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Sample records for addition combination therapy

  1. Combination therapy for hepatocellular carcinoma: Additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib

    PubMed Central

    Lachenmayer, Anja; Toffanin, Sara; Cabellos, Laia; Alsinet, Clara; Hoshida, Yujin; Villanueva, Augusto; Minguez, Beatriz; Tsai, Hung-Wen; Ward, Stephen C.; Thung, Swan; Friedman, Scott L.; Llovet, Josep M.

    2012-01-01

    Background & Aims Hepatocellular carcinoma (HCC) is a heterogeneous cancer in which sorafenib is the only approved systemic therapy. Histone deacetylases (HDAC) are commonly dysregulated in cancer and therefore represent promising targets for therapies, however their role in HCC pathogenesis is still unknown. We analyzed the expression of 11 HDACs in human HCCs and assessed the efficacy of the pan-HDAC inhibitor panobinostat alone and in combination with sorafenib in preclinical models of liver cancer. Methods Gene expression and copy number changes were analyzed in a cohort of 334 human HCCs, while the effects of panobinostat and sorafenib were evaluated in 3 liver cancer cell lines and a murine xenograft model. Results Aberrant HDAC expression was identified and validated in 91 and 243 HCCs, respectively. Upregulation of HDAC3 and 5 mRNAs were significantly correlated with DNA copy number gains. Inhibiting HDACs with panobinostat led to strong anti-tumoral effects in vitro and vivo, enhanced by the addition of sorafenib. Cell viability and proliferation declined, while apoptosis and autophagy increased. Panobinostat increased Histone H3 and HSP90 acetylation, downregulated BIRC5 (survivin) and upregulated CDH1. Combination therapy with panobinostat and sorafenib significantly decreased vessel density, and most significantly decreased tumor volume and increased survival in HCC xenografts. Conclusions Aberrant expression of several HDACs and copy number gains of HDAC3 and HDAC5 occur in HCC. Treatment with panobinostat combined with sorafenib demonstrated the highest preclinical efficacy in HCC models, providing the rationale for clinical studies with this novel combination. PMID:22322234

  2. Combinations Therapies.

    PubMed

    Reinmuth, Niels; Reck, Martin

    2015-01-01

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

  3. Overexpression of hepatocyte growth factor in SBMA model mice has an additive effect on combination therapy with castration.

    PubMed

    Ding, Ying; Adachi, Hiroaki; Katsuno, Masahisa; Huang, Zhe; Jiang, Yue-Mei; Kondo, Naohide; Iida, Madoka; Tohnai, Genki; Nakatsuji, Hideaki; Funakoshi, Hiroshi; Nakamura, Toshikazu; Sobue, Gen

    2015-12-25

    Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ)-encoding tract within the androgen receptor (AR) gene. The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of mutant AR in residual motor neurons and certain visceral organs. Hepatocyte growth factor (HGF) is a polypeptide growth factor which has neuroprotective properties. To investigate whether HGF overexpression can affect disease progression in a mouse model of SBMA, we crossed SBMA transgenic model mice expressing an AR gene with an expanded CAG repeat with mice overexpressing HGF. Here, we report that high expression of HGF induces Akt phosphorylation and modestly ameliorated motor symptoms in an SBMA transgenic mouse model treated with or without castration. These findings suggest that HGF overexpression can provide a potential therapeutic avenue as a combination therapy with disease-modifying therapies in SBMA. PMID:26551462

  4. Combination therapy of angiotensin II receptor blocker and calcium channel blocker exerts pleiotropic therapeutic effects in addition to blood pressure lowering: amlodipine and candesartan trial in Yokohama (ACTY).

    PubMed

    Maeda, Akinobu; Tamura, Kouichi; Kanaoka, Tomohiko; Ohsawa, Masato; Haku, Sona; Azushima, Kengo; Dejima, Toru; Wakui, Hiromichi; Yanagi, Mai; Okano, Yasuko; Fujikawa, Tetsuya; Toya, Yoshiyuki; Mizushima, Shunsaku; Tochikubo, Osamu; Umemura, Satoshi

