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Sample records for antifungal combination therapy

  1. Combination Antifungal Therapy for Cryptococcal Meningitis

    PubMed Central

    Day, Jeremy N.; Chau, Tran T.H.; Wolbers, Marcel; Mai, Pham P.; Dung, Nguyen T.; Mai, Nguyen H.; Phu, Nguyen H.; Nghia, Ho D.; Phong, Nguyen D.; Thai, Cao Q.; Thai, Le H.; Chuong, Ly V.; Sinh, Dinh X.; Duong, Van A.; Hoang, Thu N.; Diep, Pham T.; Campbell, James I.; Sieu, Tran P.M.; Baker, Stephen G.; Chau, Nguyen V.V.; Hien, Tran T.

    2014-01-01

    BACKGROUND Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days. METHODS We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks. RESULTS A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P = 0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P = 0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P = 0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P = 0.13). amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (−0.42 log10 colony-forming units [CFU] per milliliter per day vs. −0.31 and −0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although

  2. Antifungal combinations.

    PubMed

    Vitale, Roxana G; Afeltra, Javier; Dannaoui, Eric

    2005-01-01

    The increase in fungal infections and the change in fungal epidemiology is caused by the extensive use of antifungal agents to treat fungal infections that are being diagnosed in severly immunocompromised hosts. In addition, opportunistic fungal infections resistant to antifungal drugs have become increasingly common, and the armamentarium for treatment remains limited. A possible approach to overcoming these problems is to combine antifungal drugs, especially if the mechanisms of action are different. The in vitro test is the first step to evaluate possible antifungal combinations. In this chapter, the three most frequently used metholodologies are described: checkerboard, E-test, and time-kill curves. The description of each technique and intrepretaion of the results are addressed in detail.

  3. Use of Antifungal Combination Therapy: Agents, Order, and Timing

    PubMed Central

    Perfect, John R.

    2010-01-01

    Given the substantial morbidity and mortality related to invasive fungal infections, treatment with a combination of antifungal agents is often considered. A growing body of literature from in vitro studies, animal models, and clinical experience provides data evaluating this approach. This review describes combination antifungal strategies for the management of cryptococcal meningitis, invasive candidiasis, invasive aspergillosis, and rare mold infections. The potential effects that sequencing and timing have on the efficacy of such approaches are discussed, with a focus on recent clinical data in this arena. PMID:20574543

  4. Successful use of combination antifungal therapy in the treatment of coccidioides meningitis.

    PubMed Central

    Antony, Suresh J.; Jurczyk, Peter; Brumble, Lisa

    2006-01-01

    Coccidioidal meningitis is a highly lethal condition with a high morbidity and relapse rate caused by Coccidioides immitis. This case report highlights the difficulty in diagnosing and treating coccidioidal meningitis, and discusses a novel combination antifungal therapy (voriconazole and liposomal amphotericin B), which was used to treat this patient. Images Figure 1 Figure 2 PMID:16775917

  5. Pediatric antifungal therapy. Part I: focus on febrile neutropenia, invasive aspergillosis, combination antifungal therapy and invasive candidiasis in immunocompromised pediatric patients.

    PubMed

    Allen, U; Bow, E; Doyle, J; Richardson, S; Robinson, J; Rotstein, C; Davies, D; Hui, C; Le Saux, N; Laverdiere, M; Read, S

    2010-02-01

    The number of available antifungal agents has significantly increased in recent years. These agents are starting to take over niches that were previously occupied by conventional amphotericin B. For many of these agents, pediatric data from randomized trials are generally lacking and clinicians are faced with extrapolating from data generated in adult patients. This notwithstanding, this report summarizes recommendations that define the roles of newer antifungal agents in the treatment of selected scenarios among immunocompromised pediatric patients. The report includes the outcome of a Canadian conference on the use of antifungal agents in children, supplemented by literature reviews and incorporating information from existing national or international guidelines, where appropriate. The focus of the report is on febrile neutropenia, invasive aspergillosis, combination antifungal therapy and selected aspects of the management of invasive candidiasis.

  6. New facets of antifungal therapy.

    PubMed

    Chang, Ya-Lin; Yu, Shang-Jie; Heitman, Joseph; Wellington, Melanie; Chen, Ying-Lien

    2017-02-17

    Invasive fungal infections remain a major cause of morbidity and mortality in immunocompromised patients, and such infections are a substantial burden to healthcare systems around the world. However, the clinically available armamentarium for invasive fungal diseases is limited to 3 main classes (i.e., polyenes, triazoles, and echinocandins), and each has defined limitations related to spectrum of activity, development of resistance, and toxicity. Further, current antifungal therapies are hampered by limited clinical efficacy, high rates of toxicity, and significant variability in pharmacokinetic properties. New antifungal agents, new formulations, and novel combination regimens may improve the care of patients in the future by providing improved strategies to combat challenges associated with currently available antifungal agents. Likewise, therapeutic drug monitoring may be helpful, but its present use remains controversial due to the lack of available data. This article discusses new facets of antifungal therapy with a focus on new antifungal formulations and the synergistic effects between drugs used in combination therapy.

  7. 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

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

    PubMed

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

    2016-06-01

    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

  9. Antifungal Lock Therapy

    PubMed Central

    Walraven, Carla J.

    2013-01-01

    The widespread use of intravascular devices, such as central venous and hemodialysis catheters, in the past 2 decades has paralleled the increasing incidence of catheter-related bloodstream infections (CR-BSIs). Candida albicans is the fourth leading cause of hospital-associated BSIs. The propensity of C. albicans to form biofilms on these catheters has made these infections difficult to treat due to multiple factors, including increased resistance to antifungal agents. Thus, curing CR-BSIs caused by Candida species usually requires catheter removal in addition to systemic antifungal therapy. Alternatively, antimicrobial lock therapy has received significant interest and shown promise as a strategy to treat CR-BSIs due to Candida species. The existing in vitro, animal, and patient data for treatment of Candida-related CR-BSIs are reviewed. The most promising antifungal lock therapy (AfLT) strategies include use of amphotericin, ethanol, or echinocandins. Clinical trials are needed to further define the safety and efficacy of AfLT. PMID:23070153

  10. Combination antifungal therapy and surgery for the treatment of invasive pulmonary aspergillosis after hematopoietic stem cell transplantation

    PubMed Central

    Cesaro, Simone; Pillon, Marta; Calore, Elisabetta; Alaggio, Rita; Gamba, Piergiorgio; Bergamo, Silvia; Mainardi, Chiara; Toffolutti, Tiziana; Pegoraro, Anna; Messina, Chiara

    2011-01-01

    An 8-year old boy, affected by severe aplastic anemia, developed a probable pulmonary invasive aspergillosis (IA) early after a second unrelated allogeneic hematopoietic stem cell transplant (HSCT). He was treated promptly with the combination of liposomal amphotericin B and caspofungin. Despite the initial stabilization, the patient deteriorated and the antifungal therapy was switched to voriconazole and caspofungin. The patient gradually improved and was discharged home on day +29 post-HSCT on oral voriconazole. On day +119, a sudden episode of hemoptysis occurred and a right superior lobectomy was decided to remove the residual aspergilloma. The patient is now alive and well more than 24 months from HSCT. This case demonstrated that antifungal combination therapy and surgery are valid options to cure pulmonary IA even in patients at high-risk and severely immunosuppressed. PMID:21772955

  11. Combination antifungal therapy and surgery for the treatment of invasive pulmonary aspergillosis after hematopoietic stem cell transplantation.

    PubMed

    Cesaro, Simone; Pillon, Marta; Calore, Elisabetta; Alaggio, Rita; Gamba, Piergiorgio; Bergamo, Silvia; Mainardi, Chiara; Toffolutti, Tiziana; Pegoraro, Anna; Messina, Chiara

    2011-06-16

    An 8-year old boy, affected by severe aplastic anemia, developed a probable pulmonary invasive aspergillosis (IA) early after a second unrelated allogeneic hematopoietic stem cell transplant (HSCT). He was treated promptly with the combination of liposomal amphotericin B and caspofungin. Despite the initial stabilization, the patient deteriorated and the antifungal therapy was switched to voriconazole and caspofungin. The patient gradually improved and was discharged home on day +29 post-HSCT on oral voriconazole. On day +119, a sudden episode of hemoptysis occurred and a right superior lobectomy was decided to remove the residual aspergilloma. The patient is now alive and well more than 24 months from HSCT. This case demonstrated that antifungal combination therapy and surgery are valid options to cure pulmonary IA even in patients at high-risk and severely immunosuppressed.

  12. Resolution of disseminated fusariosis in a child with acute leukemia treated with combined antifungal therapy: a case report

    PubMed Central

    Vagace, José-Manuel; Sanz-Rodriguez, Cesar; Casado, Maria-Soledad; Alonso, Nieves; Garcia-Dominguez, Manuel; de la Llana, Francisco Garcia; Zarallo, Luis; Fajardo, Miguel; Bajo, Roberto

    2007-01-01

    Background Fusarium spp. is being isolated with increasing frequency as a pathogen in oncohematologic patients. Caspofungin and amphotericin B have been reported to have synergistic activity against Fusarium spp. Case presentation We herein report a case of disseminated fusariosis diagnosed by chest CT scan and positive blood cultures to Fusarium spp. Because the patient's clinical condition deteriorated, CRP levels increased, and blood cultures continued to yield Fusarium spp. despite liposomal amphotericin B monotherapy up to 5 mg/kg daily, treatment with caspofungin was added. Within 2 weeks of onset of combined antifungal therapy, the chest CT scan demonstrated a progressive resolution of the pulmonary lesions. Upon discontinuation of intravenous antifungals, the patient received suppressive therapy with oral voriconazole. Three months later, a chest CT scan showed no abnormalities. Twenty-five months after discontinuation of all antifungal therapy, the patient remains in complete remission of her neoplastic disease with no signs of clinical activity of the Fusarium infection. Conclusion This is the first description of successful treatment of disseminated fusariosis in a pediatric patient with acute lymphoblastic leukemia with caspofungin and amphotericin B followed by oral suppressive therapy with voriconazole. PMID:17493279

  13. Resistance to antifungal therapies.

    PubMed

    Prasad, Rajendra; Banerjee, Atanu; Shah, Abdul Haseeb

    2017-02-28

    The evolution of antifungal resistance among fungal pathogens has rendered the limited arsenal of antifungal drugs futile. Considering the recent rise in the number of nosocomial fungal infections in immunocompromised patients, the emerging clinical multidrug resistance (MDR) has become a matter of grave concern for medical professionals. Despite advances in therapeutic interventions, it has not yet been possible to devise convincing strategies to combat antifungal resistance. Comprehensive understanding of the molecular mechanisms of antifungal resistance is essential for identification of novel targets that do not promote or delay emergence of drug resistance. The present study discusses features and limitations of the currently available antifungals, mechanisms of antifungal resistance and highlights the emerging therapeutic strategies that could be deployed to combat MDR.

  14. Polymicrobial Ventilator-Associated Pneumonia: Fighting In Vitro Candida albicans-Pseudomonas aeruginosa Biofilms with Antifungal-Antibacterial Combination Therapy.

    PubMed

    Rodrigues, Maria E; Lopes, Susana P; Pereira, Cláudia R; Azevedo, Nuno F; Lourenço, Anália; Henriques, Mariana; Pereira, Maria O

    2017-01-01

    The polymicrobial nature of ventilator-associated pneumonia (VAP) is now evident, with mixed bacterial-fungal biofilms colonizing the VAP endotracheal tube (ETT) surface. The microbial interplay within this infection may contribute for enhanced pathogenesis and exert impact towards antimicrobial therapy. Consequently, the high mortality/morbidity rates associated to VAP and the worldwide increase in antibiotic resistance has promoted the search for novel therapeutic strategies to fight VAP polymicrobial infections. Under this scope, this work aimed to assess the activity of mono- vs combinational antimicrobial therapy using one antibiotic (Polymyxin B; PolyB) and one antifungal (Amphotericin B; AmB) agent against polymicrobial biofilms of Pseudomonas aeruginosa and Candida albicans. The action of isolated antimicrobials was firstly evaluated in single- and polymicrobial cultures, with AmB being more effective against C. albicans and PolyB against P. aeruginosa. Mixed planktonic cultures required equal or higher antimicrobial concentrations. In biofilms, only PolyB at relatively high concentrations could reduce P. aeruginosa in both monospecies and polymicrobial populations, with C. albicans displaying only punctual disturbances. PolyB and AmB exhibited a synergistic effect against P. aeruginosa and C. albicans mixed planktonic cultures, but only high doses (256 mg L-1) of PolyB were able to eradicate polymicrobial biofilms, with P. aeruginosa showing loss of cultivability (but not viability) at 2 h post-treatment, whilst C. albicans only started to be inhibited after 14 h. In conclusion, combination therapy involving an antibiotic and an antifungal agent holds an attractive therapeutic option to treat severe bacterial-fungal polymicrobial infections. Nevertheless, optimization of antimicrobial doses and further clinical pharmacokinetics/pharmacodynamics and toxicodynamics studies underpinning the optimal use of these drugs are urgently required to improve therapy

  15. Polymicrobial Ventilator-Associated Pneumonia: Fighting In Vitro Candida albicans-Pseudomonas aeruginosa Biofilms with Antifungal-Antibacterial Combination Therapy

    PubMed Central

    Pereira, Cláudia R.; Azevedo, Nuno F.; Lourenço, Anália; Henriques, Mariana; Pereira, Maria O.

    2017-01-01

    The polymicrobial nature of ventilator-associated pneumonia (VAP) is now evident, with mixed bacterial-fungal biofilms colonizing the VAP endotracheal tube (ETT) surface. The microbial interplay within this infection may contribute for enhanced pathogenesis and exert impact towards antimicrobial therapy. Consequently, the high mortality/morbidity rates associated to VAP and the worldwide increase in antibiotic resistance has promoted the search for novel therapeutic strategies to fight VAP polymicrobial infections. Under this scope, this work aimed to assess the activity of mono- vs combinational antimicrobial therapy using one antibiotic (Polymyxin B; PolyB) and one antifungal (Amphotericin B; AmB) agent against polymicrobial biofilms of Pseudomonas aeruginosa and Candida albicans. The action of isolated antimicrobials was firstly evaluated in single- and polymicrobial cultures, with AmB being more effective against C. albicans and PolyB against P. aeruginosa. Mixed planktonic cultures required equal or higher antimicrobial concentrations. In biofilms, only PolyB at relatively high concentrations could reduce P. aeruginosa in both monospecies and polymicrobial populations, with C. albicans displaying only punctual disturbances. PolyB and AmB exhibited a synergistic effect against P. aeruginosa and C. albicans mixed planktonic cultures, but only high doses (256 mg L-1) of PolyB were able to eradicate polymicrobial biofilms, with P. aeruginosa showing loss of cultivability (but not viability) at 2 h post-treatment, whilst C. albicans only started to be inhibited after 14 h. In conclusion, combination therapy involving an antibiotic and an antifungal agent holds an attractive therapeutic option to treat severe bacterial-fungal polymicrobial infections. Nevertheless, optimization of antimicrobial doses and further clinical pharmacokinetics/pharmacodynamics and toxicodynamics studies underpinning the optimal use of these drugs are urgently required to improve therapy

  16. Evaluation of improvement of onychomycosis in HIV-infected patients after initiation of combined antiretroviral therapy without antifungal treatment.

    PubMed

    Ruíz-López, Patricia; Moreno-Coutiño, Gabriela; Fernández-Martínez, Ramón; Espinoza-Hernández, Jessica; Rodríguez-Zulueta, Patricia; Reyes-Terán, Gustavo

    2015-09-01

    Onychomycosis in HIV-infected patients has a prevalence of 20-44% and is more frequently seen with CD4(+) T cell counts ≤450 cel μl(-1). There are case reports of improvement in onychomycosis after initiation of combined antiretroviral therapy (cART), but there are no prospective studies that prove the existence and frequency of this phenomenon. The aim of this study was to evaluate if HIV-infected patients with onychomycosis who begin cART improve and/or cure without antifungal treatment. We included HIV-infected patients with onychomycosis who had not started cART and nor received antifungal therapy during 6 months prior to the study. We evaluated affected the nails with the Onychomycosis Severity Index (OSI); nail scrapings were collected and direct microscopy with potassium hydroxide (KOH) as well as mycological culture were performed. We repeated these procedures at 3 and 6 months to assess changes. CD4 T cell counts and HIV viral load were obtained. A total of 16 patients were included, with male gender predominance (68.7%); distal and lateral subungual onychomycosis (DLSO) was the most common form (31.3%). Trichophyton rubrum was the most frequently isolated microorganism. OSI decreased 21.5% at 3 months and 40% at 6 months after initiation of antiretrovirals (P = 0.05). We found a non-significant tendency towards improvement with higher CD4(+) T cell counts and with viral loads <100 000 copies ml(-1). This could be due to the increase in CD4(+) T cells, decreased percentage of Treg (CD4(+)CD25(+)) among CD4(+) Tcells and/or a decreased viral load; further studies are necessary to prove these hypothesis.

  17. 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.

  18. 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

  19. Salvage combination antifungal therapy for acute invasive aspergillosis may improve outcomes: a systematic review and meta-analysis

    PubMed Central

    Panackal, Anil A.; Parisini, Emilio; Proschan, Michael

    2014-01-01

    Summary Objective A meta-analysis was performed to compare mold-active triazoles or lipid amphotericin B plus an echinocandin to non-echinocandin monotherapy for acute invasive aspergillosis (IA). Methods We searched PubMed, EMBASE, and other databases through May 2013 unrestricted by language. We included observational and experimental studies wherein patients with proven or probable IA by EORTC/MSG criteria underwent our comparative intervention. PRISMA and MOOSE guidelines were followed and quality was assessed using the Jadad and Newcastle–Ottawa criteria. Meta-regression with fixed and random effects and sensitivity analyses were performed. The primary study outcome measure was 12-week overall mortality. The secondary outcome assessed was complete and partial response. Results Only observational studies of primary 12-week survival showed heterogeneity (I2 = 48.96%, p = 0.05). For salvage IA therapy, fixed effects models demonstrated improved 12-week survival (Peto odds ratio (OR) 1.80, 95% confidence interval (CI) 1.08–3.01) and success (Peto OR 2.17, 95% CI 1.21–3.91) of combination therapy. Significance remained after applying random effects as a sensitivity analysis (12-week survival: Peto OR 1.90, 95% CI 1.04–3.46, and unchanged value for success). Restriction to high quality studies and including echinocandins as the comparator for refractory IA revealed an adjusted OR of 1.72 (95% CI 0.96–3.09; p = 0.07) for global success, while the survival endpoint remained unaltered. Conclusions Combination antifungals for IA demonstrate improved outcomes over monotherapy in the salvage setting. Clinicians should consider this approach in certain situations. PMID:25240416

  20. 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.

  1. Combination Antifungal Therapy in the Treatment of Scedosporium apiospermum Central Nervous System Infections

    PubMed Central

    Henao-Martínez, Andrés F.; Castillo-Mancilla, José R.; Barron, Michelle A.; Nichol, Aran Cunningham

    2013-01-01

    Treatment of Scedosporium apiospermum central nervous system (CNS) infection typically consists of an azole in combination with surgical debridement. This approach requires prolonged treatment and carries a high associated mortality. We present two cases of the successful treatment of S. apiospermum CNS infections with the combination of voriconazole and terbinafine. PMID:23738164

  2. Modern antifungal therapy for neutropenic fever.

    PubMed

    Corey, Melissa

    2006-06-01

    Empirical antifungal therapy has been shown to decrease the number of documented fungal infections in the setting of persistent fever during neutropenia. For decades, amphotericin B deoxycholate has been considered the agent of choice for first-line therapy in this setting. New antifungal agents associated with less toxicity, including the lipid formulations of amphotericin, voriconazole, and caspofungin, are now available and are considered to be suitable alternative first-line agents. In order to ensure appropriate therapy, however, the clinician must consider not only the differences between these antifungals but also patient-specific factors before initiating treatment.

  3. ASDCD: Antifungal Synergistic Drug Combination Database

    PubMed Central

    Chen, Ming; Liu, Ming-Xi; Ren, Wei; Wang, Quan-Xin; Zhang, Li-Xin; Yan, Gui-Ying

    2014-01-01

    Finding effective drugs to treat fungal infections has important clinical significance based on high mortality rates, especially in an immunodeficient population. Traditional antifungal drugs with single targets have been reported to cause serious side effects and drug resistance. Nowadays, however, drug combinations, particularly with respect to synergistic interaction, have attracted the attention of researchers. In fact, synergistic drug combinations could simultaneously affect multiple subpopulations, targets, and diseases. Therefore, a strategy that employs synergistic antifungal drug combinations could eliminate the limitations noted above and offer the opportunity to explore this emerging bioactive chemical space. However, it is first necessary to build a powerful database in order to facilitate the analysis of drug combinations. To address this gap in our knowledge, we have built the first Antifungal Synergistic Drug Combination Database (ASDCD), including previously published synergistic antifungal drug combinations, chemical structures, targets, target-related signaling pathways, indications, and other pertinent data. Its current version includes 210 antifungal synergistic drug combinations and 1225 drug-target interactions, involving 105 individual drugs from more than 12,000 references. ASDCD is freely available at http://ASDCD.amss.ac.cn. PMID:24475134

  4. 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.

  5. Evaluation of antifungal combination against Cryptococcus spp.

    PubMed

    Reichert-Lima, Franqueline; Busso-Lopes, Ariane F; Lyra, Luzia; Peron, Isabela Haddad; Taguchi, Hideaki; Mikami, Yuzuru; Kamei, Katsuiko; Moretti, Maria Luiza; Schreiber, Angelica Z

    2016-09-01

    The second cause of death among systemic mycoses, cryptococcosis treatment represents a challenge since that 5-flucytosine is not currently available in Brazil. Looking for alternatives, this study evaluated antifungal agents, alone and combined, correlating susceptibility to genotypes. Eighty Cryptococcus clinical isolates were genotyped by URA5 gene restriction fragment length polymorphism. Antifungal susceptibility was assessed following CLSI-M27A3 for amphotericin (AMB), 5-flucytosine (5FC), fluconazole (FCZ), voriconazole (VRZ), itraconazole (ITZ) and terbinafine (TRB). Drug interaction chequerboard assay evaluated: AMB + 5FC, AMB + FCZ, AMB + TRB and FCZ + TRB. Molecular typing divided isolates into 14 C. deuterogattii (VGII) and C. neoformans isolates were found to belong to genotype VNI (n = 62) and VNII (n = 4). C. neoformans VNII was significantly less susceptible than VNI (P = 0.0407) to AMB; C. deuterogattii was significantly less susceptible than VNI and VNII to VRZ (P < 0.0001). C. deuterogattii was less susceptible than C. neoformans VNI for FCZ (P = 0.0170), ITZ (P < 0.0001) and TRB (P = 0.0090). The combination FCZ + TRB showed 95.16% of synergistic effect against C. neoformans genotype VNI isolates and all combinations showed 100% of synergism against genotype VNII isolates, suggesting the relevance of cryptococcal genotyping as it is widely known that the various genotypes (now species) have significant impact in antifungal susceptibilities and clinical outcome. In difficult-to-treat cryptococcosis, terbinafine and different antifungal combinations might be alternatives to 5FC.

  6. Human mycoses and advances in antifungal therapy.

    PubMed

    Fromtling, R A

    2001-04-01

    The 11th Focus on Fungal Infections meeting was held in Washington, D.C., U.S.A., March 1416, 2001. At the conference, there were well-attended sessions that focused on the pathogenesis and therapy of fungal disease. This report focuses on new information on fungal incidence and pathogenesis as well as on the in vitro and clinical experience of established antifungal drugs (fluconazole, itraconazole, amphotericin B, liposomal formulations of amphotericin B, terbinafine) and the newer antifungal compounds approved for use (e.g., caspofungin) and in development (the new-generation azoles: voriconazole, posaconazole, ravuconazole, and the candins, micafungin and anidulafungin).

  7. 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

  8. Efficacy of combination antifungal therapy with intraperitoneally administered micafungin and aerosolized liposomal amphotericin B against murine invasive pulmonary aspergillosis.

    PubMed

    Takazono, Takahiro; Izumikawa, Koichi; Mihara, Tomo; Kosai, Kosuke; Saijo, Tomomi; Imamura, Yoshifumi; Miyazaki, Taiga; Seki, Masafumi; Kakeya, Hiroshi; Yamamoto, Yoshihiro; Yanagihara, Katsunori; Kohno, Shigeru

    2009-08-01

    Targeted intrapulmonary delivery of drugs may reduce systemic toxicity and improve treatment efficacy. In the current study, we evaluated the effects of a combination treatment consisting of inhalation of aerosolized liposomal amphotericin B (L-AMB) with intraperitoneal administration of micafungin (MCFG) against murine invasive pulmonary aspergillosis. The combination of aerosolized L-AMB with intraperitoneal MCFG significantly improved the survival rate, and the fungal burdens and histopathology findings after this treatment were superior to those of the control and both monotherapy groups.

  9. 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

  10. Sequential or combination antifungal therapy with voriconazole and liposomal amphotericin B in a Guinea pig model of invasive aspergillosis.

    PubMed

    Kirkpatrick, William R; Coco, Brent J; Patterson, Thomas F

    2006-04-01

    We evaluated combinations of voriconazole (VRC) and liposomal amphotericin B (L-AMB) in a guinea pig invasive aspergillosis model. Simultaneous VRC and L-AMB was most effective, although VRC monotherapy was also effective. These regimens as well as sequential L-AMB followed by VRC were more effective than L-AMB alone or VRC followed by L-AMB.

  11. 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

  12. Update on antifungal therapy with terbinafine.

    PubMed

    Gianni, C

    2010-06-01

    Terbinafine, a synthetic antifungal of allylamine class, has fungicidal activity against dermatophytes, moulds and certain dimorphic fungi and fungistatic activity against Candida albicans. Following oral administration the terbinafine is absorbed rapidly (>70%) and reaches within 2 hours the peak plasma concentration. The drug is highly lipophilic and keratophilic and is highly bound to plasma protein (>90%) with a bioavailability of 70% to 80%. The drug is rapidly delivered and it is present in the stratum corneum, sebum, nails and hair for months after stopping the medication. The drug has been proven to be the choice treatment in the therapy of onychomycosis as it is very effective, well tolerated and has a relatively low potential for drug interactions. The pharmacologic and pharmacokinetic properties of terbinafine give strong support to the possibility that the pulse therapy may be equally effective in onychomycoses, possibly reducing medication costs and drug exposure. Several therapeutic patterns have been proposed: weekly intermittent terbinafine (500 mg/d for 1 week each month for 4 months), or single-dose terbinafine (1000 mg per month for 4 months). Use of topical terbinafine 1% may be practical where the tinea involvement is not extensive or chronic. Recently, the terbinafine is available in a novel topical solution (film-forming solution--FFS) effective in the treatment of tinea pedis (athlete's foot).

  13. Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis.

    PubMed

    Scorzoni, Liliana; de Paula E Silva, Ana C A; Marcos, Caroline M; Assato, Patrícia A; de Melo, Wanessa C M A; de Oliveira, Haroldo C; Costa-Orlandi, Caroline B; Mendes-Giannini, Maria J S; Fusco-Almeida, Ana M

    2017-01-01

    The high rates of morbidity and mortality caused by fungal infections are associated with the current limited antifungal arsenal and the high toxicity of the compounds. Additionally, identifying novel drug targets is challenging because there are many similarities between fungal and human cells. The most common antifungal targets include fungal RNA synthesis and cell wall and membrane components, though new antifungal targets are being investigated. Nonetheless, fungi have developed resistance mechanisms, such as overexpression of efflux pump proteins and biofilm formation, emphasizing the importance of understanding these mechanisms. To address these problems, different approaches to preventing and treating fungal diseases are described in this review, with a focus on the resistance mechanisms of fungi, with the goal of developing efficient strategies to overcoming and preventing resistance as well as new advances in antifungal therapy. Due to the limited antifungal arsenal, researchers have sought to improve treatment via different approaches, and the synergistic effect obtained by the combination of antifungals contributes to reducing toxicity and could be an alternative for treatment. Another important issue is the development of new formulations for antifungal agents, and interest in nanoparticles as new types of carriers of antifungal drugs has increased. In addition, modifications to the chemical structures of traditional antifungals have improved their activity and pharmacokinetic parameters. Moreover, a different approach to preventing and treating fungal diseases is immunotherapy, which involves different mechanisms, such as vaccines, activation of the immune response and inducing the production of host antimicrobial molecules. Finally, the use of a mini-host has been encouraging for in vivo testing because these animal models demonstrate a good correlation with the mammalian model; they also increase the speediness of as well as facilitate the

  14. Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis

    PubMed Central

    Scorzoni, Liliana; de Paula e Silva, Ana C. A.; Marcos, Caroline M.; Assato, Patrícia A.; de Melo, Wanessa C. M. A.; de Oliveira, Haroldo C.; Costa-Orlandi, Caroline B.; Mendes-Giannini, Maria J. S.; Fusco-Almeida, Ana M.

    2017-01-01

    The high rates of morbidity and mortality caused by fungal infections are associated with the current limited antifungal arsenal and the high toxicity of the compounds. Additionally, identifying novel drug targets is challenging because there are many similarities between fungal and human cells. The most common antifungal targets include fungal RNA synthesis and cell wall and membrane components, though new antifungal targets are being investigated. Nonetheless, fungi have developed resistance mechanisms, such as overexpression of efflux pump proteins and biofilm formation, emphasizing the importance of understanding these mechanisms. To address these problems, different approaches to preventing and treating fungal diseases are described in this review, with a focus on the resistance mechanisms of fungi, with the goal of developing efficient strategies to overcoming and preventing resistance as well as new advances in antifungal therapy. Due to the limited antifungal arsenal, researchers have sought to improve treatment via different approaches, and the synergistic effect obtained by the combination of antifungals contributes to reducing toxicity and could be an alternative for treatment. Another important issue is the development of new formulations for antifungal agents, and interest in nanoparticles as new types of carriers of antifungal drugs has increased. In addition, modifications to the chemical structures of traditional antifungals have improved their activity and pharmacokinetic parameters. Moreover, a different approach to preventing and treating fungal diseases is immunotherapy, which involves different mechanisms, such as vaccines, activation of the immune response and inducing the production of host antimicrobial molecules. Finally, the use of a mini-host has been encouraging for in vivo testing because these animal models demonstrate a good correlation with the mammalian model; they also increase the speediness of as well as facilitate the

  15. Antifungal therapy for chronic rhinosinusitis: the controversy persists

    PubMed Central

    Rank, Matthew A.; Adolphson, Cheryl R.; Kita, Hirohito

    2014-01-01

    Purpose of review Chronic rhinosinusitis is a debilitating disease seen frequently by allergist–immunologists. Recent research examining the pathophysiological mechanisms and treatment options for chronic rhinosinusitis have yielded contradicting results, particularly in regard to the role of fungi and antifungal therapies. Recent findings Recent studies using antifungal therapies for chronic rhinosinusitis will be critically evaluated with careful attention to sample selection, length of the intervention, drug delivery system, drug stability and handling, assessment of compliance to study medications, and choice of outcome measures with attention to study power (both primary and secondary). Using this framework to evaluate currently available studies reveals limitations in studies showing a benefit for antifungal therapy and in studies showing no benefit (or harm). Summary Limitations in studies that either support or refute the benefit of antifungal therapy for chronic rhinosinusitis prevent any firm conclusions about its efficacy. PMID:19532095

  16. Empiric antifungal therapy and outcomes in extremely low birth weight infants with invasive candidiasis.

    PubMed

    Greenberg, Rachel G; Benjamin, Daniel K; Gantz, Marie G; Cotten, C Michael; Stoll, Barbara J; Walsh, Michele C; Sánchez, Pablo J; Shankaran, Seetha; Das, Abhik; Higgins, Rosemary D; Miller, Nancy A; Auten, Kathy J; Walsh, Thomas J; Laptook, Abbot R; Carlo, Waldemar A; Kennedy, Kathleen A; Finer, Neil N; Duara, Shahnaz; Schibler, Kurt; Ehrenkranz, Richard A; Van Meurs, Krisa P; Frantz, Ivan D; Phelps, Dale L; Poindexter, Brenda B; Bell, Edward F; O'Shea, T Michael; Watterberg, Kristi L; Goldberg, Ronald N; Smith, P Brian

    2012-08-01

    To assess the impact of empiric antifungal therapy for invasive candidiasis on subsequent outcomes in premature infants. This was a cohort study of infants with a birth weight ≤ 1000 g receiving care at Neonatal Research Network sites. All infants had at least one positive culture for Candida. Empiric antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of empiric antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI). A total of 136 infants developed invasive candidiasis. The incidence of death or NDI was lower in infants who received empiric antifungal therapy (19 of 38; 50%) compared with those who had not (55 of 86; 64%; OR, 0.27; 95% CI, 0.08-0.86). There was no significant difference between the groups for any single outcome or other combined outcomes. Empiric antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted. Copyright © 2012 Mosby, Inc. All rights reserved.

  17. Emperic Antifungal Therapy and Outcomes in Extremely-Low-Birth-Weight Infants with Invasive Candidiasis

    PubMed Central

    Greenberg, Rachel G.; Benjamin, Daniel K.; Gantz, Marie G.; Cotten, C. Michael; Stoll, Barbara J.; Walsh, Michele C.; Sánchez, Pablo J.; Shankaran, Seetha; Das, Abhik; Higgins, Rosemary D.; Miller, Nancy A.; Auten, Kathy J.; Walsh, T. J.; Laptook, Abbot R.; Carlo, Waldemar A.; Kennedy, Kathleen A.; Finer, Neil N.; Duara, Shahnaz; Schibler, Kurt; Ehrenkranz, Richard A.; Van Meurs, Krisa P.; Frantz, Ivan D.; Phelps, Dale L.; Poindexter, Brenda B.; Bell, Edward F.; O’Shea, T. Michael; Watterberg, Kristi L.; Goldberg, Ronald N.; Smith, P. Brian

    2012-01-01

    Objective To assess the impact of emperic antifungal therapy of invasive candidiasis on subsequent outcomes in premature infants. Study design This was a cohort study of infants ≤1000 g birth weight cared for at Neonatal Research Network sites. All infants had at least 1 positive culture for Candida. Emperic antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of emperic antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI). Results 136 infants developed invasive candidiasis. The incidence of death or NDI was lower for infants who received emperic antifungal therapy (19/38, 50%) compared with those who had not (55/86, 64%; odds ratio=0.27 [95% confidence interval 0.08–0.86]). There was no significant difference between the groups for any single outcome or other combined outcomes. Conclusions Emperic antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted. PMID:22424952

  18. 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

  19. Empiric antifungal therapy in patients with febrile neutropenia.

    PubMed

    Ferrara, Jenna J; MacDougall, Conan; Gallagher, Jason C

    2011-04-01

    Invasive fungal infections, most commonly candidiasis or aspergillosis, are a major cause of morbidity and mortality among patients with neutropenia. Difficulty in diagnosing invasive fungal infections in these patients complicates decisions regarding pharmacotherapy. Because of the difficult diagnosis and the significant morbidity and mortality of fungal infections in patients with neutropenia, systemic antifungal agents are used as empiric antifungal therapy in patients with febrile neutropenia who are not responding to antibacterial therapy. The pharmacotherapy of invasive fungal infections has evolved rapidly within the past several years as numerous antifungal agents--different formulations of amphotericin B, azoles, and echinocandins--have become available for use as empiric antifungal therapy in patients with febrile neutropenia. Various levels of evidence support the use of these agents for this indication. Their use is limited, however, by drug intolerance, drug interactions, adverse-event profiles, and limited activity with some mold species. Thus, considerations for selecting an antifungal drug for empiric use in patients with febrile neutropenia should include the epidemiology of fungal infections in the individual patient's institution and the specific clinical circumstances of the patient.

  20. Is preemptive antifungal therapy a good alternative to empirical treatment in prolonged febrile neutropenia?

    PubMed

    Koch, Erica; Rada, Gabriel

    2016-06-09

    Patients with prolonged febrile neutropenia are at high risk of invasive fungal infection, so it has been standard practice to initiate empirical antifungal therapy in these cases. However, this strategy is associated with important toxicity, so diagnostic test-guided preemptive antifungal therapy has been proposed as an alternative. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified three systematic reviews including twelve studies overall. Four randomized controlled trials addressed the question of this article. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded it is not clear whether preemptive strategy affects mortality because the certainty of the evidence is very low, but it might slightly decrease the use of antifungal agents in patients with prolonged febrile neutropenia.

  1. 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

  2. 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.

  3. 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.

  4. Design of amphotericin B oral formulation for antifungal therapy.

    PubMed

    Liu, Min; Chen, Meiwan; Yang, Zhiwen

    2017-11-01

    Amphotericin B (AmB) remains the "gold standard" for systemic antifungal therapy, even though new drugs are emerging as the attractive antifungal agents. Since AmB has negligible oral absorption as a consequence of its unfavorable physicochemical characterizations, its use is restricted to parenteral administration which is accompanied by severe side effects. As greater understanding of the gastrointestinal tract has developed, the advanced drug delivery systems are emerging with the potential to overcome the barriers of AmB oral delivery. Much research has demonstrated that oral AmB formulations such as lipid formulations may have beneficial therapeutic efficacy with reduced adverse effects and suitable for clinical application. Here we reviewed the different formulation strategies to enhance oral drug efficacy, and discussed the current trends and future perspectives for AmB oral administration in the treatment of antifungal infections.

  5. 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.

  6. 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

  7. Current Trends in the Use of Two Combination Antifungal/Corticosteroid Creams.

    PubMed

    Wheat, Chikoti M; Bickley, Ryan J; Hsueh, Yu-Han; Cohen, Bernard A

    2017-07-01

    Superficial fungal infections are among the most commonly managed skin problems by general practitioners. Although evidence shows combination antifungal/corticosteroid topicals are more expensive and less effective than single-agent antifungals, practitioners continue to prescribe combination agents. We examined current prescription trends of 2 combination antifungal/corticosteroid medications, Lotrisone and Mycolog-II. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. 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. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  9. 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

  10. Virulence and Resistance to Antifungal Therapies of Scopulariopsis Species

    PubMed Central

    Paredes, Katihuska; Mayayo, Emilio; Guarro, Josep

    2016-01-01

    Scopulariopsis is 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 of Scopulariopsis brevicaulis and Scopulariopsis 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 that S. brumptii was more virulent than S. brevicaulis. The three drugs tested, liposomal amphotericin B, posaconazole, and voriconazole, prolonged the survival of mice infected with S. brumptii, but none showed efficacy against S. 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 for Scopulariopsis infections remains unresolved. PMID:26787688

  11. Cost-effectiveness analysis of combination antifungal therapy with voriconazole and anidulafungin versus voriconazole monotherapy for primary treatment of invasive aspergillosis in Spain

    PubMed Central

    Grau, Santiago; Azanza, Jose Ramon; Ruiz, Isabel; Vallejo, Carlos; Mensa, Josep; Maertens, Johan; Heinz, Werner J; Barrueta, Jon Andoni; Peral, Carmen; Mesa, Francisco Jesús; Barrado, Miguel; Charbonneau, Claudie; Rubio-Rodríguez, Darío; Rubio-Terrés, Carlos

    2017-01-01

    Objective According to a recent randomized, double-blind clinical trial comparing the combination of voriconazole and anidulafungin (VOR+ANI) with VOR monotherapy for invasive aspergillosis (IA) in patients with hematologic disease or with hematopoietic stem cell transplant, mortality was lower after 6 weeks with VOR+ANI than with VOR monotherapy in a post hoc analysis of patients with galactomannan-based IA. The objective of this study was to compare the cost-effectiveness of VOR+ANI with VOR, from the perspective of hospitals in the Spanish National Health System. Methods An economic model with deterministic and probabilistic analyses was used to determine costs per life-year gained (LYG) for VOR+ANI versus VOR in patients with galactomannan-based IA. Mortality, adverse event rates, and life expectancy were obtained from clinical trial data. The costs (in 2015 euros [€]) of the drugs and the adverse event-related costs were obtained from Spanish sources. A Tornado plot and a Monte Carlo simulation (1,000 iterations) were used to assess uncertainty of all model variables. Results According to the deterministic analysis, for each patient treated with VOR+ANI compared with VOR monotherapy, there would be a total of 0.348 LYG (2.529 vs 2.181 years, respectively) at an incremental cost of €5,493 (€17,902 vs €12,409, respectively). Consequently, the additional cost per LYG with VOR+ANI compared with VOR would be €15,785. Deterministic sensitivity analyses confirmed the robustness of these findings. In the probabilistic analysis, the cost per LYG with VOR+ANI was €15,774 (95% confidence interval: €15,763–16,692). The probability of VOR+ANI being cost-effective compared with VOR was estimated at 82.5% and 91.9%, based on local cost-effectiveness thresholds of €30,000 and €45,000, respectively. Conclusion According to the present economic study, combination therapy with VOR+ANI is cost-effective as primary therapy of IA in galactomannan

  12. Susceptibility of clinically important dermatophytes against statins and different statin-antifungal combinations.

    PubMed

    Nyilasi, Ildikó; Kocsubé, Sándor; Krizsán, Krisztina; Galgóczy, László; Papp, Tamás; Pesti, Miklós; Nagy, Katalin; Vágvölgyi, Csaba

    2014-02-01

    The investigation of the antifungal activities of drugs whose primary activities are not related to their antimicrobial potential is in the current forefront of research. Statin compounds, which are routinely used as cholesterol-lowering drugs, may also exert direct antimicrobial effects. In this study, the in vitro antifungal activities of various statins (lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin and pravastatin) were examined against one isolate each of four dermatophyte species (Trichophyton mentagrophytes, Trichophyton rubrum, Microsporum canis and Microsporum gypseum). Basically, statins were effective in inhibiting all dermatophyte studied, but were particularly active against M. canis and T. mentagrophytes. Fluvastatin and simvastatin were active against all of the tested fungi causing a complete inhibition of their growth at very low concentrations (6.25-12.5 μg/ml). Lovastatin and rosuvastatin had inhibitory effects at higher concentrations (25-128 μg/ml), while atorvastatin and pravastatin proved the less effective. The in vitro interactions between statins and different antifungals (ketoconazole, itraconazole, fluconazole, amphotericin B, nystatin, griseofulvin, terbinafine and primycin) were also investigated using a standard chequerboard broth microdilution method. Synergetic interactions were observed in several cases, most of them were noticed when statins were combined with terbinafine and the different azoles. Some combinations were particularly active (ketoconazole-simvastatin or terbinafine-simvastatin), as they were found to exert synergistic effect against all of the investigated isolates. The other antifungals showed synergistic interactions with statins in only certain cases. These results suggest that statins exert substantial antifungal effects against dermatophyte fungi and they should be promising components in a combination therapy as they can act synergistically with a number of clinically used antifungal

  13. In vitro activity of antifungals in combination with essential oils against the oomycete Pythium insidiosum.

    PubMed

    Valente, J S; Fonseca, A O S; Denardi, L B; Dal Ben, V S; Maia Filho, F S; Zambrano, C G; Braga, C Q; Alves, S H; Botton, S A; Brayer Pereira, D I

    2016-10-01

    The aim of this study was to investigate the in vitro susceptibility of Pythium insidiosum to combinations of the antifungal drugs terbinafine or itraconazole with Melaleuca alternifolia, Mentha piperita and Origanum vulgare essential oils (EOs). In vitro combinations of antifungal drugs with EOs were evaluated by checkerboard microdilution method against 20 Brazilian isolates of P. insidiosum. The tests were performed according to protocol M38-A2, and the interpretation of each combination result was based on the values of the fractional inhibitory concentration index. The combinations of itraconazole with EOs presented prominent synergistic effects against P. insidiosum isolates, and no antagonism was observed with these combinations. However, the combinations of terbinafine with EOs resulted in indifferent or antagonistic effects. The combination of plant-derived bioactive compounds with antifungal drugs may be an alternative therapy for the control of infections caused by P. insidiosum. Studies of new therapeutic protocols involving these proposed combinations are needed. The antimicrobial combinations using EOs with terbinafine or itraconazole can be an attractive therapeutic option for controlling P. insidiosum infections. © 2016 The Society for Applied Microbiology.

  14. Current evidence of antifungal prophylaxis and therapy in pediatric patients.

    PubMed

    Giacchino, Mareva; Milano, Giuseppe Maria; Carraro, Francesca; Bezzio, Stefania; Pegoraro, Anna; Aversa, Franco; Cesaro, Simone

    2011-02-24

    Invasive fungal infections (IFI) are an important complication in pediatric haematological and oncological patients who undergo intensive chemotherapy for leukemia, solid tumour at advanced stage or relapsed, and hematopoietic stem cell transplantation. The incidence of IFI is lower than bacterial infection but mortality rate remains high. This review is designed to help paediatric oncologists in choosing the appropriate anti-fungal strategy and agents for prophylaxis, empirical, pre-emptive and specific therapy on the basis of published evidence.

  15. Current evidence of antifungal prophylaxis and therapy in pediatric patients

    PubMed Central

    Giacchino, Mareva; Milano, Giuseppe Maria; Carraro, Francesca; Bezzio, Stefania; Pegoraro, Anna; Aversa, Franco; Cesaro, Simone

    2011-01-01

    Invasive fungal infections (IFI) are an important complication in pediatric haematological and oncological patients who undergo intensive chemotherapy for leukemia, solid tumour at advanced stage or relapsed, and hematopoietic stem cell transplantation. The incidence of IFI is lower than bacterial infection but mortality rate remains high. This review is designed to help paediatric oncologists in choosing the appropriate anti-fungal strategy and agents for prophylaxis, empirical, pre-emptive and specific therapy on the basis of published evidence. PMID:21647279

  16. [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.

  17. Tinea of vellus hair: an indication for systemic antifungal therapy.

    PubMed

    Gómez-Moyano, E; Crespo-Erchiga, V

    2010-09-01

    Topical antifungal treatment is indicated in tinea of glabrous skin, except in cases of extensive, multiple or recurrent lesions, or immunocompromised patients. However, in daily practice there are cases resistant to topical treatment despite these indications. Parasitism of the hair could be the cause behind the majority of isolated lesions of ringworm of hairless skin with a poor outcome with topical antifungal treatment. To present a prospective observational study of 13 cases of tinea of glabrous skin with topical antifungal resistance during the period 2007-2009. Cases were analysed from a clinical, mycological and therapeutic standpoint. The mean age was 7 years. Eight (62%) patients reported prior contact with an animal and 10 (77%) patients had received topical corticosteroids before visiting the dermatologist. Excoriation was observed in eight (62%) patients, and follicular micropustules were seen in 11 (85%). In all patients, some short thin hairs fell easily on to the slide during the skin scraping. In all patients all the few vellus hairs identified in direct examination were affected. All identified species were zoophilic or geophilic. All cases resolved after oral antifungal treatment. In tinea of glabrous skin with low response to topical antifungal treatment we must rule out tinea of the vellus hair. Infection by nonanthropophilic dermatophytes, previous corticosteroid therapy and excoriation might be predisposing factors. Parasitism of the vellus hair, observed by direct microscopy, should be another criterion for establishing systemic treatment from the onset, as is the case in tinea capitis. © 2010 The Authors. Journal Compilation © 2010 British Association of Dermatologists.

  18. Persistent and recurrent tinea corporis in children treated with combination antifungal/ corticosteroid agents.

    PubMed

    Alston, Sharonda J; Cohen, Bernard A; Braun, Marisa

    2003-01-01

    Combination antifungal/corticosteroid preparations are widely used by nondermatologists in the treatment of superficial fungal infections in patients of all ages. Over half of the prescriptions written for the most commonly used combination agent clotrimazole 1%/betamethasone diproprionate 0.05% cream (Lotrisone, Schering, Kenilworth, NJ) were prescribed for children younger than 4 years old. Our pediatric dermatology division has recently encountered a series of children with recurrent or persistent tinea corporis, especially tinea faciei, treated initially with combination antifungal/corticosteroid cream. All children evaluated for tinea corporis in a university hospital pediatric dermatology clinic from January through June 2001 were identified from the clinic registry for a retrospective chart review. Response to therapy was confirmed by telephone survey and/or follow-up visits at least 1 month after clearing of infection. Six children ranging in age from 4 to 11 years were evaluated for tinea corporis in a pediatric dermatology clinic at our institution during the 6-month period. All 6 children were diagnosed clinically by their pediatrician with tinea corporis and initially treated with clotrimazole 1%/betamethasone diproprionate 0.05% cream for 2 to 12 months. In our pediatric dermatology clinic, patients had their diagnosis confirmed with a positive potassium hydroxide preparation and were treated with one of several oral or topical antifungal agents with clearing of all tinea infections. The use of combination clotrimazole 1% cream/betamethasone diproprionate 0.05% cream (Lotrisone) for the treatment of tinea corporis may be associated with persistent/recurrent infection.

  19. Combination angiostatic therapies: current status.

    PubMed

    Peyman, Gholam A; Fiscella, Richard; Conway, Mandi

    2009-06-01

    One of the most important obstacles to combining pharmaceutical agents to treat ocular diseases is the risk of physiochemical reactions. In intraocular administration, these reactions may produce incompatibility, instability, or both. They may change the nature of drug activity, and they may threaten normal cellular function, resulting in lens opacities, corneal toxicity, retinal cell damage, or other adverse outcomes. Although many medications have demonstrated efficacy or have shown promise when administered intravitreally, including antifungals, nonsteroidal antiinflammatory drugs, anti-tumor necrosis factor-alpha agents, mammalian target of rapamycin inhibitors, metalloproteinase inhibitors, antiviral agents, antineoplastic compounds, and antivascular endothelial growth factor therapies, these have been typically tested as single agents. The potential for these agents to be combined will be largely determined by their physiochemical compatibility.

  20. Antifungal Therapy in Hematopoietic Stem Cell Transplant Recipients

    PubMed Central

    Busca, Alessandro; Pagano, Livio

    2016-01-01

    Invasive fungal infections (IFI) represent a major hindrance to the success of hematopoietic stem cell transplantation (HSCT), contributing substantially to morbidity and infection-related mortality. During the most recent years several reports indicate an overall increase of IFI among hematologic patients, in particular, invasive aspergillosis, that may be explained, at least partially, by the fact that diagnoses only suspected in the past, are now more easily established due to the application of serum biomarkers and early use of CT scan. Along with new diagnostic options, comes the recent development of novel antifungal agents that expanded the spectrum of activity over traditional treatments contributing to the successful management of fungal diseases. When introduced in 1959, Amphotericin B deoxycholate (d-AmB) was a life-saving drug, and the clinical experience over 50 years has proven that this compound is effective although toxic. Given the superior safety profile, lipid formulations of AmB have now replaced d-AmB in many circumstances. Similarly, echinocandins have been investigated as initial therapy for IA in several clinical trials including HSCT recipients, although the results were moderately disappointing leading to a lower grade of recommendation in the majority of published guidelines. Azoles represent the backbone of therapy for treating immunocompromised patients with IFI, including voriconazole and the newcomer isavuconazole; in addition, large studies support the use of mold-active azoles, namely voriconazole and posaconazole, as antifungal prophylaxis in HSCT recipients. The aim of the present review is to summarize the clinical application of antifungal agents most commonly employed in the treatment of IFI. PMID:27648202

  1. Antifungal Therapy in Hematopoietic Stem Cell Transplant Recipients.

    PubMed

    Busca, Alessandro; Pagano, Livio

    2016-01-01

    Invasive fungal infections (IFI) represent a major hindrance to the success of hematopoietic stem cell transplantation (HSCT), contributing substantially to morbidity and infection-related mortality. During the most recent years several reports indicate an overall increase of IFI among hematologic patients, in particular, invasive aspergillosis, that may be explained, at least partially, by the fact that diagnoses only suspected in the past, are now more easily established due to the application of serum biomarkers and early use of CT scan. Along with new diagnostic options, comes the recent development of novel antifungal agents that expanded the spectrum of activity over traditional treatments contributing to the successful management of fungal diseases. When introduced in 1959, Amphotericin B deoxycholate (d-AmB) was a life-saving drug, and the clinical experience over 50 years has proven that this compound is effective although toxic. Given the superior safety profile, lipid formulations of AmB have now replaced d-AmB in many circumstances. Similarly, echinocandins have been investigated as initial therapy for IA in several clinical trials including HSCT recipients, although the results were moderately disappointing leading to a lower grade of recommendation in the majority of published guidelines. Azoles represent the backbone of therapy for treating immunocompromised patients with IFI, including voriconazole and the newcomer isavuconazole; in addition, large studies support the use of mold-active azoles, namely voriconazole and posaconazole, as antifungal prophylaxis in HSCT recipients. The aim of the present review is to summarize the clinical application of antifungal agents most commonly employed in the treatment of IFI.

