigen on sera, a biopsy specimen of the lung lesion was obtained. Histopathological and mycological investigations allowed the diagnosis of mucormycosis owing to Rhizopus microsporus. Accordingly, voriconazole was replaced with posaconazole. After 5 months, regression of the cerebral lesion was noted. Disseminated mucormycosis in solid-organ recipients is uncommon and mycological diagnosis is challenging. Mortality is high and is increased by diagnostic delay. Treating mucormycosis requires surgical debridement and appropriate antifungal therapy (usually intravenous liposomal amphotericin B). This report suggests that a combination of liposomal amphotericin B and posaconazole can be a therapeutic option in patients with a poor prognosis. PMID:25275881

  12. Combination antibiotic therapy for multidrug-resistant Gram-negative bacteria

    PubMed Central

    2014-01-01

    Combination antibiotic therapy for Gram-negative sepsis is controversial. The present review provides a brief summary of the existing knowledge on combination therapy for severe infections with multidrug-resistant Pseudomonas spp., Acinetobacter spp., and Enterobacteriaceae. Empirical combination antibiotic therapy is recommended for severe sepsis and septic shock to reduce mortality related to inappropriate antibiotic treatment. Because definitive combination therapy has not been proven superior to monotherapy in meta-analyses, it is generally advised to de-escalate antibiotic therapy when the antibiotic susceptibility profile is known, although it cannot be excluded that some subgroups of patients might still benefit from continued combination therapy. Definitive combination therapy is recommended for carbapenemase-producing Enterobacteriaceae and should also be considered for severe infections with Pseudomonas and Acinetobacter spp. when beta-lactams cannot be used. Because resistance to broad-spectrum beta-lactams is increasing in Gram-negative bacteria and because no new antibiotics are expected to become available in the near future, the antibacterial potential of combination therapy should be further explored. In vitro data suggest that combinations can be effective even if the bacteria are resistant to the individual antibiotics, although existing evidence is insufficient to support the choice of combinations and explain the synergistic effects observed. In vitro models can be used to screen for effective combinations that can later be validated in animal or clinical studies. Further, in the absence of clinical evidence, in vitro data might be useful in supporting therapeutic decisions for severe infections with multidrug-resistant Gram-negative bacteria. PMID:24666223

  13. Near-infrared light triggered photodynamic therapy in combination with gene therapy using upconversion nanoparticles for effective cancer cell killing

    NASA Astrophysics Data System (ADS)

    Wang, Xin; Liu, Kai; Yang, Guangbao; Cheng, Liang; He, Lu; Liu, Yumeng; Li, Yonggang; Guo, Liang; Liu, Zhuang

    2014-07-01

    Upconversion nanoparticles (UCNPs) have drawn much attention in cancer imaging and therapy in recent years. Herein, we for the first time report the use of UCNPs with carefully engineered surface chemistry for combined photodynamic therapy (PDT) and gene therapy of cancer. In our system, positively charged NaGdF4:Yb,Er UCNPs with multilayered polymer coatings are synthesized via a layer by layer strategy, and then loaded simultaneously with Chlorin e6 (Ce6), a photosensitizing molecule, and small interfering RNA (siRNA), which targets the Plk1 oncogene. On the one hand, under excitation by a near-infrared (NIR) light at 980 nm, which shows greatly improved tissue penetration compared with visible light, cytotoxic singlet oxygen can be generated via resonance energy transfer from UCNPs to photosensitizer Ce6, while the residual upconversion luminescence is utilized for imaging. On the other hand, the silencing of Plk1 induced by siRNA delivered with UCNPs could induce significant cancer cell apoptosis. As the result of such combined photodynamic and gene therapy, a remarkably enhanced cancer cell killing effect is realized. Our work thus highlights the promise of UCNPs for imaging guided combination therapy of cancer.Upconversion nanoparticles (UCNPs) have drawn much attention in cancer imaging and therapy in recent years. Herein, we for the first time report the use of UCNPs with carefully engineered surface chemistry for combined photodynamic therapy (PDT) and gene therapy of cancer. In our system, positively charged NaGdF4:Yb,Er UCNPs with multilayered polymer coatings are synthesized via a layer by layer strategy, and then loaded simultaneously with Chlorin e6 (Ce6), a photosensitizing molecule, and small interfering RNA (siRNA), which targets the Plk1 oncogene. On the one hand, under excitation by a near-infrared (NIR) light at 980 nm, which shows greatly improved tissue penetration compared with visible light, cytotoxic singlet oxygen can be generated via

  14. The effects of combined hyperbaric oxygen therapy on patients with post-stroke depression

    PubMed Central

    Yan, Dong; Shan, Jin; Ze, Yu; Xiao-yan, Zeng; Xiao-hua, Hu

    2015-01-01

    [Purpose] To observe the effect of combined hyperbaric oxygen therapy on patients with post-stroke depression. [Subjects] Ninety patients with post-stroke depression were randomly divided into 3 groups: fluoxetine treatment group (n = 30), hyperbaric oxygen therapy group (n = 30), and hyperbaric oxygen combined treatment group (n = 30). [Methods] Fluoxetine treatment group received anti-depression drugs (fluoxetine, 20 mg/day), hyperbaric oxygen therapy group received hyperbaric oxygen (once a day, 5 days/week), hyperbaric oxygen combined treatment group received fluoxetine and hyperbaric oxygen treatments as described above. All patients received routine rehabilitation therapy. Hamilton Depression Scale (HAMD), and Scandinavian Stroke Scale (SSS) scores were evaluated before and at the end of 4th week. The total effective rate of depression release between the 3 groups was also compared at the end of study. [Results] The end scores of HAMD and SSS in the 3 groups were significantly lower than those before treatment. The total effective rate of combined hyperbaric oxygen therapy group after treatment was higher than the other two groups. [Conclusions] Combined hyperbaric oxygen therapy plays an important role in the treatment of patients with post-stroke depression. The total effective rate of combined hyperbaric oxygen therapy was higher than other routine anti post-stroke depression treatments. PMID:26157204

  15. Overcoming tumor resistance by heterologous adeno-poxvirus combination therapy

    PubMed Central

    Vähä-Koskela, Markus; Tähtinen, Siri; Grönberg-Vähä-Koskela, Susanna; Taipale, Kristian; Saha, Dipongkor; Merisalo-Soikkeli, Maiju; Ahonen, Marko; Rouvinen-Lagerström, Noora; Hirvinen, Mari; Veckman, Ville; Matikainen, Sampsa; Zhao, Fang; Pakarinen, Päivi; Salo, Jarmo; Kanerva, Anna; Cerullo, Vincenzo; Hemminki, Akseli

    2015-01-01

    Successful cancer control relies on overcoming resistance to cell death and on activation of host antitumor immunity. Oncolytic viruses are particularly attractive in this regard, as they lyse infected tumor cells and trigger robust immune responses during the infection. However, repeated injections of the same virus promote antiviral rather than antitumor immunity and tumors may mount innate antiviral defenses to restrict oncolytic virus replication. In this article, we have explored if alternating the therapy virus could circumvent these problems. We demonstrate in two virus-resistant animal models a substantial delay in antiviral immune- and innate cellular response induction by alternating injections of two immunologically distinct oncolytic viruses, adenovirus, and vaccinia virus. Our results are in support of clinical development of heterologous adeno-/vaccinia virus therapy of cancer. PMID:27119097

  16. [Antioxidants in the combined therapy of diabetic angiopathies].

    PubMed

    Bobyreva, L E

    1998-01-01

    The participation of free-radical oxidation of lipids and polymers in the pathogenesis of diabetic angiopathies is analysed. The structure of the system of antioxidant protection and the mechanisms of damage to the vascular wall macromolecules in diabetic angiopathies is suggested. The protective effects of antioxidants in experimental studies and clinical practice are discussed. The conditions for and the principles of applying antioxidants in complex therapy of diabetic angiopathies are suggested. PMID:9575419

  17. Pharmacotherapy of acute mania: monotherapy or combination therapy with mood stabilizers and antipsychotics?

    PubMed

    Grande, Iria; Vieta, Eduard

    2015-03-01

    The use of combination therapy with mood stabilizers and antipsychotics in acute mania in bipolar disorder (BD) is widespread, although most treatment guidelines recommend monotherapy as the first option, and reserve combination therapy, which is associated with more frequent and more severe side effects, for when patients do not respond to the former treatment option. Reasons to prescribe combination therapy include the lack of efficacy of the current treatment (either real or due to undisclosed poor adherence), psychiatric comorbidities, severe previous course of illness, slow cross-tapering during treatment switching, and potential benefits from particular combinations. The decision to start with monotherapy or combination therapy may depend on the patient characteristics, and is still under debate. Clinical trials designed to ascertain whether combination therapy or monotherapy is more advantageous for patients in acute mania and beyond, according to illness severity, are urgently needed. Adding a third monotherapy arm to the conventional two-arm, adjunctive-design trials or initiating combination therapy from the beginning may help to shed some light on the issue. PMID:25711483

  18. Combined therapy of oncolytic adenovirus and temozolomide enhances lung cancer virotherapy in vitro and in vivo.

    PubMed

    Gomez-Gutierrez, Jorge G; Nitz, Jonathan; Sharma, Rajesh; Wechman, Stephen L; Riedinger, Eric; Martinez-Jaramillo, Elvis; Sam Zhou, Heshan; McMasters, Kelly M

    2016-01-01

    Oncolytic adenoviruses (OAds) are very promising for the treatment of lung cancer. However, OAd-based monotherapeutics have not been effective during clinical trials. Therefore, the effectiveness of virotherapy must be enhanced by combining OAds with other therapies. In this study, the therapeutic potential of OAd in combination with temozolomide (TMZ) was evaluated in lung cancer cells in vitro and in vivo. The combination of OAd and TMZ therapy synergistically enhanced cancer cell death; this enhanced cancer cell death may be explained via three related mechanisms: apoptosis, virus replication, and autophagy. Autophagy inhibition partially protected cancer cells from this combined therapy. This combination significantly suppressed the growth of subcutaneous H441 lung cancer xenograft tumors in athymic nude mice. In this study, we have provided an experimental rationale to test OAds in combination with TMZ in a lung cancer clinical trial. PMID:26561948

  19. Ultrasmall Biocompatible WO3- x Nanodots for Multi-Modality Imaging and Combined Therapy of Cancers.

    PubMed

    Wen, Ling; Chen, Ling; Zheng, Shimin; Zeng, Jianfeng; Duan, Guangxin; Wang, Yong; Wang, Guanglin; Chai, Zhifang; Li, Zhen; Gao, Mingyuan

    2016-07-01

    Ultrasmall biocompatible WO3 - x nanodots with an outstanding X-ray radiation sensitization effect are prepared, and demonstrated to be applicable for multi-modality tumor imaging through computed tomography and photoacoustic imaging (PAI), and effective cancer treatment combining both photothermal therapy and radiation therapy. PMID:27136070

  20. Expanding the therapeutic index of radiation therapy by combining in situ gene therapy in the treatment of prostate cancer.

    PubMed

    Tetzlaff, Michael T; Teh, Bin S; Timme, Terry L; Fujita, Tetsuo; Satoh, Takefumi; Tabata, Ken-Ichi; Mai, Wei-Yuan; Vlachaki, Maria T; Amato, Robert J; Kadmon, Dov; Miles, Brian J; Ayala, Gustavo; Wheeler, Thomas M; Aguilar-Cordova, Estuardo; Thompson, Timothy C; Butler, E Brian

    2006-02-01

    The advances in radiotherapy (3D-CRT, IMRT) have enabled high doses of radiation to be delivered with the least possible associated toxicity. However, the persistence of cancer (local recurrence after radiotherapy) despite these increased doses as well as distant failure suggesting the existence of micro-metastases, especially in the case of higher risk disease, have underscored the need for continued improvement in treatment strategies to manage local and micro-metastatic disease as definitively as possible. This has prompted the idea that an increase in the therapeutic index of radiotherapy might be achieved by combining it with in situ gene therapy. The goal of these combinatorial therapies is to maximize the selective pressure against cancer cell growth while minimizing treatment-associated toxicity. Major efforts utilizing different gene therapy strategies have been employed in conjunction with radiotherapy. We reviewed our and other published clinical trials utilizing this combined radio-genetherapy approach including their associated pre-clinical in vitro and in vivo models. The use of in situ gene therapy as an adjuvant to radiation therapy dramatically reduced cell viability in vitro and tumor growth in vivo. No significant worsening of the toxicities normally observed in single-modality approaches were identified in Phase I/II clinical studies. Enhancement of both local and systemic T-cell activation was noted with this combined approach suggesting anti-tumor immunity. Early clinical outcome including biochemical and biopsy data was very promising. These results demonstrate the increased therapeutic efficacy achieved by combining in situ gene therapy with radiotherapy in the management of local prostate cancer. The combined approach maximizes tumor control, both local-regional and systemic through radio-genetherapy induced cytotoxicity and anti-tumor immunity. PMID:16417399

  1. Photothermal combined gene therapy achieved by polyethyleneimine-grafted oxidized mesoporous carbon nanospheres.

    PubMed

    Meng, Ying; Wang, Shanshan; Li, Chengyi; Qian, Min; Yan, Xueying; Yao, Shuangchao; Peng, Xiyue; Wang, Yi; Huang, Rongqin

    2016-09-01

    Combining controllable photothermal therapy and efficacious gene therapy in a single platform holds great promise in cancer therapy due to the enhanced combined therapeutic effects. Herein, polyethyleneimine-grafted oxidized mesoporous carbon nanospheres (OP) were developed for combined photothermal combined gene therapy in vitro and in vivo. The synthesized OP was characterized to have three dimensional spherical structure with uniformed diameter, ordered mesopores with graphitic domains, high water dispersion with zeta potential of +22 mV, and good biocompatibility. Consequently, OP was exploited as the photothermal convertor with strong NIR absorption and the gene vector via electrostatic interaction, which therefore cannot only deliver the therapeutic gene (pING4) to tumors for gene therapy, but also can eliminate the tumors by photothermal ablation. Moreover, the improved gene therapy accompanied by the NIR photothermally enhanced gene release was also well achieved based on OP. The excellent combined therapeutic effects demonstrated in vitro and in vivo suggested the OP's potential for cancer therapy. PMID:27258483

  2. Single-Agent Therapies After Standard Combination Regimens.

    PubMed

    Chokshi, Saurin; Hochster, Howard S

    2016-01-01

    Increasingly prolonged survival in metastatic colorectal cancer has paralleled the approval of new agents alone and in combination. Most recently, several new agents have sought approval in the heavily pretreated setting, after treatment with standard chemotherapies, alone and in combination, and with anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor (for patients with RAS wild-type tumors). These agents have included the multitargeted tyrosine kinase inhibitor (TKI), regorafenib, and the novel antimetabolite combination, TAS-102. Both of these showed improvement in progression-free survival and overall survival compared with placebo controls and were approved in the United States and the rest of the world. Benefits of treatment and toxicities are discussed. Nintedanib, another multitargeted TKI, is already approved by the European Medicines Evaluation Agency for non-small cell lung cancer and has been studied in a similar phase III trial. Results are pending. The risks and benefits of each agent are discussed. PMID:27341600

  3. Controlled Trial of Very Low Calorie Diet, Behavior Therapy, and Their Combination in the Treatment of Obesity.

    ERIC Educational Resources Information Center

    Wadden, Thomas A; Stunkard, Albert J.

    1986-01-01

    Assessed the effectiveness of a combined program of very low calorie diet and behavior therapy in treating obesity. Combined treatment and behavior therapy alone subjects maintained weight losses; none of the diet alone subjects met the criterion used to define maintenance. Only those receiving behavior therapy alone and combined treatment showed…

  4. Dystonia with MPH/Risperidone Combined Therapy for ADHD.

    PubMed

    Millichap, J Gordon; Yee, Michelle M

    2016-01-01

    Investigators from Child Neurology and Pediatrics, University of Texas Health Science Center, Houston, report extrapyramidal symptoms in a 13-year-old boy with a psychiatric history of schizophrenia, bipolar disorder, ADHD, and autism, responsive to combination risperidone, oxcarbazepine, and MPH. PMID:27004141

  5. A combined preclinical therapy of cannabinoids and temozolomide against glioma.

    PubMed

    Torres, Sofía; Lorente, Mar; Rodríguez-Fornés, Fátima; Hernández-Tiedra, Sonia; Salazar, María; García-Taboada, Elena; Barcia, Juan; Guzmán, Manuel; Velasco, Guillermo

    2011-01-01

    Glioblastoma multiforme (GBM) is highly resistant to current anticancer treatments, which makes it crucial to find new therapeutic strategies aimed at improving the poor prognosis of patients suffering from this disease. Δ(9)-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoid receptor agonists inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells. Here, we show that the combined administration of THC and temozolomide (TMZ; the benchmark agent for the management of GBM) exerts a strong antitumoral action in glioma xenografts, an effect that is also observed in tumors that are resistant to TMZ treatment. Combined administration of THC and TMZ enhanced autophagy, whereas pharmacologic or genetic inhibition of this process prevented TMZ + THC-induced cell death, supporting that activation of autophagy plays a crucial role on the mechanism of action of this drug combination. Administration of submaximal doses of THC and cannabidiol (CBD; another plant-derived cannabinoid that also induces glioma cell death through a mechanism of action different from that of THC) remarkably reduces the growth of glioma xenografts. Moreover, treatment with TMZ and submaximal doses of THC and CBD produced a strong antitumoral action in both TMZ-sensitive and TMZ-resistant tumors. Altogether, our findings support that the combined administration of TMZ and cannabinoids could be therapeutically exploited for the management of GBM. PMID:21220494

  6. Facile preparation of hybrid core-shell nanorods for photothermal and radiation combined therapy.

    PubMed

    Deng, Yaoyao; Li, Erdong; Cheng, Xiaju; Zhu, Jing; Lu, Shuanglong; Ge, Cuicui; Gu, Hongwei; Pan, Yue

    2016-02-11

    The hybrid platinum@iron oxide core-shell nanorods with high biocompatibility were synthesized and applied for combined therapy. These hybrid nanorods exhibit a good photothermal effect on cancer cells upon irradiation with a NIR laser. Furthermore, due to the presence of a high atomic number element (platinum core), the hybrid nanorods show a synergistic effect between photothermal and radiation therapy. Therefore, the as-prepared core-shell nanorods could play an important role in facilitating synergistic therapy between photothermal and radiation therapy to achieve better therapeutic efficacy. PMID:26818657

  7. Combination Regimens of Radiation Therapy and Therapeutic Cancer Vaccines: Mechanisms and Opportunities

    PubMed Central

    Garnett-Benson, Charlie; Hodge, James W.; Gameiro, Sofia R.

    2014-01-01

    Radiation therapy is widely used with curative or palliative intent in the clinical management of multiple cancers. Although mainly aimed at direct tumor cell killing, mounting evidence suggests that radiation can alter the tumor to become an immunostimulatory milieu. Data suggest that the immunogenic effects of radiation can be exploited to promote synergistic antitumor effects in combination with immunotherapeutic agents. Here we review concepts associated with the immunogenic consequences of radiation therapy, and highlight how preclinical findings are translating into clinical benefit for patients receiving combination regimens of radiation therapy and therapeutic cancer vaccines. PMID:25481266

  8. [Combined helium-neon laser therapy in patients with ischemic heart disease].

    PubMed

    Korochkin, I M; Kartelishev, A V; Babushkina, G V; Kapustina, G M

    1990-03-01

    The paper describes the combined helium-neon-laser (HNL) therapy (intravenous and topical) developed by the authors to treat patients with coronary heart disease. A high efficacy of this therapy mode was demonstrated in patients over 70 years of age with Functional Classes III-IV angina refractory to antianginal agents. The mechanisms responsible for therapeutic efficiency of laser irradiation were studied at the membraneous and cellular levels. There is evidence that the combined HNL-therapy had advantages over topical HNL exposure in terms of higher clinical efficiency and patterns of abnormal chemical changes. PMID:2381119

  9. Two drugs are better than one. A short history of combined therapy of ovarian cancer

    PubMed Central

    Gajek, Arkadiusz; Marczak, Agnieszka

    2014-01-01

    Combined therapy of ovarian cancer has a long history. It has been applied for many years. The first drug which was commonly combined with other chemotherapeutics was cisplatin. It turned out to be effective given together with alkylating agents as well as with taxanes. Another drug which is often the basis of first-line therapy is doxorubicin. The use of traditional chemotherapy is often limited due to side effects. This is why new drugs, targeted specifically at cancer cells (e.g. monoclonal antibodies or epidermal growth factor receptor inhibitors), offer a welcome addition when used in combination with conventional anticancer agents. Drugs applied in combination should be synergistic or at least additive. To evaluate the type of interaction between drugs in a plausible sequence, isobolographic analysis is used. This method allows one to assess whether the two agents could make an efficient combination, which might improve the therapy of ovarian cancer. PMID:26793017

  10. Strategies for combining immunotherapy with radiation for anticancer therapy

    PubMed Central

    Lee, Dean A; Cortez, Maria A; Wang, Xiaohong; Niknam, Sharareh; Tang, Chad; Hong, David S; Naing, Aung; Sharma, Padmanee; Allison, James P; Chang, Joe Y; Gomez, Daniel R; Heymach, John V; Komaki, Ritsuko U; Cooper, Laurence J; Welsh, James W

    2016-01-01

    Radiation therapy controls local disease but also prompts the release of tumor-associated antigens and stress-related danger signals that primes T cells to promote tumor regression at unirradiated sites known as the abscopal effect. This may be enhanced by blocking inhibitory immune signals that modulate immune activity through a variety of mechanisms. Indeed, abscopal responses have occurred in patients with lung cancer or melanoma when given anti-CTLA4 antibody and radiation. Other approaches involve expanding and reinfusing T or NK cells or engineered T cells to express receptors that target specific tumor peptides. These approaches may be useful for immunocompromised patients receiving radiation. Preclinical and clinical studies are testing both immune checkpoint–based strategies and adoptive immunotherapies with radiation. PMID:26310908

  11. Targeted Therapy and Checkpoint Immunotherapy Combinations for the Treatment of Cancer.

    PubMed

    Hughes, Paul E; Caenepeel, Sean; Wu, Lawren C

    2016-07-01

    Many advances in the treatment of cancer have been driven by the development of targeted therapies that inhibit oncogenic signaling pathways and tumor-associated angiogenesis, as well as by the recent development of therapies that activate a patient's immune system to unleash antitumor immunity. Some targeted therapies can have effects on host immune responses, in addition to their effects on tumor biology. These immune-modulating effects, such as increasing tumor antigenicity or promoting intratumoral T cell infiltration, provide a rationale for combining these targeted therapies with immunotherapies. Here, we discuss the immune-modulating effects of targeted therapies against the MAPK and VEGF signaling pathways, and how they may synergize with immunomodulatory antibodies that target PD1/PDL1 and CTLA4. We critically examine the rationale in support of these combinations in light of the current understanding of the underlying mechanisms of action of these therapies. We also discuss the available preclinical and clinical data for these combination approaches and their implications regarding mechanisms of action. Insights from these studies provide a framework for considering additional combinations of targeted therapies and immunotherapies for the treatment of cancer. PMID:27216414

  12. The Clinical Development of Molecularly Targeted Agents in Combination With Radiation Therapy: A Pharmaceutical Perspective

    SciTech Connect

    Ataman, Ozlem U.; Sambrook, Sally J.; Wilks, Chris; Lloyd, Andrew; Taylor, Amanda E.; Wedge, Stephen R.

    2012-11-15

    Summary: This paper explores historical and current roles of pharmaceutical industry sponsorship of clinical trials testing radiation therapy combinations with molecularly targeted agents and attempts to identify potential solutions to expediting further combination studies. An analysis of clinical trials involving a combination of radiation therapy and novel cancer therapies was performed. Ongoing and completed trials were identified by searching the (clinicaltrials.gov) Web site, in the first instance, with published trials of drugs of interest identified through American Society of Clinical Oncology, European CanCer Organisation/European Society for Medical Oncology, American Society for Radiation Oncology/European Society for Therapeutic Radiology and Oncology, and PubMed databases and then cross-correlated with (clinicaltrials.gov) protocols. We examined combination trials involving radiation therapy with novel agents and determined their distribution by tumor type, predominant molecular mechanisms examined in combination to date, timing of initiation of trials relative to a novel agent's primary development, and source of sponsorship of such trials. A total of 564 studies of targeted agents in combination with radiation therapy were identified with or without concomitant chemotherapy. Most studies were in phase I/II development, with only 36 trials in phase III. The tumor site most frequently studied was head and neck (26%), followed by non-small cell lung cancer. Pharmaceutical companies were the sponsors of 33% of studies overall and provided support for only 16% of phase III studies. In terms of pharmaceutical sponsorship, Genentech was the most active sponsor of radiation therapy combinations (22%), followed by AstraZeneca (14%). Most radiation therapy combination trials do not appear to be initiated until after drug approval. In phase III studies, the most common (58%) primary endpoint was overall survival. Collectively, this analysis suggests that such

  13. The clinical development of molecularly targeted agents in combination with radiation therapy: a pharmaceutical perspective.

    PubMed

    Ataman, Ozlem U; Sambrook, Sally J; Wilks, Chris; Lloyd, Andrew; Taylor, Amanda E; Wedge, Stephen R

    2012-11-15

    This paper explores historical and current roles of pharmaceutical industry sponsorship of clinical trials testing radiation therapy combinations with molecularly targeted agents and attempts to identify potential solutions to expediting further combination studies. An analysis of clinical trials involving a combination of radiation therapy and novel cancer therapies was performed. Ongoing and completed trials were identified by searching the clinicaltrials.gov Web site, in the first instance, with published trials of drugs of interest identified through American Society of Clinical Oncology, European CanCer Organisation/European Society for Medical Oncology, American Society for Radiation Oncology/European Society for Therapeutic Radiology and Oncology, and PubMed databases and then cross-correlated with clinicaltrials.gov protocols. We examined combination trials involving radiation therapy with novel agents and determined their distribution by tumor type, predominant molecular mechanisms examined in combination to date, timing of initiation of trials relative to a novel agent's primary development, and source of sponsorship of such trials. A total of 564 studies of targeted agents in combination with radiation therapy were identified with or without concomitant chemotherapy. Most studies were in phase I/II development, with only 36 trials in phase III. The tumor site most frequently studied was head and neck (26%), followed by non-small cell lung cancer. Pharmaceutical companies were the sponsors of 33% of studies overall and provided support for only 16% of phase III studies. In terms of pharmaceutical sponsorship, Genentech was the most active sponsor of radiation therapy combinations (22%), followed by AstraZeneca (14%). Most radiation therapy combination trials do not appear to be initiated until after drug approval. In phase III studies, the most common (58%) primary endpoint was overall survival. Collectively, this analysis suggests that such trials are

  14. Combination therapy using maxacalcitol and corticosteroid lotions preliminary to monotherapy with maxacalcitol lotion for scalp psoriasis.

    PubMed

    Okubo, Yukari; Natsume, Shoko; Usui, Kae; Muro, Mayuko; Tsuboi, Ryoji

    2014-02-01

    Topical treatment with betamethasone butyrate propionate lotion on 37 patients with scalp psoriasis was replaced with a combination therapy using maxacalcitol lotion (on weekdays) and BBP (on the weekends). This combination therapy was later switched to MXA monotherapy. To identify the optimum duration of the combination therapy, the patients were divided into two groups: a 4-week group and an 8-week group, which were given combination therapy and monotherapy. In both groups, the total mean scores for the skin symptoms had significantly improved in comparison with that obtained at the outset of the study (p < 0.01). In terms of overall improvement, 20.0% of the 4-week group and 72.7% of the 8-week group yielded scores reflecting moderate or greater improvement. The treatment administered to the 8-week group was significantly more effective than that given to the 4-week group at the end of the trial (p < 0.01). This study also suggests that a 4-week combination therapy is an option before switching to monotherapy, but that an 8-week therapy is preferable in severe cases. PMID:22515652

  15. Novel radiotherapy approaches for lung cancer: combining radiation therapy with targeted and immunotherapies

    PubMed Central

    Simone, Charles B.; Burri, Stuart H.

    2015-01-01

    Targeted therapies and immunotherapies have quickly become fixtures in the treatment armamentarium for metastatic non-small cell lung cancer (NSCLC). Targeted therapies directed against epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) translocations, and ROS-1 rearrangements have demonstrated improved progression free survival (PFS) and, in selected populations, improved overall survival (OS) compared with cytotoxic chemotherapy. Immunotherapies, including checkpoint inhibitor monoclonal antibodies against programmed death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1), have now also demonstrated improved survival compared with chemotherapy. The use of these novel systemic agents in non-metastatic patient populations and in combination with radiation therapy is not well defined. As radiation therapy has become more effective and more conformal with fewer toxicities, it has increasingly been used in the oligometastatic or oligoprogression setting. This has allowed improvement in PFS and potentially OS, and in the oligoprogressive setting may overcome acquired drug resistance of a specific lesion(s) to allow patients to remain on their targeted therapies. Molecularly targeted therapies and immunotherapies for patients with metastatic NSCLC have demonstrated much success. Advances in radiation therapy and stereotactic body radiotherapy, radiation therapy have led to combination strategies with targeted therapies among patients with lung cancer. Radiation therapy has also been combined with immunotherapies predominantly in the metastatic setting. In the metastatic population, radiation therapy has the ability to provide durable local control and also augment the immune response of systemic agents, which may lead to an abscopal effect of immune-mediated tumor response in disease sites outside of the radiation field in select patients. PMID:26629423

  16. Filamentous fungal endophthalmitis: results of combination therapy with intravitreal amphotericin B and voriconazole

    PubMed Central

    Mithal, Kopal; Pathengay, Avinash; Bawdekar, Abhishek; Jindal, Animesh; Vira, Divya; Relhan, Nidhi; Choudhury, Himadri; Gupta, Namrata; Gupta, Varun; Koday, Nagendra K; Flynn, Harry W

    2015-01-01

    Purpose To report outcomes of exogenous fungal endophthalmitis treated with combination of intravitreal antifungal agents. Design Retrospective, non-randomized, interventional, consecutive case series. Methods Twelve eyes of twelve consecutive cases of filamentous fungal endophthalmitis were treated with a combination of intravitreal amphotericin-B and intravitreal voriconazole (AmB-Vo Regime) along with pars plana vitrectomy at a single center. Clinical characteristics, microbiology results, treatment strategy, visual, and anatomical outcomes were analyzed. Results Ten cases out of the twelve were postoperative endophthalmitis of which nine were part of a post cataract surgery cluster. The remaining included endophthalmitis following keratitis post pterygium excision (1) and following open globe injury (2). The most common fungus was Aspergillus terreus, which was isolated in 8/12, followed by A. flavus in 2/12 and Fusarium solani in 1/12. The presenting visual acuity ranged from light perception (LP) to counting fingers. The visual acuity at final follow-up was 20/400 or better in 7/12 eyes (58.33%) and 20/60 in 2/12 eyes (range 20/60 to LP). All eyes with corneal involvement had final visual acuity 20/400 or worse. Globe salvage was achieved in all cases. Conclusion Combining intravitreal amphotericin-B and voriconazole could be a novel treatment strategy in the management of endophthalmitis caused by filamentous fungus. Eyes with corneal involvement had poor visual outcome either with or without therapeutic penetrating keratoplasty. PMID:25926714

  17. Combination therapy in cholesterol reduction: focus on ezetimibe and statins

    PubMed Central

    Grigore, Liliana; Norata, Giuseppe Danilo; Catapano, Alberico L

    2008-01-01

    Although widely used in lipid lowering therapy, HMG CoA reductase inhibitors (even when administered at high doses) are frequently insufficient to achieve guideline-recommended LDL-C goals for many patients with hypercholesterolemia in everyday clinical practice. Many patients do not achieve LDL-C goal on the initial dose of statin and the majority of these patients does not reach their goal after 6 months. As a consequence, a wide therapeutic gap exists between target LDL-C levels and those typically achieved in clinical practice. A recent and more effective therapeutic hypocholesterolemic strategy is to treat the two main sources of cholesterol simultaneously (production of cholesterol, mainly in the liver, and absorption of cholesterol in the intestine) with a complementary mechanism of action, by co-administering ezetimibe, a novel agent inhibiting cholesterol absorption, with a statin, which inhibits cholesterol production in the liver. Ezetimibe can be effectively and safely co-administered with any dose of any statin and, compared with the single inhibition of cholesterol production, afforded by statins alone, provides consistently greater reductions in LDL-C through dual inhibition of both cholesterol production and absorption. We summarize the pivotal role of both the liver and intestine in the overall balance of cholesterol in the body and describe the clinical impact and relevance of using ezetimibe either alone or co-administered with statins in controlling elevated levels of plasma LDL cholesterol. PMID:18561502

  18. Discovery, mechanisms of action and combination therapy of artemisinin.

    PubMed

    Cui, Liwang; Su, Xin-zhuan

    2009-10-01

    Despite great international efforts, malaria still inflicts an enormous toll on human lives, especially in Africa. Throughout history, antimalarial medicines have been one of the most powerful tools in malaria control. However, the acquisition and spread of parasite strains that are resistant to multiple antimalarial drugs have become one of the greatest challenges to malaria treatment, and are associated with the increase in morbidity and mortality in many malaria-endemic countries. To deal with this grave situation, artemisinin-based combinatory therapies (ACTs) have been introduced and widely deployed in malarious regions. Artemisinin is a new class of antimalarial compounds discovered by Chinese scientists from the sweet wormwood Artemisia annua. The potential development of resistance to artemisinins by Plasmodium falciparum threatens the usable lifespan of ACTs, and therefore is a subject of close surveillance and extensive research. Studies at the Thai-Cambodian border, a historical epicenter of multidrug resistance, have detected reduced susceptibility to artemisinins as manifested by prolonged parasite-clearance times, raising considerable concerns on resistance development. Despite this significance, there is still controversy on the mode of action of artemisinins. Although a number of potential cellular targets of artemisinins have been proposed, they remain to be verified experimentally. Here, we review the history of artemisinin discovery, discuss the mode of action and potential drug targets, and present strategies to elucidate resistance mechanisms. PMID:19803708

  19. Assessing adherence in Thai patients taking combination antiretroviral therapy.

    PubMed

    Kerr, S J; Avihingsanon, A; Putcharoen, O; Chetchotisakd, P; Layton, M; Ubolyam, S; Ruxrungtham, K; Cooper, D A; Phanuphak, P; Duncombe, C

    2012-03-01

    In settings where medications and viral load (VL) monitoring are limited by cost, clinicians need reliable ways to assess patient adherence to therapy. We assessed sensitivity and specificity of two self-reported adherence tools (a visual analogue scale [VAS] and the CASE [Center for Adherence Support Evaluation] adherence index), against a standard of detectable VL, with 288 patients from three sites in Thailand. We also assessed predictors of non-adherence. The sensitivity and specificity of the VAS <95% and CASE adherence index ≤11 against a VL >50 copies/mL were 26% and 90%, 19% and 95%, respectively. Against a VL ≥1000 copies/mL sensitivities increased to 55% and 36%, respectively, and specificities were unchanged. Attending a clinic not staffed by HIV specialists (odds ratio [OR] 3.14; 95% confidence interval [CI] 1.19-8.34) and being educated to primary school level or less (OR 2.24; 95% CI 1.01-4.94) were associated with self-reported adherence <95% on the VAS in multivariate analysis. Adherence assessed by the VAS was a more accurate predictor of detectable VL. Policy-makers in resource-limited settings should ensure that treatment centres are staffed with well-trained personnel aware of the importance of good patient adherence. PMID:22581867

  20. Discovery, mechanisms of action and combination therapy of artemisinin

    PubMed Central

    Cui, Liwang; Su, Xin-zhuan

    2009-01-01

    Despite great international efforts, malaria still inflicts an enormous toll on human lives, especially in Africa. Throughout history, antimalarial medicines have been one of the most powerful tools in malaria control. However, the acquisition and spread of parasite strains that are resistant to multiple antimalarial drugs have become one of the greatest challenges to malaria treatment, and are associated with the increase in morbidity and mortality in many malaria-endemic countries. To deal with this grave situation, artemisinin-based combinatory therapies (ACTs) have been introduced and widely deployed in malarious regions. Artemisinin is a new class of antimalarial compounds discovered by Chinese scientists from the sweet wormwood Artemisia annua. The potential development of resistance to artemisinins by Plasmodium falciparum threatens the usable lifespan of ACTs, and therefore is a subject of close surveillance and extensive research. Studies at the Thai–Cambodian border, a historical epicenter of multidrug resistance, have detected reduced susceptibility to artemisinins as manifested by prolonged parasite-clearance times, raising considerable concerns on resistance development. Despite this significance, there is still controversy on the mode of action of artemisinins. Although a number of potential cellular targets of artemisinins have been proposed, they remain to be verified experimentally. Here, we review the history of artemisinin discovery, discuss the mode of action and potential drug targets, and present strategies to elucidate resistance mechanisms. PMID:19803708

  1. Daptomycin-Nonsusceptible Staphylococcus aureus: The Role of Combination Therapy with Daptomycin and Gentamicin

    PubMed Central

    Jiang, Jhih-Hang; Peleg, Anton Y.