    2012-01-01

    Recent guidelines recommend combination antihypertensive therapy to achieve the target blood pressure (BP) and to suppress target organ damage. This study aimed to examine the beneficial effects of combination therapy with candesartan and amlodipine on BP control and markers of target organ function in Japanese essential hypertensive patients (N = 20) who did not achieve the target BP level during the monotherapy period with either candesartan or amlodipine. After the monotherapy period, for patients already being treated with amlodipine, a once-daily 8 mg dose of candesartan was added on during the combination therapy period (angiotensin II receptor blocker [ARB] add-on group, N = 10), and a once-daily 5 mg dose of amlodipine was added on for those already being treated with candesartan (calcium channel blocker [CCB] add-on group, N = 10). Combination therapy with candesartan and amlodipine for 12 weeks significantly decreased clinic and home systolic blood pressure (SBP) and diastolic blood pressure (DBP). In addition, the combination therapy was able to significantly reduce urine albumin excretion without decrease in estimated glomerular filtration ratio and resulted in significant improvements in brachial-ankle pulse wave velocity, central SBP, and insulin sensitivity. Furthermore, the CCB add-on group showed a significantly greater decrease in clinic and home DBP than the ARB add-on group. The calcium channel blocker add-on group also exhibited better improvements in vascular functional parameters than the ARB add-on group. These results suggest that combination therapy with candesartan and amlodipine is an efficient therapeutic strategy for hypertension with pleiotropic benefits. PMID:22571446

  5. Combination therapy with statins.

    PubMed

    Gylling, Helena; Miettinen, Tatu A

    2002-09-01

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

  6. Comparison of hemoglobin A1c goal achievement with the addition of pioglitazone to maximal/highest tolerated doses of sulfonylurea and metformin combination therapy

    PubMed Central

    McFarland, M. Shawn; Huddleston, Lana; Tammareddi, Kumar; McKenzie, Michael; Bean, Jennifer

    2012-01-01

    Objectives It has been proposed that the combination of thiazolidinedione (TZD) therapy to metformin and sulfonylurea is beneficial due to each medication having a unique mechanism of action. Within the Veterans Affairs Hospital, specific criteria of use define when TZD therapy can be initiated. Most patients who receive TZD therapy have failed other medications prior to use. The primary objective of this study was to determine the percentage of patients achieving the American Diabetes Association (ADA) goal hemoglobin A1c (A1c) of less than 7% with the addition of pioglitazone to the maximal/highest tolerated doses of sulfonylurea and metformin combination therapy. Methods This was a six healthcare system retrospective, descriptive, analysis of type 2 diabetic patients (DM-2). Patients must have received the maximal/highest tolerated doses of sulfonylurea and metformin combination therapy and have been TZD naïve or off TZD therapy for a minimum of 6 months, a baseline A1c greater than 7%, a repeat A1c at 3 and 6 months available, and deemed medication compliant. Results We evaluated 98 total patients. The percentage of veteran patients achieving ADA goal A1c of less than 7% after the addition of pioglitazone reached statistical significance at both 3 and 6 months post TZD initiation. The mean reduction in A1c post-pioglitazone initiation was 0.67% (SD ± 0.92) and 0.78% (SD ± 0.94) at 3 and 6 months, respectively. Conclusion The addition of pioglitazone to veteran patients who were already receiving maximal/highest tolerated doses of sulfonylurea was able to achieve a higher percentage in with the ADA goal A1c of less than 7%. Initiating pioglitazone in patients with an A1c of 9% or greater did not reach statistical significance in achieving an A1c less than 7%. The initial starting dose of pioglitazone 30 mg can be considered as compared to 15 mg daily if contraindications do not exist.

  7. [Combination therapy for invasive aspergillosis].

    PubMed

    Ruiz-Camps, Isabel

    2011-03-01

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

  8. Radiation Therapy: Additional Treatment Options

    MedlinePlus

    ... This is refered to as immunotherapy . Intraoperative Radiation Therapy Radiation therapy given during surgery is called intraoperative ... external beam therapy or as brachytherapy . Novel Targeted Therapies Cancer doctors now know much more about how ...

  9. Monotherapy versus combination therapy.

    PubMed

    Patel, Shilpa M; Saravolatz, Louis D

    2006-11-01

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

  10. New combination therapies for asthma.

    PubMed

    Donohue, J F; Ohar, J A

    2001-03-01

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

  11. Targeted Therapies Combined With Immune Checkpoint Therapy.

    PubMed

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

    2016-01-01

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

  12. Combining Clozapine and Talk Therapies.

    ERIC Educational Resources Information Center

    Mulroy, Kevin

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

  13. Pharmacological properties of combination therapies for hypertension.

    PubMed

    Abernethy, D R

    1997-03-01

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

  14. Rifampin Combination Therapy for Nonmycobacterial Infections

    PubMed Central

    Forrest, Graeme N.; Tamura, Kimberly

    2010-01-01

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

  15. Combination therapy for the treatment of dyslipidemia.

    PubMed

    Streja, Dan

    2004-03-01

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

  16. Combined dispersant fluid loss control additives

    SciTech Connect

    Villa, J. L.; Zeiner, R. N.

    1985-12-31

    Water soluble polymer compositions containing polyacrylic acid and copolymer of itaconic acid and acrylamide are useful as combined dispersant and fluid loss control additives for aqueous drilling fluids, particularly fresh water, gypsum and seawater muds. An example is a polymer composition containing about 80% by weight polyacrylic acid and about 20% by weight copolymer of itaconic acid and acrylamide in its ammonium salt form.

