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Sample records for antifungal combination therapy

  1. 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

  2. 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.

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. 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

  14. 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

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. 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).

  20. 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.

  1. 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

  2. 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.

  3. 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.

  4. 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

  5. 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

  6. 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).

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. 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

  18. 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

  19. 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

  20. [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.

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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.

  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. 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.

  15. 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.

  16. 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.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  18. 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.

  19. 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

  20. 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…

  1. 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.

  2. 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

  3. 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.

  4. Combined Therapy for Postirradiation Infection

    DTIC Science & Technology

    1989-01-01

    weeks after ex- posure to ionizing radiation. Antibiotics alone do not provide adequate the- rapy for induced infections in neutropenic mice. Because... Antibiotics alone do not assure cure of infec- effect of TDM against different challenge doses tions or survival of irradiated animals of K. pneumoniae...Treated with Combined Therapy of TDM and Ceftriaxone. LD50/30 Antibiotic % Survival? .pneumoniae Therapy TDM/o TDM/s Saline Oil 5000 ceftriaxone 100 88 69

  5. 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.

  6. 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.

  7. 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.

  8. 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).

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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

  14. 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.

  15. 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.

  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. 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

  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. 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.

  20. 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

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. Antifungal polypeptides

    DOEpatents

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

    2009-09-15

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

  8. 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

  9. 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

  10. 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.

  11. 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.

  12. [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.

  13. 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.

  14. 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

  15. 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.

  16. 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

  17. 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.

  18. [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.

  19. 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

  20. 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%.

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  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. 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.

  15. 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.

  16. 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

  17. 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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  19. 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

  20. 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

  1. [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.

  2. [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.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. Clinical pharmacology of antifungal compounds.

    PubMed

    Groll, Andreas H; Gea-Banacloche, Juan C; Glasmacher, Axel; Just-Nuebling, Gudrun; Maschmeyer, Georg; Walsh, Thomas J

    2003-03-01

    Prompted by the worldwide surge in fungal infections, the past decade has witnessed a considerable expansion in antifungal drug research. New compounds have entered the clinical arena, and major progress has been made in defining paradigms of antifungal therapies. This article provides an up-to-date review on the clinical pharmacology, indications, and dosage recommendations of approved and currently investigational therapeutics for treatment of invasive fungal infections in adult and pediatric patients.

  10. 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

  11. 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

  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. 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

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  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. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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.

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. 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.

  7. 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.

  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. [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.

  12. Synergistic nanomedicine by combined gene and photothermal therapy.

    PubMed

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

    2016-03-01

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

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

    PubMed Central

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

    2000-01-01

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

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. [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.

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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

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

    PubMed

    Brown, Neil A; Goldman, Gustavo H

    2016-03-01

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

  11. [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.

  12. 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

  13. 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.

  14. 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.

  15. 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

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. [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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. 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

  11. 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

  12. [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.

  13. 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

  14. 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

  15. 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.

  16. 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.

  17. 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

  18. [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

  19. 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

  20. 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

  1. 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.

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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.

  14. 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

  15. 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.

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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.

  1. 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

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. Antifungal polypeptides

    DOEpatents

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

    2010-08-10

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

  7. 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.

  8. Antifungal polypeptides

    DOEpatents

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

    2011-04-12

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

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. [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.

  19. 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…

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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.

  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. 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

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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

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

    DTIC Science & Technology

    2013-03-01

    transport studying docetaxel pharmacokinetics in wild-type FVB and Mdr1a/ b constitutive knockout (KO) mice. For all tissues in both the FVB and KO...16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a. REPORT U b ...the role of PGP in drug PK. Dose mdr1a/ b knockout mice with LAPATINIB, DOCETAXEL, DOXORUBICIN, combination LAPATINIB and DOCETAXEL, and combination

  10. 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

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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…

  1. 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.

  2. 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.

  3. 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

  4. [An advanced metastatic breast cancer patient successfully treated with combination therapy including docetaxel, doxorubicin and cyclophosphamide (TAC) as salvage therapy].

    PubMed

    Sato, Yasushi; Takayama, Tetsuji; Sagawa, Tamotsu; Sato, Tsutomu; Okamoto, Kumiko; Takahashi, Shou; Abe, Seiichiro; Iyama, Satoshi; Murase, Kazuyuki; Kato, Junji; Niitsu, Yoshiro

    2008-03-01

    We reported here a case of advanced breast cancer successfully treated with combination therapy including docetaxel, doxorubicin and cyclophosphamide (TAC) as salvage therapy. A 56-year-old male was referred to our hospital for treatment of recurrent metastatic breast cancer. When he was admitted, his general condition was poor due to massive intraperitoneal metastasis. We administered TAC chemotherapy (docetaxel 75 mg/m(2), doxorubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2), every 3 weeks). During chemotherapy, he showed no major adverse effects except grade 3 neutropenia, which could be easily managed with G-CSF administration. Metastatic lesions almost disappeared after 4 cycles of TAC. TAC therapy was considered to be acceptable as salvage therapy for a metastatic male breast cancer patient.

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

    PubMed

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

    2011-01-01

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

  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. Etanercept‐Methotrexate Combination Therapy Initiators Have Greater Adherence and Persistence Than Triple Therapy Initiators With Rheumatoid Arthritis

    PubMed Central

    Johnson, Barbara H.; Tang, Derek H.; Shah, Neel; Harrison, David J.; Collier, David H.

    2015-01-01

    Objective To estimate adherence and persistence with etanercept plus methotrexate (ETN‐MTX) combination therapy and MTX, hydroxychloroquine, and sulfasalazine triple therapy at 1 year following treatment initiation in adults with rheumatoid arthritis (RA). Methods This retrospective analysis used data from the Truven Health MarketScan Commercial and Medicare Supplemental databases from January 2009 to July 2013. Adherence was defined as having percentage of days covered >80% for all drugs within each regimen. Persistence was defined as no treatment gap >45 days for any drug and no addition or switching to other disease‐modifying antirheumatic drugs. Multiple logistic regression models were employed in the analyses to control for potential confounders. Results A total of 3,724 ETN‐MTX patients and 818 triple therapy patients were eligible. At 1 year, 27.9% who were taking ETN‐MTX and 18.2% using triple therapy were adherent to all agents in their regimen (P < 0.0001), and 29.4% who were taking ETN‐MTX and 23.2% using triple therapy were persistent (P < 0.001). After adjusting for confounders, ETN‐MTX patients had significantly greater odds of being adherent (odds ratio [OR] 1.79, 95% confidence interval [95% CI] 1.47–2.17) and persistent (OR 1.45, 95% CI 1.20–1.72) compared with patients using triple therapy. Conclusion Patients with RA initiating treatment with ETN‐MTX combination therapy demonstrated greater adherence and persistence at 1 year than patients initiating triple therapy. PMID:26097194

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2016-02-21

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

  10. 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.

  11. 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

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

    SciTech Connect

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

    2012-11-15

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

  13. Combining oncolytic virotherapy and cytotoxic therapies to fight cancer.

    PubMed

    Fillat, Cristina; Maliandi, Maria Victoria; Mato-Berciano, Ana; Alemany, Ramon

    2014-01-01

    Oncolytic viruses (OV) are promising anti-cancer agents, capable of selectively replicating in tumour cells and killing them. Chemotherapy, on the other hand, remains the backbone of current cancer treatment, although it is limited by a narrow therapeutic index, significant toxicity, and frequent acquired resistance. There is an increasing body of evidence on a variety of chemotherapeutic agents that have been shown to be synergic with OV and result in increased response rates in preclinical studies. Several possible mechanisms have been proposed to mediate the enhanced anti-tumour activity of such combination treatment. Moreover, it has been shown how prodrug- activating enzymes armed oncolytic viruses promote synergy with prodrugs. In the present review we summarise the current knowledge concerning the benefits of the combination of OV and cytotoxic drug treatment and discuss the translational opportunities such therapeutic synergies have in the fight against cancer.

  14. Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy.

    PubMed

    Swart, Maarten; Verbrugge, Inge; Beltman, Joost B

    2016-01-01

    In healthy individuals, immune-checkpoint molecules prevent autoimmune responses and limit immune cell-mediated tissue damage. Tumors frequently exploit these molecules to evade eradication by the immune system. Over the past years, immune-checkpoint blockade of cytotoxic T lymphocyte antigen-4 and programed death-1 emerged as promising strategies to activate antitumor cytotoxic T cell responses. Although complete regression and long-term survival is achieved in some patients, not all patients respond. This review describes promising, novel combination approaches involving immune-checkpoint blockade in the context of the cancer-immunity cycle, aimed at increasing response rates to the single treatments. Specifically, we discuss combinations that promote antigen release and presentation, that further amplify T cell activation, that inhibit trafficking of regulatory T cells or MSDCs, that stimulate intratumoral T cell infiltration, that increase cancer recognition by T cells, and that stimulate tumor killing.

  15. Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy

    PubMed Central

    Swart, Maarten; Verbrugge, Inge; Beltman, Joost B.

    2016-01-01

    In healthy individuals, immune-checkpoint molecules prevent autoimmune responses and limit immune cell-mediated tissue damage. Tumors frequently exploit these molecules to evade eradication by the immune system. Over the past years, immune-checkpoint blockade of cytotoxic T lymphocyte antigen-4 and programed death-1 emerged as promising strategies to activate antitumor cytotoxic T cell responses. Although complete regression and long-term survival is achieved in some patients, not all patients respond. This review describes promising, novel combination approaches involving immune-checkpoint blockade in the context of the cancer-immunity cycle, aimed at increasing response rates to the single treatments. Specifically, we discuss combinations that promote antigen release and presentation, that further amplify T cell activation, that inhibit trafficking of regulatory T cells or MSDCs, that stimulate intratumoral T cell infiltration, that increase cancer recognition by T cells, and that stimulate tumor killing. PMID:27847783

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

    DTIC Science & Technology

    2012-09-01

    hepatic metabo- lism based on the ratio of total liver:intestinal CYP3A, the major cytochrome P450 enzyme sub-family responsible for lapatinib...combination with cyclosporin A. Alternatively, the increase in exposure was likely more resultant of competitive inhibition of cytochrome P450 enzymes by...sex on the clearance of cytochrome P450 3A substrates. Clin Pharmacokinet 44(1):33–60 27. Bischoff KB, Dedrick RL, Zaharko DS (1970) Preliminary

  17. [Antioxidant therapy in combined treatment of postoperative intestinal paresis].

    PubMed

    Magomedov, M A

    2004-01-01

    Method of treatment of postoperative intestinal paresis with antioxidant emoxipin in experiment demonstrated that stabilization of redox processes and antioxidant systems in intestinal tissues leads to compensation of energy deficiency and recovery of intestinal peristalsis. Clinical use of this method in combined treatment of patients with postoperative intestinal paresis in acute generalized peritonitis reduces time of postoperative intestinal paresis and intoxication, lethality reduced 1,7-fold.

  18. Natural Killer Cells to the Attack: Combination Therapy against Neuroblastoma.

    PubMed

    Zenarruzabeitia, Olatz; Vitallé, Joana; Astigarraga, Itziar; Borrego, Francisco

    2017-02-01

    TGFβ in the tumor microenvironment diminishes natural killer (NK) cell-mediated anti-disialoganglioside (anti-GD2) mAb elimination of neuroblastoma cells. Consequently, blockade of TGFβ signaling with galunisertib in combination with the anti-GD2 mAb dinutuximab plus adoptively transferred NK cells is a promising tool for the treatment of neuroblastoma. Clin Cancer Res; 23(3); 615-7. ©2016 AACRSee related article by Tran et al., p. 804.

  19. Use of biologic agents in combination with other therapies for the treatment of psoriasis.

    PubMed

    Cather, Jennifer C; Crowley, Jeffrey J

    2014-12-01

    Psoriasis is a chronic inflammatory skin disorder, which is associated with a significant negative impact on a patient's quality of life. Traditional therapies for psoriasis are often not able to meet desired treatment goals, and high-dose and/or long-term use is associated with toxicities that can result in end-organ damage. An improved understanding of the involvement of cytokines in the etiology of psoriasis has led to the development of biologic agents targeting tumor necrosis factor (TNF)-α and interleukins (ILs)-12/23. While biologic agents have improved treatment outcomes, they are not effective in all individuals with psoriasis. The combination of biologic agents with traditional therapies may provide improved therapeutic options for patients who inadequately respond to a single drug or when efficacy may be increased with supplementation of another treatment. In addition, combination therapy may reduce safety concerns and cumulative toxicity, as lower doses of individual agents may be efficacious when used together. This article reviews the current evidence available on the efficacy and safety of combining biologic agents with systemic therapies (methotrexate, cyclosporine, or retinoids) or with phototherapy, and the combination of biologic agents themselves. Guidance is provided to help physicians identify situations and the characteristics of patients who would benefit from combination therapy with a biologic agent. Finally, the potential clinical impact of biologic therapies in development (e.g., those targeting IL-17A, IL-17RA, or IL-23 alone) is analyzed.

  20. Enzyme and combination therapy with cyclosporin A in the rat developing adjuvant arthritis.

    PubMed

    Rovenská, E; Svík, K; Stancíková, M; Rovenský, J

    1999-01-01

    Recent knowledge of the pathophysiology of rheumatoid arthritis and the mechanism of drug effects have enabled the use of new drugs and drug combinations in rheumatoid arthritis therapy. This study investigates the efficacy of both enzyme therapy and combined therapy with cyclosporin in rats with adjuvant arthritis. Rats with adjuvant-induced arthritis were administered either cyclosporin A (2.5 or 5.0 mg/kg/day per os), a mixture of enzymes (Phlogenzym (PHL); 45 mg/kg twice daily intrarectally), or a combination of 2.5 mg cyclosporin A and 90 mg PHL for a period of 40 days from the adjuvant application. Levels of serum albumin, changes in hind paw swelling and bone erosions were measured in rats as variables of inflammation and arthritis-associated destructive changes. Treatment with 5 mg of cyclosporin A, as well as with the combination therapy with cyclosporin A plus PHL, significantly inhibited both the inflammation and destructive arthritis-associated changes. However, 2.5 mg of cyclosporin A and PHL alone inhibited these disease markers, although to a lesser extent and at a later stage of arthritis development. The results show the inhibitory effect of enzyme therapy on rat adjuvant arthritis, as well as the efficacy of a low dose of cyclosporin A given in combination with enzyme therapy, which may be useful in the treatment of rheumatoid arthritis.

  1. Immune Effects of Chemotherapy, Radiation, and Targeted Therapy and Opportunities for Combination With Immunotherapy

    PubMed Central

    Wargo, Jennifer A.; Reuben, Alexandre; Cooper, Zachary A.; Oh, Kevin S.; Sullivan, Ryan J.

    2016-01-01

    There have been significant advances in cancer treatment over the past several years through the use of chemotherapy, radiation therapy, molecularly targeted therapy, and immunotherapy. Despite these advances, treatments such as monotherapy or monomodality have significant limitations. There is increasing interest in using these strategies in combination; however, it is not completely clear how best to incorporate molecularly targeted and immune-targeted therapies into combination regimens. This is particularly pertinent when considering combinations with immunotherapy, as other types of therapy may have significant impact on host immunity, the tumor microenvironment, or both. Thus, the influence of chemotherapy, radiation therapy, and molecularly targeted therapy on the host anti-tumor immune response and the host anti-host response (ie, autoimmune toxicity) must be taken into consideration when designing immunotherapy-based combination regimens. We present data related to many of these combination approaches in the context of investigations in patients with melanoma and discuss their potential relationship to management of patients with other tumor types. Importantly, we also highlight challenges of these approaches and emphasize the need for continued translational research. PMID:26320064

  2. 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.

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

    PubMed

    Cui, Liwang; Su, Xin-zhuan

    2009-10-01

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

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

    PubMed Central

    Cui, Liwang; Su, Xin-zhuan

    2009-01-01

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

  5. Class II combination therapy (distal jet and Jasper Jumpers): a case report.

    PubMed

    Bowman, S J

    2000-09-01

    Class II combination therapy is a method that combines orthodontic and orthopedic mechanics in a single stage of treatment. Molar distalization is followed by fixed functional mechanics to reduce the dependence upon patient compliance while seeking more predictable completion of Class II correction.

  6. Combining and sequencing medication and cognitive-behaviour therapy for childhood anxiety disorders.

    PubMed

    Keeton, Courtney P; Ginsburg, Golda S

    2008-04-01

    Despite the absence of data on the efficacy of combination therapy (i.e., psychosocial and medication) for the treatment of anxiety disorders in youths, clinicians in clinical practice often utilize this treatment approach. This paper discusses issues related to sequencing, combining, and integrating cognitive behavioural and pharmacological interventions for anxiety disorders in children and adolescents. We briefly summarize the empirical evidence for mono and combination therapy and raise a variety of issues that should be considered when making treatment decisions. Finally, we present an integrated treatment model to facilitate the delivery of a comprehensive treatment approach across care providers. These suggestions are geared toward optimizing clinical outcomes for anxious youths.

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

    PubMed Central

    Macauley, Shannon L

    2017-01-01

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

  9. Nanostructured lipid carriers of artemether-lumefantrine combination for intravenous therapy of cerebral malaria.

    PubMed

    Prabhu, Priyanka; Suryavanshi, Shital; Pathak, Sulabha; Patra, Aditya; Sharma, Shobhona; Patravale, Vandana

    2016-11-20

    Patients with cerebral malaria (CM) are unable to take oral medication due to impaired consciousness and vomiting thus necessitating parenteral therapy. Quinine, artemether, and artesunate which are currently used for parenteral malaria therapy have their own drawbacks. The World Health Organization (WHO) has now banned monotherapy and recommends artemisinin-based combination therapy for malaria treatment. However, presently there is no intravenous formulation available for combination therapy of malaria. Artemether-Lumefantrine (ARM-LFN) is a WHO approved combination for oral malaria therapy. However, the low aqueous solubility of ARM and LFN hinders their intravenous delivery. The objective of this study was to formulate ARM-LFN nanostructured lipid carriers (NLC) for intravenous therapy of CM. ARM-LFN NLC were prepared by microemulsion template technique and characterized for size, drug content, entrapment efficiency, drug release, crystallinity, morphology, amenability to autoclaving, compatibility with infusion fluids, stability, antimalarial efficacy in mice, and toxicity in rats. The ARM-LFN NLC showed sustained drug release, amenability to autoclaving, compatibility with infusion fluids, good stability, complete parasite clearance and reversal of CM symptoms with 100% survival in Plasmodium berghei-infected mice, and safety in rats. The biocompatible ARM-LFN NLC fabricated by an industrially feasible technique offer a promising solution for intravenous therapy of CM.

  10. Combination Therapy for Acne Scarring: Personal Experience and Clinical Suggestions.

    PubMed

    Kroepfl, Lucija; Emer, Jason J

    2016-11-01

    Acne is one of the most prevalent skin conditions seen by dermatologists. The cosmetic sequelae of severe acne, including scarring and pigmentation, have a profound psychological impact on those in icted. Topical (eg, retinoids, antibiotics, dapsone, hydroxyacids) and oral treatments (eg, antibiotics and/or spironolactone) are often bene cial to control acne or in the instance of oral isotretinoin use, rid the acne permanently; however, these treatments have very little affect on the ultimate cosmetic outcome of the acne scarring and skin texture that results. Given the variety of scar types that can form and the variability of responses seen in various skin types and textures, treatment options are vast without appropriate guidelines for pathways that dictate best timing, combinations, and options in given clinical scenarios. Current treatment options include solo or combina- tions of energy-based (eg, laser, radiofrequency), chemical-based (eg, peels, TCA cross), surgical-based options (eg, subcision, punch excision), microneedling, and llers and/or fat injections. Most recently, fractional radiofrequency-based treatments have been used to improve acne scarring with less reported downtime as compared to lasers or chemical peels and the ability to treat darker or sensitive skin types with less risk of scarring or hyperpigmentation. In severe cystic ares, scarring treatments are often postposed till the acne is under control and in many instances this can limit the dermatologists ability to affect future cosmetic treatments. Based on personal experience of various clinical scenarios in a busy laser practice that treats a signi cant number of patients with acne scarring, fractional radiofrequency is an excellent choice for treating all forms of acne scars with minimal risk to patients, even those on concurrent treatments such as isotretinoin. Additionally, fractional radiofrequency can be used in combination with all other treatment options to speed the time to

  11. Combination Therapy of Etanercept and Fumarates versus Etanercept Monotherapy in Psoriasis: A Randomized Exploratory Study

    PubMed Central

    van Bezooijen, Ji Sun; Balak, Deepak M.W.; van Doorn, Martijn B.A.; Looman, Caspar W.N.; Schreurs, Marco W.J.; Koch, Birgit C.P.; van Gelder, Teun; Prens, Errol P.

    2016-01-01

    Background Biologics are a safe and efficacious therapy for psoriasis. The drug survival of biologics may be disappointing, primarily due to loss of efficacy. Therefore, safe combination treatments are sought to improve their clinical response. Objective To assess the efficacy, safety and tolerability of the combination therapy of etanercept with fumarates versus etanercept monotherapy. Methods Thirty-three patients with psoriasis were randomized 1:1 to receive etanercept combined with fumarates or etanercept monotherapy. The primary outcome measure was the difference in PASI-75 response after 24 weeks; additionally, a longitudinal analysis was performed. An important secondary outcome measure was the proportion of patients with a Physician Global Assessment (PGA) of clear or almost clear. Adverse events were collected throughout the study. Results In the combination therapy group, 78% (14 out of 18 patients) reached PASI-75 at week 24 versus 57% (8 out of 14 patients) in the monotherapy group (p = 0.27). The longitudinal analysis showed a PASI reduction of 5.97% per week for the combination therapy group and of 4.76% for the monotherapy group (p = 0.11). In the combination therapy group, 94% (17 out of 18 patients) of patients had a PGA of clear/almost clear versus 64% (9 out of 14 patients) in the monotherapy group (p = 0.064). The incidence of mild gastrointestinal complaints was higher in the combination group than in the monotherapy group. Conclusion Using the PGA, combination therapy showed a trend towards faster improvement in the first 24 weeks. The difference in the PASI score between the two groups was not statistically significant. Addition of fumarates to etanercept for 48 weeks appeared safe with an acceptable tolerability. PMID:27576483

  12. Prospective randomized crossover trial of combination therapy with bezafibrate and UDCA for primary biliary cirrhosis.

    PubMed

    Itakura, Jun; Izumi, Namiki; Nishimura, Yuki; Inoue, Kazunari; Ueda, Ken; Nakanishi, Hiroyuki; Tsuchiya, Kaoru; Hamano, Kosei; Asahina, Yasuhiro; Kurosaki, Masayuki; Uchihara, Masakatsu; Miyake, Shozo

    2004-08-01

    The aim of this study was to evaluate the effects of the combination therapy with bezafibrate and ursodeoxycholic acid (UDCA) for primary biliary cirrhosis (PBC), compared to UDCA monotherapy. Sixteen patients with compensated PBC were divided randomly into two groups. Group A received treatment with bezafibrate and UDCA for 6 months, while group B received UDCA alone, treatment protocols were then exchanged for another 6 months. The laboratory data was followed every month. The mean levels of alkaline phosphatase (ALP) decreased significantly more in group A than in group B in the first half of the study. Then serum ALP levels were elevated in group A after exchanged the therapy, but fell down in group B. Serum levels of gamma-glutamyl transferase (GGT), immunoglobulin M and triglycerides values were significantly lower in group B than in group A, after changing therapies from monotherapy to combination therapy with bezafibrate and UDCA. The mean levels of ALP, GGT and triglycerides were significantly lower at the end of the combination therapy than those at the end of the monotherapy. The combination therapy with bezafibrate and UDCA significantly improves the laboratory data that specific for PBC in comparison with UDCA monotherapy.

  13. [Current optimization of combined therapy for chronic obstructive pulmonary disease].