    2015-01-01

    Reduced susceptibility to daptomycin in Staphylococcus aureus has now been described, leading to clinical failures. Here we determined the impact of daptomycin and gentamicin combination therapy on bactericidal activity and resistance emergence using daptomycin-susceptible and -resistant isolates with mutations linked to previous daptomycin or vancomycin exposure. Enhanced killing of S. aureus was observed when gentamicin was combined with daptomycin, most commonly with daptomycin concentrations below the peak serum free-drug concentrations achieved with standard dosing. Synergy was seen with daptomycin-susceptible isolates and with isolates resistant to vancomycin and daptomycin. Combination therapy also prevented the emergence of resistance. Daptomycin and gentamicin combination therapy may provide the synergy required to prevent emergence of resistance when daptomycin levels are below peak serum concentrations as would be found in deep-seated, complicated infections. PMID:26633517

  2. Early use of negative pressure therapy in combination with silver dressings in a difficult breast abscess.

    PubMed

    Richards, Alastair J; Hagelstein, Sue M; Patel, Girish K; Ivins, Nicola M; Sweetland, Helen M; Harding, Keith G

    2011-12-01

    Combining silver-based dressings with negative pressure therapy after radical excision of chronically infected breast disease is a novel application of two technologies. One patient with complex, chronic, infected breast disease underwent radical excision of the affected area and was treated early with a combination of silver-based dressings and topical negative pressure therapy. The wound was then assessed sequentially using clinical measurements of wound area and depth, pain severity scores and level of exudation. It is possible to combine accepted techniques with modern dressing technologies that result in a positive outcome. In this case, the combination of a silver-based dressing with negative pressure therapy following radical excision proved safe and was well tolerated by the patient. Full epithelisation of the wound was achieved and there was no recurrence of the infection for the duration of the treatment. PMID:21883932

  3. Defining the frontiers between antifungal resistance, tolerance and the concept of persistence.

    PubMed

    Delarze, Eric; Sanglard, Dominique

    2015-11-01

    A restricted number of antifungal agents are available for the therapy of fungal diseases. With the introduction of epidemiological cut-off values for each agent in important fungal pathogens based on the distribution of minimal inhibitory concentration (MIC), the distinction between wild type and drug-resistant populations has been facilitated. Antifungal resistance has been described for all currently available antifungal agents in several pathogens and most of the associated resistance mechanisms have been deciphered at the molecular level. Clinical breakpoints for some agents have been proposed and can have predictive value for the success or failure of therapy. Tolerance to antifungals has been a much more ignored area. By definition, tolerance operates at antifungal concentrations above individual intrinsic inhibitory values. Important is that tolerance to antifungal agents favours the emergence of persister cells, which are able to survive antifungal therapy and can cause relapses. Here we will review the current knowledge on antifungal tolerance, its potential mechanisms and also evaluate the role of antifungal tolerance in the efficacy of drug treatments. PMID:26690338

  4. Combination Therapies for Lysosomal Storage Diseases: A Complex Answer to a Simple Problem.

    PubMed

    Macauley, Shannon L

    2016-06-01

    Abstract Lysosomal storage diseases (LSDs) are a group of 40-50 rare monogenic disorders that result in disrupted lysosomal function and subsequent lysosomal pathology. Depending on the protein or enzyme deficiency associated with each disease, LSDs affect an array of organ systems and elicit a complex set of secondary disease mechanisms that make many of these disorders difficult to fully treat. The etiology of most LSDs is known and the innate biology of lysosomal enzymes favors therapeutic intervention, yet most attempts at treating LSDs with enzyme replacement strategies fall short of being curative. Even with the advent of more sophisticated approaches, like substrate reduction therapy, pharmacologic chaperones, gene therapy or stem cell therapy, comprehensive treatments for LSDs have yet to be achieved. Given the limitations with individual therapies, recent research has focused on using a combination approach to treat LSDs. By coupling protein-, cell-, and gene- based therapies with small molecule drugs, researchers have found greater success in eradicating the clinical features of disease. This review seeks to discuss the positive and negatives of singular therapies used to treat LSDs, and discuss how, in combination, studies have demonstrated a more holistic benefit on pathological and functional parameters. By optimizing routes of delivery, therapeutic timing, and targeting secondary disease mechanisms, combination therapy represents the future for LSD treatment. PMID:27491211

  5. Facile preparation of hybrid core-shell nanorods for photothermal and radiation combined therapy

    NASA Astrophysics Data System (ADS)

    Deng, Yaoyao; Li, Erdong; Cheng, Xiaju; Zhu, Jing; Lu, Shuanglong; Ge, Cuicui; Gu, Hongwei; Pan, Yue

    2016-02-01

    The hybrid platinum@iron oxide core-shell nanorods with high biocompatibility were synthesized and applied for combined therapy. These hybrid nanorods exhibit a good photothermal effect on cancer cells upon irradiation with a NIR laser. Furthermore, due to the presence of a high atomic number element (platinum core), the hybrid nanorods show a synergistic effect between photothermal and radiation therapy. Therefore, the as-prepared core-shell nanorods could play an important role in facilitating synergistic therapy between photothermal and radiation therapy to achieve better therapeutic efficacy.The hybrid platinum@iron oxide core-shell nanorods with high biocompatibility were synthesized and applied for combined therapy. These hybrid nanorods exhibit a good photothermal effect on cancer cells upon irradiation with a NIR laser. Furthermore, due to the presence of a high atomic number element (platinum core), the hybrid nanorods show a synergistic effect between photothermal and radiation therapy. Therefore, the as-prepared core-shell nanorods could play an important role in facilitating synergistic therapy between photothermal and radiation therapy to achieve better therapeutic efficacy. Electronic supplementary information (ESI) available: Details of general experimental procedures. See DOI: 10.1039/c5nr09102k

  6. Creosote bush lignans for human disease treatment and prevention: Perspectives on combination therapy

    PubMed Central

    Gnabre, John; Bates, Robert; Huang, Ru Chih

    2015-01-01

    The medicinal properties of the most successful plant in the deserts of the western hemisphere, the creosote bush (Larrea tridentata), are evidenced by the long traditional usage of the plants by the Native Americans Indian tribes in Southwestern North America and the Amerindians from South America. The plant is rich in simple bisphenyl lignans and tricyclic lignans known as cyclolignans. These compounds are responsible for many of the pharmacological activities of extracts of the plants. Some of these activities, namely antiherpes, antioxidant, antifungal, and anti-inflammatory, were known a century ago. Only recently have further studies revealed other crucial activities of the same plant molecules as powerful agents against human immunodeficiency virus, human papillomavirus, cancer, neurodegenerative diseases, and symptoms of aging. Molecular mechanisms underlying the antiviral and anticancer activities have been elucidated and involve the inhibition of SP1 dependent gene transcription. This review summarizes the recent findings on creosote bush lignans. We introduce the concept of a cocktail of safe well-characterized natural products from the creosote bush that would represent a bridge between oriental herbal medicines and Western drug-based therapies. PMID:26151022

  7. Creosote bush lignans for human disease treatment and prevention: Perspectives on combination therapy.

    PubMed

    Gnabre, John; Bates, Robert; Huang, Ru Chih

    2015-07-01

    The medicinal properties of the most successful plant in the deserts of the western hemisphere, the creosote bush (Larrea tridentata), are evidenced by the long traditional usage of the plants by the Native Americans Indian tribes in Southwestern North America and the Amerindians from South America. The plant is rich in simple bisphenyl lignans and tricyclic lignans known as cyclolignans. These compounds are responsible for many of the pharmacological activities of extracts of the plants. Some of these activities, namely antiherpes, antioxidant, antifungal, and anti-inflammatory, were known a century ago. Only recently have further studies revealed other crucial activities of the same plant molecules as powerful agents against human immunodeficiency virus, human papillomavirus, cancer, neurodegenerative diseases, and symptoms of aging. Molecular mechanisms underlying the antiviral and anticancer activities have been elucidated and involve the inhibition of SP1 dependent gene transcription. This review summarizes the recent findings on creosote bush lignans. We introduce the concept of a cocktail of safe well-characterized natural products from the creosote bush that would represent a bridge between oriental herbal medicines and Western drug-based therapies. PMID:26151022

  8. A Case Report of Majocchi's Granuloma Associated with Combined Therapy of Topical Steroids and Adalimumab

    PubMed Central

    Chou, Wan-Yi; Hsu, Chih-Jung

    2016-01-01

    Abstract Currently, tumor necrosis factor alpha (TNF-alpha) inhibitors are widely used for many autoimmune disorders. However, they cause an immunocompromised status that sometimes leads to many cutaneous side effects including atypical infections. Herein, we report the first case of adalimumab-related Majocchi's granuloma. A 43-year-old Taiwanese male patient with chronic plaque-type psoriasis developed numerous tender nodules 1 month after adalimumab injection. The nodules responded poorly to bacterial folliculitis treatment. After repeated skin biopsies for pathology and tissue fungal culture, Majocchi's granuloma was confirmed. Adalimumab was withheld, and 12 weeks of terbinafine treatment was given. On completion of treatment, the nodular skin lesions and dystrophic nail lesions improved dramatically. The information, including time span, clinical features, histological findings, and improvement following withdrawal of adalimumab and treatment with an oral antifungal agent, indicates that Majocchi's granuloma was adalimumab-related. Psoriasis patients are more susceptible to dermatophyte infection due to local and systemic immunosuppressant therapy. It is important to perform a thorough examination for latent dermatophyte infection, including skin and nail lesions, before treatment with TNF-alpha inhibitors and during traditional psoriasis treatment. When atypical presentation together with treatment failure is noted in psoriasis patients prescribed biologics, clinicians should investigate evidence of dermatophyte infection and provide proper treatment. Sometimes, multiple skin biopsies and tissue fungal cultures are required to establish a correct diagnosis. PMID:26765401

  9. Recent Advances in Upconversion Nanoparticles-Based Multifunctional Nanocomposites for Combined Cancer Therapy.

    PubMed

    Tian, Gan; Zhang, Xiao; Gu, Zhanjun; Zhao, Yuliang

    2015-12-16

    Lanthanide-doped upconversion nanoparticles (UCNPs) have the ability to generate ultraviolet or visible emissions under continuous-wave near-infrared (NIR) excitation. Utilizing this special luminescence property, UCNPs are approved as a new generation of contrast agents in optical imaging with deep tissue-penetration ability and high signal-to-noise ratio. The integration of UCNPs with other functional moieties can endow them with highly enriched functionalities for imaging-guided cancer therapy, which makes composites based on UCNPs emerge as a new class of theranostic agents in biomedicine. Here, recent progress in combined cancer therapy using functional nanocomposites based on UCNPs is reviewed. Combined therapy referring to the co-delivery of two or more therapeutic agents or a combination of different treatments is becoming more popular in clinical treatment of cancer because it generates synergistic anti-cancer effects, reduces individual drug-related toxicity and suppresses multi-drug resistance through different mechanisms of action. Here, the recent advances of combined therapy contributed by UCNPs-based nanocomposites on two main branches are reviewed: i) photodynamic therapy and ii) chemotherapy, which are the two most widely adopted therapies of UCNPs-based composites. The future prospects and challenges in this emerging field will be also discussed. PMID:26505885

  10. [Repetitive facilitative exercise: recent evidence and development for combination therapy].

    PubMed

    Shimodozono, Megumi

    2013-01-01

    Repetitive facilitative exercise (RFE), a combination of high-dose (high frequency) of repetitions and neurofacilitation, is a recently developed approach to the rehabilitation of stroke-related limb impairment. We conducted a randomized controlled evaluation of RFE compared with a duration-matched conventional rehabilitation program in the treatment of subacute stroke-related upper extremity impairment (Shimodozono et al. 2013). RFE demonstrated both statistically and clinically significant benefits over conventional rehabilitation both on the Action Research Arm Test, which is designed to measure dexterity and function, and on the Fugl-Meyer Arm scores, which was chosen as measure of motor control. In the case-series study, the beneficial effect of RFE is also reported in the treatment of chronic phase of stroke. More research is needed, but RFE could conceivably be integrated with other approaches such as vibration, neuromuscular electrical stimulation, repetitive transcranial magnetic stimulation, botulinum toxin, and robotics to achieve further improvement in its capabilities. PMID:24291952

  11. Clinical Considerations for Use of Initial Combination Therapy in Type 2 Diabetes.

    PubMed

    Cahn, Avivit; Cefalu, William T

    2016-08-01

    Type 2 diabetes is a progressive disorder characterized by increasing hyperglycemia and the need to gradually intensify therapy in order to achieve and maintain glycemic control. Early initiation of combination therapy has been proposed as an approach to achieve glycemic goals earlier and delay the deterioration of glycemic control and with possible better preservation of β-cell function. We discuss in this article the pros and cons of this approach, focusing on individuals with HbA1c at diagnosis of 7.5-9.0%, where difference of opinion still exists on management. Initial combination therapy is proposed to lead to better and faster achievement of glycemic targets versus monotherapy and to impede clinical inertia and may possibly slow the deterioration of β-cell function. However, treating patients with sequential therapy is proposed to allow one to fully assess the efficacy and risk-to-benefit ratio of each drug as it is added. Furthermore, there is no evidence to support that rapid addition and titration of medications according to the glycemic profile achieved are inferior to initial combination therapy if glycemic targets are attained in a timely manner. Initial combination therapy is argued to postpone clinical inertia to the next decision point but does not eliminate it. Additionally, it may have been the agents chosen and not the timing of their initiation that led to improved β-cell function in the studies of initial combination therapy, and there are no data currently comparing use of the same drugs initiated simultaneously or sequentially. Heightened awareness of providers, individualization of therapy and setting, and reaching glycemic targets remain the mainstays of care. PMID:27440826

  12. Role of antifungal agents in the treatment of seborrheic dermatitis.

    PubMed

    Gupta, Aditya K; Nicol, Karyn; Batra, Roma

    2004-01-01

    Seborrheic dermatitis is a superficial fungal disease of the skin, occurring in areas rich in sebaceous glands. It is thought that an association exists between Malassezia yeasts and seborrheic dermatitis. This may, in part, be due to an abnormal or inflammatory immune response to these yeasts. The azoles represent the largest class of antifungals used in the treatment of this disease to date. In addition to their antifungal properties, some azoles, including bifonazole, itraconazole, and ketoconazole, have demonstrated anti-inflammatory activity, which may be beneficial in alleviating symptoms. Other topical antifungal agents, such as the allylamines (terbinafine), benzylamines (butenafine), hydroxypyridones (ciclopirox), and immunomodulators (pimecrolimus and tacrolimus), have also been effective. In addition, recent studies have revealed that tea tree oil (Melaleuca oil), honey, and cinnamic acid have antifungal activity against Malassezia species, which may be of benefit in the treatment of seborrheic dermatitis. In cases where seborrheic dermatitis is widespread, the use of an oral therapy, such as ketoconazole, itraconazole, and terbinafine, may be preferred. Essentially, antifungal therapy reduces the number of yeasts on the skin, leading to an improvement in seborrheic dermatitis. With a wide availability of preparations, including creams, shampoos, and oral formulations, antifungal agents are safe and effective in the treatment of seborrheic dermatitis. PMID:15663338

  13. Combined Immune Therapy for the Treatment of Visceral Leishmaniasis.

    PubMed

    Faleiro, Rebecca J; Kumar, Rajiv; Bunn, Patrick T; Singh, Neetu; Chauhan, Shashi Bhushan; Sheel, Meru; Amante, Fiona H; Montes de Oca, Marcela; Edwards, Chelsea L; Ng, Susanna S; Best, Shannon E; Haque, Ashraful; Beattie, Lynette; Hafner, Louise M; Sacks, David; Nylen, Susanne; Sundar, Shyam; Engwerda, Christian R

    2016-02-01

    Chronic disease caused by infections, cancer or autoimmunity can result in profound immune suppression. Immunoregulatory networks are established to prevent tissue damage caused by inflammation. Although these immune checkpoints preserve tissue function, they allow pathogens and tumors to persist, and even expand. Immune checkpoint blockade has recently been successfully employed to treat cancer. This strategy modulates immunoregulatory mechanisms to allow host immune cells to kill or control tumors. However, the utility of this approach for controlling established infections has not been extensively investigated. Here, we examined the potential of modulating glucocorticoid-induced TNF receptor-related protein (GITR) on T cells to improve anti-parasitic immunity in blood and spleen tissue from visceral leishmaniasis (VL) patients infected with Leishmania donovani. We found little effect on parasite growth or parasite-specific IFNγ production. However, this treatment reversed the improved anti-parasitic immunity achieved by IL-10 signaling blockade. Further investigations using an experimental VL model caused by infection of C57BL/6 mice with L. donovani revealed that this negative effect was prominent in the liver, dependent on parasite burden and associated with an accumulation of Th1 cells expressing high levels of KLRG-1. Nevertheless, combined anti-IL-10 and anti-GITR mAb treatment could improve anti-parasitic immunity when used with sub-optimal doses of anti-parasitic drug. However, additional studies with VL patient samples indicated that targeting GITR had no overall benefit over IL-10 signaling blockade alone at improving anti-parasitic immune responses, even with drug treatment cover. These findings identify several important factors that influence the effectiveness of immune modulation, including parasite burden, target tissue and the use of anti-parasitic drug. Critically, these results also highlight potential negative effects of combining different

  14. Combined Immune Therapy for the Treatment of Visceral Leishmaniasis

    PubMed Central

    Bunn, Patrick T.; Singh, Neetu; Chauhan, Shashi Bhushan; Sheel, Meru; Amante, Fiona H.; Montes de Oca, Marcela; Edwards, Chelsea L.; Ng, Susanna S.; Best, Shannon E.; Haque, Ashraful; Beattie, Lynette; Hafner, Louise M.; Sacks, David; Nylen, Susanne; Sundar, Shyam; Engwerda, Christian R.

    2016-01-01

    Chronic disease caused by infections, cancer or autoimmunity can result in profound immune suppression. Immunoregulatory networks are established to prevent tissue damage caused by inflammation. Although these immune checkpoints preserve tissue function, they allow pathogens and tumors to persist, and even expand. Immune checkpoint blockade has recently been successfully employed to treat cancer. This strategy modulates immunoregulatory mechanisms to allow host immune cells to kill or control tumors. However, the utility of this approach for controlling established infections has not been extensively investigated. Here, we examined the potential of modulating glucocorticoid-induced TNF receptor-related protein (GITR) on T cells to improve anti-parasitic immunity in blood and spleen tissue from visceral leishmaniasis (VL) patients infected with Leishmania donovani. We found little effect on parasite growth or parasite-specific IFNγ production. However, this treatment reversed the improved anti-parasitic immunity achieved by IL-10 signaling blockade. Further investigations using an experimental VL model caused by infection of C57BL/6 mice with L. donovani revealed that this negative effect was prominent in the liver, dependent on parasite burden and associated with an accumulation of Th1 cells expressing high levels of KLRG-1. Nevertheless, combined anti-IL-10 and anti-GITR mAb treatment could improve anti-parasitic immunity when used with sub-optimal doses of anti-parasitic drug. However, additional studies with VL patient samples indicated that targeting GITR had no overall benefit over IL-10 signaling blockade alone at improving anti-parasitic immune responses, even with drug treatment cover. These findings identify several important factors that influence the effectiveness of immune modulation, including parasite burden, target tissue and the use of anti-parasitic drug. Critically, these results also highlight potential negative effects of combining different

  15. Single-pill triple-combination therapy: an alternative to multiple-drug treatment of hypertension.

    PubMed

    Chrysant, Steven G

    2011-11-01

    Hypertension (HTN) affects an estimated 76.4 million US adults. Despite improvements in blood pressure (BP) control rates and the availability of effective antihypertensive agents, only 50% of these individuals achieve BP control. It is now recognized that many patients will require ≥ 2 antihypertensive agents to achieve BP control. Both the current US and reappraisal of the 2007 European guidelines include dual-combination regimens among recommended treatments for initial HTN therapy. For patients requiring 3 drugs, the combination of agents with complementary mechanisms of action (ie, renin-angiotensin-aldosterone system blocker, calcium channel blocker, and diuretic) has been recognized as rational and effective. Three single-pill triple-drug combinations have recently been approved for use in HTN in the United States: valsartan (VAL)/amlodipine (AML)/hydrochlorothiazide (HCTZ); olmesartan medoxomil (OM)/AML/HCTZ; and aliskiren (ALI)/VAL/HCTZ. Triple-combination regimens have resulted in a greater proportion of patients achieving BP control compared with dual-combination regimens, with significantly lower BP levels documented after only 2 weeks at maximum doses. Single-pill combinations offer convenience to address barriers to BP control such as poor adherence to therapy and therapeutic inertia. Additional benefits of combining antihypertensive agents from different classes include improved efficacy, safety, and reduction of cardiovascular risk. In patients with essential HTN for whom dual therapy is inadequate, single-pill triple-drug therapy can offer a simplified and effective treatment strategy. PMID:22104451

  16. Combination therapy for hypertension in patients with CKD: a subanalysis of the Combination Therapy of Hypertension to Prevent Cardiovascular Events trial.

    PubMed

    Rakugi, Hiromi; Ogihara, Toshio; Umemoto, Seiji; Matsuzaki, Masunori; Matsuoka, Hiroaki; Shimada, Kazuyuki; Higaki, Jitsuo; Ito, Sadayoshi; Kamiya, Akira; Suzuki, Hiromichi; Ohashi, Yasuo; Shimamoto, Kazuaki; Saruta, Takao

    2013-11-01

    The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial was a multicenter, randomized, three-arm comparative study (N=3293) undertaken to determine the optimal combination therapy, based on the occurrence of cardiovascular events in patients treated with an angiotensin II receptor blocker (ARB), a β-blocker (BB) or a thiazide diuretic (TD) in addition to the calcium antagonist benidipine as baseline medication. This subanalysis was conducted to compare the efficacy of three combination therapies in a subset of 834 patients with chronic kidney disease (CKD) (287 patients treated with benidpine-ARB, 283 patients treated with benidipine-BB and 264 patients treated with benidipine-TD). The incidence of composite cardiovascular events as the primary end point did not differ among these three groups. The incidence of hard end points and cerebrovascular events among these groups did not differ either, although the incidence among all patients in the COPE trial was lower in the benidipine-TD group than in the benidipine-BB group. The incidence of new-onset diabetes mellitus was higher in the benidipine-TD group than in the benidipine-ARB group among patients with CKD. The estimated glomerular filtration rate (eGFR) was maintained even after 12 months of treatment in patients with a baseline eGFR <60 ml min(-1) per 1.73 m(2) regardless of the treatment group, although the eGFR decreased over time in all patients in the three groups. In conclusion, in patients with CKD, all of the tested combination therapies demonstrated comparable efficacy in terms of prevention of cardiovascular events as well as maintenance of eGFR. PMID:23864054

  17. Successful therapy with tonsillectomy plus pulse therapy for the relapse of pediatric IgA nephropathy treated with multi-drugs combination therapy.

    PubMed

    Sakai, Nobuko; Kawasaki, Yukihiko; Waragai, Tomoko; Oikawa, Tomoko; Kaneko, Masatoshi; Sato, Tomoko; Suyama, Kazuhide; Hosoya, Mitsuaki

    2016-06-01

    Immunoglobulin A nephropathy (IgAN) is the most common form of chronic glomerulonephritis worldwide. In Japan, the treatment for use as an initial therapy was established in Guidelines for the Treatment of Childhood IgA nephropathy; however, no rescue therapy for recurrent or steroid-resistant pediatric IgAN was established. We report here a 15-year-old boy with severe IgAN, who was treated with combination therapy involving prednisolone, mizoribine, warfarin, and dilazep dihydrochloride for 2 years. The response to the combination therapy was good and both proteinuria and hematuria disappeared. The pathological findings at the second renal biopsy were improved and PSL was discontinued. However, due to nonadherence to the treatment regimen and tonsillitis, macrohematuria and an increase of proteinuria were again observed and the pathological findings at the third renal biopsy showed clear deterioration. The patient was, therefore, diagnosed with recurrent IgAN. Tonsillectomy plus methylprednisolone pulse therapy (TMP) was performed as a rescue therapy for the recurrence of severe IgAN. Both the proteinuria or hematuria subsequently disappeared, and no proteinuria or hematuria has been observed and kidney function has remained normal during a 5-year follow-up. The patient experienced no severe side effects associated with the drug regimens. In conclusion, our case suggests that TMP may be an effective and useful rescue therapy for recurrent IgAN after multi-drug combination therapy. PMID:27210310

  18. An Integrative Pharmacogenomic Approach Identifies Two-drug Combination Therapies for Personalized Cancer Medicine

    PubMed Central

    Liu, Yin; Fei, Teng; Zheng, Xiaoqi; Brown, Myles; Zhang, Peng; Liu, X. Shirley; Wang, Haiyun

    2016-01-01

    An individual tumor harbors multiple molecular alterations that promote cell proliferation and prevent apoptosis and differentiation. Drugs that target specific molecular alterations have been introduced into personalized cancer medicine, but their effects can be modulated by the activities of other genes or molecules. Previous studies aiming to identify multiple molecular alterations for combination therapies are limited by available data. Given the recent large scale of available pharmacogenomic data, it is possible to systematically identify multiple biomarkers that contribute jointly to drug sensitivity, and to identify combination therapies for personalized cancer medicine. In this study, we used pharmacogenomic profiling data provided from two independent cohorts in a systematic in silico investigation of perturbed genes cooperatively associated with drug sensitivity. Our study predicted many pairs of molecular biomarkers that may benefit from the use of combination therapies. One of our predicted biomarker pairs, a mutation in the BRAF gene and upregulated expression of the PIM1 gene, was experimentally validated to benefit from a therapy combining BRAF inhibitor and PIM1 inhibitor in lung cancer. This study demonstrates how pharmacogenomic data can be used to systematically identify potentially cooperative genes and provide novel insights to combination therapies in personalized cancer medicine. PMID:26916442

  19. Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

    PubMed

    Kline, Anthony E; Leary, Jacob B; Radabaugh, Hannah L; Cheng, Jeffrey P; Bondi, Corina O

    2016-07-01

    Traumatic brain injury (TBI) is a significant health care crisis that affects two million individuals in the United Sates alone and over ten million worldwide each year. While numerous monotherapies have been evaluated and shown to be beneficial at the bench, similar results have not translated to the clinic. One reason for the lack of successful translation may be due to the fact that TBI is a heterogeneous disease that affects multiple mechanisms, thus requiring a therapeutic approach that can act on complementary, rather than single, targets. Hence, the use of combination therapies (i.e., polytherapy) has emerged as a viable approach. Stringent criteria, such as verification of each individual treatment plus the combination, a focus on behavioral outcome, and post-injury vs. pre-injury treatments, were employed to determine which studies were appropriate for review. The selection process resulted in 37 papers that fit the specifications. The review, which is the first to comprehensively assess the effects of combination therapies on behavioral outcomes after TBI, encompasses five broad categories (inflammation, oxidative stress, neurotransmitter dysregulation, neurotrophins, and stem cells, with and without rehabilitative therapies). Overall, the findings suggest that combination therapies can be more beneficial than monotherapies as indicated by 46% of the studies exhibiting an additive or synergistic positive effect versus on 19% reporting a negative interaction. These encouraging findings serve as an impetus for continued combination studies after TBI and ultimately for the development of successful clinically relevant therapies. PMID:27166858

  20. An Integrative Pharmacogenomic Approach Identifies Two-drug Combination Therapies for Personalized Cancer Medicine.

    PubMed

    Liu, Yin; Fei, Teng; Zheng, Xiaoqi; Brown, Myles; Zhang, Peng; Liu, X Shirley; Wang, Haiyun

    2016-01-01

    An individual tumor harbors multiple molecular alterations that promote cell proliferation and prevent apoptosis and differentiation. Drugs that target specific molecular alterations have been introduced into personalized cancer medicine, but their effects can be modulated by the activities of other genes or molecules. Previous studies aiming to identify multiple molecular alterations for combination therapies are limited by available data. Given the recent large scale of available pharmacogenomic data, it is possible to systematically identify multiple biomarkers that contribute jointly to drug sensitivity, and to identify combination therapies for personalized cancer medicine. In this study, we used pharmacogenomic profiling data provided from two independent cohorts in a systematic in silico investigation of perturbed genes cooperatively associated with drug sensitivity. Our study predicted many pairs of molecular biomarkers that may benefit from the use of combination therapies. One of our predicted biomarker pairs, a mutation in the BRAF gene and upregulated expression of the PIM1 gene, was experimentally validated to benefit from a therapy combining BRAF inhibitor and PIM1 inhibitor in lung cancer. This study demonstrates how pharmacogenomic data can be used to systematically identify potentially cooperative genes and provide novel insights to combination therapies in personalized cancer medicine. PMID:26916442

  1. Tailored Antibiotic Combination Powders for Inhaled Rotational Antibiotic Therapy.

    PubMed

    Lee, Sie Huey; Teo, Jeanette; Heng, Desmond; Ng, Wai Kiong; Zhao, Yanli; Tan, Reginald B H

    2016-04-01

    Respiratory lung infections due to multidrug-resistant (MDR) superbugs are on a global upsurge and have very grim clinical outcomes. Their MDR profile makes therapeutic options extremely limited. Although a highly toxic antibiotic, colistin, is favored today as a "last-line" therapeutic against these hard-to-treat MDR pathogens, it is fast losing its effectiveness. This work therefore seeks to identify and tailor-make useful combination regimens (that are potentially rotatable and synergistic) as attractive alternative strategies to address the rising rates of drug resistance. Three potentially rotatable ternary dry powder inhaler constructs (each involving colistin and 2 other different-classed antibiotics chosen from rifampicin, meropenem, and tigecycline) were identified (with distinct complementary killing mechanisms), coformulated via spray drying, evaluated on their aerosol performance using a Next-Generation Impactor and tested for their efficacies against a number of MDR pathogens. The powder particles were of respirable size (d50, 3.1 ± 0.3 μm-3.4 ± 0.1 μm) and predominantly crumpled in morphology. When dispersed via a model dry powder inhaler (Aerolizer(®)) at 60 L/min, the powders showed concomitant in vitro deposition with fine particle fractions of ∼53%-70%. All formulations were successfully tested in the laboratory to be highly effective against the MDR pathogens. In addition, a favorable synergistic interaction was detected across all 3 formulations when tested against MDR Pseudomonas aeruginosa. PMID:27019964

  2. Combination therapies for the management of nocturia and its comorbidities

    PubMed Central

    Yazici, Cenk Murat; Kurt, Omer

    2015-01-01

    Nocturia is the most bothersome lower urinary tract symptom. It has a multifactorial etiology. It had been thought nocturia was a nonspecific symptom of lower urinary system dysfunction, but it has been determined that many diseases, related to different organ systems, might be reasons for this nonspecific symptom. Along with the importance of systemic diseases that cause nocturia, the symptom itself has adverse effects on patients’ health and quality of life. There are several studies reporting a direct relationship between nocturia and depression, cognitive dysfunction, mood disturbances, falls, and fractures. For this reason, it is important to treat nocturia both to increase quality of life and to decrease related complications. Treatment opportunities have been under investigation for 20 years. Most of the studies in the literature have reported the results of single-drug medication on nocturia, which may be insufficient for a situation that has such a multifactorial etiology. In this review, we evaluated the success of different treatment combinations on nocturia. PMID:25945323

  3. [The comparative effectiveness of framycetin included in combined therapy of adenoiditis in the children].

    PubMed

    Soldatskiĭ, Iu L; Denisova, O A; Ivanenko, A M

    2014-01-01

    The objective of the present study was to evaluate the effectiveness of framycetin included in combined therapy of adenoiditis in the children. The study involved 67 children at the mean age of 6.9±2.7 years. Group 1 was comprised of 35 children given framycetin as topical therapy, the patients of group 2 were treated by the endonasal administration of a 2% silver proteinate solution. It was shown that the use of framycetin as a component of combined therapy of adenoiditis enhances the effectiveness of the treatment and compliance to therapy in comparison with the same parameters in the case of the application of traditional topical antibacterial preparations. PMID:25588492

  4. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning.