  2. Antifungal Therapy for Systemic Mycosis and the Nanobiotechnology Era: Improving Efficacy, Biodistribution and Toxicity

    PubMed Central

    Souza, Ana C. O.; Amaral, Andre C.

    2017-01-01

    Fungal diseases have been emerging as an important public health problem worldwide with the increase in host predisposition factors due to immunological dysregulations, immunosuppressive and/or anticancer therapy. Antifungal therapy for systemic mycosis is limited, most of times expensive and causes important toxic effects. Nanotechnology has become an interesting strategy to improve efficacy of traditional antifungal drugs, which allows lower toxicity, better biodistribution, and drug targeting, with promising results in vitro and in vivo. In this review, we provide a discussion about conventional antifungal and nanoantifungal therapies for systemic mycosis. PMID:28326065

  3. 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

  4. EPICO 3.0. Empirical antifungal therapy in critically-ill hematology patients.

    PubMed

    Llinares, Pedro; Ruiz, Isabel; Zaragoza, Rafael; Ferrer, Ricard; Rodríguez, Alejandro H; Maseda, Emilio; Grau, Santiago

    recommended and voriconazole as second choice. Assess administering antifungal treatment in patients with high/medium risk factors and fever for more than 4 days after onset of antibiotic therapy, and in the event of a positive galactomannan and/or sinus and chest CT suggests fungal infection caused by filamentous fungi, (1) in the event the patient did not receive antifungal prophylaxis or was administered fluconazole, the recommended treatment of choice is voriconazole or liposomal amphotericin B; (2) if the patient received prophylaxis with an azole with activity against filamentous fungi, the administration of liposomal amphotericin B with caspofungin is recommended and monotherapy with liposomal amphotericin B or the combination of voriconazole and anidulafungin are recommended as second choice therapies; (3) in the event an echinocandin was administered as prophylaxis, liposomal amphotericin B or voriconazole are the recommended treatments of choice. Consider the administration of antifungal treatment in patients with high/medium risk factors and fever for more than 4 days after onset of antibiotic therapy, and in the event of a negative galactomannan and the sinus and chest CT suggests fungal infection caused by filamentous fungi, (1) if the patient did not receive prophylaxis or was administered fluconazole, the recommended treatment of choice is liposomal amphotericin B or voriconazole; (2) in the case the patient received prophylaxis with an azole with activity against filamentous fungi, the administration of liposomal amphotericin B is recommended as first choice therapy and liposomal amphotericin B combined with caspofungin as second choice; (3) in the event an echinocandin was administered as prophylaxis, liposomal amphotericin B or voriconazole are the recommended treatments of choice. The empirical antifungal approach in critically-ill hematology patients requires the application of the broad range of knowledge and skills described in our recommendations and

  5. Prospective antifungal therapy (PATH) alliance(®) : focus on mucormycosis.

    PubMed

    Kontoyiannis, Dimitrios P; Azie, Nkechi; Franks, Billy; Horn, David L

    2014-04-01

    Mucormycosis is increasingly encountered in immunosuppressed patients, such as those with haematological malignancies or stem cell transplantation. We present a descriptive analysis of 121 cases of mucormycosis from the Prospective Antifungal Therapy Alliance(®) registry (July 2004 to December 2008). Patients with proven or probable mucormycosis were enrolled and followed prospectively for 12 weeks. The most common underlying disease and site of infection were haematologic malignancy (61.2%) and lungs (46.3%) respectively. Rhizopus (n = 63; 52.1%) was the most commonly isolated species, followed by Mucor (n = 28; 23.1%), other or unknown (n = 17; 14.0%), Rhizomucor (n = 9; 7.4%) and Lichtheimia (n = 4; 3.3%). The 12-week Kaplan-Meier survival probability for all patients was 0.41; however, there was large variation in survival probabilities between species, with highest survival probability observed for Lichtheimia (0.5), followed by Rhizopus (0.47), Mucor (0.40), unknown Mucormycetes species (0.40), other Mucormycetes species (0.17) and Rhizomucor (0.15). Prior use of voriconazole decreased 12-week survival probability. Survival probability was higher in patients receiving amphotericin B by Day 3 (0.72) vs. those who started amphotericin B therapy after Day 3 (0.33). The low survival probability observed underscores the importance of further studies of mucormycosis. Optimal treatment selection and timing may improve prognosis.

  6. Successful treatment of Candida osteoarticular infections with limited duration of antifungal therapy and orthopedic surgical intervention.

    PubMed

    Miller, Andy O; Gamaletsou, Maria N; Henry, Michael W; Al-Hafez, Leen; Hussain, Kaiser; Sipsas, Nikolaos V; Kontoyiannis, Dimitrios P; Roilides, Emmanuel; Brause, Barry D; Walsh, Thomas J

    2015-03-01

    Current guidelines for treatment of Candida osteoarticular infections (COAIs) recommend a prolonged course of antifungal therapy (AFT) of 6-12 months. Based upon strategies developed at the Hospital for Special Surgery (HSS), we hypothesized that the duration of antifungal therapy may be substantially reduced for management of COAI. This was a retrospective chart review of cases of COAI treated at the HSS for the past 14 years. COAI was documented by open biopsy and direct culture in all cases. The mean (95% confidence interval, CI) duration of documented follow-up was 39 (16-61) months. Among the 23 cases of COAI, the median age was 62 years (range 22-83 years) with 61% having no underlying condition. Orthopedic appliances, including joint prostheses and fracture hardware, were present in 74% of cases. All patients had COAI as the first proven site of candidiasis. Candida albicans and Candida parapsilosis were the most common species. Hip, knee, foot, and ankle were the most common sites. All patients received aggressive surgical intervention followed by AFT administered for a mean (95% CI) duration of 45 (38-83) days. Systemic AFT consisted principally of fluconazole alone (65%) or in combination with other agents (26%). Adjunctive intraoperative amphotericin B irrigation was used in 35%. Among eight cases of CAOI that required placement of a new prosthetic joint, all were successfully treated. There were no microbiologic failures. Candida osteoarticular infections may be successfully treated with substantially limited durations of AFT when combined with a thorough surgical approach.

  7. A prospective, multicentre survey on antifungal therapy in neutropenic paediatric haematology patients.

    PubMed

    Cesaro, Simone; Pagano, Livio; Caira, Morena; Carraro, Francesca; Luciani, Matteo; Russo, Delia; Colombini, Antonella; Morello, William; Viale, Pierluigi; Rossi, Giuseppe; Tridello, Gloria; Pegoraro, Anna; Nosari, Annamaria; Aversa, Franco

    2013-01-01

    Invasive fungal infections are a frequent complication after intensive chemotherapy. The aims of this prospective study were to describe the use of antifungal therapy and to report which strategy was routinely adopted to guide the introduction of antifungal therapy. A total of 321 febrile episodes in 160 paediatric patients affected by acute leukaemia or non-Hodgkin-lymphoma were investigated. Antifungal therapy was used in 100 of 321 febrile episodes (31%), and classified as empiric in 73 episodes, diagnostic-driven in 25 episodes and targeted in 2 episodes. Switching to a second-line antifungal therapy was needed in 28 of 100 episodes (28%) and was classified as empiric in 10 episodes (36%), diagnostic-driven in 17 episodes (61%) and targeted in 1 episode (4%). In 9 of 28 episodes (32%), switching to a third-line antifungal therapy was performed and was classified as empiric in 2 episodes (22%), diagnostic-driven in 6 episodes (67%) and targeted in 1 episode (11%). Invasive fungal infections was reported in 23 of 100 episodes: confirmed in 4 episodes, probable in 8 episodes, and possible in 11 episodes. Attributable mortality was 2.8%. Antifungal therapy was still used mostly empirically, whereas as fever persisted, its modification was guided by a diagnostic-driven approach.

  8. Posaconazole after previous antifungal therapy with voriconazole for therapy of invasive aspergillus disease, a retrospective analysis.

    PubMed

    Heinz, Werner J; Egerer, Gerlinde; Lellek, Heinrich; Boehme, Angelika; Greiner, Jochen

    2013-05-01

    Invasive aspergillosis is an important cause of morbidity and mortality in haematological patients. Current guidelines recommend voriconazole as first-line therapy. A change in class of antifungal agent is generally recommended for salvage therapy. The focus of this analysis was to assess if posaconazole is suitable for salvage therapy following voriconazole treatment. This was a retrospective investigation on patients with sequential antifungal therapy of posaconazole after voriconazole identified at four German hospitals. Response rates at 30 and 60 days following start of posaconazole application and toxicity of azoles by comparing liver enzymes and cholestasis parameters were evaluated. Data were analysed by descriptive statistics. Overall, the success rate was 72.2% [15 of 36 patients showed complete response (41.7%), 11 patients partial response (30.6%) at any time point], eight patients failed treatment and two were not evaluable. Mean laboratory values increased during voriconazole and decreased during posaconazole treatment: aspartate aminotransferase (increase: 31.9 U l(-1) vs. decrease: 19.6 U l(-1) ), alanine aminotransferase (32.4 U l(-1) vs. 19.8 U l(-1) ), gamma-glutamyl transferase (124.2 U l(-1) vs. 152.3 U l(-1) ) and alkaline phosphatase (71.5 U l(-1) vs. 40.3 U l(-1) ) respectively. No patient discontinued posaconazole therapy due to an adverse event. In this analysis posaconazole was a safe and effective antifungal salvage therapy in patients with prior administration of another triazole.

  9. Antifungal therapy in the treatment of chronic rhinosinusitis: A meta-analysis

    PubMed Central

    Harvey, Richard J.; Rimmer, Janet; Gallagher, Richard M.; Sacks, Raymond

    2012-01-01

    Background: Chronic rhinosinusitis (CRS) is an inflammatory disorder of the nose and sinuses. Because fungi were postulated as a potential cause of CRS in the late 1990s, contrasting articles have advocated and refuted the use of antifungal agents in its management. Although good research shows an interaction of the immune system with fungus in CRS, e.g., allergic fungal sinusitis (AFS), this does not imply that fungi are the cause of CRS or that antifungals will be effective in management. This study was designed to assess the potential advantage of either topical or systemic antifungal therapy in the symptomatic treatment of CRS to aid physicians in making informed decisions about treating patients with CRS. Methods: A systematic review of the literature was performed with meta-analysis. All studies obtained from searches were reviewed and trials meeting the eligibility criteria were selected. CRS was defined using either the European Position Paper on Rhinosinusitis and Nasal Polyps or American Academy of Otolaryngology–Head and Neck Surgery criteria. Authors were contacted and original data were used for data analysis. Results: Five studies investigating topical antifungals and one investigating systemic antifungals met the inclusion criteria. All trials were double blinded and randomized. Pooled meta-analysis showed no statistically significant benefit of topical or systemic antifungals over placebo. Symptoms scores statistically favored the placebo group for this outcome. Adverse event reporting was higher in the antifungal group. Conclusion: Reported side-effects of antifungal therapies may outweigh any potential benefits of treatment based on this meta-analysis and the authors therefore do not advocate the use antifungal treatment in the management of CRS. PMID:22487292

  10. Antifungal therapy in the treatment of chronic rhinosinusitis: a meta-analysis.

    PubMed

    Sacks, Peta-Lee; Harvey, Richard J; Rimmer, Janet; Gallagher, Richard M; Sacks, Raymond

    2012-01-01

    Chronic rhinosinusitis (CRS) is an inflammatory disorder of the nose and sinuses. Because fungi were postulated as a potential cause of CRS in the late 1990s, contrasting articles have advocated and refuted the use of antifungal agents in its management. Although good research shows an interaction of the immune system with fungus in CRS, e.g., allergic fungal sinusitis (AFS), this does not imply that fungi are the cause of CRS or that antifungals will be effective in management. This study was designed to assess the potential advantage of either topical or systemic antifungal therapy in the symptomatic treatment of CRS to aid physicians in making informed decisions about treating patients with CRS. A systematic review of the literature was performed with meta-analysis. All studies obtained from searches were reviewed and trials meeting the eligibility criteria were selected. CRS was defined using either the European Position Paper on Rhinosinusitis and Nasal Polyps or American Academy of Otolaryngology-Head and Neck Surgery criteria. Authors were contacted and original data were used for data analysis. Five studies investigating topical antifungals and one investigating systemic antifungals met the inclusion criteria. All trials were double blinded and randomized. Pooled meta-analysis showed no statistically significant benefit of topical or systemic antifungals over placebo. Symptoms scores statistically favored the placebo group for this outcome. Adverse event reporting was higher in the antifungal group. Reported side-effects of antifungal therapies may outweigh any potential benefits of treatment based on this meta-analysis and the authors therefore do not advocate the use antifungal treatment in the management of CRS.

  11. New targets and delivery systems for antifungal therapy.

    PubMed

    Walsh, T J; Viviani, M A; Arathoon, E; Chiou, C; Ghannoum, M; Groll, A H; Odds, F C

    2000-01-01

    Development of new approaches for treatment of invasive fungal infections encompasses new delivery systems for approved and investigational compounds, as well as exploiting the cell membrane, cell wall and virulence factors as putative antifungal targets. Novel delivery systems consisting of cyclodextrins, cochleates, nanoparticles/nanospheres and long circulating ('stealth') liposomes, substantially modulate the pharmacokinetics of existing compounds, and may also be useful to enhance the delivery of antifungal agents to sites of infection. Further insights into the structure-activity relationship of the antifungal triazoles that target the biosynthesis of ergosterol in the fungal cell membrane have led to the development of highly potent broad spectrum agents, including posaconazole, ravuconazole and voriconazole. Similarly, a novel generation of cell-wall active semisynthetic echinocandin 1,3 beta-glucan inhibitors (caspofungin, FK463, and VER-002) has entered clinical development. These agents have potent and broad-spectrum activity against Candida spp, and potentially useful activity against Aspergillus spp. and Pneumocystis carinii. The ongoing convergence of the fields of molecular pathogenesis, antifungal pharmacology and vaccine development will afford the opportunity to develop novel targets to complement the existing antifungal armamentarium.

  12. Quantitative and qualitative analysis of the antifungal activity of allicin alone and in combination with antifungal drugs.

    PubMed

    Kim, Young-Sun; Kim, Kyung Sook; Han, Ihn; Kim, Mi-Hyun; Jung, Min Hyung; Park, Hun-Kuk

    2012-01-01

    The antifungal activity of allicin and its synergistic effects with the antifungal agents flucytosine and amphotericin B (AmB) were investigated in Candida albicans (C. albicans). C. albicans was treated with different conditions of compounds alone and in combination (allicin, AmB, flucytosine, allicin + AmB, allicin + flucytosine, allicin + AmB + flucytosine). After a 24-hour treatment, cells were examined by scanning electron microscopy (SEM) and atomic force microscopy (AFM) to measure morphological and biophysical properties associated with cell death. The clearing assay was conducted to confirm the effects of allicin. The viability of C. albicans treated by allicin alone or with one antifungal drug (AmB, flucytosine) in addition was more than 40% after a 24-hr treatment, but the viability of groups treated with combinations of more than two drugs was less than 32%. When the cells were treated with allicin alone or one type of drug, the morphology of the cells did not change noticeably, but when cells were treated with combinations of drugs, there were noticeable morphological changes. In particular, cells treated with allicin + AmB had significant membrane damage (burst or collapsed membranes). Classification of cells according to their cell death phase (CDP) allowed us to determine the relationship between cell viability and treatment conditions in detail. The adhesive force was decreased by the treatment in all groups compare to the control. Cells treated with AmB + allicin had a greater adhesive force than cells treated with AmB alone because of the secretion of molecules due to collapsed membranes. All cells treated with allicin or drugs were softer than the control cells. These results suggest that allicin can reduce MIC of AmB while keeping the same efficacy.

  13. The Role of Topical Antifungal Therapy for Onychomycosis and the Emergence of Newer Agents

    PubMed Central

    2014-01-01

    Onychomycosis is a common infection of the nail unit that is usually caused by a dermatophyte (tinea unguium) and most frequently affects toenails in adults. In most cases, onychomycosis is associated with limited treatment options that are effective in achieving complete clearance in many cases. In addition, recurrence rates are high in the subset of treated patients who have been effectively cleared, usually with an oral antifungal agent. There has been a conspicuous absence of medical therapies approved in the United States since the introduction of topical ciclopirox (8% nail lacquer), with no new effective agents introduced for more than 10 years. Fortunately, newer agents and formulations have been under formal development. While patients might prefer a topical therapy, efficacy with ciclopirox 8% nail lacquer, the only available agent until the very recent approval of efinaconazole 10% solution, has been disappointing. The poor therapeutic outcomes achieved with ciclopirox 8% nail lacquer were not unexpected as the cure rates achieved in the clinical trials were unimpressive, despite concomitant nail debridement, which was an integral part of the pivotal trials with ciclopirox 8% nail lacquer. Efinaconazole 10% solution and tavaborole 5% solution are new topical antifungals specifically developed for the treatment of dermatophyte onychomycosis. In Phase 3 clinical trials, both newer agents were applied once daily for 48 weeks without concomitant nail debridement. Mycologic cure rates with efinaconazole 10% solution are markedly superior to what was achieved with ciclopirox 8% nail lacquer. To add, they appear to be nearly comparable to those achieved with oral itraconazole in pivotal clinical trials. However, it is important to remember that direct comparisons between different studies are not conclusive, are not generally considered to be scientifically sound, and may not be entirely accurate due to differences in study design and other factors. Well

  14. Universal antifungal therapy is not needed in persistent febrile neutropenia: a tailored diagnostic and therapeutic approach

    PubMed Central

    Aguilar-Guisado, Manuela; Martín-Peña, Almudena; Espigado, Ildefonso; Ruiz Pérez de Pipaon, Maite; Falantes, José; de la Cruz, Fátima; Cisneros, José M.

    2012-01-01

    Background Giving antifungal therapy exclusively to selected patients with persistent febrile neutropenia may avoid over-treatment without increasing mortality. The aim of this study was to validate an innovative diagnostic and therapeutic approach based on assessing patients’ risk profile and clinical criteria in order to select those patients requiring antifungal therapy. The efficacy of this approach was compared to that of universal empirical antifungal therapy. Design and Methods This was a prospective study which included all consecutive adult hematology patients with neutropenia and fever refractory to 5 days of empirical antibacterial therapy admitted to a teaching hospital in Spain over a 2-year period. A diagnostic and therapeutic approach based on clinical criteria and risk profile was applied in order to select patients for antifungal therapy. The sensitivity, specificity and negative predictive value of this approach and also the overall success rate, according to the same criteria of efficacy described in classical clinical trials, were analyzed. Results Eighty-five episodes were included, 35 of them (41.2%) in patients at high risk of invasive fungal infections. Antifungal therapy was not indicated in 33 episodes (38.8%). The overall incidence of proven and probable invasive fungal infections was 14.1%, all of which occurred in patients who had received empirical antifungal therapy. The 30-day crude mortality rate was 15.3% and the invasive fungal infection-related mortality rate was 2.8% (2/72). The overall success rate following the diagnostic and therapeutic approach was 36.5% compared with 33.9% and 33.7% obtained in the trial by Walsh et al. The sensitivity, specificity and negative predictive value of the study approach were 100%, 52.4% and 100%, respectively. Conclusions Based on the high negative predictive value of this diagnostic and therapeutic approach in persistent febrile neutropenia patients with hematologic malignancies or patients

  15. Universal antifungal therapy is not needed in persistent febrile neutropenia: a tailored diagnostic and therapeutic approach.

    PubMed

    Aguilar-Guisado, Manuela; Martín-Peña, Almudena; Espigado, Ildefonso; Ruiz Pérez de Pipaon, Maite; Falantes, José; de la Cruz, Fátima; Cisneros, José M

    2012-03-01

    Giving antifungal therapy exclusively to selected patients with persistent febrile neutropenia may avoid over-treatment without increasing mortality. The aim of this study was to validate an innovative diagnostic and therapeutic approach based on assessing patients' risk profile and clinical criteria in order to select those patients requiring antifungal therapy. The efficacy of this approach was compared to that of universal empirical antifungal therapy. This was a prospective study which included all consecutive adult hematology patients with neutropenia and fever refractory to 5 days of empirical antibacterial therapy admitted to a teaching hospital in Spain over a 2-year period. A diagnostic and therapeutic approach based on clinical criteria and risk profile was applied in order to select patients for antifungal therapy. The sensitivity, specificity and negative predictive value of this approach and also the overall success rate, according to the same criteria of efficacy described in classical clinical trials, were analyzed. Eighty-five episodes were included, 35 of them (41.2%) in patients at high risk of invasive fungal infections. Antifungal therapy was not indicated in 33 episodes (38.8%). The overall incidence of proven and probable invasive fungal infections was 14.1%, all of which occurred in patients who had received empirical antifungal therapy. The 30-day crude mortality rate was 15.3% and the invasive fungal infection-related mortality rate was 2.8% (2/72). The overall success rate following the diagnostic and therapeutic approach was 36.5% compared with 33.9% and 33.7% obtained in the trial by Walsh et al. The sensitivity, specificity and negative predictive value of the study approach were 100%, 52.4% and 100%, respectively. Based on the high negative predictive value of this diagnostic and therapeutic approach in persistent febrile neutropenia patients with hematologic malignancies or patients who have received a hematopoietic stem cell

  16. Combination of CuO nanoparticles and fluconazole: preparation, characterization, and antifungal activity against Candida albicans

    NASA Astrophysics Data System (ADS)

    Weitz, Iris S.; Maoz, Michal; Panitz, Daniel; Eichler, Sigal; Segal, Ester

    2015-08-01

    Combination therapy becomes an important strategy in the management of invasive fungal infections and emergence of resistant fungi mutants. In this work, we examine the combination of copper oxide (CuO) nanoparticles (NPs) with fluconazole as potential treatment against the pathogenic fungi, Candida albicans. CuO NPs ( 7 nm in size) were synthesized with acetate ligands assembled on their surface, as shown by both thermal gravimetric analysis and FTIR spectroscopy. Unlike the commercial CuO (both bulk and 50 nm particles), that are poorly dispersed in water, the interaction with water allows the fine dispersion of the coated CuO NPs and their excellent colloidal stability. The addition of fluconazole to the aqueous CuO dispersion induced spontaneous self-assembly of the NPs into linear pearl-like chains network, shown by cryogenic transmission electron microscopy (cryo-TEM). The antifungal activity of the CuO NPs and their combination with fluconazole (fluconazole-CuO NPs) was studied against C. albicans. The best MIC values were obtained at concentrations as low as 0.2 and 0.3 mg/mL, respectively. The results suggest that fluconazole-CuO NPs can provide a potential alternative treatment for C. albicans infections.

  17. Dermoscopic Visualization of Vellus Hair Involvement in Tinea Corporis: A Criterion for Systemic Antifungal Therapy?

    PubMed

    Knöpfel, Nicole; del Pozo, Luis Javier; Escudero, Maria del Mar; Martín-Santiago, Ana

    2015-01-01

    Dermoscopy has been shown to be a valuable tool in the diagnosis and monitoring of several infectious diseases. We report a case of tinea corporis in an infant in whom dermoscopy helped us to determine vellus hair involvement, causing treatment to be switched from topical to systemic antifungal therapy.

  18. Topical and systemic antifungal therapy for the symptomatic treatment of chronic rhinosinusitis.

    PubMed

    Sacks, Peta-Lee; Harvey, Richard J; Rimmer, Janet; Gallagher, Richard M; Sacks, Raymond

    2011-08-10

    Chronic rhinosinusitis (CRS) is an inflammatory disorder of the nose and sinuses. Since fungi were postulated as a potential cause of CRS in the late 1990s, there has been increasing controversy about the use of both topical and systemic antifungal agents in its management. Although interaction between the immune system and fungus has been demonstrated in CRS, this does not necessarily imply that fungi are the cause of CRS or that antifungals will be effective its management. To assess the effectiveness of topical or systemic antifungal therapy in the treatment of CRS. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 8 March 2011. All randomised, placebo-controlled trials considering the use of topical or systemic antifungal therapy in the treatment of CRS and allergic fungal sinusitis (AFS). CRS was defined using either the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) or American Academy of Otolaryngology - Head and Neck Surgery (AAO-HNS) criteria. We reviewed the titles and abstracts of all studies obtained from the searches and selected trials that met the eligibility criteria. We extracted data using a pre-determined data extraction form. There was significant heterogeneity of outcome data reporting with reports containing both parametric and non-parametric representations of data for the same outcomes. Means and standard deviations for change data were unavailable for a number of trials. Due to the limited reported data, we contacted authors and used original data for data analysis. Six studies were included (380 participants). Five studies investigated topical antifungals and one study investigated systemic antifungals. The risk of bias in all included

  19. Forum report: issues in clinical trials of empirical antifungal therapy in treating febrile neutropenic patients.

    PubMed

    Bennett, John E; Powers, John; Walsh, Thomas; Viscoli, Claudio; de Pauw, Ben; Dismukes, William; Galgiani, John; Glauser, Michel; Herbrecht, Raoul; Kauffman, Carol; Lee, Jeannette; Pappas, Peter; Rex, John; Verweij, Paul

    2003-04-15

    There is inferential evidence that some patients with prolonged neutropenia and fever not responding to antibacterial agents are at sufficient risk of deep mycoses to warrant empirical therapy, although superiority of an antifungal agent over placebo has not been conclusively demonstrated. Amphotericin B deoxycholate, liposomal amphotericin B, and intravenous itraconazole followed by oral itraconazole solution are licensed in the United States for this indication. Fluconazole and voriconazole have given favorable results in clinical trials of patients with low and high risk of deep mold infections, respectively. Design features that can profoundly influence outcome of empirical trials are (1) inclusion of low-risk patients, (2) failure to blind the study, (3) obscuration of antifungal effects by changing antibacterial antibiotics, (4) failure to balance both arms of the study in terms of patients with prior antifungal prophylaxis or with severe comorbidities, (5) the merging of end points evaluating safety with those of efficacy, and (6) choice of different criteria for resolution of fever.

  20. Antifungal activities of the combination of tacrolimus and itraconazole against Trichophyton mentagrophytes.

    PubMed

    Ozawa, Hiroko; Okabayashi, Ken; Kano, Rui; Watanabe, Shinichi; Hasegawa, Atsuhiko

    2005-06-01

    Tacrolimus was reported to have no antifungal activity against dermatophytes, but it might show a synergistic fungicidal activity with azoles against dermatophytes as in the case of pathogenic yeasts. Therefore, we examined the antifungal activity of tacrolimus combined with itraconazole (ITZ) against five strains of Trichophyton mentagrophytes by measuring cell growth and performing MIC (minimum inhibitory concentration) testing. The mean colony diameter of T. mentagrophytes on 1/10 diluted Sabouraud dextrose agar (dSDA) with tacrolimus combined with ITZ was significantly shorter than that on dSDA with tacrolimus or ITZ. MICs of tacrolimus, ITZ, and tacrolimus combined with ITZ against T. mentagrophytes were determined, respectively. The results revealed a synergistic activity of tacrolimus in combination with ITZ against T. mentagrophytes.

  1. Antifungal mechanisms supporting boric acid therapy of Candida vaginitis.

    PubMed

    De Seta, Francesco; Schmidt, Martin; Vu, Bao; Essmann, Michael; Larsen, Bryan

    2009-02-01

    Boric acid is a commonly cited treatment for recurrent and resistant yeast vaginitis, but data about the extent and mechanism of its antifungal activity are lacking. The aim of this study was to use in vitro methods to understand the spectrum and mechanism of boric acid as a potential treatment for vaginal infection. Yeast and bacterial isolates were tested by agar dilution to determine the intrinsic antimicrobial activity of boric acid. Established microbial physiology methods illuminated the mechanism of the action of boric acid against Candida albicans. C. albicans strains (including fluconazole-resistant strains) were inhibited at concentrations attainable intravaginally; as were bacteria. Broth dilution MICs were between 1563 and 6250 mg/L and boric acid proved fungistatic (also reflected by a decrease in CO(2) generation); prolonged culture at 50,000 mg/L was fungicidal. Several organic acids in yeast nitrogen broth yielded a lower pH than equimolar boric acid and sodium borate but were less inhibitory. Cold or anaerobic incubation protected yeast at high boric acid concentrations. Cells maintained integrity for 6 h in boric acid at 37 degrees C, but after 24 h modest intrusion of propidium iodide occurred; loss of plate count viability preceded uptake of vital stain. Growth at sub-MIC concentrations of boric acid decreased cellular ergosterol. The drug efflux pump CDR1 did not protect Candida as CDR1 expression was abrogated by boric acid. Boric acid interfered with the development of biofilm and hyphal transformation. Boric acid is fungistatic to fungicidal depending on concentration and temperature. Inhibition of oxidative metabolism appears to be a key antifungal mechanism, but inhibition of virulence probably contributes to therapeutic efficacy in vivo.

  2. Antifungal pharmacokinetics and pharmacodynamics.

    PubMed

    Lepak, Alexander J; Andes, David R

    2014-11-10

    Successful treatment of infectious diseases requires choice of the most suitable antimicrobial agent, comprising consideration of drug pharmacokinetics (PK), including penetration into infection site, pathogen susceptibility, optimal route of drug administration, drug dose, frequency of administration, duration of therapy, and drug toxicity. Antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) studies consider these variables and have been useful in drug development, optimizing dosing regimens, determining susceptibility breakpoints, and limiting toxicity of antifungal therapy. Here the concepts of antifungal PK/PD studies are reviewed, with emphasis on methodology and application. The initial sections of this review focus on principles and methodology. Then the pharmacodynamics of each major antifungal drug class (polyenes, flucytosine, azoles, and echinocandins) is discussed. Finally, the review discusses novel areas of pharmacodynamic investigation in the study and application of combination therapy.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  4. Preemptive Antifungal Therapy for Febrile Neutropenic Hematological Malignancy Patients in China

    PubMed Central

    Yuan, Wei; Ren, Jinhai; Guo, Xiaonan; Guo, Xiaoling; Cai, Shengxin

    2016-01-01

    Background The aim of this study was to evaluate the efficiency, adverse effects, and pharmacoeconomic impact of empirical and preemptive antifungal therapy for febrile neutropenic hematological malignancy patients in China. Material/Methods Patients with febrile neutropenia during hematological malignancy were randomly divided into an empirical group and a preemptive group. The preemptive antifungal treatment was initiated if patient status was confirmed by clinical manifestation, imaging diagnosis, 1-3-β-D glucan(G) testing, and galactomannan (GM) test. The treatment was ended 2 weeks later if the patient was recovered from neutropenia. Voriconazole was used as the first-line medicine. All patients received intravenous administration of voriconazole every 12 h, with an initiating dose of 400 mg, then the dose was reduced to 200 mg. Results The overall survival rate was 97.1% and 94.6% in the empirical group and preemptive group, respectively, with no significant difference observed (χ2=1.051, P=0.305). However, the occurrence rate of invasive fungal disease (IFD) in the preemptive group was 9.2% vs. 2.2% in the empirical group. Moreover, the mortality rate due to IFD was 0.7% and 2.3% for the empirical group and preemptive group, respectively. The average duration and cost of preemptive antifungal therapy were 13.8±4.7 days and 8379.00±2253.00 RMB, respectively, which were lower than for empirical therapy. However, no significant differences were observed for incidence of adverse effects and hospital stay between the 2 groups. Conclusions Preemptive antifungal therapy for patients with febrile neutropenic hematological malignancy demonstrated a similar survival rate as with empirical therapy but is economically favorable in a Chinese population. PMID:27819257

  5. An Antifungal Combination Matrix Identifies a Rich Pool of Adjuvant Molecules that Enhance Drug Activity Against Diverse Fungal Pathogens

    PubMed Central

    Robbins, Nicole; Spitzer, Michaela; Yu, Tennison; Cerone, Robert P.; Averette, Anna K.; Bahn, Yong-Sun; Heitman, Joseph; Sheppard, Donald C.; Tyers, Mike; Wright, Gerard D.

    2015-01-01

    SUMMARY There is an urgent need to identify new treatments for fungal infections. By combining sub-lethal concentrations of the known antifungals fluconazole, caspofungin, amphotericin B, terbinafine, benomyl and cyprodinil with ~3600 compounds in diverse fungal species, we generated a deep reservoir of chemical-chemical interactions termed the Antifungal Combinations Matrix (ACM). Follow-up susceptibility testing against a fluconazole resistant isolate of C. albicans unveiled ACM combinations capable of potentiating fluconazole in this clinical strain. We used chemical genetics to elucidate the mode-of-action of the antimycobacterial drug clofazimine, a compound with unreported antifungal activity that synergized with several antifungals. Clofazimine induces a cell membrane stress for which the Pkc1 signaling pathway is required for tolerance. Further tests against additional fungal pathogens, including Aspergillus fumigatus, highlighted that clofazimine exhibits efficacy as a combination agent against multiple fungi. Thus, the ACM is a rich reservoir of chemical combinations with therapeutic potential against diverse fungal pathogens. PMID:26549450

  6. Antifungal adjuvants: Preserving and extending the antifungal arsenal.

    PubMed

    Butts, Arielle; Palmer, Glen E; Rogers, P David

    2017-02-17

    As the rates of systemic fungal infections continue to rise and antifungal drug resistance becomes more prevalent, there is an urgent need for new therapeutic options. This issue is exacerbated by the limited number of systemic antifungal drug classes. However, the discovery, development, and approval of novel antifungals is an extensive process that often takes decades. For this reason, there is growing interest and research into the possibility of combining existing therapies with various adjuvants that either enhance activity or overcome existing mechanisms of resistance. Reports of antifungal adjuvants range from plant extracts to repurposed compounds, to synthetic peptides. This approach would potentially prolong the utility of currently approved antifungals and mitigate the ongoing development of resistance.

  7. Antifungal effect of Gatifloxacin and copper ions combination.

    PubMed

    Shams, Saiba; Ali, Babar; Afzal, Muhammad; Kazmi, Imran; Al-Abbasi, Fahad A; Anwar, Firoz

    2014-07-01

    It is a well-known fact that to bring a new molecule it may take more than a decade. The existing drugs, which are known for their adverse reaction or toxicity, if utilized and allowed in different formulation, the new effective formulation may be discovered and developed. This may help in reducing various side effects, time and costs. In this study, fungal infection was inoculated superficially over the skin of guinea pigs and treated with the broad-spectrum antimicrobial (gatifloxacin) in combination with non-toxic and effective amount of copper ions. MIC of copper (0.20%) was also determined. Concentration of gatifloxacin (100 μg ml(-1)) with the combination of copper ions (MIC) at which it inhibits the visible growth of fungal strains was also evaluated. Hematological parameters, such as total leukocyte count and differential leukocyte count, were evaluated. The results have shown increase in these parameters after fungal infection, which reaches its normal value after treatment with the combination of gatifloxacin and copper ions. Outcomes of the research concluded that gatifloxacin 100 μg ml(-1) can be used by 0.20% of copper ions to prevent growth of some fungal strains (Candida albicans and Aspergillus niger), which causes skin infections with more potency.

  8. Combination of synthetic and natural products as pesticides (CSYNAP): a new class of antifungal agents.

    PubMed

    Rani, Archna; Jain, Sapna; Dureja, Prem; Tripathi, Praveen K; Singh, Kamalendra

    In the present communication some dehydrated dialdol products such as 1, 5 - Diphenyl pent - 1, 4 - diene - 3 - one (A1); 1, 9 - Diphenylnon - 1, 3, 6, 8 - tetraene - 5 - one (A2); 1, 5 - di (2 - hydroxyphenyl) pent - 1, 4 - diene - 3 - one (A3); 1, 5 - difuran pent - 1, 4 - diene - 3 - one (A4); 1, 5 - di [4 - bis (N, Ndimethyl) phenyl] pent - 1, 4 - diene - 3 - one (A5) were screened for their antifungal activity. To reduce their adverse effect on the environment, for the first time, we have attempted to screen the antifungal activity of these synthetic compounds in conjunction with selected natural products. The natural products that were used in our study include Nicotine tobaccum and Neem oil (Azadirachta indica). A set of 15 samples was tested against highly pathogenic and of extensive host range fungi Sclerotium rolfsii, Rhizactonia bataticola, Fusarium udum. The filter paper disc assay to monitor antifungal effect revealed significant and interesting results. We found that the use of the combination of natural and synthetic pesticides is more effective and environmentally healthy compared to just synthetic chemicals and/or less available natural products. These results obtained from the combined use of natural and synthetic chemicals lead us to suggest to a new class of less toxic but more effective pesticides. We call it group as CSYNAP, i. e. Combination of SYnthetic and NAtural products as Pesticides.

  9. 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. © 2016 The Societies and John Wiley & Sons Australia, Ltd.

  10. 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…

  11. Combination of different antifungal agents in oil-in-water emulsions to control strawberry jam spoilage.

    PubMed

    Ribes, Susana; Fuentes, Ana; Talens, Pau; Barat, Jose Manuel

    2018-01-15

    The combination of antifungal agents (cinnamon bark oil, zinc gluconate and trans-ferulic acid) in oil-in-water emulsions to control the fungal spoilage of strawberry jams, minimising essential oil's sensory impact, was evaluated in this work. The in vitro assays of free antifungal agents were performed against five fungal strains; meanwhile, the emulsions assays were conducted against Aspergillus niger given its strong resistance and its relevance in strawberry products. The emulsion formulated with 0.08mg/g of essential oil was able to inhibit mould growth after the incubation period. The incorporation of zinc gluconate or trans-ferulic acid, independently of the concentration used, allowed to reduce a 25% the amount of essential oil needed to inhibit the microbial growth. The combination of antifungal agents in the emulsions has demonstrated to be an effective alternative to reduce the amount of essential oil employed, maintaining the hygienic quality and sensory profile of the strawberry jam. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Interactions between Human Phagocytes and Candida albicans Biofilms Alone and in Combination with Antifungal Agents

    PubMed Central

    Katragkou, Aspasia; Kruhlak, Michael J.; Simitsopoulou, Maria; Chatzimoschou, Athanasios; Taparkou, Anna; Cotten, Catherine J.; Paliogianni, Fotini; Diza-Mataftsi, Eudoxia; Tsantali, Chaido; Walsh, Thomas J.; Roilides, Emmanuel

    2010-01-01

    Background Biofilm formation is an important component of vascular catheter infections caused by Candida albicans. Little is known about the interactions between human phagocytes and antifungal agents on Candida biofilms. Materials and Methods The interactions of C. albicans biofilms with human phagocytes alone and in combination with anidulafungin or voriconazole were investigated and compared with their corresponding planktonic counterparts using an in vitro biofilm model with clinical intravascular and green fluorescent protein (GFP) expressing strains. Phagocyte- and antifungal agent-mediated damages were determined by 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]2H-tetrazolium-5-carboxanilide assay and structural effects visualized by confocal microscopy. Oxidative burst was evaluated by flow cytometric measurement of dihydrorhodamine (DHR)-123 oxidation and cytokine release measured by EIA. Results Phagocytes alone or in combination with antifungal agents induced less damage against biofilms as compared to planktonic cells. However, additive effects occurred between phagocytes and anidulafungin against Candida biofilms. Confocal microscopy demonstrated absence of phagocytosis within biofilms, but marked destruction caused by anidulafungin and phagocytes. Anidulafungin but not voriconazole elicited a TNF-α release from phagocytes compared with untreated biofilms. Conclusions Candida albicans within biofilms are more resistant to phagocytic host defenses but are susceptible to additive effects between phagocytes and an echinocandin. PMID:20415537

  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.

  14. Optimizing azole antifungal therapy in the prophylaxis and treatment of fungal infections.

    PubMed

    Dolton, Michael J; McLachlan, Andrew J

    2014-12-01

    Azole antifungals are widely used in the prophylaxis and treatment of fungal infections, but are associated with a range of pharmacokinetic challenges and safety issues that necessitate individualized therapy to achieve optimal clinical outcomes. Recent advances in our knowledge of azole exposure-response relationships, therapeutic drug monitoring and individualized dosing strategies are reviewed as follows. Recent studies have significantly improved the understanding of exposure-response relationships for efficacy and toxicity, increasing confidence in target exposure ranges for azole antifungal agents. Population pharmacokinetic modelling of voriconazole has led to studies demonstrating the feasibility of model-guided dose individualization strategies with the drug, which holds significant promise for optimizing therapy. The recent approval of a solid oral tablet formulation of posaconazole with improved bioavailability and once-daily dosing has significantly improved the clinical utility of this agent. Further clinical experience with the investigational azole isavuconazole is needed to determine the role of individualized therapy. The coordination of CYP2C19 pharmacogenomic testing with model-guided dose individualization holds significant promise for optimizing therapy with voriconazole. Pharmacokinetic challenges with itraconazole, voriconazole and posaconazole oral suspension continue to require therapeutic drug monitoring to individualize therapy and optimize treatment outcomes.

  15. Genetic and Genomic Architecture of the Evolution of Resistance to Antifungal Drug Combinations

    PubMed Central

    Hill, Jessica A.; Ammar, Ron; Torti, Dax; Nislow, Corey; Cowen, Leah E.

    2013-01-01

    The evolution of drug resistance in fungal pathogens compromises the efficacy of the limited number of antifungal drugs. Drug combinations have emerged as a powerful strategy to enhance antifungal efficacy and abrogate drug resistance, but the impact on the evolution of drug resistance remains largely unexplored. Targeting the molecular chaperone Hsp90 or its downstream effector, the protein phosphatase calcineurin, abrogates resistance to the most widely deployed antifungals, the azoles, which inhibit ergosterol biosynthesis. Here, we evolved experimental populations of the model yeast Saccharomyces cerevisiae and the leading human fungal pathogen Candida albicans with azole and an inhibitor of Hsp90, geldanamycin, or calcineurin, FK506. To recapitulate a clinical context where Hsp90 or calcineurin inhibitors could be utilized in combination with azoles to render resistant pathogens responsive to treatment, the evolution experiment was initiated with strains that are resistant to azoles in a manner that depends on Hsp90 and calcineurin. Of the 290 lineages initiated, most went extinct, yet 14 evolved resistance to the drug combination. Drug target mutations that conferred resistance to geldanamycin or FK506 were identified and validated in five evolved lineages. Whole-genome sequencing identified mutations in a gene encoding a transcriptional activator of drug efflux pumps, PDR1, and a gene encoding a transcriptional repressor of ergosterol biosynthesis genes, MOT3, that transformed azole resistance of two lineages from dependent on calcineurin to independent of this regulator. Resistance also arose by mutation that truncated the catalytic subunit of calcineurin, and by mutation in LCB1, encoding a sphingolipid biosynthetic enzyme. Genome analysis revealed extensive aneuploidy in four of the C. albicans lineages. Thus, we identify molecular determinants of the transition of azole resistance from calcineurin dependence to independence and establish multiple

  16. Combination Therapy for Mucormycosis: Why, What, and How?

    PubMed Central

    Ibrahim, Ashraf; Roilides, Emmanuel; Lewis, Russel E.; Lortholary, Olivier; Petrikkos, George; Kontoyiannis, Dimitrios P.; Walsh, Thomas J.

    2012-01-01

    The high mortality rate of mucormycosis with currently available monotherapy, particularly in hematology patients, has stimulated interest in studying novel combinations of antifungal agents to determine whether superior outcomes might be achieved. Combination lipid polyene-echinocandin therapy is the most promising of such regimens based on safety profile, the availability of parenteral formulations of echinocandins, their synergy in murine models of mucormycosis, and observational clinical data that are concordant. Other options include combination lipid polyene plus deferasirox or posaconazole therapy. Definitive, randomized, placebo-controlled phase III clinical trials are needed to determine whether combination therapy with any of these options is superior to monotherapy. Until such studies are conducted, clinicians will continue to be placed in the unacceptable position of not knowing if and when to administer combination therapy. Such a state of confusion may lead to undertreatment if combination therapy is indeed superior but is not used and, conversely, may lead to unacceptable toxicity and cost to patients if combination therapy is not superior but is used. It is critical that sponsors step forward with funding to conduct these clinical trials to determine whether outcomes from these devastating infections can be improved. PMID:22247449

  17. 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.

  18. Effects of Photodynamic Therapy on the Growth and Antifungal Susceptibility of Scedosporium and Lomentospora spp.

    PubMed

    Lu, Qiaoyun; Sun, Yi; Tian, Dingdan; Xiang, Shoubao; Gao, Lujuan

    2017-08-23

    Scedosporium and Lomentospora species are the second most frequent colonizing, allergenic, or invasive fungal pathogens in patients with cystic fibrosis, and are responsible for infections varying from cutaneous and subcutaneous tissue infections caused by traumatic inoculation to severe systemic diseases in immunocompromised patients. The clinical relevance of fungal airway colonization for individual patients harboring Scedosporium and Lomentospora species is still an underestimated issue. The high resistance of Scedosporium and Lomentospora species to antifungal drugs has highlighted the need for alternative treatment modalities, and antimicrobial photodynamic therapy may be one such alternative. In this study, methylene blue was applied as a photosensitizing agent to 6 type strains of Scedosporium and Lomentospora species, and we irradiated the strains using a light-emitting diode (635 ± 10 nm, 12 J/cm(2)). We evaluated the effects of photodynamic therapy on strain growth and on the in vitro susceptibility of the strains to itraconazole, voriconazole, posaconazole, and amphotericin B. A colony-forming unit reduction of up to 5.2 log10 was achieved. Minimal inhibitory concentration ranges also decreased significantly with photoinactivation. Photodynamic therapy improved both the inactivation rates and the antifungal susceptibility profile of all fungal isolates tested.

  19. A prospective, randomized study of empirical antifungal therapy for the treatment of chemotherapy-induced febrile neutropenia in children.

    PubMed

    Caselli, Désirée; Cesaro, Simone; Ziino, Ottavio; Ragusa, Pietro; Pontillo, Alfredo; Pegoraro, Anna; Santoro, Nicola; Zanazzo, Giulio; Poggi, Vincenzo; Giacchino, Mareva; Livadiotti, Susanna; Melchionda, Fraia; Chiodi, Marcello; Aricò, Maurizio

    2012-07-01

    Given that the rationale for empirical antifungal therapy in neutropenic children is limited and based on adult patient data, we performed a prospective, randomized, controlled trial that evaluated 110 neutropenic children with persistent fever. Those at high risk for invasive fungal infections (IFI) received caspofungin (Arm C) or liposomal amphotericinB (Arm B); those with a lower risk were randomized to receive Arm B, C, or no antifungal treatment (Arm A). Complete response to empirical antifungal therapy was achieved in 90/104 patients (86·5%): 48/56 at high risk (85·7%) [88·0% in Arm B; 83·9% in Arm C (P = 0·72)], and 42/48 at low risk (87·5%) [87·5% in control Arm A, 80·0% Arm B, 94·1% Arm C; (P = 0·41)]. None of the variables tested by multiple logistic regression analysis showed a significant effect on the probability to achieve complete response. IFI was diagnosed in nine patients (8·2%, 95% confidence interval, 3·8-15·0). This randomized controlled study showed that empirical antifungal therapy was of no advantage in terms of survival without fever and IFI in patients aged <18 years and defined with low risk of IFI. Higher risk patients, including those with relapsed cancer, appear to be the target for empirical antifungal therapy during protracted febrile neutropenia.

  20. Can Europe afford combination therapy?

    PubMed

    Alcorn, K

    1995-12-01

    Mounting drug costs for AIDS patients in Europe are becoming problematic. An urgent need is being expressed in the UK to prove that combination therapy makes financial sense in terms of reducing patient stays, outpatient visits, and concomitant medication costs. France is currently meeting the extra costs of this therapy but the future cost escalation is worrisome. Germany will also experience problems in paying for combination therapy, as will other European countries which also face the financial burden of a steadily aging population. European governments, in a response to this problem, have pursued a policy of maximizing the rewards of employed citizens at the expense of people on the margins of society. Drug companies need to carefully consider their pricing policies before they make AIDS an unprofitable area.

  1. Success rate and risk factors for failure of empirical antifungal therapy with itraconazole in patients with hematological malignancies: a multicenter, prospective, open-label, observational study in Korea.

    PubMed

    Kim, Soo-Jeong; Cheong, June-Won; Min, Yoo Hong; Choi, Young Jin; Lee, Dong-Gun; Lee, Je-Hwan; Yang, Deok-Hwan; Lee, Sang Min; Kim, Sung-Hyun; Kim, Yang Soo; Kwak, Jae-Yong; Park, Jinny; Kim, Jin Young; Kim, Hoon-Gu; Kim, Byung Soo; Ryoo, Hun-Mo; Jang, Jun Ho; Kim, Min Kyoung; Kang, Hye Jin; Cho, In Sung; Mun, Yeung Chul; Jo, Deog-Yeon; Kim, Ho Young; Park, Byeong-Bae; Kim, Jin Seok

    2014-01-01

    We assessed the success rate of empirical antifungal therapy with itraconazole and evaluated risk factors for predicting the failure of empirical antifungal therapy. A multicenter, prospective, observational study was performed in patients with hematological malignancies who had neutropenic fever and received empirical antifungal therapy with itraconazole at 22 centers. A total of 391 patients who had abnormal findings on chest imaging tests (31.0%) or a positive result of enzyme immunoassay for serum galactomannan (17.6%) showed a 56.5% overall success rate. Positive galactomannan tests before the initiation of the empirical antifungal therapy (P=0.026, hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.10-4.69) and abnormal findings on the chest imaging tests before initiation of the empirical antifungal therapy (P=0.022, HR, 2.03; 95% CI, 1.11-3.71) were significantly associated with poor outcomes for the empirical antifungal therapy. Eight patients (2.0%) had premature discontinuation of itraconazole therapy due to toxicity. It is suggested that positive galactomannan tests and abnormal findings on the chest imaging tests at the time of initiation of the empirical antifungal therapy are risk factors for predicting the failure of the empirical antifungal therapy with itraconazole. (Clinical Trial Registration on National Cancer Institute website, NCT01060462).

  2. [Antilipemic agents in combined therapy].

    PubMed

    Márk, László; Császár, Albert

    2002-08-25

    In the prevention of coronary heart disease the aim to achieve the target cholesterol and triglyceride levels and the maximal risk reduction leads to the combination of lipid lowering agents. The importance of the combination is supported by the fact that in monotherapy use of the high dose of the drugs, the lipid lowering effect is modest and the side effects are more frequent. The combined therapy is expected to be used more frequently despite the fact, that the improperly applied combination could have serious unfavourable effects. The authors review the advantages and drawbacks of the fibrate-statin combination, which could be used in the most frequent lipid abnormality, the high cholesterol and high triglyceride level, when the combination of micronized fenofibrate and fluvastatin is recommended. Beside the co-administration of other lipid lowering drugs (nicotine acid and resins), it is discussed the combination of statins and fibrates with a new, cholesterol absorption inhibitor, ezetimibe, a well tolerated drug with advantageous safety profile. Considering further metabolic risks the combination of lipid lowering drugs with glitazones, hormone replacement therapy, homocysteine reducing agents is as well highlighted.

  3. Combined modality therapy for esophageal cancer.

    PubMed

    Minsky, Bruce D

    2003-08-01

    Treatment approaches for esophageal cancer include primary treatment (surgical or nonsurgical) or adjuvant treatment (preoperative or postoperative). Primary treatments include surgery alone, radiation therapy alone, and radiation therapy plus chemotherapy (combined modality therapy). Adjuvant therapies include preoperative or postoperative radiation therapy, preoperative chemotherapy, and preoperative combined modality therapy. There is considerable controversy as to the ideal therapeutic approach. This review will examine the results of these approaches as well as combined modality therapy using novel regimens.

  4. In Vitro Antifungal Activity of Sertraline and Synergistic Effects in Combination with Antifungal Drugs against Planktonic Forms and Biofilms of Clinical Trichosporon asahii Isolates.