    PubMed

    Popova, E N

    2015-01-01

    Testing the new combined bronchodilator Anoro Ellipta in different clinical trials gives to its high clinical efficacy and safety in chronic obstructive pulmonary disease. The drug contains the molecules of sustained-release selective β2-adrenergic receptor agonist (vilanterol) and a muscarinic cholinergic receptor antagonist (umeclidinium bromide). The bronchodilating mechanisms of umeclidinium bromide are in the competitive inhibition of the binding of acetylcholine with muscarinic acetylcholine receptors of airway smooth muscles whereas in those of vilanterol are in that with the stimulation of intracellular adenylate cyclase. On days 1 and 24 after inhalation of the first dose of vilanterol and umeclidinium bromide, there was a significant increase in the forced expiratory volume in one second as compared to placebo. No clinical effects on QT interval on an electrocardiogram and cardiac rhythm were found. The benefits of an inhalation device (Ellipta) are its innovation design ensuring the effective delivery of an aerosol dose into the airway, convenience, and simplicity.

  14. Combined Immune Therapy for the Treatment of Visceral Leishmaniasis

    PubMed Central

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

    2016-01-01

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

  15. Epigenetic polypharmacology: from combination therapy to multitargeted drugs.

    PubMed

    de Lera, Angel R; Ganesan, A

    The modern drug discovery process has largely focused its attention in the so-called magic bullets, single chemical entities that exhibit high selectivity and potency for a particular target. This approach was based on the assumption that the deregulation of a protein was causally linked to a disease state, and the pharmacological intervention through inhibition of the deregulated target was able to restore normal cell function. However, the use of cocktails or multicomponent drugs to address several targets simultaneously is also popular to treat multifactorial diseases such as cancer and neurological disorders. We review the state of the art with such combinations that have an epigenetic target as one of their mechanisms of action. Epigenetic drug discovery is a rapidly advancing field, and drugs targeting epigenetic enzymes are in the clinic for the treatment of hematological cancers. Approved and experimental epigenetic drugs are undergoing clinical trials in combination with other therapeutic agents via fused or linked pharmacophores in order to benefit from synergistic effects of polypharmacology. In addition, ligands are being discovered which, as single chemical entities, are able to modulate multiple epigenetic targets simultaneously (multitarget epigenetic drugs). These multiple ligands should in principle have a lower risk of drug-drug interactions and drug resistance compared to cocktails or multicomponent drugs. This new generation may rival the so-called magic bullets in the treatment of diseases that arise as a consequence of the deregulation of multiple signaling pathways provided the challenge of optimization of the activities shown by the pharmacophores with the different targets is addressed.

  16. Adoptive transfer of Aspergillus-specific T cells as a novel anti-fungal therapy for hematopoietic stem cell transplant recipients: Progress and challenges.

    PubMed

    Papadopoulou, Anastasia; Kaloyannidis, Panayotis; Yannaki, Evangelia; Cruz, Conrad Russell

    2016-02-01

    Although newer antifungal drugs have substantially altered the natural history of invasive aspergillosis, the disease still accounts for significant morbidity and mortality in hematopoietic stem cell transplant recipients. Both the evidence supporting a protective role of T cells against this fungal pathogen and the documented efficacy of adoptive transfer of antigen-specific T cells for prophylaxis and treatment of viral infections post-transplant have stimulated much interest towards development of Aspergillus-specific T cells (Asp-STs) for adoptive immunotherapy in the allogeneic transplant setting. In contrast to the remarkable progress with virus-specific T cells, clinical development of fungus-specific T cells is still in its infancy. Several groups have characterized Asp-STs in healthy individuals and patients with malignant hematological diseases, while others sought to develop GMP-compliant methods of expanding or bioengineering Asp-STs ex vivo as immunotherapy. This review highlights the recent advances in this field, and discusses critical issues involved in development and protocol design of Asp-ST immunotherapy.

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

    PubMed

    Chou, Wan-Yi; Hsu, Chih-Jung

    2016-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    Chou, Wan-Yi; Hsu, Chih-Jung

    2016-01-01

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

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

    PubMed

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

    2004-01-01

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

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

    NASA Astrophysics Data System (ADS)

    Halasa, Salaheldin; Dickinson, Eva

    2014-02-01

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

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

    PubMed

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

    2002-06-28

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

  3. 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

  4. Pharmacokinetics of saquinavir, zidovudine, and zalcitabine in combination therapy.

    PubMed Central

    Vanhove, G F; Kastrissios, H; Gries, J M; Verotta, D; Park, K; Collier, A C; Squires, K; Sheiner, L B; Blaschke, T F

    1997-01-01

    We investigated the pharmacokinetics of zidovudine, zalcitabine, and saquinavir in AIDS Clinical Trial Group protocol 229. Patients received either saquinavir, zalcitabine, or a combination of both, together with zidovudine three times a day. Approximately 100 patients were enrolled in each treatment arm, and intensive pharmacokinetic studies were performed on about 25 patients per arm at weeks 1 and 12. We estimated the pharmacokinetic parameters of all three drugs by using parametric and nonparametric methods. The mean values of the pharmacokinetic parameters of zidovudine (clearance [CL]/bioavailability [F], 168 liters/h; volume of distribution [V]/F, 185 liters; half-life, 0.76 h) and zalcitabine (CL/F, 25 liters/h; V/F, 92.2 liters; half-life, 2.7 h) were similar to those reported previously. For saquinavir, the mean pharmacokinetic parameter estimates using parametric methods were as follows: maximum concentration of drug in serum [Cmax], 70.8 ng/ml; time to Cmax, 3.11 h; area under the curve, 809 ng x h/ml; CL/F, 989 liters/h; V/F, 1,503 liters; half-life, 1.38 h. For all three drugs, clearance decreased with age. Weight did not influence the clearance of zidovudine, but the clearance of zalcitabine and saquinavir increased with weight. There were no differences in pharmacokinetic parameters between study weeks and arms, suggesting that there is no change in kinetics with chronic administration and that there are no significant pharmacokinetic interactions among these three drugs. PMID:9371345

  5. Gene therapy for severe combined immunodeficiency due to adenosine deaminase deficiency.

    PubMed

    Montiel-Equihua, Claudia A; Thrasher, Adrian J; Gaspar, H Bobby

    2012-02-01

    The severe combined immunodeficiency caused by the absence of adenosine deaminase (SCID-ADA) was the first monogenic disorder for which gene therapy was developed. Over 30 patients have been treated worldwide using the current protocols, and most of them have experienced clinical benefit; importantly, in the absence of any vector-related complications. In this document, we review the progress made so far in the development and establishment of gene therapy as an alternative form of treatment for ADA-SCID patients.

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

    PubMed

    Boyapati, Ann; Sinclair, Rodney

    2013-02-01

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

  7. Liver toxicity induced by combined external-beam irradiation and radioimmunoglobulin therapy

    SciTech Connect

    Wang, S.; Quadri, S.M.; Tang, X.Z.; Vriesendorp, H.M.; Stephens, L.C.; Lollo, C.P.; Bartholomew, R.M.

    1995-03-01

    High-dose radiation therapy for liver metastases of gastrointestinal malignancies might be improved by combining external-beam irradiation and radioimmunoglobulin therapy. We studied the liver toxicity of the proposed combination in healthy beagle dogs. A total dose of 30 Gy to the whole liver, delivered in 2-Gy fractions over 3 weeks, resulted in mild, temporary veno-occlusive disease (VOD) in three of three dogs. Reversible bone marrow damage was noted after two intravenous injections of 18.5 MBq of yttrium-90-labeled monoclonal antibody ZCE025 per kg body weight in three of three dogs. Administrations of the antibody were separated by 1 week. Three dogs treated by irradiation of the liver with radioimmunoglobulin therapy added during the last 2 weeks of the irradiation showed signs of radiation hepatitis (VOD) starting around 35 days after treatment. One dog had a complete recovery, and two dogs were euthanized in a stage of terminal liver failure around day 90 after treatment. Temporary bone marrow damage was observed after the combined treatment, similar to the bone marrow damage observed after radioimmunoglobulin therapy alone. Earlier studies in the same dog model showed that bone marrow is the dose-limiting organ if radioimmunoglobulin therapy is used alone. The addition of irradiation of the liver to radioimmunoglobulin therapy changes the dose-limiting organ from bone marrow to liver. The radiation hepatitis observed in dogs is very similar to that observed in humans and is reflected in early platelet consumption in the irradiated liver plus late elevations of liver enzymes and VOD in central hepatic veins on histological analysis. Future applications of combined liver irradiation and radioimmunoglobulin therapy in humans should use radioimmunoglobulin therapy agents which show minimal uptake by normal liver. 20 refs., 7 figs., 4 tabs.

  8. Corpus uteri cancer: the results of surgical, combined and complex therapy.

    PubMed

    Vishnevskaya, E E

    1991-01-01

    The Author has examined the survival rates of 1543 cases of corpus uteri cancer, comparing the patients with and without pre-operative adjuvant treatment. Pre-operative treatment consisted of irradiation therapy and also in combined chemohormonal-radiotherapy. The results also referred to the type of radiotherapy and to the clinical background of patients (older age, severe general somatic diseases). The conclusions of this study underline the benefits of pre-operative irradiation therapy.

  9. HIV-1 CCR5 gene therapy will fail unless it is combined with a suicide gene.

    PubMed

    Pandit, Aridaman; de Boer, Rob J

    2015-12-17

    Highly active antiretroviral therapy (ART) has successfully turned Human immunodeficiency virus type 1 (HIV-1) from a deadly pathogen into a manageable chronic infection. ART is a lifelong therapy which is both expensive and toxic, and HIV can become resistant to it. An alternative to lifelong ART is gene therapy that targets the CCR5 co-receptor and creates a population of genetically modified host cells that are less susceptible to viral infection. With generic mathematical models we show that gene therapy that only targets the CCR5 co-receptor fails to suppress HIV-1 (which is in agreement with current data). We predict that the same gene therapy can be markedly improved if it is combined with a suicide gene that is only expressed upon HIV-1 infection.

  10. HIV-1 CCR5 gene therapy will fail unless it is combined with a suicide gene

    PubMed Central

    Pandit, Aridaman; de Boer, Rob J.

    2015-01-01

    Highly active antiretroviral therapy (ART) has successfully turned Human immunodeficiency virus type 1 (HIV-1) from a deadly pathogen into a manageable chronic infection. ART is a lifelong therapy which is both expensive and toxic, and HIV can become resistant to it. An alternative to lifelong ART is gene therapy that targets the CCR5 co-receptor and creates a population of genetically modified host cells that are less susceptible to viral infection. With generic mathematical models we show that gene therapy that only targets the CCR5 co-receptor fails to suppress HIV-1 (which is in agreement with current data). We predict that the same gene therapy can be markedly improved if it is combined with a suicide gene that is only expressed upon HIV-1 infection. PMID:26674113

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

    PubMed Central

    Yang, Ying-Chieh; Chiang, Chi-Shiun

    2016-01-01

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

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

    PubMed Central

    Chen, Luming; Sun, Jihong; Yang, Xiaoming

    2015-01-01

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

  13. Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma

    PubMed Central

    Richter, Joshua; Neparidze, Natalia; Zhang, Lin; Nair, Shiny; Monesmith, Tamara; Sundaram, Ranjini; Miesowicz, Fred; Dhodapkar, Kavita M.

    2013-01-01

    Natural killer T (iNKT) cells can help mediate immune surveillance against tumors in mice. Prior studies targeting human iNKT cells were limited to therapy of advanced cancer and led to only modest activation of innate immunity. Clinical myeloma is preceded by an asymptomatic precursor phase. Lenalidomide was shown to mediate antigen-specific costimulation of human iNKT cells. We treated 6 patients with asymptomatic myeloma with 3 cycles of combination of α-galactosylceramide–loaded monocyte-derived dendritic cells and low-dose lenalidomide. Therapy was well tolerated and led to reduction in tumor-associated monoclonal immunoglobulin in 3 of 4 patients with measurable disease. Combination therapy led to activation-induced decline in measurable iNKT cells and activation of NK cells with an increase in NKG2D and CD56 expression. Treatment also led to activation of monocytes with an increase in CD16 expression. Each cycle of therapy was associated with induction of eosinophilia as well as an increase in serum soluble IL2 receptor. Clinical responses correlated with pre-existing or treatment-induced antitumor T-cell immunity. These data demonstrate synergistic activation of several innate immune cells by this combination and the capacity to mediate tumor regression. Combination therapies targeting iNKT cells may be of benefit toward prevention of cancer in humans (trial registered at clinicaltrials.gov: NCT00698776). PMID:23100308

  14. Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma.

    PubMed

    Richter, Joshua; Neparidze, Natalia; Zhang, Lin; Nair, Shiny; Monesmith, Tamara; Sundaram, Ranjini; Miesowicz, Fred; Dhodapkar, Kavita M; Dhodapkar, Madhav V

    2013-01-17

    Natural killer T (iNKT) cells can help mediate immune surveillance against tumors in mice. Prior studies targeting human iNKT cells were limited to therapy of advanced cancer and led to only modest activation of innate immunity. Clinical myeloma is preceded by an asymptomatic precursor phase. Lenalidomide was shown to mediate antigen-specific costimulation of human iNKT cells. We treated 6 patients with asymptomatic myeloma with 3 cycles of combination of α-galactosylceramide-loaded monocyte-derived dendritic cells and low-dose lenalidomide. Therapy was well tolerated and led to reduction in tumor-associated monoclonal immunoglobulin in 3 of 4 patients with measurable disease. Combination therapy led to activation-induced decline in measurable iNKT cells and activation of NK cells with an increase in NKG2D and CD56 expression. Treatment also led to activation of monocytes with an increase in CD16 expression. Each cycle of therapy was associated with induction of eosinophilia as well as an increase in serum soluble IL2 receptor. Clinical responses correlated with pre-existing or treatment-induced antitumor T-cell immunity. These data demonstrate synergistic activation of several innate immune cells by this combination and the capacity to mediate tumor regression. Combination therapies targeting iNKT cells may be of benefit toward prevention of cancer in humans.

  15. The Efficacy of Colchicine and Dapsone Combination Therapy in Relapsed Immune Thrombocytopenia

    PubMed Central

    Rattanathammethee, Thanawat; Theerajangkhaphichai, Wasan; Rattarittamrong, Ekarat; Hantrakool, Sasinee; Chai-Adisaksopha, Chatree; Norasetthada, Lalita; Tantiworawit, Adisak

    2017-01-01

    The aim of the present paper is to evaluate the efficacy and safety of colchicine and dapsone combination therapy in cases of steroid-dependent, relapsed and refractory immune thrombocytopenia (ITP). This is a retrospective study of ITP patients who attended the Hematology Clinic at Chiang Mai University Hospital (Thailand) from 1 January 2008 to 30 September 2014. Medical records and clinical data were reviewed for efficacy and adverse effects. Sixty-four ITP patients received the combination therapy. The median age was 46 years and 70.3% were female. The majority (65.6%) were relapsed ITP patients. Median platelet count before starting treatment was 22.6×109/L. The response rate was 82.8%, with 75.0% of patients having a complete response. Median time to response was 8 weeks. The response rate was higher in relapsed patients (90.4%) compared to refractory (61.5%) and steroid-dependent patients (77.8%). Steroid treatment was discontinued in 30 patients (50%) following combination therapy. The most common side effect was hemolysis due to dapsone which was found in eight patients (12.5%). We can therefore conclude that combination therapy with colchicine and dapsone is an alternative second-line therapy option in relapsed ITP cases with acceptable side effects. PMID:28286634

  16. Combined Space and Alertness Related Therapy of Visual Hemineglect: Effect of Therapy Frequency

    PubMed Central

    Sturm, Walter; Thimm, M.; Binkofski, F.; Horoufchin, H.; Fink, G. R.; Küst, J.; Karbe, H.; Willmes, K.

    2013-01-01

    The combined efficacy of space- and alertness related training in chronic hemineglect was tested behaviorally and in a longitudinal fMRI study. Earlier results had shown that both space as well as alertness related training as single intervention methods lead to short term improvement which, however, is not stable for longer time periods. The neurobiological data obtained in these studies revealed differential cortical reorganization patterns for the two training approaches thereby leading to the hypothesis that a combination of both trainings might result in stronger and longer lasting effects. The results of our current study, however, – at least at first glance – do not clearly corroborate this hypothesis, because neither alertness training alone nor the combination with OKS on the group level led to significant behavioral improvement, although four of the six patients after alertness and even more after combined training showed a higher percentage of behavioral improvement than during baseline. Despite the lack of clearcut behavioral training induced improvement we found right parietal or fronto-parietal increase of activation in the imaging data immediately after combined training and at follow-up 3 weeks later. The study design had called for splitting up training time between the two training approaches in order to match total training time with our earlier single training studies. The results of our current study are discussed as a possible consequence of reduced training time and intensity of both training measures under the combined training situation. PMID:23908613

  17. Fixed-dose combination therapy for the prevention of cardiovascular disease

    PubMed Central

    de Cates, Angharad N; Farr, Matthew RB; Rees, Karen; Casas, Juan P; Huffman, Mark

    2014-01-01

    This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the effectiveness of fixed-dose combination therapy on optimising CVD risk factors and reducing CVD fatal and non-fatal events for both primary and secondary prevention of CVD. Details of CVD events and risk factors included are listed in the methods. We will also determine any adverse events associated with taking fixed-dose combination therapy. This will include studies conducted in both developed and developing regions of the world. PMID:25267903

  18. Antifungal susceptibility testing.

    PubMed Central

    Rex, J H; Pfaller, M A; Rinaldi, M G; Polak, A; Galgiani, J N

    1993-01-01

    Unlike antibacterial susceptibility testing, reliable antifungal susceptibility testing is still largely in its infancy. Many methods have been described, but they produce widely discrepant results unless such factors as pH, inoculum size, medium formulation, incubation time, and incubation temperature are carefully controlled. Even when laboratories agree upon a common method, interlaboratory agreement may be poor. As a result of numerous collaborative projects carried out both independently and under the aegis of the Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards, the effects of varying these factors have been extensively studied and a standard method which minimizes interlaboratory variability during the testing of Candida spp. and Cryptococcus neoformans has been proposed. This review summarizes this work, reviews the strengths and weaknesses of the proposed susceptibility testing standard, and identifies directions for future work. PMID:8269392

  19. Assessment of combination therapy in BALB/c mice injected with carbapenem-resistant Enterobacteriaceae strains

    PubMed Central

    Salloum, Noor A.; Kissoyan, Kohar Annie B.; Fadlallah, Sukayna; Cheaito, Katia; Araj, George F.; Wakim, Rima; Kanj, Souha; Kanafani, Zeina; Dbaibo, Ghassan; Matar, Ghassan M.

    2015-01-01

    Monotherapeutic options for carbapenem resistant infections are limited. Studies suggest that combination therapy may be associated with better outcomes than monotherapies. However, this is still controversial. This study assessed, the efficacy of combination therapy against carbapenem resistant Enterobacteriaceae harboring singly various extended spectrum beta lactamase or carbapenemase encoding genes. Thus, four isolates harboring either blaCTXM-15, blaCTXM-15 and blaOXA-48, blaNDM-1, or blaKPC-2 genes were selected for testing. Minimal inhibitory concentration was determined by broth dilution method. Gene transcript levels on single and combined treatments were done in vitro and in vivo by qRT-PCR. Assessment of treatments was done in BALB/c mice according to a specific protocol. As such, the qRT-PCR revealed a significant decrease of transcript levels in all isolates upon using rifampicin or tigecycline, singly or in combination with colistin. However, variable levels were obtained using colistin singly or in combination with meropenem or fosfomycin. In vivo assessment showed that all combinations used were effective against isolates harboring blaCTXM-15, blaOXA-48, and blaNDM-1. Conversely, the most significant combination against the isolate harboring blaKPC-2 gene was colistin with either carbapenem, fosfomycin, or kanamycin. As a conclusion, combination therapy selected based on the type of carbapenemase produced, appeared to be non-toxic and might be effective in BALB/c mice. Therefore, the use of a rationally optimized combination therapy might lead to better results than monotherapy, however, clinical trials are needed for human consumption. PMID:26441926

  20. New potential chemotherapy for ovarian cancer - Combined therapy with WP 631 and epothilone B.

    PubMed

    Bukowska, Barbara; Rogalska, Aneta; Marczak, Agnieszka

    2016-04-15

    Despite more modern therapeutics approaches and the use of new drugs for chemotherapy, patients with ovarian cancer still have poor prognosis and therefore, new strategies for its cure are highly needed. One of the promising ways is combined therapy, which has many advantages as minimizing drug resistance, enhancing efficacy of treatment, and reducing toxicity. Combined therapy has rich and successful history in the field of ovarian cancer treatment. Currently use therapy is usually based on platinum-containing agent (carboplatin or cisplatin) and a member of taxanes (paclitaxel or docetaxel). In the mid-2000s this standard regimen has been expanded with bevacizumab, monoclonal antibody directed to Vascular Endothelial Growth Factor (VEGF). Another drug combination with promising perspectives is WP 631 given together with epothilone B (Epo B). WP 631 is a bisanthracycline composed of two molecules of daunorubicin linked with a p-xylenyl linker. Epo B is a 16-membered macrolide manifesting similar mechanism of action to taxanes. Their effectiveness against ovarian cancer as single agents is well established. However, the combination of WP 631 and Epo B appeared to act synergistically, meaning that it is much more potent than the single drugs. The mechanism lying under its efficacy includes disturbing essential cell cycle-regulating proteins leading to mitotic slippage and following apoptosis, as well as affecting EpCAM and HMGB1 expression. In this article, we summarized the current state of knowledge regarding combined therapy based on WP 631 and Epo B as a potential way of ovarian cancer treatment.

  1. Effectiveness of combining manual therapy and acupuncture on temporomandibular joint dysfunction: a retrospective study.

    PubMed

    Shin, Byung-Cheul; Ha, Chung-Hyo; Song, Yung-Sun; Lee, Myeong Soo

    2007-01-01

    This retrospective study investigated the effects of combining manual therapy and acupuncture on the pain and maximal mouth opening (MMO), which were associated with temporomandibular joint dysfunction (TMD). The 49 TMD patients (15 men, 34 women; mean age = 30.47 years, SD = 13.52 years) were treated with a combination of acupuncture and manual therapy two or three times a week at the hospital. The pain and maximal mouth opening were assessed before and after 1 and 4 weeks of treatment. The combination therapy produced significant changes in pain levels (p < 0.001) and mouth opening (p < 0.001). All pairwise non-parametric comparison showed a significant improvement in pain (p < 0.05 for all pairs) and MMO (p < 0.05 for all pairs). These findings suggest that combining manual therapy and acupuncture decreases the pain level and increases the MMO of TMD patients. However, future studies should further investigate the efficacy of combined treatment on TMD with more rigorous randomized clinical trials.

  2. Efficacy of mizoribine and prednisolone combination therapy in adult patients with IgA vasculitis.

    PubMed

    Mima, Akira

    2017-03-02

    Immunoglobulin (Ig)A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, is one of the most common vasculitis caused by an IgA-mediated immune complex. It occurs most frequently in childhood and less commonly in adulthood. As for the treatment of IgAV in adults, there are few studies dealing with the administration and efficacy of intravenous pulse steroid therapy or combination therapy using prednisolone (PSL) and immunosuppressive drugs. Mizoribine (MZB) is a newly developed immunosuppressive drug with few adverse effects; however, there are currently few studies using MZB in adult patients with IgAV. In this study, we evaluated the efficacy of MZB combined with a course of PSL in adult patients with IgAV. Five patients with adult onset IgAV were enrolled in the study. All patients received oral PSL (initial dose 30-50 mg/day), and MZB was administered orally at a single morning dose of 150 mg. We investigated the clinical manifestations and prognosis of these patients receiving the combination therapy of MZB and PSL retrospectively. All patients showed complete or partial remission of proteinuria and microscopic hematuria with the combination therapy of MZB and PSL. Furthermore, no significant adverse effects were observed. Although this study had an uncontrolled small group, our results indicate that the combination of MZB with PSL could be a possible new treatment for adult patients with IgAV.