    PubMed

    Aiuti, Alessandro; Slavin, Shimon; Aker, Memet; Ficara, Francesca; Deola, Sara; Mortellaro, Alessandra; Morecki, Shoshana; Andolfi, Grazia; Tabucchi, Antonella; Carlucci, Filippo; Marinello, Enrico; Cattaneo, Federica; Vai, Sergio; Servida, Paolo; Miniero, Roberto; Roncarolo, Maria Grazia; Bordignon, Claudio

    2002-06-28

    Hematopoietic stem cell (HSC) gene therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) has shown limited clinical efficacy because of the small proportion of engrafted genetically corrected HSCs. We describe an improved protocol for gene transfer into HSCs associated with nonmyeloablative conditioning. This protocol was used in two patients for whom enzyme replacement therapy was not available, which allowed the effect of gene therapy alone to be evaluated. Sustained engraftment of engineered HSCs with differentiation into multiple lineages resulted in increased lymphocyte counts, improved immune functions (including antigen-specific responses), and lower toxic metabolites. Both patients are currently at home and clinically well, with normal growth and development. These results indicate the safety and efficacy of HSC gene therapy combined with nonmyeloablative conditioning for the treatment of SCID. PMID:12089448

  5. Emergence of echinocandin-resistant Candida spp. in a hospital setting: a consequence of 10 years of increasing use of antifungal therapy?

    PubMed

    Fekkar, A; Dannaoui, E; Meyer, I; Imbert, S; Brossas, J Y; Uzunov, M; Mellon, G; Nguyen, S; Guiller, E; Caumes, E; Leblond, V; Mazier, D; Fievet, M H; Datry, A

    2014-09-01

    Since their introduction in the 2000s, echinocandin drugs have become widely used for the treatment and prophylaxis of invasive fungal infections and, notably, invasive candidiasis. Although cases of breakthrough candidiasis in patients receiving echinocandins have been reported, clinical failure during echinocandin treatment due to the acquisition of resistance by a normally susceptible Candida spp. isolate is considered rare. To date, no publications have been published correlating the use of echinocandins and the emergence of echinocandin resistance among Candida species. So, our goal is to report an initial analysis of echinocandin use in relation to the emergence of resistant Candida isolates. We report here a single-centre experience of the emergence of eight resistant isolates belonging to normally susceptible Candida species in six patients receiving echinocandins. We describe the context and analyse the use of echinocandins over the previous decade. For seven of these isolates, we identified FKS gene mutations involved in decreased susceptibility. Seven isolates were obtained in 2011, on the heels of a ten-fold increase in caspofungin use over the preceding decade. In contrast, in 2012, the use of echinocandins decreased in our institution by 19.5 % and, in that year, only one Candida-resistant isolate was detected, despite the stable global epidemiology of invasive candidaemia. This work underlines the necessity of improving the prescription of antifungal drugs. Improvement in the monitoring of strain susceptibility should also be considered in order to better detect the emergence of resistant or non-susceptible yeast strains. PMID:24715154

  6. Antifungal prophylaxis during neutropenia and immunodeficiency.

    PubMed Central

    Lortholary, O; Dupont, B

    1997-01-01

    Fungal infections represent a major source of morbidity and mortality in patients with almost all types of immunodeficiencies. These infections may be nosocomial (aspergillosis) or community acquired (cryptococcosis), or both (candidiasis). Endemic mycoses such as histoplasmosis, coccidioidomycosis, and penicilliosis may infect many immunocompromised hosts in some geographic areas and thereby create major public health problems. With the wide availability of oral azoles, antifungal prophylactic strategies have been extensively developed. However, only a few well-designed studies involving strict criteria have been performed, mostly in patients with hematological malignancies or AIDS. In these situations, the best dose and duration of administration of the antifungal drug often remain to be determined. In high-risk neutropenic or bone marrow transplant patients, fluconazole is effective for the prevention of superficial and/or systemic candidal infections but is not always able to prolong overall survival and potentially selects less susceptible or resistant Candida spp. Primary prophylaxis against aspergillosis remains investigative. At present, no standard general recommendation for primary antifungal prophylaxis can be proposed for AIDS patients or transplant recipients. However, for persistently immunocompromised patients who previously experienced a noncandidal systemic fungal infection, prolonged suppressive antifungal therapy is often indicated to prevent a relapse. Better strategies for controlling immune deficiencies should also help to avoid some potentially life-threatening deep mycoses. When prescribing antifungal prophylaxis, physicians should be aware of the potential emergence of resistant strains, drug-drug interactions, and the cost. Well-designed, randomized, multicenter clinical trials in high-risk immunocompromised hosts are urgently needed to better define how to prevent severe invasive mycoses. PMID:9227863

  7. The impact of timolol maleate on the ocular tolerability of fixed-combination glaucoma therapies

    PubMed Central

    Radcliffe, Nathan M

    2014-01-01

    Glaucomatous optic atrophy is the second most common cause of blindness worldwide, and lowering intraocular pressure (IOP) is the only proven method to slow or stop the progression of the disease. Approximately 40% of patients with elevated IOP will require more than one medication to obtain a modest 20% reduction in IOP, and as a result, some patients may require two medications, provided in either two separate bottles or in one bottle with the use of fixed-combination therapies. Each therapy has its own unique safety and efficacy profile. Topical beta-blockers have a particularly favorable ocular-tolerability profile, and several studies of fixed-combination medications containing the beta-blocker timolol maleate have shown a lower prevalence of some ocular adverse events for the fixed-combination therapy compared to the non-beta-blocker individual component. In this review, we examined clinical data pertaining to the ocular surface tolerability of fixed-combination medications containing timolol maleate in comparison to the individual components. In particular, preference was given to prospective, randomized, multicenter trials of 3 months in duration or longer that compared a fixed-combination therapy to monotherapy with the individual components. A review of the literature revealed that some fixed-combination therapies can provide a reduced risk of common side effects compared to their individual components, with conjunctival hyperemia and ocular allergy being less frequent in some timolol-containing fixed-combination therapies. This effect appears to be most significant for latanoprost 0.005%, bimatoprost 0.03%, and brimonidine 0.2%. PMID:25540579

  8. Combination of nitric oxide therapy, anti-oxidative therapy, low level laser therapy, plasma rich platelet therapy and stem cell therapy as a novel therapeutic application to manage the pain and treat many clinical conditions

    NASA Astrophysics Data System (ADS)

    Halasa, Salaheldin; Dickinson, Eva

    2014-02-01

    From hypertension to diabetes, cancer to HIV, stroke to memory loss and learning disorders to septic shock, male impotence to tuberculosis, there is probably no pathological condition where nitric oxide does not play an important role. Nitric oxide is an analgesic, immune-modulator, vasodilator, anti-apoptotic, growth modulator, angiogenetic, anti-thrombotic, anti-inflammatory and neuro-modulator. Because of the above actions of nitric oxide, many clinical conditions associated with abnormal Nitric oxide (NO) production and bioavailability. Our novel therapeutic approach is to restore the homeostasis of nitric oxide and replace the lost cells by combining nitric oxide therapy, anti-oxidative therapy, low level laser therapy, plasma rich platelet therapy and stem cell therapy.

  9. Successes and Failures of Combined Modality Therapies in Head and Neck Cancer.

    PubMed

    Bowles, Daniel W; Deutsch, Eric; Raben, David

    2016-10-01

    The paradigms for treating head and neck squamous cell carcinoma are changing as new subgroups are defined. The technical successes of improved radiation therapy are many; however, the success of novel combined therapies are few. With the emergence of human papillomavirus and the development of immunooncology agents, such as checkpoint inhibitors, are we ready to reevaluate how we use radiation and chemotherapy for locally advanced and metastatic disease-will we remain the fire or become the fire starter? PMID:27619251

  10. Combination therapy with finasteride and low-dose dutasteride in the treatment of androgenetic alopecia.

    PubMed

    Boyapati, Ann; Sinclair, Rodney

    2013-02-01

    We report on a 47-year-old man who was initially treated with finasteride for androgenetic alopecia. Despite continuous treatment, after year 4 his hair density was not as good as at year 2, and low-dose dutasteride at 0.5 mg/week was added to the finasteride therapy. This resulted in a dramatic increase in his hair density, demonstrating that combined therapy with finasteride and dutasteride can improve hair density in patients already taking finasteride. PMID:22686691

  11. Anti-rotavirus effects by combination therapy of stevioside and Sophora flavescens extract.

    PubMed

    Alfajaro, Mia Madel; Rho, Mun-Chual; Kim, Hyun-Jeong; Park, Jun-Gyu; Kim, Deok-Song; Hosmillo, Myra; Son, Kyu-Yeol; Lee, Ju-Hwan; Park, Sang-Ik; Kang, Mun-Il; Ryu, Young Bae; Park, Ki Hun; Oh, Hyun-Mee; Lee, Seung Woong; Park, Su-Jin; Lee, Woo Song; Cho, Kyoung-Oh

    2014-06-01

    Anti-rotaviral activities of Sophora flavescens extract (SFE) and stevioside (SV) from Stevia rebaudiana Bertoni either singly or in various combinations were examined in vitro and in vivo using a porcine rotavirus G5[P7] strain. Combination of SFE and SV inhibited in vitro virus replication more efficiently than each single treatment. In the piglet model, SV had no effect on rotavirus enteritis, whereas SFE improved but did not completely cure rotaviral enteritis. Interestingly, combination therapy of SFE and SV alleviated diarrhea, and markedly improved small intestinal lesion score and fecal virus shedding. Acute toxicity tests including the piglet lethal dose 50, and body weight, organ weight and pathological changes for the combination therapy did not show any adverse effect on the piglets. These preliminary data suggest that the combination therapy of SV and SFE is a potential curative medication for rotaviral diarrhea in pigs. Determination of the efficacy of this combination therapy in other species including humans needs to be addressed in the future. PMID:24704033

  12. Induction therapy with a combination of fumarates and cyclosporine: A benefit for the patient?

    PubMed

    Fallah Arani, S; Neumann, H A M; Thio, H B

    2016-08-01

    Fumarates or fumaric acid esters derivates (FAED) have appeared to be effective and less toxic than other systemic treatments for psoriasis. Due to its safe adverse event profile, FAED can be used as a long-term maintenance therapy. One of the greatest reasons why FAED are not preferred as a first-line treatment is that according to the recommended dosing schedule, clinically meaningful improvement is seen just after 6 to 8 weeks of therapy. In this manuscript, we suppose an alternative induction scheme with a combination therapy of fumarates and cyclosporine for a more rapid improvement and better compliance. PMID:26651839

  13. Combined Alloreactive CTL Cellular Therapy with Prodrug Activator Gene Therapy in a Model of Breast Cancer Metastatic to the Brain

    PubMed Central

    Hickey, Michelle J.; Malone, Colin C.; Erickson, Kate L.; Lin, Amy; Soto, Horacio; Ha, Edward T.; Kamijima, Shuichi; Inagaki, Akihito; Takahashi, Masamichi; Kato, Yuki; Kasahara, Noriyuki; Mueller, Barbara M.; Kruse, Carol A.

    2013-01-01

    Purpose Individual or combined strategies of cellular therapy with alloreactive cytotoxic T lymphocytes (alloCTL) and gene therapy employing retroviral replicating vectors (RRV) encoding a suicide prodrug activating gene were explored for the treatment of breast tumors metastatic to the brain. Experimental Design AlloCTL, sensitized to the human leukocyte antigens of MDA-MB-231 breast cancer cells, were examined in vitro for anti-tumor functionality toward breast cancer targets. RRV encoding the yeast cytosine deaminase (CD) gene was tested in vivo for virus spread, ability to infect, and kill breast cancer targets when exposed to 5-fluorocytosine (5-FC). Individual and combination treatments were tested in subcutaneous and intracranial xenograft models with 231BR, a brain tropic variant. Results AlloCTL preparations were cytotoxic, proliferated and produced interferon-gamma when coincubated with target cells displaying relevant HLA. In vivo, intratumorally-placed alloCTL trafficked through one established intracranial 231BR focus to another in contralateral brain and induced tumor cell apoptosis. RRV-CD efficiently spread in vivo, infected 231BR and induced their apoptosis upon 5-FC exposure. Subcutaneous tumor volumes were significantly reduced in alloCTL and/or gene therapy treated groups compared to control groups. Mice with established intracranial 231BR tumors treated with combined alloCTL and RRV-CD had a median survival of 97.5 days compared with single modalities (50–83 days); all experimental treatment groups survived significantly longer than sham-treated groups (median survivals 31.5 or 40 days) and exhibited good safety/toxicity profiles. Conclusion The results indicate combining cellular and suicide gene therapies is a viable strategy for the treatment of established breast tumors in the brain. PMID:23780889

  14. Challenges of Using High-Dose Fractionation Radiotherapy in Combination Therapy

    PubMed Central

    Yang, Ying-Chieh; Chiang, Chi-Shiun

    2016-01-01

    Radiotherapy is crucial and substantially contributes to multimodal cancer treatment. The combination of conventional fractionation radiotherapy (CFRT) and systemic therapy has been established as the standard treatment for many cancer types. With advances in linear accelerators and image-guided techniques, high-dose fractionation radiotherapy (HFRT) is increasingly introduced in cancer centers. Clinicians are currently integrating HFRT into multimodality treatment. The shift from CFRT to HFRT reveals different effects on the tumor microenvironment and responses, particularly the immune response. Furthermore, the combination of HFRT and drugs yields different results in different types of tumors or using different treatment schemes. We have reviewed clinical trials and preclinical evidence on the combination of HFRT with drugs, such as chemotherapy, targeted therapy, and immune therapy. Notably, HFRT apparently enhances tumor cell killing and antigen presentation, thus providing opportunities and challenges in treating cancer. PMID:27446811

  15. Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma.

    PubMed

    Wei, Wei; Shin, Young Shik; Xue, Min; Matsutani, Tomoo; Masui, Kenta; Yang, Huijun; Ikegami, Shiro; Gu, Yuchao; Herrmann, Ken; Johnson, Dazy; Ding, Xiangming; Hwang, Kiwook; Kim, Jungwoo; Zhou, Jian; Su, Yapeng; Li, Xinmin; Bonetti, Bruno; Chopra, Rajesh; James, C David; Cavenee, Webster K; Cloughesy, Timothy F; Mischel, Paul S; Heath, James R; Gini, Beatrice

    2016-04-11

    Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single-cell phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it to an analytical approach for detecting changes in signaling coordination. Alterations in the protein signaling coordination were resolved as early as 2.5 days after treatment, anticipating drug resistance long before it was clinically manifest. Combination therapies were identified that resulted in complete and sustained tumor suppression in vivo. This approach may identify actionable alterations in signal coordination that underlie adaptive resistance, which can be suppressed through combination drug therapy, including non-obvious drug combinations. PMID:27070703

  16. Radiofrequency ablation-combined multimodel therapies for hepatocellular carcinoma: Current status.

    PubMed

    Chen, Lumin; Sun, Jihong; Yang, Xiaoming

    2016-01-01

    Radiofrequency ablation (RFA) is widely accepted as a first-line interventional oncology approach for hepatocellular carcinoma (HCC) and has the advantages of high treatment efficacy and low complication risk. Local control rates equivalent to hepatic resection can be reached by RFA alone when treating small HCCs (<2 cm) in favorable locations. However, local tumor progression and recurrence rates with RFA monotherapy increase sharply when treating larger lesions (>3 cm). To address this clinical problem, recent efforts have focused on multimodel management of HCC by combining RFA with different techniques, including percutaneous ethanol injection, transarterial chemo-embolization, targeted molecular therapy, nanoparticle-mediated therapy, and immunotherapy. The combination strategy indeed leads to better outcomes in comparison to RFA alone. In this article, we review the current status of RFA-combined multimodal therapies in the management of HCC. PMID:26472630

  17. Treatment of Severe Alopecia Areata: Combination Therapy Using Systemic Cyclosporine A with Low Dose Corticosteroids

    PubMed Central

    Lee, Deborah; Oh, Doo Jin; Kim, Jung Wook; Park, Sung Wook; Oh, Min Kyung; Sung, Ho Suk

    2008-01-01

    Background Combination therapy using cyclosporine A (CsA) together with low-dose corticosteroids has adequate efficacy with little toxicity for the treatment of severe alopecia areata (AA). Objective We wanted to evaluate the clinical efficacy of combination therapy using CsA with low-dose corticosteroid for the treatment of severe AA and we also wanted to determine the safe therapeutic concentration of CsA in the peripheral blood. Methods We treated 34 cases of severe AA with combination therapy for 24 weeks and we evaluated the efficacy at 12 and 24 weeks. We monitored the peripheral blood concentration of CsA to determine the therapeutic range of CsA that has the fewest side effects. Results Of the patients, 77.4% (n=24) and 22.6% (n=10) were classified in the responder and poor-responder groups, respectively. The mean trough concentration of CsA was 95.1 and 101.2 ng/ml in the responder and poor-responder groups, respectively. For the patients with side effects associated with CsA, the mean CsA concentration was 195.8 ng/ml. Conclusion We found that combination therapy with systemic CsA and low-dose corticosteroids effectively treats severe AA and this therapy results in a safe, therapeutic concentration of CsA in the peripheral blood. PMID:27303186

  18. Synthetic Multivalent Antifungal Peptides Effective against Fungi

    PubMed Central

    Li, Jianguo; Nandhakumar, Muruganantham; Aung, Thet Tun; Goh, Eunice; Chang, Jamie Ya Ting; Saraswathi, Padhmanaban; Tang, Charles; Safie, Siti Radiah Binte; Lin, Lim Yih; Riezman, Howard; Lei, Zhou; Verma, Chandra S.; Beuerman, Roger W.

    2014-01-01

    Taking advantage of the cluster effect observed in multivalent peptides, this work describes antifungal activity and possible mechanism of action of tetravalent peptide (B4010) which carries 4 copies of the sequence RGRKVVRR through a branched lysine core. B4010 displayed better antifungal properties than natamycin and amphotericin B. The peptide retained significant activity in the presence of monovalent/divalent cations, trypsin and serum and tear fluid. Moreover, B4010 is non-haemolytic and non-toxic to mice by intraperitoneal (200 mg/kg) or intravenous (100 mg/kg) routes. S. cerevisiae mutant strains with altered membrane sterol structures and composition showed hyper senstivity to B4010. The peptide had no affinity for cell wall polysaccharides and caused rapid dissipation of membrane potential and release of vital ions and ATP when treated with C. albicans. We demonstrate that additives which alter the membrane potential or membrane rigidity protect C. albicans from B4010-induced lethality. Calcein release assay and molecular dynamics simulations showed that the peptide preferentially binds to mixed bilayer containing ergosterol over phophotidylcholine-cholesterol bilayers. The studies further suggested that the first arginine is important for mediating peptide-bilayer interactions. Replacing the first arginine led to a 2–4 fold decrease in antifungal activities and reduced membrane disruption properties. The combined in silico and in vitro approach should facilitate rational design of new tetravalent antifungal peptides. PMID:24498363

  19. Pharmacokinetics and pharmacodynamics of antifungals in children and their clinical implications.

    PubMed

    Stockmann, Chris; Constance, Jonathan E; Roberts, Jessica K; Olson, Jared; Doby, Elizabeth H; Ampofo, Krow; Stiers, Justin; Spigarelli, Michael G; Sherwin, Catherine M T

    2014-05-01

    Invasive fungal infections are a significant cause of morbidity and mortality in children. Successful management of these systemic infections requires identification of the causative pathogen, appropriate antifungal selection, and optimisation of its pharmacokinetic and pharmacodynamic properties to maximise its antifungal activity and minimise toxicity and the emergence of resistance. This review highlights salient scientific advancements in paediatric antifungal pharmacotherapies and focuses on pharmacokinetic and pharmacodynamic studies that underpin current clinical decision making. Four classes of drugs are widely used in the treatment of invasive fungal infections in children, including the polyenes, triazoles, pyrimidine analogues and echinocandins. Several lipidic formulations of the polyene amphotericin B have substantially reduced the toxicity associated with the traditional amphotericin B formulation. Monotherapy with the pyrimidine analogue flucytosine rapidly promotes the emergence of resistance and cannot be recommended. However, when used in combination with other antifungal agents, therapeutic drug monitoring of flucytosine has been shown to reduce high peak flucytosine concentrations, which are strongly associated with toxicity. The triazoles feature large inter-individual pharmacokinetic variability, although this pattern is less pronounced with fluconazole. In clinical trials, posaconazole was associated with fewer adverse effects than other members of the triazole family, though both posaconazole and itraconazole display erratic absorption that is influenced by gastric pH and the gastric emptying rate. Limited data suggest that the clinical response to therapy may be improved with higher plasma posaconazole and itraconazole concentrations. For voriconazole, pharmacokinetic studies among children have revealed that children require twice the recommended adult dose to achieve comparable blood concentrations. Voriconazole clearance is also affected

  20. Fixed-dose combination therapy for the prevention of cardiovascular disease

    PubMed Central

    de Cates, Angharad N; Farr, Matthew RB; Rees, Karen; Casas, Juan P; Huffman, Mark

    2014-01-01

    This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the effectiveness of fixed-dose combination therapy on optimising CVD risk factors and reducing CVD fatal and non-fatal events for both primary and secondary prevention of CVD. Details of CVD events and risk factors included are listed in the methods. We will also determine any adverse events associated with taking fixed-dose combination therapy. This will include studies conducted in both developed and developing regions of the world. PMID:25267903

  1. Combined Space and Alertness Related Therapy of Visual Hemineglect: Effect of Therapy Frequency

    PubMed Central

    Sturm, Walter; Thimm, M.; Binkofski, F.; Horoufchin, H.; Fink, G. R.; Küst, J.; Karbe, H.; Willmes, K.

    2013-01-01

    The combined efficacy of space- and alertness related training in chronic hemineglect was tested behaviorally and in a longitudinal fMRI study. Earlier results had shown that both space as well as alertness related training as single intervention methods lead to short term improvement which, however, is not stable for longer time periods. The neurobiological data obtained in these studies revealed differential cortical reorganization patterns for the two training approaches thereby leading to the hypothesis that a combination of both trainings might result in stronger and longer lasting effects. The results of our current study, however, – at least at first glance – do not clearly corroborate this hypothesis, because neither alertness training alone nor the combination with OKS on the group level led to significant behavioral improvement, although four of the six patients after alertness and even more after combined training showed a higher percentage of behavioral improvement than during baseline. Despite the lack of clearcut behavioral training induced improvement we found right parietal or fronto-parietal increase of activation in the imaging data immediately after combined training and at follow-up 3 weeks later. The study design had called for splitting up training time between the two training approaches in order to match total training time with our earlier single training studies. The results of our current study are discussed as a possible consequence of reduced training time and intensity of both training measures under the combined training situation. PMID:23908613

  2. Benefits and risks of combining anti-tumor necrosis factor with immunomodulator therapy in pediatric inflammatory bowel disease.

    PubMed

    Cozijnsen, Martinus A; Escher, Johanna C; Griffiths, Anne; Turner, Dan; de Ridder, Lissy

    2015-04-01

    Since the introduction of anti-tumor necrosis factor (TNF) therapy as treatment of inflammatory bowel disease (IBD), care of pediatric and adult patients with IBD has significantly improved. To further improve treatment efficacy and durability, multiple trials have compared the efficacy of combination therapy, using anti-TNF therapy combined with an immunomodulator (a thiopurine or methotrexate), with that of anti-TNF monotherapy with contradicting results. The safety of combined therapy has been questioned after several reported cases of hepatosplenic T-cell lymphoma in young patients with IBD so treated. Physicians prescribing anti-TNF therapy to patients with IBD are required to weigh the benefits of combined therapy with its risks. To inform physicians treating children with IBD of these benefits and risks, we reviewed studies in pediatric and adult patients with IBD comparing efficacy, durability, and/or safety of combined therapy with anti-TNF monotherapy. PMID:25723615

  3. Assessment of combination therapy in BALB/c mice injected with carbapenem-resistant Enterobacteriaceae strains

    PubMed Central

    Salloum, Noor A.; Kissoyan, Kohar Annie B.; Fadlallah, Sukayna; Cheaito, Katia; Araj, George F.; Wakim, Rima; Kanj, Souha; Kanafani, Zeina; Dbaibo, Ghassan; Matar, Ghassan M.

    2015-01-01

    Monotherapeutic options for carbapenem resistant infections are limited. Studies suggest that combination therapy may be associated with better outcomes than monotherapies. However, this is still controversial. This study assessed, the efficacy of combination therapy against carbapenem resistant Enterobacteriaceae harboring singly various extended spectrum beta lactamase or carbapenemase encoding genes. Thus, four isolates harboring either blaCTXM-15, blaCTXM-15 and blaOXA-48, blaNDM-1, or blaKPC-2 genes were selected for testing. Minimal inhibitory concentration was determined by broth dilution method. Gene transcript levels on single and combined treatments were done in vitro and in vivo by qRT-PCR. Assessment of treatments was done in BALB/c mice according to a specific protocol. As such, the qRT-PCR revealed a significant decrease of transcript levels in all isolates upon using rifampicin or tigecycline, singly or in combination with colistin. However, variable levels were obtained using colistin singly or in combination with meropenem or fosfomycin. In vivo assessment showed that all combinations used were effective against isolates harboring blaCTXM-15, blaOXA-48, and blaNDM-1. Conversely, the most significant combination against the isolate harboring blaKPC-2 gene was colistin with either carbapenem, fosfomycin, or kanamycin. As a conclusion, combination therapy selected based on the type of carbapenemase produced, appeared to be non-toxic and might be effective in BALB/c mice. Therefore, the use of a rationally optimized combination therapy might lead to better results than monotherapy, however, clinical trials are needed for human consumption. PMID:26441926

  4. Assessment of combination therapy in BALB/c mice injected with carbapenem-resistant Enterobacteriaceae strains.

    PubMed

    Salloum, Noor A; Kissoyan, Kohar Annie B; Fadlallah, Sukayna; Cheaito, Katia; Araj, George F; Wakim, Rima; Kanj, Souha; Kanafani, Zeina; Dbaibo, Ghassan; Matar, Ghassan M

    2015-01-01

    Monotherapeutic options for carbapenem resistant infections are limited. Studies suggest that combination therapy may be associated with better outcomes than monotherapies. However, this is still controversial. This study assessed, the efficacy of combination therapy against carbapenem resistant Enterobacteriaceae harboring singly various extended spectrum beta lactamase or carbapenemase encoding genes. Thus, four isolates harboring either bla CTXM-15, bla CTXM-15 and bla OXA-48, bla NDM-1, or bla KPC-2 genes were selected for testing. Minimal inhibitory concentration was determined by broth dilution method. Gene transcript levels on single and combined treatments were done in vitro and in vivo by qRT-PCR. Assessment of treatments was done in BALB/c mice according to a specific protocol. As such, the qRT-PCR revealed a significant decrease of transcript levels in all isolates upon using rifampicin or tigecycline, singly or in combination with colistin. However, variable levels were obtained using colistin singly or in combination with meropenem or fosfomycin. In vivo assessment showed that all combinations used were effective against isolates harboring bla CTXM-15, bla OXA-48, and bla NDM-1. Conversely, the most significant combination against the isolate harboring bla KPC-2 gene was colistin with either carbapenem, fosfomycin, or kanamycin. As a conclusion, combination therapy selected based on the type of carbapenemase produced, appeared to be non-toxic and might be effective in BALB/c mice. Therefore, the use of a rationally optimized combination therapy might lead to better results than monotherapy, however, clinical trials are needed for human consumption. PMID:26441926

  5. Micafungin alone and in combination therapy with deferasirox against Pythium insidiosum.

    PubMed

    Zanette, R A; Jesus, F P K; Pilotto, M B; Weiblen, C; Pötter, L; Ferreiro, L; Alves, S H; Santurio, J M

    2015-03-01

    This study evaluated the in vitro and in vivo activity of micafungin alone and in combination with the iron chelator deferasirox against Pythium insidiosum. Micafungin showed a poor in vitro activity when it was used alone, but synergistic interactions were observed for 88.2% of the strains when the drug was combined with deferasirox. Smaller lesions were observed in infected rabbits receiving the combination therapy, although it favored disease dissemination to the lungs. The present results show that micafungin alone is ineffective against P. insidiosum, and the combination micafungin-deferasirox might have deleterious effects for the host. PMID:25459680

  6. Efficacy and safety of antiplatelet-combination therapy after drug-eluting stent implantation

    PubMed Central

    Cho, Yun-Kyeong; Park, Hyoung-Seob; Yoon, Hyuck-Jun; Kim, Hyungseop; Hur, Seung-Ho; Kim, Yoon-Nyun; Lee, Jang-Hoon; Yang, Dong-Heon; Lee, Bong-Ryeol; Jung, Byung-Chun; Kim, Woong; Park, Jong-Seon; Lee, Jin-Bae; Kim, Kee-Sik; Kim, Kwon-Bae

    2014-01-01

    Background/Aims Combination single-pill therapy can improve cost-effectiveness in a typical medical therapy. However, there is a little evidence about the efficacy and tolerability of combination single-pill antiplatelet therapy after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). Methods From June to November 2012, in total, 142 patients who met the following criteria were enrolled: at least 18 years old; successful PCI with DES at least 3 months earlier; and regular medication of aspirin and clopidogrel with no side effects. After VerifyNow P2Y12 and aspirin assays, the combination single pill of aspirin and clopidogrel was given and laboratory tests were repeated 6 weeks later. Results At baseline, the incidence of aspirin resistance, defined as aspirin reaction unit (ARU) ≥ 550, was 9.2%, that of clopidogrel resistance, defined as P2Y12 reaction unit (PRU) ≥ 230, was 46.5%, and that of percent inhibition of PRU < 20% was 32.4%. At follow-up, the incidence of resistance by ARU value was 7.0%, 50.0% by PRU value, and 35.9% by percentage inhibition of PRU, respectively. The mean values of ARU (431.5 ± 63.6 vs. 439.8 ± 55.2; p = 0.216) and PRU (227.5 ± 71.4 vs. 223.3 ± 76.0; p = 0.350) were not significantly different before versus after antiplatelet-combination single-pill therapy. Five adverse events (3.5%) were observed during the study period. Conclusions Combination single-pill antiplatelet therapy, which may reduce daily pill burden for patients after PCI with DES, demonstrated similar efficacy to separate dual-pill antiplatelet therapy. PMID:24648804

  7. Identification of New Antifungal Compounds Targeting Thioredoxin Reductase of Paracoccidioides Genus

    PubMed Central

    Abadio, Ana Karina Rodrigues; Kioshima, Erika Seki; Leroux, Vincent; Martins, Natalia Florêncio; Maigret, Bernard; Felipe, Maria Sueli Soares

    2015-01-01

    The prevalence of invasive fungal infections worldwide has increased in the last decades. The development of specific drugs targeting pathogenic fungi without producing collateral damage to mammalian cells is a daunting pharmacological challenge. Indeed, many of the toxicities and drug interactions observed with contemporary antifungal therapies can be attributed to “nonselective” interactions with enzymes or cell membrane systems found in mammalian host cells. A computer-aided screening strategy against the TRR1 protein of Paracoccidioides lutzii is presented here. Initially, a bank of commercially available compounds from Life Chemicals provider was docked to model by virtual screening simulations. The small molecules that interact with the model were ranked and, among the best hits, twelve compounds out of 3,000 commercially-available candidates were selected. These molecules were synthesized for validation and in vitro antifungal activity assays for Paracoccidioides lutzii and P. brasiliensis were performed. From 12 molecules tested, 3 harbor inhibitory activity in antifungal assays against the two pathogenic fungi. Corroborating these findings, the molecules have inhibitory activity against the purified recombinant enzyme TRR1 in biochemical assays. Therefore, a rational combination of molecular modeling simulations and virtual screening of new drugs has provided a cost-effective solution to an early-stage medicinal challenge. These results provide a promising technique to the development of new and innovative drugs. PMID:26569405

  8. Potentiation of antifungal activity of amphotericin B by essential oil from Cinnamomum cassia.

    PubMed

    Giordani, R; Regli, P; Kaloustian, J; Portugal, H

    2006-01-01

    The antifungal activity of the essential oil from Cinnamomum cassia, alone or combined with amphotericin B, a drug widely used for most indications despite side-effects was investigated. The composition of the oil was analysed by GC/MS and characterized by its very high content of cinnamaldehyde (92.2%). The minimal inhibitory concentration (MIC 80%), used to evaluate the antifungal activity against Candida albicans, was determined by a macrobroth dilution method followed by a modelling of fungal growth. The essential oil of Cinnamomum cassia exhibited strong antifungal effect (MIC 80% = 0.169 microL/mL and K(aff) = 18,544 microL/mL). A decrease of the MIC 80% of amphotericin B was obtained when the culture medium contained essential oil concentrations ranging from 0.08 to 0.1 microL/mL. The strongest decrease (70%) was obtained when the medium contained 0.1 microL/mL of essential oil. This potentiation of amphotericin B obtained in vitro may show promise for the development of less toxic and more effective therapies especially for the treatment of HIV infection. PMID:16397923

  9. Combination therapies in the management of type 2 diabetes: the use of insulin degludec/liraglutide

    PubMed Central

    Minze, Molly G; Chastain, Lisa M

    2016-01-01

    The global burden of type 2 diabetes is estimated to currently affect over 350 million people worldwide and is anticipated to continue increasing over the next 20 years. Current treatment guidelines recommend the choice of pharmacotherapy based upon patient-specific parameters, with combination therapy for patients with a hemoglobin A1c level ≥9%. A new combination therapy of insulin degludec + liraglutide provides a long-acting basal insulin with a glucagon-like peptide agonist. In clinical trials, this combination product has reduced hemoglobin A1c and fasting plasma glucose more than the individual agents alone. Further advantages observed with this combination include weight loss and decrease in hypoglycemia compared to basal insulin alone. PMID:27099505

  10. [Photodynamic therapy in combined treatment of stage III non-small cell lung carcinoma].