    PubMed

    Cong, Lin; Liao, Yong; Yang, Suteng; Yang, Rongya

    2016-01-01

    Trichosporon asahii (T. asahii) is the major pathogen of invasive trichosporonosis which occurred mostly in immunocompromised patients. The biofilms formation ability of T. asahii may account for resistance to antifungal drugs and results a high mortality rate. Sertraline, a commonly prescribed antidepressant, has been demonstrated to show in vitro and in vivo antifungal activities against many kinds of pathogenic fungi, especially Cryptococcus species. In the present study, the in vitro activities of sertraline alone or combined with fluconazole, voriconazole, itraconazole, caspofungin and amphotericin B against planktonic forms and biofilms of 21 clinical T. asahii isolates were evaluated using broth microdilution checkerboard method and XTT reduction assay, respectively. The fractional inhibitory concentration index (FICI) was used to interpret drug interactions. Sertraline alone exhibited antifungal activities against both T. asahii planktonic cells (MICs, 4-8 μg/ml) and T. asahii biofilms (SMICs, 16-32 μg/ml). Furthermore, SRT exhibited synergistic effects against T. asahii planktonic cells in combination with amphotericin B, caspofungin or fluconazole (FICI≤0.5) and exhibited synergistic effects against T. asahii biofilms in combination with amphotericin B (FICI≤0.5). SRT exhibited mostly indifferent interactions against T. asahii biofilms in combination with three azoles in this study. Sertraline-amphotericin B combination showed the highest percentage of synergistic effects against both T. asahii planktonic cells (90.5%) and T. asahii biofilms (81.0%). No antagonistic interaction was observed. Our study suggests the therapeutic potential of sertraline against invasive T. asahii infection, especially catheter-related T. asahii infection. Further in vivo studies are needed to validate our findings.

  5. In Vitro Antifungal Activity of Sertraline and Synergistic Effects in Combination with Antifungal Drugs against Planktonic Forms and Biofilms of Clinical Trichosporon asahii Isolates

    PubMed Central

    Cong, Lin; Liao, Yong; Yang, Suteng

    2016-01-01

    Trichosporon asahii (T. asahii) is the major pathogen of invasive trichosporonosis which occurred mostly in immunocompromised patients. The biofilms formation ability of T. asahii may account for resistance to antifungal drugs and results a high mortality rate. Sertraline, a commonly prescribed antidepressant, has been demonstrated to show in vitro and in vivo antifungal activities against many kinds of pathogenic fungi, especially Cryptococcus species. In the present study, the in vitro activities of sertraline alone or combined with fluconazole, voriconazole, itraconazole, caspofungin and amphotericin B against planktonic forms and biofilms of 21 clinical T. asahii isolates were evaluated using broth microdilution checkerboard method and XTT reduction assay, respectively. The fractional inhibitory concentration index (FICI) was used to interpret drug interactions. Sertraline alone exhibited antifungal activities against both T. asahii planktonic cells (MICs, 4–8 μg/ml) and T. asahii biofilms (SMICs, 16–32 μg/ml). Furthermore, SRT exhibited synergistic effects against T. asahii planktonic cells in combination with amphotericin B, caspofungin or fluconazole (FICI≤0.5) and exhibited synergistic effects against T. asahii biofilms in combination with amphotericin B (FICI≤0.5). SRT exhibited mostly indifferent interactions against T. asahii biofilms in combination with three azoles in this study. Sertraline-amphotericin B combination showed the highest percentage of synergistic effects against both T. asahii planktonic cells (90.5%) and T. asahii biofilms (81.0%). No antagonistic interaction was observed. Our study suggests the therapeutic potential of sertraline against invasive T. asahii infection, especially catheter-related T. asahii infection. Further in vivo studies are needed to validate our findings. PMID:27930704

  6. In Vitro Antifungal Activity of Nikkomycin Z in Combination with Fluconazole or Itraconazole

    PubMed Central

    Li, R. K.; Rinaldi, M. G.

    1999-01-01

    Nikkomycins are nucleoside-peptide antibiotics produced by Streptomyces species with antifungal activities through the inhibition of chitin synthesis. We investigated the antifungal activities of nikkomycin Z alone and in combination with fluconazole and itraconazole. Checkerboard synergy studies were carried out by a macrobroth dilution procedure with RPMI 1640 medium at pH 6.0. At least 10 strains of the following fungi were tested: Candida albicans, other Candida spp., Cryptococcus neoformans, Coccidioides immitis, Aspergillus spp., and dematiacious fungi (including Exophiala jeanselmei, Exophiala spinifera, Bipolaris spicifera, Wangiella dermatitidis, Ochroconis humicola, Phaeoannellomyces werneckii, and Cladophialophora bantiana), and 2 strains each of Fusarium, Scedosporium, Paecilomyces, Penicillium, and Trichoderma spp. A total of 110 isolates were examined. Inocula of fungal elements were standardized by hemacytometer counting or spectrophotometrically. MICs and minimum lethal concentrations (MLCs) were determined visually by comparison of growth in drug-treated tubes with growth in drug-free control tubes. Additive and synergistic interactions between nikkomycin and either fluconazole or itraconazole were observed against C. albicans, Candida parapsilosis, Cryptococcus neoformans, and Coccidioides immitis. Marked synergism was also observed between nikkomycin and itraconazole against Aspergillus fumigatus and Aspergillus flavus. No antagonistic interaction between the drugs was observed with any of the strains tested. PMID:10348760

  7. Antifungal activity of silver nanoparticles in combination with nystatin and chlorhexidine digluconate against Candida albicans and Candida glabrata biofilms.

    PubMed

    Monteiro, Douglas R; Silva, Sónia; Negri, Melyssa; Gorup, Luiz F; de Camargo, Emerson R; Oliveira, Rosário; Barbosa, Debora B; Henriques, Mariana

    2013-11-01

    Although silver nanoparticles (SN) have been investigated as an alternative to conventional antifungal drugs in the control of Candida-associated denture stomatitis, the antifungal activity of SN in combination with antifungal drugs against Candida biofilms remains unknown. Therefore, the aim of this study was to evaluate the antifungal efficacy of SN in combination with nystatin (NYT) or chlorhexidine digluconate (CHG) against Candida albicans and Candida glabrata biofilms. The drugs alone or combined with SN were applied on mature Candida biofilms (48 h), and after 24 h of treatment their antibiofilm activities were assessed by total biomass quantification (by crystal violet staining) and colony forming units enumeration. The structure of Candida biofilms was analysed by scanning electron microscopy (SEM) images. The data indicated that SN combined with either NYT or CHG demonstrated synergistic antibiofilm activity, and this activity was dependent on the species and on the drug concentrations used. SEM images showed that some drug combinations were able to disrupt Candida biofilms. The results of this study suggest that the combination of SN with NYT or CHG may have clinical implications in the treatment of denture stomatitis. However, further studies are needed before recommending the use of these drugs safely in clinical situations.

  8. Pharmacoeconomic analysis of voriconazole vs. caspofungin in the empirical antifungal therapy of febrile neutropenia in Australia.

    PubMed

    Al-Badriyeh, Daoud; Liew, Danny; Stewart, Kay; Kong, David C M

    2012-05-01

    In two major clinical trials, voriconazole and caspofungin were recommended as alternatives to liposomal amphotericin B for empirical use in febrile neutropenia. This study investigated the health economic impact of using voriconazole vs. caspofungin in patients with febrile neutropenia. A decision analytic model was developed to measure downstream consequences of empirical antifungal therapy. Clinical outcomes measured were success, breakthrough infection, persistent base-line infection, persistent fever, premature discontinuation and death. Treatment transition probabilities and patterns were directly derived from data in two relevant randomised controlled trials. Resource use was estimated using an expert clinical panel. Cost inputs were obtained from latest Australian sources. The analysis adopted the perspective of the Australian hospital system. The use of caspofungin led to a lower expected mean cost per patient than voriconazole (AU$40,558 vs. AU$41,356), with a net cost saving of AU$798 (1.9%) per patient. Results were most sensitive to the duration of therapy and the alternative therapy used post-discontinuation. In uncertainty analysis, the cost associated with caspofungin is less than that with voriconazole in 65.5% of cases. This is the first economic evaluation of voriconazole vs. caspofungin for empirical therapy. Caspofungin appears to have a higher probability of having cost-savings than voriconazole for empirical therapy. The difference between the two medications does not seem to be statistically significant however.

  9. Empirical antifungal therapy in patients with neutropenia and persistent or recurrent fever of unknown origin.

    PubMed

    Martino, Rodrigo; Viscoli, Claudio

    2006-01-01

    Persistent or recurrent fever of unexplained origin (PFUO) in neutropenic patients receiving antibiotic therapy is commonly treated with empirical antifungal therapy (EAFT). EAFT was established as an adequate management of PFUO around 20 years ago with conventional amphotericin B deoxycholate (c-AmB), despite its high rate of infusional and systemic toxicities. In recent years, EAFT trials for PFUO have used less toxic agents, such as the lipid formulations of AmB, the new azoles, and the echinocandin, caspofungin. In clinical trials, the lipid formulations of AmB [especially liposomal AmB (L-AmB)] provided similar efficacy with lower toxicity but at a much higher cost. Although rarely used in clinical practice, fluconazole is equivalent to c-AmB, provided patients at high risk of Aspergillus infections are excluded. Intravenous itraconazole was shown to be equivalent to c-AmB, with a lower toxicity. Voriconazole did not meet non-inferiority criteria when compared with L-AmB. Caspofungin was shown to be non-inferior to L-AmB and more effective in treating baseline invasive fungal infections. To date, alternatives to AmB have shown less toxicity, but improved efficacy is less clear. This is probably because of the weakness of the indication and to the consequent difficulty in establishing objective and reproducible endpoints for comparisons. The new challenge for physicians in this field is probably presumptive antifungal therapy, an approach based on patient risk-group stratification for developing invasive candidiasis or aspergillosis and/or the use of new diagnostic techniques to identify patients at a very early stage of infection.

  10. Antifungal mechanism of the combination of Cinnamomum verum and Pelargonium graveolens essential oils with fluconazole against pathogenic Candida strains.

    PubMed

    Essid, Rym; Hammami, Majdi; Gharbi, Dorra; Karkouch, Ines; Hamouda, Thouraya Ben; Elkahoui, Salem; Limam, Ferid; Tabbene, Olfa

    2017-08-01

    The present study aimed to investigate the anti-Candida activity of ten essential oils (EOs) and to evaluate their potential synergism with conventional drugs. The effect on secreted aspartic protease (SAP) activity and the mechanism of action were also explored. The antifungal properties of essential oils were investigated using standard micro-broth dilution assay. Only Cinnamomum verum, Thymus capitatus, Syzygium aromaticum, and Pelargonium graveolens exhibited a broad spectrum of activity against a variety of pathogenic Candida strains. Chemical composition of active essential oils was performed by gas chromatography-mass spectrometry (GC-MS). Synergistic effect was observed with the combinations C. verum/fluconazole and P. graveolens/fluconazole, with FIC value 0.37. Investigation of the mechanism of action revealed that C. verum EO reduced the quantity of ergosterol to 83%. A total inhibition was observed for the combination C. verum/fluconazole. However, P. graveolens EO may disturb the permeability barrier of the fungal cell wall. An increase of MIC values of P. graveolens EO and the combination with fluconazole was observed with osmoprotectants (sorbitol and PEG6000). Furthermore, the combination with fluconazole may affect ergosterol biosynthesis and disturb fatty acid homeostasis in C. albicans cells as the quantity of ergosterol and oleic acid was reduced to 52.33 and 72%, respectively. The combination of P. graveolens and C. verum EOs with fluconazole inhibited 78.31 and 64.72% SAP activity, respectively. To our knowledge, this is the first report underlying the mechanism of action and the inhibitory effect of SAP activity of essential oils in synergy with fluconazole. Naturally occurring phytochemicals C. verum and P. graveolens could be effective candidate to enhance the efficacy of fluconazole-based therapy of C. albicans infections.

  11. 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.

  12. [Evaluation of PNA-FISH method for direct identification of Candida species in blood culture samples and its potential impact on guidance of antifungal therapy].

    PubMed

    Doğan, Özlem; İnkaya, Ahmet Çağkan; Gülmez, Dolunay; Uzun, Ömrüm; Akova, Murat; Arıkan Akdağlı, Sevtap

    2016-10-01

    identified by conventional methods in 23 specimens. Results of PNA-FISH and conventional methods were in full agreement in 19 of the 23 specimens (82.6%). Two specimens were negative by PNA-FISH and yielded S.capitata and C.neoformans which were not included in the test panel. In three specimens that were infected with multiple species, PNA-FISH detected only one of the species. On the other hand and in one specimen, PNA-FISH detected a second species (C.glabrata or C.krusei) that could not be isolated and identified conventionally. Species identification were obtained 72 hours (mean) earlier with PNA-FISH. PNA-FISH provided accurate species identification that were consistent with conventional methods. However and expectedly, it failed to detect species that were not included in the test panel. During the study period, 13 of the 23 patients have passed away. Apart from six patients died prior to blood culture positivity and the one that could not get any antifungal therapy during hospital stay, 16 patients received antifungal treatment. Of sixteen patients who received antifungal therapy, initial antifungal treatment was fluconazole for five and echinocandin for 10 patients. Fluconazole and amphotericin B combination was preferred for one patient. In this study, PNA-FISH result had an influence on the modification of the antifungal treatment of only for one patient in accordance with the clinical findings. We conclude that the utility of PNA-FISH method appeared to be limited in our center since the assay cannot differentiate C.albicans and C.parapsilosis, the two commonly isolated species among our candidemia isolates. However, advantages of the assay might be more pronounced for the centers where C.glabrata is a relatively more frequent species.

  13. Refractory Cryptococcus neoformans Meningoencephalitis in an Immunocompetent Patient: Paradoxical Antifungal Therapy-Induced Clinical Deterioration Related to an Immune Response to Cryptococcal Organisms.

    PubMed

    Nakajima, Hideto; Takayama, Ayami; Fujiki, Yohei; Ito, Takumi; Kitaoka, Haruko

    2015-01-01

    We present a case of refractory Cryptococcus neoformans meningoencephalitis in an immunocompetent woman. Her clinical symptoms did not improve with 6 months of antifungal therapy, and MRI abnormalities, indicating severe meningeal and cerebral inflammation, persisted despite a decreasing cryptococcal antigen titer. The patient continued to deteriorate despite antifungal therapy, and her condition clearly improved following treatment with adjunctive corticosteroid. We postulate that the paradoxical antifungal therapy-related clinical deterioration was due to an immune response to cryptococcal organisms, which responded to corticosteroids. These observations provide rationale for a further evaluation of corticosteroids in the management of select cases of C. neoformans central nervous system infection.

  14. Approaches to antifungal therapies and their effectiveness among patients with cryptococcosis.

    PubMed

    Bratton, Emily W; El Husseini, Nada; Chastain, Cody A; Lee, Michael S; Poole, Charles; Stürmer, Til; Weber, David J; Juliano, Jonathan J; Perfect, John R

    2013-06-01

    The goal of this study was to determine the degree to which the persistence of cryptococcosis, overall 1-year mortality, and 1-year mortality due to cryptococcosis were influenced by initial antifungal treatment regimen in a cohort of adults with cryptococcosis treated at a tertiary care medical center. Risk factors, underlying conditions, treatment, and mortality information were obtained for 204 adults with cryptococcosis from Duke University Medical Center (DUMC) from 1996 to 2009. Adjusted risk ratios (RR) for persistence and hazard ratios (HR) for mortality were estimated for each exposure. The all-cause mortality rate among patients with nonsevere disease (20%) was similar to that in the group with disease (26%). However, the rate of cryptococcosis-attributable mortality with nonsevere disease (5%) was much lower than with severe disease (20%). Flucytosine exposure was associated with a lower overall mortality rate (HR, 0.4; 95% confidence interval [CI], 0.2 to 0.9) and attributable mortality rate (HR, 0.5; 95% CI, 0.2 to 1.2). Receiving a nonrecommended antifungal regimen was associated with a higher relative risk of persistent infection at 4 weeks (RR, 1.9; 95% CI, 0.9 to 4.3), and the rate of attributable mortality among those not receiving the recommended dose of initial therapy was higher than that of those receiving recommended dosing (HR, 2.3; 95% CI, 1.0 to 5.0). Thus, the 2010 Infectious Diseases Society of America (IDSA) guidelines are supported by this retrospective review as a best-practice protocol for cryptococcal management. Future investigations should consider highlighting the distinction between all-cause mortality and attributable mortality so as not to overestimate the true effect of cryptococcosis on patient death.

  15. Approaches to Antifungal Therapies and Their Effectiveness among Patients with Cryptococcosis

    PubMed Central

    El Husseini, Nada; Chastain, Cody A.; Lee, Michael S.; Poole, Charles; Stürmer, Til; Weber, David J.; Juliano, Jonathan J.; Perfect, John R.

    2013-01-01

    The goal of this study was to determine the degree to which the persistence of cryptococcosis, overall 1-year mortality, and 1-year mortality due to cryptococcosis were influenced by initial antifungal treatment regimen in a cohort of adults with cryptococcosis treated at a tertiary care medical center. Risk factors, underlying conditions, treatment, and mortality information were obtained for 204 adults with cryptococcosis from Duke University Medical Center (DUMC) from 1996 to 2009. Adjusted risk ratios (RR) for persistence and hazard ratios (HR) for mortality were estimated for each exposure. The all-cause mortality rate among patients with nonsevere disease (20%) was similar to that in the group with disease (26%). However, the rate of cryptococcosis-attributable mortality with nonsevere disease (5%) was much lower than with severe disease (20%). Flucytosine exposure was associated with a lower overall mortality rate (HR, 0.4; 95% confidence interval [CI], 0.2 to 0.9) and attributable mortality rate (HR, 0.5; 95% CI, 0.2 to 1.2). Receiving a nonrecommended antifungal regimen was associated with a higher relative risk of persistent infection at 4 weeks (RR, 1.9; 95% CI, 0.9 to 4.3), and the rate of attributable mortality among those not receiving the recommended dose of initial therapy was higher than that of those receiving recommended dosing (HR, 2.3; 95% CI, 1.0 to 5.0). Thus, the 2010 Infectious Diseases Society of America (IDSA) guidelines are supported by this retrospective review as a best-practice protocol for cryptococcal management. Future investigations should consider highlighting the distinction between all-cause mortality and attributable mortality so as not to overestimate the true effect of cryptococcosis on patient death. PMID:23478968

  16. Study of immunological aspects of aspergillosis in mice and effect of polyene macrolide antibiotic (SJA-95) and IFN-γ: a possible role of IFN-γ as an adjunct in antifungal therapy.

    PubMed

    Naik, Suresh R; Thakare, Vishnu N; Desai, Sandhya K; Rahalkar, Prabhakar R

    2011-12-30

    New polyene macrolide antibiotic SJA-95 in free as well as liposomal (lip.) forms, with and without interferon-γ (IFN-γ) was studied in mice model of aspergillosis using biological and biochemical parameters viz. colony forming units (CFU) in liver, spleen, kidney, lung and brain, and serum IgG, and interleukin-4 (IL-4). Treatment with free and lip SJA-95 along with IFN-γ prolonged the survival time, reduced CFU in vital organs, decreased serum IgG and IL-4 levels. SJA-95 lip form showed greater antifungal activity as compared to free form. The combined treatment of lip SJA-95 with IFN-γ showed further enhancement in antifungal activity of SJA-95 (lip). The present experimental findings demonstrated IFN-γ might act as a potent modulator in immune reaction during fungal infection and can be a useful adjunctive in antifungal therapy in the management of deep seated systemic mycoses.

  17. 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

  18. Antifungal drug resistance to azoles and polyenes.

    PubMed

    Masiá Canuto, Mar; Gutiérrez Rodero, Félix

    2002-09-01

    There is an increased awareness of the morbidity and mortality associated with fungal infections caused by resistant fungi in various groups of patients. Epidemiological studies have identified risk factors associated with antifungal drug resistance. Selection pressure due to the continuous exposure to azoles seems to have an essential role in developing resistance to fluconazole in Candida species. Haematological malignancies, especially acute leukaemia with severe and prolonged neutropenia, seem to be the main risk factors for acquiring deep-seated mycosis caused by resistant filamentous fungi, such us Fusarium species, Scedosporium prolificans, and Aspergillus terreus. The still unacceptably high mortality rate associated with some resistant mycosis indicates that alternatives to existing therapeutic options are needed. Potential measures to overcome antifungal resistance ranges from the development of new drugs with better antifungal activity to improving current therapeutic strategies with the present antifungal agents. Among the new antifungal drugs, inhibitors of beta glucan synthesis and second-generation azole and triazole derivatives have characteristics that render them potentially suitable agents against some resistant fungi. Other strategies including the use of high doses of lipid formulations of amphotericin B, combination therapy, and adjunctive immune therapy with cytokines are under investigation. In addition, antifungal control programmes to prevent extensive and inappropriate use of antifungals may be needed.

  19. Aspergillus tanneri sp. nov., a New Pathogen That Causes Invasive Disease Refractory to Antifungal Therapy

    PubMed Central

    Sugui, Janyce A.; Peterson, Stephen W.; Clark, Lily P.; Nardone, Glenn; Folio, Les; Riedlinger, Gregory; Zerbe, Christa S.; Shea, Yvonne; Henderson, Christina M.; Zelazny, Adrian M.; Holland, Steven M.

    2012-01-01

    The most common cause of invasive aspergillosis (IA) in patients with chronic granulomatous disease (CGD) is Aspergillus fumigatus followed by A. nidulans; other aspergilli rarely cause the disease. Here we review two clinical cases of fatal IA in CGD patients and describe a new etiologic agent of IA refractory to antifungal therapy. Unlike typical IA caused by A. fumigatus, the disease caused by the new species was chronic and spread from the lung to multiple adjacent organs. Mycological characteristics and the phylogenetic relationship with other aspergilli based on the sequence analysis of Mcm7, RPB2, and Tsr1 indicated that the new species, which we named as A. tanneri, belongs to Aspergillus section Circumdati. The species has a higher amphotericin B, voriconazole, and itraconazole MIC and causes more chronic infection in CGD mice than A. fumigatus. This is the first report documenting IA in CGD patients caused by a species belonging to the Aspergillus section Circumdati that is inherently resistant to azoles and amphotericin B. Unlike the results seen with many members of Aspergillus section Circumdati, ochratoxin was not detected in filtrates of cultures grown in various media. Our phenotypic and genetic characterization of the new species and the case reports will assist future diagnosis of infection caused by A. tanneri and lead to more appropriate patient management. PMID:22855513

  20. 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.

  1. In vitro combination therapy with isavuconazole against Candida spp.

    PubMed

    Katragkou, Aspasia; McCarthy, Matthew; Meletiadis, Joseph; Hussain, Kaiser; Moradi, Patriss W; Strauss, Gittel E; Myint, Kyaw L; Zaw, Myo H; Kovanda, Laura L; Petraitiene, Ruta; Roilides, Emmanuel; Walsh, Thomas J; Petraitis, Vidmantas

    2017-11-01

    Combination therapy may be an alternative therapeutic approach for difficult-to-treat Candida infections with the aim of increasing efficacy of antifungal therapy. Whether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or polyenes for the treatment of invasive candidiasis has not been studied. We used Bliss independence drug interaction analysis and time-kill assays to examine the in vitro interactions of isavuconazole with amphotericin B or micafungin, an echinocandin, against strains of Candida albicans, Candida parapsilosis, Candida glabrata, Candida tropicalis, and Candida krusei. The Bliss independence-based drug interactions modeling showed that the combination of isavuconazole and micafungin resulted in synergistic interactions against C. albicans, C. parapsilosis, and C. krusei. The degree of synergy ranged from 1.8% to 16.7% (mean %ΔΕ value) with the highest synergy occurring against C. albicans (⊙SYN% = 8.8%-110%). Time-kill assays showed that the isavuconazole-micafungin combination demonstrated concentration-depended synergy against C. albicans and C. parapsilosis. The combined interaction by Bliss analysis between isavuconazole and amphotericin B was indifferent for C. albicans, C. parapsilosis, and C. tropicalis while for C. glabrata was antagonistic (-2% to -6%) and C. krusei synergistic (3.4% to 7%). The combination of isavuconazole-amphotericin B by time-kill assay was antagonistic against C. krusei and C. glabrata. Collectively, our findings demonstrate that combinations of isavuconazole and micafungin are synergistic against Candida spp., while those of isavuconazole and amphotericin B are indifferent in vitro. © The Author 2017. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  2. Systemic mycoses in the immunocompromised host: an update in antifungal therapy.

    PubMed

    Kontoyiannis, D P; Mantadakis, E; Samonis, G

    2003-04-01

    Despite significant advances in the management of immunosuppressed patients, invasive fungal infections remain an important life-threatening complication. In the last decade several new antifungal agents, including compounds in pre-existing classes (new generation of triazoles, polyenes in lipid formulations) and novel classes of antifungals with a unique mechanism of action (echinocandins), have been introduced in clinical practice. Ongoing and future studies will determine their exact role in the management of different mycoses. The acceleration of antifungal drug discovery offers promise for the management of these difficult to treat opportunistic infections.

  3. Antifungal catheter lock therapy for the management of a persistent Candida albicans bloodstream infection in an adult receiving hemodialysis.

    PubMed

    Paul DiMondi, V; Townsend, Mary L; Johnson, Melissa; Durkin, Michael

    2014-07-01

    Antifungal catheter lock therapy (AfLT) with liposomal amphotericin B has been used in the treatment of pediatric central line infections caused by Candida species; however, reports describing the use of liposomal amphotericin B lock therapy in the adult hemodialysis patient population are lacking. Management of central line-associated candidemia with systemic therapy alone is often challenging due to the propensity of Candida species to form biofilms on foreign bodies. We describe a 64-year-old woman who was receiving hemodialysis 3 times/week and was hospitalized with persistent fungemia. Despite receiving intravenous micafungin, she had multiple positive blood cultures for Candida albicans, which finally cleared after 7 days. Her double-lumen catheter was considered the most likely nidus of infection. Although catheter removal would have been preferred, this was not possible given her vasculopathy, history of multiple bloodstream infections, and lack of other available sites for vascular access. Catheter exchange was performed, and liposomal amphotericin B AfLT was administered in combination with intravenous micafungin for a total of 6 days. During this time, the patient experienced no discernible adverse effects secondary to AfLT. At discharge, AfLT was discontinued, and intravenous micafungin was changed to oral fluconazole. After 6 months of treatment, the patient remained culture negative and maintained her dialysis access. To our knowledge, this is the first case report of liposomal amphotericin B catheter lock therapy used to manage a persistent C. albicans bloodstream infection in an adult receiving hemodialysis. AfLT is a novel concept for treating catheter-associated fungal infections. Liposomal amphotericin B was chosen based on its favorable in vitro activity against Candida species biofilms in catheter lock environments. We identified several barriers to implementing AfLT, and these issues may prohibit the use of AfLT. This case report

  4. Combined Pharmacologic Therapy in Postmenopausal Osteoporosis.

    PubMed

    Shen, Yang; Gray, Dona L; Martinez, Dorothy S

    2017-03-01

    Antiresorptive agents for treating postmenopausal osteoporosis include selective estrogen receptor modulator (SERM), bisphosphonates and denoumab. Teriparatide is the only Food and Drug Administration-approved anabolic agent. Synergistic effects of combining teriparatide with an antiresorptive agent have been proposed and studied. This article reviews the trial designs and the outcomes of combination therapies. Results of the combination therapy for teriparatide and bisphosphonates were mixed; while small increases of bone density were observed in the combination therapy of teriparatide and estrogen/SERM and that of teriparatide and denosumab. Those clinical studies were limited by small sample sizes and lack of fracture outcomes.

  5. 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

  6. Comparison of Photodynamic Therapy versus conventional antifungal therapy for the treatment of denture stomatitis: a randomized clinical trial.

    PubMed

    Mima, E G; Vergani, C E; Machado, A L; Massucato, E M S; Colombo, A L; Bagnato, V S; Pavarina, A C

    2012-10-01

    In this randomized clinical trial, the clinical and mycological efficacy of Photodynamic Therapy (PDT) was compared with that of topical antifungal therapy for the treatment of denture stomatitis (DS) and the prevalence of Candida species was identified. Patients were randomly assigned to one of two groups (n = 20 each); in the nystatin (NYT) group patients received topical treatment with nystatin (100,000 IU) four times daily for 15 days and in the PDT group the denture and palate of patients were sprayed with 500 mg/L of Photogem(®), and after 30 min of incubation, were illuminated by light emitting-diode light at 455 nm (37.5 and 122 J/cm(2), respectively) three times a week for 15 days. Mycological cultures taken from dentures and palates and standard photographs of the palates were taken at baseline (day 0), at the end of the treatment (day 15) and at the follow-up time intervals (days 30, 60 and 90). Colonies were quantified (CFU/mL) and identified by biochemical tests. Data were analysed by Fisher's exact test, analysis of variance and Tukey tests and κ test (α = 0.05). Both treatments significantly reduced the CFU/mL at the end of the treatments and on day 30 of the follow-up period (p <0.05). The NYT and PDT groups showed clinical success rates of 53% and 45%, respectively. Candida albicans was the most prevalent species identified. PDT was as effective as topical nystatin in the treatment of DS.

  7. Antifungal effects of phytocompounds on Candida species alone and in combination with fluconazole.

    PubMed

    Lu, Mengjiao; Li, Tao; Wan, Jianjian; Li, Xiuyun; Yuan, Lei; Sun, Shujuan

    2017-02-01

    Invasive fungal infections caused by Candida spp. remain the most predominant nosocomial fungal infections. Owing to the increased use of antifungal agents, resistance of Candida spp. to antimycotics has emerged frequently, especially to fluconazole (FLC). To cope with this issue, new efforts have been dedicated to discovering novel antimycotics or new agents that can enhance the susceptibility of Candida spp. to existing antimycotics. The secondary metabolites of plants represent a large library of compounds that are important sources for new drugs or compounds suitable for further modification. Research on the anti-Candida activities of phytocompounds has been carried out in recent years and the results showed that a series of phytocompounds have anti-Candida properties, such as phenylpropanoids, flavonoids, terpenoids and alkaloids. Among these phytocompounds, some displayed potent antifungal activity, with minimum inhibitory concentrations (MICs) of ≤8 µg/mL, and several compounds were even more effective against drug-resistant Candida spp. than FLC or itraconazole (e.g. honokiol, magnolol and shikonin). Interestingly, quite a few phytocompounds not only displayed anti-Candida activity alone but also synergised with FLC against Candida spp., even leading to a reversal of FLC resistance. This review focuses on summarising the anti-Candida activities of phytocompounds as well as the interactions of phytocompounds with FLC. In addition, we briefly overview the synergistic mechanisms and present the structure of the antimycotic phytocompounds. Hopefully, this analysis will provide insight into antifungal agent discovery and new approaches against antifungal drug resistance.

  8. In vitro activity of the protegrin IB-367 alone and in combination compared with conventional antifungal agents against dermatophytes.

    PubMed

    Simonetti, Oriana; Silvestri, Carmela; Arzeni, Daniela; Cirioni, Oscar; Kamysz, Wojciech; Conte, Irene; Staffolani, Silvia; Orsetti, Elena; Morciano, Angela; Castelli, Pamela; Scalise, Alessandro; Kamysz, Elzbieta; Offidani, Anna Maria; Giacometti, Andrea; Barchiesi, Francesco

    2014-04-01

    The occurrence of resistance or side effects in patients receiving antifungal agents leads to failure in the treatment of mycosis. The aim of this experimental study was to investigate the in vitro effects of IB-367 alone and in combination with three standard antifungal drugs, fluconazole (FLU), itraconazole (ITRA) and terbinafine (TERB), against 20 clinical isolates of dermatophytes belonging to three species. Minimum inhibitory concentrations (MICs), minimal fungicidal concentrations (MFCs), synergy test, time-kill curves, fungal biomass (FB) and hyphal damage using 2,3-bis-(2-methoxy-4-nitro-5-sulfenylamino carbonil)-2H-tetrazolium hydroxide assay (XTT) were performed to study the efficacy of IB-367. In this study, we observed that TERB and ITRA had MICs lower values for all the strains compared to IB-367 and FLU. Synergy was found in 35%, 30% and 25% of IB-367/FLU, IB-367/ITRA and IB-367/TERB interactions respectively. IB-367 exerted a fungicidal activity against Trichophyton mentagrophytes, T. rubrum and Microsporum canis at concentrations starting from 1x MIC. At a concentration of 5x MIC, IB-367 showed the highest rates of hyphae damage for M. canis 53% and T. mentagrophytes 50%; against the same isolates it caused a reduction of 1 log of the total viable count cell hyphae damage. We propose IB-367 as a promising candidate for the future design of antifungal drugs.

  9. [Combination drug therapy in leprosy].

    PubMed

    Terencio de las Aguas, J

    1983-01-01

    The importance of polichemotherapy in multibacilar leprosy (LL and LD) in patients without any previous therapy as in those diagnosticated and under monotherapy most of all in the resistance patients is presented. Sulphones, clofazimine and rifampicine are selected as first rate drugs and protionamide-etionamide as second rate drugs. The therapy plans with the association of two and three drugs and the convenience of continuing indefinitely with at least one of the drugs are presented insisting on the advantages of the clofazimine-sulphones and rifampicine-sulphones associations. The necessity of immunotherapy for recover of celular immunity against the bacilus, is the only form of preventing relapses and drug resistance.

  10. Antifungal polypeptides

    DOEpatents

    Altier, Daniel J [Waukee, IA; Ellanskaya, Irina [Kyiv, UA; Ellanskaya, legal representative, Natalia; Gilliam, Jacob T [Norwalk, IA; Hunter-Cevera, Jennie [Elliott City, MD; Presnail, James K [Avondale, PA; Schepers, Eric [Port Deposit, MD; Simmons, Carl R [Des Moines, IA; Torok, Tamas [Richmond, CA; Yalpani, Nasser [Johnston, IA

    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.

  11. 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

  12. 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

  13. Comparison of denture microwave disinfection and conventional antifungal therapy in the treatment of denture stomatitis: a randomized clinical study.

    PubMed

    Silva, Mariana Montenegro; Mima, Ewerton Garcia de Oliveira; Colombo, Arnaldo Lopes; Sanitá, Paula Volpato; Jorge, Janaina Habib; Massucato, Elaine Maria Sgavioli; Vergani, Carlos Eduardo

    2012-10-01

    The aim of this study was to compare the effectiveness of denture microwave disinfection and antifungal therapy on treatment of denture stomatitis. Sixty denture wearers with denture stomatitis (3 groups; n = 20 each), were treated with nystatin or denture microwave disinfection (1 or 3 times/wk) for 14 days. Mycologic samples from palates and dentures were quantified and identified with the use of Chromagar, and clinical photographs of palates were taken. Microbiologic and clinical data were analyzed with the use of a series of statistical tests (α = .05). Both treatments similarly reduced clinical signs of denture stomatitis and growth on palates and dentures at days 14 and 30 (P > .05). At sequential appointments, the predominant species (P < .01) isolated was C. albicans (range 98%-53%), followed by C. glabrata (range 22%-12%) and C. tropicalis (range 25%-7%). Microwave disinfection, at once per week for 2 treatments, was as effective as topical antifungal therapy for treating denture stomatitis. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Cost-Effectiveness Analysis Comparing Two Approaches for Empirical Antifungal Therapy in Hematological Patients with Persistent Febrile Neutropenia

    PubMed Central

    Gil-Navarro, M. Victoria; Aguilar-Guisado, Manuela; Espigado, Ildefonso; de Pipaón, Maite Ruiz Pérez; Falantes, José; Pachón, Jerónimo

    2013-01-01

    New approaches of empirical antifungal therapy (EAT) in selected hematological patients with persistent febrile neutropenia (PFN) have been proposed in recent years, but their cost-effectiveness has not been studied. The aim of this study was to compare the cost-effectiveness of two different approaches of EAT in hematological patients with PFN: the diagnosis-driven antifungal therapy (DDAT) approach versus the standard approach of EAT. A decision tree to assess the cost-effectiveness of both approaches was developed. Outcome probabilities and treatment pathways were extrapolated from two studies: a prospective cohort study following the DDAT approach and a randomized clinical trial following the standard approach. Uncertainty was undertaken through sensitivity analyses and Monte Carlo simulation. The average effectiveness and economic advantages in the DDAT approach compared to the standard approach were 2.6% and €5,879 (33%) per PFN episode, respectively. The DDAT was the dominant approach in the 99.5% of the simulations performed with average cost-effectiveness per PFN episode of €32,671 versus €52,479 in the EAT approach. The results were robust over a wide range of variables. The DDAT approach is more cost-effective than the EAT approach in the management of PFN in hematological patients. PMID:23856767

  15. Antifungal Resistance, Metabolic Routes as Drug Targets, and New Antifungal Agents: An Overview about Endemic Dimorphic Fungi.

    PubMed

    Parente-Rocha, Juliana Alves; Bailão, Alexandre Melo; Amaral, André Correa; Taborda, Carlos Pelleschi; Paccez, Juliano Domiraci; Borges, Clayton Luiz; Pereira, Maristela

    2017-01-01

    Diseases caused by fungi can occur in healthy people, but immunocompromised patients are the major risk group for invasive fungal infections. Cases of fungal resistance and the difficulty of treatment make fungal infections a public health problem. This review explores mechanisms used by fungi to promote fungal resistance, such as the mutation or overexpression of drug targets, efflux and degradation systems, and pleiotropic drug responses. Alternative novel drug targets have been investigated; these include metabolic routes used by fungi during infection, such as trehalose and amino acid metabolism and mitochondrial proteins. An overview of new antifungal agents, including nanostructured antifungals, as well as of repositioning approaches is discussed. Studies focusing on the development of vaccines against antifungal diseases have increased in recent years, as these strategies can be applied in combination with antifungal therapy to prevent posttreatment sequelae. Studies focused on the development of a pan-fungal vaccine and antifungal drugs can improve the treatment of immunocompromised patients and reduce treatment costs.

  16. Antifungal Treatment in Stem Cell Transplantation Centers in Turkey.

    PubMed

    Akan, Hamdi; Atilla, Erden

    2016-03-05

    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.

  17. Use of newer antifungal therapies in clinical practice: what do the data tell us?

    PubMed

    Perfect, John R

    2004-11-01

    Considering the significant morbidity and mortality associated with invasive fungal infections in immunocompromised patients, it is particularly important to make the diagnosis as early as possible and to make best use of the available antifungal drugs for prophylaxis and treatment. The newer antifungal drugs include the lipid products of amphotericin B, such as amphotericin B lipid complex (ABLC) and liposomal amphotericin B; voriconazole (a triazole); and caspofungin (an echinocandin). ABLC and liposomal amphotericin B are as effective as amphotericin B deoxycholate but are less nephrotoxic; ABLC is probably the drug of choice for zygomycosis. Voriconazole is approved for use in the treatment of invasive aspergillosis and may have a role in preventing breakthrough fungal infections in patients with persistent fever and neutropenia. Caspofungin is effective against both invasive aspergillosis and invasive candidiasis.

  18. The relationship between the success rate of empirical antifungal therapy with intravenous itraconazole and clinical parameters, including plasma levels of itraconazole, in immunocompromised patients receiving itraconazole oral solution as prophylaxis: a multicenter, prospective, open-label, observational study in Korea.

    PubMed

    Kim, Jin Seok; Cheong, June-Won; Kim, Yeo-Kyeoung; Park, Jinny; Mun, Yeung-Chul; Kang, Hye Jin; Yi, Hyeon Gyu; Lee, Je-Hwan; Kim, Yang Soo; Ryoo, Hun-Mo; Kim, Sung-Hyun; Kim, Ho Young; Kim, Jin Young; Lee, Dong-Gun; Kim, Hoon-Gu; Kim, Hawk; Joo, Young-Don; Min, Yoo Hong

    2014-01-01

    To identify the role of therapeutic drug monitoring of itraconazole (ITZ) in the setting of empirical antifungal therapy with intravenous (IV) ITZ, we performed a multicenter, prospective study in patients with hematological malignancies who had received antifungal prophylaxis with ITZ oral solution (OS). We evaluated the plasma levels of ITZ and hydroxy (OH) ITZ both before initiation of IV ITZ and on days 5-7 of IV ITZ. A total of 181 patients showed an overall success rate of 68.0 %. Prolonged baseline neutropenia and accompanying cardiovascular comorbidity were significantly associated with poor outcomes of the empirical antifungal therapy (P = 0.005 and P = 0.001, respectively). A significantly higher trough plasma level of OH ITZ per body weight was found in the patients who achieved success with empirical antifungal therapy (P = 0.036). There were no significant correlations between plasma concentrations of ITZ/OH ITZ (baseline or trough levels) and toxicities. Seven patients had a discontinuation of ITZ therapy due to toxicity. This study demonstrated that IV ITZ as empirical antifungal therapy was effective and therapeutic drug monitoring was helpful to estimate the outcome of empirical antifungal therapy in patients receiving antifungal prophylaxis with ITZ OS. To predict the outcome of empirical antifungal therapy with IV ITZ, we should evaluate baseline clinical characteristics and also perform the therapeutic drug monitoring of both ITZ and OH ITZ.

  19. Advances in targeting the vacuolar proton-translocating ATPase (V-ATPase) for anti-fungal therapy

    PubMed Central

    Hayek, Summer R.; Lee, Samuel A.; Parra, Karlett J.

    2014-01-01

    Vacuolar proton-translocating ATPase (V-ATPase) is a membrane-bound, multi-subunit enzyme that uses the energy of ATP hydrolysis to pump protons across membranes. V-ATPase activity is critical for pH homeostasis and organelle acidification as well as for generation of the membrane potential that drives secondary transporters and cellular metabolism. V-ATPase is highly conserved across species and is best characterized in the model fungus Saccharomyces cerevisiae. However, recent studies in mammals have identified significant alterations from fungi, particularly in the isoform composition of the 14 subunits and in the regulation of complex disassembly. These differences could be exploited for selectivity between fungi and humans and highlight the potential for V-ATPase as an anti-fungal drug target. Candida albicans is a major human fungal pathogen and causes fatality in 35% of systemic infections, even with anti-fungal treatment. The pathogenicity of C. albicans correlates with environmental, vacuolar, and cytoplasmic pH regulation, and V-ATPase appears to play a fundamental role in each of these processes. Genetic loss of V-ATPase in pathogenic fungi leads to defective virulence, and a comprehensive picture of the mechanisms involved is emerging. Recent studies have explored the practical utility of V-ATPase as an anti-fungal drug target in C. albicans, including pharmacological inhibition, azole therapy, and targeting of downstream pathways. This overview will discuss these studies as well as hypothetical ways to target V-ATPase and novel high-throughput methods for use in future drug discovery screens. PMID:24478704

  20. Advances in targeting the vacuolar proton-translocating ATPase (V-ATPase) for anti-fungal therapy.

    PubMed

    Hayek, Summer R; Lee, Samuel A; Parra, Karlett J

    2014-01-01

    Vacuolar proton-translocating ATPase (V-ATPase) is a membrane-bound, multi-subunit enzyme that uses the energy of ATP hydrolysis to pump protons across membranes. V-ATPase activity is critical for pH homeostasis and organelle acidification as well as for generation of the membrane potential that drives secondary transporters and cellular metabolism. V-ATPase is highly conserved across species and is best characterized in the model fungus Saccharomyces cerevisiae. However, recent studies in mammals have identified significant alterations from fungi, particularly in the isoform composition of the 14 subunits and in the regulation of complex disassembly. These differences could be exploited for selectivity between fungi and humans and highlight the potential for V-ATPase as an anti-fungal drug target. Candida albicans is a major human fungal pathogen and causes fatality in 35% of systemic infections, even with anti-fungal treatment. The pathogenicity of C. albicans correlates with environmental, vacuolar, and cytoplasmic pH regulation, and V-ATPase appears to play a fundamental role in each of these processes. Genetic loss of V-ATPase in pathogenic fungi leads to defective virulence, and a comprehensive picture of the mechanisms involved is emerging. Recent studies have explored the practical utility of V-ATPase as an anti-fungal drug target in C. albicans, including pharmacological inhibition, azole therapy, and targeting of downstream pathways. This overview will discuss these studies as well as hypothetical ways to target V-ATPase and novel high-throughput methods for use in future drug discovery screens.

  1. Sequential or combination therapy for multiple myeloma.

    PubMed

    Nooka, Ajay; Lonial, Sagar

    2012-10-01

    In myeloma management, whether to offer sequential or combination therapies has largely remained elusive, partly for the reason that there are no conclusive studies evaluating this question and partly owing to the paradigm shift in myeloma outcomes over the last decade raising the same question again, but now in a different context with active agents such as immunomodulatory drugs and proteasome inhibitors being available. Historically, in myeloma, combination cytotoxic chemotherapy compared with the standard-of-care melphalan and prednisone regimen resulted in similar response rates, raising the question of efficacy of the cytotoxic combination therapies with high toxicities and the preference for sequential therapies in order to lower the toxicity of the chosen treatment. However, with the use of more active novel agents with favorable toxicity profiles such as bortezomib, thalidomide and lenalidomide, re-evaluation of this question is necessary.

  2. Intelligent design: combination therapy with oncolytic viruses.

    PubMed

    Ottolino-Perry, Kathryn; Diallo, Jean-Simon; Lichty, Brian D; Bell, John C; McCart, J Andrea

    2010-02-01

    Metastatic cancer remains an incurable disease in the majority of cases and thus novel treatment strategies such as oncolytic virotherapy are rapidly advancing toward clinical use. In order to be successful, it is likely that some type of combination therapy will be necessary to have a meaningful impact on this disease. Although it may be tempting to simply combine an oncolytic virus with the existing standard radiation or chemotherapeutics, the long-term goal of such treatments must be to have a rational, potentially synergistic combination strategy that can be safely and easily used in the clinical setting. The combination of oncolytic virotherapy with existing radiotherapy and chemotherapy modalities is reviewed along with novel biologic therapies including immunotherapies, in order to help investigators make intelligent decisions during the clinical development of these products.

  3. Anti-Aspergillus fumigatus Efficacy of Pentraxin 3 Alone and in Combination with Antifungals

    PubMed Central

    Gaziano, Roberta; Bozza, Silvia; Bellocchio, Silvia; Perruccio, Katia; Montagnoli, Claudia; Pitzurra, Lucia; Salvatori, Giovanni; De Santis, Rita; Carminati, Paolo; Mantovani, Alberto; Romani, Luigina

    2004-01-01

    The collectin pentraxin 3 (PTX3) is an essential component of host resistance to pulmonary aspergillosis. Here we examined the protective effects of administration of PTX3 alone or together with deoxycholate amphotericin B (Fungizone) or liposomal amphotericin B (AmBisome) against invasive aspergillosis in a murine model of allogeneic bone marrow transplantation. PTX3, alone or in combination with the polyenes, was given intranasally or parenterally either before, in concomitance with, or after the intranasal infection with Aspergillus fumigatus conidia. Mice were monitored for resistance to infection and parameters of innate and adaptive T-helper immunity. The results showed the following: (i) complete resistance to infection and reinfection was observed in mice treated with PTX3 alone; (ii) the protective effect of PTX3 was similar or superior to that observed with liposomal amphotericin B or deoxycholate amphotericin B, respectively; (iii) protection was associated with accelerated recovery of lung phagocytic cells and T-helper-1 lymphocytes and concomitant decrease of inflammatory pathology; and (iv) PTX3 potentiated the therapeutic efficacy of suboptimal doses of either antimycotic drug. Together, these data suggest the potential therapeutic use of PTX3 either alone or as an adjunctive therapy in A. fumigatus infections. PMID:15504871

  4. [Targeted therapies: sequential and combined treatments].

    PubMed

    Gross-Goupil, M; Escudier, B

    2010-01-01

    The treatment of metastatic kidney cancer has dramatically changed in the last three years, with demonstration of efficacy of sunitinib, sorafenib, temsirolimus, bevacizumab combined with interferon and more recently everolimus. Although the international guidelines have recently been reviewed, some major questions are still open. Particularly, the best order of administration of these targeted therapies should be considered, since sequential schedule becomes usual with the availability of these new agents. At the same time, the tolerability and efficacy of the combination of the targeted therapies are under investigation in clinical trials. We report recent studies, mainly presented during the ASCO 2007 and 2008 congress. Furthermore, other studies are ongoing to answer other important questions, to optimize the treatment of this disease, such as the role of nephrectomy in case of synchronous metastatic disease, or the efficacy of the targeted therapies in different histological subtype than clear cell carcinoma, or in neoadjuvant and adjuvant settings.

  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. Pneumonia in immunocompetent patients: combination antibiotic therapy.

    PubMed

    Salva, S; Borgatta, B; Rello, J

    2014-04-01

    Pneumonia's burden is still important worldwide not only because of its high incidence and mortality, but also for the elevated costs related to it. Despite the concerted efforts to reduce the incidence of sepsis-related complications, they continue to represent a major human and economic burden. The cornerstone of sepsis management is early appropriate empiric broad spectrum antibiotics, resuscitation, and source control. The association between inappropriate use of antibiotics and increased mortality is the rationale for the use of empiric antibiotic combination therapy in critically ill patients. The aim of this manuscript was to discuss recent literature regarding the management of severe pneumonia, both community-acquired and hospital-acquired/ventilator-associated, in critically ill patients. Use of combination therapy is warranted in severe infections with shock; considerations should be made on the importance of optimal antibiotic administration and adverse reactions, thus providing guidance for a rational use of antibiotics.

  7. [Combination therapy of chronic bacterial prostatitis].

    PubMed

    Khryanin, A A; Reshetnikov, O V

    2016-08-01

    The article discusses the possible etiological factors in the development of chronic bacterial prostatitis. The authors presented a comparative long-term analysis of morbidity from non-viral sexually transmitted infections (STIs) in Russia. Against the background of general decline in STIs incidence, a significant percentage of them is made up by urogenital trichomoniasis. The findings substantiated the advantages of combination therapy (ornidazole and ofloxacin) for bacterial urinary tract infections.

  8. 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

  9. Bortezomib Combination Therapy in Multiple Myeloma

    PubMed Central

    Kapoor, Prashant; Ramakrishnan, Vijay; Rajkumar, S. Vincent

    2012-01-01

    Bortezomib was approved for the treatment of multiple myeloma in 2003. Since then several bortezomib-based combination therapies have emerged. Although some combinations have been preceded by preclinical investigations, most have followed the inevitable process in which active (or potentially active) drugs are combined with each other to create new treatment regimens. Regimens that have combined bortezomib with corticosteroids, alkylating agents, thalidomide, and/or lenalidomide have resulted in high response rates. Despite the higher and often deeper response rates and prolongation of progression-free survival with bortezomib-based multiagent regimens, an overall survival (OS) advantage has not been demonstrated with most combinations compared to the sequential approach of utilizing anti-myeloma agents, particularly in patients less than 65 with newly diagnosed myeloma. The unique properties of some of these regimens can be taken into account when choosing a particular regimen based on the clinical scenario. For example, bortezomib, thalidomide, dexamethasone (VTD) has particular value in renal failure since none of the drugs need dose modification. Similarly, the combination chemotherapy regimen VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide) is of particular value in patients presenting with aggressive disease such as extramedullary plasmacytomas or plasma cell leukemia. Ongoing clinical trials are testing combinations of bortezomib with several other classes of agents, including monoclonal antibodies, and inhibitors of deacetylases, heat shock proteins, phosphatidyl inositol 3-kinase/Akt/mammalian target of rapamycin pathway and farnesyl transferase. PMID:22726546

  10. Multilaboratory Testing of Antifungal Combinations against a Quality Control Isolate of Candida krusei▿ †

    PubMed Central

    Chaturvedi, Vishnu; Ramani, Rama; Ghannoum, Mahmoud A.; Killian, Scott B.; Holliday, Nicole; Knapp, Cindy; Ostrosky-Zeichner, Luis; Messer, Shawn A.; Pfaller, Michael A.; Iqbal, Naureen J.; Arthington-Skaggs, Beth A.; Vazquez, Jose A.; Sein, Tin; Rex, John H.; Walsh, Thomas J.

    2008-01-01

    Candida krusei ATCC 6258 was tested by eight laboratories using 96-well plates containing checkerboard pairwise combinations of amphotericin B (AMB), posaconazole (PSC), caspofungin (CSP), and voriconazole (VRC). The methodology led to reproducible results across the laboratories. All drug combinations yielded MICs lower than the MICs of any two drugs tested singly, and combinations of AMB, PSC, CSP, and VRC were indifferent (no antagonism) by summations of fractional inhibitory concentration. PMID:18227180

  11. Utilizing combination therapy for ethnic skin.

    PubMed

    Taylor, Susan C

    2007-07-01

    A major issue in treating acne in individuals of color is the need to treat and prevent postinflammatory hyperpigmentation (PIH), which is common in this population. This subset analysis reports the pigmentary changes in subjects of color with acne who were enrolled in a community-based trial comparing 3 different topical therapeutic regimens. All subjects received combination clindamycin 1%-benzoyl peroxide (BPO) 5% topical gel containing glycerin and dimethicone. Subjects were randomized to receive this combination therapy in addition to either a tretinoin microsphere (RAM) gel at concentrations of either 0.04% or 0.1% or adapalene (AP) gel 0.1%. There was a trend toward better resolution of hyperpigmentation in the subjects receiving the clindamycin-BPO topical gel in combination with RAM gel 0.04%.