  3. Clinical translation of polymyxin-based combination therapy: Facts, challenges and future opportunities.

    PubMed

    Zhang, Xueli; Guo, Fengmei; Shao, Hua; Zheng, Xiao

    2017-02-01

    The emergence and spread of multidrug resistant Gram-negative bacteria has led to a resurgence in the clinical use of polymyxin antibiotics. However, the prevalence of polymyxin resistance is on the rise at an alarming rate, motivating the idea of combination therapy to sustain the revival of these "old" antibiotics. Although ample evidence in favor of combination therapy has emerged, it seems impracticable and confusing to find a promising combination from the diverse reports or gain adequate information on the efficacy and safety profile. With a stagnating discovery pipeline of novel antimicrobials, there is a clear need to fill the knowledge gaps in translating these basic research data to beneficial clinical practice. In this review, we examined the factors and ambiguities that stand as major hurdles in bringing polymyxin combination therapy to bedside care, highlighting the importance and urgency of incorporating translational research insights into areas of difficulty. We also discussed future research priorities that are essential to gather the necessary evidence and insights for promoting the best possible use of polymyxins in combination therapy.

  4. EUCAST breakpoints for antifungals.

    PubMed

    Rodríguez-Tudela, Juan L; Arendrup, Maiken C; Cuenca-Estrella, Manuel; Donnelly, J Peter; Lass-Flörl, Cornelia

    2010-03-01

    Susceptibility testing of fungi and development of interpretative breakpoints has become increasingly important due to the growing incidence of invasive fungal infections, the number and classes of antifungals, and the emerging reports of acquired resistance. The subcommittee on antifungal susceptibility testing of the European Committee on Antibiotic Susceptibility Testing (EUCAST) has developed standards for susceptibility testing of fermentative yeasts and molds as well as proposing breakpoints for fluconazole and voriconazole against Candida. The aim of this work is to describe the EUCAST process of setting breakpoints for antifungals. Five aspects are evaluated during the process of developing breakpoints: 1) the most common dosage used in each European country, 2) the definition of the wild-type population for each target microorganism at the species level and the determination of epidemiological cutoffs, 3) the drug's pharmacokinetics and 4) pharmacodynamics, including Monte Carlo simulations, and 5) the correlation of MICs with clinical outcome of patients treated with the compound. When insufficient data are available (e.g., due to lack of information on the clinical outcome of infections caused by isolates with an elevated MIC), epidemiological cutoff values, rather than breakpoints, are recommended until the necessary information becomes available.

  5. External beam re-irradiation, combination chemoradiotherapy, and particle therapy for the treatment of recurrent glioblastoma

    PubMed Central

    Taunk, Neil K.; Moraes, Fabio Y.; Escorcia, Freddy E.; Mendez, Lucas Castro; Beal, Kathryn; Marta, Gustavo N.

    2016-01-01

    SUMMARY Glioblastoma is a common aggressive primary malignant brain tumor, and is nearly universal in progression and mortality after initial treatment. Re-irradiation presents a promising treatment option for progressive disease, both palliating symptoms and potentially extending survival. Highly conformal radiation techniques such as stereotactic radiosurgery and hypofractionated radiosurgery are effective short courses of treatment that allow delivery of high doses of therapeutic radiation with steep dose gradients to protect normal tissue. Patients with higher performance status, younger age, and longer interval between primary treatment and progression represent the best candidates for re-irradiation. Multiple studies are also underway involving combinations of radiation and systemic therapy to bend the survival curve and improve the therapeutic index. In the multimodal treatment of recurrent high-grade glioma, the use of surgery, radiation, and systemic therapy should be highly individualized. Here we comprehensively review radiation therapy and techniques, along with discussion of combination treatment and novel strategies. PMID:26781426

  6. Esophageal ulcer caused by cytomegalovirus: resolution during combination antiretroviral therapy for acquired immunodeficiency syndrome.

    PubMed

    Mönkemüller, K E; Wilcox, C M

    2000-08-01

    A 36-year-old man with a 5-year history of untreated human immunodeficiency virus (HIV) infection had odynophagia for 14 days. Fifteen days earlier, he had begun taking trimethoprim-sulphamethoxazole and combination antiretroviral therapy that included lamivudine, zidovudine, and nelfinavir. He had no history of opportunistic infection. The CD4 lymphocyte count was 67/microL and HIV-RNA level was 359,396 copies/mL. Esophagogastroduodenoscopy revealed a large, well-circumscribed esophageal ulceration 31 cm from the incisors. Histopathologic examination of esophageal biopsy specimens showed cytopathic changes diagnostic of cytomegalovirus (CMV). In situ DNA hybridization was positive for CMV. While combination antiretroviral therapy was continued, the esophageal symptoms resolved within 4 days of endoscopy without specific therapy for CMV. Follow-up endoscopy 4 weeks later revealed a normal-appearing esophagus, and the patient has remained symptom-free for 10 months.

  7. Combining infliximab, anti-MAP and hyperbaric oxygen therapy for resistant fistulizing Crohn's disease

    PubMed Central

    Agrawal, Gaurav; Borody, Thomas; Turner, Robert; Leis, Sharyn; Campbell, Jordana

    2015-01-01

    Background: Fistulizing Crohn's disease (CD) presents a therapeutic challenge as fistulae are notoriously difficult to heal. Mycobacterium avium ss paratuberculosis (MAP) treatment in CD is gaining attention. Aim: We evaluated healing of CD fistula(e) using a novel combination therapy. Study: Nine consecutive patients who failed to heal fistulae on conventional treatment including anti-TNF, were treated with at least three doses of infliximab, 18–30 courses of hyperbaric oxygen therapy and anti-MAP antibiotics comprising rifabutin, clarithromycin and clofazimine. Results: All patients achieved complete healing of fistulae by 6–28 weeks and follow-up for mean 18 months. Conclusion: Combining infliximab, hyperbaric oxygen therapy and anti-MAP, seems to enable healing of recalcitrant fistulae and although a small case series, all nine patients achieved complete healing. PMID:28031926

  8. Novel Drugs and Combination Therapies for the Treatment of Metastatic Melanoma

    PubMed Central

    Vennepureddy, Adarsh; Thumallapally, Nishitha; Motilal Nehru, Vijeyaluxmy; Atallah, Jean-Paul; Terjanian, Terenig

    2016-01-01

    Metastatic melanoma (MM) still remains as one of the most worrisome cancer known to mankind. In last two decades, treatment of melanoma took a dramatic turn with the discovery of targeted therapy which targets the mutations in mitogen-activated protein kinase (MAPK) pathway and immune checkpoint inhibitors. These new findings have led to emergence of many novel drugs that have been approved by FDA. Targeted therapy drugs such as vemurafenib, trametinib and dabrafenib target the MAPK pathway whereas immunotherapies such as ipilimumab, nivolumab and pembrolizumab block immune checkpoint receptors on T lymphocytes. All these drugs have shown to improve the overall survival in MM. Despite these recent discoveries, treatment of MM remains challenging because of rapid development of resistance to targeted therapy. This review will discuss recently approved drugs and their adverse effects and also shed light on combination therapy in treatment of melanoma. PMID:26767073

  9. High dose simvastatin exhibits enhanced lipid lowering effects relative to simvastatin/ezetimibe combination therapy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Technical Abstract: Background: Statins are the frontline in cholesterol reduction therapies; however use in combination with agents that possess complimentary mechanisms of action may achieve further reduce in LDL-C. Methods and Results: Thirty-nine patients were treated with either 80mg simvasta...

  10. Outcomes and duration of Pneumocystis jiroveci pneumonia therapy in infants with severe combined immunodeficiency.

    PubMed

    Lundgren, Ingrid S; Englund, Janet A; Burroughs, Lauri M; Torgerson, Troy R; Skoda-Smith, Suzanne

    2012-01-01

    This retrospective review of patients with severe combined immunodeficiency and Pneumocystis jiroveci pneumonia (PCP) evaluated the relationship between duration of therapy to treat PCP and overall survival. We found that 80% of patients receiving only 21 days of antibiotics survived to 12 months beyond hematopoietic cell transplant, whereas only 25% of patients who required longer treatment for PCP survived to stem cell engraftment.

  11. Exploring Erythropoietin and G-CSF Combination Therapy in Chronic Stroke Patients

    PubMed Central

    Shin, Yoon-Kyum; Cho, Sung-Rae

    2016-01-01

    Erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) are known to have neuroprotective actions. Based on previous reports showing the synergistic effects of EPO+G-CSF combination therapy in experimental models, we investigated the safety of EPO+G-CSF combination therapy in patients with chronic stroke. In a pilot study, 3 patients were treated with EPO and G-CSF for 5 consecutive days, with follow-up on day 30. In an exploratory double-blind study, 6 patients were allocated to treatment with either EPO+G-CSF or placebo. Treatment was applied once a day for 5 days per month over 3 months. Participants were followed up for 6 months. To substantiate safety, vital signs, adverse events, and hematological values were measured on days 0, 5, and 30 in each cycle and on day 180. Functional outcomes were determined on day 0 and 180. In the laboratory measurements, EPO+G-CSF combination therapy significantly elevated erythropoietin, CD34+ hematopoietic stem cells, white blood cells, and neutrophils on day 5 of each cycle. There were no observations of serious adverse events. In the functional outcomes, the grip power of the dominant hand was increased in the EPO+G-CSF treatment group. In conclusion, this exploratory study suggests a novel strategy of EPO+G-CSF combination therapy for stroke patients. PMID:27043535

  12. Combination therapy with terbinafine and amphotericin B in a rabbit model of experimental invasive aspergillosis.

    PubMed

    Kirkpatrick, William R; Vallor, Ana C; McAtee, Robert K; Ryder, Neil S; Fothergill, Annette W; Rinaldi, Michael G; Patterson, Thomas F

    2005-11-01

    Antagonistic effects of combination therapy using amphotericin B (AmB) with agents which block ergosterol synthesis are a concern. Terbinafine was evaluated with AmB to assess antagonism or synergy in a rabbit model of invasive aspergillosis. Terbinafine had relatively little activity but did not demonstrate antagonism against AmB in our model.

  13. Optimization of combination therapy of arsenic trioxide and fractionated radiotherapy for malignant glioma

    SciTech Connect

    Ning Shoucheng; Knox, Susan J. . E-mail: sknox@stanford.edu

    2006-06-01

    Purpose: The primary objective was to optimize the combined treatment regimen using arsenic trioxide (ATO) and fractionated radiotherapy for the treatment of malignant glioma. Methods and Materials: Nude mice with human glioma xenograft tumors were treated with fractionated local tumor radiation of 250 cGy/fraction/day and 5 mg/kg ATO for 5-10 days. Results: Time course experiments demonstrated that maximal tumor growth delay occurred when ATO was administered between 0 and 4 h after radiation. The combination treatment of ATO and radiation synergistically inhibited tumor growth and produced a tumor growth delay time of 13.2 days, compared with 1.4 days and 6.5 days for ATO and radiation alone (p < 0.01), respectively. The use of concurrent therapy of radiation and ATO initially, followed by ATO as maintenance therapy, was superior to the use of preloading with ATO before combined therapy and produced a tumor growth delay time of 22.7 days as compared with 11.7 days for the ATO preloading regimen (p < 0.01). The maintenance dose of ATO after concurrent therapy was effective and important for continued inhibition of tumor growth. Conclusions: The combined use of fractionated radiation and ATO is effective for the treatment of glioma xenograft tumors. ATO was most effective when administered 0-4 h after radiation without pretreatment with ATO. These results have important implications for the optimization of treatment regimen using ATO and fractionated radiotherapy for the treatment of brain tumors.

  14. A Comparison of Cognitive-Behavioral Therapy, Sertraline, and Their Combination for Adolescent Depression

    ERIC Educational Resources Information Center

    Melvin, Glenn A.; Tonge, Bruce J.; King, Neville J.; Heyne, David; Gordon, Michael S.; Klimkeit, Ester

    2006-01-01

    Objective: To evaluate cognitive-behavioral therapy, antidepressant medication alone, and combined CBT and antidepressant medication in the treatment of depressive disorders in adolescents. Method: Seventy-three adolescents (ages 12-18 years) with a primary diagnosis of DSM-IV major depressive disorder, dysthymic disorder, or depressive disorder…

  15. Can the combination of localized "proliferative therapy" with "minor ozonated autohemotherapy" restore the natural healing process?

    PubMed

    Gracer, R I; Bocci, V

    2005-01-01

    Regenerative injection therapy (RIT), also known as proliferative therapy, has been used for over 30 years in the USA in patients with spinal and peripheral joint and ligamentous pathologies. It involves the injection of mildly irritating medications onto ligaments and tendons, most commonly at origins and insertions. These injections cause a mild inflammatory response which "turns on" the normal healing process and results in the regeneration of these structures. At the same time they strengthen and become less sensitive to pain through a combination of neurolysis of small nerve fibers (C-fibers) and increased stability of the underlying structures. Oxygen/ozone therapy is a well established complementary therapy practiced in many European countries. The ozone dissolves in body fluids and immediately reacts with biomolecules generating messengers responsible for biological and therapeutic activities. This results in an anti inflammatory response, which also results in a similar trophic reaction to that of RIT. It is logical to expect that combining these two modalities would result in enhanced healing and therefore improved clinical outcomes. Oxygen/ozone therapy, accomplished by autohemotherapy (AHT), is performed by either administering ozonated blood intravenously (Major AHT) or via intramuscular route (Minor AHT). These procedures result in stimulation of the immune and healing systems. Our concept is that the local injection of this activated blood injected directly to the ligamentous areas that are also being treated with RIT will act as a direct stimulation to the healing process. In addition, combining this with intravenous major AHT should stimulate the immune system to augment and support this process. RIT and oxygen/ozone therapy have been extensively studied separately. We propose a study of lumbosacral ligamentous pain to explore this therapeutic combination. We hope that this paper will stimulate general interest in this area of medicine and result

  16. Combining Enriched Environment, Progesterone, and Embryonic Neural Stem Cell Therapy Improves Recovery after Brain Injury.

    PubMed

    Nudi, Evan T; Jacqmain, Justin; Dubbs, Kelsey; Geeck, Katalin; Salois, Garrick; Searles, Madeleine A; Smith, Jeffrey S

    2015-07-15

    Millions of persons every year are affected by traumatic brain injury (TBI), and currently no therapies have shown efficacy in improving outcomes clinically. Recent research has suggested that enriched environments (EE), embryonic neural stem cells (eNSC), and progesterone (PROG) improve functional outcomes after TBI, and further, several investigators have suggested that a polytherapuetic approach may have greater efficacy than a single therapy. The purpose of the current study was to determine if varying combinations of post-injury EE, progesterone therapy, or eNSC transplantation would improve functional outcomes over just a single therapy. A controlled cortical impact was performed in rats to create a lesion in the medial frontal cortex. The rats were then placed in either EE or standard environments and administered 10 mg/kg progesterone or vehicle injections 4 h post-injury and every 12 h for 72 h after the initial injection. Seven days after the surgery, rats were transplanted with either eNSCs or media. Rats were then tested on the open field test, Barnes maze, Morris water maze, and Rotor-Rod tasks. Improved functional outcomes were shown on a majority of the behavioral tasks in animals that received a combination of therapies. This effect was especially prominent with therapies that were combined with EE. Immunohistochemistry showed that the transplanted eNSCs survived, migrated, and displayed neural phenotypes. These data suggest that a poly-therapeutic approach after TBI improves functional recovery to a greater magnitude. Moreover, when polytherapies are combined with EE, the effects on recovery are enhanced, leading to greater recovery of function.

  17. Combination therapy with catechins and caffeine inhibits fat accumulation in 3T3-L1 cells

    PubMed Central

    Zhu, Xiaojuan; Yang, Licong; Xu, Feng; Lin, Lezhen; Zheng, Guodong

    2017-01-01

    Catechins and caffeine, which are green tea components, have a slimming effect; however, the combinational effect of fat metabolism in 3T3-L1 cells remains unclear. In the present study, 3T3-L1 cells were treated with catechins and caffeine in combination, and it was found that combination therapy with catechins and caffeine markedly reduced intracellular fat accumulation, mRNA expression levels of peroxisome proliferator-activated receptor-γ and CCAAT/enhancer-binding protein α in the early stage of cell differentiation were significantly reduced, and mRNA expression of fatty acid synthetase(FAS) andglycerol-3-phosphate dehydrogenase protein expression levels of FAS were downregulated. Noradrenaline-induced lipolysis was enhanced by caffeine, which markedly increased the protein expression of adipose triglyceride lipase and hormone sensitive lipase. These results indicated that combination therapy with catechins and caffeine synergistically inhibited lipid accumulation by regulating the gene and protein expression levels of lipid metabolism-related enzymes. Therefore, catechins and caffeine combination therapy has potential as a functional food that may be used to prevent obesity and lifestyle-associated diseases. PMID:28352352

  18. Efficacy and safety of statin and fibrate combination therapy in lipid management.

    PubMed

    Kota, Sunil Kumar; Meher, Lalit Kumar; Rao, Epari Sanjeeva; Jammula, Sruti; Modi, Kirtikumar D

    2012-01-01

    Adequate control of hyperlipidemia is of paramount importance for prevention of vascular events. Statins and fibrates are well established treatments for hyperlipidemia. Combination therapy with a statin and fibrate offers significant therapeutic advantage for the treatment of severe or refractory mixed hyperlipidemia. Although such a combination does increase the risk of myopathy, with an incidence of approximately 0.12%, this small risk of myopathy rarely outweighs the established morbidity and mortality benefits of achieving lipid goals. Nevertheless, a higher incidence of myopathy has been reported with statin monotherapy. Statin+fibrate therapy should be considered if monotherapy or adding other drugs (e.g. cholesterol absorption inhibitors, omega-3 fatty acids or nicotinic acid) did not achieve lipid targets or is impractical. The current article focuses on recent studies highlighting the beneficial effects of this combination.

  19. Combining Dopaminergic Facilitation with Robot-Assisted Upper Limb Therapy in Stroke Survivors

    PubMed Central

    Tran, Duc A.; Pajaro-Blazquez, Marta; Daneault, Jean-Francois; Gallegos, Jaime G.; Pons, Jose; Fregni, Felipe; Bonato, Paolo; Zafonte, Ross

    2016-01-01

    ABSTRACT Despite aggressive conventional therapy, lasting hemiplegia persists in a large percentage of stroke survivors. The aim of this article is to critically review the rationale behind targeting multiple sites along the motor learning network by combining robotic therapy with pharmacotherapy and virtual reality–based reward learning to alleviate upper extremity impairment in stroke survivors. Methods for personalizing pharmacologic facilitation to each individual’s unique biology are also reviewed. At the molecular level, treatment with levodopa was shown to induce long-term potentiation-like and practice-dependent plasticity. Clinically, trials combining conventional therapy with levodopa in stroke survivors yielded statistically significant but clinically unconvincing outcomes because of limited personalization, standardization, and reproducibility. Robotic therapy can induce neuroplasticity by delivering intensive, reproducible, and functionally meaningful interventions that are objective enough for the rigors of research. Robotic therapy also provides an apt platform for virtual reality, which boosts learning by engaging reward circuits. The future of stroke rehabilitation should target distinct molecular, synaptic, and cortical sites through personalized multimodal treatments to maximize motor recovery. PMID:26829074

  20. [A case of combination therapy with MMF and steroids for idiopathic membranoproliferative glomerulonephritis].

    PubMed

    Mori, Yutaro; Ihara, Katsuhito; Yamaguchi, Wakaba; Fujii, Tetsuro; Toda, Takayuki; Nagata, Michio; Matsui, Noriaki

    2013-01-01

    A 26-year-old man diagnosed with nephrotic syndrome was administered steroid monotherapy. Urinary protein excretion was 2-3 g/day despite the therapy. Percutaneous renal biopsy revealed Type I idiopathic membranoproliferative glomerulonephritis (IMPGN). Although intravenous steroid therapy at the dose of 1,000 mg/day for 3 days was administered, proteinuria persisted at the level of 1 g/day. Renal dysfunction (cystatin C, 1.33 mg/L) was evident. Strong inflammation was suggested by occult blood (3+) and urinary (red blood cells: 30-50/high power field) sediment. We considered steroid monotherapy to be ineffective, and initiated combina-tion therapy with mycophenolate mofetil (MMF) and steroids. Consequently, urinary protein excretion moderately decreased to 0.34 g/day without adverse events or worsening of the renal function. The steroid quantity could be reduced without relapse. Subsequently, we were able to reduce the dose of MMF gradually, then terminated the medication. IMPGN is a rare disease with a poor renal prognosis. Recently, MMF therapies for IMPGN have been attempted, but there are few cases in Japan. Our case suggests that combination therapy with MMF and steroids is effective and safe for treating IMPGN.

  1. Response of spinal myoclonus to a combination therapy of autogenic training and biofeedback

    PubMed Central

    Sugimoto, Koreaki; Theoharides, Theoharis C; Kempuraj, Duraisamy; Conti, Pio

    2007-01-01

    Introduction Clinical evidence indicates that certain types of movement disorders are due to psychosomatic factors. Patients with myoclonic movements are usually treated by a variety of therapeutic agents. Autogenic training (AT), a recognized form of psychosomatic therapies, is suitable for certain types of neurological diseases. We describe a patient with myoclonus who failed to respond to conventional medical therapy. His symptoms were exaggerated by psychogenic factors, especially anger. Case presentation A 42-year-old man was admitted to our hospital, Preventive Welfare Clinic, for severe paroxysmal axial myoclonus of the left shoulder and abdominal muscles. The initial diagnosis was "combination of spinal segmental myoclonus and propriospinal myoclonus". The myoclonic movements did not occur during sleep but were aggravated by bathing, alcohol drinking, and anger. Psychological examination indicated hostile attribution. Although considered not to be a case of psychogenic myoclonus, a "psychogenic factor" was definitely involved in the induction of the organic myoclonus. The final diagnosis was "combination of spinal segmental myoclonus and propriospinal myoclonus accompanied by features of psychosomatic disorders". The patient underwent psychosomatic therapy including AT and surface electromyography (EMG)-biofeedback therapy and treatment with clonazepam and carbamazepine. Results AT and EMG-biofeedback resulted in shortening the duration and reducing the amplitude and frequency of the myoclonic discharges. Conclusion Psychosomatic therapy with AT and surface EMG-biofeedback produced excellent improvement of myoclonic movements and allowed the reduction of the dosage of conventional medications. PMID:17931427

  2. Antibody-Independent Function of Human B Cells Contributes to Antifungal T Cell Responses.

    PubMed

    Li, Rui; Rezk, Ayman; Li, Hulun; Gommerman, Jennifer L; Prat, Alexandre; Bar-Or, Amit

    2017-04-15

    Fungal infections (e.g., Candida albicans) can manifest as serious medical illnesses, especially in the elderly and immune-compromised hosts. T cells are important for Candida control. Whether and how B cells are involved in antifungal immunity has been less clear. Although patients with agammaglobulinemia exhibit normal antifungal immunity, increased fungal infections are reported following B cell-depleting therapy, together pointing to Ab-independent roles of B cells in controlling such infections. To test how human B cells may contribute to fungal-associated human T cell responses, we developed a novel Ag-specific human T cell/B cell in vitro coculture system and found that human B cells could induce C. albicans-associated, MHC class II-restricted responses of naive T cells. Activated B cells significantly enhanced C. albicans-mediated Th1 and Th17 T cell responses, which were both strongly induced by CD80/CD86 costimulation. IL-6(+)GM-CSF(+) B cells were the major responding B cell subpopulation to C. albicans and provided efficient costimulatory signals to the T cells. In vivo B cell depletion in humans resulted in reduced C. albicans-associated T responses. Of note, the decreased Th17, but not Th1, responses could be reversed by soluble factors from B cells prior to depletion, in an IL-6-dependent manner. Taken together, our results implicate an Ab-independent cytokine-defined B cell role in human antifungal T cell responses. These findings may be particularly relevant given the prospects of chronic B cell depletion therapy use in lymphoma and autoimmune disease, as patients age and are exposed to serial combination therapies.

  3. Antifungal activity of multifunctional Fe 3O 4-Ag nanocolloids

    NASA Astrophysics Data System (ADS)

    Chudasama, Bhupendra; Vala, Anjana K.; Andhariya, Nidhi; Upadhyay, R. V.; Mehta, R. V.