    PubMed

    Akopov, A L; Rusanov, A A; Molodtsova, V P; Chistiakov, I V; Kazakov, N V; Urtenova, M A; Rait, Makhmud; Papaian, G V

    2013-01-01

    The aim of the study was to evaluate the effectiveness of combined treatment of locally advanced lung cancer with the use of neoadjuvant chemotherapy and surgery with the use of pre- and intraoperative photodynamic therapy. 20 patients with IIIa (n=7) and IIIb (n=13) stage of non-small cell lung carcinoma were included. At the time of diagnosis the surgical treatment was decided to abstain because of the trachea invasion in 9 patients, wide mediastinal invasion in 2 patients and contralateral mediastinal lymph nodes metastases in 2 patients; pneumonectomy was not possible due to the poor respiratory function in 7 patients. Neoadjuvant therapy included 3 courses of chemotherapy and endobronchial photodynamic therapy. During the operation, along with the lung resection (pneumonectomy - 15, lobectomy - 5), photodynamic therapy of the resection margins were carried out. No adjuvant treatment was done. Preoperative treatment led to partial regress of the disease in all cases; the goal of surgery was the complete tumor removal. No complications of the photodynamic therapy were observed. 18 surgical interventions were radical and two non-complete microscopically (R1). Postoperative morbidity was 20%, one patient died due to massive gastrointestinal bleeding. The average follow-up period was 18 months: 19 patients were alive, of them 18 with no signs of the disease recurrence. The first experience of the combined use of neoadjuvant chemotherapy and surgery with pre- and intraoperative photodynamic therapy demonstrates safety and efficacy of the suggested treatment tactics. PMID:23612332

  11. The outcome of combining home based and clinic based amblyopia therapy among preschool children.

    PubMed

    Rokiah, O; Knight, V F; Duratul, A H

    2013-06-01

    This study determined the outcome of combining home based and clinic based amblyopia therapy among preschool children. A total of 479 preschool children were randomly selected for vision screening. Amblyopic therapy was prescribed to children whose visual acuity (VA) could not be improved to <0.1 LogMAR after a 6 week adaptation period with glasses. Intensive near work activities were conducted daily at home for 12 weeks, monitored by parents while weekly therapy was conducted at the optometry clinic by an optometrist. Six preschool children were diagnosed with refractive amblyopia, spherical equivalent (SE) was -11.25D to +0.75D. Significant improvement was found in the VA of right eye, t(6) = 3.07, left eye t(6) = 3.07 and both eyes t(6) = 3.42) p<0.05, at the end of the 12 week therapy. Combining home based and clinic based amblyopia therapy among preschool children showed a positive improvement in VA after 12 weeks of therapy. PMID:23749015

  12. EUCAST breakpoints for antifungals.

    PubMed

    Rodríguez-Tudela, Juan L; Arendrup, Maiken C; Cuenca-Estrella, Manuel; Donnelly, J Peter; Lass-Flörl, Cornelia

    2010-03-01

    Susceptibility testing of fungi and development of interpretative breakpoints has become increasingly important due to the growing incidence of invasive fungal infections, the number and classes of antifungals, and the emerging reports of acquired resistance. The subcommittee on antifungal susceptibility testing of the European Committee on Antibiotic Susceptibility Testing (EUCAST) has developed standards for susceptibility testing of fermentative yeasts and molds as well as proposing breakpoints for fluconazole and voriconazole against Candida. The aim of this work is to describe the EUCAST process of setting breakpoints for antifungals. Five aspects are evaluated during the process of developing breakpoints: 1) the most common dosage used in each European country, 2) the definition of the wild-type population for each target microorganism at the species level and the determination of epidemiological cutoffs, 3) the drug's pharmacokinetics and 4) pharmacodynamics, including Monte Carlo simulations, and 5) the correlation of MICs with clinical outcome of patients treated with the compound. When insufficient data are available (e.g., due to lack of information on the clinical outcome of infections caused by isolates with an elevated MIC), epidemiological cutoff values, rather than breakpoints, are recommended until the necessary information becomes available. PMID:20369073

  13. Burden of Antibiotic Resistance in Common Infectious Diseases: Role of Antibiotic Combination Therapy

    PubMed Central

    Dargad, Ramesh R; Borade, Dhammraj M; Swami, Onkar C

    2014-01-01

    Globally, antimicrobial resistance is alarming concern especially in commonly reported disease entities like respiratory tract infection, enteric fever and infections associated with gram-negative bacilli (GNB). Rational use of antimicrobial drugs reported significant decrease in bacterial burden and may also reduce the risk of disease progression. However, at times in particular indication, certain patient and pathogen factor limits the selection and use of specific antibiotic therapy while in some case, due to presence of additional risk factor, aggressive therapy is required to achieve clinical reemission and prevent complications. Delay in start of suitable antibiotic therapy is another imperative factor for treatment failure and rise of drug resistance. With rapidly increasing antibiotic resistance and decline in new antibiotic drug development, the toughest challenge remains to maintain and preserve the efficacy of currently available antibiotics. Therefore, the best rational approach to fight these infections is to ‘hit early and hit hard’ and kills drug-susceptible bacteria before they become resistant. The preferred approach is to deploy two antibiotics that produce a stronger effect in combination than if either drug were used alone. Various society guidelines in particular indications also justify and recommend the use of combination of antimicrobial therapy. Combination therapies have distinct advantage over monotherapy in terms of broad coverage, synergistic effect and prevention of emergence of drug resistance. PMID:25121020

  14. A Systematic Review of the Combined Use of Electroconvulsive Therapy and Psychotherapy for Depression

    PubMed Central

    McClintock, Shawn M.; Brandon, Anna R.; Husain, Mustafa M.; Jarrett, Robin B.

    2011-01-01

    Objective Electroconvulsive therapy (ECT) is one of the most effective treatments for severe Major Depressive Disorder (MDD). However, after acute phase treatment and initial remission, relapse rates are significant. Strategies to prolong remission include continuation phase ECT, pharmacotherapy, psychotherapy, or their combinations. This systematic review synthesizes extant data regarding the combined use of psychotherapy with ECT for the treatment of patients with severe MDD and offers the hypothesis that augmenting ECT with depression-specific psychotherapy represents a promising strategy for future investigation. Methods The authors performed two independent searches in PsychInfo (1806 – 2009) and MEDLINE (1948 – 2009) using combinations of the following search terms: Electroconvulsive Therapy (including ECT, ECT therapy, electroshock therapy, EST, shock therapy) and Psychotherapy (including cognitive behavioral, interpersonal, group, psychodynamic, psychoanalytic, individual, eclectic, and supportive). We included in this review a total of six articles (English language) that mentioned ECT and psychotherapy in the abstract, and provided a case report, series, or clinical trial. We examined the articles for data related to ECT and psychotherapy treatment characteristics, cohort characteristics, and therapeutic outcome. Results Although research over the past seven decades documenting the combined use of ECT and psychotherapy is limited, the available evidence suggests that testing this combination has promise and may confer additional, positive functional outcomes. Conclusions Significant methodological variability in ECT and psychotherapy procedures, heterogeneous patient cohorts, and inconsistent outcome measures prevent strong conclusions; however, existing research supports the need for future investigations of combined ECT and psychotherapy in well-designed, controlled clinical studies. Depression-specific psychotherapy approaches may need special

  15. Newcastle disease virus, rituximab, and doxorubicin combination as anti-hematological malignancy therapy

    PubMed Central

    Al-Shammari, Ahmed Majeed; Rameez, Huda; Al-Taee, Maha F

    2016-01-01

    Hematological malignancies are important diseases that need more powerful therapeutics. Even with current targeting therapies, such as rituximab and other chemotherapeutic agents, there is a need to develop new treatment strategies. Combination therapy seems the best option to target the tumor cells by different mechanisms. Virotherapy is a very promising treatment modality, as it is selective, safe, and causes cancer destruction. The Iraqi strain of Newcastle disease virus (NDV) has proved to be effective both in vitro and in vivo. In the current work, we tested its ability on anti-hematological tumors and enhanced current treatments with combination therapy, and studied this combination using Chou–Talalay analysis. p53 concentration was measured to evaluate the mechanism of this proposed synergism. The results showed that NDV was synergistic with doxorubicin in low doses on plasmacytoma cells, with no involvement of p53 pathways, but involved p53 when the combination was used on non-Hodgkin lymphoma cells. NDV in combination with rituximab showed enhanced cytotoxicity that was p53-independent. In conclusion, this work proposes a novel combination modality for treatment of some hematological malignancies. PMID:27579294

  16. Newcastle disease virus, rituximab, and doxorubicin combination as anti-hematological malignancy therapy.

    PubMed

    Al-Shammari, Ahmed Majeed; Rameez, Huda; Al-Taee, Maha F

    2016-01-01

    Hematological malignancies are important diseases that need more powerful therapeutics. Even with current targeting therapies, such as rituximab and other chemotherapeutic agents, there is a need to develop new treatment strategies. Combination therapy seems the best option to target the tumor cells by different mechanisms. Virotherapy is a very promising treatment modality, as it is selective, safe, and causes cancer destruction. The Iraqi strain of Newcastle disease virus (NDV) has proved to be effective both in vitro and in vivo. In the current work, we tested its ability on anti-hematological tumors and enhanced current treatments with combination therapy, and studied this combination using Chou-Talalay analysis. p53 concentration was measured to evaluate the mechanism of this proposed synergism. The results showed that NDV was synergistic with doxorubicin in low doses on plasmacytoma cells, with no involvement of p53 pathways, but involved p53 when the combination was used on non-Hodgkin lymphoma cells. NDV in combination with rituximab showed enhanced cytotoxicity that was p53-independent. In conclusion, this work proposes a novel combination modality for treatment of some hematological malignancies. PMID:27579294

  17. [Combined radiation therapy and androgen deprivation in the management of prostate cancer: Where do we stand?].

    PubMed

    Bellefqih, S; Hadadi, K; Mezouri, I; Maghous, A; Marnouche, E; Andaloussi, K; Elmarjany, M; Sifat, H; Mansouri, H; Benjaafar, N

    2016-04-01

    Radiotherapy and androgen deprivation therapy play a major role in the management of prostate cancer. Indeed, radiotherapy and hormone therapy are combined in a neoadjuvant and concomitant setting for intermediate risk cancers but also in an adjuvant setting in high risk or locally advanced prostate cancer. The benefice of this association was suggested by preclinical studies and demonstrated later by several randomized trials. However, as these trials were conducted before the era of dose escalation the role of androgen deprivation therapy in this case is less clear. Moreover, as hormonal therapy can lead to a significant morbidity and a decrement in quality of life its indications must be carefully weighed especially in case of intermediate risk cancer witch represent a heterogeneous group with distinct prognostic subgroups. PMID:26969245

  18. Clinical efficacy of the Nd:YAG laser for combination periodontitis therapy.

    PubMed

    Neill, M E; Mellonig, J T

    1997-08-01

    Recent results of a limited clinical trial suggest that mechanical root scaling and root planing therapy alone may not be the most effective mode of treatment for patients affected by moderate to severe adult periodontitis. However, scaling and planing combined with laser therapy utilizing a low-powered pulsed Nd:YAG laser have been shown to be successful in the elimination of the bacteria commonly associated with the development of this oral condition. The double-blind, split mouth design study involved 10 human subjects randomly assigned to one of three treatments: 1) scaling and root planing alone, 2) dental laser plus scaling and root planing, and 3) control only. This article presents the clinical results of the trial, which suggest that laser therapy is a viable adjunct to local, nonsurgical therapy such as scaling and planing. PMID:9573831

  19. External beam re-irradiation, combination chemoradiotherapy, and particle therapy for the treatment of recurrent glioblastoma

    PubMed Central

    Taunk, Neil K.; Moraes, Fabio Y.; Escorcia, Freddy E.; Mendez, Lucas Castro; Beal, Kathryn; Marta, Gustavo N.

    2016-01-01

    SUMMARY Glioblastoma is a common aggressive primary malignant brain tumor, and is nearly universal in progression and mortality after initial treatment. Re-irradiation presents a promising treatment option for progressive disease, both palliating symptoms and potentially extending survival. Highly conformal radiation techniques such as stereotactic radiosurgery and hypofractionated radiosurgery are effective short courses of treatment that allow delivery of high doses of therapeutic radiation with steep dose gradients to protect normal tissue. Patients with higher performance status, younger age, and longer interval between primary treatment and progression represent the best candidates for re-irradiation. Multiple studies are also underway involving combinations of radiation and systemic therapy to bend the survival curve and improve the therapeutic index. In the multimodal treatment of recurrent high-grade glioma, the use of surgery, radiation, and systemic therapy should be highly individualized. Here we comprehensively review radiation therapy and techniques, along with discussion of combination treatment and novel strategies. PMID:26781426

  20. Internal ribosome entry site-based vectors for combined gene therapy

    PubMed Central

    Renaud-Gabardos, Edith; Hantelys, Fransky; Morfoisse, Florent; Chaufour, Xavier; Garmy-Susini, Barbara; Prats, Anne-Catherine

    2015-01-01

    Gene therapy appears as a promising strategy to treat incurable diseases. In particular, combined gene therapy has shown improved therapeutic efficiency. Internal ribosome entry sites (IRESs), RNA elements naturally present in the 5’ untranslated regions of a few mRNAs, constitute a powerful tool to co-express several genes of interest. IRESs are translational enhancers allowing the translational machinery to start protein synthesis by internal initiation. This feature allowed the design of multi-cistronic vectors expressing several genes from a single mRNA. IRESs exhibit tissue specificity, and drive translation in stress conditions when the global cell translation is blocked, which renders them useful for gene transfer in hypoxic conditions occurring in ischemic diseases and cancer. IRES-based viral and non viral vectors have been used successfully in preclinical and clinical assays of combined gene therapy and resulted in therapeutic benefits for various pathologies including cancers, cardiovascular diseases and degenerative diseases. PMID:25699230

  1. Exploring Erythropoietin and G-CSF Combination Therapy in Chronic Stroke Patients.

    PubMed

    Shin, Yoon-Kyum; Cho, Sung-Rae

    2016-01-01

    Erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) are known to have neuroprotective actions. Based on previous reports showing the synergistic effects of EPO+G-CSF combination therapy in experimental models, we investigated the safety of EPO+G-CSF combination therapy in patients with chronic stroke. In a pilot study, 3 patients were treated with EPO and G-CSF for 5 consecutive days, with follow-up on day 30. In an exploratory double-blind study, 6 patients were allocated to treatment with either EPO+G-CSF or placebo. Treatment was applied once a day for 5 days per month over 3 months. Participants were followed up for 6 months. To substantiate safety, vital signs, adverse events, and hematological values were measured on days 0, 5, and 30 in each cycle and on day 180. Functional outcomes were determined on day 0 and 180. In the laboratory measurements, EPO+G-CSF combination therapy significantly elevated erythropoietin, CD34⁺ hematopoietic stem cells, white blood cells, and neutrophils on day 5 of each cycle. There were no observations of serious adverse events. In the functional outcomes, the grip power of the dominant hand was increased in the EPO+G-CSF treatment group. In conclusion, this exploratory study suggests a novel strategy of EPO+G-CSF combination therapy for stroke patients. PMID:27043535

  2. A Comparison of Cognitive-Behavioral Therapy, Sertraline, and Their Combination for Adolescent Depression

    ERIC Educational Resources Information Center

    Melvin, Glenn A.; Tonge, Bruce J.; King, Neville J.; Heyne, David; Gordon, Michael S.; Klimkeit, Ester

    2006-01-01

    Objective: To evaluate cognitive-behavioral therapy, antidepressant medication alone, and combined CBT and antidepressant medication in the treatment of depressive disorders in adolescents. Method: Seventy-three adolescents (ages 12-18 years) with a primary diagnosis of DSM-IV major depressive disorder, dysthymic disorder, or depressive disorder…

  3. High dose simvastatin exhibits enhanced lipid lowering effects relative to simvastatin/ezetimibe combination therapy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Technical Abstract: Background: Statins are the frontline in cholesterol reduction therapies; however use in combination with agents that possess complimentary mechanisms of action may achieve further reduce in LDL-C. Methods and Results: Thirty-nine patients were treated with either 80mg simvasta...

  4. Use of combined liothyronine and thyroxine therapy for consumptive hypothyroidism associated with hepatic haemangiomas in infancy.

    PubMed

    Peters, Catherine; Langham, Shirley; Mullis, Primus E; Dattani, Mehul T

    2010-01-01

    Hepatic haemiangiomas in infancy are rare. An association with hypothyroidism has been previously reported and is believed to be secondary to the conversion of thyroxine (fT4) to biologically inactive reverse triiodothyronine (rT3) by type 3 iodothyronine deiodinase (D3). We report a case that responded well to the combined use of liothyronine and thyroxine therapy. PMID:20516650

  5. [Postoperatively conformed effectiveness of preoperative radio therapy, combined with chemotherapy - cysplatin].

    PubMed

    Lazarov, N; Lazarov, L; Lazarov, S

    2012-01-01

    The authors present a case of a 35 years old female patient with spinocellular carcinoma of the cervix, diagnosed after byopsy and treated with radiotherapy 30 Gray, combined with Cisplatin 50 mg. per square meter, per week, 6 months before radical histerectomy and lymphonodulectomy was performed. The postoperative histology shows only traces of dysplastic epithelia, which proves preoperative therapy effective. PMID:22639781

  6. Optimization of combination therapy of arsenic trioxide and fractionated radiotherapy for malignant glioma

    SciTech Connect

    Ning Shoucheng; Knox, Susan J. . E-mail: sknox@stanford.edu

    2006-06-01

    Purpose: The primary objective was to optimize the combined treatment regimen using arsenic trioxide (ATO) and fractionated radiotherapy for the treatment of malignant glioma. Methods and Materials: Nude mice with human glioma xenograft tumors were treated with fractionated local tumor radiation of 250 cGy/fraction/day and 5 mg/kg ATO for 5-10 days. Results: Time course experiments demonstrated that maximal tumor growth delay occurred when ATO was administered between 0 and 4 h after radiation. The combination treatment of ATO and radiation synergistically inhibited tumor growth and produced a tumor growth delay time of 13.2 days, compared with 1.4 days and 6.5 days for ATO and radiation alone (p < 0.01), respectively. The use of concurrent therapy of radiation and ATO initially, followed by ATO as maintenance therapy, was superior to the use of preloading with ATO before combined therapy and produced a tumor growth delay time of 22.7 days as compared with 11.7 days for the ATO preloading regimen (p < 0.01). The maintenance dose of ATO after concurrent therapy was effective and important for continued inhibition of tumor growth. Conclusions: The combined use of fractionated radiation and ATO is effective for the treatment of glioma xenograft tumors. ATO was most effective when administered 0-4 h after radiation without pretreatment with ATO. These results have important implications for the optimization of treatment regimen using ATO and fractionated radiotherapy for the treatment of brain tumors.

  7. Exploring Erythropoietin and G-CSF Combination Therapy in Chronic Stroke Patients

    PubMed Central

    Shin, Yoon-Kyum; Cho, Sung-Rae

    2016-01-01

    Erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) are known to have neuroprotective actions. Based on previous reports showing the synergistic effects of EPO+G-CSF combination therapy in experimental models, we investigated the safety of EPO+G-CSF combination therapy in patients with chronic stroke. In a pilot study, 3 patients were treated with EPO and G-CSF for 5 consecutive days, with follow-up on day 30. In an exploratory double-blind study, 6 patients were allocated to treatment with either EPO+G-CSF or placebo. Treatment was applied once a day for 5 days per month over 3 months. Participants were followed up for 6 months. To substantiate safety, vital signs, adverse events, and hematological values were measured on days 0, 5, and 30 in each cycle and on day 180. Functional outcomes were determined on day 0 and 180. In the laboratory measurements, EPO+G-CSF combination therapy significantly elevated erythropoietin, CD34+ hematopoietic stem cells, white blood cells, and neutrophils on day 5 of each cycle. There were no observations of serious adverse events. In the functional outcomes, the grip power of the dominant hand was increased in the EPO+G-CSF treatment group. In conclusion, this exploratory study suggests a novel strategy of EPO+G-CSF combination therapy for stroke patients. PMID:27043535

  8. Combining Enriched Environment, Progesterone, and Embryonic Neural Stem Cell Therapy Improves Recovery after Brain Injury.

    PubMed

    Nudi, Evan T; Jacqmain, Justin; Dubbs, Kelsey; Geeck, Katalin; Salois, Garrick; Searles, Madeleine A; Smith, Jeffrey S

    2015-07-15

    Millions of persons every year are affected by traumatic brain injury (TBI), and currently no therapies have shown efficacy in improving outcomes clinically. Recent research has suggested that enriched environments (EE), embryonic neural stem cells (eNSC), and progesterone (PROG) improve functional outcomes after TBI, and further, several investigators have suggested that a polytherapuetic approach may have greater efficacy than a single therapy. The purpose of the current study was to determine if varying combinations of post-injury EE, progesterone therapy, or eNSC transplantation would improve functional outcomes over just a single therapy. A controlled cortical impact was performed in rats to create a lesion in the medial frontal cortex. The rats were then placed in either EE or standard environments and administered 10 mg/kg progesterone or vehicle injections 4 h post-injury and every 12 h for 72 h after the initial injection. Seven days after the surgery, rats were transplanted with either eNSCs or media. Rats were then tested on the open field test, Barnes maze, Morris water maze, and Rotor-Rod tasks. Improved functional outcomes were shown on a majority of the behavioral tasks in animals that received a combination of therapies. This effect was especially prominent with therapies that were combined with EE. Immunohistochemistry showed that the transplanted eNSCs survived, migrated, and displayed neural phenotypes. These data suggest that a poly-therapeutic approach after TBI improves functional recovery to a greater magnitude. Moreover, when polytherapies are combined with EE, the effects on recovery are enhanced, leading to greater recovery of function. PMID:25268854

  9. Evaluation of antifungal activity of carbonate and bicarbonate salts alone or in combination with biocontrol agents in control of citrus green mold.

    PubMed

    Zamani, M; Sharifi Tehrani, A; Ali Abadi, A Alizadeh

    2007-01-01

    The aim of this research was to determine if the attacks of green mold on orange could be reduced by edible salts alone or in combination with biocontrol agent. For this purpose toxicity to Pantoea digitatum and practical use of sodium carbonate (SC), sodium bicarbonate (SBC) and potassium carbonate, and potassium bicarbonate alone or in combination with antagonistic bacteria (Pseudomonas fluorescens isolate PN, Bacillus subtilis isolate VHN, Pantoea agglomerans isolate CA) to control green mold were determined. All were fungistatic. SC and SBC were equal and superior to the other salts for control of green mold on oranges inoculated 6h before treatment and were chosen for subsequent trails under cold storage conditions. The biocontrol agents were found completely tolerant to 3% sodium bicarbonate and sodium carbonate at room temperature; although their culturability was reduced by > 1000-fold after 60 min in 1% other salt solutions. Satisfactory results were also obtained with the combined treatment for control of green mold. A significant increase in biocontrol activity of all isolate was observed when combined with sodium carbonate and sodium bicarbonate. The treatments comprising CA combined with SB was as effective as fungicide treatment. Thus, use of sodium bicarbonate treatment at 3% followed by the antagonist P. agglomerans CA could be an alternative to chemical fungicides for control of green mold on oranges. PMID:18396809

  10. Recent advances in COPD disease management with fixed-dose long-acting combination therapies.

    PubMed

    Bateman, Eric D; Mahler, Donald A; Vogelmeier, Claus F; Wedzicha, Jadwiga A; Patalano, Francesco; Banerji, Donald

    2014-06-01

    Combinations of two long-acting bronchodilators and long-acting bronchodilators with inhaled corticosteroids (ICS) are recommended therapies in the management of chronic obstructive pulmonary disease (COPD). Three fixed-dose combination products have recently been approved for the treatment of COPD (the long-acting β2-agonist plus long-acting muscarinic antagonist [LABA/LAMA] combinations glycopyrronium/indacaterol [QVA149] and umeclidinium/vilanterol, and the LABA/ICS fluticasone furoate/vilanterol), with others currently in late-stage development. LABA/LAMA and LABA/ICS combination therapies demonstrate positive effects on both lung function and patient-reported outcomes, with significant improvements observed with LABA/LAMA combinations compared with placebo, each component alone and other comparators in current use. No new safety concerns have been observed with combinations of long-acting bronchodilators. Combinations of two long-acting bronchodilators represent a new and convenient treatment option in COPD. This review summarizes published efficacy and safety data from clinical trials of both LABA/LAMA and novel LABA/ICS combinations in patients with COPD. PMID:24802656

  11. Step-down therapy in well-controlled asthmatic patients using salmeterol xinafoate/fluticasone propionate combination therapy

    PubMed Central

    Horiuchi, Kazuya; Kasahara, Keita; Kuroda, Yusuke; Morohoshi, Haruna; Hagiwara, Yosuke; Ishii, Gen

    2016-01-01

    Purpose A combination therapy with inhaled corticosteroid (ICS) and a long-acting β agonist (LABA) is the standard treatment for asthmatic patients, and step-down treatment is recommended once control has been achieved. However, little data exist that evaluate the long-term outcomes after step-down treatment. Objective To compare the long-term outcomes of step-down therapy with ICS/LABA or ICS alone for asthmatic patients who have achieved well-controlled asthma by the ICS (250 µg fluticasone)/LABA (50 µg salmeterol) combination (SFC, two puffs per day). Patients and methods We randomized 40 well-controlled patients with asthma receiving SFC (250 µg) to two groups; one group of patients received step-down therapy with low-dose SFC (100 µg, two puffs daily) and another group of patients received step-down therapy with high-dose fluticasone propionate (FP) alone (500 µg, daily). The two groups were monitored over 12 months for changes in asthma control test scores, respiratory function (percent forced expiratory volume in 1 second, maximal expiratory flow rate at 50% of the vital capacity [%FEF50], and maximal expiratory flow rate at 25% of the vital capacity [%FEF25]), and the concentration of fractional exhaled nitric oxide. Results There was no significant difference in the dropout rate between the SFC and FP groups. Low-dose SFC maintained the stability of all parameters over 12 months, whereas the FP group exhibited a rapid 5% decrease in forced expiratory volume in 1 second within 2 months after discontinuation of salmeterol; furthermore, after 10 months, there was a gradual decrease in %FEF50 and %FEF25. Conclusion This study suggests that a balanced step-down protocol, including both ICS and LABA, is essential in providing long-term stability to patients with mild-to-moderate well-controlled asthma. PMID:27051309

  12. Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

    PubMed Central

    2011-01-01

    Background Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. Discussion In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect. As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. Summary Multitarget therapeutics like combined analgesics broaden the array of therapeutic

  13. Nanotechnology-based combination therapy improves treatment response in cancer models

    NASA Astrophysics Data System (ADS)

    Rai, Prakash; Chang, Sung K.; Mai, Zhiming; Neuman, Daniel; Hasan, Tayyaba

    2009-06-01

    Pancreatic cancer (PanCa) has a poor prognosis with a 5-year survival rate of only 5%. Photodynamic therapy (PDT) has shown promising results in treating PanCa. Mechanism-based combinations with PDT have enhanced treatment outcome. Agents tested with PDT include Avastin, an antibody against vascular endothelial growth factor (VEGF) which is approved for treating various cancers. Simultaneous delivery of drugs in nano-constructs could improve the treatment response of mechanism based combination therapies. Here, we investigate the effect of neutralizing VEGF using nanotechnology for the delivery of Avastin in combination with PDT. For this we used a construct called "nanocells" in which the photosensitizer was trapped inside polymer nanoparticles and these, with Avastin, were then encapsulated inside liposomes. In vitro, nanocells containing Avastin (NCA) significantly enhanced cytotoxicity in PanCa cells. NCA based PDT also significantly improved treatment response in mice that were orthotopically implanted with PanCa. Avastin delivered extracellularly in combination with PDT did not show any improvement. Here we propose a new paradigm for Avastin-based therapy by combining intracellular delivery of the antibody and PDT using nanotechnology for treating PanCa.

  14. Pharmacogenetics and the Development of Personalized Approaches for Combination Therapy in Asthma

    PubMed Central

    Miller, Stacey M.

    2013-01-01

    Asthma is a common, chronic disease of the airways that is treated with a combination of different therapies. The combination of LABA and ICS therapy results in a synergistic interaction that is efficacious in improving asthma symptom control; however, genetic variation has the potential to alter therapeutic efficacy. Both agents mediate complex molecular pathways consisting of gene variation that has been investigated with the analysis of candidate genes in the β2-adrenergic receptor and glucocorticoid pathway. These pharmacogenetic studies have been limited to retrospective analyses of clinical trial cohorts and a small number of prospective, genotype-stratified trials. More recently, genome-wide association studies in combination with replication in additional cohorts and in vitro cell-based models have been used to identify novel pathway-related pharmacogenetic variations. This review of the pharmacogenetics of the β2-adrenergic receptor and glucocorticoid pathways highlights the genotypic effects of variation in multiple genes from interacting pathways which may contribute to differential responses to inhaled beta agonists and glucocorticoids. As our understanding of these genetic mechanisms improves, panels of biomarkers may be developed to determine which combination therapies are the most effective with the least risk to an individual asthma patient. Before we can usher in an era of personalized medicine for asthma, it is first important to improve our ability to analyze large volumes of genetic data in large clinical trial cohorts using a combination of study designs, analytical methods, and in vitro functional studies. PMID:23912588

  15. Rational Design and Adaptive Management of Combination Therapies for Hepatitis C Virus Infection

    PubMed Central

    Ke, Ruian; Loverdo, Claude; Qi, Hangfei; Sun, Ren; Lloyd-Smith, James O.

    2015-01-01

    Recent discoveries of direct acting antivirals against Hepatitis C virus (HCV) have raised hopes of effective treatment via combination therapies. Yet rapid evolution and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health concern. We develop a general model incorporating viral dynamics and pharmacokinetics/ pharmacodynamics to assess how suboptimal adherence affects resistance development and clinical outcomes. We derive design principles and adaptive treatment strategies, identifying a high-risk period when missing doses is particularly risky for de novo resistance, and quantifying the number of additional doses needed to compensate when doses are missed. Using data from large-scale resistance assays, we demonstrate that the risk of resistance can be reduced substantially by applying these principles to a combination therapy of daclatasvir and asunaprevir. By providing a mechanistic framework to link patient characteristics to the risk of resistance, these findings show the potential of rational treatment design. PMID:26125950

  16. Combination therapy for portopulmonary hypertension with intravenous iloprost and oral bosentan.

    PubMed

    Halank, Michael; Kolditz, Martin; Miehlke, Stephan; Schiemanck, Steffen; Schmeisser, Alexander; Hoeffken, Gert

    2005-08-01

    Severe portopulmonary hypertension (PPHTN) is a rare complication of liver cirrhosis and carries a poor prognosis. In the last years, intravenous (IV) epoprostenol has been suggested to be the optimal medical treatment for PPHTN, and recently oral bosentan has been shown to be efficacious and safe in selected patients with PPHTN. We report a case of PPHTN suffering from recurrent right heart failure while on treatment with IV iloprost, which was successfully managed by combination therapy with IV iloprost plus oral bosentan, providing sustained cardiopulmonary stabilization for at least two years. This report documents the first case of a patient with PPHTN successfully treated with the combination of IV iloprost and oral bosentan over an extended period. Thus, combination therapy with IV iloprost and oral bosentan might be a promising new option for selected patients suffering from PPHTN and recurrent right heart failure. PMID:16160926

  17. Colistin combination therapy improves microbiologic cure in critically ill patients with multi-drug resistant gram-negative pneumonia.

    PubMed

    Parchem, N L; Bauer, K A; Cook, C H; Mangino, J E; Jones, C D; Porter, K; Murphy, C V

    2016-09-01

    Currently, in vitro synergy with colistin has not translated into improved clinical outcomes. This study aimed to compare colistin combination therapy to colistin monotherapy in critically ill patients with multi-drug resistant gram-negative (MDR-GN) pneumonia. This was a retrospective analysis of critically ill adult patients receiving intravenous colistin for MDR-GN pneumonia comparing colistin combination therapy to colistin monotherapy with a primary endpoint of clinical cure. Combination therapy was defined by administration of another antibiotic to which the MDR-GN pathogen was reported as susceptible or intermediate. Ninety patients were included for evaluation (41 combination therapy and 49 monotherapy). Baseline characteristics were similar between groups. No difference in clinical cure was observed between combination therapy and monotherapy in univariate analysis, nor when adjusted for APACHE II score and time to appropriate antibiotic therapy (57.1 vs. 63.4 %, adjusted OR 1.15, p = 0.78). Microbiological cure was significantly higher for combination therapy (87 vs. 35.5 %, p < 0.001). Colistin combination therapy was associated with a significant improvement in microbiological cure, without improvement in clinical cure. Based on the in vitro synergy and improvement in microbiological clearance, colistin combination therapy should be prescribed for MDR-GN pneumonia. Further research is warranted to determine if in vitro synergy with colistin translates into improved clinical outcomes. PMID:27230510

  18. Antifungal activity of multifunctional Fe 3O 4-Ag nanocolloids

    NASA Astrophysics Data System (ADS)

    Chudasama, Bhupendra; Vala, Anjana K.; Andhariya, Nidhi; Upadhyay, R. V.; Mehta, R. V.

    2011-05-01

    In recent years, rapid increase has been observed in the population of microbes that are resistant to conventionally used antibiotics. Antifungal drug therapy is no exception and now resistance to many of the antifungal agents in use has emerged. Therefore, there is an inevitable and urgent medical need for antibiotics with novel antimicrobial mechanisms. Aspergillus glaucus is the potential cause of fatal brain infections and hypersensitivity pneumonitis in immunocompromised patients and leads to death despite aggressive multidrug antifungal therapy. In the present article, we describe the antifungal activity of multifunctional core-shell Fe 3O 4-Ag nanocolloids against A. glaucus isolates. Controlled experiments are also carried out with Ag nanocolloids in order to understand the role of core (Fe 3O 4) in the antifungal action. The minimum inhibitory concentration (MIC) of nanocolloids is determined by the micro-dilution method. MIC of A. glaucus is 2000 μg/mL. The result is quite promising and requires further investigations in order to develop a treatment methodology against this death causing fungus in immunocompromised patients.