  17. [Combination therapy of hypopharyngeal cancer].

    PubMed

    Miyahara, H

    1987-06-01

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

  18. Object attributes combine additively in visual search.

    PubMed

    Pramod, R T; Arun, S P

    2016-01-01

    We perceive objects as containing a variety of attributes: local features, relations between features, internal details, and global properties. But we know little about how they combine. Here, we report a remarkably simple additive rule that governs how these diverse object attributes combine in vision. The perceived dissimilarity between two objects was accurately explained as a sum of (a) spatially tuned local contour-matching processes modulated by part decomposition; (b) differences in internal details, such as texture; (c) differences in emergent attributes, such as symmetry; and (d) differences in global properties, such as orientation or overall configuration of parts. Our results elucidate an enduring question in object vision by showing that the whole object is not a sum of its parts but a sum of its many attributes. PMID:26967014

  19. Object attributes combine additively in visual search

    PubMed Central

    Pramod, R. T.; Arun, S. P.

    2016-01-01

    We perceive objects as containing a variety of attributes: local features, relations between features, internal details, and global properties. But we know little about how they combine. Here, we report a remarkably simple additive rule that governs how these diverse object attributes combine in vision. The perceived dissimilarity between two objects was accurately explained as a sum of (a) spatially tuned local contour-matching processes modulated by part decomposition; (b) differences in internal details, such as texture; (c) differences in emergent attributes, such as symmetry; and (d) differences in global properties, such as orientation or overall configuration of parts. Our results elucidate an enduring question in object vision by showing that the whole object is not a sum of its parts but a sum of its many attributes. PMID:26967014

  20. Combining Individual Psychodynamics with Structural Family Therapy.

    ERIC Educational Resources Information Center

    Melito, Richard

    1988-01-01

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

  1. Promising combination therapies with gemcitabine.

    PubMed

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

    2004-04-01

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

  2. Combination Antifungal Therapy for Invasive Aspergillosis Revisited

    PubMed Central

    Panackal, Anil A.

    2016-01-01

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

  3. Statin combination therapy and cardiovascular risk reduction.

    PubMed

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

    2016-05-01

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

  4. Systemic therapy and synergies by combination.

    PubMed

    Wörns, Marcus-Alexander

    2013-01-01

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

  5. Combination therapy for erectile dysfunction: an update review

    PubMed Central

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

    2011-01-01

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

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

    PubMed

    Liu, Jun; Wang, Zhong

    2015-06-01

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

  7. Recent Advances in Combined Modality Therapy

    PubMed Central

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

    2010-01-01

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

  8. 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

  9. Combined therapy in the treatment of dyslipidemia.

    PubMed

    Reiner, Zeljko

    2010-02-01

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

  10. Combination stem cell therapy for heart failure

    PubMed Central

    2010-01-01

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

  11. Mixture dynamics: Combination therapy in oncology.

    PubMed

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

    2016-06-10

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

  12. 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

  13. Emerging targets for combination therapy in melanomas.

    PubMed

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

    2015-11-14

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

  14. Combined Therapy of Gastrointestinal Stromal Tumors.

    PubMed

    Rutkowski, Piotr; Hompes, Daphne

    2016-10-01

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

  15. Fixed-dose combination therapy for psoriasis.

    PubMed

    Guenther, Lyn C

    2004-01-01

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

  16. 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

  17. 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

  18. 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.

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

    PubMed Central

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

    2013-01-01

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

  20. 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

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

    PubMed Central

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

    2002-01-01

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

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

    PubMed

    Greco, K A; McVary, K T

    2008-12-01

    symptoms and IPSS scores. Studies have not shown an increased risk of urinary retention associated with the use of anti-muscarinics in a highly select cohort of men with BPH. The available data suggest that combination therapy can be beneficial in the treatment of BPH and associated LUTS. The greatest efficacy for the alpha(1)-ARA and 5alphaRI combination was shown in patients with larger prostate size and more severe symptoms. The combination of alpha(1)-ARAs and 5alphaRIs appears to prevent disease progression in these patients. The combination of alpha(1)-ARAs with anti-muscarinic agents is useful for relieving symptoms of bladder outlet obstruction and detrusor overactivity. Theoretic concerns regarding the risk of acute urinary retention have been refuted in several recent clinical trials; however, it must be noted that the patients in these trials were a highly select cohort of men. Men with overactive bladder and BPH who are not receiving adequate alleviation of symptoms from the first-line alpha(1)-ARAs may benefit from the addition of an anti-muscarinic agent. PMID:19002123

  3. Fixed-combination and emerging glaucoma therapies.

    PubMed

    Woodward, David F; Chen, June

    2007-05-01

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

  4. Combination therapy: New hope for alcoholic hepatitis?

    PubMed

    Gao, Bin; Shah, Vijay H

    2015-09-01

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

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

    PubMed

    Cohen, Seth A; Parsons, J Kellogg

    2012-04-01

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

  6. 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

  7. 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.