    2011-05-01

    In recent years, rapid increase has been observed in the population of microbes that are resistant to conventionally used antibiotics. Antifungal drug therapy is no exception and now resistance to many of the antifungal agents in use has emerged. Therefore, there is an inevitable and urgent medical need for antibiotics with novel antimicrobial mechanisms. Aspergillus glaucus is the potential cause of fatal brain infections and hypersensitivity pneumonitis in immunocompromised patients and leads to death despite aggressive multidrug antifungal therapy. In the present article, we describe the antifungal activity of multifunctional core-shell Fe 3O 4-Ag nanocolloids against A. glaucus isolates. Controlled experiments are also carried out with Ag nanocolloids in order to understand the role of core (Fe 3O 4) in the antifungal action. The minimum inhibitory concentration (MIC) of nanocolloids is determined by the micro-dilution method. MIC of A. glaucus is 2000 μg/mL. The result is quite promising and requires further investigations in order to develop a treatment methodology against this death causing fungus in immunocompromised patients.

  4. Cunninghamella bertholletiae exhibits increased resistance to human neutrophils with or without antifungal agents as compared to Rhizopus spp.

    PubMed

    Simitsopoulou, Maria; Georgiadou, Elpiniki; Walsh, Thomas J; Roilides, Emmanuel

    2010-08-01

    Among Zygomycetes, Cunninghamella bertholletiae occurs less frequently as the etiologic agent of human disease but causes more aggressive, refractory, and fatal infections despite antifungal therapy. Little is known about the differential innate host response against Cunninghamella and other Zygomycetes in the presence of antifungal agents. We therefore studied the activity of human neutrophils (PMNs) alone or in combination with caspofungin, posaconazole (PSC), and voriconazole (VRC) against hyphae of Rhizopus oryzae, Rhizopus microsporus and C. bertholletiae. Hyphal damage was measured by XTT metabolic assay and release of IL-6, IL-8 and TNF-alpha from PMNs by ELISA. Cunninghamella bertholletiae was more resistant to PMN-induced hyphal damage than either Rhizopus spp. at effector:target (E:T) ratios of 1:1, 5:1 and 10:1 (P < 0.05). The hyphal damage caused by caspofungin at 0.1 microg/ml or PSC and VRC at 0.5 microg/ml with C. bertholletiae and R. oryzae and by caspofungin against R. microsporus ranged from 18-29%. The PMN-induced hyphal damage was not modulated by combination with antifungal agents. Cunninghamella bertholletiae induced significantly decreased IL-8 (P < 0.05), but increased TNF-alpha release from PMNs compared to both Rhizopus spp. (P < 0.01). No IL-6 was released from PMNs exposed to the three Zygomycetes. In comparison to R. oryzae and R. microsporus, C. bertholletiae is more resistant to PMN-induced hyphal damage with or without antifungal therapy and is more capable of suppressing release of IL-8.

  5. Hyperbaric oxygen therapy in tinnitus with normal hearing in association with combined treatment.

    PubMed

    Holy, Richard; Prazenica, Pavol; Stolarikova, Eva; Dosel, Petr; Fundova, Petra; Kovar, Daniel; Astl, Jaromir

    2016-01-01

    Tinnitus is a phantom perception of sound in the absence of overt acoustic stimulation. The focus of our attention is a combined therapy of tinnitus. In this prospective study (2013-2014) we evaluated the data of normal-hearing patients with tinnitus treated with various treatment modalities. In Group 1 we evaluated the data of 84 patients/124 ears after six weeks of treatment with betahistine dihydrochloride (72 mg). In Group 2, we evaluated the data of 36 patients/ 55 ears unimproved from Group 1 who were then treated for six weeks with hyperbaric oxygen (HBO₂) therapy combined with gingko biloba extract (120 mg). In Group 1, tinnitus disappeared in 9.7%, alleviated in 18.5% and improved overall in 28.2%. Average intensity of tinnitus before/after treatment was 37 decibels (dB)/33 dB. Tinnitus intensities after treatment are statistically significantly lower (p = 0.001) than the values before treatment. In Group 2 tinnitus disappeared in 5.4%, 36.4% achieved alleviation, and 41.8% showed overall improvement. The average intensity of tinnitus before/after treatment was 41dB/ 38dB. The values of tinnitus intensity after combined therapy are statistically significantly lower (p = 0.046). We have shown that both methods treatment of tinnitus are statistically significant. HBO₂therapy was recommended for the general public.

  6. Polydopamine Nanoparticles as a Versatile Molecular Loading Platform to Enable Imaging-guided Cancer Combination Therapy

    PubMed Central

    Dong, Ziliang; Gong, Hua; Gao, Min; Zhu, Wenwen; Sun, Xiaoqi; Feng, Liangzhu; Fu, Tingting; Li, Yonggang; Liu, Zhuang

    2016-01-01

    Cancer combination therapy to treat tumors with different therapeutic approaches can efficiently improve treatment efficacy and reduce side effects. Herein, we develop a theranostic nano-platform based on polydopamine (PDA) nanoparticles, which then are exploited as a versatile carrier to allow simultaneous loading of indocyanine green (ICG), doxorubicin (DOX) and manganese ions (PDA-ICG-PEG/DOX(Mn)), to enable imaging-guided chemo & photothermal cancer therapy. In this system, ICG acts as a photothermal agent, which shows red-shifted near-infrared (NIR) absorbance and enhanced photostability compared with free ICG. DOX, a model chemotherapy drug, is then loaded onto the surface of PDA-ICG-PEG with high efficiency. With Mn2+ ions intrinsically chelated, PDA-ICG-PEG/DOX(Mn) is able to offer contrast under T1-weighted magnetic resonance (MR) imaging. In a mouse tumor model, the MR imaging-guided combined chemo- & photothermal therapy achieves a remarkable synergistic therapeutic effect compared with the respective single treatment modality. This work demonstrates that PDA nanoparticles could serve as a versatile molecular loading platform for MR imaging guided combined chemo- & photothermal therapy with minimal side effects, showing great potential for cancer theranostics. PMID:27217836

  7. Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy

    PubMed Central

    Eroglu, Zeynep; Ribas, Antoni

    2016-01-01

    Treatment with BRAF inhibitors such as vemurafenib or dabrafenib in patients with advanced BRAFV600 mutated melanoma has shown objective tumor responses in approximately half of the patients. However, the duration of responses is limited in a majority of these patients, with progression-free survival rates around 6 months due to tumor progression from development of acquired resistance. Preclinical studies have suggested that concurrent inhibition of the BRAF kinases and MEK of the mitogen-activated protein kinase (MAPK) pathway could decrease MAPK-driven acquired resistance, resulting in longer duration of responses, higher rate of tumor responses, and a decrease in the cutaneous toxicities observed from paradoxical MAPK pathway activation with BRAF inhibitor monotherapy. This review provides an overview of the currently available clinical trial data on BRAF and MEK inhibitors together and in combinations with other therapeutic agents. PMID:26753005

  8. Smart micelle@polydopamine core-shell nanoparticles for highly effective chemo-photothermal combination therapy

    NASA Astrophysics Data System (ADS)

    Zhang, Ruirui; Su, Shishuai; Hu, Kelei; Shao, Leihou; Deng, Xiongwei; Sheng, Wang; Wu, Yan

    2015-11-01

    In this investigation, we have designed and synthesized a novel core-shell polymer nanoparticle system for highly effective chemo-photothermal combination therapy. A nanoscale DSPE-PEG micelle encapsulating doxorubicin (Dox-M) was designed as a core, and then modified by a polydopamine (PDA) shell for photothermal therapy and bortezomib (Btz) administration (Dox-M@PDA-Btz). The facile conjugation of Btz to the catechol-containing PDA shell can form a reversible pH-sensitive boronic acid-catechol conjugate to create a stimuli-responsive drug carrier system. As expected, the micelle@PDA core-shell nanoparticles exhibited satisfactory photothermal efficiency, which has potential for thermal ablation of malignant tissues. In addition, on account of the PDA modification, both Dox and Btz release processes were pH-dependent and NIR-dependent. Both in vitro and in vivo studies illustrated that the Dox-M@PDA-Btz nanoparticles coupled with laser irradiation could enhance the cytotoxicity, and thus combinational therapy efficacy was achieved when integrating Dox, Btz, and PDA into a single nanoplatform. Altogether, our current study indicated that the micelle@polydopamine core-shell nanoparticles could be applied for NIR/pH-responsive sustained-release and synergized chemo-photothermal therapy for breast cancer.In this investigation, we have designed and synthesized a novel core-shell polymer nanoparticle system for highly effective chemo-photothermal combination therapy. A nanoscale DSPE-PEG micelle encapsulating doxorubicin (Dox-M) was designed as a core, and then modified by a polydopamine (PDA) shell for photothermal therapy and bortezomib (Btz) administration (Dox-M@PDA-Btz). The facile conjugation of Btz to the catechol-containing PDA shell can form a reversible pH-sensitive boronic acid-catechol conjugate to create a stimuli-responsive drug carrier system. As expected, the micelle@PDA core-shell nanoparticles exhibited satisfactory photothermal efficiency, which has

  9. Combination therapy with GLP-1 receptor agonists and basal insulin: a systematic review of the literature

    PubMed Central

    Balena, R; Hensley, I E; Miller, S; Barnett, A H

    2013-01-01

    Treatment algorithms for type 2 diabetes call for intensification of therapy over time as the disease progresses and glycaemic control worsens. If diet, exercise and oral antihyperglycaemic medications (OAMs) fail to maintain glycaemic control then basal insulin is added and ultimately prandial insulin may be required. However, such an intensification strategy carries risk of increased hypoglycaemia and weight gain, both of which are associated with worse long-term outcomes. An alternative strategy is to intensify therapy by the addition of a short-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) rather than prandial insulin. Short-acting GLP-1 RAs such as exenatide twice daily are particularly effective at reducing postprandial glucose while basal insulin has a greater effect on fasting glucose, providing a physiological rationale for this complementary approach. This review analyzes the latest randomized controlled clinical trials of insulin/GLP-1 RA combination therapy and examines results from ‘real-world’ use of the combinations as reported through observational and clinical practice studies. The most common finding across all types of studies was that combination therapy improved glycaemic control without weight gain or an increased risk of hypoglycaemia. Many studies reported weight loss and a reduction in insulin use when a GLP-1 RA was added to existing insulin therapy. Overall, the relative degree of benefit to glycaemic control and weight was influenced by the insulin titration employed in conjunction with the GLP-1 RA. The greatest glycaemic benefits were observed in studies with structured titration of insulin to glycaemic targets while the greatest weight benefits were observed in studies with a protocol-specified focus on insulin sparing. The adverse event profile of GLP-1 RAs in the reviewed trials was similar to that reported with GLP-1 RAs as monotherapy or in combination with OAMs with gastrointestinal events being the most commonly

  10. A multicentre study of antifungal strategies and outcome of Candida spp. peritonitis in intensive-care units.

    PubMed

    Montravers, P; Mira, J-P; Gangneux, J-P; Leroy, O; Lortholary, O

    2011-07-01

    Information on the species causing Candida peritonitis, their in vitro susceptibility, antifungal strategies in this setting and patient outcome is still scarce. AmarCand was a prospective, non-interventional study in 271 adult intensive-care unit (ICU) patients with proven invasive Candida infection who received systemic antifungal therapy (France, 2005-2006). Of these ICU patients, 93 (median age 65 years, simplified acute physiology score II 52) had Candida peritonitis, including 73 nosocomial peritonitis, 53 concomitant bacterial peritoneal infections and 26 candidaemias. Candida species were C. albicans (n = 63/108 isolates, 58%), C. glabrata (n = 22, 20%), C. krusei (n = 9), C. kefyr (n = 5), C. parapsilosis (n = 3), C. tropicalis (n = 3), C. ciferii (n = 2) and C. lusitaniae (n = 1). Of tested isolates, 28% were fluconazole-resistant or susceptible dose-dependent (C. albicans 3/32, C. glabrata 9/14, C. krusei 4/4). Empiric antifungal treatment was started 1 day (median) after peritonitis diagnosis, with fluconazole (n = 2 patients), caspofungin (n = 12), voriconazole (n = 3), amphotericin B (n = 2), or a combination (n = 4). Following susceptibility testing, empiric antifungal treatment was judged inadequate in 9/45 (20%) patients and modified in 30 patients (fluconazole was replaced by caspofungin (n = 14) or voriconazole (n = 4)). Mortality in ICU was 38% (35/93) and was not influenced by type of Candida species, fluconazole susceptibility, time to treatment, candidaemia, nosocomial acquisition, or concomitant bacterial infection. No specific factors for death were identified. In summary, a high proportion of fluconazole-resistant or susceptible dose-dependent strains was cultured. These results confirm the high mortality rates of Candida peritonitis and plead for additional investigation in this population. Antifungal treatment for severe cases of Candida peritonitis in ICU patients remains the standard care.

  11. Impact of combination therapy on managed care. Based on a presentation by Lisa Latts, MD, MSPH.

    PubMed

    1999-06-01

    The major objectives of managed care are particularly applicable to hypertension, a very common disease that affects about 30% of the adult population. Although managed care organizations know that adequate blood pressure control has a considerable impact on reducing hypertension-related morbidity and mortality, managed care is, at present, doing a generally poor job of monitoring antihypertensive therapy. One of the major reasons for this is the difficulty in gathering the necessary data from administrative sources; only chart review, which is very costly and very time consuming, can provide the data needed. The value of disease management lies in its capacity to optimize clinical and economic outcomes as well as to improve service and quality of life, using inputs such as cost, time, clinical resources, and patient satisfaction. Disease management programs are instituted because they can lead to improved quality of life and reduced costs. While the focus in managed care has traditionally been on promoting risk modification behavior, providing patient education, and encouraging medication compliance, the treatment of hypertension itself has not been a major focus in most disease management programs. Measuring the effectiveness of the hypertension treatment is, however, one of the proposed measures for the Health Plan Employer Data and Information Set (HEDIS 2000) to profile health plan quality. From a managed care perspective, the potential benefits of combination therapy for hypertension include improved blood pressure control and improved patient compliance as a result of needing fewer pills and experiencing fewer side effects with low-dose therapy. Among the obstacles to combination therapy in the managed care setting are the addition of the combinations onto a formulary and lack of acceptance among physicians. Fixed-dose combination therapy with a calcium channel blocker and an angiotensin-converting enzyme (ACE) inhibitor can potentially reduce pharmacy costs

  12. Tissue Penetration of Antifungal Agents

    PubMed Central

    Felton, Timothy; Troke, Peter F.

    2014-01-01

    SUMMARY Understanding the tissue penetration of systemically administered antifungal agents is critical for a proper appreciation of their antifungal efficacy in animals and humans. Both the time course of an antifungal drug and its absolute concentrations within tissues may differ significantly from those observed in the bloodstream. In addition, tissue concentrations must also be interpreted within the context of the pathogenesis of the various invasive fungal infections, which differ significantly. There are major technical obstacles to the estimation of concentrations of antifungal agents in various tissue subcompartments, yet these agents, even those within the same class, may exhibit markedly different tissue distributions. This review explores these issues and provides a summary of tissue concentrations of 11 currently licensed systemic antifungal agents. It also explores the therapeutic implications of their distribution at various sites of infection. PMID:24396137

  13. Can We Predict Individual Combined Benefit and Harm of Therapy? Warfarin Therapy for Atrial Fibrillation as a Test Case

    PubMed Central

    Li, Guowei; Thabane, Lehana; Delate, Thomas; Witt, Daniel M.; Levine, Mitchell A. H.; Cheng, Ji; Holbrook, Anne

    2016-01-01

    Objectives To construct and validate a prediction model for individual combined benefit and harm outcomes (stroke with no major bleeding, major bleeding with no stroke, neither event, or both) in patients with atrial fibrillation (AF) with and without warfarin therapy. Methods Using the Kaiser Permanente Colorado databases, we included patients newly diagnosed with AF between January 1, 2005 and December 31, 2012 for model construction and validation. The primary outcome was a prediction model of composite of stroke or major bleeding using polytomous logistic regression (PLR) modelling. The secondary outcome was a prediction model of all-cause mortality using the Cox regression modelling. Results We included 9074 patients with 4537 and 4537 warfarin users and non-users, respectively. In the derivation cohort (n = 4632), there were 136 strokes (2.94%), 280 major bleedings (6.04%) and 1194 deaths (25.78%) occurred. In the prediction models, warfarin use was not significantly associated with risk of stroke, but increased the risk of major bleeding and decreased the risk of death. Both the PLR and Cox models were robust, internally and externally validated, and with acceptable model performances. Conclusions In this study, we introduce a new methodology for predicting individual combined benefit and harm outcomes associated with warfarin therapy for patients with AF. Should this approach be validated in other patient populations, it has potential advantages over existing risk stratification approaches as a patient-physician aid for shared decision-making PMID:27513986

  14. Radiotherapy combined with hormonal therapy in prostate cancer: the state of the art.

    PubMed

    Milecki, Piotr; Martenka, Piotr; Antczak, Andrzej; Kwias, Zbigniew

    2010-10-11

    Androgen-deprivation therapy (ADT) is used routinely in combination with definitive external beam radiation therapy (EBRT) in patients with high-risk clinically localized or locally advanced disease. The combined treatment (ADT-EBRT) also seems to play a significant role in improving treatment results in the intermediate-risk group of prostate cancer patients. On the other hand, there is a growing body of evidence that treatment with ADT can be associated with serious and lifelong adverse events including osteoporosis, cardiovascular disease, diabetes, and many others. Almost all ADT adverse events are time dependant and tend to increase in severity with prolongation of hormonal manipulation. Therefore, it is crucial to clearly state the optimal schedule for ADT in combination with EBRT, that maintaining the positive effect on treatment efficacy would keep the adverse events risk at reasonable level. To achieve this goal, treatment schedule may have to be highly individualized on the basis of the patient-specific potential vulnerability to adverse events. In this study, the concise and evidence-based review of current literature concerning the general rationales for combining radiotherapy and hormonal therapy, its mechanism, treatment results, and toxicity profile is presented.

  15. Combining targeted therapy with immunotherapy in BRAF-mutant melanoma: promise and challenges.

    PubMed

    Hu-Lieskovan, Siwen; Robert, Lidia; Homet Moreno, Blanca; Ribas, Antoni

    2014-07-20

    Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAF(V600)-mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAF(V600) driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non-BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.

  16. Combining Targeted Therapy With Immunotherapy in BRAF-Mutant Melanoma: Promise and Challenges

    PubMed Central

    Hu-Lieskovan, Siwen; Robert, Lidia; Homet Moreno, Blanca; Ribas, Antoni

    2014-01-01

    Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAFV600-mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAFV600 driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non–BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials. PMID:24958825

  17. Immunotherapy regimens for combination with photodynamic therapy aimed at eradication of solid cancers

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen

    2000-06-01

    Due to inflammatory/immune responses elicited by photodynamic therapy (PDT), this modality is particularly suitable in combination with various forms of immunotherapy for an improved therapeutic gain. A wide variety of approaches that may be applicable in this context include those focusing on amplifying the activity of particular immune cell types (neutrophils, macrophages, dendritic cells, natural killer cells, helper or cytotoxic T lymphocytes). Another type of approach is to focus on a specific phase of immune response development, which comprises the activation of non-specific inflammatory immune effectors, immune recognition, immune memory, immune rejection, or blocking of immune suppression. These different strategies call for a variety of immunotherapeutic protocols to be employed in combination with PDT. These include treatments such as: (1) non-specific immunoactivators (e.g. bacterial vaccines), (2) specific immune agents (cytokines, or other activating factors), (3) adoptive immunotherapy treatments (transfer of dendritic cells, tumor-sensitized T lymphocytes or natural killer cells), or (4) their combinations. Techniques of gene therapy employed in some of these protocols offer novel opportunities for securing a potent and persistent immune activity. Using PDT and immunotherapy represents an attractive combination for cancer therapy that is capable of eradicating both localized and disseminated malignant lesions.

  18. Progress in antibacterial and antifungal chemotherapy.

    PubMed

    Fromtling, R A

    2000-08-01

    The European Society of Clinical Microbiology and Infectious Diseases sponsored the 10th European Congress on Clinical Microbiology and Infectious Diseases in Stockholm, Sweden, May 28-31, 2000. At the ECMID, well-attended sessions were held which focused on the pathogenesis and therapy of viral, bacterial and fungal diseases. This report focuses on new information on resistance to antibacterial agents, including data from recent surveillance studies, and the in vitro and investigational clinical activity of new antibacterial (moxifloxacin, telithromycin) and antifungal (fluconazole, itraconazole, voriconazole, amphotericin B, liposomal formulations of amphotericin B, terbinafine and the candins) drugs.

  19. Histone deacetylases: Targets for antifungal drug development

    PubMed Central

    Kmetzsch, Livia

    2015-01-01

    The interaction of pathogens and its hosts causes a drastic change in the transcriptional landscape in both cells. Among the several mechanisms of gene regulation, transcriptional initiation is probably the main point. In such scenario, the access of transcriptional machinery to promoter is highly regulated by post-translational modification of histones, such as acetylation, phosphorylation and others. Inhibition of histone deacetylases is able to reduce fungal pathogens fitness during infection and, therefore, is currently being considered for the development of new antifungal therapy strategies. PMID:26151486

  20. Mechanisms of echinocandin antifungal drug resistance

    PubMed Central

    Perlin, David S.

    2015-01-01

    Fungal infections due to Candida and Aspergillus species cause extensive morbidity and mortality, especially among immunosuppressed patients, and antifungal therapy is critical to patient management. Yet only a few drug classes are available to treat invasive fungal diseases, and this problem is compounded by the emergence of antifungal resistance. Echinocandin drugs are the preferred choice to treat candidiasis. They are the first cell wall–active agents and target the fungal-specific enzyme glucan synthase, which catalyzes the biosynthesis of β-1,3-glucan, a key cell wall polymer. Therapeutic failures occur rarely among common Candida species, with the exception of Candida glabrata, which are frequently multidrug resistant. Echinocandin resistance in susceptible species is always acquired during therapy. The mechanism of resistance involves amino acid changes in hot-spot regions of Fks subunits of glucan synthase, which decrease the sensitivity of the enzyme to drug. Cellular stress response pathways lead to drug adaptation, which promote the formation of resistant fks strains. Clinical factors promoting echinocandin resistance include empiric therapy, prophylaxis, gastrointestinal reservoirs, and intra-abdominal infections. A better understanding of the echinocandin resistance mechanism, along with cellular and clinical factors promoting resistance, will promote more effective strategies to overcome and prevent echinocandin resistance. PMID:26190298

  1. Combination therapy with spironolactone and candesartan protects against streptozotocin-induced diabetic nephropathy in rats.

    PubMed

    Hofni, Amal; El-Moselhy, Mohamed A; Taye, Ashraf; Khalifa, Mohamed M

    2014-12-05

    Diabetic nephropathy is one of the most common causes of end-stage kidney disease. Aldosterone and angiotensin II appear to play a crucial role in the pathogenesis of this disease. The present study aimed to investigate effects of the combination therapy with spironolactone and candesartan on diabetic nephropathy and elucidate the underlying mechanism(s) involved. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (STZ) (55 mg/kg). The diabetic rats were orally treated with spironolactone (50 mg/kg/day) and/or candesartan (1 mg/kg/day) for 8 weeks. Administration of STZ caused a marked elevation in the serum level of creatinine, urea and urinary albumin-creatinine ratio (ACR). This was associated with upregulated renal protein levels of nuclear factor-kappa B (NF-κB), transforming growth factor (TGF)-β, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) alongside increasing the renal superoxide anion (O2(-)) production, malondialdehyde (MDA) level and the systolic blood pressure. There was a marked decrease in nitric oxide (NO) bioavailability and antioxidant enzyme capacity. The combined therapy of spironolactone and candesartan significantly normalized the oxidative stress and fibrotic/inflammatory alterations. Additionally, the elevated blood pressure was attenuated by administration of candesartan alone or in combination. This was associated with improving the renal function parameters. The combined therapy exhibited more profound response compared to the monotherapy. In conclusion, our results demonstrate that the combined therapy of spironolactone and candesartan can confer an additive benefit over the use of either drug alone against STZ-induced diabetic nephropathy, presumably via attenuating the inflammatory responses and oxidative status markers.