  12. 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

  13. Combined surgery and photodynamic therapy of cancer

    NASA Astrophysics Data System (ADS)

    Douplik, Alexandre

    According to the recent guidelines, the gold standard is resecting an extra 0.5-3 cm beyond the lesion margins that are visually detected and/or biopsy confirmed depending on type of malignancy and its localisation to avoid missing the residuals of the tumour. Often, such a large resection leads to dysfunctions of the organ or tissues, which underwent the surgery. In some cases, an extra tumour-free margin cannot be achieved because of tumour proximity to vital sites such as major vascular or nerve structures. Photodynamic Therapy (PDT) is an emerging clinical modality to locally destroy cancer lesions selectively. The limitation of photodynamic therapy is the curable depth of an order of one centimetre or less. A combination of cancer surgery following by PDT can bring a benefit to reduce the resection and minimise the impact on the organ or tissue functionality. Combination of cancer surgery and photodynamic therapy provides another opportunity-fluorescence image guidance of cancer removal. Most of the photosensitizers intensively fluoresce and hence facilitate a strong fluorescence contrast versus healthy adjacent tissues.

  14. In Vitro Antifungal Activity of Isavuconazole against Madurella mycetomatis

    PubMed Central

    Meis, Jacques F.; Curfs-Breuker, Ilse; Fahal, Ahmed H.

    2012-01-01

    Currently, therapy of black-grain mycetoma caused by Madurella mycetomatis consists of extensive debridement of the infected tissue combined with prolonged antifungal therapy with ketoconazole or itraconazole. In the present study, the in vitro activity of the new triazole isavuconazole toward M. mycetomatis was evaluated. Isavuconazole appeared to have high activity against M. mycetomatis, with MICs ranging from ≤0.016 to 0.125 μg/ml. Due to its favorable pharmacokinetics, isavuconazole could be a promising antifungal agent in the treatment of mycetoma. PMID:22964246

  15. Tumor Static Concentration Curves in Combination Therapy.

    PubMed

    Cardilin, Tim; Almquist, Joachim; Jirstrand, Mats; Sostelly, Alexandre; Amendt, Christiane; El Bawab, Samer; Gabrielsson, Johan

    2017-03-01

    Combination therapies are widely accepted as a cornerstone for treatment of different cancer types. A tumor growth inhibition (TGI) model is developed for combinations of cetuximab and cisplatin obtained from xenograft mice. Unlike traditional TGI models, both natural cell growth and cell death are considered explicitly. The growth rate was estimated to 0.006 h(-1) and the natural cell death to 0.0039 h(-1) resulting in a tumor doubling time of 14 days. The tumor static concentrations (TSC) are predicted for each individual compound. When the compounds are given as single-agents, the required concentrations were computed to be 506 μg · mL(-1) and 56 ng · mL(-1) for cetuximab and cisplatin, respectively. A TSC curve is constructed for different combinations of the two drugs, which separates concentration combinations into regions of tumor shrinkage and tumor growth. The more concave the TSC curve is, the lower is the total exposure to test compounds necessary to achieve tumor regression. The TSC curve for cetuximab and cisplatin showed weak concavity. TSC values and TSC curves were estimated that predict tumor regression for 95% of the population by taking between-subject variability into account. The TSC concept is further discussed for different concentration-effect relationships and for combinations of three or more compounds.

  16. Combined GC- and UHPLC-HR-MS Based Metabolomics to Analyze Durable Anti-fungal Resistance Processes in Cereals.

    PubMed

    Bucher, Rahel; Veyel, Daniel; Willmitzer, Lothar; Krattinger, Simon; Keller, Beat; Biglera, Laurent

    2017-04-26

    Introduction of durable resistance genes in crops is an important strategy to prevent yield loss caused by pathogens. The durable multi-pathogen resistance gene Lr34 originating from wheat is widely used in breeding, and is functionally transferable to barley and rice. The molecular resistance mechanism of Lr34, encoding for an adenosine triphosphate-binding cassette transporter, is not known yet. To understand the molecular function and the defense response of durable disease resistance in cereals, the metabolic response of Lr34 was investigated in, except for the Lr34 gene, genetically identical lines of barley, rice and wheat. A broad range of compounds including primary, secondary and lipophilic metabolites were analyzed by a combination of gas (GC) and liquid chromatography (LC) mass spectrometry (MS) based methods. Data from metabolomics correlated well with transcriptomics data for plant defense responses such as the formation of anti-fungal hordatines or the components of the glyoxylate cycle. Induction of the glyoxylate cycle found in transgenic Lr34 rice grown in the greenhouse was confirmed in field-grown natural Lr34 wheat. Constitutively active plant defense responses were observed in the different cereals.

  17. Efficacy of Antifungal Therapy in a Nonneutropenic Murine Model of Zygomycosis

    PubMed Central

    Dannaoui, Eric; Mouton, Johan W.; Meis, Jacques F. G. M.; Verweij, Paul E.

    2002-01-01

    Three isolates of zygomycetes belonging to three different genera (Rhizopus microsporus, Absidia corymbifera, and Apophysomyces elegans) were used to produce a disseminated infection in nonimmunocompromised mice. The therapeutic efficacy of amphotericin B, given intraperitoneally at doses ranging from 0.5 to 4.5 mg/kg of body weight/day, oral itraconazole at 100 mg/kg/day, and oral terbinafine at 150 mg/kg/day was evaluated in this model. The markers of antifungal efficacy were the median survival time, the mortality rate, and the percentage of infected organs. Organ culture was performed along with microscopic direct examinations of tissues to assess the presence of an active infection. An acute and lethal infection was obtained in untreated mice challenged with each of the three strains. The data obtained for direct examinations and qualitative cultures indicate that, due to the nonseptate nature of the hyphae, each technique gives different information and should be used together with the others. Against all three strains, amphotericin B yielded a 90 to 100% survival rate. Itraconazole was inactive against R. microsporus but significantly reduced mortality in mice infected with A. corymbifera or A. elegans. Terbinafine had no beneficial effects against R. microsporus and A. corymbifera despite documented absorption of the drug. Overall, only limited correlations were observed between MICs determined in vitro and in vivo efficacy of the drugs. The efficacy of itraconazole in these models of zygomycosis suggests that this drug, as well as the new azole compounds presently under development, warrants close evaluation. PMID:12019114

  18. Combination therapies in ophthalmology: implications for intravitreal delivery.

    PubMed

    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.

  19. 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

  20. 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.

  1. Small RNA combination therapy for lung cancer.

    PubMed

    Xue, Wen; Dahlman, James E; Tammela, Tuomas; Khan, Omar F; Sood, Sabina; Dave, Apeksha; Cai, Wenxin; Chirino, Leilani M; Yang, Gillian R; Bronson, Roderick; Crowley, Denise G; Sahay, Gaurav; Schroeder, Avi; Langer, Robert; Anderson, Daniel G; Jacks, Tyler

    2014-08-26

    MicroRNAs (miRNAs) and siRNAs have enormous potential as cancer therapeutics, but their effective delivery to most solid tumors has been difficult. Here, we show that a new lung-targeting nanoparticle is capable of delivering miRNA mimics and siRNAs to lung adenocarcinoma cells in vitro and to tumors in a genetically engineered mouse model of lung cancer based on activation of oncogenic Kirsten rat sarcoma viral oncogene homolog (Kras) and loss of p53 function. Therapeutic delivery of miR-34a, a p53-regulated tumor suppressor miRNA, restored miR-34a levels in lung tumors, specifically down-regulated miR-34a target genes, and slowed tumor growth. The delivery of siRNAs targeting Kras reduced Kras gene expression and MAPK signaling, increased apoptosis, and inhibited tumor growth. The combination of miR-34a and siRNA targeting Kras improved therapeutic responses over those observed with either small RNA alone, leading to tumor regression. Furthermore, nanoparticle-mediated small RNA delivery plus conventional, cisplatin-based chemotherapy prolonged survival in this model compared with chemotherapy alone. These findings demonstrate that RNA combination therapy is possible in an autochthonous model of lung cancer and provide preclinical support for the use of small RNA therapies in patients who have cancer.

  2. Hybrid nanoparticles for combination therapy of cancer

    PubMed Central

    He, Chunbai; Lu, Jianqin; Lin, Wenbin

    2015-01-01

    Nanoparticle anticancer drug delivery enhances therapeutic efficacies and reduces side effects by improving pharmacokinetics and biodistributions of the drug payloads in animal models. Despite promising preclinical efficacy results, monotherapy nanomedicines have failed to produce enhanced response rates over conventional chemotherapy in human clinical trials. The discrepancy between preclinical data and clinical outcomes is believed to result from the less pronounced enhanced permeability and retention (EPR) effect in and the heterogeneity of human tumors as well as the intrinsic/acquired drug resistance to monotherapy over the treatment course. To address these issues, recent efforts have been devoted to developing nanocarriers that can efficiently deliver multiple therapeutics with controlled release properties and increased tumor deposition. In ideal scenarios, the drug or therapeutic modality combinations have different mechanisms of action to afford synergistic effects. In this review, we summarize recent progress in designing hybrid nanoparticles for the co-delivery of combination therapies, including multiple chemotherapeutics, chemotherapeutics and biologics, chemotherapeutics and photodynamic therapy, and chemotherapeutics and radiotherapy. The in vitro and in vivo anticancer effects are also discussed. PMID:26387745

  3. Hybrid nanoparticles for combination therapy of cancer.

    PubMed

    He, Chunbai; Lu, Jianqin; Lin, Wenbin

    2015-12-10

    Nanoparticle anticancer drug delivery enhances therapeutic efficacies and reduces side effects by improving pharmacokinetics and biodistributions of the drug payloads in animal models. Despite promising preclinical efficacy results, monotherapy nanomedicines have failed to produce enhanced response rates over conventional chemotherapy in human clinical trials. The discrepancy between preclinical data and clinical outcomes is believed to result from the less pronounced enhanced permeability and retention (EPR) effect in and the heterogeneity of human tumors as well as the intrinsic/acquired drug resistance to monotherapy over the treatment course. To address these issues, recent efforts have been devoted to developing nanocarriers that can efficiently deliver multiple therapeutics with controlled release properties and increased tumor deposition. In ideal scenarios, the drug or therapeutic modality combinations have different mechanisms of action to afford synergistic effects. In this review, we summarize recent progress in designing hybrid nanoparticles for the co-delivery of combination therapies, including multiple chemotherapeutics, chemotherapeutics and biologics, chemotherapeutics and photodynamic therapy, and chemotherapeutics and radiotherapy. The in vitro and in vivo anticancer effects are also discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Ectopic pregnancy treatment by combination therapy

    PubMed Central

    Chudecka-Głaz, Anita; Kuźniak, Sławomir; Menkiszak, Janusz

    2016-01-01

    Abstract Detectability of early stages of ectopic pregnancies has increased due to improvements in ultrasonographic and biochemical techniques. Since the patients’ future procreative plans must be taken into consideration when commencing treatment, the goal of this work was to compare the effects of treatment methods and their impact on fertility. The study included 91 patients treated surgically for ectopic pregnancy. The choice of treatment depended on patients’ general condition, ultrasonographic evaluation and serum level of beta-hCG. A combination of laparoscopic and conservative systemic treatment was applied in 70% of cases. More rapid beta-hCG reduction was noted when laparoscopy and intra-oviductal injection of hyperosmolar glucose or methotrexate (MTX) were combined with intramuscular administration of MTX at a dose of 50 mg/m2. Follow-up examination of 66 patients revealed that the greatest number of spontaneous pregnancies (48%) resulted after this combination therapy. We conclude that this combination treatment is safe and provides satisfactory results in terms of future fertility. PMID:28352846

  5. Combination therapy for airflow limitation in COPD.

    PubMed

    Ghanei, Mostafa; Nezhad, Leila Hoseini; Harandi, Ali Amini; Alaeddini, Farshid; Shohrati, Majid; Aslani, Jafar

    2012-01-01

    Background and the purpose of the study Existing evidence confirms that no pharmacologic agent ameliorates the decline in the lung function or changes the prognosis of chronic obstructive pulmonary disease (COPD). We tried a critical combination therapy for management of COPD. Current or past smoker (passive or active) COPD patients with moderate to severe COPD who did not respond to primitive therapy (i.e., oral prednisolone (50 mg in the morning) for 5 days; with Beclomethasone Fort (3 puff q12h, totally 1500 micrograms/day), Salmeterol (2 puffs q12h, 50 micrograms/puff) and ipratropium bromide (4 puffs q8h) for two months, enrolled to study. Furthermore they were received N-Acetylcysteine (1200 mg/daily), Azithromycin (tablet 250 mg/every other day) and Theophylline (100 mg BD). The study group consisted of 44 men and 4 women, with a mean age and standard deviation of 63.6 ± 12.7 years (range 22-86 years). Thirteen of 48 patients (27.0%) was responder based on 15% increasing in FEV 1 (27.7 ± 7.9) after 6.7 ± 6.1 months (57.9 ± 12.9 year old). There were statistically significant differences in age and smoking between responders and non-responders (P value was 0.05 and 0.04 respectively). There was no difference in emphysema and air trapping between two groups (p = 0.13). Interestingly considerable proportion of patients with COPD can be reversible using combination drug therapy and patients will greatly benefit from different and synergic action of the drugs. The treatment was more effective in younger patients who smoke less.

  6. Current status of multimodal & combination therapy for hepatocellular carcinoma.

    PubMed

    Yang, Jian; Yan, Lunan; Wang, Wentao

    2012-09-01

    Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Surgery offers the only hope for cure. However, the potentially curable method is only possible for a small proportion of those afflicted, for the rest, palliative treatment is indicated. Despite all the treatment options when used as monotherapy, patients with HCC have a poor long term prognosis. In this setting, multimodal and combination therapy has emerged as an alternative treatment modality for HCC. Studies have looked at various forms of combination therapy, including neoadjuvant/adjuvant/downstaging therapy for surgery and the combined modality of non-operative therapies. The novel molecular targeted therapies are also being used as combination regimens for surgery or other non-operative therapies. Some forms of combination therapies, including downstaging therapy for surgery, salvage transplantation, and molecular targeted therapy have been shown to provide survival benefits for well selected patients, and need to be encouraged in the future. And others such as pre-operative bridging therapy for liver transplantation, adjuvant therapy for hepatic resection and combination of local and regional therapies have also shown some benefits in preliminary results, which need confirmation in further studies. In conclusion, multimodal and combination therapy is an encouraging treatment modality for HCC. Future research should continue to unravel the role of combination therapy with properly selected patients and appropriate end points.

  7. Sporothrix schenckii COMPLEX: SUSCEPTIBILITIES TO COMBINED ANTIFUNGAL AGENTS AND CHARACTERIZATION OF ENZYMATIC PROFILES

    PubMed Central

    OLIVEIRA, Daniele Carvalho; de LORETO, Érico Silva; MARIO, Débora Alves Nunes; LOPES, Paulo G. Markus; NEVES, Louise Vignolles; da ROCHA, Marta Pires; SANTURIO, Janio Morais; ALVES, Sydney Hartz

    2015-01-01

    SUMMARY Sporothrix schenckiiwas reclassified as a complex encompassing six cryptic species, which calls for the reassessment of clinical and epidemiological data of these new species. We evaluated the susceptibility of Sporothrix albicans (n = 1) , S. brasiliensis (n = 6) , S. globosa (n = 1), S. mexicana(n = 1) and S. schenckii(n = 36) to terbinafine (TRB) alone and in combination with itraconazole (ITZ), ketoconazole (KTZ), and voriconazole (VRZ) by a checkerboard microdilution method and determined the enzymatic profile of these species with the API-ZYM kit. Most interactions were additive (27.5%, 32.5% and 5%) or indifferent (70%, 50% and 52.5%) for TRB+KTZ, TRB+ITZ and TRB+VRZ, respectively. Antagonisms were observed in 42.5% of isolates for the TRB+VRZ combination. Based on enzymatic profiling, the Sporothrix schenckii strains were categorized into 14 biotypes. Leucine arylamidase (LA) activity was observed only for S. albicans and S. mexicana. The species S. globosaand S. mexicanawere the only species without β-glucosidase (GS) activity. Our results may contribute to a better understanding of virulence and resistance among species of the genus Sporothrixin further studies. PMID:26422151

  8. In vitro antifungal susceptibility of coelomycete agents of black grain eumycetoma to eight antifungals.

    PubMed

    Ahmed, Sarah Abdalla; de Hoog, G Sybren; Stevens, David A; Fahal, Ahmed H; van de Sande, Wendy W J

    2015-04-01

    Fungal mycetoma (eumycetoma) represents one of the most difficult infections to appropriately manage. The current recommended treatment is based on extensive surgical debridement combined with prolonged antifungal therapy with ketoconazole or itraconazole. Despite the different phylogenetic positions of black-grain eumycetoma species, they are all treated with the same antifungal agents. The in vitro antifungal susceptibility of coelomycetous eumycetoma agents in the order of Pleosporales presently is largely unknown. Here we determined the in vitro activity of eight antifungal agents against seven species causing human eumycetoma using the Sensititre YeastOne method. High minimum inhibitory concentrations (MICs) were found with fluconazole, caspofungin, flucytosine, and amphotericin B. Voriconazole and posaconazole were found to be active against all species tested. Of the species included in the investigation, MICs of Medicopsis romeroi differed from the rest of the mycetoma causative agents belonging to the order of the Pleosporales. We found significantly lower MICs for amphotericin B and significantly higher MICs for fluconazole, ketoconazole, and itraconazole against this species. Our results emphasised that identification of black grain mycetoma agent is important as well as performing susceptibility testing before starting of antifungal treatment. © The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. Combination antiretroviral therapy and cancer risk.

    PubMed

    Borges, Álvaro H

    2017-01-01

    To review the newest research about the effects of combination antiretroviral therapy (cART) on cancer risk. HIV+ persons are at increased risk of cancer. As this risk is higher for malignancies driven by viral and bacterial coinfections, classifying malignancies into infection-related and infection-unrelated has been an emerging trend. Cohorts have detected major reductions in the incidence of Kaposi sarcoma and non-Hodgkin lymphoma (NHL) following cART initiation among immunosuppressed HIV+ persons. However, recent randomized data indicate that cART reduces risk of Kaposi sarcoma and NHL also during early HIV infection before overt immunosuppression occurs. Long-term effects of cART exposure on cancer risk are not well defined; according to basic and epidemiological research, there might be specific associations of each cART class with distinct patterns of cancer risk. The relationship between cART exposure and cancer risk is complex and nuanced. It is an intriguing fact that, whether initiated during severe immunosuppression or not, cART reduces risk of Kaposi sarcoma and NHL. Further research should identify mediators of the benefit of immediate cART initiation in reducing cancer risk, understand the relationship between long-term cART exposure and cancer incidence and assess whether adjuvant anti-inflammatory therapies can reduce cancer risk during treated HIV infection.

  10. Efficacy of debridement alone versus debridement combined with topical antifungal nail lacquer for the treatment of pedal onychomycosis: a randomized, controlled trial.

    PubMed

    Malay, D Scot; Yi, Sang; Borowsky, Pamela; Downey, Michael S; Mlodzienski, Alan J

    2009-01-01

    Pedal onychomycosis is a common malady caused by dermatophytes, saprophytes, and yeasts. Traditional treatment options for this condition include toenail debridement, and pharmacological therapies that range from the application of topical agents to the oral administration of antifungal medications. In this study, 55 patients (289 toenails) were randomly allocated to either nail debridement (27 [49.09%] patients) or debridement plus application of topical antifungal nail lacquer (28 [50.91%] patients). The primary outcome was mycological cure, and secondary outcomes included foot-related quality of life, and a number of clinically important toenail characteristics. After a median follow-up of 10.5 months (range, 3.25-14.25) months), patients in the antifungal nail lacquer group improved statistically significantly more than did those in the debridement alone group, and displayed a 76.74% rate of mycological cure. None of the patients in the debridement-only group experienced mycological cure. Variables that statistically significantly decreased the likelihood of cure included yeast on culture, pedal hyperhidrosis, cigarette smoking, involvement of the lunula, and involvement of >50% of the transverse width of the nail. Variables statistically significantly associated with an increased likelihood of cure included intervention before 6 months' duration, treatment at a large, urban practice, black race, and loss of protective sensation. 1.

  11. The biology and chemistry of antifungal agents: a review.

    PubMed

    Kathiravan, Muthu K; Salake, Amol B; Chothe, Aparna S; Dudhe, Prashik B; Watode, Rahul P; Mukta, Maheshwar S; Gadhwe, Sandeep

    2012-10-01

    In recent years their has been an increased use of antifungal agents and has resulted in the development of resistance to drugs. Currently, use of standard antifungal therapies can be limited because of toxicity, low efficacy rates. Different types of mechanisms contribute to the development of resistance to antifungals. This has given raise to search for a new heterocycle with distinct action or multitargeted combination therapy. This review addresses the areas such as the underlying mechanisms, eight different targets such as ergosterol synthesis, chitin synthesis, ergosterol disruptors, glucan synthesis, squalene epoxidase, nucleic acid synthesis, protein synthesis, microtubules synthesis. The clinically employed drugs along with the current research work going on worldwide on different heterocycles are discussed. In recent advances various heterocycles including imidazole, benzimidazole etc., twenty three scaffolds and their lead identification are discussed.

  12. 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

  13. 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.

  14. Special Issue: Novel Antifungal Drug Discovery

    PubMed Central

    Poeta, Maurizio Del

    2016-01-01

    This Special Issue is designed to highlight the latest research and development on new antifungal compounds with mechanisms of action different from the ones of polyenes, azoles, and echinocandins. The papers presented here highlight new pathways and targets that could be exploited for the future development of new antifungal agents to be used alone or in combination with existing antifungals. A computational model for better predicting antifungal drug resistance is also presented. PMID:28058254

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

    USDA-ARS?s Scientific Manuscript database

    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/...

  16. Photodynamic therapy has antifungal effect and reduces inflammatory signals in Candida albicans-induced murine vaginitis.

    PubMed

    Machado-de-Sena, R M; Corrêa, L; Kato, I T; Prates, R A; Senna, A M; Santos, C C; Picanço, D A; Ribeiro, M S

    2014-09-01

    Vaginal candidiasis (VC) is a disease that affects thousands of women of childbearing age, mainly caused by Candida albicans fungus. Photodynamic therapy (PDT) uses photosensitizing substances that are nontoxic in the dark, but able to produce reactive oxygen species when they are subjected to a light source. In this work our purpose was to investigate PDT effects on fungal burden and inflammatory cells in a murine model of C. albicans-induced vaginal candidiasis. Female BALB/c mice 6-10 weeks were estrogenized and maintained in this state during all experiment. After 72h, mices were inoculated intravaginally (IV) with 20μL of 2×10(5)C. albicans cells suspension. Mice were separated into 5 groups after five days: H (healthy), PBS (control), laser, MB (methylene blue) and PDT. PDT and MB groups received IV 20μL solution with 1mM of MB, others received PBS. PDT and laser groups were irradiated with a red laser (100mW, 660nm) in one (36J, 6min) or two sessions (18J, 3min). After the end of treatment, mice were submitted to microbiological and histomorphometric analysis with ImageJ software. Data were plotted by mean values and standard deviations of CFU/mL and percentage of inflammatory cells area. ANOVA and Bonferroni post-test were used and data were considered significant when p<0.05. PDT significantly reduced C. albicans after the two tested protocols, however, percentage area of inflammatory cells was significantly reduced just with two sessions of PDT. PDT with MB and red laser is a promising therapy for VC. It is able to reduce fungal infection in biofilm and inflammatory signals associated with VC in a murine model of vaginitis. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. A randomized, double-blind, multicenter study of caspofungin versus liposomal amphotericin B for empiric antifungal therapy in pediatric patients with persistent fever and neutropenia.

    PubMed

    Maertens, Johan A; Madero, Luis; Reilly, Anne F; Lehrnbecher, Thomas; Groll, Andreas H; Jafri, Hasan S; Green, Michael; Nania, Joseph J; Bourque, Michael R; Wise, Beth Ann; Strohmaier, Kim M; Taylor, Arlene F; Kartsonis, Nicholas A; Chow, Joseph W; Arndt, Carola A S; DePauw, Ben E; Walsh, Thomas J

    2010-05-01

    Persistently febrile neutropenic children at risk for invasive fungal infections receive empiric antifungal therapy as a standard of care. However, little is known about the role of echinocandins and liposomal amphotericin B (L-AmB) for empiric antifungal therapy in pediatric patients. Patients between the ages of 2 to 17 years with persistent fever and neutropenia were randomly assigned to receive caspofungin (70 mg/m loading dose on day 1, then 50 mg/m daily [maximum 70 mg/d]) or L-AmB (3 mg/kg daily) in a 2:1 ratio. Evaluation of safety was the primary objective of the study. Efficacy was also evaluated, with a successful outcome defined as fulfilling all components of a prespecified 5-part composite endpoint. Suspected invasive fungal infections were evaluated by an independent, treatment-blinded adjudication committee. Eighty-two patients received study therapy (caspofungin 56, L-AmB 26), and 81 were evaluated for efficacy (caspofungin 56; L-AmB 25). Outcomes for safety and efficacy endpoints were similar for both study arms. Adverse drug-related event rates [95% confidence interval] were similar between the caspofungin and L-AmB groups (clinical 48.2% [34.7-62.0] versus 46.2% [26.6-66.6]; laboratory 10.7% [4.0-21.9] versus 19.2% [6.6-39.4]). Serious drug-related adverse events occurred in 1 (1.8%) of caspofungin-treated patients and 3 (11.5%) of L-AmB-treated patients. Overall success rates [95% CI] were 46.4% [33.4-59.5] for caspofungin and 32.0% [13.7-50.3] for L-AmB. Caspofungin and L-AmB were comparable in tolerability, safety, and efficacy as empiric antifungal therapy for persistently febrile neutropenic pediatric patients.

  18. Antifungal agents in neonates: issues and recommendations.

    PubMed

    Almirante, Benito; Rodríguez, Dolors

    2007-01-01

    Fungal infections are responsible for considerable morbidity and mortality in the neonatal period, particularly among premature neonates. Four classes of antifungal agents are commonly used in the treatment of fungal infections in pediatric patients: polyene macrolides, fluorinated pyrimidines, triazoles, and echinocandins. Due to the paucity of pediatric data, many recommendations for the use of antifungal agents in this population are derived from the experience in adults. The purpose of this article was to review the published data on fungal infections and antifungal agents, with a focus on neonatal patients, and to provide an overview of the differences in antifungal pharmacology in neonates compared with adults. Pharmacokinetic data suggest dosing differences in children versus adult patients with some antifungals, but not all agents have been fully evaluated. The available pharmacokinetic data on the amphotericin B deoxycholate formulation in neonates exhibit considerable variability; nevertheless, the dosage regimen suggested in the neonatal population is similar to that used in adults. More pharmacokinetic information is available on the liposomal and lipid complex preparations of amphotericin B and fluconazole, and it supports their use in neonates; however, the optimal dosage and duration of therapy is difficult to establish. All amphotericin-B formulations, frequently used in combination with flucytosine, are useful for treating disseminated fungal infections and Candida meningitis in neonates. Fluconazole, with potent in vitro activity against Cryptococcus neoformans and almost all Candida spp., has been used in neonates with invasive candidiasis at dosages of 6 mg/kg/day, and for antifungal prophylaxis in high-risk neonates. There are limited data on itraconazole, voriconazole, and posaconazole use in neonates. Caspofungin, which is active against Candida spp. and Aspergillus spp., requires higher doses in children relative to adults, and dosing is

  19. 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.

  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. 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.

  2. 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. © 2016 Blackwell Verlag GmbH.

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

    PubMed Central

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

    2013-01-01

    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

  4. Usefulness of defined daily dose and days of therapy in pediatrics and obstetrics-gynecology: a comparative analysis of antifungal drugs (2000-2001, 2005-2006, and 2010-2011).

    PubMed

    Guillot, Justine; Lebel, Denis; Roy, Hélène; Ovetchkine, Philippe; Bussières, Jean-François

    2014-07-01

    The objective was to describe antifungal drug use by using the number of defined daily doses (DDD)/1000 patient-days per antifungal, the number of days of therapy (DOT)/1000 patient-days per antifungal, and the mean dose in mg/kg/day per antifungal during a 10-year period. Retrospective, cross-sectional, descriptive study, in a mother-child university hospital center, with 400 pediatric beds and 100 obstetrics-gynecology beds. All inpatients who received 1 of the 7 authorized antifungals on the institution's local formulary in 2000-2001, 2005-2006, or 2010-2011 were included. Prescriptions for emergency department and outpatient clinics were excluded. The data were extracted from the patients' computerized medication profiles linked to patient admission, discharge, and transfer data. The DDD, DOT, and the mean dose in mg/kg/day were calculated for each antifungal and overall. There was a 2.97-fold increase in the overall number of DDD/1000 patient-days, from 14.8 in 2000-2001 to 37.5 in 2005-2006 and 43.9 in 2010-2011. There was a 2.97-fold increase in the overall number of DOT/1000 patient-days, from 22.8 in 2000-2001 to 50.3 in 2005-2006 and 67.8 in 2010-2011. It can be difficult to compare the use of antifungal drugs among institutions, owing to numerous factors, but it gives an idea about the consumption outside the studied center. Moreover, these ratios help to evaluate the use of antifungals within a same institution. These data could be correlated among others, with resistance patterns, in order to improve our daily practice concerning antifungal prescription.

  5. 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.

  6. [Combined therapy with etanercept and systemic drugs or phototherapy].

    PubMed

    Belinchón, I; Ballester, I

    2010-05-01

    Biological therapy has been shown to have a very satisfactory antipsoriasic effect. However, this response is not always achieved in all the patients and may be insufficient for others. Thus, strategies have recently been designed, among which the use of combined therapies with biological and systemic drugs or phototherapy have been designed. In this work, we have reviewed the combined therapy with etanercept, systemic drugs and phototherapy and present the case of a patient with psoriasis treated with etanercept and narrow band UVB.

  7. Targeting efflux pumps to overcome antifungal drug resistance.

    PubMed

    Holmes, Ann R; Cardno, Tony S; Strouse, J Jacob; Ivnitski-Steele, Irena; Keniya, Mikhail V; Lackovic, Kurt; Monk, Brian C; Sklar, Larry A; Cannon, Richard D

    2016-08-01

    Resistance to antifungal drugs is an increasingly significant clinical problem. The most common antifungal resistance encountered is efflux pump-mediated resistance of Candida species to azole drugs. One approach to overcome this resistance is to inhibit the pumps and chemosensitize resistant strains to azole drugs. Drug discovery targeting fungal efflux pumps could thus result in the development of azole-enhancing combination therapy. Heterologous expression of fungal efflux pumps in Saccharomyces cerevisiae provides a versatile system for screening for pump inhibitors. Fungal efflux pumps transport a range of xenobiotics including fluorescent compounds. This enables the use of fluorescence-based detection, as well as growth inhibition assays, in screens to discover compounds targeting efflux-mediated antifungal drug resistance. A variety of medium- and high-throughput screens have been used to identify a number of chemical entities that inhibit fungal efflux pumps.

  8. Combining Immunotherapy with Standard Glioblastoma Therapy

    Cancer.gov

    This clinical trial is testing standard therapy (surgery, radiation and temozolomide) plus immunotherapy with pembrolizumab with or without a cancer treatment vaccine for patients with newly diagnosed glioblastoma, a common and deadly type of brain tumor.

  9. Candidaemia and antifungal therapy in a French University Hospital: rough trends over a decade and possible links

    PubMed Central

    Sendid, Boualem; Cotteau, Angélique; François, Nadine; D'Haveloose, Annie; Standaert, Annie; Camus, Daniel; Poulain, Daniel

    2006-01-01

    Background Evidence for an increased prevalence of candidaemia and for high associated mortality in the 1990s led to a number of different recommendations concerning the management of at risk patients as well as an increase in the availability and prescription of new antifungal agents. The aim of this study was to parallel in our hospital candidemia incidence with the nature of prescribed antifungal drugs between 1993 and 2003. Methods During this 10-year period we reviewed all cases of candidemia, and collected all the data about annual consumption of prescribed antifungal drugs Results Our centralised clinical mycology laboratory isolates and identifies all yeasts grown from blood cultures obtained from a 3300 bed teaching hospital. Between 1993 and 2003, 430 blood yeast isolates were identified. Examination of the trends in isolation revealed a clear decrease in number of yeast isolates recovered between 1995–2000, whereas the number of positive blood cultures in 2003 rose to 1993 levels. The relative prevalence of Candida albicans and C. glabrata was similar in 1993 and 2003 in contrast to the period 1995–2000 where an increased prevalence of C. glabrata was observed. When these quantitative and qualitative data were compared to the amount and type of antifungal agents prescribed during the same period (annual mean defined daily dose: 2662741; annual mean cost: 615629 €) a single correlation was found between the decrease in number of yeast isolates, the increased prevalence of C. glabrata and the high level of prescription of fluconazole at prophylactic doses between 1995–2000. Conclusion Between 1993 and 2000, the number of cases of candidemia halved, with an increase of C. glabrata prevalence. These findings were probably linked to the use of Fluconazole prophylaxis. Although it is not possible to make any recommendations from this data the information is nevertheless interesting and may have considerable implications with the introduction of new

  10. [Combination of Targeted Therapy and Immunotherapy for Cancer].

    PubMed

    Kadowaki, Norimitsu

    2015-09-01

    Targeted therapies and immunotherapies attack tumor cells through different mechanisms. In addition, these therapies exhibit quick and delayed effects, respectively, and therefore, these therapies are complementary. Furthermore, targeted therapies may enhance the function of immune cells, and therefore, both the therapies are expected to have a synergistic effect. Antitumor immune responses comprise several steps including dendritic cell activation, T cell activation, and dampening tumor-induced immunosuppression; targeted drugs that work at each step have been reported. Clinical trials of rational combinations of both therapies, while avoiding severe adverse events, will greatly advance cancer treatments in the near future.

  11. Opportunities and challenges in combination gene cancer therapy.

    PubMed

    Nastiuk, Kent L; Krolewski, John J

    2016-03-01

    Treatment for solid tumor malignancies, which constitute the majority of human cancers, is still dominated by surgery and radiotherapies. This is especially true for many localized solid tumors, which are often curable with these treatments. However, metastatic cancers are beyond the reach of these therapies, and many localized cancers that are initially treated with surgery and radiation will recur and metastasize. Thus, for over 60years there has been a concerted effort to develop effective drug treatments for metastatic cancers. Combination therapies are an increasingly important part of the anti-cancer drug armamentarium. In the case of cytotoxic chemotherapy, multi-drug regimens rapidly became the norm, as the earliest single agents were relatively ineffective. In contrast to chemotherapy, where combination therapies were required in order to achieve treatment efficacy, for both hormonal and targeted therapies the impetus to move toward the use of combination therapies is to prevent or reverse the development of treatment resistance. In addition, emerging evidence suggests that combination therapy may also improve cancer treatment by neutralizing an emerging treatment side effect termed therapy-induced metastasis, which accompanies some effective single agent therapies. Finally, although gene therapy is still far from use in the clinic, we propose that combination therapies may enhance its effectiveness. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Short-term therapy with luliconazole, a novel topical antifungal imidazole, in guinea pig models of tinea corporis and tinea pedis.

    PubMed

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

    2012-06-01

    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.

  13. 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

  14. Cognitive Behavioral Therapy, Sertraline, or a Combination in Childhood Anxiety

    PubMed Central

    Walkup, John T.; Albano, Anne Marie; Piacentini, John; Birmaher, Boris; Compton, Scott N.; Sherrill, Joel T.; Ginsburg, Golda S.; Rynn, Moira A.; McCracken, James; Waslick, Bruce; Iyengar, Satish; March, John S.; Kendall, Philip C.

    2009-01-01

    Background Anxiety disorders are common psychiatric conditions affecting children and adolescents. Although cognitive behavioral therapy and selective serotonin-reuptake inhibitors have shown efficacy in treating these disorders, little is known about their relative or combined efficacy. Methods In this randomized, controlled trial, we assigned 488 children between the ages of 7 and 17 years who had a primary diagnosis of separation anxiety disorder, generalized anxiety disorder, or social phobia to receive 14 sessions of cognitive behavioral therapy, sertraline (at a dose of up to 200 mg per day), a combination of sertraline and cognitive behavioral therapy, or a placebo drug for 12 weeks in a 2:2:2:1 ratio. We administered categorical and dimensional ratings of anxiety severity and impairment at baseline and at weeks 4, 8, and 12. Results The percentages of children who were rated as very much or much improved on the Clinician Global Impression-Improvement scale were 80.7% for combination therapy (P<0.001), 59.7% for cognitive behavioral therapy (P<0.001), and 54.9% for sertraline (P<0.001); all therapies were superior to placebo (23.7%). Combination therapy was superior to both monotherapies (P<0.001). Results on the Pediatric Anxiety Rating Scale documented a similar magnitude and pattern of response; combination therapy had a greater response than cognitive behavioral therapy, which was equivalent to sertraline, and all therapies were superior to placebo. Adverse events, including suicidal and homicidal ideation, were no more frequent in the sertraline group than in the placebo group. No child attempted suicide. There was less insomnia, fatigue, sedation, and restlessness associated with cognitive behavioral therapy than with sertraline. Conclusions Both cognitive behavioral therapy and sertraline reduced the severity of anxiety in children with anxiety disorders; a combination of the two therapies had a superior response rate. (ClinicalTrials.gov number, NCT

  15. 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

  16. 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.

  17. Mechanisms of Antifungal Drug Resistance

    PubMed Central

    Cowen, Leah E.; Sanglard, Dominique; Howard, Susan J.; Rogers, P. David; Perlin, David S.

    2015-01-01

    Antifungal therapy is a central component of patient management for acute and chronic mycoses. Yet, treatment choices are restricted because of the sparse number of antifungal drug classes. Clinical management of fungal diseases is further compromised by the emergence of antifungal drug resistance, which eliminates available drug classes as treatment options. Once considered a rare occurrence, antifungal drug resistance is on the rise in many high-risk medical centers. Most concerning is the evolution of multidrug- resistant organisms refractory to several different classes of antifungal agents, especially among common Candida species. The mechanisms responsible are mostly shared by both resistant strains displaying inherently reduced susceptibility and those acquiring resistance during therapy. The molecular mechanisms include altered drug affinity and target abundance, reduced intracellular drug levels caused by efflux pumps, and formation of biofilms. New insights into genetic factors regulating these mechanisms, as well as cellular factors important for stress adaptation, provide a foundation to better understand the emergence of antifungal drug resistance. PMID:25384768

  18. 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

  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. Antifungal Resistance, Metabolic Routes as Drug Targets, and New Antifungal Agents: An Overview about Endemic Dimorphic Fungi

    PubMed Central

    Parente-Rocha, Juliana Alves; Bailão, Alexandre Melo; Amaral, André Correa; Paccez, Juliano Domiraci; Borges, Clayton Luiz

    2017-01-01

    Diseases caused by fungi can occur in healthy people, but immunocompromised patients are the major risk group for invasive fungal infections. Cases of fungal resistance and the difficulty of treatment make fungal infections a public health problem. This review explores mechanisms used by fungi to promote fungal resistance, such as the mutation or overexpression of drug targets, efflux and degradation systems, and pleiotropic drug responses. Alternative novel drug targets have been investigated; these include metabolic routes used by fungi during infection, such as trehalose and amino acid metabolism and mitochondrial proteins. An overview of new antifungal agents, including nanostructured antifungals, as well as of repositioning approaches is discussed. Studies focusing on the development of vaccines against antifungal diseases have increased in recent years, as these strategies can be applied in combination with antifungal therapy to prevent posttreatment sequelae. Studies focused on the development of a pan-fungal vaccine and antifungal drugs can improve the treatment of immunocompromised patients and reduce treatment costs. PMID:28694566

  1. Terbinafine in combination with other antifungal agents for treatment of resistant or refractory mycoses: investigating optimal dosing regimens using a physiologically based pharmacokinetic model.

    PubMed

    Dolton, Michael J; Perera, Vidya; Pont, Lisa G; McLachlan, Andrew J

    2014-01-01

    Terbinafine is increasingly used in combination with other antifungal agents to treat resistant or refractory mycoses due to synergistic in vitro antifungal activity; high doses are commonly used, but limited data are available on systemic exposure, and no assessment of pharmacodynamic target attainment has been made. Using a physiologically based pharmacokinetic (PBPK) model for terbinafine, this study aimed to predict total and unbound terbinafine concentrations in plasma with a range of high-dose regimens and also calculate predicted pharmacodynamic parameters for terbinafine. Predicted terbinafine concentrations accumulated significantly during the first 28 days of treatment; the area under the concentration-time curve (AUC)/MIC ratios and AUC for the free, unbound fraction (fAUC)/MIC ratios increased by 54 to 62% on day 7 of treatment and by 80 to 92% on day 28 compared to day 1, depending on the dose regimen. Of the high-dose regimens investigated, 500 mg of terbinafine taken every 12 h provided the highest systemic exposure; on day 7 of treatment, the predicted AUC, maximum concentration (Cmax), and minimum concentration (Cmin) were approximately 4-fold, 1.9-fold, and 4.4-fold higher than with a standard-dose regimen of 250 mg once daily. Close agreement was seen between the concentrations predicted by the PBPK model and the observed concentrations, indicating good predictive performance. This study provides the first report of predicted terbinafine exposure in plasma with a range of high-dose regimens.

  2. Combination treatment including targeted therapy for advanced hepatocellular carcinoma

    PubMed Central

    Xie, Yuan; Wang, Anqiang; Zhang, Haohai; Yang, Xiaobo; Wan, Xueshuai; Lu, Xin; Sang, Xinting; Zhao, Haitao

    2016-01-01

    Management of advanced hepatocellular carcinoma (HCC), one of the most lethal cancers worldwide, has presented a therapeutic challenge over past decades. Most patients with advanced HCC and a low possibility of surgical resection have limited treatment options and no alternative but to accept local or palliative treatment. In the new era of cancer therapy, increasing numbers of molecular targeted agents (MTAs) have been applied in the treatment of advanced HCC. However, mono-targeted therapy has shown disappointing outcomes in disease control, primarily because of tumor heterogeneity and complex cell signal transduction. Because incapacitation of a single target is insufficient for cancer suppression, combination treatment for targeted therapy has been proposed and experimentally tested in several clinical trials. In this article, we review research studies aimed to enhance the efficacy of targeted therapy for HCC through combination strategies. Combination treatments involving targeted therapy for advanced HCC are compared and discussed. PMID:27626176

  3. Immediate versus deferred empirical antifungal (IDEA) therapy in high-risk patients with febrile neutropenia: a randomized, double-blind, placebo-controlled, multicenter study.

    PubMed

    Maschmeyer, G; Heinz, W J; Hertenstein, B; Horst, H-A; Requadt, C; Wagner, T; Cornely, O A; Löffler, J; Ruhnke, M

    2013-05-01

    Empirical antifungal therapy is widely used in high-risk neutropenic hematology patients with fever persisting for more than 4 days. This clinical trial assessed whether immediate empirical therapy with voriconazole could lower the rates of invasive fungal infections (IFIs) compared with this approach. In a double-blind, placebo-controlled, multicenter study, patients with acute leukemia undergoing chemotherapy or allogeneic hematopoietic stem cell transplantation (HSCT) recipients were randomized to broad-spectrum antibacterial therapy plus voriconazole (immediate) or placebo (deferred) after the onset of neutropenic fever. If fever persisted for 96 h, patients were switched to open-label intravenous voriconazole; oral treatment was permitted after 96 h. The primary endpoint was the rate of proven/probable IFIs between Days 2 and 28 after fever onset in the modified intent-to-treat (mITT) complete-case population. One hundred and forty-seven patients were randomized to immediate (n = 81) or deferred (n = 66) voriconazole. In the mITT population, six patients in the immediate group and nine in the deferred group developed proven/probable IFI between Days 2 and 28 (p = 0.258). The safety profiles were similar in both groups. While immediate empirical therapy with voriconazole appears to be safe in febrile neutropenic high-risk patients, it was not associated with a significant reduction in IFIs compared with therapy deferred for 96 h after fever onset.

  4. Combined versus monotherapy or concurrent therapy for treatment of thalassaemia.

    PubMed

    Song, Ta-Shu; Hsieh, Yow-Wen; Peng, Ching-Tien; Chen, Tai-Lin; Lee, Hong-Zin; Chung, Jing-Gung; Hour, Mann-Jen

    2014-01-01

    A combined deferasirox (DFX) and deferiprone (DFP) treatment protocol for relieving thalassemia patients' iron-overload was designed and the pharmacokinetic study was performed by LC-MS/MS. For this open-label, randomized trial, eight patients were recruited and randomly allocated to different treatment regimens: (A) monotherapy with single oral dose of DFX 30 mg/kg, (B) monotherapy with DFP 80 mg/kg/day, twice daily, (C) combined therapy with DFX and DFP (DFX 30 mg/kg for first dose, DFP 40 mg/kg 7 hours later, and DFP 40 mg/kg after another 7 h) and (D) concurrent therapy with DFX 30 mg/kg and DFP 80 mg/kg. Descriptive statistics evaluated pharmacokinetic parameters, AUC0-t, AUC0-inf, Cmax, Tmax, T1/2 and MRT. A positive pharmacokinetic drug interaction was observed in combined therapy. In case of DFX, combined therapy tallied about 2-fold larger than monotherapy in AUC, 1.5-fold larger in Cmax, 1 h longer in Tmax, but 1 h shorter in T1/2. Regarding DFP, most such parameters of combined therapy concurred with monotherapy. Conversely, negative drug interaction was observed in concurrent therapy. With DFX, concurrent therapy attained 1.2- to 2.2-fold lower than monotherapy in AUC0-t and Cmax, 0.6-h shorter in Tmax, and 3-fold longer in T1/2. With DFP, concurrent therapy proved approximately 2-fold larger than monotherapy in AUC and Cmax, 2.5-fold longer in T1/2, and 1.4-fold longer in MRT. Follow-up of subjects' clinical examinations and subjective symptoms showed no adverse events. Our findings showed the combined therapy had advantages, safe, convenient and painless for patients, over the existing concurrent therapy with deferoxamine (DFO) and DFX. Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  5. Combined modality therapy for rectal cancer.

    PubMed

    Minsky, Bruce D; Röedel, Claus; Valentini, Vincenzo

    2010-01-01

    The standard adjuvant treatment for cT3 and/or N+ rectal cancer is preoperative chemoradiation. However, there are many controversies regarding this approach. These include the role of short course radiation, whether postoperative adjuvant chemotherapy necessary for all patients and whether the type of surgery after chemoradiation should be based on the response rate. More accurate imaging techniques and/or molecular markers may help identify patients with positive pelvic nodes to reduce the chance of overtreatment with preoperative therapy. Will more effective systemic agents both improve the results of radiation as well as modify the need for pelvic radiation? These questions and others remain active areas of clinical investigation.

  6. Cutaneous Manifestation of Underlying Disseminated Histoplasmosis in an Immunocompetent Host of Nonendemic Area with Reversible CD4 Cell Depletion and its Recovery on Antifungal Therapy.

    PubMed

    Bharti, Praveen; Bala, Kiran; Gupta, Naresh

    2015-10-01

    We present the case of an 18-year-old male patient admitted with complaints of fever and rapid weight loss since 3 months. Patient had multiple umbilicated papular to nodular lesions over chin and forehead region. Complete blood count revealed bicytopenia. An excisional biopsy of the skin lesions had revealed cutaneous histoplasmosis. On further investigations for bicytopenia, histoplasmosis had been diagnosed on bone marrow trephine biopsy. For the immune status, patient's serology against HIV was negative and his CD4 lymphocyte counts were low at 161. Patient received antifungal therapy including amphotericin B and itraconazole. He showed remarkable improvement in his general condition and blood counts. A repeat CD4 count showed normal counts, and idiopathic CD4 lymphocytopenia was excluded. Disseminated histoplasmosis presenting as cutaneous lesions in an immunocompetent host is very rare, and we are not aware of any case report in the literature where there is reversible depletion of CD4 counts following antifungal treatment in an immunocompetent host of nonendemic area.

  7. Monotherapy or combination therapy? The Pseudomonas aeruginosa conundrum.

    PubMed

    Traugott, Kristi A; Echevarria, Kelly; Maxwell, Pamela; Green, Kay; Lewis, James S

    2011-06-01

    Abstract The use of combination antibiotic therapy for severe pseudomonal infections is a standard practice in many hospitals; however, the data supporting its use are somewhat unclear. Possible benefits of combination therapy for Pseudomonas aeruginosa infections include in vitro antibiotic synergy, prevention of the emergence of bacterial resistance while receiving therapy, and improved adequacy of empiric therapy. Unfortunately, the potential disadvantages are also considerable, the most worrisome of which are drug toxicity and creation of multidrug-resistant organisms in the environment. Many in vitro and animal studies have attempted to shed light on this clinically challenging issue; however, these studies have often yielded conflicting results and used different study methods, which limits the clinical utility of the results. Clinical studies have also attempted to clarify this issue, particularly in patients with serious pseudomonal infections such as bacteremia and ventilator-associated pneumonia, but again, often resulted in conflicting conclusions. Thus, we performed a MEDLINE search (1950-May 2010) of clinical and in vitro studies evaluating the use of antibiotic combination therapy and monotherapy for bacteremia and pneumonia due to P. aeruginosa. Although a clear answer still eludes this controversy, combination therapy for seriously ill patients suspected of having pseudomonal infection has been shown, with considerable evidence, to improve the likelihood of an active agent being included in the initial antibiotic regimen of these patients. The clinical status of the patient and true likelihood of encountering a multidrug-resistant organism should be evaluated before deciding on empiric combination therapy. Future research may be able to better identify which patient populations might receive the most benefit from combination therapy rather than using combination therapy for everyone at risk for these infections.

  8. Combination therapy of biologics with traditional agents in psoriasis.

    PubMed

    Guenther, Lyn C

    2011-06-01

    Although biologics are very efficacious as monotherapy in patients with psoriasis, combination treatment with traditional systemic and topical therapies may increase the speed of onset and enhance efficacy without significant additional toxicity. In contrast, in psoriatic arthritis, the addition of methotrexate to anti-tumour necrosis factor-alpha therapy does not enhance efficacy in either the skin or joints.

  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.

  10. 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

  11. Predicting the Toxicity of Adjuvant Breast Cancer Drug Combination Therapy

    DTIC Science & Technology

    2012-09-01

    TITLE: Predicting the Toxicity of Adjuvant Breast Cancer Drug Combination Therapy PRINCIPAL INVESTIGATOR: Susan F Hudachek, MS, PhD...toxicity of adjuvant breast cancer drug combination therapy 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-09-1-0457 5c. PROGRAM ELEMENT NUMBER 6...breast cancer. However, co-administration of drugs , particularly agents that are substrates for or inhibitors of p-glycoprotein, can result in

  12. Carfilzomib Triple Combination Therapy: A Review in Relapsed Multiple Myeloma.

    PubMed

    Hoy, Sheridan M

    2016-04-01

    Carfilzomib (Kyprolis®) is a proteasome inhibitor that binds selectively and irreversibly to the 20S proteasome (the proteolytic core particle within the 26S proteasome), inducing growth arrest and apoptosis. This intravenous drug is approved in the EU and the USA as combination therapy with oral lenalidomide and intravenous or oral dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. In the multinational, phase III ASPIRE study in this patient population, carfilzomib triple combination therapy significantly prolonged progression-free survival (PFS), reflecting a clinically relevant gain in PFS of 8.7 months, compared with lenalidomide plus dexamethasone. Improvements in overall response rate and patients' global health status were also observed with carfilzomib triple combination therapy. A significant improvement in overall survival (OS) is yet to be demonstrated, with the prespecified stopping boundary not crossed at the time of the prespecified interim analysis, although OS data were not mature by the cut-off date. Carfilzomib triple combination therapy had a manageable tolerability profile. The incidences of the most frequently reported grade 3 or higher adverse events of special interest (with the exception of neutropenia, anaemia and thrombocytopenia) were low in both the carfilzomib triple combination therapy and lenalidomide plus dexamethasone groups. Although final OS data are awaited, current evidence suggests carfilzomib in combination with lenalidomide and dexamethasone is a welcome addition to the treatment options currently available for patients with relapsed multiple myeloma.