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

    PubMed

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

    1977-03-21

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

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

    PubMed Central

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

    2012-01-01

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

  10. 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.

  11. 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.

  12. Combining Locoregional Therapies in the Treatment of Hepatocellular Carcinoma

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  14. 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.

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

    SciTech Connect

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

    1980-05-01

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

  16. 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

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

    PubMed Central

    Rafi, Mohammad A.

    2011-01-01

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

  18. Innovative approaches of clinical photodynamic therapy combined with immunotherapy

    NASA Astrophysics Data System (ADS)

    Huang, Zheng

    2006-02-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

    Moon, Yong S K; Kashyap, Moti L

    2002-12-01

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

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

    PubMed Central

    Gajek, Arkadiusz; Marczak, Agnieszka

    2014-01-01

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

  4. A combination therapy for cystic fibrosis.

    PubMed

    Brodsky, Jeffrey L; Frizzell, Raymond A

    2015-09-24

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

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

    PubMed Central

    Casey, Colleen L; Murray, Christine A

    2008-01-01

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

  6. Defense style changes with the addition of psychodynamic group therapy to clonazepam in social anxiety disorder.

    PubMed

    Knijnik, Daniela Z; Salum, Giovanni Abrahão; Blanco, Carlos; Moraes, Carolina; Hauck, Simone; Mombach, Clarissa K; Strapasson, Atahualpa C P; Manfro, Gisele G; Eizirik, Cláudio L

    2009-07-01

    Psychodynamic Group Therapy (PGT) and clonazepam are strategies to reduce symptoms of generalized social anxiety disorder (GSAD). The addition of PGT might lead to changes in defense styles. The objective of this study is to examine changes in defense styles when comparing clonazepam to psychodynamic group therapy plus clonazepam in GSAD during 12 weeks. Fifty-seven patients that met DSM-IV criteria for GSAD participated. social anxiety disorder symptoms were evaluated with the Liebowitz Social Anxiety Scale, and defense styles with the Defense Style Questionnaire. All defense styles changed overtime for both groups, especially mature defense style, which increased independently of the treatment allocation group. Regression analyses found that overtime there was a reduction in neurotic defenses in the combined group, whereas there was an increase in the clonazepam group. Neurotic defense style can change toward greater adaptiveness with the addition of PGT to clonazepam in GSAD, even in 12 weeks. PMID:19597364

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

    PubMed

    Hiele, M; Rutgeerts, P

    2000-06-01

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

  8. Tumorigenicity of a combination of psoriasis therapies.

    PubMed Central

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

    1994-01-01

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

  9. Combination of phytochemicals as adjuvants for cancer therapy.

    PubMed

    Ho, John W S; Cheung, Matt W M

    2014-01-01

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

  10. 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.

  11. Drug combination therapy increases successful drug repositioning.

    PubMed

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

    2016-07-01

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

  12. Combined cannabinoid therapy via an oromucosal spray.

    PubMed

    Perez, Jordi

    2006-08-01

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

  13. Pet Therapy: A New Way of Reaching Students with Additional Disabilities

    ERIC Educational Resources Information Center

    Mockler, Kimberly

    2010-01-01

    In this article, the author discusses pet therapy, using therapy dogs, as a new way of reaching students with additional disabilities. Therapy dogs aid in instruction in a variety of ways. They are particularly suited to work with preschool-aged children and special needs populations where the curriculum most easily can incorporate a therapy dog…

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

    PubMed Central

    Vaishampayan, Ulka

    2015-01-01

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

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

    PubMed

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

    2016-07-01

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

  16. Rocket based combined cycle (RBCC) propulsion systems offer additional options

    NASA Astrophysics Data System (ADS)

    Czysz, Paul A.

    The propulsion cycles presented at the 1991 IAF Congress in Montreal, and at The World Hydrogen Conference 1992 in Paris were the subject of an IAF paper for the 1992 World Space Conference in Washington DC. RBCC propulsion systems from several nations were analyzed in terms of a SSTO space launcher with a 7-Mg payload. The RBCC concept emerged from the advanced injector ramjet research of the early 1960s. The performance of the current RBCC propulsion systems such that the specific thrust of a rocket is combined with the specific impulse of an airbreather. This performance offers a new perspective to the options available. In a brief review of the present RBCC the reasons for these options are developed. The spectrum of the system options is presented in three examples, a LACE VTOL SSTO, an HTOL SSTO and a HTOL TSTO. Results using the present RBCC are dramatically different from the past concept of the Conventional Combined Cycle propulsion system, i.e., combinations of separate engines. The integration of the engine cycles into a single thermodynamically integrated system significantly changes the propulsion performance.