  2. Treatment of depression: an update on antidepressant monotherapy and combination therapy.

    PubMed

    Lenderts, Susan; Kalali, Amir

    2009-08-01

    We analyzed the trends in product regimens used to treat depression to investigate whether there has been a shift in treatment patterns following the May 2008 launch of desvenalfaxine in the United States and the approval of an atypical antipsychotic as add-on therapy to antidepressants. Our analysis suggests that antidepressant monotherapy continues to be the most widely used drug treatment approach, accounting for 84 percent of depression treatment regimens. Antidepressant monotherapy is more prevalent among primary care physician-prescribed treatment regimens (92%) than psychiatry-prescribed regimens (73%). Combination treatment regimens have become increasingly more common as physician perception of disease severity increases, with antidepressant combination therapy accounting for eight percent, 17 percent, and 27 percent of treatment regimens for mild, moderate, and severe depression, respectively. The most commonly used agents in addition to an antidepressant in combination treatment regimens include another antidepressant (40% of combination regimens), an anxiety agent (40%), and/or atypical antipsychotics (18%). A trend analysis suggests that combination regimens that include an antidepressant plus an atypical antipsychotic, anxiety agent, or a prescription sleep aid comprise a greater share of combination regimens in 12 months ending May 2009 than they did in 12 months ending June 2008.

  3. [Estimation of efficiency of anti-helicobacter therapy in patients with a chronic pancreatitis combined with an erosive gastropathy].

    PubMed

    Koval', V Iu; Kotsiubniak, L A; Moskal', O M

    2014-01-01

    SUMMARY Eradikacion therapy at patients with chronic pancreatitis and combined with Helicobacter associated erosive gastropathy in a month after treatment appeared successful at 75% patients which accepted therapy of the first line--pantoprazol, amoksicillin, klaritromicin. Inclusion in antihelicobakter therapy of seknidazol in place of klaritromicin rendered a positive antihelicobakter effect at 85% patients with a chronic pancreatitis. Therapy with the use of seknidazole was better tolerated. Application of synbiotik laktiale on a background antihelicobakter therapy helped normalizations of chair and was comfortable in application, which is important in the treatment of patients. Application of synbiotika laktiale on a background antigelikobakter therapy is helped in the improvement of clinical effect.

  4. Development of gene therapy: potential in severe combined immunodeficiency due to adenosine deaminase deficiency

    PubMed Central

    Montiel-Equihua, Claudia A; Thrasher, Adrian J; Gaspar, H Bobby

    2010-01-01

    The history of stem cell gene therapy is strongly linked to the development of gene therapy for severe combined immunodeficiencies (SCID) and especially adenosine deaminase (ADA)-deficient SCID. Here we discuss the developments achieved in over two decades of clinical and laboratory research that led to the establishment of a protocol for the autologous transplant of retroviral vector-mediated gene-modified hematopoietic stem cells, which has proved to be both successful and, to date, safe. Patients in trials in three different countries have shown long-term immunological and metabolic correction. Nevertheless, improvements to the safety profile of viral vectors are underway and will undoubtedly reinforce the position of stem cell gene therapy as a treatment option for ADA-SCID. PMID:24198507

  5. Development of gene therapy: potential in severe combined immunodeficiency due to adenosine deaminase deficiency.

    PubMed

    Montiel-Equihua, Claudia A; Thrasher, Adrian J; Gaspar, H Bobby

    2009-12-22

    The history of stem cell gene therapy is strongly linked to the development of gene therapy for severe combined immunodeficiencies (SCID) and especially adenosine deaminase (ADA)-deficient SCID. Here we discuss the developments achieved in over two decades of clinical and laboratory research that led to the establishment of a protocol for the autologous transplant of retroviral vector-mediated gene-modified hematopoietic stem cells, which has proved to be both successful and, to date, safe. Patients in trials in three different countries have shown long-term immunological and metabolic correction. Nevertheless, improvements to the safety profile of viral vectors are underway and will undoubtedly reinforce the position of stem cell gene therapy as a treatment option for ADA-SCID.

  6. Case of acne conglobata successfully treated by CO(2) laser combined with topical tretinoin therapy.

    PubMed

    Hasegawa, Toshio; Matsukura, Tomoyuki; Suga, Yasushi; Muramatsu, Shigenori; Mizuno, Yuki; Tsuchihashi, Hitoshi; Haruna, Kunitaka; Ogawa, Hideoki; Ikeda, Shigaku

    2007-08-01

    Acne conglobata is an uncommon disorder characterized by the presence of nodulocystic lesions. Conservative therapy with oral and topical antibiotics is of limited efficacy in many cases, and surgical excision is often needed for removal of the cystic lesions. Treatment is particularly difficult in cases with lesions located in aesthetically sensitive areas, such as the face. We successfully treated a case of acne conglobata by CO(2) laser ablation to remove the top of the sinuses and their tracts. In addition, topical tretinoin therapy was also initiated simultaneously to prevent the appearance of new acne lesions. Based on the results, we propose that the use of CO(2) laser for opening the cysts, combined with topical tretinoin therapy to prevent the appearance of new lesions, is a powerful treatment option for acne conglobata.

  7. Combination therapy with biologic agents in rheumatic diseases: current and future prospects

    PubMed Central

    Inui, Kentaro; Koike, Tatsuya

    2016-01-01

    Strategies in rheumatoid arthritis (RA) based on ‘treat to target’ aim to control disease activity, minimize structural damage, and promote longer life. Several disease-modifying antirheumatic drugs (DMARDs) have been shown to be effective including biological DMARDs (bDMARDs). Treatment guidelines and recommendations for RA have also been published. According to those guidelines, conventional synthetic DMARDs (csDMARDs), as monotherapy or combination therapy, should be used in DMARD-naïve patients, irrespective of the addition of glucocorticoids (GCs). Combination therapies with bDMARDs are also essential for conducting treatment strategies for RA, because in every recommendation or guideline for the management of RA, combination therapies of csDMARDs with bDMARDs are recommended for RA patients with moderate or high disease activity after failure of csDMARD treatment. bDMARDs are more efficacious if used concomitantly with methotrexate (MTX) than with MTX monotherapy or bDMARD monotherapy. Thus, retention has been reported to be longer when combined with MTX. The superior efficacy of combination therapy compared with MTX monotherapy or bDMARD monotherapy could be because: (1) it could help to minimize MTX toxicity by reducing the dose of MTX, thus retention rate of the same therapeutic regimen would become high; (2) anti-bDMARD antibodies are observed at lower concentrations when using MTX concomitantly, so less clearance of bDMARDs via less formation of bDMARD and an anti-bDMARD immune complex; (3) of the additive effects of MTX to bDMARD, especially the combination of tumor necrosis factor inhibitors (TNFis) with MTX. Hence, evidence suggests that combination therapy with bDMARDs is more efficacious than monotherapy using a csDMARD or bDMARD, and that MTX is the best drug for this purpose (if MTX is not contraindicated). Finding the most effective drug regimen at the lowest cost will be the aim of RA treatment in the future. PMID:27721905

  8. Novel Microdilution Method to Assess Double and Triple Antibiotic Combination Therapy In Vitro.

    PubMed

    El-Azizi, Mohamed

    2016-01-01

    An in vitro microdilution method was developed to assess double and triple combinations of antibiotics. Five antibiotics including ciprofloxacin, amikacin, ceftazidime, piperacillin, and imipenem were tested against 10 clinical isolates of Pseudomonas aeruginosa. Each isolate was tested against ten double and nine triple combinations of the antibiotics. A 96-well plate was used to test three antibiotics, each one alone and in double and triple combinations against each isolate. The minimum bacteriostatic and bactericidal concentrations in combination were determined with respect to the most potent antibiotic. An Interaction Code (IC) was generated for each combination, where a numerical value was designated based on the 2-fold increase or decrease in the MICs with respect to the most potent antibiotic. The results of the combinations were verified by time-kill assay at constant concentrations of the antibiotics and in a chemostat. Only 13% of the double combinations were synergistic, whereas 5% showed antagonism. Forty-three percent of the triple combinations were synergistic with no antagonism observed, and 100% synergism was observed in combination of ciprofloxacin, amikacin, and ceftazidime. The presented protocol is simple and fast and can help the clinicians in the early selection of the effective antibiotic therapy for treatment of severe infections.

  9. In vitro therapeutic effect of PDT combined with VEGF-A gene therapy

    NASA Astrophysics Data System (ADS)

    Lecaros, Rumwald Leo G.; Huang, Leaf; Hsu, Yih-Chih

    2014-02-01

    Vascular endothelial growth factor A (VEGF-A), commonly known as VEGF, is one of the primary factors that affect tumor angiogenesis. It was found to be expressed in cancer cell lines including oral squamous cell carcinoma. Photodynamic therapy (PDT) is a novel therapeutic modality to treat cancer by using a photosensitizer which is activated by a light source to produce reactive oxygen species and mediates oxygen-independent hypoxic conditions to tumor. Another emerging treatment to cure cancer is the use of interference RNA (e.g. siRNA) to silence a specific mRNA sequence. VEGF-A was found to be expressed in oral squamous cell carcinoma and overexpressed after 24 hour post-PDT by Western blot analysis. Cell viability was found to decrease at 25 nM of transfected VEGF-A siRNA. In vitro combined therapy of PDT and VEGF-A siRNA showed better response as compared with PDT and gene therapy alone. The results suggest that PDT combined with targeted gene therapy has a potential mean to achieve better therapeutic outcome.

  10. Combination of photodynamic and ultrasonic therapy for treatment of infected wounds in animal model

    NASA Astrophysics Data System (ADS)

    Menyaev, Yulian A.; Zharov, Vladimir P.

    2006-02-01

    One of the important problems of modern medicine is treatment of infected wounds. There are many diversified expedients of treatment, but none of them obey the modern physician completely. The aim of this study is to develop and test a new combined method of photodynamic ultrasonic therapy (PDUST) for treatment of infected wounds with focus on experimental trials. PDUST is based on a combination of two methods: photodynamic (PD) therapy (PDT) with photosensitizer and low frequency ultrasonic (US) therapy with antibiotic as tools for treatment of wounds and effectively killing bacteria. The main parameters are: US frequency - 26.5 kHz; US tip elongation - 40+/-20 μm wavelength of light emitting diodes (LED) array - 660+/-10 nm; light intensity on biotissue surface - 1-2 mW/cm2; photosensitizer - an aluminum disulfonated phtalocyanine dissolved in a physiological solution in concentration 10 mg/l. The experiments were carried out with 70 male chinchilla rabbits divided into 7 groups, thus the dynamics of wounds healing were studied in different modes of PDUST. The PD and US methods supplement each other and in conjunction provide additive and especially synergetic effects. The experimental data demonstrated advantages of new technology in comparison with conventional methods in cases of treatment of extended suppurative inflammatory and profound wounds. The more detailed study of PDUST method's mechanism, which is based on low intensity of LED light, PD therapy and US influence is required.

  11. Technologies and combination therapies for enhancing movement training for people with a disability

    PubMed Central

    2012-01-01

    There has been a dramatic increase over the last decade in research on technologies for enhancing movement training and exercise for people with a disability. This paper reviews some of the recent developments in this area, using examples from a National Science Foundation initiated study of mobility research projects in Europe to illustrate important themes and key directions for future research. This paper also reviews several recent studies aimed at combining movement training with plasticity or regeneration therapies, again drawing in part from European research examples. Such combination therapies will likely involve complex interactions with motor training that must be understood in order to achieve the goal of eliminating severe motor impairment. PMID:22463132

  12. The application and efficacy of combined neurofeedback therapy and imagery training in adolescents with Tourette syndrome.

    PubMed

    Zhuo, Chuanjun; Li, Li

    2014-07-01

    We aimed to examine the effectiveness of combined neurofeedback therapy and imagery training in adolescent patients with refractory Tourette syndrome. Two patients, aged respectively 14 and 16 years, had been treated with haloperidol and tiapride; however, this medication was ineffective and accompanied by intolerable side effects. In this study, the patients completed 80 sessions of neurofeedback treatment followed by imagery training. The patients were assessed with behavior rating scales both before and after the treatment as well as during follow-up examinations to evaluate the effect of the combined therapy. Patients showed significant improvement in motor tic and vocal tic symptoms, exemplified by a reduction in the frequency and intensity of tics, indicating that neurofeedback, together with imagery training, has a positive therapeutic effect on adolescent patients with medication-refractory Tourette syndrome.

  13. Successful treatment of intracardiac and intraocular blastomycosis in a dog with combination azole therapy.

    PubMed

    Langlois, Daniel K; Pelosi, Augusta; Kruger, John M

    2013-01-01

    A 4 yr old spayed female Labrador retriever with clinical signs of blindness, cutaneous lesions, coughing, inappetence, and lethargy was diagnosed with disseminated blastomycosis based on cytologic (skin and lymph node aspirates) and histopathologic (skin biopsy) examinations of tissue samples. The dog deteriorated clinically during hospitalization and developed sustained ventricular tachycardia. Echocardiography revealed pericardial effusion, a nodule associated with the left ventricular papillary muscle, and a right atrial mural lesion. Therapy for myocardial performance and glaucoma was initiated. A combination of itraconazole and fluconazole successfully treated the dog. The dog regained vision in the left eye (oculus sinister [OS]) and had no residual cardiac disease detectable by either electrocardiography or echocardiography. This report is unique in documenting survival from intracardiac blastomycosis and in the use of combination azole therapy for treating disseminated disease with intraocular involvement.

  14. Optimization of Antifungal Extracts from Ficus hirta Fruits Using Response Surface Methodology and Antifungal Activity Tests.

    PubMed

    Chen, Chuying; Wan, Chunpeng; Peng, Xuan; Chen, Yuhuan; Chen, Ming; Chen, Jinyin

    2015-10-29

    The fruits of Ficus hirta (FH) display strong antifungal activity against Penicillium italicum and Penicillium digitatum. In order to optimize the extraction conditions of antifungal extracts from FH fruit, various extraction parameters, such as ethanol concentration, extraction time, solvent to solid ratio and temperature, were chosen to identify their effects on the diameters of inhibition zones (DIZs) against these two Penicillium molds. Response surface methodology (RSM) was applied to obtain the optimal combination of these parameters. Results showed that the optimal extraction parameters for maximum antifungal activity were: 90% (v/v) ethanol concentration, 65 min extraction time, 31 mL/g solvent to solid ratio and 51 °C temperature. Under the abovementioned extraction conditions, the experimental DIZs values obtained experimentally were 57.17 ± 0.75 and 39.33 ± 0.82 mm, which were very close to the values of 57.26 and 39.29 mm predicted by the model. Further, nine kinds of phytopathogens were tested in vitro to explore the antifungal activity of the FH extracts. It was found for the first time that the FH extracts showed significant inhibition on the growth of P. italicum, A. citri, P. vexans, P. cytosporella and P. digitatum.

  15. Combined orthodontic and surgical therapy for a deeply impacted third molar related with a dentigerous cyst.

    PubMed

    Celebi, Nukhet; Canakci, Gulfesan Y; Sakin, Caglar; Kurt, Gokmen; Alkan, Alper

    2015-03-01

    The dentigerous cysts are the common cause that inhibits the eruption of the teeth. Large dentigerous cysts can cause pathological fractures in mandible. Temporary or permanent inferior alveolar and lingual nerve damage can occur associated with deeply impacted third molar surgery. We treated the dentigerous cyst arised from deeply impacted mandibular third molar with orthodontic extraction combined with the marsupialization therapy. This orthodontic-surgical procedure reduced the risk of nerve damage and pathological fracture of the mandible.

  16. Outcomes and Duration of Pneumocystis jirovecii Pneumonia Therapy in Infants with Severe Combined Immunodeficiency

    PubMed Central

    Lundgren, Ingrid S.; Englund, Janet A.; Burroughs, Lauri M.; Torgerson, Troy R.; Skoda-Smith, Suzanne

    2011-01-01

    This retrospective review of patients with severe combined immunodeficiency and Pneumocystis jirovecii pneumonia (PCP) evaluated the relationship between duration of therapy to treat PCP and overall survival. We found that 80% of patients receiving only 21 days of antibiotics survived to 12 months beyond hematopoetic cell transplant, whereas only 25% of patients who required longer treatment for PCP survived to stem cell engraftment. PMID:21817949

  17. Response of Human Immunodeficiency Virus-Associated Cerebral Angiitis to the Combined Antiretroviral Therapy

    PubMed Central

    Cheron, Julian; Wyndham-Thomas, Chloé; Sadeghi, Niloufar; Naeije, Gilles

    2017-01-01

    When secondary causes are excluded, mechanisms underlying central nervous system angiitis (ACNS) in human immunodeficiency virus (HIV)-infected patients are still not understood and optimal treatment remains undefined. We report here a patient with an untreated HIV infection who presented multiple ischemic strokes probably due to HIV-ACNS. ACNS signs on vessel-wall imaging magnetic resonance monitoring retracted with combined antiretroviral therapy without adjunct immunosuppressive drugs. PMID:28348548

  18. Radiofrequency Ablation Therapy Combined with Cementoplasty for Painful Bone Metastases: Initial Experience

    SciTech Connect

    Toyota, Naoyuki Naito, Akira; Kakizawa, Hideaki; Hieda, Masashi; Hirai, Nobuhiko; Tachikake, Toshihiro; Kimura, Tomoki; Fukuda, Hideki; Ito, Katsuhide

    2005-06-15

    The purpose of this study was to assess the efficacy and safety of percutaneous radiofrequency (RF) ablation therapy combined with cementoplasty under computed tomography and fluoroscopic guidance for painful bone metastases. Seventeen adult patients with 23 painful bone metastases underwent RF ablation therapy combined with cementoplasty during a 2-year period. The mean tumor size was 52 x 40 x 59 mm. Initial pain relief, reduction of analgesics, duration of pain relief, recurrence rate of pain, survival rate, and complications were analyzed. The technical success rate was 100%. Initial pain relief was achieved in 100% of patients (n = 17). The mean VAS scores dropped from 63 to 24 (p < 0.001) (n = 8). Analgesic reduction was achieved in 41% (7 out of 17 patients). The mean duration of pain relief was 7.3 months (median: 6 months). Pain recurred in three patients (17.6%) from 2 weeks to 3 months. Eight patients died and 8 patients are still alive (a patient was lost to follow-up). The one-year survival rate was 40% (observation period: 1-30 months). No major complications occurred, but one patient treated with this combined therapy broke his right femur 2 days later. There was transient local pain in most cases, and a hematoma in the psoas muscle (n = 1) and a hematoma at the puncture site (n = 1) occurred as minor complications. Percutaneous RF ablation therapy combined with cementoplasty for painful bone metastases is effective and safe, in particular, for bulky tumors extending to extraosseous regions. A comparison with cementoplasty or RF ablation alone and their long-term efficacies is needed.

  19. Combination of internal radiation therapy and hyperthermia to treat liver cancer

    SciTech Connect

    Grady, E.D.; McLaren, J.; Auda, S.P.; McGinley, P.H.

    1983-09-01

    Sixteen patients were treated for liver cancer (primary and metastatic) by a combination of internal radiation therapy with intra-arterial yttrium 90 microspheres and regional hyperthermia with electromagnetic radiation. Four patients have their liver disease apparently controlled; two had a partial regression of more than 50%; and two had a partial regression of less than 50%. The complications consisted of one case of radiation hepatitis and one of peptic ulcer.

  20. Radiofrequency ablation therapy combined with cementoplasty for painful bone metastases: initial experience.

    PubMed

    Toyota, Naoyuki; Naito, Akira; Kakizawa, Hideaki; Hieda, Masashi; Hirai, Nobuhiko; Tachikake, Toshihiro; Kimura, Tomoki; Fukuda, Hideki; Ito, Katsuhide

    2005-01-01

    The purpose of this study was to assess the efficacy and safety of percutaneous radiofrequency (RF) ablation therapy combined with cementoplasty under computed tomography and fluoroscopic guidance for painful bone metastases. Seventeen adult patients with 23 painful bone metastases underwent RF ablation therapy combined with cementoplasty during a 2-year period. The mean tumor size was 52 x 40 x 59 mm. Initial pain relief, reduction of analgesics, duration of pain relief, recurrence rate of pain, survival rate, and complications were analyzed. The technical success rate was 100%. Initial pain relief was achieved in 100% of patients (n=17). The mean VAS scores dropped from 63 to 24 (p<0.001) (n=8). Analgesic reduction was achieved in 41% (7 out of 17 patients). The mean duration of pain relief was 7.3 months (median: 6 months). Pain recurred in three patients (17.6%) from 2 weeks to 3 months. Eight patients died and 8 patients are still alive (a patient was lost to follow-up). The one-year survival rate was 40% (observation period: 1--30 months). No major complications occurred, but one patient treated with this combined therapy broke his right femur 2 days later. There was transient local pain in most cases, and a hematoma in the psoas muscle (n=1) and a hematoma at the puncture site (n=1) occurred as minor complications. Percutaneous RF ablation therapy combined with cementoplasty for painful bone metastases is effective and safe, in particular, for bulky tumors extending to extraosseous regions. A comparison with cementoplasty or RF ablation alone and their long-term efficacies is needed.

  1. [Liver Atrophy and Failure Associated with Paclitaxel and Bevacizumab Combination Therapy for Metastatic Breast Cancer].

    PubMed

    Yamamoto, Mari; Ikeda, Masahiko; Kubo, Shinichiro; Tsukioki, Takahiro; Nakamoto, Shougo

    2016-07-01

    We managed 6 cases of severe liver atrophy and failure associated with paclitaxel and bevacizumab combination therapy (PB therapy)for HER2-negative metastatic breast cancer. In this case-controlstudy, we examined the records of these 6 patients to investigate past treatment, medication history, and degree of atrophy, and compared their data with that of 67 patients without liver atrophy. The degree of the liver atrophy used SYNAPSE VINCENT®of the image analysis software. The results showed that patients with liver atrophy had a longer pretreatment period than those without liver atrophy(33.5 months vs 15.5 months), and they also experienced a longer median time to treatment failure with PB therapy than other patients(11 months vs 6 months). The ratio of individuals presenting with diffuse liver metastasis among patients with liver metastasis was 80% with liver atrophy, compared to 8% without liver atrophy. The degree of liver atrophy was an average of 67%in terms of volume ratio before/after PB therapy(57-82%). The individualwith the greatest extent of liver atrophy died of liver failure, not as a result of breast cancer progression. The direct causal link between bevacizumab and liver atrophy and failure is unclear, but the individuals in this study had a long previous history of treatment, and diffuse liver metastases may develop in patients undergoing long periods of PB therapy, which may also cause liver atrophy; therefore, the possibility of liver failure should be considered in such cases.