  13. Combined aspirin and anticoagulant therapy in patients with atrial fibrillation.

    PubMed

    So, Charlotte H; Eckman, Mark H

    2017-01-01

    The combined use of aspirin and oral anticoagulant therapy in patients with atrial fibrillation (AF) and stable coronary artery disease (CAD) has been questioned due to an increased risk of major bleeding with little to no benefit in preventing ischemic events. (1) To better understand patterns and indications for combined antiplatelet and anticoagulant therapy and identify patients who might reasonably be treated with oral anticoagulant (OAC) therapy alone. (2) To perform an updated literature review regarding the use of combined antiplatelet and OAC therapy in patients with AF and stable CAD. Retrospective review. Patients within the University of Cincinnati Health System with a diagnosis of non-valvular AF, excluding those with acute coronary syndrome or revascularization within the last 12 months. Numbers and indications for combined antiplatelet and anticoagulant therapy and sequence of events leading to the initiation of each. Of 948 patients receiving OAC, 430 (45 %) were receiving concomitant OAC and aspirin. Among patients receiving combined antiplatelet and anticoagulant therapy, 49 and 42 % of patients respectively, had CAD or DM. In a more detailed analysis including chart review of 219 patients receiving combined OAC and aspirin, 27 % had a diagnosis of CAD and 14 % had a diagnosis of DM prior to the development of AF. These patients were initially treated with aspirin. Warfarin was added when they subsequently developed AF but aspirin wasn't discontinued. A surprisingly large proportion of patients (22.8 %) had no obvious indication for dual therapy. Prior myocardial infarction, CAD, vascular disease and DM (among others) increase the likelihood of receiving combined antiplatelet and anticoagulant therapy among patients with AF. A literature review suggests this may lead to increased major bleeding with little benefit in decreasing either AF-related stroke or cardiovascular events.

  14. 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.

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

    PubMed Central

    Fernández-Ruiz, M.; Aguado, J. M.; Merino, P.; Lora-Pablos, D.; Martín-Dávila, P.; Cuenca-Estrella, M.

    2016-01-01

    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

  16. 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

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

    PubMed

    Casey, Colleen L; Murray, Christine A

    2008-01-01

    Abstract: The goal ofpostmenopausal 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.

  18. Patterns of infection in patients with myelodysplastic syndromes and acute myeloid leukemia receiving azacitidine as salvage therapy. Implications for primary antifungal prophylaxis.

    PubMed

    Falantes, Jose F; Calderón, Cristina; Márquez-Malaver, Francisco J; Aguilar-Guisado, Manuela; Martín-Peña, Almudena; Martino, María L; Montero, Isabel; González, Jose; Parody, Rocío; Pérez-Simón, Jose A; Espigado, Ildefonso

    2014-02-01

    Incidence, etiology, and outcome of infectious episodes in patients with myeloid neoplasms receiving azacitidine are uncertain, with no prospective data available in this group of patients. The aim of the current study was to analyze the incidence and factors related to the probability of infection in a cohort of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) treated with azacitidine who did not receive any type of antimicrobial prophylaxis. Significantly, the group of patients who received prior intensive chemotherapy had more infectious episodes (P = 10(-4)), and particularly, invasive aspergillosis (P = .015), than patients who received frontline azacitidine. Primary antifungal prophylaxis might be recommended in MDS and AML patients receiving azacitidine as salvage therapy after intensive regimens.

  19. Primary combined-modality therapy for esophageal cancer.

    PubMed

    Minsky, Bruce D

    2006-04-01

    Based on positive results from the Radiation Therapy Oncology Group (RTOG) 85-01 trial, the conventional nonsurgical treatment of esophageal carcinoma is combined-modality therapy. Dose intensification of the RTOG 85-01 regimen, examined in the Intergroup (INT)-0123/RTOG 94-05 trial, did not improve local control or survival. Areas of clinical investigation include the development of combined-modality therapy regimens with newer systemic agents, the use of 18F-fluorodeoxyglucose positron-emission tomography to assist in the development of innovative radiation treatment planning techniques, and the identification of prognostic molecular markers. The addition of surgery following primary combined-modality therapy apparently does not improve survival, but this finding is controversial.

  20. 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.

  1. 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.

  2. Oxaliplatin-based combined-modality therapy for rectal cancer.

    PubMed

    Minsky, Bruce D

    2003-08-01

    There are two conventional treatments for clinically resectable rectal cancer. The first is surgery, and, if the tumor is T3 and/or N1-2, this is followed by postoperative combined-modality therapy. The second, for patients with ultrasound T3 or clinical T4 disease, is preoperative combined-modality therapy followed by surgery and postoperative chemotherapy. In this review, the results of these approaches as well as novel combined-modality approaches using oxaliplatin-based regimens will be presented.

  3. Laser-electromagnetism combined therapy in chronic prostatitis

    NASA Astrophysics Data System (ADS)

    Chen, Rong; Liu, Lina; Ye, Meiyun; Li, Yongzeng; Lin, Aizhen

    2005-01-01

    The therapeutic effectiveness of laser-electromagnetism combined therapy in chronic prostatitis is studied. Four patients were treated by irradiating the prostate"s correlative parts and acupoints with 650nm semiconductor laser and pulse electromagnetism respectively. Three of them were recovery and only one was ineffective. This demonstrates the feasibility of using laser-combined electromagnetism for assistant treatment on chronic prostatitis. A further study on combined therapy of chronic prostatitis using 810nm, 650nm semiconductor laser and pulse electromagnetic wave is also introduced.

  4. Combination Therapies for Melanoma: A New Standard of Care?

    PubMed

    Smalley, Keiran S M; Eroglu, Zeynep; Sondak, Vernon K

    2016-04-01

    Recent data have demonstrated improved survival with targeted and immune therapies in patients with advanced melanoma, leading to much excitement amongst the oncology community and the widespread use of these drugs in combination regimens. However, the place of these combination therapies in the treatment of advanced melanoma remains to be fully determined. In this perspectives article, we critically review the available data and outline the rationale for these combinations being adopted as the standard of care for patients with advanced melanoma in the future.

  5. Combination azelaic acid therapy for acne vulgaris.

    PubMed

    Webster, G

    2000-08-01

    There is no topical antiacne medication that acts against all four of the major pathophysiologic features of acne: hyperkeratinization, sebum production, bacterial proliferation, and inflammation. Topical azelaic acid cream helps both to normalize keratinization and to reduce the proliferation of Propionibacterium acnes, and has proven to be effective against both noninflammatory and inflammatory lesions. The results of a recent study now demonstrate that its efficacy can be enhanced, and patient ratings of overall impression improved, when it is used in combination with other topical medications such as benzoyl peroxide 4% gel, clindamycin 1% gel, tretinoin 0.025% cream, and erythromycin 3%/benzoyl peroxide 5% gel. Furthermore, another study has shown that azelaic acid plus benzoyl peroxide achieves greater efficacy and higher patient ratings of convenience than monotherapy with erythromycin-benzoyl peroxide gel.

  6. Levofloxacin and indolicidin for combination antimicrobial therapy.

    PubMed

    Ghaffar, Khairunnisa Abdul; Hussein, Waleed M; Khalil, Zeinab G; Capon, Robert J; Skwarczynski, Mariusz; Toth, Istvan

    2015-01-01

    Despite the increasing need for antibiotics to fight infectious diseases, fewer new antibiotics are available on the market. Unfortunately, developing a new class of antibiotics is associated with high commercial risk. Therefore, modification or combination of existing antibiotics to improve their efficacy is a promising strategy. Herein, we conjugated the antibiotic, levofloxacin, with two peptides, i.e. an antimicrobial peptide indolicidin and a cell penetrating peptide (TAT). Glycolic acid and glycine linkers were used between levofloxacin and peptides. We developed an optimized condition for coupling of levofloxacin via its carboxylic group to glycolic acid using solid phase peptide synthesis (SPPS). Antibacterial and haemolytic assays were carried out on the conjugates and only the levofloxacin-indolicidin conjugate demonstrated moderate antibacterial activity. Interestingly, physical mixture of levofloxacin and indolicidin showed improvement in the activity against Gram-positive bacteria.

  7. Combining Cancer Immunotherapy and Targeted Therapy

    PubMed Central

    Ribas, Antoni; Wolchok, Jedd D.

    2013-01-01

    The ability to pharmacologically modulate key signaling pathways that drive tumor growth and progression, but do not negatively impact the function of lymphocytes, provides avenues for rational combinatorial approaches to improve the antitumor activity of tumor immunotherapies. Novel targeted agents can very specifically block oncogenic events in cancer cells, leading to a pro-apoptotic milieu and a potential increase in sensitivity to recognition and attack by cytotoxic T lymphocytes. Furthermore, targeted pathway modulation in lymphocytes may change their function and have activating effects in some instances. When tested together with recently developed powerful tumor immunotherapies, such combinations may exploit the highly specific targeting of oncogenes with small molecule inhibitors to lead to high frequency of tumor regressions, and merge this benefit with the durable responses achievable with effective tumor immunotherapies. PMID:23561594

  8. Practical combination therapy based on pathophysiology of type 2 diabetes

    PubMed Central

    Levin, Philip A

    2016-01-01

    Type 2 diabetes is a complex, chronic, and progressive condition that often necessitates the use of multiple medications to achieve glycemic goals. Clinical guidelines generally recommend intensifying pharmacotherapy if glycemic goals are not achieved after 3 months of treatment. However, for many patients with type 2 diabetes, treatment intensification is delayed or does not occur. Initiating combination therapy early in the disease course has the potential to delay disease progression and improve patient outcomes. Guidelines generally provide a list of agents that may be used in combination regimens and emphasize individualization of treatment. The purpose of this review is to discuss the rationale for combination therapy, considering treatment effects on pathophysiologic aspects of type 2 diabetes and individual drug profiles. The combination of newer antidiabetes therapies with complementary mechanisms of action provides the opportunity to target multiple sites of tissue, organ, and cellular dysfunction. PMID:27826204

  9. Addressing current medical needs in invasive fungal infection prevention and treatment with new antifungal agents, strategies and formulations.

    PubMed

    Pitman, Stuart K; Drew, Richard H; Perfect, John R

    2011-09-01

    Introduction: Morbidity and mortality associated with invasive fungal infections (IFIs) remains unacceptably high. Such diseases represent a substantial burden to the healthcare system. New options are needed to address antifungal resistance in existing and emerging pathogens and improve treatment outcomes while minimizing drug-related toxicities and interactions. Awareness of new and potential future options is of great value for those healthcare professionals who care for patients with IFIs. Areas covered: A search of PubMed, infectious diseases conference abstracts and reference lists from relevant publications was conducted and relevant information abstracted. This review describes the limitations of existing systemic antifungal therapies (e.g., resistance, drug-drug interactions, drug-related toxicities) and summarizes data regarding several emerging antifungal compounds including (but not limited to) new triazoles (e.g. isavuconazole, ravuconazole), echinocandins (e.g., aminocandin) and nikkomycin Z. Agents in clinical trials such as (but not limited to) new triazoles (e.g., isavuconazole, ravuconazole), echinocandins (e.g., aminocandin) and nikkomycin are included. New formulations of existing drugs including reformulations of miconazole, posaconazole and amphotericin B are also reviewed. Finally, new or novel administration strategies for existing drugs such as combination antifungal therapy, antifungal dose escalation, adjunctive use of iron chelators and preemptive therapy are discussed. Expert opinion: All present antifungal agents have some deficiencies in antifungal spectra, toxicity, pharmacokinetics and/or drug-drug interactions, making them less than ideal for some fungal infections. Therefore, there remains an urgent need to find safe, effective, rapidly fungicidal, broad-spectrum antifungal agents with excellent pharmacodynamics to effectively eliminate the fungus from the body with short antifungal courses.

  10. Combination therapy as initial treatment in glaucoma and suspected glaucoma.

    PubMed

    Mikelberg, Frederick S; Etminan, Mahyar

    2012-06-01

    We hypothesize that there may be an inappropriate overuse of initial combination therapy in patients with glaucoma and in those who are glaucoma suspects. To test this hypothesis, we examined the British Columbia Population DataBase to determine the frequency of prescription of combination eye drops as initial therapy in glaucoma patients or glaucoma suspects. Cohort study. The study cohort included all those who visited an ophthalmologist's office between 2004 and 2007. Within the cohort we identified all those who were newly prescribed any ocular hypotensive eye drop. Specifically, we identified those who had been newly prescribed any ocular hypotensive eye drop within 60 days of receiving diagnoses of glaucoma, as defined by having received an international classification for disease code ICD-9 for glaucoma 365. We used the Population Data British Columbia (POP Data BC) as the main data source for this study. POP Data BC is a provincially linkable database that captures the physician visits (including inpatient procedures); hospital admissions; demographics; and prescription drug use of 4.5 million residents of British Columbia. Between 2004 and 2007, the percentage of combination therapy as the first ocular hypotensive prescription rose from 12.29% to 18.63%. The high percentage of combination therapy as initial therapy suggests that ophthalmologists either require additional education in principles of pharmacologic therapy or are unduly influenced by their interaction with the pharmaceutical industry. Copyright © 2012 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.

  11. Propranolol, doxycycline and combination therapy for the treatment of rosacea.

    PubMed

    Park, Jung-Min; Mun, Je-Ho; Song, Margaret; Kim, Hoon-Soo; Kim, Byung-Soo; Kim, Moon-Bum; Ko, Hyun-Chang

    2015-01-01

    Doxycycline is the standard systemic treatment for rosacea. Recently, there have been a few reports on β-adrenergic blockers such as nadolol, carvedilol and propranolol for suppressing flushing reactions in rosacea. To our knowledge, there are no comparative studies of propranolol and doxycycline, and combination therapy using both. The aim of this study was to investigate and compare the efficacy and safety of monotherapy of propranolol, doxycycline and combination therapy. A total of 78 patients who visited Pusan National University Hospital and were diagnosed with rosacea were included in this study. Among them, 28 patients were in the propranolol group, 22 the doxycycline group and 28 the combination group. We investigated the patient global assessment (PGA), investigator global assessment (IGA), assessment of rosacea clinical score (ARCS) and adverse effects. Improvement in PGA and IGA scores from baseline was noted in all groups, and the combination therapy was found to be the most effective during the entire period, but this was statistically insignificant. The reduction rate of ARCS during the treatment period was also highest in the combination group (57.4%), followed by the doxycycline group (52.2%) and the propranolol group (51.0%). Three patients in the combination group had mild and transient gastrointestinal disturbances but there was no significant difference from the other groups. We conclude that the combination therapy of doxycycline and propranolol is effective and safe treatment for rosacea and successful for reducing both flushing and papulation in particular.

  12. Sono-photodynamic combination therapy: a review on sensitizers.

    PubMed

    Sadanala, Krishna Chaitanya; Chaturvedi, Pankaj Kumar; Seo, You Mi; Kim, Jeung Mo; Jo, Yong Sam; Lee, Yang Koo; Ahn, Woong Shick

    2014-09-01

    Cancer is characterized by the dysregulation of cell signaling pathways at several steps. The majority of current anticancer therapies involve the modulation of a single target. A tumor-targeting drug-delivery system consists of a tumor detection moiety and a cytotoxic material joined directly or through a suitable linker to form a conjugate. Photodynamic therapy has been used for more than 100 years to treat tumors. One of the present goals of photodynamic therapy research is to enhance the selective targeting of tumor cells in order to reduce the risk and extension of unwanted side-effects, caused by normal cell damage. Sonodynamic therapy is a promising new treatment for patients with cancer. It treats cancer with ultrasound and sonosensitive agents. Porphyrin compounds often serve as photosensitive and sonosensitive agents. The combination of these two methods makes cancer treatment more effective. The present review provides an overview of photodynamic therapy, sonodynamic therapy, sono-photodynamic therapy and the four sensitizers which are suitable candidates for combined sono-photodynamic therapy. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  13. Impact of Combination Glaucoma Therapies on β-Blocker Exposure.

    PubMed

    Xu, Kunyong; Campbell, Erica de L P; Gill, Sudeep S; Nesdole, Robert; Campbell, Robert J

    2017-02-01

    β-adrenergic receptor antagonists (β-blockers) used in the treatment of glaucoma are an often-overlooked source of systemic adverse events. Ophthalmic timolol has been associated with severe systemic adverse events including numerous cases resulting in death. In recent years the number of fixed-dose combination therapies for glaucoma has grown rapidly, and among available combination therapies only the nonselective β-blocker timolol is used as the β-blocker component. A population-based study was conducted in Ontario, Canada between January 1, 2001 and December 31, 2012 to assess the shift to combination therapies in the management of glaucoma, and to investigate the impact of this shift on the relative use of selective and nonselective β-blockers in patients with this disease. Between 2001 and 2012 timolol (nonselective β-blocker) use grew at an average annual rate of 2.2% (P<0.0001), whereas betaxolol (selective β-blocker) use declined by 14.1% per year (P<0.0001). These changes in the relative use of betaxolol and timolol coincided with changes in the relative use of combination and single-drug therapies. Over the study period, the use of β-blockers as single-drug therapy decreased by 7.7% annually (P<0.0001). In contrast, the use of combination therapies containing a β-blocker increased by 7.6% annually (P<0.0001). The introduction of fixed combination glaucoma therapies has been associated with a significant shift to greater use of nonselective β-blockers. In vulnerable older populations, this may have an important impact on patient safety that warrants further study.

  14. 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.

  15. The role of combination therapy in the treatment of hypertension.

    PubMed

    Ruilope, L M; Coca, A

    1998-01-01

    Antihypertensive therapy is indicated for reducing the risk of cardiovascular morbidity and mortality that accompanies arterial hypertension. Usually, pharmacological treatment is started as monotherapy, which, if unsuccessful, is followed by sequential monotherapy, or by combination therapy. Recent data indicate that combination therapy is required in more than 50% of the hypertensive population when the goal is to reduce blood pressure to below 140/90 mm Hg. The choice and doses of drugs used in combination therapy should be such that their synergistic effect on blood pressure is maximized, the tolerability of the drugs is maintained and side-effects are minimized. The combination of a dihydropyridine calcium antagonist with a beta-blocker or an angiotensin-converting enzyme (ACE) inhibitor is one of the most commonly used combination therapies. Two randomized, double-blind, parallel-group studies compared the antihypertensive effects of the dihydropyridine, barnidipine, with the beta-blocker, atenolol (n = 247), and the ACE inhibitor, enalapril (n = 155). The efficacy and tolerability of barnidipine in combination with either atenolol or enalapril was also investigated. Monotherapy with barnidipine was as effective in reducing blood pressure as monotherapy with either atenolol or enalapril. Combining barnidipine with either atenolol or enalapril reduced blood pressure further, and significantly increased the percentage of patients attaining the required reduction in blood pressure. When patients whose blood pressure was not adequately controlled by enalapril monotherapy were switched to barnidipine monotherapy, the majority then achieved the desired reduction in blood pressure. These results indicate that if barnidipine monotherapy fails to lower blood pressure to the desired values, its combination with either a beta-blocker or an ACE inhibitor is effective and well tolerated.

  16. Combination therapies in the CNS: engineering the environment.

    PubMed

    McCreedy, Dylan A; Sakiyama-Elbert, Shelly E

    2012-06-25

    The inhibitory extracellular environment that develops in response to traumatic brain injury and spinal cord injury hinders axon growth thereby limiting restoration of function. Several strategies have been developed to engineer a more permissive central nervous system (CNS) environment to promote regeneration and functional recovery. The multi-faced inhibitory nature of the CNS lesion suggests that therapies used in combination may be more effective. In this mini-review we summarize the most recent attempts to engineer the CNS extracellular environment after injury using combinatorial strategies. The advantages and limits of various combination therapies utilizing neurotrophin delivery, cell transplantation, and biomaterial scaffolds are discussed. Treatments that reduce the inhibition by chondroitin sulfate proteoglycans, myelin-associated inhibitors, and other barriers to axon regeneration are also reviewed. Based on the current state of the field, future directions are suggested for research on combination therapies in the CNS. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  17. Results of surgery for chronic pulmonary Aspergillosis, optimal antifungal therapy and proposed high risk factors for recurrence - a National Centre’s experience

    PubMed Central

    2013-01-01

    Background Surgery for pulmonary aspergillosis is infrequent and often challenging. Risk assessment is imprecise and new antifungals may ameliorate some surgical risks. We evaluated the medical and surgical management of these patients, including perioperative and postoperative antifungal therapy. Methods Retrospective study of patients who underwent surgery for pulmonary aspergillosis between September 1996 and September 2011. Results 30 patients underwent surgery with 23 having a preoperative tissue diagnosis while 7 were confirmed post-resection. The median age was 57 years (17–78). The commonest presenting symptoms were cough (40%, n = 12) and haemoptysis (43%, n = 13). Twelve (40%) patients had simple aspergilloma (including 2 with Aspergillus nodules) while the remaining 18 (60%) had chronic cavitary pulmonary aspergillosis (CCPA) (complex aspergilloma). Most of the patients had underlying lung disease: tuberculosis (20%, n = 6), asthma (26%, n = 8) and COPD (20%, n = 6). The procedures included lobectomy 50% (n = 15), pneumonectomy 10% (n = 3), sublobar resection 27% (n = 8), decortication 7% (n = 2), segmentectomy 3% (n = 1), thoracoplasty 3% (n = 1), bullectomy and pleurectomy 3% (n = 1), 6% (n = 2) lung transplantation for associated disease. Median hospital stay was 9.5 days (3–37). There was no operative and 30 day mortality. Main complications were prolonged air leak (n = 7, 23%), empyema (n = 6, 20%), respiratory failure requiring tracheostomy /reintubation (n = 4, 13%). Recurrence of CCPA was noted in 8 patients (26%), most having prior CCPA (75%). Taurolidine 2% was active against all 9 A. fumigatus isolates and used for pleural decontamination during surgery. Conclusions Surgery in patients with chronic pulmonary aspergillosis offered good outcomes with an acceptable morbidity in a difficult clinical situation; recurrence is problematic. PMID:23915502

  18. A Randomized, Placebo-controlled Trial of Preemptive Antifungal Therapy for the Prevention of Invasive Candidiasis Following Gastrointestinal Surgery for Intra-abdominal Infections

    PubMed Central

    Knitsch, Wolfgang; Vincent, Jean-Louis; Utzolino, Stefan; François, Bruno; Dinya, Tamás; Dimopoulos, George; Özgüneş, İlhan; Valía, Juan Carlos; Eggimann, Philippe; León, Cristóbal; Montravers, Philippe; Phillips, Stephen; Tweddle, Lorraine; Karas, Andreas; Brown, Malcolm; Cornely, Oliver A.

    2015-01-01

    Background. Patients undergoing emergency gastrointestinal surgery for intra-abdominal infection are at risk of invasive candidiasis (IC) and candidates for preemptive antifungal therapy. Methods. This exploratory, randomized, double-blind, placebo-controlled trial assessed a preemptive antifungal approach with micafungin (100 mg/d) in intensive care unit patients requiring surgery for intra-abdominal infection. Coprimary efficacy variables were the incidence of IC and the time from baseline to first IC in the full analysis set; an independent data review board confirmed IC. An exploratory biomarker analysis was performed using logistic regression. Results. The full analysis set comprised 124 placebo- and 117 micafungin-treated patients. The incidence of IC was 8.9% for placebo and 11.1% for micafungin (difference, 2.24%; [95% confidence interval, −5.52 to 10.20]). There was no difference between the arms in median time to IC. The estimated odds ratio showed that patients with a positive (1,3)-β-d-glucan (ßDG) result were 3.66 (95% confidence interval, 1.01–13.29) times more likely to have confirmed IC than those with a negative result. Conclusions. This study was unable to provide evidence that preemptive administration of an echinocandin was effective in preventing IC in high-risk surgical intensive care unit patients with intra-abdominal infections. This may have been because the drug was administered too late to prevent IC coupled with an overall low number of IC events. It does provide some support for using ßDG to identify patients at high risk of IC. Clinical Trials Registration. NCT01122368. PMID:26270686

  19. Combination Therapy for Rheumatoid Arthritis in the Era of Biologicals

    PubMed Central

    2006-01-01

    Early, aggressive disease management is critical for halting disease progression and joint destruction in patients with rheumatoid arthritis. Combination therapy with at least two disease-modifying antirheumatic drugs, such as methotrexate (MTX), sulfasalazine, or hydroxychloroquine, is often more effective than monotherapy in reducing disease activity. Biologic therapies represent more effective and tolerable treatment options that, when combined with MTX, have been shown to dramatically reduce inflammation, inhibit radiographic progression, and induce remission. Although several types of treatment strategies are used in clinical practice, the most aggressive approaches that target early disease have shown the most promise in reversing disease progression and reducing disease-related costs. PMID:18751844

  20. 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

  1. Antifungal Application of Nonantifungal Drugs

    PubMed Central

    Stylianou, Marios; Kulesskiy, Evgeny; Lopes, José Pedro; Granlund, Margareta; Wennerberg, Krister

    2014-01-01

    Candida species are the cause of 60% of all mycoses in immunosuppressed individuals, leading to ∼150,000 deaths annually due to systemic infections, whereas the current antifungal therapies either have toxic side effects or are insufficiently efficient. We performed a screening of two compound libraries, the Enzo and the Institute for Molecular Medicine Finland (FIMM) oncology collection library, for anti-Candida activity based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. From a total of 844 drugs, 26 agents showed activity against Candida albicans. Of those, 12 were standard antifungal drugs (SADs) and 7 were off-target drugs previously reported to be active against Candida spp. The remaining 7 off-target drugs, amonafide, tosedostat, megestrol acetate, melengestrol acetate, stanozolol, trifluperidol, and haloperidol, were identified with this screen. The anti-Candida activities of the new agents were investigated by three individual assays using optical density, ATP levels, and microscopy. The antifungal activities of these drugs were comparable to those of the SADs found in the screen. The aminopeptidase inhibitor tosedostat, which is currently in a clinical trial phase for anticancer therapy, displayed a broad antifungal activity against different Candida spp., including Candida glabrata. Thus, this screen reveals agents that were previously unknown to be anti-Candida agents, which allows for the design of novel therapies against invasive candidiasis. PMID:24277040

  2. Nanoparticle-Based Combination Therapy for Cancer Treatment.

    PubMed

    Yhee, Ji Young; Son, Sejin; Lee, Hyukjin; Kim, Kwangmeyung

    2015-01-01

    In recent years, combination of different types of therapies using nanoparticles has emerged as an advanced strategy for cancer treatment. Most of all, combination of chemotherapeutic drug and siRNA in nanoformulation has shown a great potential, because siRNA-mediated specific gene silencing can compensate for the incomplete anti-cancer actions of chemotherapy. In this article, nanoparticle-based combination therapy for cancer treatment is introduced to be focused on the therapeutic chemical and siRNA combination. It is classified into 3 groups: 1) general chemotherapy combined with siRNA carrying nanoparticle, 2) co-delivery of chemical and siRNA therapeutics within a single nanoparticle, and 3) Use of multiple nanoparticles for chemical and siRNA therapeutics. The purpose of the combination and the mechanisms of anti-cancer action was described according to the categories. Examples of some recent developments of nanotechnology-based chemo- and siRNA- therapeutics combination therapy are summarized for better understanding of its practical application.

  3. Treatment of postnatal depression with cognitive behavioural therapy, sertraline and combination therapy: a randomised controlled trial.

    PubMed

    Milgrom, Jeannette; Gemmill, Alan W; Ericksen, Jennifer; Burrows, Graham; Buist, Anne; Reece, John

    2015-03-01

    Both antidepressant medications and psychological therapy are common treatments for depression in postpartum women. Antidepressant treatment may have a number of practical disadvantages, including a preference by women to avoid medication while breastfeeding. Consequently, more information about the relative benefits of the two modalities in the perinatal period is helpful. In the treatment of depressive disorders there is some evidence that combination therapies (pharmacological plus psychological treatment) may be more efficacious than either form of mono-therapy in isolation. However, in the treatment of postnatal depression, such evidence is limited. Forty five postpartum women with a DSM-IV diagnosis of depression were randomised to receive either: 1) cognitive behavioural therapy (CBT); 2) sertraline, or 3) a combination of both treatment modalities. Psychometric measures were collected weekly for 12 weeks, with a follow-up at 24 weeks. Symptoms of depression and anxiety were reduced to a significant degree following all three treatments. CBT mono-therapy was found to be superior to both sertraline mono-therapy and combination therapy after 12 weeks. The CBT mono-therapy group appeared to display the most rapid initial gains after treatment commencement. In this sample, a specialised CBT program for postnatal depression was found to be superior as a mono-therapy compared to sertraline, a commonly prescribed SSRI antidepressant. This is in contrast to previous studies which have found no detectable difference in the efficacies of drug and psychological treatment for postnatal depression. Unlike some previous work, this study allowed a statistically independent evaluation of CBT mono-therapy for postnatal depression compared to both antidepressant and combination therapy. In line with previous studies in postpartum women, there was no detectable advantage of combining pharmacological and psychological treatments in the short term. © The Royal Australian and

  4. Study Of Laser Hyperthermia, Photodynamic Therapy And The Combined Therapy For Human Pancreatic Cancer Cell Line

    NASA Astrophysics Data System (ADS)

    Tajiri, Hisao

    1988-06-01

    I have conducted laser hyperthermia, photodynamic therapy (PDT) and the combined therapy of laser hyperthermia and PDT for solid tumor of human pancreatic carcinoma transplanted to nude mice. Following experimental therapies have begun 5-6 weeks after transplantation. 1) Laser hyperthermia: The Frosted Probe was punctured under controlling temperature near the margin of a tumor at 42-43C with 3W for 10 minutes. This therapy caused 70-80% necrosis of the total area of pancreatic tumors after 7 days of the treatment. 2) PDT: Argon dye laser was irradiated into a tumor with 300-400mW in 72 hours after hematoporphyrine derivative (HpD) in a dose of 3mg/kg was intravenously injected. Histological changes detected 7 days after the therapy were coagulated necrosis and fibrosis in the tissues ranging from 30-50% of the area. 3) The combined therapy of laser hyperthermia and PDT: A new quartz fiber, which was originally designed to deliver both Nd:YAG laser and argon dye laser simultaneously, was used. Conditions of laser hyperthermia and PDT were same as above. Necrosis amounted 100% of the total area in tumors of 3 out of 6 mice histopathologically 7 days after the therapy. As for the remaining 3 mice, almost all tissues changed into necrosis. Effects of thermal and laser energy to the tumor tissues were also studied by in vitro experiments under the same conditions. The most remarkable decrease in viability was recognized in the combined therapy of laser hyperthermia and PDT among three types of therapies in vitro. The combined therapy of laser hyperthermia and PDT has proven to be highly effective by in vivo and in vitro study using human pancreatic cancer cell line. It will thus be possible to adopt the therapy, with the use of the new quartz fiber, as one of the useful endoscopic laser therapies.

  5. Update on Antifungal Drug Resistance

    PubMed Central

    Shor, Erika; Zhao, Yanan

    2015-01-01

    Invasive fungal infections remain a major source of global morbidity and mortality, especially among patients with underlying immune suppression. Successful patient management requires antifungal therapy. Yet, treatment choices are restricted due to limited classes of antifungal agents and the emergence of antifungal drug resistance. In some settings, the evolution of multidrug-resistant strains insensitive to several classes of antifungal agents is a major concern. The resistance mechanisms responsible for acquired resistance are well characterized and include changes in drug target affinity and abundance, and reduction in the intracellular level of drug by biofilms and efflux pumps. The development of high-level and multidrug resistance occurs through a stepwise evolution of diverse mechanisms. The genetic factors that influence these mechanisms are emerging and they form a complex symphony of cellular interactions that enable the cell to adapt and/or overcome drug-induced stress. Drivers of resistance involve a complex blend of host and microbial factors. Understanding these mechanisms will facilitate development of better diagnostics and therapeutic strategies to overcome and prevent antifungal resistance. PMID:26120512

  6. Newer approaches in topical combination therapy for acne.

    PubMed

    Fu, Lisa W; Vender, Ronald B

    2011-10-01

    Acne vulgaris is a common chronic inflammatory cutaneous disease involving the pilosebaceous unit. Its pathophysiology is multifactorial and complex, including obstruction of the pilosebaceous unit due to increased sebum production, abnormal keratinization, proliferation of Propionibacterium acnes (P. acnes), and inflammation. Topical agents are the most commonly used therapy for acne. First generation topicals mainly consist of single agent retinoids, benzoyl peroxide (BPO) and antibacterials that target comedones, P. acnes, and inflammation. Novel topical therapies include combination products with advanced vehicle formulations that target multiple acne pathophysiologies and offer simplified treatment regimes. For example, the combination of clindamycin and tretinoin in a unique vehicle formulation allows for progressive follicle penetration and decreased irritation, resulting in increased efficacy. Furthermore, adapalene or clindamycin with BPO combinations target comedones, inflammation, and P. acnes synergistically. These newer combination products have the potential to increase both efficacy and patient adherence when compared with single agent treatment.

  7. Combined and alternating paracetamol and ibuprofen therapy for febrile children.

    PubMed

    Wong, Tiffany; Stang, Antonia S; Ganshorn, Heather; Hartling, Lisa; Maconochie, Ian K; Thomsen, Anna M; Johnson, David W

    2014-09-01

    Health professionals frequently recommend fever treatment regimens for children that either combine paracetamol and ibuprofen or alternate them. However, there is uncertainty about whether these regimens are better than the use of single agents, and about the adverse effect profile of combination regimens. To assess the effects and side effects of combining paracetamol and ibuprofen, or alternating them on consecutive treatments, compared with monotherapy for treating fever in children. In September 2013, we searched Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; and International Pharmaceutical Abstracts (2009-2011). We included randomized controlled trials comparing alternating or combined paracetamol and ibuprofen regimens with monotherapy in children with fever. One review author and two assistants independently screened the searches and applied inclusion criteria. Two authors assessed risk of bias and graded the evidence independently. We conducted separate analyses for different comparison groups (combined therapy versus monotherapy, alternating therapy versus monotherapy, combined therapy versus alternating therapy). Six studies, enrolling 915 participants, are included. Compared to giving a single antipyretic alone, giving combined paracetamol and ibuprofen to febrile children can result in a lower mean temperature at one hour after treatment (MD -0.27 °Celsius, 95% CI -0.45 to -0.08, two trials, 163 participants, moderate quality evidence). If no further antipyretics are given, combined treatment probably also results in a lower mean temperature at four hours (MD -0.70 °Celsius, 95% CI -1.05 to -0.35, two trials, 196 participants, moderate quality evidence), and in fewer children remaining or becoming febrile for at least four hours after treatment (RR 0.08, 95% CI 0.02 to 0.42, two trials, 196 participants, moderate quality evidence). Only one trial assessed a

  8. Combination DMARD therapy including corticosteroids in early rheumatoid arthritis.

    PubMed

    Möttönen, T T; Hannonen, P J; Boers, M

    1999-01-01

    A number of reports indicating the growing acceptance of simultaneous therapy with multiple disease-modifying anti-rheumatic drugs (DMARDs), as well as the use of more aggressive treatment measures in the early phases of disease to combat rheumatoid arthritis (RA), have appeared during the last decade. However, only a few randomized controlled clinical trials have been conducted on the use of DMARD combinations in early RA. We review these trials in this article. In two separate one-year studies combination therapy with sulphasalazine (SSZ) and methotrexate (MTX) seemed to offer no benefits compared to either drug used as monotherapy. On the other hand, the DMARD combinations so far proven to be superior to single DMARDs have initially also included a corticosteroid component. In the COBRA study (Combinatietherapie Bij Reumatoide Artritis) the combination of SSZ (2 gm/day), MTX (7.5 mg/week for 40 weeks), and prednisolone (Prd) (initially 60 mg/day, tapered in 6 weekly steps to 7.5 mg/day and stopped after 28 weeks) compared to SSZ alone (2 gm/day) resulted in significantly better clinical outcomes at week 28. Although the difference in clinical response between the treatment arms was lost at week 58, the progression of joint damage remained statistically significantly slower at week 80 in the patients initially assigned to the combination therapy. Furthermore, in the FIN-RACo trial (Finnish Rheumatoid Arthritis Combination Therapy Trial), therapy using a "tailored-steps" strategy with SSZ (1-2 gm/day), MTX (7.5-1.5 mg/week), hydroxychloroquine (300 mg/day), and Prd (up to 10 mg/day) yielded a significantly increased remission rate and less peripheral joint damage at two years than the single DMARD treatment strategy (initially SSZ 2 gm/day), with or without Prd. Adverse effects in both study arms were comparable. Two additional preliminary reports (in abstract form) suggest that intensive local therapy in the form of intra-articular injections added to single or

  9. Combination antibiotic therapy for community-acquired pneumonia.

    PubMed

    Caballero, Jesus; Rello, Jordi

    2011-11-23

    Community-acquired pneumonia (CAP) is a common and potentially serious illness that is associated with morbidity and mortality. Although medical care has improved during the past decades, it is still potentially lethal. Streptococcus pneumoniae is the most frequent microorganism isolated. Treatment includes mandatory antibiotic therapy and organ support as needed. There are several antibiotic therapy regimens that include β-lactams or macrolides or fluoroquinolones alone or in combination. Combination antibiotic therapy achieves a better outcome compared with monotherapy and it should be given in the following subset of patients with CAP: outpatients with comorbidities and previous antibiotic therapy, nursing home patients with CAP, hospitalized patients with severe CAP, bacteremic pneumococcal CAP, presence of shock, and necessity of mechanical ventilation. Better outcome is associated with combination therapy that includes a macrolide for wide coverage of atypical pneumonia, polymicrobial pneumonia, or resistant Streptococcus pneumoniae. Macrolides have shown different properties other than antimicrobial activity, such as anti-inflammatory properties. Although this evidence comes from observational, most of them retrospective and nonblinded studies, the findings are consistent. Ideally, a prospective, multicenter, randomized trial should be performed to confirm these findings.

  10. Combination therapy in hypertension: an Asia-Pacific consensus viewpoint.

    PubMed

    Abdul Rahman, Abdul Rashid; Reyes, Eugenio B; Sritara, Piyamitr; Pancholia, Arvind; Van Phuoc, Dang; Tomlinson, Brian

    2015-05-01

    Hypertension incurs a significant healthcare burden in Asia-Pacific countries, which have suboptimal rates of blood pressure (BP) treatment and control. A consensus meeting of hypertension experts from the Asia-Pacific region convened in Hanoi, Vietnam, in April 2013. The principal objectives were to discuss the growing problem of hypertension in the Asia-Pacific region, and to develop consensus recommendations to promote standards of care across the region. A particular focus was recommendations for combination therapy, since it is known that most patients with hypertension will require two or more antihypertensive drugs to achieve BP control, and also that combinations of drugs with complementary mechanisms of action achieve BP targets more effectively than monotherapy. The expert panel reviewed guidelines for hypertension management from the USA and Europe, as well as individual Asia-Pacific countries, and devised a treatment matrix/guide, in which they propose the preferred combination therapy regimens for patients with hypertension, both with and without compelling indications. This report summarizes key recommendations from the group, including recommended antihypertensive combinations for specific patient populations. These strategies generally entail initiating therapy with free drug combinations, starting with the lowest available dosage, followed by treatment with single-pill combinations once the BP target has been achieved. A single reference for the whole Asia-Pacific region may contribute to increased consistency of treatment and greater proportions of patients achieving BP control, and hence reducing hypertension-related morbidity and mortality.

  11. Recent advances in antifungal pharmacotherapy for invasive fungal infections.

    PubMed

    Gallagher, Jason C; MacDougall, Conan; Ashley, Elizabeth S Dodds; Perfect, John R

    2004-04-01

    Invasive fungal infections carry significant morbidity and mortality. Candida species have become one of the most frequent causes of bloodstream infections, and infections caused by molds such as Aspergillus are becoming more frequent in immunocompromised patients. As this population grows, more invasive fungal infections can be anticipated. In the past, treatment options have been limited for many of these infections due to toxicity and efficacy concerns with the available antifungals. Fortunately, the past few years have brought exciting developments in antifungal pharmacotherapy. Lipid-based formulations of amphotericin B were introduced in the 1990s to attenuate adverse effects caused by amphotericin B deoxycholate (Fungizone, Bristol-Myers Squibb). Most recently, the echinocandins have been added to our antifungal regimen with the introduction of caspofungin (Cancidas, Merck and Co.) and voriconazole (Vfend, Pfizer), a new triazole, has come to market. The introduction of the echinocandins has invigorated the discussion about combination antifungal therapy. Evidence-based studies using these new agents are accumulating, and they are assuming important roles in the pharmacotherapy of invasive fungal infections in seriously ill and complex patients.

  12. Polydopamine Nanoparticles for Combined Chemo- and Photothermal Cancer Therapy.

    PubMed

    Zhu, Zhijun; Su, Ming

    2017-06-29

    Cancer therapy with two different modalities can enhance treatment efficacy and reduce side effects. This paper describes a new method for combined chemo- and photothermal therapy of cancer using poly dopamine nanoparticles (PDA-NPs), where PDA-NPs serve not only as a photothermal agent with strong near infrared absorbance and high energy conversion efficiency, but also as a carrier to deliver cisplatin via interaction between cisplatin and catechol groups on PDA-NPs. Polyethylene glycol (PEG) was introduced through Michael addition reaction to improve the stability of PDA-NPs in physiological condition. A remarkable synergistic therapeutic effect has been achieved compared with respective single treatments. This work suggests that the PDA-based nanoplatform can be a universal scaffold for combined chemo- and photothermal therapy of cancer.

  13. Polydopamine Nanoparticles for Combined Chemo- and Photothermal Cancer Therapy

    PubMed Central

    Zhu, Zhijun; Su, Ming

    2017-01-01

    Cancer therapy with two different modalities can enhance treatment efficacy and reduce side effects. This paper describes a new method for combined chemo- and photothermal therapy of cancer using poly dopamine nanoparticles (PDA-NPs), where PDA-NPs serve not only as a photothermal agent with strong near infrared absorbance and high energy conversion efficiency, but also as a carrier to deliver cisplatin via interaction between cisplatin and catechol groups on PDA-NPs. Polyethylene glycol (PEG) was introduced through Michael addition reaction to improve the stability of PDA-NPs in physiological condition. A remarkable synergistic therapeutic effect has been achieved compared with respective single treatments. This work suggests that the PDA-based nanoplatform can be a universal scaffold for combined chemo- and photothermal therapy of cancer. PMID:28661423

  14. 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.

  15. [Local combined therapy of vaginal infections by nifuratel-nistatin].

    PubMed

    Jahić, Mahira; Balić, Adem; Nurkić, Mahmud; Dragović, Jasmina; Adzajlić, Amela; Habibović, Amra; Mesalić, Lejla; Zigić, Aza

    2010-02-01

    A test included 40 women in the reproductive age with clinical symptoms of vaginitis and microbiological examination. They were treated by combined therapy of vaginal tablets of nifuratel, 500 mg and nistatin 200 000 i. u. during six days, after which they underwent gynaecological reexamination and repeated microbiological examination of vaginal and cervical smears. An analiysis of vaginal secretion found bacterial flora in 34 smears (65%), fungus (Candida albicans) in 15 (24%) and Trichomonas vaginalis in 7 (11%). Local vaginal therapy in vaginitis caused by Trichomonas vaginalis was successfull in all 7 patients, vaginitis caused by Candida albicans was successly treated in 14 (93%) patients. Bacterial vaginitis was cured in 29 (71%) patients during this tharapy. Local vaginal combined therapy of nifuratel and nistatin is eficient in patients with vaginitis caused by fungi and Trichomonas vaginalis too.

  16. Combination therapy for salvaging a failing, experimental skin flap.

    PubMed

    Shah, D K; Zhang, W X; Forman, D L; Prabhat, A; Urken, M L; Weinberg, H

    1996-08-01

    The failing free flap remains a major problem for the reconstructive surgeon. Many and varied pharmacologic agents have been utilized to reverse the effects of ischemia in these flaps. Treatments have been aimed at inhibiting presumed causative factors in the no-reflow phenomenon. Therapy has generally been single in nature and designed to affect only one of these presumed factors. In this study, several pharmacologic agents were utilized individually or in combination therapy as postischemic washouts, in an effort to attack the multiple causative factors in the no-reflow phenomenon and to improve flap survival in a rat abdominal skin flap model. The treatment agents included lactated Ringer's, superoxide dismutase, and urokinase, with each used independently as a postischemic perfusion washout. Combination therapy utilized an initial postischemic perfusion with urokinase, followed by a second perfusion washout with superoxide dismutase. After 18 hr of primary ischemia, there was increased flap survival in the animals undergoing perfusion washout with either superoxide dismutase alone or with combined urokinase and superoxide dismutase washouts, compared to all other treatments (p < 0.001). It was found that flaps undergoing combined urokinase and superoxide dismutase postischemic perfusion washouts demonstrated significantly improved survival after 20 hr of primary ischemia, compared to all other therapies (p < 0.05). By demonstrating improved survival when a thrombolytic agent is used in conjunction with an oxygen free radical scavenger, these findings may have implications in the treatment of clinically failing free flaps.

  17. Smoking Intervention: A Combination Therapy Approach to Cessation.

    ERIC Educational Resources Information Center

    Glover, Penny Neathery

    1993-01-01

    Provides an overview of the Start SMART smoking cessation program which combines nicotine withdrawal therapy with behavior modification. The Start SMART program provides seven, intensive one-hour group sessions that are shown to be a most effective intervention with a specific population--motivated, yet highly dependent smokers. (GLR)

  18. 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

  19. 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

  20. Anabolic and antiresorptive therapy for osteoporosis: combination and sequential approaches.

    PubMed

    Cosman, Felicia

    2014-12-01

    In the recent Bone Key Reports review, it was noted that combinations of anabolic and antiresorptive agents have potential to improve bone density and bone strength more than either agent as monotherapy. Small clinical trials have been performed evaluating combinations of PTH1-34 (TPTD) or PTH1-84 (PTH) with a variety of antiresorptives including hormone/estrogen therapy, raloxifene, alendronate, risedronate, ibandronate, zoledronic acid, and denosumab. Most of the studies evaluate dual-energy X-ray absorptiometry outcomes, and a few trials report volumetric mineral density (BMD) by quantitative computed tomography, followed by finite element modeling to calculate bone strength. None of the studies has been powered to assess differences in fracture incidence between combination therapy and monotherapy. BMD outcomes vary based on the timing of introduction of the anabolic agent (before, during, or after antiresorptive treatment), as well as the specific anabolic and antiresorptive used. Furthermore, effects of combination therapies are site-dependent. The most consistent effect of combining antiresorptive agents with PTH or TPTD is a superior hip BMD outcome compared with TPTD/PTH alone. This is most evident when TPTD/PTH is combined with a bisphosphonate or denosumab. In contrast to findings in the hip, in the majority of studies, there is no benefit to spine BMD with combination therapy vs monotherapy. The 2 exceptions to this are when TPTD is combined with denosumab and when TPTD is given as monotherapy first for 9 months, followed by the addition of alendronate (with continuation administration of TPTD). Based on what we now know, in patients previously treated with bisphosphonates who suffer hip fractures or who have very low or declining hip BMD, strong consideration should be given to starting TPTD and continuing a potent antiresorptive agent (possibly switching to zoledronic acid or denosumab) to improve hip BMD and strength quickly. Furthermore, in

  1. Combining HDAC inhibitors with oncolytic virotherapy for cancer therapy.

    PubMed

    Nakashima, Hiroshi; Nguyen, Tran; Chiocca, Ennio Antonio

    2015-01-01

    Histone deacetylase (HDAC) enzymes play a critical role in the epigenetic regulation of cellular functions and signaling pathways in many cancers. HDAC inhibitors (HDACi) have been validated for single use or in combination with other drugs in oncologic therapeutics. An even more novel combination therapy with HDACi is to use them with an oncolytic virus. HDACi may lead to an amplification of tumor-specific lytic effects by facilitating increased cycles of viral replication, but there may also be direct anticancer effects of the drug by itself. Here, we review the molecular mechanisms of anti-cancer effects of the combination of oncolytic viruses with HDACi.

  2. 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.

  3. 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

  4. [Antifungal agents in dermatophytic disease: failure of griseofulvin, ketoconazole and itraconazole].

    PubMed

    Boudghène-Stambouli, O; Mérad-Boudia, A

    1990-01-01

    The dermatophytic disease is a rare, severe affection caused by banal dermatophytes. A genetically predisposed basis could explain the frequent failure of antifungal therapeutics. We report here the case of a 28-year-old male. Despite 2 years of griseofulvin, 23 months of ketoconazole and 8 months of itraconazole, the therapeutic failure was evident: circinate herpes, papulo-nodules, vegetating plaques, ulceration, superficial and profound adenopathies, cerebral involvement, and deterioration of the general state. The correction of the immuno-deficient state combined with antifungals could be the best therapy.

  5. 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.

  6. 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.

  7. Evolutionary dynamics of cancer in response to targeted combination therapy

    PubMed Central

    Bozic, Ivana; Reiter, Johannes G; Allen, Benjamin; Antal, Tibor; Chatterjee, Krishnendu; Shah, Preya; Moon, Yo Sup; Yaqubie, Amin; Kelly, Nicole; Le, Dung T; Lipson, Evan J; Chapman, Paul B; Diaz, Luis A; Vogelstein, Bert; Nowak, Martin A

    2013-01-01

    In solid tumors, targeted treatments can lead to dramatic regressions, but responses are often short-lived because resistant cancer cells arise. The major strategy proposed for overcoming resistance is combination therapy. We present a mathematical model describing the evolutionary dynamics of lesions in response to treatment. We first studied 20 melanoma patients receiving vemurafenib. We then applied our model to an independent set of pancreatic, colorectal, and melanoma cancer patients with metastatic disease. We find that dual therapy results in long-term disease control for most patients, if there are no single mutations that cause cross-resistance to both drugs; in patients with large disease burden, triple therapy is needed. We also find that simultaneous therapy with two drugs is much more effective than sequential therapy. Our results provide realistic expectations for the efficacy of new drug combinations and inform the design of trials for new cancer therapeutics. DOI: http://dx.doi.org/10.7554/eLife.00747.001 PMID:23805382

  8. 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

    2015-10-09

    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.

  9. [First fixed dose combination perindopril arginine-indapamide-amlodipine: new approach in combination therapy in hypertension].

    PubMed

    Jr, Jiří Widimský

    2014-09-01

    Use of fixed combination of antihypertensive drugs clearly improves compliance to the pharmacological therapy, control of hypertension and prognosis. Based on the current guidelines triple antihypertensive therapy with RAS-blocker, calcium channel blocker (CCB) and diuretic represents the standard and best option. The article introduces first and innovative fixed triple combination of perindopril arginine + indapamide + amlodipine (Triplixam®). This type of therapy is suitable for patients already treated with free combinations of three antihypertensive drugs or in those hypertensives with uncontrolled hypertension on two antihypertensive molecules (approx. 60% of all hypertensive population). Fixed combination of perindopril arginine + indapamid + amlodipin is indicated also in severe hypertension (approx. 30% of pts). Large clinical data from various morbidity-mortality studies related to each of these substances are discussed as well as basic pharmacological characteristics. Based on the results from ADVANCE-CCB study combination of perindopril arginine + indapamide + CCB decreases total mortality in hypertension by 28%. Another discussed study-PIANIST confirmed significant antihypertensive effect of Triplixam® on large sample of patients with various stages of hypertension. Triplixam® in addition to that has very good tolerance with low side effects profile, flexibility of the dosages and large body of evidence of positive impact on prognosis of hypertensive patients. Use of Triplixam® may improve control of hypertension in the Czech Republic.Key words: amlodipine - fixed combination - hypertension - indapamide - perindopril arginine - therapy.

  10. [Surgical treatment of chronic macular oedema with a combination therapy].

    PubMed

    Kolarov, D; Just, A; Wirbelauer, C

    2014-01-01

    The treatment of therapy-resistent chronic macular oedema remains a challenge. Therefore a combination therapy, consisting of medical, biological and mechanical components was assessed. A surgical treatment was performed in 35 eyes (34 patients) with chronic and therapy-resistant macular oedema, resulting from diabetic maculopathy (n = 25), vitreoretinal traction (n = 7) or following a retinal venous occlusion (n = 3). An intravitreal injection of bevacizumab was given on the day before surgery, consisting of pars plana vitrectomy with ILM peeling with Brilliant Blue G (BBG), as well as an air tamponade combined with postoperative prone positioning. The visual function and the central retinal thickness were measured in follow-up. Functionally, the visual acuity could be stabilised to an average of 0.18 and macular oedema was reduced in most patients. Anatomically, a significant reduction in central macular thickness by 193 µm (29 %), from 598 µm to 405 µm (p < 0.001), and a regression in the intraretinal cystoid changes were observed. No significant complications occurred, whereas in 6 patients additional consecutive treatment was necessary. A stabilisation of the visual acuity and an improvement in the structural retinal situation could be achieved by an elaborate combination therapy, based on a pharmacological, a biological and a mechanical approach. Long-term follow-up and consecutive supplementary treatments are necessary to ensure the functional stability. Georg Thieme Verlag KG Stuttgart · New York.