  19. Combining Dopaminergic Facilitation with Robot-Assisted Upper Limb Therapy in Stroke Survivors: A Focused Review.

    PubMed

    Tran, Duc A; Pajaro-Blazquez, Marta; Daneault, Jean-Francois; Gallegos, Jaime G; Pons, Jose; Fregni, Felipe; Bonato, Paolo; Zafonte, Ross

    2016-06-01

    Despite aggressive conventional therapy, lasting hemiplegia persists in a large percentage of stroke survivors. The aim of this article is to critically review the rationale behind targeting multiple sites along the motor learning network by combining robotic therapy with pharmacotherapy and virtual reality-based reward learning to alleviate upper extremity impairment in stroke survivors. Methods for personalizing pharmacologic facilitation to each individual's unique biology are also reviewed. At the molecular level, treatment with levodopa was shown to induce long-term potentiation-like and practice-dependent plasticity. Clinically, trials combining conventional therapy with levodopa in stroke survivors yielded statistically significant but clinically unconvincing outcomes because of limited personalization, standardization, and reproducibility. Robotic therapy can induce neuroplasticity by delivering intensive, reproducible, and functionally meaningful interventions that are objective enough for the rigors of research. Robotic therapy also provides an apt platform for virtual reality, which boosts learning by engaging reward circuits. The future of stroke rehabilitation should target distinct molecular, synaptic, and cortical sites through personalized multimodal treatments to maximize motor recovery. PMID:26829074

  20. Combining Dopaminergic Facilitation with Robot-Assisted Upper Limb Therapy in Stroke Survivors

    PubMed Central

    Tran, Duc A.; Pajaro-Blazquez, Marta; Daneault, Jean-Francois; Gallegos, Jaime G.; Pons, Jose; Fregni, Felipe; Bonato, Paolo; Zafonte, Ross

    2016-01-01

    ABSTRACT Despite aggressive conventional therapy, lasting hemiplegia persists in a large percentage of stroke survivors. The aim of this article is to critically review the rationale behind targeting multiple sites along the motor learning network by combining robotic therapy with pharmacotherapy and virtual reality–based reward learning to alleviate upper extremity impairment in stroke survivors. Methods for personalizing pharmacologic facilitation to each individual’s unique biology are also reviewed. At the molecular level, treatment with levodopa was shown to induce long-term potentiation-like and practice-dependent plasticity. Clinically, trials combining conventional therapy with levodopa in stroke survivors yielded statistically significant but clinically unconvincing outcomes because of limited personalization, standardization, and reproducibility. Robotic therapy can induce neuroplasticity by delivering intensive, reproducible, and functionally meaningful interventions that are objective enough for the rigors of research. Robotic therapy also provides an apt platform for virtual reality, which boosts learning by engaging reward circuits. The future of stroke rehabilitation should target distinct molecular, synaptic, and cortical sites through personalized multimodal treatments to maximize motor recovery. PMID:26829074

  1. Options for empagliflozin in combination therapy in type 2 diabetes mellitus

    PubMed Central

    Hershon, Kenneth S

    2016-01-01

    Objective To update clinicians with an overview of empagliflozin for the treatment of type 2 diabetes mellitus (T2DM), with focus on use in combination regimens. Methods Keyword searches were conducted in the Medline database to identify literature reporting clinical trials of at least 12 weeks’ duration using empagliflozin treatment in patients with T2DM. Results When given as monotherapy or in combination therapy (as add-on or single-pill therapy) with metformin, pioglitazone, sulfonylurea, linagliptin, and insulin, empagliflozin produced clinically meaningful reductions in glycated hemoglobin levels, plasma glucose concentrations, bodyweight, and blood pressure. These changes were sustained during long-term treatment. In a dedicated cardiovascular event trial, empagliflozin on top of standard of care demonstrated a significant reduction in the risk of cardiovascular mortality and all-cause mortality. Across the clinical trials, empagliflozin combination therapies were well tolerated, and empagliflozin used alone was not associated with increased risk of hypoglycemia versus placebo. Indeed, the combination of empagliflozin and metformin had a significantly reduced rate of hypoglycemia compared with the combination of metformin and a sulfonylurea. On the other hand, empagliflozin treatment did have increased risk of genital infections compared with placebo. In clinical trials to date, diabetic ketoacidosis was not seen more frequently with empagliflozin than with placebo, but physicians should be alert to the possibility of this rare event. Conclusion Empagliflozin has the potential to make an important contribution to the treatment of patients with T2DM. In some patients, empagliflozin may be used as monotherapy, but it is most likely to be used in combination with other therapies. Given the reduced risk of mortality seen when empagliflozin was added to standard care in patients at high cardiovascular risk, as well as the lack of alternative options for

  2. Initial combination therapy for type 2 diabetes mellitus: is it ready for prime time?

    PubMed

    Zinman, Bernard

    2011-01-01

    The increased prevalence of type 2 diabetes mellitus is primarily being driven by the increasing global rates of overweight/obesity. Given the magnitude of this epidemic, we can expect these metabolic abnormalities to play an increasing role in the development of cardiovascular disease. In a pathophysiologic sense, type 2 diabetes is a multiorgan, multifactorial condition, characterized by β-cell dysfunction, insulin resistance in peripheral tissues and the liver, defective incretin activity, and elevated levels of free fatty acids and proinflammatory mediators. Despite the considerable burden of disease associated with type 2 diabetes, most patients are not at, or are unable to achieve, recommended glycemic control guideline targets. In part, this is because of the relentlessly progressive nature of the disease, but it may also be attributable to the current diabetes treatment paradigm, which is characterized by ineffective lifestyle interventions, followed by monotherapy and frequent early treatment failure with prolonged periods of elevated glucose as a consequence of clinical inertia. Thus, it is most appropriate to rethink the current treatment paradigm for type 2 diabetes in the context of a more aggressive initial therapy; specifically with early initiation of combination therapy. Our current understanding of the complex pathophysiology of the disease and the progressive deterioration in glycemic control over time supports the philosophy of earlier intervention with a more comprehensive initial therapy. Thus, while control of hyperglycemia remains the paramount goal, focusing on the underlying pathophysiology of type 2 diabetes is increasingly becoming the therapeutic strategy, with the aim of potentially providing disease modification. Although this is a logical approach, it remains to be demonstrated that early combination therapy will result in disease modification in a clinical setting. Not surprisingly, the incretin-based therapies have gained a great

  3. Hyperbaric oxygen therapy in tinnitus with normal hearing in association with combined treatment.

    PubMed

    Holy, Richard; Prazenica, Pavol; Stolarikova, Eva; Dosel, Petr; Fundova, Petra; Kovar, Daniel; Astl, Jaromir

    2016-01-01

    Tinnitus is a phantom perception of sound in the absence of overt acoustic stimulation. The focus of our attention is a combined therapy of tinnitus. In this prospective study (2013-2014) we evaluated the data of normal-hearing patients with tinnitus treated with various treatment modalities. In Group 1 we evaluated the data of 84 patients/124 ears after six weeks of treatment with betahistine dihydrochloride (72 mg). In Group 2, we evaluated the data of 36 patients/ 55 ears unimproved from Group 1 who were then treated for six weeks with hyperbaric oxygen (HBO₂) therapy combined with gingko biloba extract (120 mg). In Group 1, tinnitus disappeared in 9.7%, alleviated in 18.5% and improved overall in 28.2%. Average intensity of tinnitus before/after treatment was 37 decibels (dB)/33 dB. Tinnitus intensities after treatment are statistically significantly lower (p = 0.001) than the values before treatment. In Group 2 tinnitus disappeared in 5.4%, 36.4% achieved alleviation, and 41.8% showed overall improvement. The average intensity of tinnitus before/after treatment was 41dB/ 38dB. The values of tinnitus intensity after combined therapy are statistically significantly lower (p = 0.046). We have shown that both methods treatment of tinnitus are statistically significant. HBO₂therapy was recommended for the general public. PMID:27416687

  4. Combined pharmacotherapy and cognitive behavior therapy in the treatment of panic disorder.

    PubMed

    Gelder, M G

    1998-12-01

    Cognitive behavior therapy (CBT) has been combined with pharmacotherapy in the treatment of panic disorder in three ways: (1) to treat agoraphobic symptoms in the condition of panic with agoraphobia; (2) to reduce withdrawal effects during drug taper; and (3) to treat panic attacks. Exposure treatment and pharmacotherapy have a modest additive effect, although more patients drop out of exposure therapy combined with imipramine treatment compared with exposure therapy alone. CBT reduces symptoms of withdrawal from alprazolam and other benzodiazepines and improves the outcome of drug treatment. At present, sufficient data are not available to determine whether the effects of CBT combined with drug therapy are additive in treating panic disorder. The results of a large trial are awaited. Current CBT consists of 12 sessions and is not widely offered to patients because of cost considerations. Efforts are being made to decrease the number of sessions necessary by improving cognitive techniques. One of these models is the subject of an ongoing trial. Finally, efforts to educate and counsel patients in the clinical setting regarding the psychopathology of panic attacks may improve the outcome of pharmacotherapy. PMID:9872706

  5. Influence of Interferon-Alpha Combined with Chemo (Radio) Therapy on Immunological Parameters in Pancreatic Adenocarcinoma

    PubMed Central

    Karakhanova, Svetlana; Mosl, Beate; Harig, Sabine; von Ahn, Katharina; Fritz, Jasmin; Schmidt, Jan; Jäger, Dirk; Werner, Jens; Bazhin, Alexandr V.

    2014-01-01

    Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combination of chemo (radio) therapies with interferon-2α. Low doses of interferon-2α led to a decrease in total leukocyte and an increase in monocyte counts. Furthermore, we observed a positive effect of interferon-2α therapy on the dendritic cells and NK (natural killer) cell activation immediately after the first injection. In addition, we recorded an increased amount of interferon-γ and IL-10 in the serum following the interferon-2α therapy. These data clearly demonstrate that pancreatic carcinoma patients also show an immunomodulatory response to interferon-2α therapy. Analysis of immunosuppressive cells in the Panc02 orthotopic mouse model of pancreatic cancer revealed an accumulation of the myeloid-derived suppressor cells in spleens and tumors of the mice treated with interferon-2α and 5-fluorouracil. The direct effect of the drugs on myeloid-derived suppressor cells was also registered in vitro. These data expose the importance of immunosuppressive mechanisms induced by combined chemo-immunotherapy. PMID:24608924

  6. Influence of interferon-alpha combined with chemo (radio) therapy on immunological parameters in pancreatic adenocarcinoma.

    PubMed

    Karakhanova, Svetlana; Mosl, Beate; Harig, Sabine; von Ahn, Katharina; Fritz, Jasmin; Schmidt, Jan; Jäger, Dirk; Werner, Jens; Bazhin, Alexandr V

    2014-01-01

    Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combination of chemo (radio) therapies with interferon-2α. Low doses of interferon-2α led to a decrease in total leukocyte and an increase in monocyte counts. Furthermore, we observed a positive effect of interferon-2α therapy on the dendritic cells and NK (natural killer) cell activation immediately after the first injection. In addition, we recorded an increased amount of interferon-γ and IL-10 in the serum following the interferon-2α therapy. These data clearly demonstrate that pancreatic carcinoma patients also show an immunomodulatory response to interferon-2α therapy. Analysis of immunosuppressive cells in the Panc02 orthotopic mouse model of pancreatic cancer revealed an accumulation of the myeloid-derived suppressor cells in spleens and tumors of the mice treated with interferon-2α and 5-fluorouracil. The direct effect of the drugs on myeloid-derived suppressor cells was also registered in vitro. These data expose the importance of immunosuppressive mechanisms induced by combined chemo-immunotherapy. PMID:24608924

  7. Polydopamine Nanoparticles as a Versatile Molecular Loading Platform to Enable Imaging-guided Cancer Combination Therapy

    PubMed Central

    Dong, Ziliang; Gong, Hua; Gao, Min; Zhu, Wenwen; Sun, Xiaoqi; Feng, Liangzhu; Fu, Tingting; Li, Yonggang; Liu, Zhuang

    2016-01-01

    Cancer combination therapy to treat tumors with different therapeutic approaches can efficiently improve treatment efficacy and reduce side effects. Herein, we develop a theranostic nano-platform based on polydopamine (PDA) nanoparticles, which then are exploited as a versatile carrier to allow simultaneous loading of indocyanine green (ICG), doxorubicin (DOX) and manganese ions (PDA-ICG-PEG/DOX(Mn)), to enable imaging-guided chemo & photothermal cancer therapy. In this system, ICG acts as a photothermal agent, which shows red-shifted near-infrared (NIR) absorbance and enhanced photostability compared with free ICG. DOX, a model chemotherapy drug, is then loaded onto the surface of PDA-ICG-PEG with high efficiency. With Mn2+ ions intrinsically chelated, PDA-ICG-PEG/DOX(Mn) is able to offer contrast under T1-weighted magnetic resonance (MR) imaging. In a mouse tumor model, the MR imaging-guided combined chemo- & photothermal therapy achieves a remarkable synergistic therapeutic effect compared with the respective single treatment modality. This work demonstrates that PDA nanoparticles could serve as a versatile molecular loading platform for MR imaging guided combined chemo- & photothermal therapy with minimal side effects, showing great potential for cancer theranostics. PMID:27217836

  8. Dynamics of tumor growth and combination of anti-angiogenic and cytotoxic therapies

    NASA Astrophysics Data System (ADS)

    Kohandel, M.; Kardar, M.; Milosevic, M.; Sivaloganathan, S.

    2007-07-01

    Tumors cannot grow beyond a certain size (about 1-2 mm in diameter) through simple diffusion of oxygen and other essential nutrients into the tumor. Angiogenesis, the formation of blood vessels from pre-existing vessels, is a crucial and observed step, through which a tumor obtains its own blood supply. Thus, strategies that interfere with the development of this tumor vasculature, known as anti-angiogenic therapy, represent a novel approach to controlling tumor growth. Several pre-clinical studies have suggested that currently available angiogenesis inhibitors are unlikely to yield significant sustained improvements in tumor control on their own, but rather will need to be used in combination with conventional treatments to achieve maximal benefit. Optimal sequencing of anti-angiogenic treatment and radiotherapy or chemotherapy is essential to the success of these combined treatment strategies. Hence, a major challenge to mathematical modeling and computer simulations is to find appropriate dosages, schedules and sequencing of combination therapies to control or eliminate tumor growth. Here, we present a mathematical model that incorporates tumor cells and the vascular network, as well as their interplay. We can then include the effects of two different treatments, conventional cytotoxic therapy and anti-angiogenic therapy. The results are compared with available experimental and clinical data.

  9. HSP90 Inhibitor Encapsulated Photo-Theranostic Nanoparticles for Synergistic Combination Cancer Therapy

    PubMed Central

    Lin, Tzu-yin; Guo, Wenchang; Long, Qilai; Ma, Aihong; Liu, Qiangqiang; Zhang, Hongyong; Huang, Yee; Chandrasekaran, Siddarth; Pan, Chongxian; Lam, Kit S.; Li, Yuanpei

    2016-01-01

    Photodynamic therapy (PDT) is a promising non-invasive therapeutic modality that has been proposed for treating prostate cancer, but the procedure is associated with limited efficacy, tumor recurrence and photo-toxicity. In the present study, we proposed to develop a novel multifunctional nano-platform for targeted delivery of heat, reactive oxygen species (ROS) and heat shock protein 90 (Hsp90) inhibitor simultaneously for combination therapy against prostate cancer. This new nano-platform combines two newly developed entities: 1) a unique organic and biocompatible nanoporphyrin-based drug delivery system that can generate efficient heat and ROS simultaneously with light activation at the tumor sites for dual-modal photothermal- and photodynamic- therapy (PTT/PDT), and 2) new nano-formulations of Hsp90 inhibitors that can decrease the levels of pro-survival and angiogenic signaling molecules induced by phototherapy, therefore, further sensitizing cancer cells to phototherapy. Furthermore, the nanoparticles have activatable near infrared (NIR) fluorescence for optical imaging to conveniently monitor the real-time drug delivery in both subcutaneous and orthotopic mouse models bearing prostate cancer xenograft. This novel multifunctional nano-platform has great potential to improve the care of prostate cancer patients through targeted combination therapy. PMID:27375782

  10. In Vitro Combination of Voriconazole and Miltefosine against Clinically Relevant Molds

    PubMed Central

    Imbert, S.; Palous, M.; Meyer, I.; Dannaoui, E.; Mazier, D.; Datry, A.

    2014-01-01

    Invasive infections caused by filamentous fungi are a major threat for immunocompromised patients. Innate/acquired resistance to antifungal drugs might necessitate combination therapies. We assessed the potential combination of voriconazole with miltefosine, an original drug with antifungal activity against 33 clinically relevant mold isolates, including both azole-susceptible and -resistant Aspergillus. Using complete inhibition as an endpoint, interactions were indifferent for 32/33 isolates. An alternative 50% inhibition endpoint showed synergistic interactions for 14/33 isolates. Antagonism was absent. PMID:25199776

  11. Generalized Granuloma Annulare Treated with Monthly Rifampicin, Ofloxacin, and Minocycline Combination Therapy

    PubMed Central

    Garg, Shilpa; Baveja, Sukriti

    2013-01-01

    Granuloma annulare (GA) is a disease characterized by granulomatous inflammation of the dermis. A variant form of the disease, generalized granuloma annulare (GGA), can be observed in 15% of affected patients. Localized GA is likely to resolve spontaneously within months or a few years, whereas GGA can persist for decades. There are various therapies for treating GGA. Monthly combination therapy of rifampicin 600 mg, ofloxacin 400 mg, and minocycline 100 mg (ROM) is used for treating paucibacillary leprosy which shares both clinical and histopathologic similarities with GA. Therefore, we decided to evaluate the possible efficacy of monthly ROM in a patient with GGA. PMID:23723470

  12. Smart micelle@polydopamine core-shell nanoparticles for highly effective chemo-photothermal combination therapy

    NASA Astrophysics Data System (ADS)

    Zhang, Ruirui; Su, Shishuai; Hu, Kelei; Shao, Leihou; Deng, Xiongwei; Sheng, Wang; Wu, Yan

    2015-11-01

    In this investigation, we have designed and synthesized a novel core-shell polymer nanoparticle system for highly effective chemo-photothermal combination therapy. A nanoscale DSPE-PEG micelle encapsulating doxorubicin (Dox-M) was designed as a core, and then modified by a polydopamine (PDA) shell for photothermal therapy and bortezomib (Btz) administration (Dox-M@PDA-Btz). The facile conjugation of Btz to the catechol-containing PDA shell can form a reversible pH-sensitive boronic acid-catechol conjugate to create a stimuli-responsive drug carrier system. As expected, the micelle@PDA core-shell nanoparticles exhibited satisfactory photothermal efficiency, which has potential for thermal ablation of malignant tissues. In addition, on account of the PDA modification, both Dox and Btz release processes were pH-dependent and NIR-dependent. Both in vitro and in vivo studies illustrated that the Dox-M@PDA-Btz nanoparticles coupled with laser irradiation could enhance the cytotoxicity, and thus combinational therapy efficacy was achieved when integrating Dox, Btz, and PDA into a single nanoplatform. Altogether, our current study indicated that the micelle@polydopamine core-shell nanoparticles could be applied for NIR/pH-responsive sustained-release and synergized chemo-photothermal therapy for breast cancer.In this investigation, we have designed and synthesized a novel core-shell polymer nanoparticle system for highly effective chemo-photothermal combination therapy. A nanoscale DSPE-PEG micelle encapsulating doxorubicin (Dox-M) was designed as a core, and then modified by a polydopamine (PDA) shell for photothermal therapy and bortezomib (Btz) administration (Dox-M@PDA-Btz). The facile conjugation of Btz to the catechol-containing PDA shell can form a reversible pH-sensitive boronic acid-catechol conjugate to create a stimuli-responsive drug carrier system. As expected, the micelle@PDA core-shell nanoparticles exhibited satisfactory photothermal efficiency, which has

  13. CD20-targeting in B-cell malignancies: novel prospects for antibodies and combination therapies.

    PubMed

    Safdari, Yaghoub; Ahmadzadeh, Vahideh; Farajnia, Safar

    2016-08-01

    Expression of CD20 antigen by the most of transformed B cells is believed to be the driving force for targeting this molecule by using anti-CD20 monoclonal antibodies. While it is true that most lymphoma/leukemia patients can be cured, these regimens are limited by the emergence of treatment resistance. Based on these observations, development of anti-CD20 monoclonal antibodies and combination therapies have been recently proposed, in particular with the aim to optimize the cytotoxic activity. Here we outline a range of new experimental agents concerning the CD20 positive B-cell tumors which provide high benefit from conventional therapy. PMID:27075017

  14. Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy

    PubMed Central

    Eroglu, Zeynep; Ribas, Antoni

    2016-01-01

    Treatment with BRAF inhibitors such as vemurafenib or dabrafenib in patients with advanced BRAFV600 mutated melanoma has shown objective tumor responses in approximately half of the patients. However, the duration of responses is limited in a majority of these patients, with progression-free survival rates around 6 months due to tumor progression from development of acquired resistance. Preclinical studies have suggested that concurrent inhibition of the BRAF kinases and MEK of the mitogen-activated protein kinase (MAPK) pathway could decrease MAPK-driven acquired resistance, resulting in longer duration of responses, higher rate of tumor responses, and a decrease in the cutaneous toxicities observed from paradoxical MAPK pathway activation with BRAF inhibitor monotherapy. This review provides an overview of the currently available clinical trial data on BRAF and MEK inhibitors together and in combinations with other therapeutic agents. PMID:26753005

  15. Combined tar-anthralin versus anthralin treatment lowers irritancy with unchanged antipsoriatic efficacy. Modifications of short-contact therapy and Ingram therapy.

    PubMed

    Schulze, H J; Schauder, S; Mahrle, G; Steigleder, G K

    1987-07-01

    In 44 patients with chronic plaque psoriasis anthralin therapy was used as high-strength short-contact therapy in a bilateral comparison of anthralin versus 5% crude coal tar-anthralin combination. These two trials were undertaken with and without ultraviolet (UV) irradiation immediately after anthralin therapy. The combined tar-anthralin therapy was significantly less of an irritant during the first 3 weeks of treatment than anthralin alone, and it did not decrease the antipsoriatic efficacy. The use of UV irradiation, either with anthralin or tar-anthralin combination, did not produce an additional therapeutic effect. These findings lead us to prefer combined tar-anthralin therapy because of its lower irritancy in comparison with anthralin alone and they show the ineffectiveness of additional UV irradiation under the conditions of this study. PMID:3611453

  16. Genotype-Selective Combination Therapies for Melanoma Identified by High Throughput Drug Screening

    PubMed Central

    Held, Matthew A.; Langdon, Casey G.; Platt, James T.; Graham-Steed, Tisheeka; Liu, Zongzhi; Chakraborty, Ashok; Bacchiocchi, Antonella; Koo, Andrew; Bosenberg, Marcus W.; Stern, David F.

    2012-01-01

    Resistance and partial responses to targeted monotherapy are major obstacles in cancer treatment. Systematic approaches to identify efficacious drug combinations for cancer are not well established, especially in the context of genotype. To address this, we have tested pairwise combinations of an array of small molecule inhibitors on early passage melanoma cultures using combinatorial drug screening. Results reveal several inhibitor combinations effective for melanomas with activating RAS or BRAF mutations, including mutant BRAF melanomas with intrinsic or acquired resistance to vemurafenib. Inhibition of both EGFR and AKT sensitized treatment-resistant BRAF-mutant melanoma cultures to vemurafenib. Melanomas with RAS mutations were more resistant to combination therapies relative to BRAF mutants, but were sensitive to combinations of statins and cyclin-dependent kinase inhibitors in vitro and in vivo. These results demonstrate the utility of combinatorial drug screening for discovering unique treatment regimens that overcome resistance phenotypes of mutant BRAF and RAS driven melanomas. PMID:23239741

  17. Radiobiological Optimization of Combination Radiopharmaceutical Therapy Applied to Myeloablative Treatment of Non-Hodgkin’s Lymphoma

    PubMed Central

    Hobbs, Robert F; Wahl, Richard L; Frey, Eric C; Kasamon, Yvette; Song, Hong; Huang, Peng; Jones, Richard J; Sgouros, George

    2014-01-01

    Combination treatment is a hallmark of cancer therapy. Although the rationale for combination radiopharmaceutical therapy was described in the mid ‘90s, such treatment strategies have only been implemented clinically recently, and without a rigorous methodology for treatment optimization. Radiobiological and quantitative imaging-based dosimetry tools are now available that enable rational implementation of combined targeted radiopharmaceutical therapy. Optimal implementation should simultaneously account for radiobiological normal organ tolerance while optimizing the ratio of two different radiopharmaceuticals required to maximize tumor control. We have developed such a methodology and applied it to hypothetical myeloablative treatment of non-hodgkin’s lymphoma (NHL) patients using 131I-tositumomab and 90Y-ibritumomab tiuxetan. Methods The range of potential administered activities (AA) is limited by the normal organ maximum tolerated biologic effective doses (MTBEDs) arising from the combined radiopharmaceuticals. Dose limiting normal organs are expected to be the lungs for 131I-tositumomab and the liver for 90Y-ibritumomab tiuxetan in myeloablative NHL treatment regimens. By plotting the limiting normal organ constraints as a function of the AAs and calculating tumor biological effective dose (BED) along the normal organ MTBED limits, the optimal combination of activities is obtained. The model was tested using previously acquired patient normal organ and tumor kinetic data and MTBED values taken from the literature. Results The average AA values based solely on normal organ constraints was (19.0 ± 8.2) GBq with a range of 3.9 – 36.9 GBq for 131I-tositumomab, and (2.77 ± 1.64) GBq with a range of 0.42 – 7.54 GBq for 90Y-ibritumomab tiuxetan. Tumor BED optimization results were calculated and plotted as a function of AA for 5 different cases, established using patient normal organ kinetics for the two radiopharmaceuticals. Results included AA ranges

  18. Tissue Penetration of Antifungal Agents

    PubMed Central

    Felton, Timothy; Troke, Peter F.

    2014-01-01

    SUMMARY Understanding the tissue penetration of systemically administered antifungal agents is critical for a proper appreciation of their antifungal efficacy in animals and humans. Both the time course of an antifungal drug and its absolute concentrations within tissues may differ significantly from those observed in the bloodstream. In addition, tissue concentrations must also be interpreted within the context of the pathogenesis of the various invasive fungal infections, which differ significantly. There are major technical obstacles to the estimation of concentrations of antifungal agents in various tissue subcompartments, yet these agents, even those within the same class, may exhibit markedly different tissue distributions. This review explores these issues and provides a summary of tissue concentrations of 11 currently licensed systemic antifungal agents. It also explores the therapeutic implications of their distribution at various sites of infection. PMID:24396137

  19. Triple Combination Therapy for Global Cardiovascular Risk: Atorvastatin, Perindopril, and Amlodipine.

    PubMed

    Bertrand, Michel E; Vlachopoulos, Charalambos; Mourad, Jean-Jacques

    2016-08-01

    Statins, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers (CCBs) have markedly changed the clinical progression of patients with coronary artery disease (CAD). The goal of this paper is to review the rationale and evidence for combining these three drug classes in hypertensive patients with hypercholesterolemia or CAD. Data sources include a literature search for publications on the use of a statin combined with various antihypertensive drugs in patients with hypertension and hypercholesterolemia or stable CAD. Hypercholesterolemia and hypertension constitute major physiological risk factors of ischemic heart disease. Current guidelines recommend a global approach to risk management, using agents that address as many risk factors as possible. Dual combination therapies are an important component of guideline-recommended therapy in hypertension. Our review of the literature indicates that triple therapy with a statin, ACE inhibitor, and CCB is associated with a significant reduction in major cardiovascular events. For example, a post hoc analysis in 1056 patients with stable CAD participating in the EUROPA trial indicated that the addition of perindopril to a CCB and a lipid-lowering agent was associated with a 46 % reduction in the composite of cardiovascular death, myocardial infarction, and resuscitated cardiac arrest (p = 0.023). In addition, single pill formulations are known to result in better adherence to the treatment. Single-pill formulations that combine a statin, an ACE inhibitor, and a CCB appear to offer an effective approach to the management of global cardiovascular risk. PMID:27256435

  20. In silico analysis suggests differential response to bevacizumab and radiation combination therapy in newly diagnosed glioblastoma

    PubMed Central

    Hawkins-Daarud, Andrea; Rockne, Russell; Corwin, David; Anderson, Alexander R. A.; Kinahan, Paul; Swanson, Kristin R.

    2015-01-01

    Recently, two phase III studies of bevacizumab, an anti-angiogenic, for newly diagnosed glioblastoma (GBM) patients were released. While they were unable to statistically significantly demonstrate that bevacizumab in combination with other therapies increases the overall survival of GBM patients, there remains a question of potential benefits for subpopulations of patients. We use a mathematical model of GBM growth to investigate differential benefits of combining surgical resection, radiation and bevacizumab across observed tumour growth kinetics. The differential hypoxic burden after gross total resection (GTR) was assessed along with the change in radiation cell kill from bevacizumab-induced tissue re-normalization when starting therapy for tumours at different diagnostic sizes. Depending on the tumour size at the time of treatment, our model predicted that GTR would remove a variable portion of the hypoxic burden ranging from 11% to 99.99%. Further, our model predicted that the combination of bevacizumab with radiation resulted in an additional cell kill ranging from 2.6×107 to 1.1×1010 cells. By considering the outcomes given individual tumour kinetics, our results indicate that the subpopulation of patients who would receive the greatest benefit from bevacizumab and radiation combination therapy are those with large, aggressive tumours and who are not eligible for GTR. PMID:26202682

  1. Combining Targeted Therapy With Immunotherapy in BRAF-Mutant Melanoma: Promise and Challenges

    PubMed Central

    Hu-Lieskovan, Siwen; Robert, Lidia; Homet Moreno, Blanca; Ribas, Antoni

    2014-01-01

    Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAFV600-mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAFV600 driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non–BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials. PMID:24958825

  2. Immunotherapy regimens for combination with photodynamic therapy aimed at eradication of solid cancers

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen

    2000-06-01

    Due to inflammatory/immune responses elicited by photodynamic therapy (PDT), this modality is particularly suitable in combination with various forms of immunotherapy for an improved therapeutic gain. A wide variety of approaches that may be applicable in this context include those focusing on amplifying the activity of particular immune cell types (neutrophils, macrophages, dendritic cells, natural killer cells, helper or cytotoxic T lymphocytes). Another type of approach is to focus on a specific phase of immune response development, which comprises the activation of non-specific inflammatory immune effectors, immune recognition, immune memory, immune rejection, or blocking of immune suppression. These different strategies call for a variety of immunotherapeutic protocols to be employed in combination with PDT. These include treatments such as: (1) non-specific immunoactivators (e.g. bacterial vaccines), (2) specific immune agents (cytokines, or other activating factors), (3) adoptive immunotherapy treatments (transfer of dendritic cells, tumor-sensitized T lymphocytes or natural killer cells), or (4) their combinations. Techniques of gene therapy employed in some of these protocols offer novel opportunities for securing a potent and persistent immune activity. Using PDT and immunotherapy represents an attractive combination for cancer therapy that is capable of eradicating both localized and disseminated malignant lesions.

  3. Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance

    PubMed Central

    Khdair, Ayman; Chen, Di; Patil, Yogesh; Ma, Linan; Dou, Q. Ping; Shekhar, Malathy P.V.; Panyam, Jayanth

    2013-01-01

    Tumor drug resistance significantly limits the success of chemotherapy in the clinic. Tumor cells utilize multiple mechanisms to prevent the accumulation of anticancer drugs at their intracellular site of action. In this study, we investigated the anticancer efficacy of doxorubicin in combination with photodynamic therapy using methylene blue in a drug-resistant mouse tumor model. Surfactant-polymer hybrid nanoparticles formulated using an anionic surfactant, Aerosol-OT™ (AOT), and a naturally occurring polysaccharide polymer, sodium alginate, were used for synchronized delivery of the two drugs. Balb/c mice bearing syngeneic JC tumors (mammary adenocarcinoma) were used as a drug-resistant tumor model. Nanoparticle-mediated combination therapy significantly inhibited tumor growth and improved animal survival. Nanoparticle-mediated combination treatment resulted in enhanced tumor accumulation of both doxorubicin and methylene blue, significant inhibition of tumor cell proliferation, and increased induction of apoptosis. These data suggest that nanoparticle-mediated combination chemotherapy and photodynamic therapy using doxorubicin and methylene blue has significant therapeutic potential against drug-resistant tumors. PMID:19751777

  4. Histone deacetylases: Targets for antifungal drug development

    PubMed Central

    Kmetzsch, Livia

    2015-01-01

    The interaction of pathogens and its hosts causes a drastic change in the transcriptional landscape in both cells. Among the several mechanisms of gene regulation, transcriptional initiation is probably the main point. In such scenario, the access of transcriptional machinery to promoter is highly regulated by post-translational modification of histones, such as acetylation, phosphorylation and others. Inhibition of histone deacetylases is able to reduce fungal pathogens fitness during infection and, therefore, is currently being considered for the development of new antifungal therapy strategies. PMID:26151486

  5. Mechanisms of echinocandin antifungal drug resistance

    PubMed Central

    Perlin, David S.

    2015-01-01

    Fungal infections due to Candida and Aspergillus species cause extensive morbidity and mortality, especially among immunosuppressed patients, and antifungal therapy is critical to patient management. Yet only a few drug classes are available to treat invasive fungal diseases, and this problem is compounded by the emergence of antifungal resistance. Echinocandin drugs are the preferred choice to treat candidiasis. They are the first cell wall–active agents and target the fungal-specific enzyme glucan synthase, which catalyzes the biosynthesis of β-1,3-glucan, a key cell wall polymer. Therapeutic failures occur rarely among common Candida species, with the exception of Candida glabrata, which are frequently multidrug resistant. Echinocandin resistance in susceptible species is always acquired during therapy. The mechanism of resistance involves amino acid changes in hot-spot regions of Fks subunits of glucan synthase, which decrease the sensitivity of the enzyme to drug. Cellular stress response pathways lead to drug adaptation, which promote the formation of resistant fks strains. Clinical factors promoting echinocandin resistance include empiric therapy, prophylaxis, gastrointestinal reservoirs, and intra-abdominal infections. A better understanding of the echinocandin resistance mechanism, along with cellular and clinical factors promoting resistance, will promote more effective strategies to overcome and prevent echinocandin resistance. PMID:26190298

  6. New potential chemotherapy for ovarian cancer - Combined therapy with WP 631 and epothilone B.

    PubMed

    Bukowska, Barbara; Rogalska, Aneta; Marczak, Agnieszka

    2016-04-15

    Despite more modern therapeutics approaches and the use of new drugs for chemotherapy, patients with ovarian cancer still have poor prognosis and therefore, new strategies for its cure are highly needed. One of the promising ways is combined therapy, which has many advantages as minimizing drug resistance, enhancing efficacy of treatment, and reducing toxicity. Combined therapy has rich and successful history in the field of ovarian cancer treatment. Currently use therapy is usually based on platinum-containing agent (carboplatin or cisplatin) and a member of taxanes (paclitaxel or docetaxel). In the mid-2000s this standard regimen has been expanded with bevacizumab, monoclonal antibody directed to Vascular Endothelial Growth Factor (VEGF). Another drug combination with promising perspectives is WP 631 given together with epothilone B (Epo B). WP 631 is a bisanthracycline composed of two molecules of daunorubicin linked with a p-xylenyl linker. Epo B is a 16-membered macrolide manifesting similar mechanism of action to taxanes. Their effectiveness against ovarian cancer as single agents is well established. However, the combination of WP 631 and Epo B appeared to act synergistically, meaning that it is much more potent than the single drugs. The mechanism lying under its efficacy includes disturbing essential cell cycle-regulating proteins leading to mitotic slippage and following apoptosis, as well as affecting EpCAM and HMGB1 expression. In this article, we summarized the current state of knowledge regarding combined therapy based on WP 631 and Epo B as a potential way of ovarian cancer treatment. PMID:26944437

  7. [A case of HER2-positive metastatic breast cancer responding to trastuzumab plus gemcitabine combination therapy].