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

    PubMed Central

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

    2016-01-01

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

  18. 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.

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

    PubMed

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

    2016-05-01

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

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

    PubMed

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

    2016-01-01

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

  1. 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

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

    PubMed

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

    2015-01-01

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

  3. Optimal combination of antiangiogenic therapy for hepatocellular carcinoma

    PubMed Central

    Ch’ang, Hui-Ju

    2015-01-01

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

  4. Combined tar-anthralin versus anthralin treatment lowers irritancy with unchanged antipsoriatic efficacy. Modifications of short-contact therapy and Ingram therapy.

    PubMed

    Schulze, H J; Schauder, S; Mahrle, G; Steigleder, G K

    1987-07-01

    In 44 patients with chronic plaque psoriasis anthralin therapy was used as high-strength short-contact therapy in a bilateral comparison of anthralin versus 5% crude coal tar-anthralin combination. These two trials were undertaken with and without ultraviolet (UV) irradiation immediately after anthralin therapy. The combined tar-anthralin therapy was significantly less of an irritant during the first 3 weeks of treatment than anthralin alone, and it did not decrease the antipsoriatic efficacy. The use of UV irradiation, either with anthralin or tar-anthralin combination, did not produce an additional therapeutic effect. These findings lead us to prefer combined tar-anthralin therapy because of its lower irritancy in comparison with anthralin alone and they show the ineffectiveness of additional UV irradiation under the conditions of this study. PMID:3611453

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

    PubMed

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

    2014-01-01

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

  6. Combined cetuximab and genistein treatment shows additive anti-cancer effect on oral squamous cell carcinoma.

    PubMed

    Park, Sung-Jin; Kim, Myung-Jin; Kim, Yu-Kyoung; Kim, Soung-Min; Park, Ju-Yong; Myoung, Hoon

    2010-06-01

    The purpose of this study was to evaluate the potency of EGFR pathway inhibition achieved by combining cetuximab, an anti-EGFR monoclonal antibody, and genistein, a tyrosine kinase inhibitor, which target extracellular and intracellular domains of the receptor, respectively, in oral squamous cell carcinoma (OSCC) in vitro and in vivo. Two OSCC cell lines, HSC3 and KB, were treated with cetuximab (C, 0-400mug/ml), genistein (G, 0-80muM), or a combination of both at a range of concentrations. Downstream protein expression of EGFR, p-EGFR, and p-Akt were evaluated by Western blot. Cell proliferation and apoptosis indices were calculated to assess anti-cancer effects in vitro. The in vivo effects of cetuximab and genistein on tumor cell growth were examined using an OSCC xenografted nude mouse model and immunohistochemical analyses of proliferation (PCNA) and microvessel density (CD31). Treatment of cells with dual anti-EGFR agents reduced the expressions of p-EGFR, and p-Akt in HSC3 cell line, but there was no significant difference in downregulation between cetuximab alone and in combination with genistein in KB cells. Both HSC3 and KB cells showed a dose-dependent decrease in cell proliferation significantly with single agent treatment and combination (p<0.05). In low concentration, combined cetuximab and genistein therapy resulted in additive growth inhibition and more apoptosis compared to that achieved with single-agent exposure in both cell lines. A combination of cetuximab and genistein significantly inhibited tumor growth and caused a substantial growth delay in in vivo models of both cell lines while each single-agent exposure caused no delay of tumor growth. Immunohistochemical staining with PCNA revealed that the group receiving combined cetuximab and genistein exhibited the lowest number of proliferating cells and microvessel density (p<0.05). Combined therapy with genistein and cetuximab can add the potency of EGFR signaling inhibition. Because not all

  7. Synergistic nanomedicine by combined gene and photothermal therapy.

    PubMed

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

    2016-03-01

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

  8. 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

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

    PubMed

    Seidel, W

    2004-10-01

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

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

    PubMed

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

    2014-08-01

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

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

    PubMed

    Cahn, Avivit; Cefalu, William T

    2016-08-01

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

  12. Longitudinal Slit Procedure in Addition to Negative Pressure Wound Therapy for a Refractory Wound With Exposed Achilles Tendon

    PubMed Central

    Ohata, Erika; Mishima, Yoshito; Matsuo, Kiyoshi

    2015-01-01

    Objective: This case report reviews features of negative pressure wound therapy, particularly for the exposed Achilles tendon, and describes an additional effective procedure. Methods: An 87-year-old man presented with a soft-tissue defect measuring 3×5 cm with the exposed Achilles tendon as a sequela of deep burn. The condition of his affected leg was ischemic because of arteriosclerosis. We used negative pressure wound therapy and made 2 longitudinal slits penetrating the tendon to induce blood flow from the ventral side to the dorsal surface. Results: By this combination therapy, the surface of the exposed Achilles tendon was completely epithelialized and the tendon was spared without disuse syndrome. Conclusions: The authors conclude that this combination therapy is useful for covering the widely exposed tendon in aged patients. PMID:25848445

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

    PubMed

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

    2015-03-01

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

  14. 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.