  11. Effectiveness of Manual Therapy Combined With Physical Therapy in Treatment of Patellofemoral Pain Syndrome: Systematic Review.

    PubMed

    Espí-López, Gemma Victoria; Arnal-Gómez, Anna; Balasch-Bernat, Mercè; Inglés, Marta

    2017-06-01

    The purpose of this study was to conduct a review of randomized controlled trials (RCTs) to determine the treatment effectiveness of the combination of manual therapy (MT) with other physical therapy techniques. Systematic searches of scientific literature were undertaken on PubMed and the Cochrane Library (2004-2014). The following terms were used: "patellofemoral pain syndrome," "physical therapy," "manual therapy," and "manipulation." RCTs that studied adults diagnosed with patellofemoral pain syndrome (PFPS) treated by MT and physical therapy approaches were included. The quality of the studies was assessed by the Jadad Scale. Five RCTs with an acceptable methodological quality (Jadad ≥ 3) were selected. The studies indicated that MT combined with physical therapy has some effect on reducing pain and improving function in PFPS, especially when applied on the full kinetic chain and when strengthening hip and knee muscles. The different combinations of MT and physical therapy programs analyzed in this review suggest that giving more emphasis to proximal stabilization and full kinetic chain treatments in PFPS will help better alleviation of symptoms.

  12. Innovative treatment approaches for rheumatoid arthritis. Combination therapy.

    PubMed

    Borigini, M J; Paulus, H E

    1995-11-01

    It is accepted that combination DMARD therapy is a useful tool in current rheumatological practice. However, well-designed, large, long-term, controlled clinical trials are needed to determine which combinations, dosage schedules, and sequences of administration are most beneficial and least toxic. Until we develop treatment regimens that reliably induce and sustain acceptable control of disease manifestations in all patients for the rest of their natural lifespan, daily oral prednisone will continue to be a troublesome component of 'bridge' therapy, as it becomes the sole surviving constant in complex regimens whose other components are eventually discontinued because of toxicity, lack of efficacy, or non-compliance. We have often seen patients in whom the replacement of a well-tolerated but presumable ineffective DMARD with another DMARD has led to worsening of disease, when the modest benefits of the discontinued DMARD were lost before the hoped for onset of benefit from its replacement became evident. Since the toxicity of combinations of DMARDs has not appeared to be excessive, one can reasonably add the second DMARD to the first, while carefully monitoring for adverse effects and planning ton continue the combination until increased benefit occurs. Subsequently, if the second DMARD is not tolerated, the partial benefit from the first has not been given up, and a longer duration of treatment with the initial DMARD is sometimes associated with satisfactory improvement. If better control of rheumatoid arthritis is evident after 3-6 months of treatment with the combination of DMARDs, one must still decide whether to stop the first DMARD, stop the second, or continue with the combination. In the absence of major toxicity, we are most likely to choose to continue the combination if the patient has had a good response, thus inadvertently embarking on prolonged combined DMARD therapy (Paulus, 1990). Of course, other drugs besides those discussed above are available

  13. Optimizing antimicrobial therapy of sepsis and septic shock: focus on antibiotic combination therapy.

    PubMed

    Vazquez-Grande, Gloria; Kumar, Anand

    2015-02-01

    There has been little improvement in septic shock mortality in the past 70 years, despite ever more broad-spectrum and potent antimicrobials. In the past, resuscitative elements have been the primary area of clinical septic shock management and research. The question of the optimal use of antimicrobial therapy was relatively ignored in recent decades. This review explores the pathophysiology of sepsis in an attempt to produce a better understanding and define key determinants of antimicrobial therapy response in septic shock. Optimizing existing antimicrobials delivery can drive significant improvements in the outcome of sepsis and septic shock. Inappropriate antimicrobial selection and dosing or delays in the administration substantially increase mortality and morbidity in life-threatening infections. Definitive combination therapy (where a pathogen known to be susceptible to a given agent is additionally covered by another agent) remains controversial. Although some in vitro studies, animal models, and clinical studies of infection including endocarditis, gram-negative bacteremia, and neutropenic infections have supported combination therapy, the potential clinical benefit in other severe infections has been questioned. Several meta-analyses have failed to demonstrate improvement of outcome with combination therapy in immunocompetent patients with sepsis and/or gram-negative bacteremia. These meta-analyses did not undertake subgroup analyses of the septic shock population. This article reviews the existing evidence supporting combination therapy for severe infections, sepsis, and septic shock.

  14. Combining molecular targeted agents with radiation therapy for malignant gliomas

    PubMed Central

    Scaringi, Claudia; Enrici, Riccardo Maurizi; Minniti, Giuseppe

    2013-01-01

    The expansion in understanding the molecular biology that characterizes cancer cells has led to the rapid development of new agents to target important molecular pathways associated with aberrant activation or suppression of cellular signal transduction pathways involved in gliomagenesis, including epidermal growth factor receptor, vascular endothelial growth factor receptor, mammalian target of rapamycin, and integrins signaling pathways. The use of antiangiogenic agent bevacizumab, epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib, mammalian target of rapamycin inhibitors temsirolimus and everolimus, and integrin inhibitor cilengitide, in combination with radiation therapy, has been supported by encouraging preclinical data, resulting in a rapid translation into clinical trials. Currently, the majority of published clinical studies on the use of these agents in combination with radiation and cytotoxic therapies have shown only modest survival benefits at best. Tumor heterogeneity and genetic instability may, at least in part, explain the poor results observed with a single-target approach. Much remains to be learned regarding the optimal combination of targeted agents with conventional chemoradiation, including the use of multipathways-targeted therapies, the selection of patients who may benefit from combined treatments based on molecular biomarkers, and the verification of effective blockade of signaling pathways. PMID:23966794

  15. Effects of thermal therapy combining sauna therapy and underwater exercise in patients with fibromyalgia.

    PubMed

    Matsumoto, Shuji; Shimodozono, Megumi; Etoh, Seiji; Miyata, Ryuji; Kawahira, Kazumi

    2011-08-01

    Fibromyalgia syndrome (FMS) is a chronic disorder that is characterized by widespread pain with localized tenderness. We aimed to investigate whether thermal therapy combining sauna therapy and underwater exercise improved pain, symptoms, and quality of life (QOL) in FMS patients. Forty-four female FMS patients who fulfilled the American College of Rheumatology (ACR) criteria received 12-week thermal therapy program comprising sauna therapy once daily for 3 days/week and underwater exercise once daily for 2 days/week. Pain, symptoms, and QOL were assessed using a pain visual analog scale (VAS), a fibromyalgia impact questionnaire (FIQ), and a short form 36-item questionnaire (SF-36), respectively. All of the patients reported significant reductions in pain and symptoms of 31-77% after the 12-week thermal therapy program, which remained relatively stable (28-68%) during the 6-month follow-up period (that is, the thermal therapy program improved both the short-term and the long-term VAS and FIQ scores). Improvements were also observed in the SF-36 score. Thermal therapy combining sauna therapy and underwater exercise improved the QOL as well as the pain and symptoms of FMS patients.

  16. Management of drug and food interactions with azole antifungal agents in transplant recipients.

    PubMed

    Dodds-Ashley, Elizabeth

    2010-08-01

    Azole antifungal agents are frequently used in hematopoietic stem cell and solid organ transplant recipients for prevention or treatment of invasive fungal infections. However, because of metabolism by or substrate activity for various isoenzymes of the cytochrome P450 system and/or P-glycoprotein, azole antifungals have the potential to interact with many of the drugs commonly used in these patient populations. Thus, to identify drug interactions that may result between azole antifungals and other drugs, we conducted a literature search of the MEDLINE database (1966-December 2009) for English-language articles on drug interaction studies involving the azole antifungal agents fluconazole, itraconazole, voriconazole, and posaconazole. Another literature search between each of the azoles and the immunosuppressants cyclosporine, tacrolimus, and sirolimus, as well as the corticosteroids methylprednisolone, dexamethasone, prednisolone, and prednisone, was also conducted. Concomitant administration of azoles and immunosuppressive agents may cause clinically significant drug interactions resulting in extreme immunosuppression or toxicity. The magnitude and duration of an interaction between azoles and immunosuppressants are not class effects of the azoles, but differ between drug combinations and are subject to interpatient variability. Drug interactions in the transplant recipient receiving azole therapy may also occur with antibiotics, chemotherapeutic agents, and acid-suppressive therapies, among other drugs. Initiation of an azole antifungal in transplant recipients nearly ensures a drug-drug interaction, but often these drugs are required. Management of these interactions first involves knowledge of the potential drug interaction, appropriate dosage adjustments when necessary, and therapeutic or clinical monitoring at an appropriate point in therapy to assess the drug-drug interaction (e.g., immunosuppressive drug concentrations, signs and symptoms of toxicity

  17. Considerations in glaucoma therapy: fixed combinations versus their component medications

    PubMed Central

    Higginbotham, Eve J

    2010-01-01

    Fixed combinations of medications that lower intraocular pressure (IOP) are increasingly used in the treatment of glaucoma and ocular hypertension and offer several potential advantages over combined use of the separate component medications including enhanced convenience, improved adherence, reduced exposure to preservatives, and possible cost savings. This review aims to examine the current role of IOP-lowering fixed combinations in disease management. The results of studies that compared the efficacy and safety of IOP-lowering fixed combinations with their component medications are summarized, including those fixed combinations that consist of a prostaglandin analog and timolol. The fixed combinations currently available for use in the United States are fixed-combination dorzolamide/timolol (FCDT) and fixed-combination brimonidine/timolol (FCBT). Both of these fixed combinations reduce IOP more effectively than their component medications used separately as monotherapy. FCBT therapy also demonstrates a more favorable safety profile and reduced ocular allergy compared to monotherapy with brimonidine, a component medication. Few studies have directly compared the efficacy and safety of FCDT and FCBT, but available evidence suggests that FCBT is at least as effective as FCDT in lowering IOP and is more comfortable and better tolerated. Additional studies are needed to further evaluate the comparative efficacy and tolerability of FCDT and FCBT in the management of glaucoma and ocular hypertension. PMID:20169043

  18. Considerations in glaucoma therapy: fixed combinations versus their component medications.

    PubMed

    Higginbotham, Eve J

    2010-02-02

    Fixed combinations of medications that lower intraocular pressure (IOP) are increasingly used in the treatment of glaucoma and ocular hypertension and offer several potential advantages over combined use of the separate component medications including enhanced convenience, improved adherence, reduced exposure to preservatives, and possible cost savings. This review aims to examine the current role of IOP-lowering fixed combinations in disease management. The results of studies that compared the efficacy and safety of IOP-lowering fixed combinations with their component medications are summarized, including those fixed combinations that consist of a prostaglandin analog and timolol. The fixed combinations currently available for use in the United States are fixed-combination dorzolamide/timolol (FCDT) and fixed-combination brimonidine/timolol (FCBT). Both of these fixed combinations reduce IOP more effectively than their component medications used separately as monotherapy. FCBT therapy also demonstrates a more favorable safety profile and reduced ocular allergy compared to monotherapy with brimonidine, a component medication. Few studies have directly compared the efficacy and safety of FCDT and FCBT, but available evidence suggests that FCBT is at least as effective as FCDT in lowering IOP and is more comfortable and better tolerated. Additional studies are needed to further evaluate the comparative efficacy and tolerability of FCDT and FCBT in the management of glaucoma and ocular hypertension.

  19. A treatment planning methodology for sequentially combining radiopharmaceutical therapy (RPT) and external radiation therapy (XRT)

    PubMed Central

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

    2010-01-01

    Purpose Effective cancer treatment generally requires combination therapy. The combination of external beam therapy (XRT) with radiopharmaceutical therapy (RPT) requires accurate 3-D dose calculations to avoid toxicity and evaluate efficacy. We have developed and tested a treatment planning methodology, using the patient-specific 3-dimensional dosimetry package 3D-RD, for sequentially combined RPT/XRT therapy designed to limit toxicity to organs at risk. Methods The biological effective dose (BED) was used to translate voxelized RPT absorbed dose (DRPT) values into a normalized total dose (or equivalent two-Gray-fraction XRT absorbed dose), NTDRPT map. The BED was calculated numerically using an algorithmic approach, which enabled a more accurate calculation of BED and NTDRPT. A treatment plan from the combined Samarium-153 and external beam was designed which would deliver a tumoricidal dose while delivering no more than 50 Gy of NTDsum to the spinal cord of a patient with a paraspinal tumor. Results The average voxel NTDRPT to tumor from RPT was 22.6 Gy (1-85 Gy range); the maximum spinal cord voxel NTDRPT from RPT was 6.8 Gy. The combined therapy NTDsum to tumor was 71.5 Gy (40-135 Gy range) for a maximum voxel spinal cord NTDsum equal to the maximum tolerated dose of 50 Gy. Conclusions A methodology which 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. PMID:20950958

  20. 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.

  1. Combined Radiation Therapy and Immune Checkpoint Blockade Therapy for Breast Cancer.

    PubMed

    Hu, Zishuo I; Ho, Alice Y; McArthur, Heather L

    2017-09-01

    Treatment with checkpoint inhibitors has shown durable responses in a number of solid tumors, including melanoma, lung, and renal cell carcinoma. However, most breast cancers are resistant to monotherapy with checkpoint inhibitors. Radiation therapy (RT) has been shown to have a number of immunostimulatory effects, including priming the immune system, recruiting immune cells to the tumor environment, and altering the immunosuppressive effects of the tumor microenvironment. RT therefore represents a promising adjuvant therapy to checkpoint blockade in breast cancer. We review the data from the checkpoint blockade studies on breast cancer reported to date, the mechanisms by which RT potentiates immune responses, the preclinical and clinical data of checkpoint blockade and RT combinations, and the landscape of current clinical trials of RT and immune checkpoint inhibitor combinations in breast cancer. Clinical trials with checkpoint blockade therapy have demonstrated response rates of up to 19% in breast cancer, and many of the responses are durable. Preclinical data indicate that RT combined with checkpoint inhibition synergizes not only to enhance antitumor efficacy but also to induce responses outside of the radiation field. Thus multiple clinical trials are currently investigating the combination of checkpoint inhibition with RT. The use of combination strategies that incorporate chemotherapy and/or local strategies such as RT may be needed to augment responses to immune therapy in breast cancer. Preclinical and clinical results show that RT in combination with checkpoint blockade may be a promising therapeutic option in breast cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Ghrelin as a Novel Therapy for Radiation Combined Injury

    PubMed Central

    Jacob, Asha; Shah, Kavin G; Wu, Rongqian; Wang, Ping

    2010-01-01

    The threat of nuclear terrorism has led to growing worldwide concern about exposure to radiation. Acute radiation syndrome, or radiation sickness, develops after whole-body or a partial-body irradiation with a high dose of radiation. In the terrorist radiation exposure scenario, however, radiation victims likely suffer from additional injuries such as trauma, burns, wounds or sepsis. Thus, high-dose radiation injuries and appropriate therapeutic interventions must be studied. Despite advances in our understanding of the pathophysiology of radiation injury, very little information is available on the therapeutic approaches to radiation combined injury. In this review, we describe briefly the pathological consequences of ionizing radiation and provide an overview of the animal models of radiation combined injury. We highlight the combined radiation and sepsis model we recently established and suggest the use of ghrelin, a novel gastrointestinal hormone, as a potential therapy for radiation combined injury. PMID:20101281

  3. Combined-modality therapy for rectal cancer using irinotecan.

    PubMed

    Minsky, Bruce D

    2002-05-01

    Preoperative or postoperative pelvic radiation plus concurrent fluorouracil-based chemotherapy is standard adjuvant treatment for patients with T3 and/or N1/2 rectal cancer. Newer chemotherapeutic regimens have been developed for the treatment of patients with metastatic disease. Irinotecan (CPT-11, Camptosar)-based regimens have improved survival in patients with metastatic disease and are being actively investigated in combination with pelvic radiation therapy for patients with rectal cancer.

  4. Optimising treatment for COPD--new strategies for combination therapy.

    PubMed

    Welte, T

    2009-08-01

    Chronic obstructive pulmonary disease (COPD) is a multi-component disease characterised by airflow limitation and airway inflammation. Exacerbations of COPD have a considerable impact on the quality of life, daily activities and general well-being of patients and are a great burden on the health system. Thus, the aims of COPD management include not only relieving symptoms and preventing disease progression but also preventing and treating exacerbations. Attention towards the day-to-day burden of the disease is also required in light of evidence that suggests COPD may be variable throughout the day with morning being the time when symptoms are most severe and patients' ability to perform regular morning activities the most problematic. While available therapies improve clinical symptoms and decrease airway inflammation, they do not unequivocally slow long-term progression or address all disease components. With the burden of COPD continuing to increase, research into new and improved treatment strategies to optimise pharmacotherapy is ongoing - in particular, combination therapies, with a view to their complementary modes of action enabling multiple components of the disease to be addressed. Evidence from recent clinical trials indicates that triple therapy, combining an anticholinergic with an inhaled corticosteroid and a long-acting beta(2)-agonist, may provide clinical benefits additional to those associated with each treatment alone in patients with more severe COPD. This article reviews the evidence for treatment strategies used in COPD with a focus on combination therapies and introduces the 3-month CLIMB study (Evaluation of Efficacy and Safety of Symbicort as an Add-on Treatment to Spiriva in Patients With Severe COPD) which investigated the potential treatment benefits of combining tiotropium with budesonide/formoterol in patients with COPD with regard to lung function, exacerbations, symptoms and morning activities.

  5. Optimal Lipid Modification: The Rationale for Combination Therapy

    PubMed Central

    Backes, James M; Gibson, Cheryl A; Howard, Patricia A

    2005-01-01

    Background An emphasis on more aggressive lipid-lowering, particularly of low-density lipoprotein cholesterol, to improve patient outcomes has led to an increased use of combination lipid-lowering drugs. This strategy, while potentially beneficial, has triggered concerns regarding fears of adverse effects, harmful drug interactions, and patient nonadherence. Objective To present key data regarding combination lipid-altering therapy including use, rationale, major trials, benefits, potential adverse effects, compliance issues, and limitations. Method Literature was obtained from MEDLINE (1966 – June 2005) and references from selected articles. Results A substantial body of evidence from epidemiological data and clinical trials indicates that aggressive lipid modification, especially low-density lipoprotein reduction, is associated with reduced cardiovascular events. Numerous studies utilizing various combinations of cholesterol-lowering agents including statin/fibrate, statin/niacin, statin/bile acid resin, and statin/ezetimibe have demonstrated significant changes in the lipid profile with acceptable safety. Long-term trials of combination therapy evaluating clinical outcomes or surrogate markers of cardiovascular disease, while limited, are promising. Conclusion Combining lipid-altering agents results in additional improvements in lipoproteins and has the potential to further reduce cardiovascular events beyond that of monotherapy. PMID:17315604

  6. Combined modality therapy with TRAIL or agonistic death receptor antibodies

    PubMed Central

    Amm, Hope M; Oliver, Patsy G; Lee, Choo Hyung; Li, Yufeng

    2011-01-01

    Molecularly targeted therapies, such as antibodies and small molecule inhibitors have emerged as an important breakthrough in the treatment of many human cancers. One targeted therapy under development is tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) due to its ability to induce apoptosis in a variety of human cancer cell lines and xenografts, while lacking toxicity in most normal cells. TRAIL and apoptosis-inducing agonistic antibodies to the TRAIL death receptors have been the subject of many preclinical and clinical studies in the past decade. However, the sensitivity of individual cancer cell lines of a particular tumor type to these agents varies from highly sensitive to resistant. Various chemotherapy agents have been shown to enhance the apoptosis-inducing capacity of TRAIL receptor-targeted therapies and induce sensitization of TRAIL-resistant cells. This review provides an overview of the mechanisms associated with chemotherapy enhancement of TRAIL receptor-targeted therapies including modulation of the apoptotic (death receptor expression, FLIP and Bcl-2 or inhibitors of apoptosis [IAP] families) as well as cell signaling (NFκB, Akt, p53) pathways. These mechanisms will be important in establishing effective combinations to pursue clinically and in determining relevant targets for future cancer therapies. PMID:21263219

  7. Drug delivery systems for differential release in combination therapy.

    PubMed

    Zhang, Hongbin; Wang, Guojie; Yang, Huai

    2011-02-01

    Combination therapy with multiple therapeutic agents has wide applicability in medical and surgical treatment, especially in the treatment of cancer. Thus, new drug delivery systems that can differentially release two or more drugs are desired. Utilizing new techniques to engineer the established drug delivery systems and synthesizing new materials and designing carriers with new structures are feasible ways to fabricate proper multi-agent delivery systems, which are critical to meet requirements in the clinic and improve therapeutic efficacy. This paper aims to give an overview about the multi-agent delivery systems developed in the last decade for differential release in combination therapy. Multi-agent delivery systems from nanoscale to bulk scale, such as liposomes, micelles, polymer conjugates, nano/microparticles and hydrogels, developed over the last 10 years, have been collected and summarized. The characteristics of different delivery systems are described and discussed, including the structure of drug carriers, drug-loading techniques, release behaviors and consequent evaluation in biological assays. The chemical structure of drug delivery systems is the key to controlling the release of therapeutic agents in combination therapy, and the differential release of multiple drugs could be realized by the successful design of a proper delivery system. Besides biological evaluation in vitro and in vivo, it is important to speed up practical application of the resulting delivery systems.

  8. Photodynamic Therapy and Its Role in Combined Modality Anticancer Treatment.

    PubMed

    Brodin, N Patrik; Guha, Chandan; Tomé, Wolfgang A

    2015-08-01

    Photodynamic therapy (PDT) is a relatively new modality for anticancer treatment and although the interest has increased greatly in the recent years, it is still far from clinical routine. As PDT consists of administering a nontoxic photosensitizing chemical and subsequently illuminating the tumor with visible light, the treatment is not subject to dose-limiting toxicity, which is the case for established anticancer treatments like radiation therapy or chemotherapy. This makes PDT an attractive adjuvant therapy in a combined modality treatment regimen, as PDT provides an antitumor immune response through its ability to elicit the release of damage-associated molecular patterns and tumor antigens, thus providing an increased antitumor efficacy, potentially without increasing the risk of treatment-related toxicity. There is great interest in the elicited immune response after PDT and the potential of combining PDT with other forms of treatment to provide potent antitumor vaccines. This review summarizes recent studies investigating PDT as part of combined modality treatment, hopefully providing an accessible overview of the current knowledge that may act as a basis for new ideas or systematic evaluations of already promising results. © The Author(s) 2014.

  9. Antifungal and antiviral products of marine organisms

    PubMed Central

    Cheung, Randy Chi Fai; 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

    2017-01-01

    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 afore-mentioned 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

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

    PubMed

    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

    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. Female B6D2F(1)/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 demonstrated that the lethal dose for 50% at 30 days (LD(50/30)) of B6D2F(1)/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. 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.

  11. 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

  12. EFFECTS OF DIFFERENT HYDROPONIC SUBSTRATE COMBINATIONS AND WATERING REGIMES ON PHYSIOLOGICAL AND ANTI-FUNGAL PROPERTIES OF SIPHONOCHILUS AETHIOPICUS.

    PubMed

    S, Xego; L, Kambizi; F, Nchu

    2017-01-01

    Production of medicinal plants in controlled environments, particularly hydroponic technology, provides opportunities for high quality biomass accumulation and optimizes production of secondary metabolites. Applying special watering regimes in combination with efficient soil draining is an encouraging new tool for the production of pharmaceutical relevant plants. The purpose of this paper was to evaluate the effect of substrate combinations and watering regimes on nutrient uptake, anti-F. oxysporum activity and secondary metabolite profile of S. aethiopicus. Coir was used as the main component for the preparation of media in different combinations; TI (Coir + vermiculite + perlite + bark), T2 (Coir + bark), T3 (Coir + perlite) and T4 (Coir + vermiculite). Plants in different treatments were grown under two watering regimes: 3 and 5-days watering intervals. At 9 weeks post treatment, plants were harvested, oven dried and tissue nutrient content, anti-F. oxysporum activity and secondary metabolites were analyzed. The results showed that there were significant differences (P < 0.05) on the uptake of P, K, N, Mg, Fe, Cu, B and NH4(-).The highest mean values for most nutrients were obtained in treatments under 3-days interval. Acetone extracts of S. aethiopicus under 5-days interval were the most bioactive against F. oxysporum. The MIC values obtained are relatively lower for the rhizomes, ranging from 0.078 - 0.3125 mg/ml compared to the higher MIC values (0.375 - 0.75 mg/ml) obtained in the leaves. LC-MS analysis of acetone extracts revealed the presence of phytochemicals such as caffeic acid, quercetin, p-hydroxybenzoic acid, rutin, kaempferol, epicatechin, naringenin, hesperetin and protocatechuic acid. The antimicrobial activity and/or the phytochemical profile of the crude extracts were affected by watering regimes.

  13. EFFECTS OF DIFFERENT HYDROPONIC SUBSTRATE COMBINATIONS AND WATERING REGIMES ON PHYSIOLOGICAL AND ANTI-FUNGAL PROPERTIES OF SIPHONOCHILUS AETHIOPICUS

    PubMed Central

    S, Xego; L, Kambizi; F, Nchu

    2017-01-01

    Background: Production of medicinal plants in controlled environments, particularly hydroponic technology, provides opportunities for high quality biomass accumulation and optimizes production of secondary metabolites. Applying special watering regimes in combination with efficient soil draining is an encouraging new tool for the production of pharmaceutical relevant plants. The purpose of this paper was to evaluate the effect of substrate combinations and watering regimes on nutrient uptake, anti-F. oxysporum activity and secondary metabolite profile of S. aethiopicus. Materials and Methods: Coir was used as the main component for the preparation of media in different combinations; TI (Coir + vermiculite + perlite + bark), T2 (Coir + bark), T3 (Coir + perlite) and T4 (Coir + vermiculite). Plants in different treatments were grown under two watering regimes: 3 and 5-days watering intervals. At 9 weeks post treatment, plants were harvested, oven dried and tissue nutrient content, anti-F. oxysporum activity and secondary metabolites were analyzed. Results: The results showed that there were significant differences (P < 0.05) on the uptake of P, K, N, Mg, Fe, Cu, B and NH4-.The highest mean values for most nutrients were obtained in treatments under 3-days interval. Acetone extracts of S. aethiopicus under 5-days interval were the most bioactive against F. oxysporum. The MIC values obtained are relatively lower for the rhizomes, ranging from 0.078 - 0.3125 mg/ml compared to the higher MIC values (0.375 - 0.75 mg/ml) obtained in the leaves. LC-MS analysis of acetone extracts revealed the presence of phytochemicals such as caffeic acid, quercetin, p-hydroxybenzoic acid, rutin, kaempferol, epicatechin, naringenin, hesperetin and protocatechuic acid. Conclusion: The antimicrobial activity and/or the phytochemical profile of the crude extracts were affected by watering regimes. PMID:28480420

  14. Azilsartan/chlorthalidone combination therapy for blood pressure control.

    PubMed

    Cheng, Judy Wm

    2013-01-01

    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. To review the pharmacology, pharmacokinetics, efficacy, safety, tolerability, and role of azilsartan plus chlorthalidone for hypertension management. 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. 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. 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/chlorthalidone will be the most appropriate combination therapy for an individual

  15. 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

  16. 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

  17. Fixed-dose combination therapy in hypertension: pros.

    PubMed

    Taddei, Stefano

    2012-06-01

    Effective treatment of high blood pressure represents a key strategy for reducing the burden of hypertension-related cardiovascular diseases, mostly myocardial infarction and stroke. Despite these well established concepts, however, hypertension remains poorly controlled, worldwide. In addition, treated hypertensive patients often remain at higher risk compared with the normotensive population, even when a satisfactory blood pressure control is achieved, due to the high or very high added cardiovascular risk profile observed in these patients. An emerging strategy to improve blood pressure control and achieve this unmet target for cardiovascular disease prevention in hypertensive patients is represented by a more extensive use of rational and effective combination therapies with respect to monotherapy. Such an approach has been recently proposed even as first-line strategy in hypertensive patients at high added cardiovascular risk or in those in whom strict blood pressure control is required. Within the possible antihypertensive drug combinations currently available for the clinical management of hypertension, those based on the association of drugs inhibiting the renin-angiotensin system and thiazide diuretics or calcium channel blockers have demonstrated to be effective and safe in lowering both systolic and diastolic blood pressure levels with a good tolerability profile. In addition, these strategies have provided evidence for effective cardiovascular protection compared with conventional antihypertensive therapies. Among the antihypertensive drugs able to counteract the deleterious effects of abnormal activation of the renin-angiotensin system, angiotensin II receptor blockers have demonstrated to provide better tolerability profile and greater cardiovascular protection on hypertension-related organ damage compared with ACE inhibitors in randomized controlled clinical trials, in the presence of similar antihypertensive efficacy and safety. In particular, these

  18. Usage of antifungal drugs for therapy of genital Candida infections, purchased as over-the-counter products or by prescription: 2. Factors that may have influenced the marked changes in sales volumes during the 1990s.

    PubMed

    Mårdh, Per-Anders; Wågström, Jolanta; Landgren, Maria; Holmén, Jan

    2004-06-01

    The epidemiology of vulvovaginal candidiasis (VVC) and such recurrent infections (RVVC) has been difficult to study as the majority of episodes of these conditions are self-treated by the women affected. In Sweden, all pharmacies are owned by the state and all prescriptions and over-the-counter (OTC) products, such as antifungals, are registered in a database, which offers unique possibilities to study the epidemiology of VVC/RVVC. To analyze all prescriptions and OTC products purchased for therapy of VVC/RVVC and to establish reasons for any observed variation in the sales figures. Sales figures in the Swedish county of Skåne of antifungal drugs for therapy of VVC/RVVC were analyzed by the aid of the 'ACS' database of the National Corporation of Swedish Pharmacies for the years 1990--1999. The size of the female population in the county is approximately half a million. The study showed that 93% of all antifungal drugs for VVC/RVVC were sold as OTC products. An increase in sales of the drugs occurred until mid- 1993/94, followed by a decrease until end of the study period in 1999. Demographic factors (e.g. the number of female inhabitants in the county, pharmacies and health-care units), the pregnancy rate and pharmacy-dependent factors (such as the introduction of shelves for self-selection of antifungal products) did not explain the observed variations in sales. Distinct short-term variations in the number of prescriptions of fluconazole and itraconazole could be explained by drugs company sales campaigns and logistics factors in drug distribution. The sales volumes in the 33 municipalities in the county correlated with the density of the population, which was not the case for the total number of prescriptions made in the county during the 1990s. The variation in antifungal drug sales was similar to that of hormonal intrauterine devices, but this was not the case for oral contraceptives. The total Swedish usage of antibiotics showed a similar variation to that

  19. Carfilzomib boosted combination therapy for relapsed multiple myeloma

    PubMed Central

    Steiner, Raphael E; Manasanch, Elisabet E

    2017-01-01

    Carfilzomib is a proteasome inhibitor that binds selectively and irreversibly to the 20S proteasome, the proteolytic core particle within the 26S proteasome, resulting in the accumulation of proteasome substrates and ultimately growth arrest and apoptosis of tumor cells. The development and ultimate approval of this medication by regulatory agencies has been an important step toward improving clinical outcomes in multiple myeloma. Although initially approved as a single agent for the treatment of multiply relapsed and/or refractory myeloma, in the USA, it is now widely used in the early relapse setting in combination with lenalidomide and dexamethasone. Carfilzomib has also been studied in combination with second-generation immunomodulatory drugs, histone deacetylase inhibitors, alkylating agents and other novel medications. In this review article, we will discuss the efficacy, safety, tolerability and quality of life of carfilzomib-based combination therapies, as well as novel agents, for relapsed multiple myeloma. PMID:28243125

  20. Carfilzomib boosted combination therapy for relapsed multiple myeloma.

    PubMed

    Steiner, Raphael E; Manasanch, Elisabet E

    2017-01-01

    Carfilzomib is a proteasome inhibitor that binds selectively and irreversibly to the 20S proteasome, the proteolytic core particle within the 26S proteasome, resulting in the accumulation of proteasome substrates and ultimately growth arrest and apoptosis of tumor cells. The development and ultimate approval of this medication by regulatory agencies has been an important step toward improving clinical outcomes in multiple myeloma. Although initially approved as a single agent for the treatment of multiply relapsed and/or refractory myeloma, in the USA, it is now widely used in the early relapse setting in combination with lenalidomide and dexamethasone. Carfilzomib has also been studied in combination with second-generation immunomodulatory drugs, histone deacetylase inhibitors, alkylating agents and other novel medications. In this review article, we will discuss the efficacy, safety, tolerability and quality of life of carfilzomib-based combination therapies, as well as novel agents, for relapsed multiple myeloma.

  1. Combination therapy in rheumatoid arthritis: updated systematic review.

    PubMed

    Verhoeven, A C; Boers, M; Tugwell, P

    1998-06-01

    In a second update of a systematic review, many new developments in the combined drug treatment of rheumatoid arthritis (RA) are highlighted. In early RA patients, step-down bridge therapy that includes corticosteroids leads to much enhanced efficacy at acceptable or low toxicity. The effects on joint damage may be persistent, but the symptomatic effects are probably dependent on continued corticosteroid dosing. In late patients, cyclosporin improves a suboptimal clinical response to methotrexate, and the triple combination of methotrexate, sulphasalazine and hydroxychloroquine appears to be clinically better than the components. Other combinations are either untested, tested at low sample size, or show negative interaction. In view of the low volume of evidence, most studies need confirmation by replication.

  2. 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. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Combined medication and cognitive therapy for generalized anxiety disorder.

    PubMed

    Crits-Christoph, Paul; Newman, Michelle G; Rickels, Karl; Gallop, Robert; Gibbons, Mary Beth Connolly; Hamilton, Jessica L; Ring-Kurtz, Sarah; Pastva, Amy M

    2011-12-01

    The current study assessed efficacy of combined cognitive behavioral therapy (CBT) and venlafaxine XR compared to venlafaxine XR alone in the treatment of generalized anxiety disorder (GAD) within settings where medication is typically offered as the treatment for this disorder. Patients with DSM-IV-diagnosed GAD who were recently enrolled in a long-term venlafaxine XR study were randomly offered (n=77), or not offered (n=40), the option of adding 12 sessions of CBT. Of those offered CBT, 33% (n=26) accepted and attended at least one treatment session. There were no differences between the combined treatment group and the medication only group on primary or secondary efficacy measures in any of the sample comparisons. Many patients who present in medical/psychopharmacology settings seeking treatment for GAD decline the opportunity to receive adjunctive treatment. Of those that receive CBT, there appears to be no additional benefit of combined treatment compared to venlafaxine XR alone.

  4. Combined Medication and Cognitive Therapy for Generalized Anxiety Disorder

    PubMed Central

    Crits-Christoph, Paul; Newman, Michelle G.; Rickels, Karl; Gallop, Robert; Gibbons, Mary Beth Connolly; Hamilton, Jessica L.; Ring-Kurtz, Sarah; Pastva, Amy M.

    2011-01-01

    The current study assessed efficacy of combined cognitive behavioral therapy (CBT) and venlafaxine XR compared to venlafaxine XR alone in the treatment of generalized anxiety disorder (GAD) within settings where medication is typically offered as the treatment for this disorder. Patients with DSM-IV–diagnosed GAD who were recently enrolled in a long-term venlafaxine XR study were randomly offered (n=77), or not offered (n=40), the option of adding 12 sessions of CBT. Of those offered CBT, 33% (n=26) accepted and attended at least one treatment session. There were no differences between the combined treatment group and the medication only group on primary or secondary efficacy measures in any of the sample comparisons. Many patients who present in medical/psychopharmacology settings seeking treatment for GAD decline the opportunity to receive adjunctive treatment. Of those that receive CBT, there appears to be no additional benefit of combined treatment compared to venlafaxine XR alone. PMID:21840164

  5. Combined therapy using acupressure therapy, hypnotherapy, and transcendental meditation versus placebo in type 2 diabetes.

    PubMed

    Bay, Roohallah; Bay, Fatemeh

    2011-09-01

    Type 2 diabetes is one of the most widespread diseases in the world. The main aim of this research was to evaluate the effect of combined therapy using acupressure therapy, hypnotherapy, and transcendental meditation (TM) on the blood sugar (BS) level in comparison with placebo in type 2 diabetic patients. We used "convenience sampling" for selection of patients with type 2 diabetes; 20 patients were recruited. For collection of data, we used an identical quasi-experimental design called "nonequivalent control group." Therapy sessions each lasting 60-90 min were carried out on 10 successive days. We prescribed 2 capsules (containing 3g of wheat flour each) for each member of the placebo group (one for evening and one for morning). Pre-tests, post-tests, and follow-up tests were conducted in a medical laboratory recognized by the Ministry of Health and Medical Education of Iran. Mean BS level in the post-tests and follow-up tests for the experimental group was reduced significantly in comparison with the pre-tests whereas in the placebo group no changes were observed. Combined therapy including acupressure therapy, hypnotherapy, and TM reduced BS of type 2 diabetic patients and was more effective than placebo therapy on this parameter.

  6. 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

  7. Targeted Therapies in Combination With Immune Therapies for the Treatment of Metastatic Melanoma.

    PubMed

    Christiansen, Shelly A; Khan, Shaheer; Gibney, Geoffrey T

    In recent years, the field of oncology has witnessed many breakthroughs in the treatment of advanced malignancies, particularly in patients with advanced melanoma. Targeted and immune checkpoint therapies have emerged as the primary treatment strategies for these patients. Molecular profiling of melanoma is incorporated into routine practice to identify potential therapeutic targets, and patients are offered either a targeted or immune checkpoint inhibitor therapy approach. Both strategies have limitations where not all patients experience durable responses. Preclinical data have demonstrated the ability of targeted therapy to enhance activity of effector T cells, reduce immunosuppressive cytokine production, and increase tumor cell antigen presentation, which can augment antitumor immunity. In vivo models have shown synergy with improved tumor control when targeted and immune checkpoint agents are combined. Therefore, combination strategies with targeted and immune checkpoint therapy may improve patient outcomes. Early clinical data with anti-programmed cell-death protein 1/programmed cell-death ligand 1 agents in combination with targeted inhibitors appear to have acceptable toxicity rates and the potential for enhanced antitumor activity. This review explores the current status of preclinical and clinical development for these combination approaches in patients with advanced melanoma.

  8. 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. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  9. 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

  10. [Arterial injuries combined with open fractures--management and therapy].

    PubMed

    Gäbel, G; Pyrc, J; Hinterseher, I; Zwipp, H; Saeger, H-D; Bergert, H

    2009-08-01

    Vascular injuries are an uncommon finding. In times of peace vascular injuries occur in approximately 1-4 % during traffic accidents. Especially challenging is the treatment of open fractures combined with arterial lesions. These fractures are usually accompanied with severe soft tissue damage and injuries to neurological structures. The overall prognosis of these trauma patients is dependent on fast and sufficient diagnostics and therapy. In particular, for unstable patients time-consuming diagnostics can be dispensed and a primarily operative therapy should be targeted. Vascular reconstruction by direct suture is sometimes only possible with interposition and should be the primary goal. Interposition should be performed with autologous vein material because of the high risk of infection. Here we demonstrate on the basis of our patients the interdisciplinary -management of such trauma patients in our hospital.

  11. 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

  12. Cancer nanomedicine: from targeted delivery to combination therapy.

    PubMed

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

    2015-04-01

    The advent of nanomedicine marks an unparalleled opportunity to advance the treatment of various diseases, including cancer. The unique properties of nanoparticles (NPs), such as large surface-to-volume ratio, small size, the ability to encapsulate various drugs, and tunable surface chemistry, give 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 NPs a mode of treatment potentially superior to conventional cancer therapies. This review highlights the most recent developments in cancer treatment using NPs as drug delivery vehicles, including promising opportunities in targeted and combination therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. 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.

  14. Combination Therapies for Traumatic Brain Injury: Retrospective Considerations

    PubMed Central

    Anderson, Gail; Atif, Fahim; Badaut, Jerome; Clark, Robert; Empey, Philip; Guseva, Maria; Hoane, Michael; Huh, Jimmy; Pauly, Jim; Raghupathi, Ramesh; Scheff, Stephen; Stein, Donald; Tang, Huiling; Hicks, Mona

    2016-01-01

    Abstract Patients enrolled in clinical trials for traumatic brain injury (TBI) may present with heterogeneous features over a range of injury severity, such as diffuse axonal injury, ischemia, edema, hemorrhage, oxidative damage, mitochondrial and metabolic dysfunction, excitotoxicity, inflammation, and other pathophysiological processes. To determine whether combination therapies might be more effective than monotherapy at attenuating moderate TBI or promoting recovery, the National Institutes of Health funded six preclinical studies in adult and immature male rats to evaluate promising acute treatments alone and in combination. Each of the studies had a solid rationale for its approach based on previous research, but only one reported significant improvements in long-term outcomes across a battery of behavioral tests. Four studies had equivocal results because of a lack of sensitivity of the outcome assessments. One study demonstrated worse results with the combination in comparison with monotherapies. While specific research findings are reported elsewhere, this article provides an overview of the study designs, insights, and recommendations for future research aimed at therapy development for TBI. PMID:25970337

  15. Combination therapy of donepezil and vitamin E in Alzheimer disease.

    PubMed

    Klatte, Emily T; Scharre, Douglas W; Nagaraja, Haikady N; Davis, Rebecca A; Beversdorf, David Q

    2003-01-01

    A retrospective chart review was performed on 130 patients from the Ohio State University Memory Disorders Clinic to examine the long-term effects of combination therapy with donepezil and vitamin E on patients with Alzheimer disease. Subjects were included if they met National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer disease, had taken at least 5 mg donepezil and at least 1000 U vitamin E daily, had at least a 1-year follow-up while continuing these medications, and had a Mini-Mental State Examination score of 10-24. The Mini-Mental State Examination was then recorded annually thereafter. These data were compared with the Consortium to Establish a Registry for Alzheimer's Disease database for patients collected prior to the availability of these treatment options. Patients declined at a significantly lower rate as compared with the Consortium to Establish a Registry for Alzheimer's Disease data. The long-term combination therapy of donepezil and vitamin E appears beneficial for patients with Alzheimer disease. Future prospective studies would be needed to compare combination treatment to vitamin E and donepezil alone.

  16. 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

  17. Combining field therapies for actinic keratoses: novel approaches that intensify photodynamic therapy.

    PubMed

    Kaminska, Edidiong Celestine Ntuen; Tsoukas, Maria M

    2013-01-01

    Actinic keratosis (AK) is a common dermatologic condition resulting from long-term sun exposure. It is considered a precancerous lesion that may convert into a squamous cell carcinoma, which highlights the importance of prompt identification, early treatment and eradication of AK, and recurrence monitoring. Currently, there are many treatments available for widespread AKs that include a combination of local lesion destruction along with stimulation of an individual's immune response. Preliminary data from combination therapy studies demonstrate that these may offer improved efficacy, tolerability, and long-term results compared with monotherapy. The authors investigate combination systems aimed at intensifying photodynamic therapy for the treatment of AKs as reported at the 8th World Congress of the International Academy of Cosmetic Dermatology in Cancun, Mexico, and include a comprehensive literature review. Further investigations and data collection are in progress in order to solidify these promising results.

  18. 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

  19. Addressing genetic tumor heterogeneity through computationally predictive combination therapy.

    PubMed

    Zhao, Boyang; Pritchard, Justin R; Lauffenburger, Douglas A; Hemann, Michael T

    2014-02-01

    Recent tumor sequencing data suggest an urgent need to develop a methodology to directly address intratumoral heterogeneity in the design of anticancer treatment regimens. We use RNA interference to model heterogeneous tumors, and demonstrate successful validation of computational predictions for how optimized drug combinations can yield superior effects on these tumors both in vitro and in vivo. Importantly, we discover here that for many such tumors knowledge of the predominant subpopulation is insufficient for determining the best drug combination. Surprisingly, in some cases, the optimal drug combination does not include drugs that would treat any particular subpopulation most effectively, challenging straightforward intuition. We confirm examples of such a case with survival studies in a murine preclinical lymphoma model. Altogether, our approach provides new insights about design principles for combination therapy in the context of intratumoral diversity, data that should inform the development of drug regimens superior for complex tumors. This study provides the first example of how combination drug regimens, using existing chemotherapies, can be rationally designed to maximize tumor cell death, while minimizing the outgrowth of clonal subpopulations. 2013 AACR

  20. 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

  1. 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.

  2. Repurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathway

    PubMed Central

    Thangamani, Shankar; Maland, Matthew; Mohammad, Haroon; Pascuzzi, Pete E.; Avramova, Larisa; Koehler, Carla M.; Hazbun, Tony R.; Seleem, Mohamed N.

    2017-01-01

    Current antifungal therapies have limited effectiveness in treating invasive fungal infections. Furthermore, the development of new antifungal is currently unable to keep pace with the urgent demand for safe and effective new drugs. Auranofin, an FDA-approved drug for the treatment of rheumatoid arthritis, inhibits growth of a diverse array of clinical isolates of fungi and represents a new antifungal agent with a previously unexploited mechanism of action. In addition to auranofin's potent antifungal activity against planktonic fungi, this drug significantly reduces the metabolic activity of Candida cells encased in a biofilm. Unbiased chemogenomic profiling, using heterozygous S. cerevisiae deletion strains, combined with growth assays revealed three probable targets for auranofin's antifungal activity—mia40, acn9, and coa4. Mia40 is of particular interest given its essential role in oxidation of cysteine rich proteins imported into the mitochondria. Biochemical analysis confirmed auranofin targets the Mia40-Erv1 pathway as the drug inhibited Mia40 from interacting with its substrate, Cmc1, in a dose-dependent manner similar to the control, MB-7. Furthermore, yeast mitochondria overexpressing Erv1 were shown to exhibit resistance to auranofin as an increase in Cmc1 import was observed compared to wild-type yeast. Further in vivo antifungal activity of auranofin was examined in a Caenorhabditis elegans animal model of Cryptococcus neoformans infection. Auranofin significantly reduced the fungal load in infected C. elegans. Collectively, the present study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antifungal agent and may offer a safe, effective, and quick supplement to current approaches for treating fungal infections. PMID:28149831

  3. Radionuclide therapy using nanoparticle of 131I-Lactosome in combination with percutaneous ethanol injection therapy

    NASA Astrophysics Data System (ADS)

    Hara, Eri; Makino, Akira; Kurihara, Kensuke; Ueda, Motoki; Hara, Isao; Kawabe, Takashi; Yamamoto, Fumihiko; Ozeki, Eiichi; Togashi, Kaori; Kimura, Shunsaku

    2013-12-01

    We present here a radionuclide therapy using nanoparticle of 131I-labeled Lactosome (131I-Lactosome) is effective as a tumor therapy when combined with the local therapy of the percutaneous ethanol injection therapy (PEIT). A mixture of 131I-labeled poly( l-lactic acid)30 and amphiphilic block polymer of poly(sarcosine)64- block-poly( l-lactic acid)30 was dispersed in saline to generate polymeric micelles of 131I-Lactosome (the diameter of 46 nm with PDI of 0.057). Mice were transplanted with murine mammary cancer (4T1) cells, and a relatively small amount of ethanol was injected percutaneously to the tumor region, followed by intravenous administration of 131I-Lactosome (2.0 × 102 MBq/kg). At 16 days after the 131I-Lactosome dosage with PEIT, the relative tumor volume (RTV) was suppressed as low as 5.32 ± 1.06, while the RTV values became significant to be 15.9 ± 5.0 with PEIT alone and 17.4 ± 3.9 with 131I-Lactosome alone. Indeed, 131I-accumulation in the transplanted tumor region at 48 h after 131I-Lactosome dosage became three times higher with PEIT than that without PEIT. The nanoparticle-based radionuclide therapy in combination with PEIT was, therefore, effective in suppression of tumor proliferation.

  4. In Vitro Antifungal Activity of Epigallocatechin 3-O-Gallate against Clinical Isolates of Dermatophytes

    PubMed Central

    Park, Bong Joo; Taguchi, Hideaki; Kamei, Katsuhiko; Matsuzawa, Tetsuhiro; Hyon, Suong-Hyu

    2011-01-01

    Previously, we reported that epigallocatechin 3-O-gallate (EGCg) has growth-inhibitory effect on clinical isolates of Candida species. In this study, we investigated the antifungal activity of EGCg and antifungal agents against thirty-five of dermatophytes clinically isolated by the international guidelines (M38-A2). All isolates exhibited good susceptibility to EGCg (MIC50, 2-4 µg/mL, MIC90, 4-8 µg/mL, and geometric mean (GM) MICs, 3.36-4 µg/mL) than those of fluconazole (MIC50, 2-16 µg/mL, MIC90, 4-32 µg/mL, and GM MICs, 3.45-25.8 µg/mL) and flucytosin (MIC50, MIC90, and GM MICs, >64 µg/mL), although they were less susceptible to other antifungal agents, such as amphotericin B, itraconazole, and miconazole. These activities of EGCg were approximately 4-fold higher than those of fluconazole, and were 4 to 16-fold higher than flucytosin. This result indicates that EGCg can inhibit pathogenic dermatophyte species. Therefore, we suggest that EGCg may be effectively used solely as a possible agent or combined with other antifungal agents for antifungal therapy in dermatophytosis. PMID:21488200

  5. Combining alprazolam with systematic desensitization therapy for dental injection phobia.

    PubMed

    Coldwell, Susan E; Wilhelm, Frank H; Milgrom, Peter; Prall, Christopher W; Getz, Tracy; Spadafora, Agnes; Chiu, I-Yu; Leroux, Brian G; Ramsay, Douglas S

    2007-01-01

    To determine whether a benzodiazepine facilitates systematic desensitization, 144 subjects with dental injection phobia received systematic desensitization in combination with placebo or one of two doses of alprazolam (0.5mg or 0.75mg). Systematic desensitization therapy included computer-controlled presentation of digitized video segments followed by in vivo exposure segments, culminating in an actual dental injection. Subjects advanced to the next hierarchy segment when low anxiety was reported during a segment. Alprazolam and placebo groups progressed at the same rate. The 0.75mg group had elevated heart rates while watching video segments compared with placebo. In a subsequent behavioral avoidance test (during which subjects were randomized to a new drug condition), there was no indication that state-dependent learning had occurred. Dental fear was reduced similarly in all groups for 1 year after study completion. No advantage was found to combining alprazolam with systematic desensitization for dental injection phobia.

  6. Combining chemotherapy and targeted therapies in metastatic colorectal cancer

    PubMed Central

    Rodriguez, J; Zarate, R; Bandres, E; Viudez, A; Chopitea, A; García-Foncillas, J; Gil-Bazo, I

    2007-01-01

    Colorectal cancer remains one of the major causes of cancer death worldwide. During the past years, the development of new effective treatment options has led to a considerable improvement in the outcome of this disease. The advent of agents such as capecitabine, irinotecan, oxaliplatin, cetuximab and bevacizumab has translated into median survival times in the range of 2 years. Intense efforts have focused on identifying novel agents targeting specific growth factor receptors, critical signal transduction pathways or mediators of angiogenesis. In addition, several clinical trials have suggested that some of these molecularly targeted drugs can be safely and effectively used in combination with conventional chemotherapy. In this article we review various treatment options combining cytotoxic and targeted therapies currently available for patients with metastatic colorectal cancer. PMID:17990352

  7. 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.

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

    PubMed Central

    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

  9. [Combined Antihypertensive Therapy in Patients at High Risk].

    PubMed

    Lyamina, N P; Kotelnikova, E V; Nalivaeva, A V

    2015-10-01

    Presents opportunities to increase the effectiveness of combination antihypertensive therapy (AHT) in patients with arterial hypertension (AH) and high cardiovascular risk. Displaying increase in the proportion of patients with target blood pressure up to 82.4%; high commitment combined AHT (96%) and medical recommendations for lifestyle changes (54%) using the power of information computer technology (ICT) in order to carry out continuous monitoring of blood pressure and other risk factors (RF), commitment to the patients drug and non-drug assignments. Thus, ICT can be seen as a tool that can give a real idea of the scale and nature of the deviation from the medical recommendations that can serve as a basis for personalized AHT.