    PubMed

    Sugie, Tomoharu; Nagai, Toshihiro; Ohgaki, Kazuhisa

    2008-04-01

    A 60-year-old woman was admitted to the hospital with left thigh pain. She had undergone mastectomy and axillary lymph node dissection for right breast cancer (T3N2M0) five years and two months earlier. The pathological diagnosis then was invasive ductal carcinoma with axillaryly mph node metastases. Hormone receptors and HER2 status were negative and positive (3+), respectively. The patient received adjuvant chemotherapy and radiotherapy, but bone metastases appeared 18 months after surgery. Although trastuzumab-combination chemotherapy with taxane and/or capecitabine was given, bone metastases in thoracic vertebra resulted in incomplete paralysis in both legs. She underwent thoraco-lumbar vertebral fixation 10 months before admission. A PET/CT revealed multiple bone metastases in the left femur as well as vertebrae, and CEA rose markedly. She received radiotherapy and trastuzumab monotherapy in addition to bisphosphonate. Temporarily, CEA decreased, but because recurrence nests were recognized in the supraclavicle and mediastinum after the eight-month treatment, trastuzumab monotherapy was followed by trastuzumab plus vinorelbine combined therapy. This regimen markedly reduced CEA after three months, but it rose again over the following three months. As S-1-combined therapy was not effective, trastuzumab+gemcitabine (1 g/week and two weeks on/one week off) combined therapy was started. CEA decreased markedly after 4 cycles, and FDG accumulation in the recurrence region was markedly improved. The adverse event during this treatment was minor, and PS was sufficiently maintained. These results suggest that trastuzumab plus gemcitabine combination therapy is effective for HER2-positive metastatic breast cancer. PMID:18408445

  8. Targeted Therapy of Cancer Using Photodynamic Therapy in Combination with Multi-faceted Anti-Tumor Modalities

    PubMed Central

    Olivo, Malini; Bhuvaneswari, Ramaswamy; Lucky, Sasidharan Swarnalatha; Dendukuri, Nagamani; Thong, Patricia Soo-Ping

    2010-01-01

    Photodynamic therapy (PDT) has emerged as one of the important therapeutic options in the management of cancer and other diseases. PDT involves a tumor-localized photosensitizer (PS), which when appropriately illuminated by visible light converts oxygen into cytotoxic reactive oxygen species (ROS), that attack key structural entities within the targeted cells, ultimately resulting in necrosis or apoptosis. Though PDT is a selective modality, it can be further enhanced by combining other targeted therapeutic strategies that include the use of synthetic peptides and nanoparticles for selective delivery of photosensitizers. Another potentially promising strategy is the application of targeted therapeutics that exploit a myriad of critical pathways involved in tumorigenesis and metastasis. Vascular disrupting agents that eradicate tumor vasculature during PDT and anti-angiogenic agents that targets specific molecular pathways and prevent the formation of new blood vessels are novel therapeutic approaches that have been shown to improve treatment outcome. In addition to the well-documented mechanisms of direct cell killing and damage to the tumor vasculature, PDT can also activate the body’s immune response against tumors. Numerous pre-clinical studies and clinical observations have demonstrated the immuno-stimulatory capability of PDT. Herein, we aim to integrate the most important findings with regard to the combination of PDT and other novel targeted therapy approaches, detailing its potential in cancer photomedicine.

  9. Can We Predict Individual Combined Benefit and Harm of Therapy? Warfarin Therapy for Atrial Fibrillation as a Test Case

    PubMed Central

    Li, Guowei; Thabane, Lehana; Delate, Thomas; Witt, Daniel M.; Levine, Mitchell A. H.; Cheng, Ji; Holbrook, Anne

    2016-01-01

    Objectives To construct and validate a prediction model for individual combined benefit and harm outcomes (stroke with no major bleeding, major bleeding with no stroke, neither event, or both) in patients with atrial fibrillation (AF) with and without warfarin therapy. Methods Using the Kaiser Permanente Colorado databases, we included patients newly diagnosed with AF between January 1, 2005 and December 31, 2012 for model construction and validation. The primary outcome was a prediction model of composite of stroke or major bleeding using polytomous logistic regression (PLR) modelling. The secondary outcome was a prediction model of all-cause mortality using the Cox regression modelling. Results We included 9074 patients with 4537 and 4537 warfarin users and non-users, respectively. In the derivation cohort (n = 4632), there were 136 strokes (2.94%), 280 major bleedings (6.04%) and 1194 deaths (25.78%) occurred. In the prediction models, warfarin use was not significantly associated with risk of stroke, but increased the risk of major bleeding and decreased the risk of death. Both the PLR and Cox models were robust, internally and externally validated, and with acceptable model performances. Conclusions In this study, we introduce a new methodology for predicting individual combined benefit and harm outcomes associated with warfarin therapy for patients with AF. Should this approach be validated in other patient populations, it has potential advantages over existing risk stratification approaches as a patient-physician aid for shared decision-making PMID:27513986

  10. Cost-Effectiveness Analysis of Combination Therapies for Visceral Leishmaniasis in the Indian Subcontinent

    PubMed Central

    Meheus, Filip; Balasegaram, Manica; Olliaro, Piero; Sundar, Shyam; Rijal, Suman; Faiz, Md. Abul; Boelaert, Marleen

    2010-01-01

    Background Visceral leishmaniasis is a systemic parasitic disease that is fatal unless treated. We assessed the cost and cost-effectiveness of alternative strategies for the treatment of visceral leishmaniasis in the Indian subcontinent. In particular we examined whether combination therapies are a cost-effective alternative compared to monotherapies. Methods and Findings We assessed the cost-effectiveness of all possible mono- and combination therapies for the treatment of visceral leishmaniasis in the Indian subcontinent (India, Nepal and Bangladesh) from a societal perspective using a decision analytical model based on a decision tree. Primary data collected in each country was combined with data from the literature and an expert poll (Delphi method). The cost per patient treated and average and incremental cost-effectiveness ratios expressed as cost per death averted were calculated. Extensive sensitivity analysis was done to evaluate the robustness of our estimations and conclusions. With a cost of US$92 per death averted, the combination miltefosine-paromomycin was the most cost-effective treatment strategy. The next best alternative was a combination of liposomal amphotericin B with paromomycin with an incremental cost-effectiveness of $652 per death averted. All other strategies were dominated with the exception of a single dose of 10mg per kg of liposomal amphotericin B. While strategies based on liposomal amphotericin B (AmBisome) were found to be the most effective, its current drug cost of US$20 per vial resulted in a higher average cost-effectiveness. Sensitivity analysis showed the conclusion to be robust to variations in the input parameters over their plausible range. Conclusions Combination treatments are a cost-effective alternative to current monotherapy for VL. Given their expected impact on the emergence of drug resistance, a switch to combination therapy should be considered once final results from clinical trials are available. PMID:20838649

  11. Fixed-dose combination therapy with dutasteride and tamsulosin in the management of benign prostatic hyperplasia.

    PubMed

    Dimitropoulos, Konstantinos; Gravas, Stavros

    2016-02-01

    Despite their multifactorial etiology, male lower urinary tract symptoms (LUTS) have been traditionally associated with benign prostatic enlargement (BPE) because of benign prostatic hyperplasia (BPH). Several pharmaceutical therapies have been used to manage LUTS, with α1-adrenergic receptor antagonists (α1-blockers) and inhibitors of 5α-reductase (5α-RIs) representing the most commonly prescribed agents currently in use for LUTS treatment. Due to their different modes of action, combined use of α1-blockers and 5α-RIs has been proven to offer more optimal control of symptoms and better associated quality of life, even though higher rates of adverse events have been shown. Following previous studies on the separate administration of dutasteride and tamsulosin, a fixed-dose combination capsule of tamsulosin 0.4 mg and dutasteride 0.5 mg has been approved and released for clinical use in men with BPH. The present review aims to discuss the rationale behind the combined use of tamsulosin and dutasteride for treating male LUTS, and to present the available data on the role of combination therapy in the management of BPH-related symptoms in terms of efficacy and safety. Special attention is given to the impact of combination treatment on the prevention of clinical progression of BPH. Cost-effectiveness of fixed-dose combination and patients' adherence to treatment are also discussed. PMID:26834837

  12. Fixed-dose combination therapy with dutasteride and tamsulosin in the management of benign prostatic hyperplasia

    PubMed Central

    Dimitropoulos, Konstantinos; Gravas, Stavros

    2016-01-01

    Despite their multifactorial etiology, male lower urinary tract symptoms (LUTS) have been traditionally associated with benign prostatic enlargement (BPE) because of benign prostatic hyperplasia (BPH). Several pharmaceutical therapies have been used to manage LUTS, with α1-adrenergic receptor antagonists (α1-blockers) and inhibitors of 5α-reductase (5α-RIs) representing the most commonly prescribed agents currently in use for LUTS treatment. Due to their different modes of action, combined use of α1-blockers and 5α-RIs has been proven to offer more optimal control of symptoms and better associated quality of life, even though higher rates of adverse events have been shown. Following previous studies on the separate administration of dutasteride and tamsulosin, a fixed-dose combination capsule of tamsulosin 0.4 mg and dutasteride 0.5 mg has been approved and released for clinical use in men with BPH. The present review aims to discuss the rationale behind the combined use of tamsulosin and dutasteride for treating male LUTS, and to present the available data on the role of combination therapy in the management of BPH-related symptoms in terms of efficacy and safety. Special attention is given to the impact of combination treatment on the prevention of clinical progression of BPH. Cost-effectiveness of fixed-dose combination and patients’ adherence to treatment are also discussed. PMID:26834837

  13. [Estimation of efficiency of anti-helicobacter therapy in patients with a chronic pancreatitis combined with an erosive gastropathy].

    PubMed

    Koval', V Iu; Kotsiubniak, L A; Moskal', O M

    2014-01-01

    SUMMARY Eradikacion therapy at patients with chronic pancreatitis and combined with Helicobacter associated erosive gastropathy in a month after treatment appeared successful at 75% patients which accepted therapy of the first line--pantoprazol, amoksicillin, klaritromicin. Inclusion in antihelicobakter therapy of seknidazol in place of klaritromicin rendered a positive antihelicobakter effect at 85% patients with a chronic pancreatitis. Therapy with the use of seknidazole was better tolerated. Application of synbiotik laktiale on a background antihelicobakter therapy helped normalizations of chair and was comfortable in application, which is important in the treatment of patients. Application of synbiotika laktiale on a background antigelikobakter therapy is helped in the improvement of clinical effect. PMID:25796863

  14. Chalcone derivatives as potential antifungal agents: Synthesis, and antifungal activity.

    PubMed

    Gupta, Deepa; Jain, D K

    2015-01-01

    Much research has been carried out with the aim to discover the therapeutic values of chalcone derivatives. Chalcones possess wide range of pharmacological activity such as antibacterial, antimalarial, antiprotozoal, antitubercular, anticancer, and antifungal agents etc. The presence of reactive α,β-unsaturated keto group in chalcones is found to be responsible for their biological activity. The rapid developments of resistance to antifungal agents, led to design, and synthesize the new antifungal agents. The derivatives of chalcones were prepared using Claisen-Schmidt condensation scheme with appropriate tetralone and aldehyde derivatives. Ten derivatives were synthesized and were biologically screened for antifungal activity. The newly synthesized derivatives of chalcone showed antifungal activity against fungal species, Microsporum gypseum. The results so obtained were superior or comparable to ketoconazole. It was observed that none of the compounds tested showed positive results for fungi Candida albicans nor against fungi Aspergillus niger. Chalcone derivatives showed inhibitory effect against M. gypseum species of fungus. It was found that among the chalcone derivatives so synthesized, two of them, that is, 4-chloro derivative, and unsubstituted derivative of chalcone showed antifungal activity superior to ketoconazole. Thus, these can be the potential new molecule as antifungal agent. PMID:26317075

  15. Percutaneous Drainage Combined with Hyperbaric Oxygen Therapy for Pyogenic Spondylitis with Iliopsoas Abscess

    PubMed Central

    Koga, Hiroaki; Komiya, Setsuro

    2014-01-01

    Study Design A retrospective study. Purpose The purpose of this study was to evaluate outcomes in patients with pyogenic spondylitis accompanied by iliopsoas abscess who were treated by percutaneous drainage combined with hyperbaric oxygen (HBO) therapy. Overview of Literature To the best of our knowledge, there have been no previous reports of the use of percutaneous drainage combined with HBO therapy for the treatment of this condition. Methods Twenty-three patients (13 men, 10 women; mean age, 69.0 years; range, 45-85 years) were treated with percutaneous drainage combined with HBO therapy in addition to commonly used conservative therapy. Mean follow-up duration was 27.7 months (range, 12-48 months). Clinical outcomes and imaging examinations were retrospectively investigated. Results Symptoms such as low back pain, radicular pain, and hip pain resolved in all patients immediately after treatment. Mean time from the start of treatment to the return of C-reactive protein levels to normal or baseline values recorded before the onset of spondylitis was 28.3 days (range, 8-56 days). In the final set of follow-up radiographic studies, all patients were free from progressive destructive changes. Follow-up magnetic resonance images or computed tomography with contrast enhancement confirmed the disappearance or near-total resolution of the iliopsoas abscess cavity with healing of the pyogenic spondylitis in all 23 patients. No recurrences were observed during follow-up. Conclusions The present study suggests that patients with pyogenic spondylitis accompanied by iliopsoas abscess can be cured without a prolonged period of therapy or recurrence using this treatment. PMID:24967038

  16. Novel Microdilution Method to Assess Double and Triple Antibiotic Combination Therapy In Vitro

    PubMed Central

    El-Azizi, Mohamed

    2016-01-01

    An in vitro microdilution method was developed to assess double and triple combinations of antibiotics. Five antibiotics including ciprofloxacin, amikacin, ceftazidime, piperacillin, and imipenem were tested against 10 clinical isolates of Pseudomonas aeruginosa. Each isolate was tested against ten double and nine triple combinations of the antibiotics. A 96-well plate was used to test three antibiotics, each one alone and in double and triple combinations against each isolate. The minimum bacteriostatic and bactericidal concentrations in combination were determined with respect to the most potent antibiotic. An Interaction Code (IC) was generated for each combination, where a numerical value was designated based on the 2-fold increase or decrease in the MICs with respect to the most potent antibiotic. The results of the combinations were verified by time-kill assay at constant concentrations of the antibiotics and in a chemostat. Only 13% of the double combinations were synergistic, whereas 5% showed antagonism. Forty-three percent of the triple combinations were synergistic with no antagonism observed, and 100% synergism was observed in combination of ciprofloxacin, amikacin, and ceftazidime. The presented protocol is simple and fast and can help the clinicians in the early selection of the effective antibiotic therapy for treatment of severe infections. PMID:27195009

  17. Update on azole antifungals.

    PubMed

    Zonios, Dimitrios I; Bennett, John E

    2008-04-01

    This is a comprehensive, clinically oriented review of the four commercially available triazoles: fluconazole, itraconazole, voriconazole, and posaconazole. Emphasis is placed in pharmacology, drug interactions, adverse events, antifungal activity, and the evolving perspective of their clinical use. Key clinical trials are briefly discussed, and specific drug indications summarized. Fluconazole remains a valuable low-cost choice for the treatment of various fungal infections, including candidiasis and cryptococcosis. It has relatively few drug interactions and is safe but lacks activity against filamentous fungi. The use of itraconazole is historically plagued by erratic bioavailability of the oral capsule, improved with the oral solution. Drug interactions are numerous. Itraconazole exhibits significant activity against Aspergillus and the endemic fungi. Voriconazole has revolutionized the treatment of aspergillosis in severely immunocompromised patients, but its use is compromised by complicated pharmacokinetics, notable drug interactions, and relatively significant adverse events. Finally, posaconazole is the last addition to the azole armamentarium with extended antifungal spectrum, significant activity against the zygomycetes, and, apparently, optimal safety profile. Posaconazole has a significant role for the prophylaxis of invasive fungal infections in severely immunocompromised patients. Multiple daily dosing, a need for fatty foods for absorption, and absence of an intravenous formulation restrict its use to selected populations. PMID:18366001

  18. In vitro therapeutic effect of PDT combined with VEGF-A gene therapy

    NASA Astrophysics Data System (ADS)

    Lecaros, Rumwald Leo G.; Huang, Leaf; Hsu, Yih-Chih

    2014-02-01

    Vascular endothelial growth factor A (VEGF-A), commonly known as VEGF, is one of the primary factors that affect tumor angiogenesis. It was found to be expressed in cancer cell lines including oral squamous cell carcinoma. Photodynamic therapy (PDT) is a novel therapeutic modality to treat cancer by using a photosensitizer which is activated by a light source to produce reactive oxygen species and mediates oxygen-independent hypoxic conditions to tumor. Another emerging treatment to cure cancer is the use of interference RNA (e.g. siRNA) to silence a specific mRNA sequence. VEGF-A was found to be expressed in oral squamous cell carcinoma and overexpressed after 24 hour post-PDT by Western blot analysis. Cell viability was found to decrease at 25 nM of transfected VEGF-A siRNA. In vitro combined therapy of PDT and VEGF-A siRNA showed better response as compared with PDT and gene therapy alone. The results suggest that PDT combined with targeted gene therapy has a potential mean to achieve better therapeutic outcome.

  19. Smart micelle@polydopamine core-shell nanoparticles for highly effective chemo-photothermal combination therapy.

    PubMed

    Zhang, Ruirui; Su, Shishuai; Hu, Kelei; Shao, Leihou; Deng, Xiongwei; Sheng, Wang; Wu, Yan

    2015-12-14

    In this investigation, we have designed and synthesized a novel core-shell polymer nanoparticle system for highly effective chemo-photothermal combination therapy. A nanoscale DSPE-PEG micelle encapsulating doxorubicin (Dox-M) was designed as a core, and then modified by a polydopamine (PDA) shell for photothermal therapy and bortezomib (Btz) administration (Dox-M@PDA-Btz). The facile conjugation of Btz to the catechol-containing PDA shell can form a reversible pH-sensitive boronic acid-catechol conjugate to create a stimuli-responsive drug carrier system. As expected, the micelle@PDA core-shell nanoparticles exhibited satisfactory photothermal efficiency, which has potential for thermal ablation of malignant tissues. In addition, on account of the PDA modification, both Dox and Btz release processes were pH-dependent and NIR-dependent. Both in vitro and in vivo studies illustrated that the Dox-M@PDA-Btz nanoparticles coupled with laser irradiation could enhance the cytotoxicity, and thus combinational therapy efficacy was achieved when integrating Dox, Btz, and PDA into a single nanoplatform. Altogether, our current study indicated that the micelle@polydopamine core-shell nanoparticles could be applied for NIR/pH-responsive sustained-release and synergized chemo-photothermal therapy for breast cancer. PMID:26556382

  20. Combination of photodynamic and ultrasonic therapy for treatment of infected wounds in animal model

    NASA Astrophysics Data System (ADS)

    Menyaev, Yulian A.; Zharov, Vladimir P.

    2006-02-01

    One of the important problems of modern medicine is treatment of infected wounds. There are many diversified expedients of treatment, but none of them obey the modern physician completely. The aim of this study is to develop and test a new combined method of photodynamic ultrasonic therapy (PDUST) for treatment of infected wounds with focus on experimental trials. PDUST is based on a combination of two methods: photodynamic (PD) therapy (PDT) with photosensitizer and low frequency ultrasonic (US) therapy with antibiotic as tools for treatment of wounds and effectively killing bacteria. The main parameters are: US frequency - 26.5 kHz; US tip elongation - 40+/-20 μm wavelength of light emitting diodes (LED) array - 660+/-10 nm; light intensity on biotissue surface - 1-2 mW/cm2; photosensitizer - an aluminum disulfonated phtalocyanine dissolved in a physiological solution in concentration 10 mg/l. The experiments were carried out with 70 male chinchilla rabbits divided into 7 groups, thus the dynamics of wounds healing were studied in different modes of PDUST. The PD and US methods supplement each other and in conjunction provide additive and especially synergetic effects. The experimental data demonstrated advantages of new technology in comparison with conventional methods in cases of treatment of extended suppurative inflammatory and profound wounds. The more detailed study of PDUST method's mechanism, which is based on low intensity of LED light, PD therapy and US influence is required.

  1. [Combined telaprevir plus ribavirin and pegylated interferon therapy for patients with chronic hepatitis C].

    PubMed

    Mochida, Satoshi

    2015-02-01

    Antiviral efficacy of combined Peg-IFN-α2b plus ribavirin therapy was improved by the addition of telaprevir, a first-generation NS3/4A protease inhibitor, in patients with chronic hepatitis due to HCV infection. A multicenter prospective study revealed that the triple therapy with telaprevir administered according to an algorithm based on the drug adherence, IL28B polymorphism and viral response yielded a high SVR rate through attenuation of viral relapse by prolonged ribavirin/Peg-IFN-α2b administration. Such triple therapy, however, may provoke various adverse effects potentially necessitating treatment discontinuation; dermatitis, hemolytic anemia, hyperuricemia, renal impairment and retinopathy. Thus, the role of telaprevir as a direct-acting antiviral agent used in combination with Peg-IFN and ribavirin for patients with genotype 1b HCV infection was replaced by simeprevir, a second-generation NS3/4A protease inhibitor. However, telaprevir still plays an important role in the treatment for patients with genotypes 2a and 2b HCV infection as well as those showing viral breakthrough after antiviral therapies using second-generation NS3/4A protease inhibitors. PMID:25764680

  2. Benign Prostatic Hyperplasia - An economic assessment of fixed combination therapy based on a literature review.

    PubMed

    Messina, Roberto; Mirone, Vincenzo

    2015-09-01

    FederAnziani Senior Italia and SIU - Italian Society of Urology - have decided to work together to draft a document focussing on Benign Prostatic Hyperplasia (BPH), and to stress the importance of adherence with pharmacological treatment in this setting, from both a scientific and a patient standpoint. Starting from a literature search, the two associations analysed to what extent an increase in treatment adherence amongst these patients influences hospital savings and to what extent therapy persistence levels are affected by monotherapy rather than free drug combinations. These estimates were performed only on patients taking medicinal products belonging to the 5 α-reductase inhibitors (5ARI) class that, although not indispensable, are the compounds that bring the greatest benefits, especially in the elderly and for which we know that every additional 30 days of therapy reduced the likelihood of acute urinary retention (AUR) and surgery by 14% and 11% respectively *. The results show that the use of fixed combination therapy would involve an increase in persistence due to the lower rate of patients abandoning treatment over time. Each 30 day-increment of 5ARI therapy, i.e. for an expenditure of 10.6 million euros extra per year for 5ARI medication, savings of approximately 24.3 million euros in hospital costs could be achieved. PMID:26428637

  3. "Smart" nickel oxide based core-shell nanoparticles for combined chemo and photodynamic cancer therapy.

    PubMed

    Bano, Shazia; Nazir, Samina; Munir, Saeeda; AlAjmi, Mohamed Fahad; Afzal, Muhammad; Mazhar, Kehkashan

    2016-01-01

    We report "smart" nickel oxide nanoparticles (NOPs) as multimodal cancer therapy agent. Water-dispersible and light-sensitive NiO core was synthesized with folic acid (FA) connected bovine serum albumin (BSA) shell on entrapped doxorubicin (DOX). The entrapped drug from NOP-DOX@BSA-FA was released in a sustained way (64 hours, pH=5.5, dark conditions) while a robust release was found under red light exposure (in 1/2 hour under λmax=655 nm, 50 mW/cm(2), at pH=5.5). The cell viability, thiobarbituric acid reactive substances and diphenylisobenzofuran assays conducted under light and dark conditions revealed a high photodynamic therapy potential of our construct. Furthermore, we found that the combined effect of DOX and NOPs from NOP-DOX@BSA-FA resulted in cell death approximately eightfold high compared to free DOX. We propose that NOP-DOX@BSA-FA is a potential photodynamic therapy agent and a collective drug delivery system for the systemic administration of cancer chemotherapeutics resulting in combination therapy. PMID:27471383

  4. Technologies and combination therapies for enhancing movement training for people with a disability

    PubMed Central

    2012-01-01

    There has been a dramatic increase over the last decade in research on technologies for enhancing movement training and exercise for people with a disability. This paper reviews some of the recent developments in this area, using examples from a National Science Foundation initiated study of mobility research projects in Europe to illustrate important themes and key directions for future research. This paper also reviews several recent studies aimed at combining movement training with plasticity or regeneration therapies, again drawing in part from European research examples. Such combination therapies will likely involve complex interactions with motor training that must be understood in order to achieve the goal of eliminating severe motor impairment. PMID:22463132

  5. Effect of hyperbaric oxygen therapy combined with autologous platelet concentrate applied in rabbit fibula fraction healing

    PubMed Central

    Neves, Paulo César Fagundes; de Campos Vieira Abib, Simone; Neves, Rogério Fagundes; Pircchio, Oronzo; Saad, Karen Ruggeri; Saad, Paulo Fernandes; Simões, Ricardo Santos; Moreira, Marcia Bento; de Souza Laurino, Cristiano Frota

    2013-01-01

    OBJECTIVES: The purpose is to study the effects of hyperbaric oxygen therapy and autologous platelet concentrates in healing the fibula bone of rabbits after induced fractures. METHODS: A total of 128 male New Zealand albino rabbits, between 6–8 months old, were subjected to a total osteotomy of the proximal portion of the right fibula. After surgery, the animals were divided into four groups (n = 32 each): control group, in which animals were subjected to osteotomy; autologous platelet concentrate group, in which animals were subjected to osteotomy and autologous platelet concentrate applied at the fracture site; hyperbaric oxygen group, in which animals were subjected to osteotomy and 9 consecutive daily hyperbaric oxygen therapy sessions; and autologous platelet concentrate and hyperbaric oxygen group, in which animals were subjected to osteotomy, autologous platelet concentrate applied at the fracture site, and 9 consecutive daily hyperbaric oxygen therapy sessions. Each group was divided into 4 subgroups according to a pre-determined euthanasia time points: 2, 4, 6, and 8 weeks postoperative. After euthanasia at a specific time point, the fibula containing the osseous callus was prepared histologically and stained with hematoxylin and eosin or picrosirius red. RESULTS: Autologous platelet concentrates and hyperbaric oxygen therapy, applied together or separately, increased the rate of bone healing compared with the control group. CONCLUSION: Hyperbaric oxygen therapy and autologous platelet concentrate combined increased the rate of bone healing in this experimental model. PMID:24141841

  6. Mediated Moderation in Combined Cognitive Behavioral Therapy Versus Component Treatments for Generalized Anxiety Disorder

    PubMed Central

    Newman, Michelle G.; Fisher, Aaron J.

    2015-01-01

    Objective This study examined (a) duration of generalized anxiety disorder (GAD) as a moderator of cognitive behavioral therapy (CBT) versus its components (cognitive therapy and self-control desensitization) and (b) increases in dynamic flexibility of anxious symptoms during the course of psychotherapy as a mediator of this moderation. Degree of dynamic flexibility in daily symptoms was quantified as the inverse of spectral power due to daily to intradaily oscillations in four-times-daily diary data (Fisher, Newman, & Molenaar, 2011). Method This was a secondary analysis of the data of Borkovec, Newman, Pincus, and Lytle (2002). Seventy-six participants with a principle diagnosis of GAD were assigned randomly to combined CBT (n = 24), cognitive therapy (n = 25), or self-control desensitization (n = 27). Results Duration of GAD moderated outcome such that those with longer duration showed greater reliable change from component treatments than they showed from CBT, whereas those with shorter duration fared better in response to CBT. Decreasing predictability in daily and intradaily oscillations of anxiety symptoms during therapy reflected less rigidity and more flexible responding. Increases in flexibility over the course of therapy fully mediated the moderating effect of GAD duration on condition, indicating a mediated moderation process. Conclusions Individuals with longer duration of GAD may respond better to more focused treatments, whereas those with shorter duration of GAD may respond better to a treatment that offers more coping strategies. Importantly, the mechanism by which this moderation occurs appears to be the establishment of flexible responding during treatment. PMID:23398493

  7. [Liver Atrophy and Failure Associated with Paclitaxel and Bevacizumab Combination Therapy for Metastatic Breast Cancer].

    PubMed

    Yamamoto, Mari; Ikeda, Masahiko; Kubo, Shinichiro; Tsukioki, Takahiro; Nakamoto, Shougo

    2016-07-01

    We managed 6 cases of severe liver atrophy and failure associated with paclitaxel and bevacizumab combination therapy (PB therapy)for HER2-negative metastatic breast cancer. In this case-controlstudy, we examined the records of these 6 patients to investigate past treatment, medication history, and degree of atrophy, and compared their data with that of 67 patients without liver atrophy. The degree of the liver atrophy used SYNAPSE VINCENT®of the image analysis software. The results showed that patients with liver atrophy had a longer pretreatment period than those without liver atrophy(33.5 months vs 15.5 months), and they also experienced a longer median time to treatment failure with PB therapy than other patients(11 months vs 6 months). The ratio of individuals presenting with diffuse liver metastasis among patients with liver metastasis was 80% with liver atrophy, compared to 8% without liver atrophy. The degree of liver atrophy was an average of 67%in terms of volume ratio before/after PB therapy(57-82%). The individualwith the greatest extent of liver atrophy died of liver failure, not as a result of breast cancer progression. The direct causal link between bevacizumab and liver atrophy and failure is unclear, but the individuals in this study had a long previous history of treatment, and diffuse liver metastases may develop in patients undergoing long periods of PB therapy, which may also cause liver atrophy; therefore, the possibility of liver failure should be considered in such cases. PMID:27431631

  8. [Helium-neon laser therapy in the combined treatment of unstable stenocardia].

    PubMed

    Korochkin, I M; Kapustina, G M; Babenko, E V; Zhuravleva, N Iu

    1990-01-01

    He-Ne laser therapy included in complex of therapeutic methods for patients with unstable angina pectoris is a highly effective treatment modality; it helps essentially reduce the risk of acute myocardial infarction in these patients. Clinical efficacy of laser therapy is confirmed by its favorable action on hemostasis plasma factors, consisting in reduction of fibrinogen level, normalization of antithrombin-III (AT-III), decrease of the level of soluble fibrinomonomer complexes, this indicating a lowering of the blood coagulation potential. Absence of significant changes in plasminogen level may be an indicator of the nonenzymic route of fibrinogen system activation. Sessions of intravenous laser therapy should be administered 2-3 times a week to unstable angina pectoris patients with low AT-III levels, whereas for patients with initially high or normal AT-III levels combined laser therapy is advisable (4-5 daily invasive procedures and 6-8 skin surface ones on the Zakharyin-Head's zones). Measurements of endogenic anticoagulants is an effective means for monitoring laser therapy in this patient population. PMID:1973307

  9. Role of targeted therapy in combination with surgery in renal cell carcinoma.

    PubMed

    Bex, Axel; Powles, Thomas; Karam, Jose A

    2016-01-01

    Surgical complete resection is the only curative treatment of renal cell carcinoma including patients with locally advanced disease and those with limited metastatic disease. Patients at high risk of recurrence after complete resection might theoretically benefit from adjuvant and neoadjuvant systemic treatment strategies to prolong disease-free survival and ultimately overall survival. Another rationale for using targeted therapy includes downsizing/downstaging of surgically complex locally advanced renal cell carcinoma to facilitate complete resection or primary tumors to allow for nephron-sparing strategies. Unfortunately, a considerable percentage of patients are diagnosed with metastatic disease at first presentation. Although large population-based studies consistently show a survival benefit after cytoreductive nephrectomy in the targeted therapy era, confounding factors preclude definite conclusions for this heterogeneous patient group until ongoing phase III trials are published. Presurgical targeted therapy has been proposed to identify patients with clinical benefit and potentially long-term survival after cytoreductive nephrectomy. Recently, the use of targeted therapy before or after local treatment of metastases has been reported in small retrospective series. The present review revisits the current evidence base of targeted therapy in combination with surgery for the various disease stages in renal cell carcinoma. PMID:26238981

  10. Combination of internal radiation therapy and hyperthermia to treat liver cancer

    SciTech Connect

    Grady, E.D.; McLaren, J.; Auda, S.P.; McGinley, P.H.

    1983-09-01

    Sixteen patients were treated for liver cancer (primary and metastatic) by a combination of internal radiation therapy with intra-arterial yttrium 90 microspheres and regional hyperthermia with electromagnetic radiation. Four patients have their liver disease apparently controlled; two had a partial regression of more than 50%; and two had a partial regression of less than 50%. The complications consisted of one case of radiation hepatitis and one of peptic ulcer.

  11. Apremilast and Secukinumab Combined Therapy in a Patient With Recalcitrant Plaque Psoriasis.

    PubMed

    Rothstein, Brooke E; McQuade, Brianna; Greb, Jacqueline E; Goldminz, Ari M; Gottlieb, Alice B

    2016-05-01

    We report a 67-year-old Caucasian man with a long-term history of recalcitrant plaque psoriasis and psoriatic arthritis who was initiated on a treatment regimen of apremilast and secukinumab after failing multiple topical, photo, and systemic therapies. This combination provided significant skin improvement with minimal drug side effects.