  15. Addition of prokinetics to PPI therapy in gastroesophageal reflux disease: A meta-analysis

    PubMed Central

    Ren, Li-Hua; Chen, Wei-Xu; Qian, Li-Juan; Li, Shuo; Gu, Min; Shi, Rui-Hua

    2014-01-01

    AIM: To investigate the efficacy of adding prokinetics to proton pump inhibitors (PPIs) for the treatment of gastroesophageal reflux disease (GERD). METHODS: PubMed, Cochrane Library, and Web of Knowledge databases (prior to October 2013) were systematically searched for randomized controlled trials (RCTs) that compared therapeutic efficacy of PPI alone (single therapy) or PPI plus prokinetics (combined therapy) for GERD. The primary outcome of those selected trials was complete or partial relief of non-erosive reflux disease symptoms or mucosal healing in erosive reflux esophagitis. Using the test of heterogeneity, we established a fixed or random effects model where the risk ratio was the primary readout for measuring efficacy. RESULTS: Twelve RCTs including 2403 patients in total were enrolled in this study. Combined therapy was not associated with significant relief of symptoms or alterations in endoscopic response relative to single therapy (95%CI: 1.0-1.2, P = 0.05; 95%CI: 0.66-2.61, P = 0.44). However, combined therapy was associated with a greater symptom score change (95%CI: 2.14-3.02, P < 0.00001). Although there was a reduction in the number of reflux episodes in GERD [95%CI: -5.96-(-1.78), P = 0.0003] with the combined therapy, there was no significant effect on acid exposure time (95%CI: -0.37-0.60, P = 0.65). The proportion of patients with adverse effects undergoing combined therapy was significantly higher than for PPI therapy alone (95%CI: 1.06-1.36, P = 0.005) when the difference between 5-HT receptor agonist and PPI combined therapy and single therapy (95%CI: 0.84-1.39, P = 0.53) was excluded. CONCLUSION: Combined therapy may partially improve patient quality of life, but has no significant effect on symptom or endoscopic response of GERD. PMID:24605040

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

    PubMed

    Chrysant, Steven G

    2011-11-01

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

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

    PubMed Central

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

    2016-01-01

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

  18. Multifunctional nanoparticle systems for combined chemoand photothermal cancer therapy

    NASA Astrophysics Data System (ADS)

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

    2013-06-01

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

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

    PubMed

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

    2014-04-01

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

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

    PubMed

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

    2016-07-01

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

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

    PubMed

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

    2009-10-15

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

  2. 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.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

    Petersen, Jorg; Dandri, Maura

    2015-01-01

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

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

    PubMed

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

    2014-01-01

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

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

    PubMed

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

    2015-03-01

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

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

    PubMed

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

    2012-07-01

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

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

    PubMed

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

    2016-06-01

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

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

    PubMed

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

    2009-09-01

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

  10. Azilsartan/chlorthalidone combination therapy for blood pressure control

    PubMed Central

    Cheng, Judy WM

    2013-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

    Cheung, Belamy B

    2015-01-01

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

  13. 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

  14. 5-Alpha-Reductase Inhibitors and Combination Therapy.

    PubMed

    Füllhase, Claudius; Schneider, Marc P

    2016-08-01

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

  15. 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

  16. Cancer Nanomedicine: From Targeted Delivery to Combination Therapy

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2016-02-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  20. Reappraisal of trimodal combination therapy for maxillary sinus carcinoma

    SciTech Connect

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

    1982-12-15

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

  1. 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

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

    PubMed Central

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

    2015-01-01

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

  3. Burden of Antibiotic Resistance in Common Infectious Diseases: Role of Antibiotic Combination Therapy

    PubMed Central

    Dargad, Ramesh R; Borade, Dhammraj M; Swami, Onkar C

    2014-01-01

    Globally, antimicrobial resistance is alarming concern especially in commonly reported disease entities like respiratory tract infection, enteric fever and infections associated with gram-negative bacilli (GNB). Rational use of antimicrobial drugs reported significant decrease in bacterial burden and may also reduce the risk of disease progression. However, at times in particular indication, certain patient and pathogen factor limits the selection and use of specific antibiotic therapy while in some case, due to presence of additional risk factor, aggressive therapy is required to achieve clinical reemission and prevent complications. Delay in start of suitable antibiotic therapy is another imperative factor for treatment failure and rise of drug resistance. With rapidly increasing antibiotic resistance and decline in new antibiotic drug development, the toughest challenge remains to maintain and preserve the efficacy of currently available antibiotics. Therefore, the best rational approach to fight these infections is to ‘hit early and hit hard’ and kills drug-susceptible bacteria before they become resistant. The preferred approach is to deploy two antibiotics that produce a stronger effect in combination than if either drug were used alone. Various society guidelines in particular indications also justify and recommend the use of combination of antimicrobial therapy. Combination therapies have distinct advantage over monotherapy in terms of broad coverage, synergistic effect and prevention of emergence of drug resistance. PMID:25121020