  10. Catamenial hemoptysis accompanied by subcutaneous endometriosis treated with combination therapy

    PubMed Central

    Jang, Hye-In; Kim, Sung-Eun; Lee, Yoo-Young; Choi, Chel-Hun; Lee, Jeong-Won; Kim, Byoung-Gie; Bae, Duk-Soo

    2017-01-01

    Extra pelvic endometriosis is considered to be rare. This paper reports a case of catamenial hemoptysis accompanied by subcutaneous endometriosis in 26-year-old woman. A computed tomography scan of the chest revealed a focal ground-glass opacity lesion in the posterior segment of the right upper lobe. Histopathology confirmed the diagnosis of endometriosis of right lung and concurrent subcutaneous endometriosis. She was treated with surgical resection of the endometriosis lesions on two different sites and perioperative gonadotropin-releasing hormone agonist therapy. The 6-month follow-up after combination treatment showed no recurrence. Though long-term follow-up result is needed, aggressive treatment using combination treatment (surgery and perioperative medication) should be considered for symptomatic extra pelvic endometriosis. PMID:28344969

  11. Glucosamine/chondroitin/primorine combination therapy for osteoarthritis.

    PubMed

    Fox, Beth Anne; Stephens, Mary M

    2009-01-01

    Osteoarthritis (OA) is the most common arthritis affecting the aging population. This degenerative disease can cause significant pain and functional disability in affected individuals. Despite advances in the retardation of rheumatoid arthritis with disease-modifying agents, comparable oral agents have been relatively unavailable for OA. The mainstays of therapy continue to be acetaminophen and nonsteroidal antiinflammatory medications to manage symptoms. Unfortunately, these medications can precipitate severe adverse events in some patients or may be contraindicated, leaving few choices remaining to control pain and suffering. Glucosamine sulfate and chondroitin sulfate have been evaluated in many studies as agents to relieve pain, improve functional activity, and slow disease progression in OA especially of the hip and knee. Studies have reported conflicting results regarding improvement in the pain and disability associated with OA with the use of glucosamine and chondroitin as single agents; however, when improvement has been demonstrated, the formulation has primarily been glucosamine sulfate combined with chondroitin sulfate. Recently, as a result of information implicating the role of reactive oxygen species and oxidative cellular stress reactions on the onset of neurodegenerative and inflammatory disorders, it has been theorized that medications that could control or alter these reactions might improve or prevent the onset of these conditions. Primorine is a combination of products thought to alter these biochemical oxidative byproducts. Based on current evidence, the use of a combination product of glucosamine sulfate and chondroitin sulfate seems to have the greatest potential as a therapeutic intervention for patients at increased risk from the adverse events of accepted current oral therapies. The use of primorine and its combination of products as an intervention in OA has theoretical advantages but its benefits are unproven. A new product, relamine

  12. Combination Therapy with Isavuconazole and Micafungin for Treatment of Experimental Invasive Pulmonary Aspergillosis.

    PubMed

    Petraitis, Vidmantas; Petraitiene, Ruta; McCarthy, Matthew W; Kovanda, Laura L; Zaw, Myo H; Hussain, Kaiser; Shaikh, Naima; Maung, Bo Bo W; Sekhon, Navjot K; Hope, William W; Walsh, Thomas J

    2017-09-01

    Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity and mortality in immunocompromised patients. We hypothesized that simultaneous inhibition of biosynthesis of ergosterol in the fungal cell membrane and (1→3)-β-d-glucan in the cell wall, respectively, by the antifungal triazole isavuconazole (ISA) and the echinocandin micafungin (MFG) may result in improved outcomes in experimental IPA in persistently neutropenic rabbits. Treatments included ISA at 20 mg/kg of body weight/day (ISA20), 40 mg/kg/day (ISA40), and 60 mg/kg/day (ISA60); MFG at 2 mg/kg/day (MFG2); combinations of ISA20 and MFG2, ISA40 and MFG2, and ISA60 and MFG2; and no treatment (untreated controls [UC]). The galactomannan index (GMI) and (1→3)-β-d-glucan levels in serum were measured. The residual fungal burden (number of CFU per gram) was significantly reduced in ISA20-, ISA40-, ISA60-, ISA20-MFG2-, ISA40-MFG2-, and ISA60-MFG2-treated rabbits compared with that in MFG2-treated or UC rabbits (P < 0.01). Measures of organism-mediated pulmonary injury, lung weights, and pulmonary infarct score were lower in ISA40-MFG2-treated rabbits than in rabbits treated with ISA40 or MFG2 alone (P < 0.01). Survival was prolonged in ISA40-MFG2-treated rabbits in comparison to those treated with ISA40 or MFG2 alone (P < 0.01). These outcome variables correlated directly with significant declines in GMI and serum (1→3)-β-d-glucan levels during therapy. The GMI correlated with measures of organism-mediated pulmonary injury, lung weights (r = 0.764; P < 0.001), and pulmonary infarct score (r = 0.911; P < 0.001). In summary, rabbits receiving combination therapy with isavuconazole and micafungin demonstrated a significant dose-dependent reduction in the residual fungal burden, decreased pulmonary injury, prolonged survival, a lower GMI, and lower serum (1→3)-β-d-glucan levels in comparison to rabbits receiving isavuconazole or micafungin as a single agent. Copyright © 2017 American

  13. 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

  14. [Combined surgical-orthodontic therapy for compound odontoma].

    PubMed

    Dukić, Walter; Kuna, Tihomir; Lapter-Varga, Marina; Jurić, Hrvoje; Lulić-Dukić, Olga

    2007-09-01

    Odontogenic tumor is a rare condition in dental medicine that mostly proceeds unrecognized until the occurrence of clinical symptoms such as delayed eruption, or is incidentally detected on routine x-ray examination. The exact cause is not known, however, previous dental trauma and infection have been postulated as the potential factors in the development of odontogenic tumor. The earliest possible operative extirpation of the tumorous growth is recommended to eliminate permanent tooth impaction and to enable normal growth of the teeth. In some cases, corticotomy, including complete removal of the bony coat of the tooth, may be needed to additionally facilitate and precipitate its eruption. Orthodontic therapy is also of great importance in correct alignment of the teeth 'n the dental arch as well as in the management of other anomalies that may be associated with odontogenic tumor. A patient with compound odontoma is presented, along with the course of combined surgical-orthodontic therapy. The patient reported previous intrusion trauma that had occurred at the age of 4 years, which may have been the potential factor in the development of odontoma. In this case, there was a massive odontogenic tumor which had compromised the growth of permanent teeth, and the growth impulse was almost at the end since the patient was 11 years old and the apexes of the upper incisors were partially closed. The first operation included complete removal of the tumorous mass that had interrupted spontaneous eruption of the upper permanent incisors. It did not result in immediate spontaneous tooth eruption, so an additional operation was needed. The objective of the second operative procedure was complete removal of the covering bone over the unerupted upper permanent incisors in order to eliminate the physical barrier to tooth growth and eruption. The objective of fixed orthodontic therapy was full eruption of the partially erupted upper incisors. After 16 months, the upper incisors

  15. 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.

  16. Synthesis, antifungal activity of caffeic acid derivative esters, and their synergism with fluconazole and nystatin against Candida spp.

    PubMed

    Sardi, Janaína de Cássia Orlandi; Gullo, Fernanda Patrícia; Freires, Irlan Almeida; Pitangui, Nayla de Souza; Segalla, Maicon Petrônio; Fusco-Almeida, Ana Marisa; Rosalen, Pedro Luiz; Regasini, Luís Octávio; Mendes-Giannini, Maria José Soares

    2016-12-01

    We tested the antifungal potential of caffeic acid and 8 of its derivative esters against Candidaalbicans ATCC 90028 and 9 clinical isolatesand carried out a synergism assay with fluconazole and nystatin. Propyl caffeate (C3) showed the best antifungal activity against the tested strains. When in combination, C3 markedly reduced the MIC of fluconazole and nystatin with synergistic effect up to 64-fold. Finally, C3 showed a high IC50 value and selective indexagainst oral keratinocytes, demonstrating low toxicity against this cell type and selectivity for yeast cells. Further research should confirm its antifungal potential for development of combined therapy to treat C. albicans infections. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. A Framework for Combining rTMS with Behavioral Therapy.

    PubMed

    Tsagaris, K Zoe; Labar, Douglas R; Edwards, Dylan J

    2016-01-01

    Upon its inception, repetitive transcranial magnetic stimulation (rTMS) was delivered at rest, without regard to the potential impact of activity occurring during or around the time of stimulation. rTMS was considered an experimental intervention imposed on the brain; therefore, the myriad features that might suppress or enhance its desired effects had not yet been explored. The field of rTMS has since grown substantially and therapeutic benefits have been reported, albeit with modest and inconsistent improvements. Work in this field accelerated following approval of a psychiatric application (depression), and it is now expanding to other applications and disciplines. In the last decade, experimental enquiry has sought new ways to improve the therapeutic benefits of rTMS, intended to enhance underlying brain reorganization and functional recovery by combining it with behavioral therapy. This concept is appealing, but poorly defined and requires clarity. We provide an overview of how combined rTMS and behavioral therapy has been delineated in the literature, highlighting the diversity of approaches. We outline a framework for study design and reporting such that the effects of this emerging method can be better understood.

  18. A Framework for Combining rTMS with Behavioral Therapy

    PubMed Central

    Tsagaris, K. Zoe; Labar, Douglas R.; Edwards, Dylan J.

    2016-01-01

    Upon its inception, repetitive transcranial magnetic stimulation (rTMS) was delivered at rest, without regard to the potential impact of activity occurring during or around the time of stimulation. rTMS was considered an experimental intervention imposed on the brain; therefore, the myriad features that might suppress or enhance its desired effects had not yet been explored. The field of rTMS has since grown substantially and therapeutic benefits have been reported, albeit with modest and inconsistent improvements. Work in this field accelerated following approval of a psychiatric application (depression), and it is now expanding to other applications and disciplines. In the last decade, experimental enquiry has sought new ways to improve the therapeutic benefits of rTMS, intended to enhance underlying brain reorganization and functional recovery by combining it with behavioral therapy. This concept is appealing, but poorly defined and requires clarity. We provide an overview of how combined rTMS and behavioral therapy has been delineated in the literature, highlighting the diversity of approaches. We outline a framework for study design and reporting such that the effects of this emerging method can be better understood. PMID:27895557

  19. Antifungal therapy for patients with proven or suspected Candida peritonitis: Amarcand2, a prospective cohort study in French intensive care units.

    PubMed

    Montravers, P; Perrigault, P F; Timsit, J F; Mira, J P; Lortholary, O; Leroy, O; Gangneux, J P; Guillemot, D; Bensoussan, C; Bailly, S; Azoulay, E; Constantin, J M; Dupont, H

    2017-02-01

    The clinical characteristics and prognosis of patients treated for Candida peritonitis (CP) were compared according to the type of systemic antifungal therapy (SAT), empiric (EAF) or targeted (TAF) therapies, and the final diagnosis of infection. Patients in intensive care units (ICU) treated for CP were selected among the AmarCAND2 cohort, to compare patients receiving EAF for unconfirmed suspicion of CP (EAF/nonCP), to those with suspected secondarily confirmed CP (EAF/CP), or with primarily proven CP receiving TAF. In all, 279 patients were evaluated (43.4% EAF/nonCP, 29.7% EAF/CP and 25.8% TAF patients). At SAT initiation, the severity of illness was similar among EAF/nonCP and EAF/CP patients, lower among TAF patients (median Simplified Acute Physiology Score II (SAPS II) 49 and 51 versus 35, respectively; p 0.001). Candida albicans was involved in 67%, Candida glabrata in 15.6%. All strains were susceptible to echinocandin; 84% to fluconazole. Echinocandin was administered to 51.2% EAF/nonCP, 49% EAF/CP and 40% TAF patients. At day 28, 72%, 76% and 75% of EAF/nonCP, EAF/CP and TAF patients, respectively, were alive. An increased mortality was observed in patients with a Sequential Organ Failure Assessment (SOFA) score <7 if SAT was delayed by ≥6 days (p 0.04). Healthcare-associated CP (OR 3.82, 95% CI 1.52-9.64, p 0.004), SOFA ≥8 at ICU admission (OR 2.61, 95% CI 1.08-6.34; p 0.03), and SAPS II ≥45 at SAT initiation (OR 5.08, 95% CI 1.04-12.67; p 0.001) impacted the 28-day mortality. In summary, only 56.6% of ICU patients receiving SAT had CP. Most strains were susceptible to SAT. A similar 28-day mortality rate was observed among groups; the late administration of SAT significantly worsened the prognosis of patients with less severe CP. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  20. 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

  1. Pancreatic cancer: systemic combination therapies for a heterogeneous disease.

    PubMed

    Melisi, Davide; Calvetti, Lorenzo; Frizziero, Melissa; Tortora, Giampaolo

    2014-01-01

    Pancreatic cancer is the only human malignancy for which patients' survival has not improved substantially during the past 30 years. Despite advances in the comprehension of the molecular mechanisms underlying pancreatic carcinogenesis, current systemic treatments offer only a modest benefit in tumor-related symptoms and survival. Over the past decades, gemcitabine and its combination with other standard cytotoxic agents have been the reference treatments for advanced pancreatic cancer patients. The recent introduction of the three-drug combination regimen FOLFIRINOX or the new taxane nab-paclitaxel represent key advances for a better control of the disease. Novel agents targeting molecular mechanisms involved in cancer development and maintenance are currently under clinical investigation. This review describes the most important findings in the field of systemic combination therapies for the treatment of pancreatic cancer. We discuss the emerging evidences for the clinical activity of combination treatments with standard chemotherapy plus novel agents targeting tumor cell-autonomous and tumor microenvironment signaling pathways. We present some of the most important advances in the comprehension of the molecular mechanisms responsible for the chemoresistance of pancreatic cancer and the emerging therapeutic targets to overcome this resistance.

  2. Docetaxel combined with targeted therapies in metastatic breast cancer.

    PubMed

    Cortes, Javier; Roché, Henri

    2012-08-01

    The treatment of metastatic breast cancer (MBC) is essentially palliative and should be based on hormone therapy or optimized chemotherapy designed to delay disease progression and maximize survival with good quality of life. Novel chemotherapeutic agents introduced in the 1990 s include the taxanes (notably docetaxel), which are among the most potent of current anticancer drugs. Current research is also focusing on molecular targeted agents including those against the HER family of transmembrane receptors and vascular endothelial growth factor. Optimal effects are obtained when these compounds are used in combination with chemotherapy, as shown in preclinical models and more recently in clinical trials. Results of a large randomized trial have demonstrated a significant survival advantage for trastuzumab plus docetaxel compared with docetaxel monotherapy. Docetaxel plus bevacizumab combinations have recently been shown to significantly improve progression-free survival and objective response rate compared with docetaxel monotherapy. Overall, docetaxel in combination with novel targeted agents in MBC appears to be highly active in patients with MBC, and such combinations represent promising treatment regimens for clinical investigation. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. 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

  4. 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.

  5. Antifungal nanoparticles and surfaces.

    PubMed

    Paulo, Cristiana S O; Vidal, Maria; Ferreira, Lino S

    2010-10-11

    Nosocomial fungal infections, an increasing healthcare concern worldwide, are often associated with medical devices. We have developed antifungal nanoparticle conjugates that can act in suspension or attach to a surface, efficiently killing fungi. For that purpose, we immobilized covalently amphotericin B (AmB), a potent antifungal agent approved by the FDA, widely used in clinical practice and effective against a large spectrum of fungi, into silica nanoparticles. These antifungal nanoparticle conjugates are fungicidal against several strains of Candida sp., mainly by contact. In addition, they can be reused up to 5 cycles without losing their activity. Our results show that the antifungal nanoparticle conjugates are more fungistatic and fungicidal than 10 nm colloidal silver. The antifungal activity of the antifungal nanoparticle conjugates is maintained when they are immobilized on a surface using a chemical adhesive formed by polydopamine. The antifungal nanocoatings have no hemolytic or cytotoxic effect against red blood cells and blood mononuclear cells, respectively. Surfaces coated with these antifungal nanoparticle conjugates can be very useful to render medical devices with antifungal properties.

  6. Epidemiology and Outcomes of Invasive Candidiasis Due to Non-albicans Species of Candida in 2,496 Patients: Data from the Prospective Antifungal Therapy (PATH) Registry 2004–2008

    PubMed Central

    Pfaller, Michael A.; Andes, David R.; Diekema, Daniel J.; Horn, David L.; Reboli, Annette C.; Rotstein, Coleman; Franks, Billy; Azie, Nkechi E.

    2014-01-01

    This analysis describes the epidemiology and outcomes of invasive candidiasis caused by non-albicans species of Candida in patients enrolled in the Prospective Antifungal Therapy Alliance (PATH Alliance) registry from 2004 to 2008. A total of 2,496 patients with non-albicans species of Candida isolates were identified. The identified species were C. glabrata (46.4%), C. parapsilosis (24.7%), C. tropicalis (13.9%), C. krusei (5.5%), C. lusitaniae (1.6%), C. dubliniensis (1.5%) and C. guilliermondii (0.4%); 111 infections involved two or more species of Candida (4.4%). Non-albicans species accounted for more than 50% of all cases of invasive candidiasis in 15 of the 24 sites (62.5%) that contributed more than one case to the survey. Among solid organ transplant recipients, patients with non-transplant surgery, and patients with solid tumors, the most prevalent non-albicans species was C. glabrata at 63.7%, 48.0%, and 53.8%, respectively. In 1,883 patients receiving antifungal therapy on day 3, fluconazole (30.5%) and echinocandins (47.5%) were the most frequently administered monotherapies. Among the 15 reported species, 90-day survival was highest for patients infected with either C. parapsilosis (70.7%) or C. lusitaniae (74.5%) and lowest for patients infected with an unknown species (46.7%) or two or more species (53.2%). In conclusion, this study expands the current knowledge of the epidemiology and outcomes of invasive candidiasis caused by non-albicans species of Candida in North America. The variability in species distribution in these centers underscores the importance of local epidemiology in guiding the selection of antifungal therapy. PMID:24991967

  7. Epidemiology and outcomes of invasive candidiasis due to non-albicans species of Candida in 2,496 patients: data from the Prospective Antifungal Therapy (PATH) registry 2004-2008.

    PubMed

    Pfaller, Michael A; Andes, David R; Diekema, Daniel J; Horn, David L; Reboli, Annette C; Rotstein, Coleman; Franks, Billy; Azie, Nkechi E

    2014-01-01

    This analysis describes the epidemiology and outcomes of invasive candidiasis caused by non-albicans species of Candida in patients enrolled in the Prospective Antifungal Therapy Alliance (PATH Alliance) registry from 2004 to 2008. A total of 2,496 patients with non-albicans species of Candida isolates were identified. The identified species were C. glabrata (46.4%), C. parapsilosis (24.7%), C. tropicalis (13.9%), C. krusei (5.5%), C. lusitaniae (1.6%), C. dubliniensis (1.5%) and C. guilliermondii (0.4%); 111 infections involved two or more species of Candida (4.4%). Non-albicans species accounted for more than 50% of all cases of invasive candidiasis in 15 of the 24 sites (62.5%) that contributed more than one case to the survey. Among solid organ transplant recipients, patients with non-transplant surgery, and patients with solid tumors, the most prevalent non-albicans species was C. glabrata at 63.7%, 48.0%, and 53.8%, respectively. In 1,883 patients receiving antifungal therapy on day 3, fluconazole (30.5%) and echinocandins (47.5%) were the most frequently administered monotherapies. Among the 15 reported species, 90-day survival was highest for patients infected with either C. parapsilosis (70.7%) or C. lusitaniae (74.5%) and lowest for patients infected with an unknown species (46.7%) or two or more species (53.2%). In conclusion, this study expands the current knowledge of the epidemiology and outcomes of invasive candidiasis caused by non-albicans species of Candida in North America. The variability in species distribution in these centers underscores the importance of local epidemiology in guiding the selection of antifungal therapy.

  8. Effects of combination lipid therapy in type 2 diabetes mellitus.

    PubMed

    Ginsberg, Henry N; Elam, Marshall B; Lovato, Laura C; Crouse, John R; Leiter, Lawrence A; Linz, Peter; Friedewald, William T; Buse, John B; Gerstein, Hertzel C; Probstfield, Jeffrey; Grimm, Richard H; Ismail-Beigi, Faramarz; Bigger, J Thomas; Goff, David C; Cushman, William C; Simons-Morton, Denise G; Byington, Robert P

    2010-04-29

    We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease. We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P=0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P=0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P=0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P=0.057 for interaction). The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.) 2010 Massachusetts Medical Society

  9. 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

  10. 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.

  11. Antifungal polypeptides

    DOEpatents

    Altier, Daniel J [Granger, IA; Dahlbacka, Glen [Oakland, CA; Ellanskaya, Irina [Kyiv, UA; Ellanskaya, legal representative, Natalia; Herrmann, Rafael [Wilmington, DE; Hunter-Cevera, Jennie [Elliott City, MD; McCutchen, Billy F [College Station, TX; Presnail, James K [Avondale, PA; Rice, Janet A [Wilmington, DE; Schepers, Eric [Port Deposit, MD; Simmons, Carl R [Des Moines, IA; Torok, Tamas [Richmond, CA; Yalpani, Nasser [Johnston, IA

    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.

  12. 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.

  13. Antifungal polypeptides

    DOEpatents

    Altier, Daniel J [Waukee, IA; Dahlbacka, Glen [Oakland, CA; Elleskaya, Irina [Kyiv, UA; Ellanskaya, legal representative, Natalia; Herrmann, Rafael [Wilmington, DE; Hunter-Cevera, Jennie [Elliott City, MD; McCutchen, Billy F [College Station, IA; Presnail, James K [Avondale, PA; Rice, Janet A [Wilmington, DE; Schepers, Eric [Port Deposit, MD; Simmons, Carl R [Des Moines, IA; Torok, Tamas [Richmond, CA; Yalpani, Nasser [Johnston, IA

    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.

  14. 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

  15. Gene therapy for brain cancer: combination therapies provide enhanced efficacy and safety.

    PubMed

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

    2009-10-01

    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.

  16. Combinational therapy of crizotinib and afatinib for malignant pleural mesothelioma

    PubMed Central

    Huang, Liyan; Cai, Muyan; Zhang, Xu; Wang, Fang; Chen, Likun; Xu, Meng; Yang, Ke; Chen, Zhen; Wang, Xiaokun; Fu, Liwu

    2017-01-01

    Malignant pleural mesothelioma (MPM) is a relative rare but highly aggressive neoplasm which is associated with asbestos exposure in most patients. The majority of patients are diagnosed in advanced stages so patients neither benefit from chemotherapy (e.g. pemetrexed-platinum combination) nor from surgery. It has been reported that cellular-mesenchymal to epithelial transition factor (MET) and epidermal growth factor receptor (EGFR) were critical for MPM cell proliferation. Moreover, targeting MET and EGFR drugs have gained promising results on anti-tumor therapy. Here, a striking difference in overall survival was observed between the MET and EGFR co-expression group (median survival time = 13.5 months) and non-co-expression group (median survival time = 20.5 months). In addition, treatment with combination of crizotinib and afatinib showed stronger inhibition on cell proliferation of MPM than the treatment by either one in vitro and in vivo. In conclusion, our data illustrated that crizotinib combined with afatinib may be a potentially effective strategy for treating MPM patients with over-expression of MET and EGFR. PMID:28337371

  17. 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.

  18. Chemogenomic profiling predicts antifungal synergies

    PubMed Central

    Jansen, Gregor; Lee, Anna Y; Epp, Elias; Fredette, Amélie; Surprenant, Jamie; Harcus, Doreen; Scott, Michelle; Tan, Elaine; Nishimura, Tamiko; Whiteway, Malcolm; Hallett, Michael; Thomas, David Y

    2009-01-01

    Chemotherapies, HIV infections, and treatments to block organ transplant rejection are creating a population of immunocompromised individuals at serious risk of systemic fungal infections. Since single-agent therapies are susceptible to failure due to either inherent or acquired resistance, alternative therapeutic approaches such as multi-agent therapies are needed. We have developed a bioinformatics-driven approach that efficiently predicts compound synergy for such combinatorial therapies. The approach uses chemogenomic profiles in order to identify compound profiles that have a statistically significant degree of similarity to a fluconazole profile. The compounds identified were then experimentally verified to be synergistic with fluconazole and with each other, in both Saccharomyces cerevisiae and the fungal pathogen Candida albicans. Our method is therefore capable of accurately predicting compound synergy to aid the development of combinatorial antifungal therapies. PMID:20029371

  19. The pyrazinamide susceptibility breakpoint above which combination therapy fails

    PubMed Central

    Gumbo, Tawanda; Chigutsa, Emmanuel; Pasipanodya, Jotam; Visser, Marianne; van Helden, Paul D.; Sirgel, Frederick A; McIlleron, Helen

    2014-01-01

    Objectives To identify the pyrazinamide MIC above which standard combination therapy fails. Methods MICs of pyrazinamide were determined for Mycobacterium tuberculosis isolates, cultured from 58 patients in a previous randomized clinical trial in Cape Town, South Africa. The MICs were determined using BACTEC MGIT 960 for isolates that were collected before standard treatment with isoniazid, rifampicin, pyrazinamide and ethambutol commenced. Weekly sputum collections were subsequently made for 8 weeks in order to culture M. tuberculosis in Middlebrook broth medium. Classification and regression tree (CART) analysis was utilized to identify the pyrazinamide MIC predictive of sputum culture results at the end of pyrazinamide therapy. The machine learning-derived susceptibility breakpoints were then confirmed using standard association statistics that took into account confounders of 2 month sputum conversion. Results The pyrazinamide MIC range was 12.5 to >100 mg/L for the isolates prior to therapy. The epidemiological 95% cut-off value was >100 mg/L. The 2 month sputum conversion rate in liquid cultures was 26% by stringent criteria and 48% by less stringent criteria. CART analysis identified an MIC breakpoint of 50 mg/L, above which patients had poor sputum conversion rates. The relative risk of poor sputum conversion was 1.5 (95% CI: 1.2–1.8) for an MIC >50 mg/L compared with an MIC ≤50 mg/L. Conclusions We propose a pyrazinamide susceptibility breakpoint of 50 mg/L for clinical decision making and for development of rapid susceptibility assays. This breakpoint is identical to that identified using computer-aided simulations of hollow fibre system output. PMID:24821594

  20. 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

  1. Early Combination Antiretroviral Therapy Limits HIV-1 Persistence in Children.

    PubMed

    Luzuriaga, Katherine

    2016-01-01

    Globally, 240,000 infants are newly infected with HIV-1 each year and 3.2 million children are living with the infection. Combination antiretroviral therapy (cART) has reduced HIV-1-related disease and mortality in children but is not curative owing to the early generation of a latent reservoir of long-lived memory CD4(+) T cells bearing replication-competent HIV-1 provirus integrated into cellular DNA. This review focuses on recent advances in our understanding of the establishment of HIV-1 persistence in children and how early initiation of cART in the setting of the developing infant immune system limits the formation of the long-lived latent CD4(+) cell reservoir that remains a barrier to remission or cure.

  2. Combination bacteriolytic therapy for the treatment of experimental tumors

    PubMed Central

    Dang, Long H.; Bettegowda, Chetan; Huso, David L.; Kinzler, Kenneth W.; Vogelstein, Bert

    2001-01-01

    Current chemotherapeutic approaches for cancer are in part limited by the inability of drugs to destroy neoplastic cells within poorly vascularized compartments of tumors. We have here systematically assessed anaerobic bacteria for their capacity to grow expansively within avascular compartments of transplanted tumors. Among 26 different strains tested, one (Clostridium novyi) appeared particularly promising. We created a strain of C. novyi devoid of its lethal toxin (C. novyi-NT) and showed that intravenously injected C. novyi-NT spores germinated within the avascular regions of tumors in mice and destroyed surrounding viable tumor cells. When C. novyi-NT spores were administered together with conventional chemotherapeutic drugs, extensive hemorrhagic necrosis of tumors often developed within 24 h, resulting in significant and prolonged antitumor effects. This strategy, called combination bacteriolytic therapy (COBALT), has the potential to add a new dimension to the treatment of cancer. PMID:11724950

  3. Combining Immunotherapy and Targeted Therapies in Cancer Treatment

    PubMed Central

    Vanneman, Matthew; Dranoff, Glenn

    2014-01-01

    Preface During the past two decades, the paradigm for cancer treatment has evolved from relatively non-specific cytotoxic agents to selective, mechanism-based therapeutics. Cancer chemotherapies were initially identified through screens for compounds that killed rapidly dividing cells. These drugs remain a backbone of current treatment, but are limited by a narrow therapeutic index, significant toxicities, and frequently acquired resistance. More recently, an improved understanding of cancer pathogenesis has given rise to new treatment options, including targeted agents and cancer immunotherapy. Targeted approaches aim to inhibit molecular pathways that are critical to tumor growth and maintenance, whereas immunotherapy endeavors to stimulate a host response that effectuates long-lived tumor destruction. Targeted therapies and cytotoxic agents also modulate immune responses, which raises the possibility that these treatment strategies might be effectively combined with immunotherapy to improve clinical outcomes. PMID:22437869

  4. Nosocomial Candidiasis: Antifungal Stewardship and the Importance of Rapid Diagnosis.

    PubMed

    Pfaller, Michael A; Castanheira, Mariana

    2016-01-01

    Candidemia and other forms of candidiasis are associated with considerable excess mortality and costs. Despite the addition of several new antifungal agents with improved spectrum and potency, the frequency of Candida infection and associated mortality have not decreased in the past two decades. The lack of rapid and sensitive diagnostic tests has led to considerable overuse of antifungal agents resulting in increased costs, selection pressure for resistance, unnecessary drug toxicity, and adverse drug interactions. Both the lack of timely diagnostic tests and emergence of antifungal resistance pose considerable problems for antifungal stewardship. Whereas antifungal stewardship with a focus on nosocomial candidiasis should be able to improve the administration of antifungal therapy in terms of drug selection, proper dose and duration, source control and de-escalation therapy, an important parameter, timeliness of antifungal therapy, remains a victim of slow and insensitive diagnostic tests. Fortunately, new proteomic and molecular diagnostic tools are improving the time to species identification and detection. In this review we will describe the potential impact that rapid diagnostic testing and antifungal stewardship can have on the management of nosocomial candidiasis.

  5. Combined intravitreal bevacizumab and photodynamic therapy for retinal angiomatous proliferation.

    PubMed

    Saito, Masaaki; Shiragami, Chieko; Shiraga, Fumio; Nagayama, Dai; Iida, Tomohiro

    2008-12-01

    To clarify the efficiency of combined therapy with intravitreal bevacizumab injections and photodynamic therapy (PDT) in patients with retinal angiomatous proliferation (RAP). Retrospective, observational, consecutive case series. We retrospectively reviewed 11 consecutive eyes with RAP (10 patients; six men, four women) treated with intravitreal bevacizumab injection and PDT. Patients ranged in age from 63 to 89 years old (average, 79 years). No patients had undergone previous treatment, and patients were followed for at least six months. PDT was applied one or two days after the intravitreal bevacizumab (1.25 mg) injection. The mean best-corrected visual acuity (BCVA) levels at baseline and one, three, and six months after treatment were 0.16, 0.27, 0.31, and 0.29, respectively. A significant improvement in the mean BCVA was observed one, three, and six months after intravitreal bevacizumab injection and PDT (P < .01). The mean improvement in BCVA six months from baseline was 2.64 lines. The BCVA at six months improved in six eyes (54.5%, improved by three lines or more) and was stable in five eyes (45.5%). No patient had a decrease in the BCVA of three or more lines during any six months. The central retinal thickness significantly decreased from 496 +/- 189 microm to 175 +/- 33 microm at six months (P < .001). No patients required retreatment during any six months. No complications such as severe vision loss, endophthalmitis, or systemic events developed. Combined intravitreal bevacizumab and PDT for RAP effectively maintained or improved VA and reduced or eliminated edema in the short-term.

  6. Combination Therapy with Lenalidomide and Nanoceria Ameliorates CNS Autoimmunity

    PubMed Central

    Eitan, Erez; Hutchison, Emmette R.; Greig, Nigel H.; Tweedie, David; Celik, Hasan; Ghosh, Soumita; Fishbein, Kenneth W.; Spencer, Richard G.; Sasaki, Carl Y.; Ghosh, Paritosh; Das, Soumen; Chigurapati, Susheela; Raymick, James; Sarkar, Sumit; Chigurupati, Srinivasulu; Seal, Sudipta; Mattson, Mark P.

    2015-01-01

    Objective Multiple sclerosis (MS) is a debilitating neurological disorder involving an autoimmune reaction to oligodendrocytes and degeneration of the axons they ensheath in the CNS. Because the damage to oligodendrocytes and axons involves local inflammation and associated oxidative stress, we tested the therapeutic efficacy of combined treatment with a potent anti-inflammatory thalidomide analog (lenalidomide) and novel synthetic anti-oxidant cerium oxide nanoparticles (nanoceria) in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Methods C57BL/6 mice were randomly assigned to a control (no EAE) group, or one of four myelin oligodendrocyte glycoprotein-induced EAE groups: vehicle, lenalidomide, nanoceria, or lenalidomide plus nanoceria. During a 23 day period, clinical EAE symptoms were evaluated daily, and MRI brain scans were performed at 11-13 days and 20-22 days. Histological and biochemical analyses of brain tissue samples were performed to quantify myelin loss and local inflammation. Results Lenalidomide treatment alone delayed symptom onset, while nanoceria treatment had no effect on symptom onset or severity, but did promote recovery; lenalidomide and nanoceria each significantly attenuated white matter pathology and associated inflammation. Combined treatment with lenalidomide and nanoceria resulted in a near elimination of EAE symptoms, and reduced white matter pathology and inflammatory cell responses to a much greater extent than either treatment alone. Interpretation By suppressing inflammation and oxidative stress, combined treatment with lenalidomide and nanoceria can reduce demyelination and associated neurological symptoms in EAE mice. Our preclinical data suggest a potential application of this combination therapy in MS. PMID:26277686

  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. Defensins: antifungal lessons from eukaryotes.

    PubMed

    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.

  9. 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

  10. 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.

  11. X-Ray Induced Photodynamic Therapy: A Combination of Radiotherapy and Photodynamic Therapy

    PubMed Central

    Wang, Geoffrey D.; Nguyen, Ha T.; Chen, Hongmin; Cox, Phillip B.; Wang, Lianchun; Nagata, Koichi; Hao, Zhonglin; Wang, Andrew; Li, Zibo; Xie, Jin

    2016-01-01

    Conventional photodynamic therapy (PDT)'s clinical application is limited by depth of penetration by light. To address the issue, we have recently developed X-ray induced photodynamic therapy (X-PDT) which utilizes X-ray as an energy source to activate a PDT process. In addition to breaking the shallow tissue penetration dogma, our studies found more efficient tumor cell killing with X-PDT than with radiotherapy (RT) alone. The mechanisms behind the cytotoxicity, however, have not been elucidated. In the present study, we investigate the mechanisms of action of X-PDT on cancer cells. Our results demonstrate that X-PDT is more than just a PDT derivative but is essentially a PDT and RT combination. The two modalities target different cellular components (cell membrane and DNA, respectively), leading to enhanced therapy effects. As a result, X-PDT not only reduces short-term viability of cancer cells but also their clonogenecity in the long-run. From this perspective, X-PDT can also be viewed as a unique radiosensitizing method, and as such it affords clear advantages over RT in tumor therapy, especially for radioresistant cells. This is demonstrated not only in vitro but also in vivo with H1299 tumors that were either subcutaneously inoculated or implanted into the lung of mice. These findings and advances are of great importance to the developments of X-PDT as a novel treatment modality against cancer. PMID:27877235

  12. Therapy of Severe Heatshock in Combination With Multiple Organ Dysfunction With Continuous Renal Replacement Therapy

    PubMed Central

    Chen, Guang-Ming; Chen, Yang-Hong; Zhang, Wei; Yu, Yi; Chen, Jin-Hua; Chen, Jian

    2015-01-01

    Abstract This study aimed to compare the clinical effects of continuous renal replacement therapy (CRRT) and routine therapy in heatshock (HS) patients. We retrospectively reviewed the clinical information of 33 severe exertional HS patients who were treated from February 1998 to October 2013. On the basis of whether or not CRRT therapy was used in addition to conventional therapy, patients were divided into a CRRT group (n = 15) and a control group (n = 18). Body temperature, blood gas analysis, routine blood tests, blood eletrolytes, enzymes and kidney function data, and APACHE II scores were obtained and compared between the 2 groups on admission and 3, 5, and 7 days after admission. Mortality was also compared between the 2 groups. CRRT treatment combined with conventional treatment resulted in a higher hospital-discharge rate, a faster return to normal of body temperature, greater increase in platelets, a greater decrease in WBC, neutrophils, and serum markers for liver and kidney dysfunction, greater improvement of organ dysfunction, and lower APACHE II scores than conventional treatment used alone. The addition of CRRT to conventional treatment for HS improves survival and causes a faster return to normal of serum markers and organ function. PMID:26252279

  13. Combining Mindfulness Meditation with Cognitive-Behavior Therapy for Insomnia

    PubMed Central

    Ong, Jason C.; Shapiro, Shauna L.; Manber, Rachel

    2009-01-01

    This treatment-development study is a Stage I evaluation of an intervention that combines mindfulness meditation with cognitive-behavior therapy for insomnia (CBT-I). Thirty adults who met research diagnostic criteria for Psychophysiological Insomnia (Edinger et al., 2004) participated in a 6-week, multi-component group intervention using mindfulness meditation, sleep restriction, stimulus control, sleep education, and sleep hygiene. Sleep diaries and self-reported pre-sleep arousal were assessed weekly while secondary measures of insomnia severity, arousal, mindfulness skills, and daytime functioning were assessed at pre-treatment and post-treatment. Data collected on recruitment, retention, compliance, and satisfaction indicate that the treatment protocol is feasible to deliver and is acceptable for individuals seeking treatment for insomnia. The overall patterns of change with treatment demonstrated statistically and clinically significant improvements in several nighttime symptoms of insomnia as well as statistically significant reductions in pre-sleep arousal, sleep effort, and dysfunctional sleep-related cognitions. In addition, a significant correlation was found between the number of meditation sessions and changes on a trait measure of arousal. Together, the findings indicate that mindfulness meditation can be combined with CBT-I and this integrated intervention is associated with reductions in both sleep and sleep-related arousal. Further testing of this intervention using randomized controlled trials is warranted to evaluate the efficacy of the intervention for this population and the specific effects of each component on sleep and both psychological and physiological arousal. PMID:18502250

  14. 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

  15. Quantifying the pharmacology of antimalarial drug combination therapy

    PubMed Central

    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

  16. Combination therapy with conditionally replicating adenovirus and replication defective adenovirus.

    PubMed

    Lee, Choon-Taek; Park, Kyung-Ho; Yanagisawa, Kiyoshi; Adachi, Yasushi; Ohm, Joyce E; Nadaf, Sorena; Dikov, Mikhail M; Curiel, David T; Carbone, David P

    2004-09-15

    Low gene transfer rate is the most substantial hurdle in the practical application of gene therapy. One strategy to improve transfer efficiency is the use of a conditionally replicating adenovirus (CRAD) that can selectively replicate in tumor cells. We hypothesized that conventional E1-deleted adenoviruses (ad) can become replication-competent when cotransduced with a CRAD to selectively supply E1 in trans in tumors. The resulting selective production of large numbers of the E1-deleted ad within the tumor mass will increase the transduction efficiency. We used a CRAD (Delta24RGD) that produces a mutant E1 without the ability to bind retinoblastoma but retaining viral replication competence in cancer cells with a defective pRb/p16. Ad-lacZ, adenovirus-luciferase (ad-luc), and adenovirus insulin-like growth factor-1R/dominant-negative (ad-IGF-1R/dn; 482, 950) are E1-deleted replication-defective adenoviruses. The combination of CRAD and ad-lacZ increased the transduction efficiency of lacZ to 100% from 15% observed with ad-lacZ alone. Transfer of media of CRAD and ad-lacZ cotransduced cells induced the transfer of lacZ (media transferable bystander effect). Combination of CRAD and ad-IGF-1R/dn increased the production of truncated IGF-1R or soluble IGF-1R > 10 times compared with transduction with ad-IGF-1R/dn alone. Combined intratumoral injection of CRAD and ad-luc increased the luciferase expression about 70 times compared with ad-luc alone without substantial systemic spread. Combined intratumoral injection of CRAD and ad-IGF-1R/482 induced stronger growth suppression of established lung cancer xenografts than single injections. The combination of CRAD and E1-deleted ad induced tumor-specific replication of CRAD and E1-deleted ad and increased the transduction rate and therapeutic efficacy of these viruses in model tumors.

  17. Fixed combination therapy of hypertension: focus on valsartan/hydrochlorothiazide combination (Diovan/HCT).

    PubMed

    Chrysant, Steven G

    2003-09-01

    Hypertension is a major risk factor for cardiovascular morbidity and mortality. Monotherapy of hypertension is often ineffective, since it controls approximately 50% of the blood pressure of hypertensive patients. For lowering blood pressure to less than 140/90 mmHg (or <130/80 mmHg among people with diabetes or chronic renal disease) according to JNC-7 guidelines, combination therapy of two or more drugs is often necessary. The combination of a diuretic with an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) is effective and provides the additional benefit of blocking the effects of angiotensin II, which is responsible for cardiovascular remodeling and its complications. ARBs may have an advantage over the ACEIs because they block the action of all angiotensin II directly, whereas ACEIs are ineffective in blocking angiotensin II generated by nonclassical ACE pathways. Valsartan (Diovan, Novartis) is one of the seven currently approved ARBs in the USA for the treatment of hypertension, and it has been shown to be very effective in controlling blood pressure given once-daily in doses of 80-160 or 320 mg. Its fixed combination with hydrochlorothiazide (HCT) is even more effective in controlling blood pressure in 70% of the cases. The most commonly used combinations are valsartan/HCT (Diovan/HCT), 80/12.5 and 160/12.5 mg given once-daily.

  18. Combine and conquer: challenges for targeted therapy combinations in early phase trials.

    PubMed

    Lopez, Juanita S; Banerji, Udai

    2017-01-01

    Our increasing understanding of cancer biology has led to the development of molecularly targeted anticancer drugs. The full potential of these agents has not, however, been realised, owing to the presence of de novo (intrinsic) resistance, often resulting from compensatory signalling pathways, or the development of acquired resistance in cancer cells via clonal evolution under the selective pressures of treatment. Combinations of targeted treatments can circumvent some mechanisms of resistance to yield a clinical benefit. We explore the challenges in identifying the best drug combinations and the best combination strategies, as well as the complexities of delivering these treatments to patients. Recognizing treatment-induced toxicity and the inability to use continuous pharmacodynamically effective doses of many targeted treatments necessitates creative intermittent scheduling. Serial tumour profiling and the use of parallel co-clinical trials can contribute to understanding mechanisms of resistance, and will guide the development of adaptive clinical trial designs that can accommodate hypothesis testing, in order to realize the full potential of combination therapies.

  19. The Antifungal Activity of Lactoferrin and Its Derived Peptides: Mechanisms of Action and Synergy with Drugs against Fungal Pathogens

    PubMed Central

    Fernandes, Kenya E.; Carter, Dee A.

    2017-01-01

    Lactoferrin is a multifunctional iron-binding glycoprotein belonging to the transferrin family. It is found abundantly in milk and is present as a major protein in human exocrine secretions where it plays a role in the innate immune response. Various antifungal functions of lactoferrin have been reported including a wide spectrum of activity across yeasts and molds and synergy with other antifungal drugs in combination therapy, and various modes of action have been proposed. Bioactive peptides derived from lactoferrin can also exhibit strong antifungal activity, with some surpassing the potency of the whole protein. This paper reviews current knowledge of the spectrum of activity, proposed mechanisms of action, and capacity for synergy of lactoferrin and its peptides, including the three most studied derivatives: lactoferricin, lactoferrampin, and Lf(1–11), as well as some lactoferrin-derived variants and modified peptides. PMID:28149293

  20. The Antifungal Activity of Lactoferrin and Its Derived Peptides: Mechanisms of Action and Synergy with Drugs against Fungal Pathogens.

    PubMed

    Fernandes, Kenya E; Carter, Dee A

    2017-01-01

    Lactoferrin is a multifunctional iron-binding glycoprotein belonging to the transferrin family. It is found abundantly in milk and is present as a major protein in human exocrine secretions where it plays a role in the innate immune response. Various antifungal functions of lactoferrin have been reported including a wide spectrum of activity across yeasts and molds and synergy with other antifungal drugs in combination therapy, and various modes of action have been proposed. Bioactive peptides derived from lactoferrin can also exhibit strong antifungal activity, with some surpassing the potency of the whole protein. This paper reviews current knowledge of the spectrum of activity, proposed mechanisms of action, and capacity for synergy of lactoferrin and its peptides, including the three most studied derivatives: lactoferricin, lactoferrampin, and Lf(1-11), as well as some lactoferrin-derived variants and modified peptides.

  1. 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.

  2. 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

  3. Correlating HIV tropism with immunological response under combination antiretroviral therapy.

    PubMed

    Bader, J; Schöni-Affolter, F; Böni, J; Gorgievski-Hrisoho, M; Martinetti, G; Battegay, M; Klimkait, T

    2016-09-01

    A significant percentage of patients infected with HIV-1 experience only suboptimal CD4 cell recovery while treated with combination therapy (cART). It is still unclear whether viral properties such as cell tropism play a major role in this incomplete immune response. This study therefore intended to follow the tropism evolution of the HIV-1 envelope during periods of suppressive cART. Viruses from two distinct patient groups, one with good and another one with poor CD4 recovery after 5 years of suppressive cART, were genotypically analysed for viral tropism at baseline and at the end of the study period. Patients with CCR5-tropic CC-motif chemokine receptor 5 viruses at baseline tended to maintain this tropism to the study end. Patients who had a CXCR4-tropic CXC-motif chemokine receptor 4 virus at baseline were overrepresented in the poor CD4 recovery group. Overall, however, the majority of patients presented with CCR5-tropic viruses at follow-up. Our data lend support to the hypothesis that tropism determination can be used as a parameter for disease progression even if analysed long before the establishment of a poorer immune response. Moreover, the lasting predominating CCR5-tropism during periods of full viral control suggests the involvement of cellular mechanisms that preferentially reduce CXCR4-tropic viruses during cART. © 2016 British HIV Association.

  4. 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

  5. [Combined treatment of palmoplantar syndrome in patients under antitumor therapy].

    PubMed

    Kruglova, L S; Shatokhina, E A; Elfimov, M A; Illarionov, V E; Chervinskaya, A V; Portnov, V V; Filatova, E V; Petrova, M S

    2016-01-01

    Observation covered 12 patients under various antitumor medications. Group 1 was formed of patients with developed palmoplantar syndrome varying in severity, who received complex treatment including IR-therapy and local antioxidant medication. Group 2 included patients without palmoplantar syndrome, who received preventive treatment with IR-therapy. All patients of group 1 demonstrated lower severity of palmoplantar syndrome manifestations. In group 2, 80% of the patients avoided palmoplantar syndrome development, and 20% of the patients had light course of the syndrome manifestations. Patients at high risk of palmoplantar syndrome under antitumor therapy are recommended to undergo IR-therapy and local antioxidant medication.

  6. Antifungal compounds from cyanobacteria.

    PubMed

    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

    2015-04-13

    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.

  7. Life expectancy after initiation of combination antiretroviral therapy in Thailand.

    PubMed

    Teeraananchai, Sirinya; Chaivooth, Suchada; Kerr, Stephen J; Bhakeecheep, Sorakij; Avihingsanon, Anchalee; Teeraratkul, Achara; Sirinirund, Petchsri; Law, Matthew G; Ruxrungtham, Kiat

    2017-01-05

    Access to combination antiretroviral therapy (cART) has decreased mortality in HIV-positive people. We aimed to estimate the expected additional years of life in HIV-positive Thai people after starting cART through the National AIDS Program (NAP), administered by the Thai National Health Security Office (NHSO). The NHSO database collects characteristics of all Thai HIV-infected patients through the National AIDS Program, including linkage with the National Death Registry for vital status. This study included patients aged ≥15 years at cART initiation between 2008 and 2014. The abridged life table method was used to construct life tables stratified by sex and baseline CD4(+) T-cell count. Life expectancy was defined as the additional years of life from age at starting cART. 201,688 eligible patients were included in analyses, contributing 618,837 person-years of follow-up. Median CD4(+) T-cell count was 109 cells/mm(3) and median age 37 years. The overall life expectancy after cART initiation at age 20 was 25.4 (95% CI, 25.3, 25.6) years and 20.6 (95% CI, 20.5, 20.7) at age 35 years. Life expectancy at baseline CD4(+) T-cell count ≥350 cells/mm(3) was 51.9 (95% CI, 51.0, 52.9) years for age 20 years and 43.2 (95% CI, 42.4, 44.1) years for age 35 years, close to life expectancy in the general Thai population. Increasing life expectancy with higher baseline CD4(+) T-cell counts supports the guideline recommendations to start cART irrespective of CD4(+) T-cell count. These results are beneficial to forecast the treatment cost and develop health policies for people living with HIV in Thailand and Asia.

  8. 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

  9. A Randomized Controlled Trial of Cognitive-Behavioral Therapy, Light Therapy, and Their Combination for Seasonal Affective Disorder

    ERIC Educational Resources Information Center

    Rohan, Kelly J.; Roecklein, Kathryn A.; Tierney Lindsey, Kathryn; Johnson, Leigh G.; Lippy, Robert D.; Lacy, Timothy J.; Barton, Franca B.

    2007-01-01

    This first controlled psychotherapy trial for seasonal affective disorder (SAD) compared SAD-tailored cognitive-behavioral therapy (CBT), light therapy (LT), and their combination to a concurrent wait-list control. Adults (N = 61) with major depression, recurrent with seasonal pattern, were randomized to one of four 6-week conditions: CBT (1.5-hr…

  10. A Randomized Controlled Trial of Cognitive-Behavioral Therapy, Light Therapy, and Their Combination for Seasonal Affective Disorder

    ERIC Educational Resources Information Center

    Rohan, Kelly J.; Roecklein, Kathryn A.; Tierney Lindsey, Kathryn; Johnson, Leigh G.; Lippy, Robert D.; Lacy, Timothy J.; Barton, Franca B.

    2007-01-01

    This first controlled psychotherapy trial for seasonal affective disorder (SAD) compared SAD-tailored cognitive-behavioral therapy (CBT), light therapy (LT), and their combination to a concurrent wait-list control. Adults (N = 61) with major depression, recurrent with seasonal pattern, were randomized to one of four 6-week conditions: CBT (1.5-hr…

  11. 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.

  12. 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.

  13. Autologous bone marrow-derived cell therapy combined with physical therapy induces functional improvement in chronic spinal cord injury patients.

    PubMed

    El-Kheir, Wael Abo; Gabr, Hala; Awad, Mohamed Reda; Ghannam, Osama; Barakat, Yousef; Farghali, Haithem A M A; El Maadawi, Zeinab M; Ewes, Ibrahim; Sabaawy, Hatem E

    2014-04-01

    Spinal cord injuries (SCI) cause sensory loss and motor paralysis. They are normally treated with physical therapy, but most patients fail to recover due to limited neural regeneration. Here we describe a strategy in which treatment with autologous adherent bone marrow cells is combined with physical therapy to improve motor and sensory functions in early stage chronic SCI patients. In a phase I/II controlled single-blind clinical trial (clinicaltrials.gov identifier: NCT00816803), 70 chronic cervical and thoracic SCI patients with injury durations of at least 12 months were treated with either intrathecal injection(s) of autologous adherent bone marrow cells combined with physical therapy or with physical therapy alone. Patients were evaluated with clinical and neurological examinations using the American Spinal Injury Association (ASIA) Impairment Scale (AIS), electrophysiological somatosensory-evoked potential, magnetic resonance imaging (MRI), and functional independence measurements. Chronic cervical and thoracic SCI patients (15 AIS A and 35 AIS B) treated with autologous adherent bone marrow cells combined with physical therapy showed functional improvements over patients in the control group (10 AIS A and 10 AIS B) treated with physical therapy alone, and there were no long-term cell therapy-related side effects. At 18 months posttreatment, 23 of the 50 cell therapy-treated cases (46%) showed sustained functional improvement. Compared to those patients with cervical injuries, a higher rate of functional improvement was achieved in thoracic SCI patients with shorter durations of injury and smaller cord lesions. Therefore, when combined with physical therapy, autologous adherent bone marrow cell therapy appears to be a safe and promising therapy for patients with chronic SCI of traumatic origin. Randomized controlled multicenter trials are warranted.

  14. [Acupuncture combined with catgut embedding therapy for treatment of 158 cases of facial paralysis].