    J Drugs Dermatol. 2016;15(5):648-649. PMID:27168275

  12. Radiofrequency Ablation Therapy Combined with Cementoplasty for Painful Bone Metastases: Initial Experience

    SciTech Connect

    Toyota, Naoyuki Naito, Akira; Kakizawa, Hideaki; Hieda, Masashi; Hirai, Nobuhiko; Tachikake, Toshihiro; Kimura, Tomoki; Fukuda, Hideki; Ito, Katsuhide

    2005-06-15

    The purpose of this study was to assess the efficacy and safety of percutaneous radiofrequency (RF) ablation therapy combined with cementoplasty under computed tomography and fluoroscopic guidance for painful bone metastases. Seventeen adult patients with 23 painful bone metastases underwent RF ablation therapy combined with cementoplasty during a 2-year period. The mean tumor size was 52 x 40 x 59 mm. Initial pain relief, reduction of analgesics, duration of pain relief, recurrence rate of pain, survival rate, and complications were analyzed. The technical success rate was 100%. Initial pain relief was achieved in 100% of patients (n = 17). The mean VAS scores dropped from 63 to 24 (p < 0.001) (n = 8). Analgesic reduction was achieved in 41% (7 out of 17 patients). The mean duration of pain relief was 7.3 months (median: 6 months). Pain recurred in three patients (17.6%) from 2 weeks to 3 months. Eight patients died and 8 patients are still alive (a patient was lost to follow-up). The one-year survival rate was 40% (observation period: 1-30 months). No major complications occurred, but one patient treated with this combined therapy broke his right femur 2 days later. There was transient local pain in most cases, and a hematoma in the psoas muscle (n = 1) and a hematoma at the puncture site (n = 1) occurred as minor complications. Percutaneous RF ablation therapy combined with cementoplasty for painful bone metastases is effective and safe, in particular, for bulky tumors extending to extraosseous regions. A comparison with cementoplasty or RF ablation alone and their long-term efficacies is needed.

  13. Complications of combined radical hysterectomy-postoperative radiation therapy in women with early stage cervical cancer

    SciTech Connect

    Barter, J.F.; Soong, S.J.; Shingleton, H.M.; Hatch, K.D.; Orr, J.W. Jr.

    1989-03-01

    Fifty patients with cervical cancer were treated with radical hysterectomy and lymphadenectomy followed by postoperative radiation therapy for high risk factors (nodal metastases, lymphvascular space invasion, close or involved margins) at the University of Alabama at Birmingham Medical Center from 1969 to 1984. Fifteen (30%) of the patients treated had serious complications, 8 (16%) requiring an operation, and 1 (2%) dying as a result of treatment-related problems. This combined modality approach is associated with significant complications.

  14. [Monotherapy vs. combined therapy in the treatment of multi-drug resistance gramnegative bacteria].

    PubMed

    Martínez-Sagasti, F; González-Gallego, M A; Moneo-González, A

    2016-09-01

    The increasing number of multidrug resistant gram negative bacteria, particularly in patients with risk factors, but in those who suffer community infections as well, is doing more and more difficult to choose the appropriate treatment. The most challenging cases are due to the production of extended-spectrum-β-lactamases (ESBL) and carbapenemases. This mini-review will discuss the adequacy of administering carbapenems when suspecting infections due to ESBL that could be modified after knowing the MIC of the isolated bacteria and the combined therapy in cases of carbapenemases, being particularly important to include a carbapenem and/or colistine at high dosages in this combination. PMID:27608313

  15. The role of chemotherapy in managing chronic lymphocytic leukemia: optimizing combinations with targeted therapy.

    PubMed

    Nastoupil, Loretta J; Sinha, Rajni; Flowers, Christopher R

    2013-09-01

    For many years, alkylating agents were the standard treatment for chronic lymphocytic leukemia (CLL). The advent of purine analogs improved response rates, but not overall survival, and although the monoclonal antibody rituximab is generally active against B-cell malignancies, it has demonstrated limited benefits as monotherapy for the treatment of CLL. However, specific combinations of chemotherapy, antibodies and targeted therapies have demonstrated additive or synergistic activity in CLL cells and deliver substantial clinical benefits. A greater understanding of the actions of chemotherapies and targeted agents on cellular pathways will advance the development of rationally designed combinations corresponding to individual patients' disease profiles. PMID:23919536

  16. Combined concurrent nanoshell loaded macrophage-mediated photothermal and photodynamic therapies

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry; Trinidad, Anthony; Christie, Catherine E.; Peng, Qian; Kwon, Young J.; Madsen, Steen

    2015-02-01

    Macrophages loaded with gold nanoshells (AuNS), that convert near infrared light to heat, can be used as transport vectors for photothermal hyperthermia of tumors. The purpose of this study was to investigate the effects of combined macrophage mediated photothermal therapy (PTT) and PDT on head and neck squamous cell carcinoma (HNSCC). The results provide proof of concept for the use of macrophages as a delivery vector of AuNS for photothermal enhancement of the effects of PDT on squamous cell carcinoma. A significant synergy was demonstrated with combined PDT and PTT compared to each modality applied separately.

  17. Targeted therapy with propranolol and metronomic chemotherapy combination: sustained complete response of a relapsing metastatic angiosarcoma

    PubMed Central

    Banavali, Shripad; Pasquier, Eddy; Andre, Nicolas

    2015-01-01

    We report here a case of a 69-year-old woman with a relapsing metastatic angiosarcoma treated with a combination of metronomic chemotherapy and propranolol. The beta blockers were added since the tumour was positive for betaadrenergic receptor. A complete response was quickly obtained and lasted for 20 months. With this case, the combination of metronomic chemotherapy and propranolol in angiosarcoma warrants additional studies and illustrates the potential of metronomics to generate innovative yet inexpensive targeted therapies for both high-income and low-/middle-income countries. PMID:25624880

  18. Targeted therapy with propranolol and metronomic chemotherapy combination: sustained complete response of a relapsing metastatic angiosarcoma.

    PubMed

    Banavali, Shripad; Pasquier, Eddy; Andre, Nicolas

    2015-01-01

    We report here a case of a 69-year-old woman with a relapsing metastatic angiosarcoma treated with a combination of metronomic chemotherapy and propranolol. The beta blockers were added since the tumour was positive for betaadrenergic receptor. A complete response was quickly obtained and lasted for 20 months. With this case, the combination of metronomic chemotherapy and propranolol in angiosarcoma warrants additional studies and illustrates the potential of metronomics to generate innovative yet inexpensive targeted therapies for both high-income and low-/middle-income countries. PMID:25624880

  19. Calcitriol in Combination Therapy for Prostate Cancer: Pharmacokinetic and Pharmacodynamic Interactions

    PubMed Central

    Ben-Eltriki, Mohamed; Deb, Subrata; Guns, Emma S. Tomlinson

    2016-01-01

    Epidemiological studies indicate that vitamin D insufficiency could have an etiological role in prostate cancer. In addition, calcitriol, used in combination with currently available drugs, has the potential to potentiate their anticancer effects or act synergistically by inhibiting distinct mechanisms involved in prostate cancer growth. Clinical data have not yet provided sufficient evidence to demonstrate benefit of vitamin D due to the limited and underpowered studies that have been published to date. Here, we review the preclinical and clinical studies that describe the activity of calcitriol, applied either alone or in combination and assessed the mechanistic basis of pharmacodynamic and pharmacokinetic interactions with calcitriol. Important considerations for calcitriol use in combination therapy with respect to safety and clinical outcomes have been discussed. Many of these combinations have therapeutic potential for the treatment of several cancer types and it is anticipated that future clinical research will put emphasis on well‑designed clinical trials to establish efficacy. PMID:26918053

  20. Calcitriol in Combination Therapy for Prostate Cancer: Pharmacokinetic and Pharmacodynamic Interactions.

    PubMed

    Ben-Eltriki, Mohamed; Deb, Subrata; Guns, Emma S Tomlinson

    2016-01-01

    Epidemiological studies indicate that vitamin D insufficiency could have an etiological role in prostate cancer. In addition, calcitriol, used in combination with currently available drugs, has the potential to potentiate their anticancer effects or act synergistically by inhibiting distinct mechanisms involved in prostate cancer growth. Clinical data have not yet provided sufficient evidence to demonstrate benefit of vitamin D due to the limited and underpowered studies that have been published to date. Here, we review the preclinical and clinical studies that describe the activity of calcitriol, applied either alone or in combination and assessed the mechanistic basis of pharmacodynamic and pharmacokinetic interactions with calcitriol. Important considerations for calcitriol use in combination therapy with respect to safety and clinical outcomes have been discussed. Many of these combinations have therapeutic potential for the treatment of several cancer types and it is anticipated that future clinical research will put emphasis on well‑designed clinical trials to establish efficacy. PMID:26918053

  1. Neuroprotective Effect of Combination Therapy of Glatiramer Acetate and Epigallocatechin-3-Gallate in Neuroinflammation

    PubMed Central

    Hentschel, Nicole; Infante-Duarte, Carmen; Aktas, Orhan; Zipp, Frauke

    2011-01-01

    Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system. However, studies of MS and the animal model, experimental autoimmune encephalomyelitis (EAE), indicate that neuronal pathology is the principle cause of clinical disability. Thus, there is need to develop new therapeutic strategies that not only address immunomodulation but also neuroprotection. Here we show that the combination therapy of Glatiramer acetate (GA), an immunomodulatory MS therapeutic, and the neuroprotectant epigallocatechin-3-gallate (EGCG), the main phenol in green tea, have synergistic protective effects in vitro and in the EAE model. EGCG and GA together led to increased protection from glutamate- and TRAIL-induced neuronal cell death in vitro. EGCG combined with GA induced regeneration of hippocampal axons in an outgrowth assay. The combined application of EGCG and GA did not result in unexpected adverse events in vivo. Neuroprotective and neuroregenerative effects could be translated in the in vivo model, where combination treatment with EGCG and GA significantly delayed disease onset, strongly reduced clinical severity, even after onset of symptoms and reduced inflammatory infiltrates. These results illustrate the promise of combining neuroprotective and anti-inflammatory treatments and strengthen the prospects of EGCG as an adjunct therapy for neuroinflammatory and neurodegenerative diseases. PMID:22022398

  2. Combined Hyperthermia and Photodynamic Therapy Using a Sub-THz Gyrotron as a Radiation Source

    NASA Astrophysics Data System (ADS)

    Miyoshi, Norio; Idehara, Toshitaka; Khutoryan, Eduard; Fukunaga, Yukihiro; Bibin, Andriana Bintang; Ito, Shinji; Sabchevski, Svilen Petrov

    2016-08-01

    In this paper, we present results of a hyperthermia treatment of malignant tumors using a gyrotron as a radiation source for heating of the cancerous tissue. They clearly demonstrate the efficiency of the irradiation by sub-THz waves, which leads to steady decrease of the volume of the tumor and finally to its disappearance. A combination of hyperthermia and photodynamic therapy (PDT) that utilizes a novel multifunctional photosensitizer has also been explored. In the latter case, the results are even more convincing and promising. In particular, while after a hyperthermia treatment sometimes a regrowth of the tumor is being observed, in the case of combined hyperthermia and PDT such regrowth has never been noticed. Another combined therapy is based on a preheating of the tumor by gyrotron radiation to temperatures lower than the hyperthermia temperature of 43 °C and followed then by PDT. The results show that such combination significantly increases the efficiency of the treatment. We consider this phenomenon as a synergy effect since it is absent when hyperthermia and PDT are applied separately, and manifests itself only when both methods are combined.

  3. Combination therapy of dipeptidyl peptidase-4 inhibitors and metformin in type 2 diabetes: rationale and evidence.

    PubMed

    Liu, Y; Hong, T

    2014-02-01

    The main pathogenesis of type 2 diabetes mellitus (T2DM) includes insulin resistance and pancreatic islet dysfunction. Metformin, which attenuates insulin resistance, has been recommended as the first-line antidiabetic medication. Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel oral hypoglycaemic agents that protect glucagon-like peptide-1 (GLP-1) from degradation, maintain the bioactivity of endogenous GLP-1, and thus improve islet dysfunction. Results from clinical trials have shown that the combination therapy of DPP-4 inhibitors and metformin [as an add-on, an initial combination or a fixed-dose combination (FDC)] provides excellent efficacy and safety in patients with T2DM. Moreover, recent studies have suggested that metformin enhances the biological effect of GLP-1 by increasing GLP-1 secretion, suppressing activity of DPP-4 and upregulating the expression of GLP-1 receptor in pancreatic β-cells. Conversely, DPP-4 inhibitors have a favourable effect on insulin sensitivity in patients with T2DM. Therefore, the combination of DPP-4 inhibitors and metformin provides an additive or even synergistic effect on metabolic control in patients with T2DM. This article provides an overview of clinical evidence and discusses the rationale for the combination therapy of DPP-4 inhibitors and metformin. PMID:23668534

  4. Augmenting antifungal activity of oxidizing agent with kojic acid: Control of Penicillium strains infecting crops

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Oxidative treatment is a strategy for preventing Penicillium contamination in foods or crops. Antifungal efficacy of oxidant [hydrogen peroxide (H2O2)], biotic effector [kojic acid (KA)] and abiotic stress (heat), alone or in combination, was investigated in Penicillium. The levels of antifungal int...

  5. Capecitabine and radiation therapy preceded and followed by combination chemotherapy in advanced pancreatic cancer

    SciTech Connect

    Schneider, Bryan J.; McGinn, Cornelius J.; Chang, Alfred E.; Colletti, Lisa M.; Normolle, Daniel P.; Hejna, Gwen F. P.A.; Zalupski, Mark M. . E-mail: Zalupski@umich.edu

    2005-12-01

    Purpose: The primary objective of this study was to evaluate the tolerance and toxicity of radiation therapy (RT) and capecitabine in patients with advanced, unresectable pancreatic carcinoma. To control micrometastatic disease, combination chemotherapy (gemcitabine and cisplatin) before and after combined modality therapy (CMT) was planned. Methods and Materials: Patients with unresectable or metastatic pancreatic cancer were eligible. Gemcitabine 1000 mg/m{sup 2} and cisplatin 35 mg/m{sup 2} were administered on Days 1 and 8 of a 21-day cycle for two cycles. RT was then given to a dose of 50.4 Gy in 1.8 Gy fractions. Patients were treated with capecitabine 1330 mg/m{sup 2} daily during RT. After CMT, two additional cycles of gemcitabine and cisplatin completed the treatment. Results: Twenty-three patients were treated. Eighteen patients completed CMT. One patient was removed from study during CMT for toxicity issues. Treatment delays and dose reductions were common during the final two cycles of gemcitabine and cisplatin as a result of myelosuppression. Median survival was 10.1 months (95% confidence interval [CI] = 7.6, 13.7) for all 23 patients and 12.8 months (95% CI = 8.2, 18.9) for 18 patients without metastasis. Conclusion: Combined modality therapy with RT and capecitabine was well tolerated. Chemotherapy after CMT was difficult to complete owing to cumulative myelosuppression. Survival, response, and toxicity were comparable to infusional 5-fluorouracil and RT.

  6. Combination of vascular endothelial growth factor inhibitors and laser therapy for diabetic macular oedema: a review.

    PubMed

    Mehta, Hemal; Gillies, Mark C; Fraser-Bell, Samantha

    2016-05-01

    This review provides a perspective on published and ongoing clinical trials of vascular endothelial growth factor inhibitors (anti-VEGF agents) combined with laser therapy for diabetic macular oedema (DMO). Although there was little short-term benefit in combining prompt macular laser with anti-VEGF therapy for centre-involving DMO in the Diabetic Retinopathy Clinical Research Network (DRCRnet) Protocol I study, deferred macular laser was still required in over 40% of study eyes in DRCRnet Protocol T. Macular laser was applied in more than 30% of eyes with centre-involving DMO receiving ranibizumab in the RISE and RIDE studies. For non centre-involving DMO the evidence-base still supports use of focal macular laser alone, although clinicians should be cautious about applying laser too close to the foveal avascular zone with the availability of pharmacotherapy. Ongoing clinical trials are assessing whether selectively targeting areas of peripheral retinal ischaemia with laser reduces the number of anti-VEGF injections to stabilise DMO and whether combining macular micropulse laser with anti-VEGF therapy is beneficial in DMO. PMID:27061760

  7. L-dopa-carbidopa: combined therapy for the treatment of Parkinson's disease.

    PubMed

    Celesia, G G; Wanamaker, W M

    1976-03-01

    It is now generally acknowledged that L-Dopa is the therapy of choice for Parkinson's Disease. However, L-Dopa has some short comings: It requires large daily dosage, the therapeutic benefits are achieved only after a delayed onset of 1-2 months, and it has a number of side effects both central and peripheral. In the last few years there has been an intense search for agents that are less toxic, more efficient and more rapidly acting that L-Dopa. The ideal agent has not yet been found. However, a combination therapy with L-Dopa and dopa decarboxylase inhibitors has shown promise. The decarboxylase inhibitors used have a large molecule which does not cross the blood brain barrier. Thus when L-Dopa and the decarboxylase inhibitor are given togehher, peripheral production of dopamine from L-Dopa is inhibited, therefore, rendering L-Dopa more readily and rapidly available for brain metabolism. In the present paper we present the results of the treatment of 50 patients on combined therapy using L-Dopa combined with Carbidopa. PMID:1253661

  8. Multifunctional hollow gold nanoparticles designed for triple combination therapy and CT imaging.

    PubMed

    Park, Jaesook; Park, Jin; Ju, Eun Jin; Park, Seok Soon; Choi, Jinhyang; Lee, Jae Hee; Lee, Kyoung Jin; Shin, Seol Hwa; Ko, Eun Jung; Park, Intae; Kim, Chulhee; Hwang, Jung Jin; Lee, Jung Shin; Song, Si Yeol; Jeong, Seong-Yun; Choi, Eun Kyung

    2015-06-10

    Hollow gold nanoparticles (HGNP) are a novel class of hybrid metal nanoparticles whose unique optical and morphological properties have spawned new applications including more effective cancer therapy. The shell thickness of HGNPs can tune the surface plasmon resonance to the near infrared light, resulting in photothermal ablation of tumors with optimal light penetration in tissue. The hollow cavity within a HGNP is able to accommodate a high payload of chemotherapeutic agents. They have also been used for enhancing radiosensitization in tumors during radiotherapy due to the high X-ray absorption capability of gold particles. However, no report has yet been published that utilize HGNPs for the triple combination therapy and CT imaging. In this study, we synthesized HGNPs which exhibit better response to radiation for therapy and imaging and demonstrated the effects of combined chemotherapy, thermal and radiotherapy. This combination strategy presented delayed tumor growth by 4.3-fold and reduced tumor's weight by 6.8-fold compared to control tumors. In addition, we demonstrated the feasibility of HGNP as a CT imaging agent. It is expected that translating these capabilities to human cancer patients could dramatically increase the antitumor effect and potentially overcome resistance to chemotherapeutic agents and radiation. PMID:25863273

  9. Atazanavir/ritonavir-based combination antiretroviral therapy for treatment of HIV-1 infection in adults.

    PubMed

    Achenbach, Chad J; Darin, Kristin M; Murphy, Robert L; Katlama, Christine

    2011-02-01

    In the past 15 years, improvements in the management of HIV infection have dramatically reduced morbidity and mortality. Similarly, rapid advances in antiretroviral medications have resulted in the possibility of life-long therapy with simple and tolerable regimens. Protease inhibitors have been important medications in regimens of combination antiretroviral therapy for the treatment of HIV. One of the recommended and commonly used therapies in this class is once-daily-administered atazanavir, pharmacologically boosted with ritonavir (atazanavir/r). Clinical studies and practice have shown these drugs, in combination with other antiretroviral agents, to be potent, safe and easy to use in a variety of settings. Atazanavir/r has minimal short-term toxicity, including benign bilirubin elevation, and has less potential for long-term complications of hyperlipidemia and insulin resistance compared with other protease inhibitors. A high genetic barrier to resistance and a favorable resistance profile make it an excellent option for initial HIV treatment or as the first drug utilized in the protease inhibitors class. Atazanavir/r is also currently being studied in novel treatment strategies, including combinations with new classes of antiretrovirals to assess nucleoside reverse transcriptase inhibitor-sparing regimens. In this article we review atazanavir/r as a treatment for HIV infection and discuss the latest information on its pharmacology, efficacy and toxicity. PMID:21731578

  10. Combination therapy in the management of giardiasis: What laboratory and clinical studies tell us, so far.

    PubMed

    Escobedo, Angel A; Lalle, Marco; Hrastnik, Nana I; Rodríguez-Morales, Alfonso J; Castro-Sánchez, Enrique; Cimerman, Sérgio; Almirall, Pedro; Jones, Jony

    2016-10-01

    Treatment failures in patients suffering from giardiasis are not uncommon feature. The most frequent approach in these cases is to treat these patients with longer repeated courses and/or higher doses of the primary therapy, or using drugs from a different class to avoid potential cross-resistance. However, a higher rate of adverse events may limit this strategy. In this context, combination therapy (CT) is emerging as a valuable option against refractory giardiasis. In the attempt to evaluate the benefits of CT, a number of experimental studies, clinical series, and randomized clinical trials (RCTs), as well as several veterinary studies have been performed, with varying results. Here, we present a critical analysis of the available information regarding CT for the treatment of Giardia infection, as well as the authors' opinion with respect to its use. RCTs of combination therapy are limited and the optimal combinations and administration strategies need yet to be clarified. Analyses of the cost-effectiveness and RCTs of CTs for Giardia infection are required to assess the role of these drugs for the control of giardiasis, mainly in the case of treatment failures linked to suspected drug tolerance are the case. PMID:27349189

  11. Azithromycin plus chloroquine: combination therapy for protection against malaria and sexually transmitted infections in pregnancy

    PubMed Central

    Chico, R Matthew; Chandramohan, Daniel

    2011-01-01

    Introduction: The first-line therapy for the intermittent preventive treatment of malaria in pregnancy (IPTp) is sulphadoxine-pyrimethamine (SP). There is an urgent need to identify safe, well-tolerated and efficacious alternatives to SP due to widespread Plasmodium falciparum resistance. Combination therapy using azithromycin and chloroquine is one possibility that has demonstrated adequate parasitological response > 95% in clinical trials of non-pregnant adults in sub-Saharan Africa and where IPTp is a government policy in 33 countries. Areas covered: Key safety, tolerability and efficacy data are presented for azithromycin and chloroquine, alone and/or in combination, when used to prevent and/or treat P. falciparum, P. vivax, and several curable sexually transmitted and reproductive tract infections (STI/RTI). Pharmacokinetic evidence from pregnant women is also summarized for both compounds. Expert opinion: The azithromycin-chloroquine regimen that has demonstrated consistent efficacy in non-pregnant adults has been a 3-day course containing daily doses of 1 g of azithromycin and 600 mg base of chloroquine. The pharmacokinetic evidence of these compounds individually suggests that dose adjustments may not be necessary when used in combination for treatment efficacy against P. falciparum, P. vivax, as well as several curable STI/ RTI among pregnant women, although clinical confirmation will be necessary. Mass trachoma-treatment campaigns have shown that azithromycin selects for macrolide resistance in the pneumococcus, which reverses following the completion of therapy. Most importantly, no evidence to date suggests that azithromycin induces pneumococcal resistance to penicillin. PMID:21736423

  12. Intensive combined modality therapy including low-dose TBI in high-risk Ewing's sarcoma patients

    SciTech Connect

    Kinsella, T.J.; Glaubiger, D.; Diesseroth, A.; Makuch, R.; Waller, B.; Pizzo, P.; Glatstein, E.

    1983-12-01

    Twenty-four high-risk Ewing's sarcoma patients were treated on an intensive combined modality protocol including low-dose fractionated total body irradiaiton (TBI) and autologous bone marrow infusion (ABMI). Twenty patients (83%) achieved a complete clinical response to the primary and/or metastatic sites following induction therapy. The median disease-free interval was 18 months, and nine patients remain disease-free with a follow-up of 22 to 72 months. Local failure as a manifestation of initial relapse occurred in only three patients (15%), each having synchronous distant failure. Eight patients failed initially with only distant metastases, usually within 1-2 years following a complete clinical response. Two patterns of granulocyte recovery following consolidative therapy (including TBI and ABMI) were recognized. The time to platelet recovery was different for the groups with early and late granulocyte recovery. Patients with late recovery did not tolerate maintenance chemotherapy. However, there was no difference in disease-free and overall survival, when comparing the groups with early and late granulocyte recovery. It is concluded that these high-risk Ewing's sarcoma patients remain a poor-prognosis group in spite of intensive combined modality therapy including low-dose TBI. The control of microscopic systemic disease remains the major challenge to improving the cure rate. A new combined modality protocol with high-dose 'therapeutic' TBI (800 rad/2 fractions) is being used and the protocol design is outlined.

  13. Atazanavir/ritonavir-based combination antiretroviral therapy for treatment of HIV-1 infection in adults

    PubMed Central

    Achenbach, Chad J; Darin, Kristin M; Murphy, Robert L; Katlama, Christine

    2011-01-01

    In the past 15 years, improvements in the management of HIV infection have dramatically reduced morbidity and mortality. Similarly, rapid advances in antiretroviral medications have resulted in the possibility of life-long therapy with simple and tolerable regimens. Protease inhibitors have been important medications in regimens of combination antiretroviral therapy for the treatment of HIV. One of the recommended and commonly used therapies in this class is once-daily-administered atazanavir, pharmacologically boosted with ritonavir (atazanavir/r). Clinical studies and practice have shown these drugs, in combination with other antiretroviral agents, to be potent, safe and easy to use in a variety of settings. Atazanavir/r has minimal short-term toxicity, including benign bilirubin elevation, and has less potential for long-term complications of hyperlipidemia and insulin resistance compared with other protease inhibitors. A high genetic barrier to resistance and a favorable resistance profile make it an excellent option for initial HIV treatment or as the first drug utilized in the protease inhibitors class. Atazanavir/r is also currently being studied in novel treatment strategies, including combinations with new classes of antiretrovirals to assess nucleoside reverse transcriptase inhibitor-sparing regimens. In this article we review atazanavir/r as a treatment for HIV infection and discuss the latest information on its pharmacology, efficacy and toxicity. PMID:21731578

  14. Tolerability of Combined Modality Therapy for Rectal Cancer in Elderly Patients Aged 75 Years and Older

    SciTech Connect

    Margalit, Danielle N.; Mamon, Harvey J.; Ryan, David P.; Blaszkowsky, Lawrence S.; Clark, Jeffrey; Willett, Christopher G.; Hong, Theodore S.

    2011-12-01

    Purpose: To determine the rate of treatment deviations during combined modality therapy for rectal cancer in elderly patients aged 75 years and older. Methods and Materials: We reviewed the records of consecutively treated patients with rectal cancer aged 75 years and older treated with combined modality therapy at Massachusetts General Hospital and Brigham and Women's Hospital from 2002 to 2007. The primary endpoint was the rate of treatment deviation, defined as a treatment break, dose reduction, early discontinuation of therapy, or hospitalization during combined modality therapy. Patient comorbidity was rated using the validated Adult Comorbidity Evaluation 27 Test (ACE-27) comorbidity index. Fisher's exact test and the Mantel-Haenszel trend test were used to identify predictors of treatment tolerability. Results: Thirty-six eligible patients had a median age of 79.0 years (range, 75-87 years); 53% (19/36) had no or mild comorbidity and 47% (17/36) had moderate or severe comorbidity. In all, 58% of patients (21/36) were treated with preoperative chemoradiotherapy (CRT) and 33% (12/36) with postoperative CRT. Although 92% patients (33/36) completed the planned radiotherapy (RT) dose, 25% (9/36) required an RT-treatment break, 11% (4/36) were hospitalized, and 33% (12/36) had a dose reduction, break, or discontinuation of concurrent chemotherapy. In all, 39% of patients (14/36) completed {>=}4 months of adjuvant chemotherapy, and 17% (6/36) completed therapy without a treatment deviation. More patients with no to mild comorbidity completed treatment than did patients with moderate to severe comorbidity (21% vs. 12%, p = 0.66). The rate of deviation did not differ between patients who had preoperative or postoperative CRT (19% vs. 17%, p = 1.0). Conclusions: The majority of elderly patients with rectal cancer in this series required early termination of treatment, treatment interruptions, or dose reductions. These data suggest that further intensification of

  15. [New antifungal agents: voriconazole and caspofungin].

    PubMed

    Dupont, B

    2003-12-01

    Among new available antifungal agents voriconazole is a new triazole with an intravenous (i.v.) and oral formulation, and caspofungin is an echinocandin, new family with a new mode of action on the cell wall. It is available as an i.v. preparation. Both drugs have a broad spectrum targeting most of the usual pathogens: Candida and Aspergillus, even with low suceptibility or resistance to other antifungals. Voriconazole is also active on Scedosporium and Fusarium. The efficacy of these molecules was established in vitro and in experimental infections in animals either normal or immunosuppressed. Voriconazole is active in oropharyngeal and esophageal candidiasis, in refractory invasive candidiasis and as a first line treatment of invasive aspergillosis with better results than amphotéricine B. It was also effective in scedosporiosis and in fusariosis. Caspofungin is active in oropharyngeal and esophageal candidiasis, in invasive candidiasis ranking among the best drugs in non neutropenic patients. It was shown effective in refractory aspergillosis. As empirical treatment of febrile neutropenic patients, these molecules should probably be restricted to the highest risk-population. Safety is good, side effects are a rare cause of discontinuation of treatment, class specific drug-drug interactions occur with voriconazole. These molecules open an important field of investigations with combination of antifungal agents. PMID:15022787

  16. Current and Emerging Azole Antifungal Agents

    PubMed Central

    Sheehan, Daniel J.; Hitchcock, Christopher A.; Sibley, Carol M.

    1999-01-01

    Major developments in research into the azole class of antifungal agents during the 1990s have provided expanded options for the treatment of many opportunistic and endemic fungal infections. Fluconazole and itraconazole have proved to be safer than both amphotericin B and ketoconazole. Despite these advances, serious fungal infections remain difficult to treat, and resistance to the available drugs is emerging. This review describes present and future uses of the currently available azole antifungal agents in the treatment of systemic and superficial fungal infections and provides a brief overview of the current status of in vitro susceptibility testing and the growing problem of clinical resistance to the azoles. Use of the currently available azoles in combination with other antifungal agents with different mechanisms of action is likely to provide enhanced efficacy. Detailed information on some of the second-generation triazoles being developed to provide extended coverage of opportunistic, endemic, and emerging fungal pathogens, as well as those in which resistance to older agents is becoming problematic, is provided. PMID:9880474

  17. What’s next after metformin? focus on sulphonylurea: add-on or combination therapy

    PubMed Central

    Lim, Phei C.; Chong, Chee P.

    2015-01-01

    Introduction: The pathophysiology of type 2 diabetes (T2DM) mainly focused on insulin resistance and insulin deficiency over the past decades. Currently, the pathophysiologies expanded to ominous octet and guidelines were updated with newer generation of antidiabetic drug classes. However, many patients had yet to achieve their target glycaemic control. Although all the guidelines suggested metformin as first line, there was no definite consensus on the second line drug agents as variety of drug classes were recommended. Objectives: The aim of this review was to evaluate the drug class after metformin especially sulphonylurea and issues around add-on or fixed dose combination therapy. Methods: Extensive literature search for English language articles, clinical practice guidelines and references was performed using electronic databases. Results: Adding sulphonylurea to metformin targeted both insulin resistance and insulin deficiency. Sulphonylurea was efficacious and cheaper than thiazolidinedione, dipeptidyl peptidase-4 inhibitor, glucagon-like peptide 1 analogue and insulin. The main side effect of sulphonylurea was hypoglycaemia but there was no effect on the body weight when combining with metformin. Fixed dose sulphonylurea/metformin was more efficacious at lower dose and reported to have fewer side effects with better adherence. Furthermore, fixed dose combination was cheaper than add-on therapy. In conclusion, sulphonylurea was feasible as the second line agent after metformin as the combination targeted on two pathways, efficacious, cost-effective and had long safety history. Fixed dose combination tablet could improve patient’s adherence and offered an inexpensive and more efficacious option regardless of original or generic product as compared to add-on therapy. PMID:26445623

  18. Combination Therapy of Sorafenib and TACE for Unresectable HCC: A Systematic Review and Meta-Analysis

    PubMed Central

    Zhao, Yan; Cai, Guohong; Qi, Xingshun; Han, Guohong

    2014-01-01

    Background and Aim A large number of studies have tried to combine sorafenib with TACE for patients with unresectable hepatocellular carcinoma (HCC) and the results were controversial. We conducted this systematic review and meta-analysis to evaluate the safety and efficacy of combination therapy of sorafenib and TACE in the management of unresectable HCC. Methods MEDLINE, PsycINFO, Scopus, EMBASE, and the Cochrane Library were searched from January 1990 to October 2013 and these databases were searched for appropriate studies combining TACE and sorafenib in treatment of HCC. Two authors independently reviewed the databases and extracted the data and disagreements were resolved by discussion. Effective value and safety were analyzed. Effective value included disease control rate (DCR), time to progression (TTP) and overall survival (OS). Results 17 studies were included in the study. In the 10 noncomparative studies, DCR ranged from 18.4 to 91.2%. Median TTP ranged from 7.1 to 9.0 months, and median OS ranged from 12 to 27 months. In the 7 comparative studies, the hazard ratio (HR) for TTP was found to be 0.76 (95% CI 0.66–0.89; P<0.001) with low heterogeneity among studies (P = 0.243; I2 = 25.5%). However, the HR for OS was found to be 0.81 (95% CI 0.65–1.01; P = 0.061) with low heterogeneity among studies (P = 0.259; I2 = 25.4%). The common toxicities included fatigue, diarrhea, nausea, hand foot skin reaction (HFSR), hematological events, hepatotoxicity, alopecia, hepatotoxicity, hypertension and rash/desquamation. AEs are generally manageable with dose reductions. Conclusions Combination therapy may bring benefits for unresectable HCC patients in terms of TTP but not OS. Further well-designed randomized controlled studies are needed to confirm the efficacy of combination therapy. PMID:24651044

  19. Combination therapy with molecular hydrogen and hyperoxia in a murine model of polymicrobial sepsis.

    PubMed

    Xie, Keliang; Fu, Wenzheng; Xing, Weibin; Li, Ailin; Chen, Hongguang; Han, Huanzhi; Yu, Yonghao; Wang, Guolin

    2012-12-01

    Sepsis is the most common cause of death in intensive care units. Some studies have found that hyperoxia may be beneficial to sepsis. However, the clinical use of hyperoxia is hindered by concerns that it could exacerbate organ injury by increasing free radical formation. Recently, it has been suggested that molecular hydrogen (H2) at low concentration can exert a therapeutic antioxidant activity and effectively protect against sepsis by reducing oxidative stress. Therefore, we hypothesized that combination therapy with H2 and hyperoxia might afford more potent therapeutic strategies for sepsis. In the present study, we found that inhalation of H2 (2%) or hyperoxia (98%) alone improved the 14-day survival rate of septic mice with moderate cecal ligation and puncture (CLP) from 40% to 80% or 70%, respectively. However, combination therapy with H2 and hyperoxia could increase the 14-day survival rate of moderate CLP mice to 100% and improve the 7-day survival rate of severe CLP mice from 0% to 70%. Moreover, moderate CLP mice showed significant organ damage characterized by the increases in lung myeloperoxidase activity, lung wet-to-dry weight ratio, protein concentration in bronchoalveolar lavage, serum biochemical parameters (alanine aminotransferase, aspartate aminotransferase, creatinine, and blood urea nitrogen), and organ histopathological scores (lung, liver, and kidney), as well as the decrease in PaO2/FIO2 ratio at 24 h, which was attenuated by either H2 or hyperoxia alone. However, combination therapy with H2 and hyperoxia had a more beneficial effect against lung, liver, and kidney damage of moderate or severe CLP mice. Furthermore, we found that the beneficial effect of this combination therapy was associated with the decreased levels of oxidative product (8-iso-prostaglandin F2α), increased activities of antioxidant enzymes (superoxide dismutase and catalase) and anti-inflammatory cytokine (interleukin 10), and reduced levels of proinflammatory

  20. Fixed-dose combination therapy for the prevention of cardiovascular disease

    PubMed Central

    de Cates, Angharad N; Farr, Matthew RB; Wright, Nicola; Jarvis, Morag C; Rees, Karen; Ebrahim, Shah; Huffman, Mark D

    2014-01-01

    Background Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, yet CVD risk factor control and secondary prevention rates remain low. A fixed-dose combination of blood pressure and cholesterol lowering and antiplatelet treatments into a single pill, or polypill, has been proposed as one strategy to reduce the global burden of CVD by up to 80% given its potential for better adherence and lower costs. Objectives To determine the effectiveness of fixed-dose combination therapy on reducing fatal and non-fatal CVD events and on improving blood pressure and lipid CVD risk factors for both primary and secondary prevention of CVD. We also aimed to determine discontinuation rates, adverse events, health-related quality of life, and costs of fixed-dose combination therapy. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library(2013, Issue 6), MEDLINE Ovid (1946 to week 2 July 2013), EMBASE Ovid (1980 to Week 28 2013), ISI Web of Science (1970 to 19 July 2013), and the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database (HTA), and Health Economics Evaluations Database (HEED) (2011, Issue 4) in The Cochrane Library. We used no language restrictions. Selection criteria We included randomised controlled trials of a fixed-dose combination therapy including at least one blood pressure lowering and one lipid lowering component versus usual care, placebo, or a single drug active component for any treatment duration in adults ≥ 18 years old with no restrictions on presence or absence of pre-existing cardiovascular disease. Data collection and analysis Three review authors independently selected studies for inclusion and extracted the data. We evaluated risk of bias using the Cochrane risk of bias assessment tool. We sought to include outcome data on all-cause mortality, fatal and non-fatal CVD events, adverse events, changes in systolic and diastolic blood

  1. Facing the challenges of new melanoma-targeted therapies: Treatment of severe fevers associated with dabrafenib/trametinib combination therapy.