  2. Efficacy of Gene Therapy for X-Linked Severe Combined Immunodeficiency

    PubMed Central

    Hacein-Bey-Abina, Salima; Hauer, Julia; Lim, Annick; Picard, Capucine; Wang, Gary P.; Berry, Charles C.; Martinache, Chantal; Rieux-Laucat, Frédéric; Latour, Sylvain; Belohradsky, Bernd H.; Leiva, Lily; Sorensen, Ricardo; Debré, Marianne; Casanova, Jean Laurent; Blanche, Stephane; Durandy, Anne; Bushman, Frederic D.; Fischer, Alain; Cavazzana-Calvo, Marina

    2010-01-01

    BACKGROUND The outcomes of gene therapy to correct congenital immunodeficiencies are unknown. We reviewed long-term outcomes after gene therapy in nine patients with X-linked severe combined immunodeficiency (SCID-X1), which is characterized by the absence of the cytokine receptor common γ chain. METHODS The nine patients, who lacked an HLA-identical donor, underwent ex vivo retrovirus-mediated transfer of γ chain to autologous CD34+ bone marrow cells between 1999 and 2002. We assessed clinical events and immune function on long-term follow-up. RESULTS Eight patients were alive after a median follow-up period of 9 years (range, 8 to 11). Gene therapy was initially successful at correcting immune dysfunction in eight of the nine patients. However, acute leukemia developed in four patients, and one died. Transduced T cells were detected for up to 10.7 years after gene therapy. Seven patients, including the three survivors of leukemia, had sustained immune reconstitution; three patients required immunoglobulin-replacement therapy. Sustained thymopoiesis was established by the persistent presence of naive T cells, even after chemotherapy in three patients. The T-cell–receptor repertoire was diverse in all patients. Transduced B cells were not detected. Correction of the immunodeficiency improved the patients’ health. CONCLUSIONS After nearly 10 years of follow-up, gene therapy was shown to have corrected the immunodeficiency associated with SCID-X1. Gene therapy may be an option for patients who do not have an HLA-identical donor for hematopoietic stem-cell transplantation and for whom the risks are deemed acceptable. This treatment is associated with a risk of acute leukemia. (Funded by INSERM and others.) PMID:20660403

  3. Combined concurrent nanoshell loaded macrophage-mediated photothermal and photodynamic therapies

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry; Trinidad, Anthony; Christie, Catherine E.; Peng, Qian; Kwon, Young J.; Madsen, Steen

    2015-02-01

    Macrophages loaded with gold nanoshells (AuNS), that convert near infrared light to heat, can be used as transport vectors for photothermal hyperthermia of tumors. The purpose of this study was to investigate the effects of combined macrophage mediated photothermal therapy (PTT) and PDT on head and neck squamous cell carcinoma (HNSCC). The results provide proof of concept for the use of macrophages as a delivery vector of AuNS for photothermal enhancement of the effects of PDT on squamous cell carcinoma. A significant synergy was demonstrated with combined PDT and PTT compared to each modality applied separately.

  4. Antihypertensive combination therapy: optimizing blood pressure control and cardiovascular risk reduction.

    PubMed

    Nesbitt, Shawna D

    2007-11-01

    Treating hypertension reduces the rates of myocardial infarction, stroke, and renal disease; however, clinical trial experience suggests that monotherapy is not likely to be successful for achieving goal blood pressure (BP) levels in many hypertensive patients. In multiple recent clinical trials including various subsets of hypertensive patients, the achievement of BP goal has typically required the combination of 2 or more medications, particularly in patients with BP levels>160/100 mm Hg. When initiating combination therapy for hypertension, careful consideration must be given to the choice of medication. Clinical trial evidence has shown the efficacy of various combinations of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and diuretics in reducing BP and cardiovascular risk. Ongoing trials should provide additional guidance on the optimal choice of combination regimens in specific clinical settings.

  5. Calcitriol in Combination Therapy for Prostate Cancer: Pharmacokinetic and Pharmacodynamic Interactions

    PubMed Central

    Ben-Eltriki, Mohamed; Deb, Subrata; Guns, Emma S. Tomlinson

    2016-01-01

    Epidemiological studies indicate that vitamin D insufficiency could have an etiological role in prostate cancer. In addition, calcitriol, used in combination with currently available drugs, has the potential to potentiate their anticancer effects or act synergistically by inhibiting distinct mechanisms involved in prostate cancer growth. Clinical data have not yet provided sufficient evidence to demonstrate benefit of vitamin D due to the limited and underpowered studies that have been published to date. Here, we review the preclinical and clinical studies that describe the activity of calcitriol, applied either alone or in combination and assessed the mechanistic basis of pharmacodynamic and pharmacokinetic interactions with calcitriol. Important considerations for calcitriol use in combination therapy with respect to safety and clinical outcomes have been discussed. Many of these combinations have therapeutic potential for the treatment of several cancer types and it is anticipated that future clinical research will put emphasis on well‑designed clinical trials to establish efficacy. PMID:26918053

  6. Suppression of immune regulatory cells with combined therapy of celecoxib and sunitinib in renal cell carcinoma

    PubMed Central

    Zhao, Qi; Guo, Jianming; Wang, Guomin; Chu, Yiwei; Hu, Xiaoyi

    2017-01-01

    Objective To observe the the potential benefit of sunitinib in combination with cyclooxygenase-2(COX-2) inhibitor in renal cell carcinoma therapy. Methods 769-p cell lines were treated with sunitinib, celecoxib, or in combination at different concentrations respectively. We investigated the expression of granulocyte-macrophage colony stimulating factor (GM-CSF) in 769-p and cell proliferation in vitro. BALB/c mice implanted with Renca cells were divided into 4 groups and administered orally by gavage with sunitinib, COX-2 inhibitor (celecoxib) monotherapy or combination, and PBS respectively. Tumor growth and animal survival were observed. The myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in peripheral blood and spleen were determined by flow cytometry. The MDSCs protein was extracted for STAT3 analysis by western blot. Results 769-p cell lines were suppressed in a dose and time-dependent manner. The expression of GM-CSF was substantially inhibited by celecoxib and sunitinib. Combination of sunitinib and celecoxib in vivo could effectively reduce the MDSCs than those in control group. Meanwhile, the CD4+ lymphocytes were strongly increased and the expression of signal transducer and activator of transcription 3 (STAT3) in MDSCs were significantly reduced. Conclusion Combination therapy with sunitinib and celecoxib intensified the curative effects to renal cell carcinoma by suppressing immune regulatory cells. PMID:27926489

  7. Optimized combination therapy using bortezomib, TRAIL and TLR agonists in established breast tumors.

    PubMed

    Lee, Sujin; Yagita, Hideo; Sayers, Thomas J; Celis, Esteban

    2010-07-01

    TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptosis in various tumor cells by engaging the receptors, DR4 and DR5. Bortezomib (Velcade) is a proteasome inhibitor that has been approved for patients with multiple myeloma. There is some experimental evidence in preclinical models that bortezomib can enhance the susceptibility of tumors to TRAIL-induced apoptosis. In this study, we investigated the effects of TRAIL-induced death using an agonistic antibody to the TRAIL receptor DR5 (alpha-DR5) in combination with bortezomib administered to mice previously injected with breast cancer cells (TUBO). This combination had some beneficial therapeutic effect, which was significantly enhanced by the co-administration of a Toll-like receptor 9 agonist (CpG). In contrast, single agent treatments had little effect on tumor growth. In addition, we evaluated the effect of combination with alpha-DR5, bortezomib, and CpG in the prevention/treatment of spontaneous mammary tumors in Balb-neuT mice. In this model, which is more difficult to treat, we observed dramatic antitumor effects of alpha-DR5, bortezomib and CpG combination therapy. Since such a mouse model more accurately reflects the immunological tolerance that exists in human cancer, our results strongly suggest that these combination strategies could be directly applied to the therapy for cancer patients.

  8. Combined Hyperthermia and Photodynamic Therapy Using a Sub-THz Gyrotron as a Radiation Source

    NASA Astrophysics Data System (ADS)

    Miyoshi, Norio; Idehara, Toshitaka; Khutoryan, Eduard; Fukunaga, Yukihiro; Bibin, Andriana Bintang; Ito, Shinji; Sabchevski, Svilen Petrov

    2016-08-01

    In this paper, we present results of a hyperthermia treatment of malignant tumors using a gyrotron as a radiation source for heating of the cancerous tissue. They clearly demonstrate the efficiency of the irradiation by sub-THz waves, which leads to steady decrease of the volume of the tumor and finally to its disappearance. A combination of hyperthermia and photodynamic therapy (PDT) that utilizes a novel multifunctional photosensitizer has also been explored. In the latter case, the results are even more convincing and promising. In particular, while after a hyperthermia treatment sometimes a regrowth of the tumor is being observed, in the case of combined hyperthermia and PDT such regrowth has never been noticed. Another combined therapy is based on a preheating of the tumor by gyrotron radiation to temperatures lower than the hyperthermia temperature of 43 °C and followed then by PDT. The results show that such combination significantly increases the efficiency of the treatment. We consider this phenomenon as a synergy effect since it is absent when hyperthermia and PDT are applied separately, and manifests itself only when both methods are combined.

  9. Intensive combined modality therapy including low-dose TBI in high-risk Ewing's sarcoma patients

    SciTech Connect

    Kinsella, T.J.; Glaubiger, D.; Diesseroth, A.; Makuch, R.; Waller, B.; Pizzo, P.; Glatstein, E.

    1983-12-01

    Twenty-four high-risk Ewing's sarcoma patients were treated on an intensive combined modality protocol including low-dose fractionated total body irradiaiton (TBI) and autologous bone marrow infusion (ABMI). Twenty patients (83%) achieved a complete clinical response to the primary and/or metastatic sites following induction therapy. The median disease-free interval was 18 months, and nine patients remain disease-free with a follow-up of 22 to 72 months. Local failure as a manifestation of initial relapse occurred in only three patients (15%), each having synchronous distant failure. Eight patients failed initially with only distant metastases, usually within 1-2 years following a complete clinical response. Two patterns of granulocyte recovery following consolidative therapy (including TBI and ABMI) were recognized. The time to platelet recovery was different for the groups with early and late granulocyte recovery. Patients with late recovery did not tolerate maintenance chemotherapy. However, there was no difference in disease-free and overall survival, when comparing the groups with early and late granulocyte recovery. It is concluded that these high-risk Ewing's sarcoma patients remain a poor-prognosis group in spite of intensive combined modality therapy including low-dose TBI. The control of microscopic systemic disease remains the major challenge to improving the cure rate. A new combined modality protocol with high-dose 'therapeutic' TBI (800 rad/2 fractions) is being used and the protocol design is outlined.

  10. Combination therapy in the management of giardiasis: What laboratory and clinical studies tell us, so far.

    PubMed

    Escobedo, Angel A; Lalle, Marco; Hrastnik, Nana I; Rodríguez-Morales, Alfonso J; Castro-Sánchez, Enrique; Cimerman, Sérgio; Almirall, Pedro; Jones, Jony

    2016-10-01

    Treatment failures in patients suffering from giardiasis are not uncommon feature. The most frequent approach in these cases is to treat these patients with longer repeated courses and/or higher doses of the primary therapy, or using drugs from a different class to avoid potential cross-resistance. However, a higher rate of adverse events may limit this strategy. In this context, combination therapy (CT) is emerging as a valuable option against refractory giardiasis. In the attempt to evaluate the benefits of CT, a number of experimental studies, clinical series, and randomized clinical trials (RCTs), as well as several veterinary studies have been performed, with varying results. Here, we present a critical analysis of the available information regarding CT for the treatment of Giardia infection, as well as the authors' opinion with respect to its use. RCTs of combination therapy are limited and the optimal combinations and administration strategies need yet to be clarified. Analyses of the cost-effectiveness and RCTs of CTs for Giardia infection are required to assess the role of these drugs for the control of giardiasis, mainly in the case of treatment failures linked to suspected drug tolerance are the case.

  11. Origins of Combination Therapy for Tuberculosis: Lessons for Future Antimicrobial Development and Application

    PubMed Central

    Kerantzas, Christopher A.

    2017-01-01

    ABSTRACT Tuberculosis is a global health problem that causes the death of approximately 1.5 million people worldwide each year (WHO, p. 1–126, Global Tuberculosis Report, 2015). Treatment of drug-susceptible tuberculosis requires combination antimicrobial therapy with a minimum of four antimicrobial agents applied over the course of 6 months. The first instance of combination antimicrobial therapy applied to tuberculosis was the joint use of streptomycin and para-aminosalicylic acid as documented by the Medical Research Council of the United Kingdom in 1950. These antimicrobial drugs were the product of many decades of investigation into both organism-derived antibiotics and synthetic chemotherapy and were the first agents in those respective categories to show substantial clinical efficacy and widespread use for tuberculosis. The events leading to the discovery and application of these two agents demonstrate that investments in all aspects of research, from basic science to clinical application, are necessary for the continued success of science in finding treatments for human disease. This observation is especially worth considering given the expanded role that combination therapy may play in combating the current rise in resistance to antimicrobial drugs. PMID:28292983

  12. Combination therapies - the next logical step for the treatment of synucleinopathies?

    PubMed Central

    Valera, E.; Masliah, E.

    2015-01-01

    Currently there are no disease-modifying alternatives for the treatment of most neurodegenerative disorders. The available therapies for diseases such as Parkinson’s disease (PD), PD dementia (PDD), Dementia with Lewy bodies (DLB) and Multiple system atrophy (MSA), in which the protein alpha-synuclein (α-syn) accumulates within neurons and glial cells with toxic consequences, are focused on managing the disease symptoms. However, utilizing strategic drug combinations and/or multi-target drugs might increase the treatment efficiency when compared to monotherapies. Synucleinopathies are complex disorders that progress through several stages, and toxic α-syn aggregates exhibit prion-like behavior spreading from cell to cell. Therefore, it follows that these neurodegenerative disorders might require equally complex therapeutic approaches in order to obtain significant and long-lasting results. Hypothetically, therapies aimed at reducing α-syn accumulation and cell-to-cell transfer, such as immunotherapy against α-syn, could be combined with agents that reduce neuroinflammation with potential synergistic outcomes. Here we review the current evidence supporting this type of approach, suggesting that such rational therapy combinations, together with the use of multi-target drugs, may hold promise as the next logical step for the treatment of synucleinopathies. PMID:26388203

  13. Capecitabine and radiation therapy preceded and followed by combination chemotherapy in advanced pancreatic cancer

    SciTech Connect

    Schneider, Bryan J.; McGinn, Cornelius J.; Chang, Alfred E.; Colletti, Lisa M.; Normolle, Daniel P.; Hejna, Gwen F. P.A.; Zalupski, Mark M. . E-mail: Zalupski@umich.edu

    2005-12-01

    Purpose: The primary objective of this study was to evaluate the tolerance and toxicity of radiation therapy (RT) and capecitabine in patients with advanced, unresectable pancreatic carcinoma. To control micrometastatic disease, combination chemotherapy (gemcitabine and cisplatin) before and after combined modality therapy (CMT) was planned. Methods and Materials: Patients with unresectable or metastatic pancreatic cancer were eligible. Gemcitabine 1000 mg/m{sup 2} and cisplatin 35 mg/m{sup 2} were administered on Days 1 and 8 of a 21-day cycle for two cycles. RT was then given to a dose of 50.4 Gy in 1.8 Gy fractions. Patients were treated with capecitabine 1330 mg/m{sup 2} daily during RT. After CMT, two additional cycles of gemcitabine and cisplatin completed the treatment. Results: Twenty-three patients were treated. Eighteen patients completed CMT. One patient was removed from study during CMT for toxicity issues. Treatment delays and dose reductions were common during the final two cycles of gemcitabine and cisplatin as a result of myelosuppression. Median survival was 10.1 months (95% confidence interval [CI] = 7.6, 13.7) for all 23 patients and 12.8 months (95% CI = 8.2, 18.9) for 18 patients without metastasis. Conclusion: Combined modality therapy with RT and capecitabine was well tolerated. Chemotherapy after CMT was difficult to complete owing to cumulative myelosuppression. Survival, response, and toxicity were comparable to infusional 5-fluorouracil and RT.

  14. Combination therapy with copanlisib and ABL tyrosine kinase inhibitors against Philadelphia chromosome-positive resistant cells

    PubMed Central

    Okabe, Seiichi; Tauchi, Tetsuzo; Tanaka, Yuko; Sakuta, Juri; Ohyashiki, Kazuma

    2016-01-01

    ABL tyrosine kinase inhibitor (TKI) therapy has improved the survival of patients with Philadelphia (Ph) chromosome-positive leukemia. However, ABL TKIs cannot eradicate leukemia stem cells. Therefore, new therapeutic approaches for Ph-positive leukemia are needed. Aberrant activation of phosphoinositide 3-kinase (PI3K) signaling is important for the initiation and maintenance of human cancers. Copanlisib (BAY80-6946) is a potent inhibitor of PI3Kα and PI3K-δ. Here we investigated the efficacy of combination therapy of copanlisib with an ABL TKI (imatinib, nilotinib, or ponatinib) using BCR-ABL-positive cells. Although the effects of the ABL TKI treatment were reduced in the presence of the feeder cell line, HS-5, copanlisib inhibited cell growth. Upon combining ABL TKI and copanlisib, cell growth was reduced. Ponatinib and copanlisib combined therapy reduced tumor volume and increased survival in mouse allograft models, respectively. These results indicate that the PI3Kα and -δ inhibitors overcame the chemoprotective effects of the feeder cells and enhanced ABL TKI cytotoxicity. Thus, co-treatment with ABL TKI and copanlisib may be a powerful strategy against ABL TKI-resistant cells, including those harboring the related T315I mutation. PMID:27437766

  15. Combination therapy with copanlisib and ABL tyrosine kinase inhibitors against Philadelphia chromosome-positive resistant cells.

    PubMed

    Okabe, Seiichi; Tauchi, Tetsuzo; Tanaka, Yuko; Sakuta, Juri; Ohyashiki, Kazuma

    2016-08-16

    ABL tyrosine kinase inhibitor (TKI) therapy has improved the survival of patients with Philadelphia (Ph) chromosome-positive leukemia. However, ABL TKIs cannot eradicate leukemia stem cells. Therefore, new therapeutic approaches for Ph-positive leukemia are needed. Aberrant activation of phosphoinositide 3-kinase (PI3K) signaling is important for the initiation and maintenance of human cancers. Copanlisib (BAY80-6946) is a potent inhibitor of PI3Kα and PI3K-δ. Here we investigated the efficacy of combination therapy of copanlisib with an ABL TKI (imatinib, nilotinib, or ponatinib) using BCR-ABL-positive cells. Although the effects of the ABL TKI treatment were reduced in the presence of the feeder cell line, HS-5, copanlisib inhibited cell growth. Upon combining ABL TKI and copanlisib, cell growth was reduced. Ponatinib and copanlisib combined therapy reduced tumor volume and increased survival in mouse allograft models, respectively. These results indicate that the PI3Kα and -δ inhibitors overcame the chemoprotective effects of the feeder cells and enhanced ABL TKI cytotoxicity. Thus, co-treatment with ABL TKI and copanlisib may be a powerful strategy against ABL TKI-resistant cells, including those harboring the related T315I mutation.

  16. Augmenting antifungal activity of oxidizing agent with kojic acid: Control of Penicillium strains infecting crops

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Oxidative treatment is a strategy for preventing Penicillium contamination in foods or crops. Antifungal efficacy of oxidant [hydrogen peroxide (H2O2)], biotic effector [kojic acid (KA)] and abiotic stress (heat), alone or in combination, was investigated in Penicillium. The levels of antifungal int...

  17. Tolerability of Combined Modality Therapy for Rectal Cancer in Elderly Patients Aged 75 Years and Older

    SciTech Connect

    Margalit, Danielle N.; Mamon, Harvey J.; Ryan, David P.; Blaszkowsky, Lawrence S.; Clark, Jeffrey; Willett, Christopher G.; Hong, Theodore S.

    2011-12-01

    Purpose: To determine the rate of treatment deviations during combined modality therapy for rectal cancer in elderly patients aged 75 years and older. Methods and Materials: We reviewed the records of consecutively treated patients with rectal cancer aged 75 years and older treated with combined modality therapy at Massachusetts General Hospital and Brigham and Women's Hospital from 2002 to 2007. The primary endpoint was the rate of treatment deviation, defined as a treatment break, dose reduction, early discontinuation of therapy, or hospitalization during combined modality therapy. Patient comorbidity was rated using the validated Adult Comorbidity Evaluation 27 Test (ACE-27) comorbidity index. Fisher's exact test and the Mantel-Haenszel trend test were used to identify predictors of treatment tolerability. Results: Thirty-six eligible patients had a median age of 79.0 years (range, 75-87 years); 53% (19/36) had no or mild comorbidity and 47% (17/36) had moderate or severe comorbidity. In all, 58% of patients (21/36) were treated with preoperative chemoradiotherapy (CRT) and 33% (12/36) with postoperative CRT. Although 92% patients (33/36) completed the planned radiotherapy (RT) dose, 25% (9/36) required an RT-treatment break, 11% (4/36) were hospitalized, and 33% (12/36) had a dose reduction, break, or discontinuation of concurrent chemotherapy. In all, 39% of patients (14/36) completed {>=}4 months of adjuvant chemotherapy, and 17% (6/36) completed therapy without a treatment deviation. More patients with no to mild comorbidity completed treatment than did patients with moderate to severe comorbidity (21% vs. 12%, p = 0.66). The rate of deviation did not differ between patients who had preoperative or postoperative CRT (19% vs. 17%, p = 1.0). Conclusions: The majority of elderly patients with rectal cancer in this series required early termination of treatment, treatment interruptions, or dose reductions. These data suggest that further intensification of

  18. Current and Emerging Azole Antifungal Agents

    PubMed Central

    Sheehan, Daniel J.; Hitchcock, Christopher A.; Sibley, Carol M.

    1999-01-01

    Major developments in research into the azole class of antifungal agents during the 1990s have provided expanded options for the treatment of many opportunistic and endemic fungal infections. Fluconazole and itraconazole have proved to be safer than both amphotericin B and ketoconazole. Despite these advances, serious fungal infections remain difficult to treat, and resistance to the available drugs is emerging. This review describes present and future uses of the currently available azole antifungal agents in the treatment of systemic and superficial fungal infections and provides a brief overview of the current status of in vitro susceptibility testing and the growing problem of clinical resistance to the azoles. Use of the currently available azoles in combination with other antifungal agents with different mechanisms of action is likely to provide enhanced efficacy. Detailed information on some of the second-generation triazoles being developed to provide extended coverage of opportunistic, endemic, and emerging fungal pathogens, as well as those in which resistance to older agents is becoming problematic, is provided. PMID:9880474

  19. Antifungal drug resistance among Candida species: mechanisms and clinical impact.

    PubMed

    Sanguinetti, Maurizio; Posteraro, Brunella; Lass-Flörl, Cornelia

    2015-06-01

    The epidemiology of Candida infections has changed in recent years. Although Candida albicans is still the main cause of invasive candidiasis in most clinical settings, a substantial proportion of patients is now infected with non-albicans Candida species. The various Candida species vary in their susceptibility to the most commonly used antifungal agents, and the intrinsic resistance to antifungal therapy seen in some species, along with the development of acquired resistance during treatment in others, is becoming a major problem in the management of Candida infection. A better understanding of the mechanisms and clinical impact of antifungal drug resistance is essential for the efficient treatment of patients with Candida infection and for improving treatment outcomes. Herein, we report resistance to the azoles and echinocandins among Candida species.

  20. Efficacy in treatment of cervical HRHPV infection by combination of beta interferon, and herbal therapy in woman with different cervical lesions.

    PubMed

    Iljazović, Ermina; Ljuca, Dzenita; Sahimpasić, Ademir; Avdić, Silvija

    2006-11-01

    Cervical dysplasia, a premalignant lesion that can progress to cervical cancer, is caused primarily by a sexually transmitted infection with an oncogenic strain of the human papillomavirus (HPV). The HPV infections are treated through destroying the clinical lesions: laser, cryotherapy, podophyllin... The hope is that by causing local tissue inflammation that the body will be stimulated to mount an antibody response and thereby prevent recurrence. In contrast to other prevention approaches, vaccines can reduce susceptibility in uninfected partners by stimulating the immune system. Aloe vera has also been reported to retard tumour growth and stimulate the immune response to viruses. A list of possible actions of propolis includes: antibacterial, antifungal, antiviral, antioxidant, anticarcinogenic, antithrombotic and immunomodulatory. Research on the possible role of some B vitamins in preventing cancer began in the last few decades, but however this complex have an influence on immune status. The aim of our study is to try to treat the HPV infection as confirmed cause of neoplastic transformation with some herbal therapy and interferon and to try define the guidelines in the management of the HPV positive patients. Goal of this paper is to search for evidence of efficacy of any treatment for HPV infection of the cervix mostly in woman with no concomitant CIN. Fifty five woman affected by HPV genital infection were enrolled in the study from September 2005 to April 2006. Patients were classified according to the results of the HPV testing prior and after the therapy. Patients were randomized into two groups: the first group was HPV positive woman treated with other than recommended therapy (n=20), (control group); the second group was pharmacologically treated with intravaginal administration of an interferon and aloe vera-propolis in recommended scheme (n=35) with treatment of the possible fungal or bacterial genital infection prior to the specific therapy. The

  1. An in Vivo shRNA-Drug Screen to Identify Novel Targeted Therapy Combinations for KRAS Mutant Cancers

    DTIC Science & Technology

    2014-12-01

    AWARD NUMBER: W81XWH-12-1-0420 TITLE: An in Vivo shRNA-Drug Screen to Identify Novel Targeted Therapy Combinations for KRAS Mutant Cancers...2012 - 31 Aug 2014 4. TITLE AND SUBTITLE An in Vivo shRNA-Drug Screen to Identify Novel Targeted Therapy Combinations for KRAS Mutant Cancers...through the MAPK pathway, a key KRAS effector) to kill KRAS mutant pancreatic cancer cells in order to develop novel therapeutic combinations for these

  2. Combination radiation-adriamycin therapy: renoprival growth, functional and structural effects in the immature mouse

    SciTech Connect

    Donaldson, S.S.; Moskowitz, P.S.; Canty, E.L.; Fajardo, L.F.