    PubMed

    Li, Ling

    2005-03-01

    To observe therapeutic effect of acupuncture combined with catgut embedding therapy on peripheral facial paralysis. Treatment group of 158 cases were treated by acupuncture combined with catgut embedding therapy and control group of 54 cases were treated by acupuncture, and their therapeutic effects were compared. There was no significant difference in the total effective rate (P > 0.05), but the cured rate in the treatment group was significantly higher than that in the control group (P < 0.01). Acupuncture combined with catgut embedding therapy is a better therapy for facial paralysis.

  15. Combination therapy with caspofungin and liposomal amphotericin B for invasive aspergillosis.

    PubMed

    Elanjikal, Ziju; Sörensen, Jan; Schmidt, Helga; Dupuis, Wolfgang; Tintelnot, Kathrin; Jautzke, Günter; Klingebiel, Thomas; Lehrnbecher, Thomas

    2003-07-01

    Ina 24-month-old girl with acute lymphoblastic leukemia and invasive aspergillosis, only combination therapy with liposomal amphotericin B and caspofungin achieved a good response. Combination therapy could be a useful treatment option in children with invasive fungal disease, but before it can be routinely recommended, carefully controlled in vivo studies and well-designed randomized clinical trials are needed.

  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.

  18. Aldosterone breakthrough during aliskiren, valsartan, and combination (aliskiren + valsartan) therapy.

    PubMed

    Bomback, Andrew S; Rekhtman, Yelena; Klemmer, Philip J; Canetta, Pietro A; Radhakrishnan, Jai; Appel, Gerald B

    2012-01-01

    Aldosterone levels increase in 30%-40% of patients on angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers over the long term. This "aldosterone breakthrough" may carry important clinical consequences given aldosterone's nonepithelial, pro-fibrotic actions. The renin inhibitor, aliskiren, by suppressing the renin-angiotensin-aldosterone system (RAAS) proximally, may limit breakthrough compared to conventional RAAS blockade. This open-label study (NCT01129557) randomized subjects to aliskiren 300 mg daily (A), valsartan 320 mg daily (V), or aliskiren 150 mg + valsartan 160 mg daily (A+V) for 9 months. Eligible subjects had proteinuria >300 mg/day, estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m(2), and systolic blood pressure (BP) >130 or diastolic BP >80 mm Hg. Serum and 24-hour urine aldosterone (indexed to 24-hour urine Na) were checked before initiation of therapy and at 3, 6, and 9 months. Aldosterone breakthrough was defined as a sustained increase from baseline aldosterone by study end. The study was intended to enroll 120 subjects but was terminated early by the sponsor. We present here the results of 33 subjects who completed the protocol, of which 12 were randomized to A, 11 were randomized to V, and 10 were randomized to A+V. Mean baseline eGFR was 75.5 (±23.3) mL/min/1.73 m(2); baseline proteinuria was 3104 (±2943) mg/day; and baseline BP was 134.7 (±10.5)/84.8 (±8.4) mm Hg. Three (27%) subjects on V, three (25%) subjects on A, and three (30%) subjects on A+V had aldosterone breakthrough. Mean proteinuria reduction was 31% from baseline in all subjects: 30% in subjects with breakthrough vs. 32% in subjects without breakthrough. Mean BP reduction was 11.0/8.8 mm Hg in all subjects: 8.4/6.1 mm Hg in subjects with breakthrough vs. 12.0/9.8 mm Hg in subjects without breakthrough. Aliskiren, alone or in combination with valsartan, did not reduce the incidence of aldosterone breakthrough in subjects with hypertension

  19. 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.

  20. Topical antifungals for seborrhoeic dermatitis

    PubMed Central

    Okokon, Enembe O; Verbeek, Jos H; Ruotsalainen, Jani H; Ojo, Olumuyiwa A; Bakhoya, Victor Nyange

    2015-01-01

    symptoms were less clear and were inconsistent, possibly because of difficulties encountered in measuring these symptoms. Evidence was insufficient to conclude that dose or mode of delivery influenced treatment outcome. Only one study reported on treatment compliance. No study assessed quality of life. One study assessed the maximum rash-free period but provided insufficient data for analysis. One small study in patients with HIV compared the effect of lithium versus placebo on seborrhoeic dermatitis of the face, but treatment outcomes were similar. Authors' conclusions Ketoconazole and ciclopirox are more effective than placebo, but limited evidence suggests that either of these agents is more effective than any other agent within the same class. Very few studies have assessed symptom clearance for longer periods than four weeks. Ketoconazole produced findings similar to those of steroids, but side effects were fewer. Treatment effect on overall quality of life remains unknown. Better outcome measures, studies of better quality and better reporting are all needed to improve the evidence base for antifungals for seborrhoeic dermatitis. Plain Language Summary Antifungal treatments applied to the skin to treat seborrhoeic dermatitis Background Seborrhoeic dermatitis is a chronic inflammatory skin condition found throughout the world, with rashes with varying degrees of redness, scaling and itching. It affects people of both sexes but is more common among men. The disease usually starts after puberty and can lead to personal discomfort and cosmetic concerns when rashes occur at prominent skin sites. Drugs that act against moulds, also called antifungal agents, have been commonly used on their own or in combination. Review question Do antifungal treatments applied to the skin clear up the rashes and itching of seborrhoeic dermatitis? Study characteristics We included 51 studies with 9052 participants. Trials typically were four weeks long, and very few trials were longer. In

  1. 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

  2. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Is there a decline in cognitive functions after combined electroconvulsive therapy and antipsychotic therapy in treatment-refractory schizophrenia?

    PubMed

    Pawełczyk, Agnieszka; Kołodziej-Kowalska, Emilia; Pawełczyk, Tomasz; Rabe-Jabłońska, Jolanta

    2015-03-01

    An analysis of literature shows that there is still little evidence concerning the efficacy of electroconvulsive therapy (ECT) combined with antipsychotic therapy in a group of treatment-resistant schizophrenia patients. More precisely, its influence on cognitive functions is still equivocal. The aim of this study was to assess the influence of ECT combined with antipsychotic therapy on working memory, attention, and executive functions in a group of treatment-refractory schizophrenia patients. Twenty-seven patients completed the study: 14 men and 13 women, aged 21 to 55 years (mean age, 32.8 years), diagnosed with treatment-resistant schizophrenia. Each patient underwent a course of ECT sessions and was treated with antipsychotic medications. Before the ECT and within 3 days after the last ECT session, the participants were assessed with the following neuropsychological tests: Trail Making Test (TMT) and Wisconsin Cart Sorting Test (WCST). There were no significant differences in the TMT and WCST results after combined ECT and antipsychotic therapy in treatment-refractory schizophrenia patients. According to the results of the neuropsychological tests, there was no decline in attention, executive functions, or working memory. The current study shows no significant difference in attention, working memory, or executive functions after treatment with a combination of electroconvulsive and antipsychotic therapy. This suggests that combined electroconvulsive therapy may not have a negative influence on the neuropsychological functioning of patients with treatment resistant schizophrenia.

  4. Combination therapy--a way to forestall artemisinin resistance and optimize uncomplicated malaria treatment.

    PubMed

    Ștefan, I

    2015-01-01

    Artemisinin resistance represents a global concern, which requires a concerted and coordinated effort at a global level. Lessons learned from the experience of drug combination therapies in HIV, TB, and HCV infections showed that combination therapies reduce the risk of drug resistance development. In order to maximize the effectiveness of artemisinin and its derivates and to protect it from the development of resistance, WHO recommended that they should be combined with other drugs that have different mechanisms of action and longer half-lives. Until the attainment of new pharmaceuticals, artemisinin-based combination therapy (ACT) is the way to forestall artemisinin resistance and optimize uncomplicated malaria treatment.

  5. A review of therapies for diabetic macular oedema and rationale for combination therapy

    PubMed Central

    Amoaku, W M K; Saker, S; Stewart, E A

    2015-01-01

    Diabetic macular oedema (DMO) is responsible for significant visual impairment in diabetic patients. The primary cause of DMO is fluid leakage resulting from increased vascular permeability through contributory anatomical and biochemical changes. These include endothelial cell (EC) death or dysfunction, pericyte loss or dysfunction, thickened basement membrane, loss or dysfunction of glial cells, and loss/change of EC Glycocalyx. The molecular changes include increased reactive oxygen species, pro-inflammatory changes: advanced glycation end products, intracellular adhesion molecule-1, Complement 5–9 deposition and cytokines, which result in increased paracellular permeability, tight junction disruption, and increased transcellular permeability. Laser photocoagulation has been the mainstay of treatment until recently when pharmacological treatments were introduced. The current treatments for DMO target reducing vascular leak in the macula once it has occurred, they do not attempt to treat the underlying pathology. These pharmacological treatments are aimed at antagonising vascular endothelial growth factor (VEGF) or non-VEGF inflammatory pathways, and include intravitreal injections of anti-VEGFs (ranibizumab, aflibercept or bevacizumab) or steroids (fluocinolone, dexamethasone or triamcinolone) as single therapies. The available evidence suggests that each individual treatment modality in DMO does not result in a completely dry macula in most cases. The ideal treatment for DMO should improve vision and improve morphological changes in the macular (eg, reduce macular oedema) for a significant duration, reduced adverse events, reduced treatment burden and costs, and be well tolerated by patients. This review evaluates the individual treatments available as monotherapies, and discusses the rationale and potential for combination therapy in DMO. A comprehensive review of clinical trials related to DMO and their outcomes was completed. Where phase III randomised

  6. Effects of intensive insulin therapy combined with low molecular weight heparin anticoagulant therapy on severe pancreatitis

    PubMed Central

    DU, JUN-DONG; ZHENG, XI; HUANG, ZHI-QIANG; CAI, SHOU-WANG; TAN, JING-WANG; LI, ZHAN-LIANG; YAO, YONG-MING; JIAO, HUA-BO; YIN, HUI-NAN; ZHU, ZI-MAN

    2014-01-01

    The current study explored the effects of intensive insulin therapy (IIT) combined with low molecular weight heparin (LMWH) anticoagulant therapy on severe acute pancreatitis (SAP). A total of 134 patients with SAP that received treatment between June 2008 and June 2012 were divided randomly into groups A (control; n=33), B (IIT; n=33), C (LMWH; n=34) and D (IIT + LMWH; n=34). Group A were treated routinely. Group B received continuous pumped insulin, as well as the routine treatment, to maintain the blood sugar level between 4.4 and 6.1 mmol/l. Group C received a subcutaneous injection of LMWH every 12 h in addition to the routine treatment. Group D received IIT + LMWH and the routine treatment. The white blood cell count, hemodiastase, serum albumin, arterial partial pressure of oxygen and prothrombin time were recorded prior to treatment and 1, 3, 5, 7 and 14 days after the initiation of treatment. The intestinal function recovery time, incidence rate of multiple organ failure (MOF), length of hospitalization and fatality rates were observed. IIT + LMWH noticeably increased the white blood cell count, hemodiastase level, serum albumin level and the arterial partial pressure of oxygen in the patients with SAP (P<0.05). It markedly shortened the intestinal recovery time and the length of stay and reduced the incidence rate of MOF, the surgery rate and the fatality rate (P<0.05). It did not aggravate the hemorrhagic tendency of SAP (P>0.05). IIT + LMWH had a noticeably improved clinical curative effect on SAP compared with that of the other treatments. PMID:24944612

  7. 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

  8. Comparison of therapy persistence for fixed versus free combination antihypertensives: a retrospective cohort study

    PubMed Central

    Grimmsmann, Thomas; Himmel, Wolfgang

    2016-01-01

    Objectives The aim of the study was to compare therapy persistence among patients who started with one of three drug regimens: a monotherapy, or combination therapy either as a fixed combination (ie, ‘single pill’) or as a free combination (ie, two separate antihypertensive agents). Design In a secondary data analysis, we used descriptive statistics and multivariate logistic regression to measure the effect of the three therapy regimens on therapy persistence over 4 years. Setting Prescription data from a large German statutory health insurance provider. Participants All patients who started with a new antihypertensive therapy in 2007 or 2008 (n=8032) were included and followed for 4 years. Primary outcome measure Therapy persistence, defined as receiving a refill prescription no later than within 180 days. Results The persistence rates after 4 years were nearly identical among patients who started with a monotherapy (40.3%) or a fixed combination of two drugs (39.8%). However, significantly more patients who started with free-drug combinations remained therapy persistent (56.4%), resulting in an OR of 2.00 (95% CI 1.6 to 2.5; p<0.0001) for free combinations versus fixed combinations. This trend was observed in all age groups and for men and women. At the end of the study period, the number of different antihypertensive agents was still similar between patients who started with a fixed combination (2.41) and patients who started with a free combination (2.28). Conclusions While single-pill combinations make it easier to take different drugs at once, the risk is high that these several substances are stopped at once. Therapy persistence was significantly better for patients who started with a free-drug combination without taking much fewer different antihypertensive drugs as those with a fixed combination. PMID:27881519

  9. Comparison of therapy persistence for fixed versus free combination antihypertensives: a retrospective cohort study.

    PubMed

    Grimmsmann, Thomas; Himmel, Wolfgang

    2016-11-22

    The aim of the study was to compare therapy persistence among patients who started with one of three drug regimens: a monotherapy, or combination therapy either as a fixed combination (ie, 'single pill') or as a free combination (ie, two separate antihypertensive agents). In a secondary data analysis, we used descriptive statistics and multivariate logistic regression to measure the effect of the three therapy regimens on therapy persistence over 4 years. Prescription data from a large German statutory health insurance provider. All patients who started with a new antihypertensive therapy in 2007 or 2008 (n=8032) were included and followed for 4 years. Therapy persistence, defined as receiving a refill prescription no later than within 180 days. The persistence rates after 4 years were nearly identical among patients who started with a monotherapy (40.3%) or a fixed combination of two drugs (39.8%). However, significantly more patients who started with free-drug combinations remained therapy persistent (56.4%), resulting in an OR of 2.00 (95% CI 1.6 to 2.5; p<0.0001) for free combinations versus fixed combinations. This trend was observed in all age groups and for men and women. At the end of the study period, the number of different antihypertensive agents was still similar between patients who started with a fixed combination (2.41) and patients who started with a free combination (2.28). While single-pill combinations make it easier to take different drugs at once, the risk is high that these several substances are stopped at once. Therapy persistence was significantly better for patients who started with a free-drug combination without taking much fewer different antihypertensive drugs as those with a fixed combination. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  10. The use of capecitabine in the combined-modality therapy for rectal cancer.

    PubMed

    Liauw, Stanley L; Minsky, Bruce D

    2008-03-01

    Locally advanced rectal adenocarcinoma is treated by combined-modality therapy, which consists of surgery, chemotherapy, and radiation therapy. A series of randomized trials established a preferred treatment sequence of preoperative radiation therapy and 5-fluorouracil(5-FU)-based chemotherapy, total mesorectal excision, and adjuvant 5-FU-based chemotherapy for patients with stage II/III disease. Capecitabine is an oral prodrug of 5-FU that has potential advantages compared with intravenous 5-FU, including ease of administration and potentially increased therapeutic effect. Capecitabine is converted by a 3-step enzymatic process; the last step involves the enzyme thymidine phosphorylase, which is overexpressed in tumor tissues and is stimulated by concurrent radiation therapy. Over the past 5 years, several phase I/II trials of capecitabine-based therapy were reported. This review discusses the evolution of combined-modality therapy for rectal cancer with specific attention given to the use of capecitabine in conjunction with radiation therapy.

  11. Microsphere delivery of Risperidone as an alternative to combination therapy.

    PubMed

    D'Souza, Susan; Faraj, Jabar; DeLuca, Patrick

    2013-11-01

    attaining steady state with Risperdal Consta® was attributed to the 3 week latency in drug release from the microspheres and was in accordance with previous studies indicating a good corroboration with clinical findings. Calculated cumulative AUC (area under the curve) levels for Formulation C were similar to the Risperdal Consta®, though there were marked differences in AUC levels at the early time points. Comparison of Risperidal Consta® and Formulation C by multiple dosing in vivo experiments revealed that the marketed preparation demonstrated a substantial delay in providing an initial loading dose, continuous circulating levels, and attainment of steady state; all of which were observed rapidly with Formulation C. Findings from the current study strongly suggest that a microsphere dosage form of Risperidone can be formulated with an optimum particle size and drug loading to provide an initial bolus followed by maintenance levels, thereby eliminating combination therapy and improving patient compliance.

  12. Antifungal Amphiphilic Aminoglycosides

    PubMed Central

    Chang, C.-W. T.; Takemoto, J.Y.

    2014-01-01

    The attachment of alkyl and other hydrophobic groups to traditional antibacterial kanamycins and neomycins creates amphiphilic aminoglycosides with altered antimicrobial properties. In this review, we summarize the discovery of amphiphilic kanamycins that are antifungal, but not antibacterial, and that inhibit the growth of fungi by perturbation of plasma membrane functions. With low toxicities against plant and mammalian cells, they appear to specifically target the fungal plasma membrane. These new antifungal agents offer new options for fighting fungal pathogens and are examples of reviving old drugs to confront new therapeutic challenges. PMID:25110571

  13. Combined gene and stem cell therapy for cutaneous wound healing.

    PubMed

    Gauglitz, Gerd G; Jeschke, Marc G

    2011-10-03

    In current medical practice, wound therapy remains a clinical challenge and much effort has been focused on the development of novel therapeutic approaches for wound treatment. Gene therapy, initially developed for treatment of congenital defects, represents a promising option for enhancing wound repair. In order to accelerate wound closure, genes encoding for growth factors or cytokines have shown the most potential. The majority of gene delivery systems are based on viral transfection, naked DNA application, high pressure injection, and liposomal vectors. Besides advances stemming from breakthroughs in recombinant growth factors and bioengineered skin, there has been a significant increase in the understanding of stem cell biology in the field of cutaneous wound healing. A variety of sources, such as bone marrow, umbilical cord blood, adipose tissue and skin/hair follicles, have been utilized to isolate stem cells and to modulate the healing response of acute and chronic wounds. Recent data have demonstrated the feasibility of autologous adult stem cell therapy in cutaneous repair and regeneration. Very recently, stem cell based skin engineering in conjunction with gene recombination, in which the stem cells act as both the seed cells and the vehicle for gene delivery to the wound site, represents the most attractive field for generating a regenerative strategy for wound therapy. The aim of this article is to discuss the use and the potential of these novel technologies in order to improve wound healing capacities.

  14. Azole antifungal agents: emphasis on new triazoles.

    PubMed Central

    Saag, M S; Dismukes, W E

    1988-01-01

    Many advances have been made in antifungal therapy over the last three decades. Itraconazole and fluconazole, two investigational triazole agents, are the most recent additions to the list of antifungal drugs. This review has focused primarily on their mechanisms of action, favorable pharmacologic properties, and spectra of activity against a broad range of systemic pathogens. Itraconazole and fluconazole show much promise as orally active agents, with less potential for toxicity than the currently available azoles. Fluconazole and, to a lesser degree, itraconazole are especially promising therapies for cryptococcal meningitis. In addition, fluconazole may prove to be highly effective in urinary tract infections caused by Candida species and other fungi. Ongoing and future clinical trials will more clearly define the specific roles of itraconazole and fluconazole in the treatment of systemic mycoses. PMID:2831809

  15. [Therapeutic efficacy of a topical antifungal solution preparation formulated with pyrrolnitrin and clotrimazole in combination (Pyroace W) in guinea pig model of tinea pedis].

    PubMed

    Uchida, K; Ymaguchi, H

    1999-01-01

    The therapeutic efficacy of a topical antifungal solution containing a mixture of 0.2% pyrrolnitrin and 0.4% clotrimazole (Pyroace W) was tested in a guinea pig model of tinea pedis using a 1% newly solution formulated preparation of miconazole (Dermalin-L) as a reference drug. Infected animals were treated once or twice daily with the testing drug and once daily with the reference drug for 4 weeks. Therapeutic efficacy was evaluated on the basis of the extent of the yield of fungal cultures from the infected skin tissues (infection intensity) and the relative number of culture-negative animals at the end of the treatment period. In an animal group treated once daily with the testing drug, the infection intensity was significantly lower than that for untreated or vehicle-treated control group (p < 0.0001) although there was no culture-negative animal. A similar extent of therapeutic efficacy was obtained with a once daily treatment with the reference drug, yielding one of ten culture-negative animal. A better efficacy was seen in animals treated twice daily with the testing drug; the infection intensity was further decreased to a significant level and eight of ten animals became culture-negative. These results demonstrated that twice daily treatment with the testing drug was highly effective in guinea pig model of tinea pedis, 80% of infected animals being mycologically cured. It confirms the clinical usefulness of this regimen in the treatment of patients with tinea pedis or other types of dermatophytosis.

  16. Hematopoietic toxicity of regional radiation therapy. Correlations for combined modality therapy with systemic chemotherapy

    SciTech Connect

    Abrams, R.A.; Lichter, A.S.; Bromer, R.H.; Minna, J.D.; Cohen, M.H.; Deisseroth, A.B.

    1985-04-01

    Using circulating granulocyte-monocyte precursor colony-forming units in culture (CFUc) numbers as a probe along with standard blood count (CBC), the authors have quantitatively examined the hematopoietic toxicity of conventionally fractionated radiation therapy (RT) when combined with concurrent systemic chemotherapy or when used alone. Among 20 patients with limited stage small cell lung cancer receiving systemic chemotherapy with cyclophosphamide, CCNU, and methotrexate, the addition of involved field chest RT resulted in increased hematopoietic toxicity as judged by increased need for platelet transfusion (P less than 0.05) and decreased frequency of measurable CFUc (P less than 0.04). Among 22 patients receiving regional radiotherapy alone consistent hematopoietic toxicity was also observed. This toxicity, although generally of only mild to moderate clinical significance, was detected earlier and to a greater degree in patients who required radiation to larger treatment volumes, who had significant amounts of bone marrow in the port, and who had a high percentage of cardiac output flowing through the port. These data suggest that the hematopoietic toxicity of regional radiotherapy may be additive to that of concurrent systemic chemotherapy and may occur more promptly and to a greater degree when treatment volumes are larger or incorporate increased amounts of marrow volume or cardiac output.

  17. Anti-cancer effects of oncolytic viral therapy combined with photodynamic therapy in human pancreatic cancer cell lines.

    PubMed

    Khaled, Yazan S; Wright, Kathleen; Melcher, Alan; Jayne, David

    2015-02-26

    Oncolytic viral therapy and photodynamic therapy are potential therapies for inoperable or advanced pancreatic cancer. Our aim was to investigate the anti-cancer killing effects of reovirus therapy combined with protoporphyrin IX (PpIX)-mediated photodynamic therapy on a variety of human pancreatic cancer cell lines. Pancreatic cancer cell lines (PsPC-1 and BXPC-3) and a non-cancer control cell line (HEK293) were infected with reovirus serotype 3 strain Dearing (T3D) at 0, 0·1, 1, and 10 plaque-forming units (PFU) per cell for 48 h. Cells were incubated with PpIX pro-drug 5-aminolevulinic acid (5-ALA) at 0, 1, 2, 3, and 4 mM for 4 h. Then, cells were photo-irradiated for 15 min with visible red light-emitting diodes with a light-fluence of 0·54 J/cm(2) of 653 nm (PpIX optimal excitation wavelength). The killing effects of reovirus combined with PpIX-mediated photodynamic therapy were analysed in methylthiazoltetrazolium (MTT) and trypan blue assays. The effect of adding reovirus after photodynamic therapy was also assessed. The statistical significance of the difference between groups was assessed with the two-tailed Student's t test. p<0·05 was considered statistically significant. Reovirus monotherapy induced cell death in the two pancreatic lines (mean 57% [SE 10·2] at 10 PFU per cell). PpIX-mediated PDT monotherapy induced cell death in a dose-dependent manner (mean 10% [SE 2·2], 30 [6·4], 50 [8·2], and 70 [13·2] after 1, 2, 3, and 4 mM 5-ALA, respectively). Reovirus with PpIX-mediated photodynamic therapy resulted in a significantly increased cytotoxic effect compared with reovirus monotherapy and photodynamic therapy (p=0·042) with 100% cell death observed across pancreatic cell lines with 10 PFU per cell combined with 1 and 2 mM 5-ALA. There was no difference in cytotoxicity observed between added reovirus before or after photodynamic therapy. To our knowledge, this is the first in-vitro study to combine reovirus oncolytic viral therapy with Pp

  18. Nanotechnology-based combination therapy for overcoming multidrug-resistant cancer

    PubMed Central

    Zhang, Meng; Liu, Ergang; Cui, Yanna; Huang, Yongzhuo

    2017-01-01

    Multidrug resistance (MDR) is a major obstacle to successful cancer treatment and is crucial to cancer metastasis and relapse. Combination therapy is an effective strategy for overcoming MDR. However, the different pharmacokinetic (PK) profiles of combined drugs often undermine the combination effect in vivo, especially when greatly different physicochemical properties (e.g., those of macromolecules and small drugs) combine. To address this issue, nanotechnology-based codelivery techniques have been actively explored. They possess great advantages for tumor targeting, controlled drug release, and identical drug PK profiles. Thus, a powerful tool for combination therapy is provided, and the translation from in vitro to in vivo is facilitated. In this review, we present a summary of various combination strategies for overcoming MDR and the nanotechnology-based combination therapy. PMID:28884039

  19. 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.

  20. Cancer prevention and treatment using combination therapy with plant- and animal-derived compounds.

    PubMed

    Uzoigwe, Jacinta; Sauter, Edward R

    2012-11-01

    Compounds naturally occurring in plants and animals play an essential role in the prevention and treatment of various cancers. There are more than 100 plant- and animal-based natural compounds currently in clinical use. Similar to synthetic compounds, these natural compounds are associated with dose-related toxicity that limits efficacy. Scientists have investigated combination therapy with compounds that have different toxicities in order to optimize efficacy. These combination therapies may work additively or synergistically, there may be no effect or they may promote tumor formation. Combination therapy with agents that have similar mechanisms of action may increase toxicity. In this article, combination therapies that have been investigated, their rationale, mechanism of action and findings are reviewed. When the data warrant it, combined (pharmacologic and natural; two or more natural) interventions that appear to increase efficacy (compared with monotherapy) while minimizing toxicity have been highlighted.

  1. 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.

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

    PubMed

    Tängdén, Thomas

    2014-05-01

    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.

  3. Lipid-based antifungal agents: current status.

    PubMed

    Arikan, S; Rex, J H

    2001-03-01

    Immunocompromised patients are well known to be predisposed to developing invasive fungal infections. These infections are usually difficult to diagnose and more importantly, the resulting mortality rate is high. The limited number of antifungal agents available and their high rate of toxicity are the major factors complicating the issue. However, the development of lipid-based formulations of existing antifungal agents has opened a new era in antifungal therapy. The best examples are the lipid-based amphotericin B preparations, amphotericin B lipid complex (ABLC; Abelcet), amphotericin B colloidal dispersion (ABCD; Amphotec or Amphocil), and liposomal amphotericin B (AmBisome). These formulations have shown that antifungal activity is maintained while toxicity is reduced. This progress is followed by the incorporation of nystatin into liposomes. Liposomal nystatin formulation is under development and studies of it have provided encouraging data. Finally, lipid-based formulations of hamycin, miconazole, and ketoconazole have been developed but remain experimental. Advances in technology of liposomes and other lipid formulations have provided promising new tools for management of fungal infections.

  4. Sequential combination of robot-assisted therapy and constraint-induced therapy in stroke rehabilitation: a randomized controlled trial.

    PubMed

    Hsieh, Yu-Wei; Lin, Keh-Chung; Horng, Yi-Shiung; Wu, Ching-Yi; Wu, Tai-Chieh; Ku, Fang-Ling

    2014-05-01

    Robot-assisted therapy (RT) and constraint-induced therapy (CIT) both show great promise to improve stroke rehabilitation outcomes. Although the respective treatment efficacy of RT and CIT has been validated, the additive effects of RT combined with CIT remain unknown. This study investigated the treatment effects of RT in sequential combination with a distributed form of CIT (RT + dCIT) compared with RT and conventional rehabilitation (CR). Forty-eight patients with stroke were enrolled and randomized to receive one of the three interventions for 4 weeks. Primary outcomes assessed the changes of motor impairment and motor function on the Fugl-Meyer Assessment (FMA) and Wolf Motor Function Test (WMFT). Secondary outcomes, including the Motor Activity Log (MAL) and accelerometers, examined functional performance during daily activities. The three treatment groups improved significantly on most primary and secondary outcomes over time. The combined RT + dCIT group exhibited significantly greater improvement on the FMA and functional ability subscale of the WMFT than the RT and CR groups. The improvements on the MAL and accelerometers were not significantly different among the three groups. RT in sequential combination with CIT led to additive effects on participants' motor ability and functional ability to perform motor tasks after stroke, which support that combined therapy can be an effective means to intensify outcomes. Further research investigating the potential long-term effects of combination therapy, especially on real-life performance, would be valuable.

  5. [Wobenzym in the combined pathogenetic therapy of chronic urethrogenic prostatitis].

    PubMed

    Martynenko, A V

    1998-08-01

    The paper addresses the issues of pathogenetic therapy of uretrogenous prostatitis, its key features being as follows: 1) association with pancreatic pathology; 2) the presence of noninfectious agent; 3) autoimmune character. The proposed treatment scheme includes wobenzyme, a polyenzymic drug preparation, capable of exerting positive effects in the treatment of the pathology in question, which fact bears relation to intimate mechanisms of evolution of chronic urethrogenous prostatitis.

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

    PubMed

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

    2015-05-01

    [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.

  7. Newer antifungal agents.

    PubMed

    Türel, Ozden

    2011-03-01

    The frequency and spectrum of fungal infections have been increasing steadily over the last several decades. The reason for this increase may be explained by the increase in the number of immunocompromised patients due to malignancies, AIDS, invasive surgical procedures and transplantation. In parallel with this increase, several therapeutic options have become available but problems such as intrinsic or acquired antifungal resistance have led researchers to develop new antifungal drugs with expanded effectiveness. Reduced toxicity, enhancement of bioavailability and counteraction of resistance are features desired by clinicians. The aim of this article is to summarize the studies involving isavuconazole, ravuconazole, albaconazole, aminocandin and some other investigational antifungal agents. Most data on the clinical use of ravuconazole, isavuconazole and albaconazole are mainly available as meeting abstracts or limited to animal studies or Phase I/II studies in humans. These new antifungal agents in development offer extended half-lives, possibly reduced drug interaction profiles and good tolerance. In addition to activity against Candida and Aspergillus spp., they have a broad spectrum of activity including activity against resistant and emerging pathogens. The real possibilities of these agents will only be fully understood after adequate randomized clinical trials.

  8. 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

  9. Antifungal activity of medicinal plant extracts; preliminary screening studies.

    PubMed

    Webster, Duncan; Taschereau, Pierre; Belland, René J; Sand, Crystal; Rennie, Robert P

    2008-01-04

    In the setting of HIV and organ transplantation, opportunistic fungal infections have become a common cause of morbidity and mortality. Thus antifungal therapy is playing a greater role in health care. Traditional plants are a valuable source of novel antifungals. To assess in vitro antifungal activity of aqueous plant extracts. The minimum inhibitory concentrations were determined for each extract in the setting of human pathogenic fungal isolates. Plants were harvested and identification verified. Aqueous extracts were obtained and antifungal susceptibilities determined using serial dilutional extracts with a standardized microdilution broth methodology. Twenty-three fungal isolates were cultured and exposed to the plant extracts. Five known antifungals were used as positive controls. Results were read at 48 and 72 h. Of the 14 plants analyzed, Fragaria virginiana Duchesne, Epilobium angustifolium L. and Potentilla simplex Michx. demonstrated strong antifungal potential overall. Fragaria virginiana had some degree of activity against all of the fungal pathogens. Alnus viridis DC., Betula alleghaniensis Britt. and Solidago gigantea Ait. also demonstrated a significant degree of activity against many of the yeast isolates. Fragaria virginiana, Epilobium angustifolium and Potentilla simplex demonstrate promising antifungal potential.

  10. Grazoprevir/elbasvir combination therapy for HCV infection

    PubMed Central

    Vallet-Pichard, Anaïs; Pol, Stanislas

    2016-01-01

    Interferon-free regimens combine different second-wave direct-acting antiviral agents (DAAs), which target the main viral proteins involved in the replication cycle of hepatitis C virus (HCV): NS3/4A protease inhibitors (simeprevir or paritaprevir boosted by ritonavir), NS5B nucleos(t)idic (sofosbuvir) and nonnucleos(t)idic (dasabuvir) polymerase inhibitors, NS5A replication complex inhibitors (daclatasvir, ledipasvir, elbasvir, velpatasvir). Combinations of two or three DAAs, given for 8–24 weeks reach sustained virology response (SVR) rates greater than 90% with good tolerance. SVR rates and safety are similar in clinical trials and in real life, usually higher than 95% in the per-protocol analysis. Next-generation DAAs are now expected. To be competitive, these new combinations need to prove their added value regarding the pill burden, the reduced duration of treatment, the drug–drug interaction profile and safety. Zepatier is a fixed-dose combination product coformulating MK-5172 [grazoprevir (GZR), 100 mg QD] and MK-8742 [elbasvir or (EBR) 50 mg QD]: it combines highly potent inhibitors of the HCV NS3/4A protease and NS5A replication complex, respectively. This review provides a summary of the main evidence available for the use of GZR/EBR and highlights the strength of this combination. PMID:28286567

  11. Combining Voice Therapy and Physical Therapy: A Novel Approach to Treating Muscle Tension Dysphonia

    PubMed Central

    Craig, Jennifer; Tomlinson, Carey; Stevens, Kristin; Kotagal, Kiran; Fornadley, Judith; Jacobson, Barbara; Garrett, C. Gaelyn; Francis, David O.

    2015-01-01

    Objective This study investigated the role of a specialized physical therapy program for muscle tension dysphonia patients as an adjunct to standard of care voice therapy. Study Design Retrospective Cohort Study Methods Adult MTD patients seen between 2007 and 2012 were identified from the clinical database. They were prescribed voice therapy and, if concomitant neck pain, adjunctive physical therapy. In a pragmatic observational cohort design, patients underwent one of four potential treatment approaches: voice therapy alone (VT), voice therapy and physical therapy (VT+PT), physical therapy alone (PT), or incomplete/no treatment. Voice handicap outcomes were compared between treatment approaches. Results Of 153 patients meeting criteria (Median age 48 years, 68% female, and 30% had fibromyalgia, chronic pain, chronic fatigue, depression, and/or anxiety), there was a similar distribution of patients with moderate or severe pre-treatment VHI scores across treatment groups (VT 45.5%, VT+PT 43.8%, PT 50%, no treatment 59.1%; p=0.45). Patients treated with VT alone had significantly greater median improvement in VHI than those not treated: 10-point vs. 2-point (p=0.02). Interestingly, median VHI improvement in patients with baseline moderate-severe VHI scores was no different between VT (10), VT+PT (8) and PT alone (10; p=0.99). Conclusions Findings show voice therapy to be an effective approach to treating MTD. Importantly, other treatment modalities incorporating physical therapy had a similar, albeit not significant, improvement in VHI. This preliminary study suggests that physical therapy techniques may have a role in the treatment of a subset of MTD patients. Larger, comparative studies are needed to better characterize the role of physical therapy in this population. PMID:26012419

  12. 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.

  13. Combined Therapy of Oncolytic Adenovirus and Temozolomide Enhances Lung Cancer Virotherapy In Vitro and In Vivo

    PubMed Central

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

    2015-01-01

    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

  14. Combination therapy of murine mucormycosis or aspergillosis with iron chelation, polyenes, and echinocandins.

    PubMed

    Ibrahim, Ashraf S; Gebremariam, Teclegiorgis; Luo, Guanpingsheng; Fu, Yue; French, Samuel W; Edwards, John E; Spellberg, Brad

    2011-04-01

    Liposomal amphotericin B (LAmB) combined wither either micafungin or deferasirox was synergistic in previous murine studies with mucormycosis or aspergillosis. We hypothesized that triple therapy using LAmB, micafungin, and deferasirox could further improve outcomes of mucormycosis or aspergillosis. Triple therapy improved survival and reduced tissue fungal burden of mice with mucormycosis and to a lesser extent with aspergillosis. Continued investigation into the use of triple therapy against mucormycosis and aspergillosis is warranted.

  15. [Application of photodynamic therapy combined with compound betamethasone in treatment of hypertrophic scar].

    PubMed

    Fang, Fang; Hong, Zhang; Yan, Zhao; Meiling, Lin

    2015-09-01

    To investigate the effect of photodynamic therapy combined with compound betamethasone in the treatment of hypertrophic scar. 37 cases of keloid were divided into two groups, 19 cases in the treatment group, 18 cases in the control group. The patients in treatment group were treated with photodynamic therapy combined with compound betamethasone injection therapy. The patients in the control group were treated by compound betamethasone injection. The effect and recurrence rate were compared before and after treatment. The effective rate was 89.5% in the treatment group, 55. 6% in the control group, showing significant difference between the two groups (P = 0.029) The relapse rate in treatment group was significantly lower than that in the control group (P = 0.047) CONCLUSIONS: Photodynamic therapy combined with compound betamethasone has good effect and safety for the treatment of hypertrophic scar. The combined treatment can reduce the treatment period and side effects

  16. Synergistic Combination Agent for Cancer Therapy | NCI Technology Transfer Center | TTC

    Cancer.gov

    The Nanotechnology Characterization Laboratory of the Frederick National Laboratory for Biomedical Research seeks parties interested in collaborative research to co-develop a ceramide and vinca alkaloid combination therapy for treatment of cancer.

  17. Combination ACE inhibitor and angiotensin receptor blocker therapy - future considerations.

    PubMed

    Sica, Domenic A

    2007-01-01

    Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are regularly prescribed for the management of hypertension. Each of these drug classes has also been shown to provide survival benefits for patients with heart failure, proteinuric chronic kidney disease, and/or a high cardiac risk profile. The individual gains seen with each of these drug classes have led to speculation that their combination might offer additive if not synergistic outcome benefits. The foundation of this hypothesis, although biologically possible, has thus far not been sufficiently well proven to support the everyday use of these 2 drug classes in combination. Additional outcomes trials, which are currently proceeding to their conclusion, may provide the necessary proof to support an expanded use of these 2 drug classes in combination.

  18. Mirror therapy combined with functional electrical stimulation for rehabilitation of stroke survivors' ankle dorsiflexion.

    PubMed

    Salhab, Ghadir; Sarraj, Ahmad Rifaii; Saleh, Soha

    2016-08-01

    This study investigates the effect of combining both mirror therapy with Electrical Stimulation (ES) on improvement of the function of lower extremity compared to conventional therapy. 18 stroke survivors (sub acute stage) were recruited, 9 of them were randomly assigned to receive conventional treatment and another 9 started the mirror therapy combined with ES treatment. Duration of each session in both interventions was 50 minutes, done 4 times per week over two weeks. After 2 weeks, subjects took one week rest before switching they type of treatment; those started with conventional therapy continued with mirror therapy combined with ES, and vice versa. The duration of this phase was 2 weeks with same schedule as the 1st one. Ankle dorsi-flexion range of motion, lower extremity sensory-motor function, and walking duration were measured at baseline, after 1st 2 weeks, and immediately after the last two weeks, and 4 weeks after end of training (retention test). Repeated Measures ANCOVA was done to compare outcome measures scores in both groups and between all testing days, and paired T-test was used measure the difference between groups. Significant increase in all outcome measures was found after the (MT+ES) training, which is higher than conventional therapy training (p<;0.0001). In conclusion, the results suggest that combination of mirror therapy and ES is more effective than conventional therapy in improving lower limb motor function after stroke.

  19. Migraine responds better to a combination of medical therapy and trigger point management than routine medical therapy alone.

    PubMed

    Ghanbari, Ali; Askarzadeh, Saghar; Petramfar, Peyman; Mohamadi, Marzieh

    2015-01-01

    Migraine is one of the most frequent headaches. Cervical myofascial and trigger point disorders are effective factors on accession of this type of headache. PRT is an indirect technique that treats trigger points. The purpose of this study was to compare the effectiveness of trigger points' management by positional release therapy (PRT) combined with routine medical therapy and routine medical therapy alone in treatment of migraine headache. Forty-four patients with active trigger points in cervical muscles entered to the study. They were randomly assigned to PRT-medical therapy or medical therapy group. Headache frequency, intensity, duration and tablet count were recorded by use of a daily headache diary. The sensitivity of trigger points was assessed by the use of a digital force gauge (Wagner-FDIX). Cervical range of motion was measured by a goniometer. Both groups showed significant reduction in headache intensity, frequency, duration and tablet count after 4 months follow up. The sensitivity of trigger points and all cervical range of motions significantly increased in PRT-medical group after 4 months follow up; however in medication group except cervical right lateral flexion, right and left rotation the other factors showed no change after 4 months follow up. In comparison of the two study groups, there was no significant difference in headache-related variables. Apart from the headache intensity and tablet count, the trends of other factors were significantly different between the two groups (p <  0.05). The combined PRT-medical therapy is more effective than the medical therapy alone. Thus, the combination of PRT and medical therapy is suggested as a treatment choice for patients with migraine headache.

  20. Combination therapy of statin and ezetimibe for the treatment of familial hypercholesterolemia

    PubMed Central

    Hamilton-Craig, Ian; Kostner, Karam; Colquhoun, David; Woodhouse, Stan

    2010-01-01

    High-dose potent statin therapy in combination with ezetimibe is now standard practice for the treatment of adult patients with heterozygous familial hypercholesterolemia (heFH), as the result of numerous studies in patients with primary hypercholesterolemia or heFH. These studies have shown the combination to be both effective and safe in the short to medium term. Recently, short-term ezetimibe therapy has also been shown to be effective and safe in combination with statin therapy for children and adolescents with heFH. Effective statin–ezetimibe combination therapy is capable of achieving near-normal lipid profiles in heFH patients, with expected improvement in risk for cardiovascular disease (CVD) and improved life expectancy resulting predominantly from reduction in levels of low-density lipoprotein cholesterol. There are few data to support a pleiotropic action of ezetimibe with regard to CVD benefit, unlike therapy with statins. No serious and unexpected clinical adverse effects of combination statin–ezetimibe therapy have emerged till date, although data are limited in children and adolescents, for whom longer-term studies are required. Recent data suggesting possible proatherogenic effects of ezetimibe require confirmation. One large long-term randomized controlled clinical outcomes trial is in progress in non-FH patients to determine the efficacy and safety of ezetimibe therapy; it is unlikely that such a trial will ever be performed in patients with FH. PMID:21127699

  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.

  2. Adjuvant combined ozone therapy for extensive wound over tibia

    PubMed Central

    Shah, Prasham; Shyam, Ashok K; Shah, Sambhav

    2011-01-01

    Disinfectant and antibacterial properties of ozone are utilized in the treatment of nonhealing or ischemic wounds. We present here a case of 59 years old woman with compartment syndrome following surgical treatment of stress fracture of proximal tibia with extensively infected wound and exposed tibia to about 4/5 of its extent. The knee joint was also infected with active pus draining from a medial wound. At presentation the patient had already taken treatment for 15 days in the form of repeated wound debridements and parenteral antibiotics, which failed to heal the wound and she was advised amputation. Topical ozone therapy twice daily and ozone autohemotherapy once daily were given to the patient along with daily dressings and parenteral antibiotics. Within 5 days, the wound was healthy enough for spilt thickness skin graft to provide biological dressing to the exposed tibia bone. Topical ozone therapy was continued for further 5 days till the knee wound healed. On the 15th day, implant removal, intramedullary nailing, and latissimus dorsi pedicle flap were performed. Both the bone and the soft tissue healed without further complications and at 20 months follow-up, the patient was walking independently with minimal disability. PMID:21772635

  3. Adjuvant combined ozone therapy for extensive wound over tibia.

    PubMed

    Shah, Prasham; Shyam, Ashok K; Shah, Sambhav

    2011-07-01

    Disinfectant and antibacterial properties of ozone are utilized in the treatment of nonhealing or ischemic wounds. We present here a case of 59 years old woman with compartment syndrome following surgical treatment of stress fracture of proximal tibia with extensively infected wound and exposed tibia to about 4/5 of its extent. The knee joint was also infected with active pus draining from a medial wound. At presentation the patient had already taken treatment for 15 days in the form of repeated wound debridements and parenteral antibiotics, which failed to heal the wound and she was advised amputation. Topical ozone therapy twice daily and ozone autohemotherapy once daily were given to the patient along with daily dressings and parenteral antibiotics. Within 5 days, the wound was healthy enough for spilt thickness skin graft to provide biological dressing to the exposed tibia bone. Topical ozone therapy was continued for further 5 days till the knee wound healed. On the 15(th) day, implant removal, intramedullary nailing, and latissimus dorsi pedicle flap were performed. Both the bone and the soft tissue healed without further complications and at 20 months follow-up, the patient was walking independently with minimal disability.

  4. Novel Extracorporeal Therapies for Combined Renal-Pulmonary Dysfunction.

    PubMed

    Romagnoli, Stefano; Ricci, Zaccaria; Ronco, Claudio

    2016-01-01

    In modern intensive care medicine, lungs and kidneys frequently are involved in the context of multiorgan failure. When organ dysfunction occurs, the primary clinical management of critically ill patients is based on support/replacement of organ function until recovery. Mechanical ventilation is the first-line intervention in case of respiratory failure, but in most severe cases may, itself, cause ventilator-induced lung injury. The same inflammatory mechanism also may harm the kidney through mediator spillover from the injured lungs into the bloodstream. To limit the deleterious effects of mechanical ventilation and avoid excessive carbon dioxide accumulation, devices for extracorporeal CO2 removal (ECCO2R), have been developed. Some consistent clinical experience currently has been reached in patients with obstructive pulmonary disease and acute respiratory distress syndrome. Interestingly, ECCO2R recently has been coupled with continuous renal replacement therapy systems into specific lung-renal support. The results from the first experimental and clinical applications are encouraging: it is expected that a system including continuous renal replacement therapy and ECCO2R will develop from the current pioneering attempts into a feasible multiple-organ support platform to become commonly used as a routine tool in intensive care units. This review focuses on recent literature and clinical applications of renal-pulmonary support with specific attention to technical aspects of the most recent materials and devices.

  5. 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.

  6. Combined Therapy against Recurrent Hemangiopericytoma: A Case Report

    PubMed Central

    Li, Xiao-dong; Jiang, Jing-ting; Wu, Chang-ping

    2012-01-01

    Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China A patient with a seven-year history of recurrent metastatic hemangiopericytoma (HPC) was admitted. During his treatment, he received surgical resection, radiotherapy, radiofrequency hyperthermia and chemotherapy using combined doxorubicin, dacarbazin, vincristine, ginsenoside Rg3, and recombinant human endostatin. This synergistic method provides an encouraging model for treating HPC. PMID:23691471

  7. 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.

  8. 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.

  9. [Control of blood pressure in hypertensive patients on combination therapy].

    PubMed

    de la Sierra, Alejandro; Oliveras, Anna; Armario, Pedro; Lucas, Silvia

    2015-02-20

    The impact of antihypertensive treatment on blood pressure (BP) control is fairly unknown. The aim of the study was to evaluate the degree of BP control and its relationship with treatment-related factors in hypertensive patients treated with 2 or 3 agents and attended in referral units. We studied 1,337 hypertensive subjects (41% women) with a mean age (SD) of 63 (12) years, who were receiving 2 or 3 antihypertensive drugs. The degree of BP control was estimated in a single visit by the proportion of patients with BP below 140/90mmHg. BP was controlled in 767 patients (57%). Lack of BP control was related to older age (12% risk for each 10-year increase) and the presence of microalbuminuria (64% risk increase). In those treated with 2 agents, BP control was 61%, without differences between those treated with fixed-drug or free combinations. BP control in those treated with 3 agents was 55%, higher in those receiving 3 agents in a fixed-drug combination (68%) compared with those on 3 agents administered separately (52%; P=.025). Drug classes used in combinations did not influence the degree of BP control. The degree of BP control in patients treated with 2 or 3 agents is 57%. Microalbuminuria is related to a lack of BP control. In those receiving 3 agents, the use of fixed-drug combinations is associated with better BP control. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

  10. 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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Combined-modality therapy of rectal cancer with oxaliplatin-based regimens.

    PubMed

    Minsky, Bruce D

    2004-06-01

    There are 2 conventional treatments for clinically resectable rectal cancer. First is surgery and, if the tumor is stage T3 and/or N1/2, this is followed by postoperative combined modality therapy. The second is preoperative combined modality therapy followed by surgery and postoperative combined modality therapy if the tumor is stage uT3/4 and/or node-positive. There are a number of new chemotherapeutic agents that have been developed for the treatment of patients with colorectal cancer. Phase I/II trials examining the use of these new chemotherapeutic agents in combination with pelvic radiation therapy, most commonly in the preoperative setting are in progress and suggest higher complete response rates. There is considerable interest in integrating oxaliplatin into preoperative combined modality therapy regimens for rectal cancer. Based on results from phase I/II trials, the recommended regimen for patients who receive oxaliplatin-based combined modality therapy is continuous infusion 5-fluorouracil or capecitabine with pelvic radiation.

  12. Combined-modality therapy of rectal cancer with irinotecan-based regimens.

    PubMed

    Minsky, Bruce D

    2004-12-01

    There are two conventional treatments for clinically resectable rectal cancer. The first is surgery followed by postoperative combined-modality therapy if the tumor is T3 and/or N1/2. The second, if the tumor is ultrasound T3 or clinical T4, is preoperative combined-modality therapy followed by surgery and postoperative chemotherapy. There are a number of new chemotherapeutic agents that have been developed for the treatment of colorectal cancer. Phase I/II trials are examining the use of new chemotherapeutic agents in combination with pelvic radiation therapy, most commonly in the preoperative setting. There is considerable interest in integrating irinotecan (Camptosar) into preoperative combined-modality therapy regimens for rectal cancer. Based on these trials, the recommended regimen for patients who receive irinotecan-based combined-modality therapy is continuous infusion fluorouracil (5-FU), irinotecan, and pelvic radiation. New trials examining preoperative combined-modality therapy regimens substituting capecitabine (Xeloda) for continuous infusion 5-FU are in progress.

  13. 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

  14. Effectiveness of standardized combination therapy for migraine treatment in the pediatric emergency department.

    PubMed

    Leung, Stephanie; Bulloch, Blake; Young, Christine; Yonker, Marcy; Hostetler, Mark

    2013-03-01

    To compare outcomes of pediatric migraine patients treated in an emergency department (ED) before and after implementation of a standardized combination intravenous therapy regimen aimed toward improving and standardizing abortive migraine therapy. In a pediatric ED, migraines represent 8-18% of all headache visits. Despite this large number, no standard treatment for acute migraine therapy currently exists. The study utilized a retrospective chart review of patients seeking acute migraine treatment at a tertiary care, pediatric ED from August 2006 to March 2010. Inclusion criteria were pediatric migraine patients as defined by International Headache Society guidelines. The comparison population received various migraine therapies based on attending practice preference. After October 2008, patients received standardized intravenous combination therapy involving a normal saline fluid bolus, ketorolac, prochlorperazine, and diphenhydramine. Occasionally, metoclopramide was substituted during prochlorperazine shortages. Reduction in headache pain score was the primary outcome. Secondary outcome measures included length of ED stay, hospital admission rate, and ED readmission rate within 48 hours. The study yielded 87 patients who received standardized combination therapy and 165 comparison patients. No significant difference in patient characteristics existed when evaluating patient demographics, outpatient medication use, and initial headache pain score. When compared with the non-standardized therapy population, the combination therapy patients revealed significant reductions in pain score (decrease of 5.3 vs. 6.9, difference -1.6, 95% confidence interval -2.2 to -0.8, P < .001), length of ED stay (5.3 vs. 4.4 hours, difference 0.9, 95% confidence interval 0.2-1.6, P = .008), and hospital admission rate (32% vs. 3%, P < .001) without changes in ED return rate (7% vs. 2%, P = .148). Standardized combination therapy is effective for acute pediatric

  15. 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…

  16. 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…

  17. Healing the wounded self: combining hypnotherapy with ego state therapy.

    PubMed

    Alladin, Assen

    2013-07-01

    The purpose of this article is to formulate a theoretical conceptualization for utilizing ego state therapy (EST) as an adjunct with cognitive hypnotherapy (CH) for depression. As the relationship between life events and onset of depression is very complex, it is not clear from current literature how stressors cause depressive symptoms. The notion of "wounded self," derived from the work of Wolfe (2005, 2006), is examined as a potential unifying concept for binding the role of risk factors in the precipitation of depression. By incorporating wounded self, the circular feedback model of depression, on which CH for depression is based, is expanded. This revised version provides conceptual and empirical underpinnings for integrating EST with CH in the management of depression.

  18. [Combination therapy of prostatitis-associated copulative dysfunction].

    PubMed

    Bliumberg, B I; Shat