    PubMed

    Lindsay, Julian N; Barras, Michael

    2015-08-01

    With the emergence of new oral therapies for metastatic melanoma to the market, as well as ongoing pre-marketing trials and special access schemes, it is important to keep up to date with the side effect profiles of these medications. A common side effect associated with the BRAF inhibitor dabrafenib is severe fever symptoms such as pyrexia and rigors/chills; however, treatment options are limited. We report a patient who was debilitated by severe pyrexia and rigors caused by dabrafenib used in combination with trametinib to treat metastatic melanoma, who was treated with low-dose steroids. To our knowledge, the use of prednisolone for the treatment and prevention of further dabrafenib-associated pyrexia is not published; however, it is a low risk and low cost option that was very effective in this case. PMID:24664475

  2. Antihypertensive combination therapy in primary care offices: results of a cross-sectional survey in Switzerland

    PubMed Central

    Roas, Susanne; Bernhart, Felix; Schwarz, Michael; Kaiser, Walter; Noll, Georg

    2014-01-01

    Background Most hypertensive patients need more than one substance to reach their target blood pressure (BP). Several clinical studies indicate the high efficacy of antihypertensive combinations, and recent guidelines recommend them in some situations even as initial therapies. In general practice they seem widespread, but only limited data are available on their effectiveness under the conditions of everyday life. The objectives of this survey among Swiss primary care physicians treating hypertensive patients were: to know the frequency of application of different treatment modalities (monotherapies, free individual combinations, single-pill combinations); to see whether there are relationships between prescribed treatment modalities and patient characteristics, especially age, treatment duration, and comorbidities; and to determine the response rate (percentage of patients reaching target BP) of different treatment modalities under the conditions of daily practice. Methods This cross-sectional, observational survey among 228 randomly chosen Swiss primary care physicians analyzed data for 3,888 consecutive hypertensive patients collected at one single consultation. Results In this survey, 31.9% of patients received monotherapy, 41.2% two substances, 20.9% three substances, and 4.7% more than three substances. By combination mode, 34.9% took free individual combinations and 30.0% took fixed-dose single-pill combinations. Combinations were more frequently given to older patients with a long history of hypertension and/or comorbidities. In total, 67.8% of patients achieved their BP target according to their physician’s judgment. When compared, single-pill combinations were associated with a higher percentage of patients achieving target BP than free individual combinations and monotherapies for the total sample and for patients with comorbidity. Conclusion Antihypertensive combination therapy was widely used in Swiss primary care practices. The number of prescribed

  3. Efficacy and safety of combination therapy for preventing bone damage in rheumatoid arthritis.

    PubMed

    Iannone, Florenzo; Lopalco, Giuseppe; Cantarini, Luca; Galeazzi, Mauro; Lapadula, Giovanni

    2016-01-01

    The main outcomes of the therapies for rheumatoid arthritis (RA) must be preventing, or at least lessening, the development of structural damage. Biological disease-modifying anti-rheumatic drugs (bDMARDs), targeting tumour necrosis factor-α (TNF-α) or other key steps (IL-1, IL-6, T cells, B cells) in the pathogenesis of RA, have given clues to be effective and safe as treatments for RA, being capable of improving disease activity, ameliorating functional ability and halting joint damage. A large body of evidence, stemming from randomized clinical trials, observational studies, and registries, has shown that the beneficial effects of the bDMARDs become optimal when combined with synthetic (s)-DMARDs, mainly methotrexate (MTX). Despite combination therapy is advocated by the international guidelines for the management of RA, data from the daily standard of care indicate that almost one third of RA patients are treated with bDMARDs as monotherapy. Many reasons may be taken into account to explain this gap from official recommendations, among which the fact that in real-life settings, the assessment of clinical outcomes is exclusively based on clinical indices, disregarding the evolution of bone damage. Furthermore, some bDMARDs have been launched in the market with the official approval to be used as monotherapy. But even for the latter, there is no conclusive proof that monotherapy regimen is comparable to co-therapy with MTX in preventing articular damage. In conclusion, the most recent published data show that combination therapy with bDMARDs and MTX represents the best therapeutic option for the treatment of RA since it can stop or at least slow the progression of disabling structural damage. PMID:26581205

  4. Effect of combined psycho-physiological stretching and breathing therapy on sexual satisfaction

    PubMed Central

    2013-01-01

    Background During the last few decades, marital tensions and stresses have influenced various dimensions of life. The objective of the current study was to examine the effects of combined psycho-physiological therapy (stretching therapy combined with breathing exercise) on sexual satisfaction among heterosexual men. Methods For this research, we used “convenience sampling” to select 80 males, who were then split equally into two groups, the intervention group and the control group, both groups containing men who had voiced a desire to be in the experimental group. For collection of data, we used an identical quasi-experimental design called the “nonequivalent control group.” Therapy sessions, each lasting 90 to 120 min, were carried out on the same 3 days of the week (Sunday, Tuesday, and Thursday) for a total of 20 sessions. The volunteers were selected from heterosexual men with stable relationships, who had been married a minimum of 6 months and were ages 20 to 55 years of age. Pre-tests, post-tests, and follow-up tests were conducted in a clinic at the Hospital Universiti Sains Malaysia (HUSM [1] ). For assessment, we used the sexual satisfaction subscale of the ENRICH [2] questionnaire. Results The intervention group had better post-test scores than the control group. Also, follow-up test scores for the intervention group were marginally better than those for the control group, but the difference did not reach statistical significance. Conclusions Combined psycho-physiological therapy including stretching and breathing exercise leads to improved sexual satisfaction. PMID:23522405

  5. Theragnosis-based combined cancer therapy using doxorubicin-conjugated microRNA-221 molecular beacon.

    PubMed

    Lee, Jonghwan; Choi, Kyung-Ju; Moon, Sung Ung; Kim, Soonhag

    2016-01-01

    Recently, microRNA (miRNA or miR) has emerged as a new cancer biomarker because of its high expression level in various cancer types and its role in the control of tumor suppressor genes. In cancer studies, molecular imaging and treatment based on target cancer markers have been combined to facilitate simultaneous cancer diagnosis and therapy. In this study, for combined therapy with diagnosis of cancer, we developed a doxorubicin-conjugated miR-221 molecular beacon (miR-221 DOXO MB) in a single platform composed of three different nucleotides: miR-221 binding sequence, black hole quencher 1 (BHQ1), and doxorubicin binding site. Imaging of endogenous miR-221 was achieved by specific hybridization between miR-221 and the miR-221 binding site in miR-221 DOXO MB. The presence of miR-221 triggered detachment of the quencher oligo and subsequent activation of a fluorescent signal of miR-221 DOXO MB. Simultaneous cancer therapy in C6 astrocytoma cells and nude mice was achieved by inhibition of miRNA-221 function that downregulates tumor suppressor genes. The detection of miR-221 expression and inhibition of miR-221 function by miR-221 DOXO MB provide the feasibility as a cancer theragnostic probe. Furthermore, a cytotoxic effect was induced by unloading of doxorubicin intercalated into miR-221 DOXO MB inside cells. Loss of miR-221 function and cytotoxicity induced by the miR-221 DOXO MB provides combined therapeutic efficacy against cancers. This method could be used as a new theragnostic probe with enhanced therapy to detect and inhibit many cancer-related miRNAs. PMID:26454049

  6. Detection and partial characterization of antifungal bioactivity from the secretions of the medicinal maggot, Lucilia sericata.

    PubMed

    Evans, Rhys; Dudley, Ed; Nigam, Yamni

    2015-01-01

    The antibacterial properties of the excretions/secretions (ES) of the medicinal maggot, Lucilia sericata have long been known and the effectiveness of maggot debridement therapy in relation to the clearance of bacteria from the surface of wounds has been the source of much research over recent years. Less well known, however, are the antifungal properties of L. sericata ES. Here, we show by means of the colony forming unit assay and optical density assays, that L. sericata native ES possess significant antifungal properties and appears to possess a highly heat stable, freeze/thaw, and lyophilization resistant antifungal component. We also show that the antifungal activity present in the native ES consists of a number of antifungal components present in three fraction masses consisting of >10, 10-0.5, and <0.5 kDa, with the greatest level of activity being seen in the <0.5 kDa fraction. PMID:25847128

  7. Quantifying the Combined Effect of Radiation Therapy and Hyperthermia in Terms of Equivalent Dose Distributions

    SciTech Connect

    Kok, H. Petra; Crezee, Johannes; Franken, Nicolaas A.P.; Barendsen, Gerrit W.

    2014-03-01

    Purpose: To develop a method to quantify the therapeutic effect of radiosensitization by hyperthermia; to this end, a numerical method was proposed to convert radiation therapy dose distributions with hyperthermia to equivalent dose distributions without hyperthermia. Methods and Materials: Clinical intensity modulated radiation therapy plans were created for 15 prostate cancer cases. To simulate a clinically relevant heterogeneous temperature distribution, hyperthermia treatment planning was performed for heating with the AMC-8 system. The temperature-dependent parameters α (Gy{sup −1}) and β (Gy{sup −2}) of the linear–quadratic model for prostate cancer were estimated from the literature. No thermal enhancement was assumed for normal tissue. The intensity modulated radiation therapy plans and temperature distributions were exported to our in-house-developed radiation therapy treatment planning system, APlan, and equivalent dose distributions without hyperthermia were calculated voxel by voxel using the linear–quadratic model. Results: The planned average tumor temperatures T90, T50, and T10 in the planning target volume were 40.5°C, 41.6°C, and 42.4°C, respectively. The planned minimum, mean, and maximum radiation therapy doses were 62.9 Gy, 76.0 Gy, and 81.0 Gy, respectively. Adding hyperthermia yielded an equivalent dose distribution with an extended 95% isodose level. The equivalent minimum, mean, and maximum doses reflecting the radiosensitization by hyperthermia were 70.3 Gy, 86.3 Gy, and 93.6 Gy, respectively, for a linear increase of α with temperature. This can be considered similar to a dose escalation with a substantial increase in tumor control probability for high-risk prostate carcinoma. Conclusion: A model to quantify the effect of combined radiation therapy and hyperthermia in terms of equivalent dose distributions was presented. This model is particularly instructive to estimate the potential effects of interaction from different

  8. Multicenter study of combination DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis

    PubMed Central

    Wang, Yini; Huang, Wenqiu; Hu, Liangding; Cen, Xinan; Li, Lihong; Wang, Jijun; Shen, Jianliang; Wei, Na

    2015-01-01

    Hemophagocytic lymphohistiocytosis (HLH) is a refractory immune disorder with a significant risk of death. Although standard therapy has dramatically improved survival in HLH patients, approximately 30%, especially adults, show no response to current treatment strategies. This prospective study aimed to investigate the efficacy of liposomal doxorubicin treatment combined with etoposide and methylprednisolone (doxorubicin-etoposide-methylprednisolone; DEP) as a salvage therapy for adult refractory HLH. Adult patients who did not achieve at least partial response 2 weeks after initial standard HLH therapy were enrolled in this study between June 2013 and June 2014. Response to salvage therapy was assessed at 2 and 4 weeks after initiation of DEP therapy and patients were followed until death or until November 2014. Sixty-three refractory HLH patients were enrolled, including 29 cases of lymphoma-associated HLH, 22 cases of Epstein-Barr virus–associated HLH, and 4 cases of familial HLH. There were 8 cases with unknown underlying diseases. Seventeen cases (27.0%) achieved complete response and 31 cases (49.2%) achieved partial response. The overall response was 76.2% (48/63). Patients who showed no response to DEP died within 4 weeks after salvage therapy. Twenty-nine of the 48 patients who achieved partial or complete response survived to subsequent chemotherapy, allogenic hematopoietic stem cell transplantation, or splenectomy. Our study suggests that DEP regimen is an effective salvage regimen for adult refractory HLH, which can prolong patient survival as we continue to understand the responsible mechanisms and bridge the gap between HLH and its underlying diseases. This study was registered in the Chinese Clinical Trials Registry Platform (http://www.chictr.org.cn/) as ChiCTR-IPC-14005514. PMID:26289641

  9. Renoprotective effects of combined SGLT2 and ACE inhibitor therapy in diabetic Dahl S rats

    PubMed Central

    Kojima, Naoki; Williams, Jan M; Slaughter, Tiffani N; Kato, Sota; Takahashi, Teisuke; Miyata, Noriyuki; Roman, Richard J

    2015-01-01

    This study examined whether control of hyperglycemia with a new SGLT2 inhibitor, luseogliflozin, given alone or in combination with lisinopril could prevent the development of renal injury in diabetic Dahl salt-sensitive (Dahl S) rats treated with streptozotocin (Dahl-STZ). Blood glucose levels increased from normoglycemic to hyperglycemic levels after treatment of STZ in Dahl S rats. Chronic treatment of Dahl-STZ rats with luseogliflozin (10 mg/kg/day) increased the fractional excretion of glucose and normalized blood glucose and HbA1c levels. Lisinopril (20 mg/kg/day) reduced blood pressure from 145 ± 9 to 120 ± 5 mmHg in Dahl-STZ rats, while luseogliflozin had no effect on blood pressure. Combination therapy reduced blood pressure more than that seen in the rats treated with luseogliflozin or lisinopril alone. Dahl-STZ rats exhibited hyperfiltration, mesangial matrix expansion, severe progressive proteinuria, focal glomerulosclerosis and interstitial fibrosis. Control of hyperglycemia with luseogliflozin reduced the degree of hyperfiltration and renal injury but had no effect on blood pressure or the development of proteinuria. Treatment with lisinopril reduced hyperfiltration, proteinuria and renal injury in Dahl-STZ rats. Combination therapy afforded greater renoprotection than administration of either drug alone. These results suggest that long-term control of hyperglycemia with luseogliflozin, especially in combination with lisinopril to lower blood pressure, attenuates the development of renal injury in this rat model of advanced diabetic nephropathy. PMID:26169541

  10. Acneiform eruption in a patient with metastatic melanoma after ceasing combination dabrafenib/trametinib therapy.

    PubMed

    Uribe, Pablo; Anforth, Rachael M; Kefford, Richard F; Fernandez-Peñas, Pablo

    2014-10-01

    BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) increase survival in BRAF mutant metastatic melanoma patients; however, they induce a well-known spectrum of cutaneous side effects during treatment. Whereas the BRAFi dabrafenib induces cutaneous squamous cell carcinomas and verrucal keratosis, the MEKi trametinib frequently induces acneiform eruptions that are reversible after drug discontinuation. Furthermore, when dabrafenib and trametinib are used in combination, there are fewer cutaneous toxicities. We report a patient with BRAF mutant metastatic melanoma treated with the BRAFi/MEKi combination therapy who developed an acneiform eruption after treatment discontinuation rather than during active therapy. Moreover, the eruption resolved when the combination treatment was reintroduced and recurred after increasing the dose of trametinib. The eruption may be explained by the longer half-life of trametinib (4.5 days) compared with dabrafenib (5.2 h). This is the first case reported with this particular side effect induced after stopping the treatment and could become more frequent as the BRAFi/MEKi combination of drugs is more frequently prescribed. PMID:24922191

  11. Combination therapy with polymyxin B and netropsin against clinical isolates of multidrug-resistant Acinetobacter baumannii.

    PubMed

    Chung, Joon-Hui; Bhat, Abhayprasad; Kim, Chang-Jin; Yong, Dongeun; Ryu, Choong-Min

    2016-01-01

    Polymyxins are last-resort antibiotics for treating infections of Gram-negative bacteria. The recent emergence of polymyxin-resistant bacteria, however, urgently demands clinical optimisation of polymyxin use to minimise further evolution of resistance. In this study we developed a novel combination therapy using minimal concentrations of polymyxin B. After large-scale screening of Streptomyces secondary metabolites, we identified a reliable polymixin synergist and confirmed as netropsin using high-pressure liquid chromatography, nuclear magnetic resonance, and mass spectrometry followed by in vitro assays using various Gram-negative pathogenic bacteria. To evaluate the effectiveness of combining polymixin B and netropsin in vivo, we performed survival analysis on greater wax moth Galleria mellonella infected with colistin-resistant clinical Acinetobacter baumannii isolates as well as Escherichia coli, Shigella flexineri, Salmonella typhimuruim, and Pseudomonas aeruginosa. The survival of infected G. mellonella was significantly higher when treated with polymyxin B and netropsin in combination than when treated with polymyxin B or netropsin alone. We propose a netropsin combination therapy that minimises the use of polymyxin B when treating infections with multidrug resistant Gram-negative bacteria. PMID:27306928

  12. Combination therapy with polymyxin B and netropsin against clinical isolates of multidrug-resistant Acinetobacter baumannii

    PubMed Central

    Chung, Joon-hui; Bhat, Abhayprasad; Kim, Chang-Jin; Yong, Dongeun; Ryu, Choong-Min

    2016-01-01

    Polymyxins are last-resort antibiotics for treating infections of Gram-negative bacteria. The recent emergence of polymyxin-resistant bacteria, however, urgently demands clinical optimisation of polymyxin use to minimise further evolution of resistance. In this study we developed a novel combination therapy using minimal concentrations of polymyxin B. After large-scale screening of Streptomyces secondary metabolites, we identified a reliable polymixin synergist and confirmed as netropsin using high-pressure liquid chromatography, nuclear magnetic resonance, and mass spectrometry followed by in vitro assays using various Gram-negative pathogenic bacteria. To evaluate the effectiveness of combining polymixin B and netropsin in vivo, we performed survival analysis on greater wax moth Galleria mellonella infected with colistin-resistant clinical Acinetobacter baumannii isolates as well as Escherichia coli, Shigella flexineri, Salmonella typhimuruim, and Pseudomonas aeruginosa. The survival of infected G. mellonella was significantly higher when treated with polymyxin B and netropsin in combination than when treated with polymyxin B or netropsin alone. We propose a netropsin combination therapy that minimises the use of polymyxin B when treating infections with multidrug resistant Gram-negative bacteria. PMID:27306928

  13. Comparison possibilities of ultrasound and its combination with laser in surgery and therapy

    NASA Astrophysics Data System (ADS)

    Zharov, Vladimir P.; Menyaev, Yulian A.; Kabisov, Ruslan K.; Alkov, Sergey V.; Nesterov, A. V.; Loshchilov, Vladimir I.; Suen, James Y.

    2000-05-01

    This article presents the further developments of combined laser-ultrasound medical technologies with paying attention the possibility ultrasound in surgery and therapy. The analyses of main effects at the low frequency ultrasonic treatment of biotissues including cavitation, acoustic streams, acoustic pressure, mechanical influence etc are analyzed. The main promising areas of application of low frequency ultrasound are considered including bactericidal treatment of infections wounds, spray treatment of wounds in head and neck surgery, tumor treatment etc. In particular the clinical result of using ultrasonic devices based on imposing ultrasonic oscillations in a range of 22-66 kHz on a cutting instrument with a special form, radiation intensity up to 10 W/cm2 and oscillation amplitude up to 40-60 micrometers with respect to oncology for halt bleeding from a tumor, liquidating pain, acoustic denervation are presented. Some limitation of medical application of ultrasound are discussed and perspective combination with laser for increasing efficiency of new combined technologies are found. Among them: combination photodynamic therapy and ultrasonic treatment of tumors, laser-ultrasonic treatment of infections wounds including using spray, laser-ultrasonic drug delivery. The preliminary result of experimental study of some of above-mentioned technologies are presented.

  14. Involved-Node Proton Therapy in Combined Modality Therapy for Hodgkin Lymphoma: Results of a Phase 2 Study

    SciTech Connect

    Hoppe, Bradford S.; Flampouri, Stella; Zaiden, Robert; Slayton, William; Sandler, Eric; Dang, Nam H.; Lynch, James W.; Li, Zuofeng; Morris, Christopher G.; Mendenhall, Nancy P.

    2014-08-01

    Purpose: This study describes the early clinical outcomes of a prospective phase 2 study of consolidative involved-node proton therapy (INPT) as a component of combined-mode therapy in patients with stages I to III Hodgkin lymphoma (HL) with mediastinal involvement. Methods and Materials: Between September 2009 and June 2013, 15 patients with newly diagnosed HL received INPT after completing chemotherapy in an institutional review board-approved protocol comparing the dosimetric impact of PT with those of three-dimensional conformal radiation therapy (3DCRT) and intensity modulated RT. Based on {sup 18}F-Fluorodeoxyglucose positron emission tomography/computed tomography ({sup 18}F-FDG PET/CT) response, 5 children received 15 to 25.5 cobalt Gy equivalent (CGE) of INPT after receiving 4 cycles of Adriamycin, Bleomycin, Vincristine, Etoposide, Prednisone, Cyclophosphamide or Vincristine, adriamycin, methotrexate, Prednisone chemotherapy, and 10 adults received 30.6 to 39.6 CGE of INPT after 3 to 6 cycles of Adriamycin, Bleomycine, Vinblastine, Dacarbazine. Patients were routinely evaluated for toxicity during and after treatment, using Common Terminology Criteria for Adverse Events, version 3.0, and for relapse by physical examination and routine imaging. Relapse-free survival (RFS) and event-free survival (EFS) rates were calculated using the Kaplan-Meier method from the time of diagnosis. Results: The median follow-up was 37 months (range, 26-55). Two events occurred during follow-up: 1 relapse (inside and outside the targeted field) and 1 transformation into a primary mediastinal large B cell lymphoma. The 3-year RFS rate was 93%, and the 3-year EFS rate was 87%. No acute or late grade 3 nonhematologic toxicities were observed. Conclusions: Although decades of follow-up will be needed to realize the likely benefit of PT in reducing the risk of radiation-induced late effects, PT following chemotherapy in patients with HL is well-tolerated, and disease outcomes

  15. Gold Nanostructures as a Platform for Combinational Therapy in Future Cancer Therapeutics

    PubMed Central

    Jelveh, Salomeh; Chithrani, Devika B.

    2011-01-01

    The field of nanotechnology is currently undergoing explosive development on many fronts. The technology is expected to generate innovations and play a critical role in cancer therapeutics. Among other nanoparticle (NP) systems, there has been tremendous progress made in the use of spherical gold NPs (GNPs), gold nanorods (GNRs), gold nanoshells (GNSs) and gold nanocages (GNCs) in cancer therapeutics. In treating cancer, radiation therapy and chemotherapy remain the most widely used treatment options and recent developments in cancer research show that the incorporation of gold nanostructures into these protocols has enhanced tumor cell killing. These nanostructures further provide strategies for better loading, targeting, and controlling the release of drugs to minimize the side effects of highly toxic anticancer drugs used in chemotherapy and photodynamic therapy. In addition, the heat generation capability of gold nanostructures upon exposure to UV or near infrared light is being used to damage tumor cells locally in photothermal therapy. Hence, gold nanostructures provide a versatile platform to integrate many therapeutic options leading to effective combinational therapy in the fight against cancer. In this review article, the recent progress in the development of gold-based NPs towards improved therapeutics will be discussed. A multifunctional platform based on gold nanostructures with targeting ligands, therapeutic molecules, and imaging contrast agents, holds an array of promising directions for cancer research. PMID:24212654

  16. Initial Experience of Sorafenib Neoadjuvant Therapy Combined with Retroperitoneoscopy in Treating T2 Large Renal Carcinoma

    PubMed Central

    Lin, Chun-hua; Yuan, He-jia; Wang, Ke; Wu, Ji-tao; Liu, Qing-zuo; Yu, Sheng-qiang; Men, Chang-ping; Gao, Zhen-li; Wang, Jiahui

    2015-01-01

    Objectives. To investigate the safety and feasibility of sorafenib neoadjuvant therapy combined with retroperitoneoscopic radical nephrectomy (RRN) in treating T2 large renal cell carcinoma (RCC). Methods. Retrospectively analyzed 5 cases (2 males and 3 females, aged 52–73 years) of T2 stage large RCC who receive preoperative sorafenib targeted treatment (400 mg bid for 1–3 months) and RRN between March, 2013, and July, 2014. Patient information, therapeutic regimen, drug adverse effect, tumor changes before and after surgery, and perioperative parameters were recorded. Results. During the sorafenib therapy adverse effects included 2 cases of hypertension (Grade I toxicity), 1 case of hand-foot syndrome (Grade I), and 1 case of diarrhea (Grade II), which were all tolerable for patients. CT scan and histopathological tests confirmed significant reduction in the longest dimension (LD) and medium density (MD) of the tumor after therapy as well as tumor hemorrhage, necrosis, and cystic degeneration. All 5 patients received RRN surgery successfully around 2 weeks after drug discontinuation with only 1 case of perioperative complication. Conclusions. Sorafenib neoadjuvant therapy could significantly reduce the size and aggressiveness of T2 large renal tumors, thus reducing the operative challenge and enabling patients who were previously disqualified for operation to receive surgical treatment. PMID:26421296

  17. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency.

    PubMed

    De Ravin, Suk See; Wu, Xiaolin; Moir, Susan; Anaya-O'Brien, Sandra; Kwatemaa, Nana; Littel, Patricia; Theobald, Narda; Choi, Uimook; Su, Ling; Marquesen, Martha; Hilligoss, Dianne; Lee, Janet; Buckner, Clarissa M; Zarember, Kol A; O'Connor, Geraldine; McVicar, Daniel; Kuhns, Douglas; Throm, Robert E; Zhou, Sheng; Notarangelo, Luigi D; Hanson, I Celine; Cowan, Mort J; Kang, Elizabeth; Hadigan, Coleen; Meagher, Michael; Gray, John T; Sorrentino, Brian P; Malech, Harry L

    2016-04-20

    X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations inIL2RGencoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector γc transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been achieved in three younger patients, albeit with only 6 to 9 months of follow-up. Lentiviral gene therapy with reduced-intensity conditioning appears safe and can restore humoral immune function to posthaploidentical transplant older patients with SCID-X1. PMID:27099176

  18. [Resection of Advanced Intrahepatic Cholangiocarcinoma after an Effective Response to S-1 and Gemcitabine Combination Therapy].

    PubMed

    Kuga, Yoshio; Moriya, Takashi; Fukuda, Saburo; Nishida, Toshihiro

    2016-06-01

    We report curative resection of an advanced intrahepatic cholangiocarcinoma that responded well to combined S-1 and gemcitabine chemotherapy(GS therapy). A 67-year-old woman was admitted to our hospital in July 2011 for upper right abdominal pain. She was diagnosed with intrahepatic cholangiocarcinoma with abdominal para-aortic lymph node metastasis on the basis of the computed tomography (CT) findings. She was treated with GS therapy. One course of S-1(80 mg/m(3)) consisted of the administration of the drug for 14 days, followed by 14 days of rest; GEM(1,000 mg/m(3)) was administered on days 1 and 15 after initiating S-1. After 2 courses of treatment, the sizes of the primary tumor and the lymph node metastasis were observed to be reduced on CT. In September, partial hepatectomy and regional lymph node dissection were performed. The patient subsequently received 22 postoperative courses of GS therapy. The patient's postoperative course was uneventful, and she remains free of recurrence 49 months since diagnosis. Therefore, GS therapy is a possible option for the management of advanced intrahepatic cholangiocarcinoma. PMID:27306819

  19. [Pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C].

    PubMed

    Oze, Tsugiko; Hiramatsu, Naoki; Takehara, Tetsuo

    2015-02-01

    The antiviral therapy for patients with chronic hepatitis C virus(HCV) infection has changed from interferon(IFN) monotherapy to dual therapy with IFN plus ribavirin(RBV), moreover pegylated IFN(Peg-IFN) plus RBV. The sustained virologic response(SVR), defined as HCV RNA negativiation at 24 weeks after the treatment, were obtained 50% among the patients with genotype 1 (48 weeks treatment) and 80% among those with genotype 2 (24 weeks treatment) in Peg-IFN plus RBV combination therapy. The baseline host factors such as age, the degree of liver fibrosis progression and a genetic polymorphism near the IL28B gene, the viral factors such as HCV genotype, mutant virus at HCV core region and interferon sensitivity determining region, the treatment factors such as drug adherence and treatment duration have been reported to be associated with SVR. The risk for hepatocellular carcinoma (HCC) incidence was significantly lower in SVR patients than non-SVR patients. Especially, alpha-fetoprotein (AFP) levels decreased through therapy, and the patients with < 5 ng/mL had a low potential of HCC incidence regardless of HCV eradication. It is suggested that AFP levels at 24 weeks after the treatment can be a good surrogate marker for HCC incidence irrespective of the virologic response. PMID:25764679

  20. Radiation therapy alone or in combination with surgery in head and neck cancer

    SciTech Connect

    Marcial, V.A.; Pajak, T.F.

    1985-05-01

    Radiation therapy alone, surgery alone, or the combination of these two modalities, remain the accepted treatments in the management of epidermoid carcinomas of the mucosa of the head and neck. These modalities of therapy produce comparable results; but, radiotherapy alone has the advantage that it can conserve anatomy and function. Irradiation with teletherapy techniques, at times supplemented by interstitial brachytherapy, with doses ranging from 6600 to 8000 cGy, results in satisfactory tumor response (CR). The CR of T1N0 and T2N0 lesions will be 99% and 90% respectively, but only 29% in T4N3 tumors treated with radiation only. To improve on the limited CR rate achieved in the advanced stages, surgery is combined pre or post-irradiation, or reserved for the salvage of failures. In the oral cavity and oropharynx, these possible options give comparable tumor control and survival, but in the supraglottic larynx post-operative irradiation is superior to pre- operative radiotherapy. Tumor recurrence rates in the head and neck range from 15 to 34% depending on initial site, stage and type of therapy. Cancer control activities that emphasize prevention and early diagnosis should present a better future for these patients.

  1. Costs associated with combination antiretroviral therapy in HIV-infected patients.

    PubMed

    Yazdanpanah, Yazdan

    2004-04-01

    As more effective HIV therapies have become available, resource constraints and cost-effectiveness have increasingly been at the centre of the debate on HIV care. Economic analysis is an important methodological approach to the understanding and establishment of priorities for health interventions designed to combat HIV in both high-income and low-income countries. In this paper, I briefly discuss different types of clinical economic analysis, and then consider the cost, affordability and cost-effectiveness of combination antiretroviral therapy in HIV patients in high-income and low-income countries. In high-income countries, HIV disease has become an expensive treatable chronic disease, with annual expenditures per patient of about US$ 20 000. Cost-effectiveness analyses show that antiretroviral therapeutic regimens offer good value for the resources spent compared to many other accepted health care interventions. In low-income countries, major programmes of combination antiretroviral therapy distribution are being planned and becoming operational as drug prices plummet and resources increase. More refined cost-effectiveness analyses are needed to evaluate available HIV/AIDS prevention, treatment, and care, and to identify the interventions that provide the best value for money. PMID:14985277

  2. Multifunctional Fe2O3@PPy-PEG nanocomposite for combination cancer therapy with MR imaging

    NASA Astrophysics Data System (ADS)

    Zhou, Jun; Li, Jinghua; Ding, Xingwei; Liu, Junjie; Luo, Zhong; Liu, Yun; Ran, Qichun; Cai, Kaiyong

    2015-10-01

    In recent years, magnetic hyperthermia nanoparticles have drawn great attention for cancer therapy because they have no limitation of tissue penetration during the therapy process. In this study, cubic nanoporous Fe2O3 nanoparticles derived from cubic Prussian blue nanoparticles were used as magnetic cores to generate heat by alternating the current magnetic field (AMF) for killing cancer cells. In addition, polypyrrole (PPy) was coated on the surfaces of the cubic Fe2O3 nanoparticles to load doxorubicin hydrochloride (DOX). The PEG component was then physically adsorbed onto the surfaces of the nanoparticles, resulting in a Fe2O3@PPy-DOX-PEG nanocomposite. The nanocomposite was triggered by acid stimulus and AMF to release DOX, resulting in a remarkable combination therapeutic effect via chemotherapy and magnetic hyperthermia. Furthermore, the nanocomposite could realize magnetic resonance imaging (MRI) due to the magnetic core structure. The study provides an alternative for the development of new nanocomposites for combination cancer therapy with MR imaging in vivo.

  3. Malignant Esophagogastric Junction Obstruction: Efficacy of Balloon Dilation Combined with Chemotherapy and/or Radiation Therapy