    1980-07-01

    The normal tissue effects of radiation-adriamycin combination therapy were studied in the renoprival weanling mouse in an attempt to determine whether compensatory renal growth inhibition from radiation and chemotherapy could be associated with structural or functional abnormalities. Weanling BLc/sub Fl/ mice underwent unilateral nephrectomy, then single fraction renal irradiation, LD 1/21 doses of adriamycin in 5 daily doses, or combination therapy with radiation and adriamycin. Animals were sacrificed at 3, 12, and 24 weeks. Compensatory renal growth, body growth, serum blood urea nitrogen (BUN), and renal morphology by light microscopy were evaluated. Significant compensatory renal growth inhibition from radiation-adriamycin therapy exceeded that produced by adriamycin alone and radiation alone, at all time periods (p < 0.005). Body growth inhibition from radiation-adriamycin therapy or adriamycin alone significantly exceeded that produced by radiation alone (p < 0.005). Kidney and body growth inhibition from radiation-adriamycin therapy was proportionately severe. Kidney growth inhibition proportionately exceeded body growth inhibition with radiation alone; body growth inhibition proportionately exceeded kidney growth inhibition with adriamycin alone. Comparable azotemia developed by 24 weeks in both the radiation alone (p < .005) and radiation-adriamycin animals (p < 0.005), but not in the adriamycin only animals. Morphologic alterations consisting of increased glomerular density, tubular atrophy, and stromal fibrosis occurred with greater severity in the radiation-adriamycin animals than in the radiation only animals by 24 weeks; no alterations were seen in the adriamycin only animals. Using histologic criteria 750 rad plus adriamycin produced comparable injury as seen with 1000 rad alone, thus adriamycin produced an apparent dose-modifying factor of 1.33.

  3. Fixed-dose combination therapy for the prevention of cardiovascular disease

    PubMed Central

    de Cates, Angharad N; Farr, Matthew RB; Wright, Nicola; Jarvis, Morag C; Rees, Karen; Ebrahim, Shah; Huffman, Mark D

    2014-01-01

    Background Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, yet CVD risk factor control and secondary prevention rates remain low. A fixed-dose combination of blood pressure and cholesterol lowering and antiplatelet treatments into a single pill, or polypill, has been proposed as one strategy to reduce the global burden of CVD by up to 80% given its potential for better adherence and lower costs. Objectives To determine the effectiveness of fixed-dose combination therapy on reducing fatal and non-fatal CVD events and on improving blood pressure and lipid CVD risk factors for both primary and secondary prevention of CVD. We also aimed to determine discontinuation rates, adverse events, health-related quality of life, and costs of fixed-dose combination therapy. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library(2013, Issue 6), MEDLINE Ovid (1946 to week 2 July 2013), EMBASE Ovid (1980 to Week 28 2013), ISI Web of Science (1970 to 19 July 2013), and the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database (HTA), and Health Economics Evaluations Database (HEED) (2011, Issue 4) in The Cochrane Library. We used no language restrictions. Selection criteria We included randomised controlled trials of a fixed-dose combination therapy including at least one blood pressure lowering and one lipid lowering component versus usual care, placebo, or a single drug active component for any treatment duration in adults ≥ 18 years old with no restrictions on presence or absence of pre-existing cardiovascular disease. Data collection and analysis Three review authors independently selected studies for inclusion and extracted the data. We evaluated risk of bias using the Cochrane risk of bias assessment tool. We sought to include outcome data on all-cause mortality, fatal and non-fatal CVD events, adverse events, changes in systolic and diastolic blood

  4. Proteasome Inhibition and Combination Therapy for Non-Hodgkin's Lymphoma: From Bench to Bedside

    PubMed Central

    Feldman, Tatyana; Goy, André

    2012-01-01

    Although patients with B-cell non-Hodgkin's lymphoma (NHL) usually respond to initial conventional chemotherapy, they often relapse and mortality has continued to increase over the last three decades in spite of salvage therapy or high dose therapy and stem cell transplantation. Outcomes vary by subtype, but there continues to be a need for novel options that can help overcome chemotherapy resistance, offer new options as consolidation or maintenance therapy postinduction, and offer potentially less toxic combinations, especially in the elderly population. The bulk of these emerging novel agents for cancer treatment target important biological cellular processes. Bortezomib is the first in the class of proteasome inhibitors (PIs), which target the critical process of intracellular protein degradation or recycling and editing through the proteasome. Bortezomib is approved for the treatment of relapsed or refractory mantle cell lymphoma. The mechanisms of proteasome inhibition are very complex by nature (because they affect many pathways) and not fully understood. However, mechanisms of action shared by bortezomib and investigational PIs such as carfilzomib, marizomib, ONX-0912, and MLN9708 are distinct from those of other NHL treatments, making them attractive options for combination therapy. Preclinical evidence suggests that the PIs have additive and/or synergistic activity with a large number of agents both in vitro and in vivo, from cytotoxics to new biologicals, supporting a growing number of combination studies currently underway in NHL patients, as reviewed in this article. The results of these studies will help our understanding about how to best integrate proteasome inhibition in the management of NHL and continue to improve patient outcomes. PMID:22566373

  5. Aspirin and proton pump inhibitor combination therapy for prevention of cardiovascular disease and Barrett's esophagus.

    PubMed

    Peura, David A; Wilcox, C Mel

    2014-01-01

    Aspirin, used at low doses (75-325 mg daily), prevents aggregation of platelets and is prescribed for patients as pharmacologic prevention of cardiovascular disease. Despite the well-documented beneficial effects of aspirin, prolonged use is associated with damage to the gastrointestinal (GI) mucosa in the upper and lower GI tract. Patient risk of hemorrhage and peptic ulcer formation is increased with older age, previous ulcer history, Helicobacter pylori infection, and concomitant use of nonsteroidal anti-inflammatory drugs, corticosteroids, or antithrombotic agents. As termination of aspirin therapy can precipitate a cardiovascular event, patients at risk need co-therapy with gastroprotective agents, such as proton pump inhibitors (PPIs), to reduce the GI side effects of aspirin treatment. Fixed-dose combinations of low-dose aspirin and gastroprotective agents have been designed to increase medication compliance, improve clinical outcomes, and reduce the overall cost of therapy. Prolonged use of PPIs may, however, lead to serious adverse effects or, in some cases, reduce the cardioprotective effects of aspirin. Hence, physicians need to carefully consider the benefits and risks associated with the condition of each patient to optimize clinical outcomes of combination therapy. A growing body of clinical evidence indicates that aspirin may decrease the risk of colorectal and other GI cancers, as well as reduce progression from Barrett's esophagus (BE) to esophageal adenocarcinoma. Furthermore, PPIs have recently been shown to reduce neoplastic transformation in patients with BE. Thus, the use of a fixed-dose aspirin/PPI combination could potentially provide chemopreventive benefit to patients with BE, and, at the same time, treat the underlying gastroesophageal reflux responsible for the condition.

  6. Theragnosis-based combined cancer therapy using doxorubicin-conjugated microRNA-221 molecular beacon.

    PubMed

    Lee, Jonghwan; Choi, Kyung-Ju; Moon, Sung Ung; Kim, Soonhag

    2016-01-01

    Recently, microRNA (miRNA or miR) has emerged as a new cancer biomarker because of its high expression level in various cancer types and its role in the control of tumor suppressor genes. In cancer studies, molecular imaging and treatment based on target cancer markers have been combined to facilitate simultaneous cancer diagnosis and therapy. In this study, for combined therapy with diagnosis of cancer, we developed a doxorubicin-conjugated miR-221 molecular beacon (miR-221 DOXO MB) in a single platform composed of three different nucleotides: miR-221 binding sequence, black hole quencher 1 (BHQ1), and doxorubicin binding site. Imaging of endogenous miR-221 was achieved by specific hybridization between miR-221 and the miR-221 binding site in miR-221 DOXO MB. The presence of miR-221 triggered detachment of the quencher oligo and subsequent activation of a fluorescent signal of miR-221 DOXO MB. Simultaneous cancer therapy in C6 astrocytoma cells and nude mice was achieved by inhibition of miRNA-221 function that downregulates tumor suppressor genes. The detection of miR-221 expression and inhibition of miR-221 function by miR-221 DOXO MB provide the feasibility as a cancer theragnostic probe. Furthermore, a cytotoxic effect was induced by unloading of doxorubicin intercalated into miR-221 DOXO MB inside cells. Loss of miR-221 function and cytotoxicity induced by the miR-221 DOXO MB provides combined therapeutic efficacy against cancers. This method could be used as a new theragnostic probe with enhanced therapy to detect and inhibit many cancer-related miRNAs.

  7. Renoprotective effects of combined SGLT2 and ACE inhibitor therapy in diabetic Dahl S rats

    PubMed Central

    Kojima, Naoki; Williams, Jan M; Slaughter, Tiffani N; Kato, Sota; Takahashi, Teisuke; Miyata, Noriyuki; Roman, Richard J

    2015-01-01

    This study examined whether control of hyperglycemia with a new SGLT2 inhibitor, luseogliflozin, given alone or in combination with lisinopril could prevent the development of renal injury in diabetic Dahl salt-sensitive (Dahl S) rats treated with streptozotocin (Dahl-STZ). Blood glucose levels increased from normoglycemic to hyperglycemic levels after treatment of STZ in Dahl S rats. Chronic treatment of Dahl-STZ rats with luseogliflozin (10 mg/kg/day) increased the fractional excretion of glucose and normalized blood glucose and HbA1c levels. Lisinopril (20 mg/kg/day) reduced blood pressure from 145 ± 9 to 120 ± 5 mmHg in Dahl-STZ rats, while luseogliflozin had no effect on blood pressure. Combination therapy reduced blood pressure more than that seen in the rats treated with luseogliflozin or lisinopril alone. Dahl-STZ rats exhibited hyperfiltration, mesangial matrix expansion, severe progressive proteinuria, focal glomerulosclerosis and interstitial fibrosis. Control of hyperglycemia with luseogliflozin reduced the degree of hyperfiltration and renal injury but had no effect on blood pressure or the development of proteinuria. Treatment with lisinopril reduced hyperfiltration, proteinuria and renal injury in Dahl-STZ rats. Combination therapy afforded greater renoprotection than administration of either drug alone. These results suggest that long-term control of hyperglycemia with luseogliflozin, especially in combination with lisinopril to lower blood pressure, attenuates the development of renal injury in this rat model of advanced diabetic nephropathy. PMID:26169541

  8. Comparison possibilities of ultrasound and its combination with laser in surgery and therapy

    NASA Astrophysics Data System (ADS)

    Zharov, Vladimir P.; Menyaev, Yulian A.; Kabisov, Ruslan K.; Alkov, Sergey V.; Nesterov, A. V.; Loshchilov, Vladimir I.; Suen, James Y.

    2000-05-01

    This article presents the further developments of combined laser-ultrasound medical technologies with paying attention the possibility ultrasound in surgery and therapy. The analyses of main effects at the low frequency ultrasonic treatment of biotissues including cavitation, acoustic streams, acoustic pressure, mechanical influence etc are analyzed. The main promising areas of application of low frequency ultrasound are considered including bactericidal treatment of infections wounds, spray treatment of wounds in head and neck surgery, tumor treatment etc. In particular the clinical result of using ultrasonic devices based on imposing ultrasonic oscillations in a range of 22-66 kHz on a cutting instrument with a special form, radiation intensity up to 10 W/cm2 and oscillation amplitude up to 40-60 micrometers with respect to oncology for halt bleeding from a tumor, liquidating pain, acoustic denervation are presented. Some limitation of medical application of ultrasound are discussed and perspective combination with laser for increasing efficiency of new combined technologies are found. Among them: combination photodynamic therapy and ultrasonic treatment of tumors, laser-ultrasonic treatment of infections wounds including using spray, laser-ultrasonic drug delivery. The preliminary result of experimental study of some of above-mentioned technologies are presented.

  9. [Sildenafil and alprostadil in the combined drug therapy of erectile dysfunction].

    PubMed

    Mazo, E B; Dmitriev, D G; Gamidov, S I; Ovchinnikov, R I

    2002-01-01

    Forty-four patients with erectile dysfunction (ED) aged 21-72 years aged 21-72 years (mean age 61 years) were examined and treated with sildenafil and alprostadil monotherapy or combined therapy. ED was psychogenic in 9(20.5%), arterial in 12(27.2%), vein occlusive in 9(20.5%) and neurogenic in 14(31.8%) patients. Monotherapy was most effective in psychogenic ED (alprostadil--100%, sildenafil--88.9%), least effective in vein occlusive ED (alprostadil--33.3%, sildenafil--22.2%). Alprostadil was more effective in arterial and neurogenic ED (83.3 vs 66.7 and 78.6 vs 57.1%, respectively). Combination of the two drugs produced much high response: 100, 85.7 and 55.5% in arterial, neurogenic and vein occlusive ED, respectively. Thus, combined treatment with sildenafil and alprostadil is a method of choice in the treatment of ED in failure of monotherapy with these drugs or in vein occlusive ED. In the combined treatment dose of the drugs, number of side effects and cost of therapy are lower.

  10. Combination therapy with polymyxin B and netropsin against clinical isolates of multidrug-resistant Acinetobacter baumannii

    PubMed Central

    Chung, Joon-hui; Bhat, Abhayprasad; Kim, Chang-Jin; Yong, Dongeun; Ryu, Choong-Min

    2016-01-01

    Polymyxins are last-resort antibiotics for treating infections of Gram-negative bacteria. The recent emergence of polymyxin-resistant bacteria, however, urgently demands clinical optimisation of polymyxin use to minimise further evolution of resistance. In this study we developed a novel combination therapy using minimal concentrations of polymyxin B. After large-scale screening of Streptomyces secondary metabolites, we identified a reliable polymixin synergist and confirmed as netropsin using high-pressure liquid chromatography, nuclear magnetic resonance, and mass spectrometry followed by in vitro assays using various Gram-negative pathogenic bacteria. To evaluate the effectiveness of combining polymixin B and netropsin in vivo, we performed survival analysis on greater wax moth Galleria mellonella infected with colistin-resistant clinical Acinetobacter baumannii isolates as well as Escherichia coli, Shigella flexineri, Salmonella typhimuruim, and Pseudomonas aeruginosa. The survival of infected G. mellonella was significantly higher when treated with polymyxin B and netropsin in combination than when treated with polymyxin B or netropsin alone. We propose a netropsin combination therapy that minimises the use of polymyxin B when treating infections with multidrug resistant Gram-negative bacteria. PMID:27306928

  11. Combination therapy including serratiopeptidase improves outcomes of mechanical-antibiotic treatment of periimplantitis.

    PubMed

    Sannino, G; Gigola, P; Puttini, M; Pera, F; Passariello, C

    2013-01-01

    This study was designed as a retrospective analysis of clinical outcomes of cases of periimplantitis treated by mechanical debridement and the administration of antibiotics combined or not with the administration of either the proteolytic enzyme serratiopeptidase (SPEP) or non-steroidal anti-inflammatory drugs (NSAIDs). Clinical charts of 544 partially edentulous patients treated for periimplantitis between June 1996 and December 2010 were analyzed to obtain clinical data of the affected implants just before the beginning of treatment and 12 months later to evaluate the outcomes of combined mechanical antibiotic treatment alone or in combination with the co-administration of the anti-inflammatory SPEP or NSAIDs. The comparative analysis revealed that therapeutic outcomes were significantly different in the three groups. Failure rate in the group that received SPEP (6 percent) was significantly lower compared to the group that received NSAIDS (16.9 percent; P less than 0.01) and to the group that received no anti-inflammatory therapy (18.9 percent; P less than 0.01). Treatment including SPEP was associated with significantly better healing also when successful treatments alone were considered. The data reported in this paper strongly support the hypothesis that SPEP is a valid addition to protocols for the combined therapy of peri-implantitis. In fact, it allows to enhance success rates significantly and also favors better tissue repair around successfully treated implants as compared to other regimens.

  12. Multicenter study of combination DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis

    PubMed Central

    Wang, Yini; Huang, Wenqiu; Hu, Liangding; Cen, Xinan; Li, Lihong; Wang, Jijun; Shen, Jianliang; Wei, Na

    2015-01-01

    Hemophagocytic lymphohistiocytosis (HLH) is a refractory immune disorder with a significant risk of death. Although standard therapy has dramatically improved survival in HLH patients, approximately 30%, especially adults, show no response to current treatment strategies. This prospective study aimed to investigate the efficacy of liposomal doxorubicin treatment combined with etoposide and methylprednisolone (doxorubicin-etoposide-methylprednisolone; DEP) as a salvage therapy for adult refractory HLH. Adult patients who did not achieve at least partial response 2 weeks after initial standard HLH therapy were enrolled in this study between June 2013 and June 2014. Response to salvage therapy was assessed at 2 and 4 weeks after initiation of DEP therapy and patients were followed until death or until November 2014. Sixty-three refractory HLH patients were enrolled, including 29 cases of lymphoma-associated HLH, 22 cases of Epstein-Barr virus–associated HLH, and 4 cases of familial HLH. There were 8 cases with unknown underlying diseases. Seventeen cases (27.0%) achieved complete response and 31 cases (49.2%) achieved partial response. The overall response was 76.2% (48/63). Patients who showed no response to DEP died within 4 weeks after salvage therapy. Twenty-nine of the 48 patients who achieved partial or complete response survived to subsequent chemotherapy, allogenic hematopoietic stem cell transplantation, or splenectomy. Our study suggests that DEP regimen is an effective salvage regimen for adult refractory HLH, which can prolong patient survival as we continue to understand the responsible mechanisms and bridge the gap between HLH and its underlying diseases. This study was registered in the Chinese Clinical Trials Registry Platform (http://www.chictr.org.cn/) as ChiCTR-IPC-14005514. PMID:26289641

  13. Quantifying the Combined Effect of Radiation Therapy and Hyperthermia in Terms of Equivalent Dose Distributions

    SciTech Connect

    Kok, H. Petra; Crezee, Johannes; Franken, Nicolaas A.P.; Barendsen, Gerrit W.

    2014-03-01

    Purpose: To develop a method to quantify the therapeutic effect of radiosensitization by hyperthermia; to this end, a numerical method was proposed to convert radiation therapy dose distributions with hyperthermia to equivalent dose distributions without hyperthermia. Methods and Materials: Clinical intensity modulated radiation therapy plans were created for 15 prostate cancer cases. To simulate a clinically relevant heterogeneous temperature distribution, hyperthermia treatment planning was performed for heating with the AMC-8 system. The temperature-dependent parameters α (Gy{sup −1}) and β (Gy{sup −2}) of the linear–quadratic model for prostate cancer were estimated from the literature. No thermal enhancement was assumed for normal tissue. The intensity modulated radiation therapy plans and temperature distributions were exported to our in-house-developed radiation therapy treatment planning system, APlan, and equivalent dose distributions without hyperthermia were calculated voxel by voxel using the linear–quadratic model. Results: The planned average tumor temperatures T90, T50, and T10 in the planning target volume were 40.5°C, 41.6°C, and 42.4°C, respectively. The planned minimum, mean, and maximum radiation therapy doses were 62.9 Gy, 76.0 Gy, and 81.0 Gy, respectively. Adding hyperthermia yielded an equivalent dose distribution with an extended 95% isodose level. The equivalent minimum, mean, and maximum doses reflecting the radiosensitization by hyperthermia were 70.3 Gy, 86.3 Gy, and 93.6 Gy, respectively, for a linear increase of α with temperature. This can be considered similar to a dose escalation with a substantial increase in tumor control probability for high-risk prostate carcinoma. Conclusion: A model to quantify the effect of combined radiation therapy and hyperthermia in terms of equivalent dose distributions was presented. This model is particularly instructive to estimate the potential effects of interaction from different

  14. Long-term results in 144 localized Ewing's sarcoma patients treated with combined therapy

    SciTech Connect

    Bacci, G.; Toni, A.; Avella, M.; Manfrini, M.; Sudanese, A.; Ciaroni, D.; Boriani, S.; Emiliani, E.; Campanacci, M.

    1989-04-15

    The results of 144 previously untreated cases of primary Ewing's sarcoma of bone are reported with a minimum follow-up of 5 years. This series was treated between 1972 and 1982 at Istituto Ortopedico Rizzoli with a combined therapy. The local control of the disease consisted of amputation (ten cases), resection followed by radiation therapy (35-45 Gy) (48 cases) and radiation therapy alone (40-60 Gy) (86 cases). Adjuvant chemotherapy, rigorously standardized, was performed according two different protocols: the first (85 cases treated in the period 1972-1978) consisted of vincristine (VCR) Adriamycin (doxorubicin) (ADM), and cyclophosphamide (EDX); the second (59 cases treated in the period 1979-1982) of VCR, ADM, EDX and dactinomycin (DACT). At a follow-up of 5 to 16 years (median, 9), 59 patients (41%) are continuously disease-free (CDF), 81 (56%) developed metastatic disease and/or local recurrence, and four (3%) had a second malignancy. Three factors seem to be correlated to prognosis: the site of the initial lesion (only 23% of the pelvic lesions are represented in the CDF group versus 46% of the other locations); the chemotherapy protocol (32% of the cases in the first protocol are CDF versus 54% in the second); the type of local treatment (60% of the patients treated with amputation or resection plus radiotherapy versus 28% of those treated with radiation therapy alone are CDF). A local recurrence was observed in 24% of the patients (8% in the group locally treated with surgery or surgery plus radiation therapy versus 36% in the group treated with radiation therapy alone). These data suggest that even though adjuvant chemotherapy can improve the long-term results in localized Ewing's sarcoma patients, this disease still represents, in a high percentage of cases, a lethal process whose final prognosis widely depends on the local control of the lesion.

  15. Involved-Node Proton Therapy in Combined Modality Therapy for Hodgkin Lymphoma: Results of a Phase 2 Study

    SciTech Connect

    Hoppe, Bradford S.; Flampouri, Stella; Zaiden, Robert; Slayton, William; Sandler, Eric; Dang, Nam H.; Lynch, James W.; Li, Zuofeng; Morris, Christopher G.; Mendenhall, Nancy P.