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

    PubMed

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

    2013-11-01

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

  5. 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

  6. Combined pharmacotherapy and cognitive behavior therapy in the treatment of panic disorder.

    PubMed

    Gelder, M G

    1998-12-01

    Cognitive behavior therapy (CBT) has been combined with pharmacotherapy in the treatment of panic disorder in three ways: (1) to treat agoraphobic symptoms in the condition of panic with agoraphobia; (2) to reduce withdrawal effects during drug taper; and (3) to treat panic attacks. Exposure treatment and pharmacotherapy have a modest additive effect, although more patients drop out of exposure therapy combined with imipramine treatment compared with exposure therapy alone. CBT reduces symptoms of withdrawal from alprazolam and other benzodiazepines and improves the outcome of drug treatment. At present, sufficient data are not available to determine whether the effects of CBT combined with drug therapy are additive in treating panic disorder. The results of a large trial are awaited. Current CBT consists of 12 sessions and is not widely offered to patients because of cost considerations. Efforts are being made to decrease the number of sessions necessary by improving cognitive techniques. One of these models is the subject of an ongoing trial. Finally, efforts to educate and counsel patients in the clinical setting regarding the psychopathology of panic attacks may improve the outcome of pharmacotherapy. PMID:9872706

  7. Rational Design and Adaptive Management of Combination Therapies for Hepatitis C Virus Infection

    PubMed Central

    Ke, Ruian; Loverdo, Claude; Qi, Hangfei; Sun, Ren; Lloyd-Smith, James O.

    2015-01-01

    Recent discoveries of direct acting antivirals against Hepatitis C virus (HCV) have raised hopes of effective treatment via combination therapies. Yet rapid evolution and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health concern. We develop a general model incorporating viral dynamics and pharmacokinetics/ pharmacodynamics to assess how suboptimal adherence affects resistance development and clinical outcomes. We derive design principles and adaptive treatment strategies, identifying a high-risk period when missing doses is particularly risky for de novo resistance, and quantifying the number of additional doses needed to compensate when doses are missed. Using data from large-scale resistance assays, we demonstrate that the risk of resistance can be reduced substantially by applying these principles to a combination therapy of daclatasvir and asunaprevir. By providing a mechanistic framework to link patient characteristics to the risk of resistance, these findings show the potential of rational treatment design. PMID:26125950

  8. Combination topical therapy in the treatment of acne.

    PubMed

    Del Rosso, James Q

    2006-08-01

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

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

    PubMed

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

    2014-01-01

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

  10. A Systematic Review of the Combined Use of Electroconvulsive Therapy and Psychotherapy for Depression

    PubMed Central

    McClintock, Shawn M.; Brandon, Anna R.; Husain, Mustafa M.; Jarrett, Robin B.

    2011-01-01

    Objective Electroconvulsive therapy (ECT) is one of the most effective treatments for severe Major Depressive Disorder (MDD). However, after acute phase treatment and initial remission, relapse rates are significant. Strategies to prolong remission include continuation phase ECT, pharmacotherapy, psychotherapy, or their combinations. This systematic review synthesizes extant data regarding the combined use of psychotherapy with ECT for the treatment of patients with severe MDD and offers the hypothesis that augmenting ECT with depression-specific psychotherapy represents a promising strategy for future investigation. Methods The authors performed two independent searches in PsychInfo (1806 – 2009) and MEDLINE (1948 – 2009) using combinations of the following search terms: Electroconvulsive Therapy (including ECT, ECT therapy, electroshock therapy, EST, shock therapy) and Psychotherapy (including cognitive behavioral, interpersonal, group, psychodynamic, psychoanalytic, individual, eclectic, and supportive). We included in this review a total of six articles (English language) that mentioned ECT and psychotherapy in the abstract, and provided a case report, series, or clinical trial. We examined the articles for data related to ECT and psychotherapy treatment characteristics, cohort characteristics, and therapeutic outcome. Results Although research over the past seven decades documenting the combined use of ECT and psychotherapy is limited, the available evidence suggests that testing this combination has promise and may confer additional, positive functional outcomes. Conclusions Significant methodological variability in ECT and psychotherapy procedures, heterogeneous patient cohorts, and inconsistent outcome measures prevent strong conclusions; however, existing research supports the need for future investigations of combined ECT and psychotherapy in well-designed, controlled clinical studies. Depression-specific psychotherapy approaches may need special