    2014-08-01

    Purpose: This study describes the early clinical outcomes of a prospective phase 2 study of consolidative involved-node proton therapy (INPT) as a component of combined-mode therapy in patients with stages I to III Hodgkin lymphoma (HL) with mediastinal involvement. Methods and Materials: Between September 2009 and June 2013, 15 patients with newly diagnosed HL received INPT after completing chemotherapy in an institutional review board-approved protocol comparing the dosimetric impact of PT with those of three-dimensional conformal radiation therapy (3DCRT) and intensity modulated RT. Based on {sup 18}F-Fluorodeoxyglucose positron emission tomography/computed tomography ({sup 18}F-FDG PET/CT) response, 5 children received 15 to 25.5 cobalt Gy equivalent (CGE) of INPT after receiving 4 cycles of Adriamycin, Bleomycin, Vincristine, Etoposide, Prednisone, Cyclophosphamide or Vincristine, adriamycin, methotrexate, Prednisone chemotherapy, and 10 adults received 30.6 to 39.6 CGE of INPT after 3 to 6 cycles of Adriamycin, Bleomycine, Vinblastine, Dacarbazine. Patients were routinely evaluated for toxicity during and after treatment, using Common Terminology Criteria for Adverse Events, version 3.0, and for relapse by physical examination and routine imaging. Relapse-free survival (RFS) and event-free survival (EFS) rates were calculated using the Kaplan-Meier method from the time of diagnosis. Results: The median follow-up was 37 months (range, 26-55). Two events occurred during follow-up: 1 relapse (inside and outside the targeted field) and 1 transformation into a primary mediastinal large B cell lymphoma. The 3-year RFS rate was 93%, and the 3-year EFS rate was 87%. No acute or late grade 3 nonhematologic toxicities were observed. Conclusions: Although decades of follow-up will be needed to realize the likely benefit of PT in reducing the risk of radiation-induced late effects, PT following chemotherapy in patients with HL is well-tolerated, and disease outcomes

  16. Enhanced Radiosensitization of Gold Nanospikes via Hyperthermia in Combined Cancer Radiation and Photothermal Therapy.

    PubMed

    Ma, Ningning; Jiang, Yao-Wen; Zhang, Xiaodong; Wu, Hao; Myers, John N; Liu, Peidang; Jin, Haizhen; Gu, Ning; He, Nongyue; Wu, Fu-Gen; Chen, Zhan

    2016-10-14

    Metallic nanostructures as excellent candidates for nanosensitizers have shown enormous potentials in cancer radiotherapy and photothermal therapy. Clinically, a relatively low and safe radiation dose is highly desired to avoid damage to normal tissues. Therefore, the synergistic effect of the low-dosed X-ray radiation and other therapeutic approaches (or so-called "combined therapeutic strategy") is needed. Herein, we have synthesized hollow and spike-like gold nanostructures by a facile galvanic replacement reaction. Such gold nanospikes (GNSs) with low cytotoxicity exhibited high photothermal conversion efficiency (η = 50.3%) and had excellent photostability under cyclic near-infrared (NIR) laser irradiations. We have demonstrated that these GNSs can be successfully used for in vitro and in vivo X-ray radiation therapy and NIR photothermal therapy. For the in vitro study, colony formation assay clearly demonstrated that GNS-mediated photothermal therapy and X-ray radiotherapy reduced the cell survival fraction to 89% and 51%, respectively. In contrast, the cell survival fraction of the combined radio- and photothermal treatment decreased to 33%. The synergistic cancer treatment performance was attributable to the effect of hyperthermia, which efficiently enhanced the radiosensitizing effect of hypoxic cancer cells that were resistant to ionizing radiation. The sensitization enhancement ratio (SER) of GNSs alone was calculated to be about 1.38, which increased to 1.63 when the GNS treatment was combined with the NIR irradiation, confirming that GNSs are effective radiation sensitizers to enhance X-ray radiation effect through hyperpyrexia. In vivo tumor growth study indicated that the tumor growth inhibition (TGI) in the synergistically treated group reached 92.2%, which was much higher than that of the group treated with the GNS-enhanced X-ray radiation (TGI = 29.8%) or the group treated with the GNS-mediated photothermal therapy (TGI = 70.5%). This research

  17. Successful achievement of sustained virological response to triple combination therapy containing simeprevir in two patients with chronic hepatitis C who had failed asunaprevir:Daclatasvir combination therapy.

    PubMed

    Ozeki, Itaru; Nakajima, Tomoaki; Yamaguchi, Masakatsu; Kimura, Mutsuumi; Arakawa, Tomohiro; Kuwata, Yasuaki; Ohmura, Takumi; Sato, Takahiro; Hige, Shuhei; Karino, Yoshiyasu; Toyota, Joji

    2016-10-01

    Patients 1 and 2 were treatment-naive women who had genotype 1b chronic hepatitis C. Both had IL-28B genotype TT, and amino acid substitutions of core 70 and 91 were both wild type. Search for the presence of resistance-associated variants (RAV) in non-structural (NS)3 and NS5A regions confirmed wild-type D168 and L31, along with Y93H, in both patients. These patients participated in a Japanese phase III clinical study of asunaprevir and daclatasvir at the age of 52 and 67 years, respectively, and were treated with the combination regimen for 24 weeks. However, both experienced post-treatment relapse, and then treated with triple combination therapy with simeprevir, pegylated interferon (IFN) and ribavirin at the age of 53 and 68 years, respectively, and achieved sustained virological response. A search for RAV prior to simeprevir treatment identified multiple resistance including D168E, Y93H and L31V in both patients. It has been demonstrated that, in many cases, a treatment failure with a combination of asunaprevir and daclatasvir results in acquisition of RAV in NS3 and NS5A regions and that drug-resistant mutants, particularly those in the NS5A region, survive for a long time. In these cases, direct-acting antivirals targeted towards the NS5A region may have a limited efficacy. The present case report is based on an idea that a regimen containing IFN with simeprevir could be a therapeutic option particularly for those who are likely to be highly sensitive and tolerable to IFN.

  18. Poor compliance with antifungal drug use guidelines by transplant physicians: a framework for educational guidelines and an international consensus on patient safety.

    PubMed

    Muñoz, Patricia; Rojas, Loreto; Cervera, Carlos; Garrido, Gregorio; Fariñas, Maria Carmen; Valerio, Maricela; Giannella, Maddalena; Bouza, Emilio

    2012-01-01

    The rate of compliance with antifungal drug use guidelines by transplant physicians is mostly unknown. We performed a nationwide electronic survey to assess antifungal use by different types of transplant physicians. Sixty-one percent (53/87) of the transplant programs responded (accounting for 85% of heart transplant procedures, 65% of kidney transplantations, and 71.5% of liver transplantations). Antifungal prophylaxis was used in 41.5% programs (liver 93.3%, heart 30.8%, and kidney 16%). Prophylaxis was universal in 32% of the programs and targeted only to selected patients in 68%, mainly indicated after re-transplantation (73.3%), re-intervention (66.7%) and hemodialysis (60%). Main drugs for universal prophylaxis were fluconazole and itraconazole (42.9% each), while fluconazole (60%), L-amphotericin B (AMB), and caspofungin (13.4% each) were preferred for targeted prophylaxis. Overall, 84.9% of the programs used galactomannan for the diagnosis of invasive aspergillosis (only 34% in BAL) and 66.6% used voriconazole as first-line monotherapy. Combination first-line therapy for invasive aspergillosis was used by 31.3%, mainly with voriconazole with caspofungin (40%) or anidulafungin (26.7%) or L-AMB-caspofungin (26.7%). Adherence of transplant physicians to current recommendations on antifungal treatment and prophylaxis is poor. An international consensus that responds to differences in patients and centers and emphasizes patient safety is clearly needed.

  19. Empagliflozin/Linagliptin: Combination therapy in patients with type 2 diabetes.

    PubMed

    Tan, Xueying; Hu, Jingbo

    2016-10-01

    Glyxambi(®) (empagliflozin/linagliptin) is a fixed-dose, once-daily tablet combining a sodium glucose co-transporter-2 (SGLT2) inhibitor with a dipeptidyl peptidase-4 (DPP-4) inhibitor. Glyxambi(®) is served as an adjuvant to diet and exercise to improve glycemic control in adults with type 2 diabetes when both empagliflozin and linagliptin are appropriate treatments. Glyxambi(®) combines 10mg or 25mg empagliflozin with 5mg linagliptin, with different, complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes. Empagliflozin removes glucose through the urine by blocking blood glucose re-absorption in the kidney, and linagliptin exerts glucose-lowering activity by increasing hormones that stimulate the pancreas to produce more insulin and decreasing the levels of glucagon in the circulation. In addition, this combination therapy modestly reduces body weight and blood pressure without significant safety issues.

  20. Radiation therapy alone or in combination with surgery in head and neck cancer

    SciTech Connect

    Marcial, V.A.; Pajak, T.F.

    1985-05-01

    Radiation therapy alone, surgery alone, or the combination of these two modalities, remain the accepted treatments in the management of epidermoid carcinomas of the mucosa of the head and neck. These modalities of therapy produce comparable results; but, radiotherapy alone has the advantage that it can conserve anatomy and function. Irradiation with teletherapy techniques, at times supplemented by interstitial brachytherapy, with doses ranging from 6600 to 8000 cGy, results in satisfactory tumor response (CR). The CR of T1N0 and T2N0 lesions will be 99% and 90% respectively, but only 29% in T4N3 tumors treated with radiation only. To improve on the limited CR rate achieved in the advanced stages, surgery is combined pre or post-irradiation, or reserved for the salvage of failures. In the oral cavity and oropharynx, these possible options give comparable tumor control and survival, but in the supraglottic larynx post-operative irradiation is superior to pre- operative radiotherapy. Tumor recurrence rates in the head and neck range from 15 to 34% depending on initial site, stage and type of therapy. Cancer control activities that emphasize prevention and early diagnosis should present a better future for these patients.

  1. Experimental Bothrops atrox envenomation: Efficacy of antivenom therapy and the combination of Bothrops antivenom with dexamethasone.

    PubMed

    Santos Barreto, Gabriella Neves Leal; de Oliveira, Sâmella Silva; Dos Anjos, Isabelle Valle; Chalkidis, Hipocrates de Menezes; Mourão, Rosa Helena Veras; da Silva, Ana Maria Moura; Sano-Martins, Ida Sigueko; Gonçalves, Luis Roberto de Camargo

    2017-03-17

    Bothrops atrox snakes are the leading cause of snake bites in Northern Brazil. The venom of this snake is not included in the antigen pool used to obtain the Bothrops antivenom. There are discrepancies in reports on the effectiveness of this antivenom to treat victims bitten by B. atrox snakes. However, these studies were performed using a pre-incubation of the venom with the antivenom and, thus, did not simulate a true case of envenomation treatment. In addition, the local lesions induced by Bothrops venoms are not well resolved by antivenom therapy. Here, we investigated the efficacy of the Bothrops antivenom in treating the signs and symptoms caused by B. atrox venom in mice and evaluated whether the combination of dexamethasone and antivenom therapy enhanced the healing of local lesions induced by this envenomation. In animals that were administered the antivenom 10 minutes after the envenomation, we observed an important reduction of edema, dermonecrosis, and myonecrosis. When the antivenom was given 45 minutes after the envenomation, the edema and myonecrosis were reduced, and the fibrinogen levels and platelet counts were restored. The groups treated with the combination of antivenom and dexamethasone had an enhanced decrease in edema and a faster recovery of the damaged skeletal muscle. Our results show that Bothrops antivenom effectively treats the envenomation caused by Bothrops atrox and that the use of dexamethasone as an adjunct to the antivenom therapy could be useful to improve the treatment of local symptoms observed in envenomation caused by Bothrops snakes.

  2. Improved outcomes with intensity modulated radiation therapy combined with temozolomide for newly diagnosed glioblastoma multiforme.

    PubMed

    Aherne, Noel J; Benjamin, Linus C; Horsley, Patrick J; Silva, Thomaz; Wilcox, Shea; Amalaseelan, Julan; Dwyer, Patrick; Tahir, Abdul M R; Hill, Jacques; Last, Andrew; Hansen, Carmen; McLachlan, Craig S; Lee, Yvonne L; McKay, Michael J; Shakespeare, Thomas P

    2014-01-01

    Purpose. Glioblastoma multiforme (GBM) is optimally treated by maximal debulking followed by combined chemoradiation. Intensity modulated radiation therapy (IMRT) is gaining widespread acceptance in other tumour sites, although evidence to support its use over three-dimensional conformal radiation therapy (3DCRT) in the treatment of gliomas is currently lacking. We examined the survival outcomes for patients with GBM treated with IMRT and Temozolomide. Methods and Materials. In all, 31 patients with GBM were treated with IMRT and 23 of these received chemoradiation with Temozolomide. We correlated survival outcomes with patient functional status, extent of surgery, radiation dose, and use of chemotherapy. Results. Median survival for all patients was 11.3 months, with a median survival of 7.2 months for patients receiving 40.05 Gray (Gy) and a median survival of 17.4 months for patients receiving 60 Gy. Conclusions. We report one of the few series of IMRT in patients with GBM. In our group, median survival for those receiving 60 Gy with Temozolomide compared favourably to the combined therapy arm of the largest randomised trial of chemoradiation versus radiation to date (17.4 months versus 14.6 months). We propose that IMRT should be considered as an alternative to 3DCRT for patients with GBM.

  3. Detoxification combining fasting with fluid therapy for refractory cases of severe atopic dermatitis.

    PubMed

    Kim, Kyu Seok; Nam, Hae Jeong

    2013-01-01

    To introduce and determine the clinical benefits of a detoxification program that combines fasting with fluid therapy for refractory cases of severe atopic dermatitis (AD), we performed a retrospective chart review of inpatients with AD from March 2010 to February 2012 at the Department of Ophthalmology, Otorhinolaryngology and Dermatology of Korean Medicine in the Kyung Hee Medical Center. Patients were treated with the detoxification program, which combined fasting with fluid therapy, and herbal medicine, herbal wet wrap dressings, or acupuncture treatment when clinically necessary. The primary outcome was the SCORAD total index. The secondary outcome was the pruritus visual analogue scale (VAS) score in SCORAD as evaluated by a trained dermatology specialist. Among the 130 inpatients that have done detoxification, 7 patients met the inclusion criteria. The mean total SCORAD scores significantly decreased from 64.67 ± 11.72 to 26.26 ± 11.01 (P = 0.018) after the detoxification program. There was also a significant decrease in VAS score for pruritus from 8.00 ± 1.16 to 2.57 ± 0.98 (P = 0.016) between admission and discharge. We suggest that fasting with fluid therapy as a complementary and alternative treatment method may provide some benefits for patients with refractory cases of severe atopic dermatitis.

  4. Malignant Esophagogastric Junction Obstruction: Efficacy of Balloon Dilation Combined with Chemotherapy and/or Radiation Therapy

    SciTech Connect

    Ko, Gi-Young; Song, Ho-Young Hong, Heuk-Jin; Sung, Kyu-Bo; Seo, Tae-Seok; Yoon, Hyun-Ki

    2003-04-15

    Purpose: To assess the efficacy of balloon dilation combined with chemotherapy and/or radiation therapy for palliation of dysphagia due to malignant esophagogastric junction strictures. Methods: Fluoroscopically guided balloon dilation was attempted in 20 patients. The causes of strictures were gastric adenocarcinoma (n = 10) and esophageal squamous cell carcinoma (n = 10). Scheduled chemotherapy and/or radiation therapy followed balloon dilation in all patients. Results: There were no technical failures or major complications. After balloon dilation, 15 (75%) patients showed improvement of dysphagia. No patient complained of reflux esophagitis during the follow-up period. Among the 15 patients, seven needed no further treatment for palliation of dysphagia until their deaths. The remaining eight patients underwent repeat balloon dilation(n = 4) or stent placement (n = 4)3-43 weeks (mean 15 weeks) after the initial balloon dilation because of recurrent dysphagia. Conclusion: Balloon dilation combined with chemotherapy and/or radiation therapy seems to be an easy and reasonably effective palliative treatment for malignant esophagogastric strictures.

  5. Multifunctional Fe2O3@PPy-PEG nanocomposite for combination cancer therapy with MR imaging

    NASA Astrophysics Data System (ADS)

    Zhou, Jun; Li, Jinghua; Ding, Xingwei; Liu, Junjie; Luo, Zhong; Liu, Yun; Ran, Qichun; Cai, Kaiyong

    2015-10-01

    In recent years, magnetic hyperthermia nanoparticles have drawn great attention for cancer therapy because they have no limitation of tissue penetration during the therapy process. In this study, cubic nanoporous Fe2O3 nanoparticles derived from cubic Prussian blue nanoparticles were used as magnetic cores to generate heat by alternating the current magnetic field (AMF) for killing cancer cells. In addition, polypyrrole (PPy) was coated on the surfaces of the cubic Fe2O3 nanoparticles to load doxorubicin hydrochloride (DOX). The PEG component was then physically adsorbed onto the surfaces of the nanoparticles, resulting in a Fe2O3@PPy-DOX-PEG nanocomposite. The nanocomposite was triggered by acid stimulus and AMF to release DOX, resulting in a remarkable combination therapeutic effect via chemotherapy and magnetic hyperthermia. Furthermore, the nanocomposite could realize magnetic resonance imaging (MRI) due to the magnetic core structure. The study provides an alternative for the development of new nanocomposites for combination cancer therapy with MR imaging in vivo.

  6. The role of fluticasone propionate/salmeterol combination therapy in preventing exacerbations of COPD

    PubMed Central

    Yawn, Barbara P; Raphiou, Ibrahim; Hurley, Judith S; Dalal, Anand A

    2010-01-01

    Exacerbations contribute significantly to the morbidity of COPD, leading to an accelerated decline in lung function, reduced functional status, reduced health status and quality of life, poorer prognosis and increased mortality. Prevention of exacerbations is thus an important goal of COPD management. In patients with COPD, treatment with a combination of the inhaled corticosteroid fluticasone propionate (250 μg) and the long-acting β2-agonist salmeterol (50 μg) in a single inhaler (250/50 μg) is an effective therapy option that has been shown to reduce the frequency of exacerbations, to improve lung function, dyspnea and health status, and to be relatively cost-effective as a COPD maintenance therapy. Importantly, results of various studies suggest that fluticasone propionate and salmeterol have synergistic effects when administered together that improve their efficacy in controlling symptoms and reducing exacerbations. The present non-systematic review summarizes the role of fluticasone propionate/salmeterol combination therapy in the prevention of exacerbations of COPD and its related effects on lung function, survival, health status, and healthcare costs. PMID:20631816

  7. Experimental Bothrops atrox envenomation: Efficacy of antivenom therapy and the combination of Bothrops antivenom with dexamethasone

    PubMed Central

    dos Anjos, Isabelle Valle; Chalkidis, Hipocrates de Menezes; Mourão, Rosa Helena Veras; Moura-da-Silva, Ana Maria; Sano-Martins, Ida Sigueko; Gonçalves, Luis Roberto de Camargo

    2017-01-01

    Bothrops atrox snakes are the leading cause of snake bites in Northern Brazil. The venom of this snake is not included in the antigen pool used to obtain the Bothrops antivenom. There are discrepancies in reports on the effectiveness of this antivenom to treat victims bitten by B. atrox snakes. However, these studies were performed using a pre-incubation of the venom with the antivenom and, thus, did not simulate a true case of envenomation treatment. In addition, the local lesions induced by Bothrops venoms are not well resolved by antivenom therapy. Here, we investigated the efficacy of the Bothrops antivenom in treating the signs and symptoms caused by B. atrox venom in mice and evaluated whether the combination of dexamethasone and antivenom therapy enhanced the healing of local lesions induced by this envenomation. In animals that were administered the antivenom 10 minutes after the envenomation, we observed an important reduction of edema, dermonecrosis, and myonecrosis. When the antivenom was given 45 minutes after the envenomation, the edema and myonecrosis were reduced, and the fibrinogen levels and platelet counts were restored. The groups treated with the combination of antivenom and dexamethasone had an enhanced decrease in edema and a faster recovery of the damaged skeletal muscle. Our results show that Bothrops antivenom effectively treats the envenomation caused by Bothrops atrox and that the use of dexamethasone as an adjunct to the antivenom therapy could be useful to improve the treatment of local symptoms observed in envenomation caused by Bothrops snakes. PMID:28306718

  8. Percutaneous and combined percutaneous and intralesional Nd:YAG-laser therapy for vascular malformations.

    PubMed

    Wimmershoff, M B; Landthaler, M; Hohenleutner, U

    1999-01-01

    The numerous types of vascular abnormality are classified in groups according to their pathological and anatomical features. We present case histories of 2 patients who had vascular malformations of the face since birth or early childhood. Application methods, side-effects and complications of percutaneous and intra-lesional Nd:YAG-laser therapy are reviewed for these patients. A 54-year-old woman was treated percutaneously with the Nd: YAG-laser at 1064 nm, with 20 30 W, cw 1-5 s pulses and 2 - 3 mm spot size. A 59-year-old woman was treated with the combined percutaneous and intralesional laser therapy with 30 W, cw 1-5 s pulses and 2-3 mm spot size. In both cases, percutaneous or combined percutaneous and intra-lesional Nd: YAG-laser application resulted in a significant shrinking of the lesion. The Nd:YAG-laser radiation at 1064 nm presents an effective treatment of vascular malformations due to its deep penetration into the tissue. No standardized guidelines for Nd: YAG-laser therapy exist and the treatment parameters should be chosen individually according to the type of vascular malformation.

  9. Combined Tbet and IL12 gene therapy elicits and recruits superior antitumor immunity in vivo.

    PubMed

    Qu, Yanyan; Chen, Lu; Lowe, Devin B; Storkus, Walter J; Taylor, Jennifer L

    2012-03-01

    We have recently shown that intratumor (i.t.) injection of syngenic dendritic cells (DC) engineered to express the transcription factor Tbet (TBX21) promotes protective type-1 T cell-mediated immunity via a mechanism that is largely interleukin (IL)-12p70-independent. Since IL-12 is a classical promoter of type-1 immunity, the current study was undertaken to determine whether gene therapy using combined Tbet and IL-12 complementary DNA (cDNA) would yield improved antitumor efficacy based on the complementary/synergistic action of these biologic modifiers. Mice bearing established subcutaneous (s.c.) tumors injected with DC concomitantly expressing ectopic Tbet and IL12 (i.e., DC.Tbet/IL12) displayed superior (i) rates of tumor rejection and extended overall survival, (ii) cross-priming of Tc1 reactive against antigens expressed within the tumor microenvironment, and (iii) infiltration of CD8(+) T cells into treated tumors in association with elevated locoregional production of CXCR3 ligand chemokines. In established bilateral tumor models, i.t. delivery of DC.Tbet/IL12 into a single lesion led to slowed growth or regression at both tumor sites. Furthermore, DC.Tbet/IL12 pulsed with tumor antigen-derived peptides and injected as a therapy distal to the tumor site prevented tumor growth and activated robust antigen-specific Tc1 responses. These data support the translation use of combined Tbet and IL-12p70 gene therapy in the cancer setting.

  10. Clinical trial success rates of anti-obesity agents: the importance of combination therapies.

    PubMed

    Hussain, H T; Parker, J L; Sharma, A M

    2015-09-01

    The objective of this study was to construct a clinical trial profile assessing the risk of drug failure among anti-obesity agents. Research was conducted by looking at anti-obesity therapies currently on the market or in clinical trials (phases I to III) conducted from 1998 to September 2014, with the exclusion of any drugs whose phase I trial was conducted prior to January 1998. This was completed primarily through a search on http://clinicaltrials.gov where a total of 51 drugs met the search criteria. The transition probabilities were then calculated based on various classifications and compared against industry standards. The transition probability of anti-obesity agents was 8.50% whereas the transition probability of industry standards was 10.40%. Combination therapies had four times the transition probability than monotherapies, 40% and 4.75%, respectively. Therefore, it was determined that 92% of drugs fail during clinical trial testing for this indication and combination therapy appears to improve clinical trial success rates to 10-fold.

  11. A sweet polydopamine nanoplatform for synergistic combination of targeted chemo-photothermal therapy.

    PubMed

    Gao, Yanqin; Wu, Xingjie; Zhou, Linzhu; Su, Yue; Dong, Chang-Ming

    2015-05-01

    Inspired by sweet or sugar-coated bullets that are used for medications in clinics and the structure and function of biological melanin, a novel kind of sweet polydopamine nanoparticles and their anticancer drug doxorubicin loaded counterparts are prepared, which integrate an active targeting function, photothermal therapy, and chemotherapy into one polymeric nanocarrier. The oxidative polymerization of lactosylated dopamine and/or with dopamine are performed under mild conditions and the resulting sweet nanoparticles are thoroughly characterized. When exposed to an 808 nm continuous-wave diode laser, the magnitude of