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-07-01

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

  14. Epigenetic therapy in gastrointestinal cancer: the right combination

    PubMed Central

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

    2016-01-01

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

  15. Triple Combination Therapy for Global Cardiovascular Risk: Atorvastatin, Perindopril, and Amlodipine.

    PubMed

    Bertrand, Michel E; Vlachopoulos, Charalambos; Mourad, Jean-Jacques

    2016-08-01

    Statins, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers (CCBs) have markedly changed the clinical progression of patients with coronary artery disease (CAD). The goal of this paper is to review the rationale and evidence for combining these three drug classes in hypertensive patients with hypercholesterolemia or CAD. Data sources include a literature search for publications on the use of a statin combined with various antihypertensive drugs in patients with hypertension and hypercholesterolemia or stable CAD. Hypercholesterolemia and hypertension constitute major physiological risk factors of ischemic heart disease. Current guidelines recommend a global approach to risk management, using agents that address as many risk factors as possible. Dual combination therapies are an important component of guideline-recommended therapy in hypertension. Our review of the literature indicates that triple therapy with a statin, ACE inhibitor, and CCB is associated with a significant reduction in major cardiovascular events. For example, a post hoc analysis in 1056 patients with stable CAD participating in the EUROPA trial indicated that the addition of perindopril to a CCB and a lipid-lowering agent was associated with a 46 % reduction in the composite of cardiovascular death, myocardial infarction, and resuscitated cardiac arrest (p = 0.023). In addition, single pill formulations are known to result in better adherence to the treatment. Single-pill formulations that combine a statin, an ACE inhibitor, and a CCB appear to offer an effective approach to the management of global cardiovascular risk. PMID:27256435

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

    PubMed

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

    2013-01-01

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

  17. 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

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

    PubMed Central

    Hama, Aldric; Sagen, Jacqueline

    2012-01-01

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

  19. Pharmacogenetics and the Development of Personalized Approaches for Combination Therapy in Asthma

    PubMed Central

    Miller, Stacey M.

    2013-01-01

    Asthma is a common, chronic disease of the airways that is treated with a combination of different therapies. The combination of LABA and ICS therapy results in a synergistic interaction that is efficacious in improving asthma symptom control; however, genetic variation has the potential to alter therapeutic efficacy. Both agents mediate complex molecular pathways consisting of gene variation that has been investigated with the analysis of candidate genes in the β2-adrenergic receptor and glucocorticoid pathway. These pharmacogenetic studies have been limited to retrospective analyses of clinical trial cohorts and a small number of prospective, genotype-stratified trials. More recently, genome-wide association studies in combination with replication in additional cohorts and in vitro cell-based models have been used to identify novel pathway-related pharmacogenetic variations. This review of the pharmacogenetics of the β2-adrenergic receptor and glucocorticoid pathways highlights the genotypic effects of variation in multiple genes from interacting pathways which may contribute to differential responses to inhaled beta agonists and glucocorticoids. As our understanding of these genetic mechanisms improves, panels of biomarkers may be developed to determine which combination therapies are the most effective with the least risk to an individual asthma patient. Before we can usher in an era of personalized medicine for asthma, it is first important to improve our ability to analyze large volumes of genetic data in large clinical trial cohorts using a combination of study designs, analytical methods, and in vitro functional studies. PMID:23912588

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

    PubMed Central

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

    2009-01-01

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

  1. Addition of DHA Synergistically Enhances the Efficacy of Regorafenib for Kidney Cancer Therapy.

    PubMed

    Kim, Jeffrey; Ulu, Arzu; Wan, Debin; Yang, Jun; Hammock, Bruce D; Weiss, Robert H

    2016-05-01

    Kidney cancer is the sixth most common cancer in the United States, and its incidence is increasing. The treatment of this malignancy took a major step forward with the recent introduction of targeted therapeutics, such as kinase inhibitors. Unfortunately, kinase inhibition is associated with the onset of resistance after 1 to 2 years of treatment. Regorafenib, like many multikinase inhibitors, was designed to block the activities of several key kinase pathways involved in oncogenesis (Ras/Raf/MEK/ERK) and tumor angiogenesis (VEGF-receptors), and we have recently shown that it also possesses soluble epoxide hydrolase (sEH) inhibitory activity, which may be contributing to its salutary effects in patients. Because sEH inhibition results in increases in the DHA-derived epoxydocosapentaenoic acids that we have previously described to possess anticancer properties, we asked whether the addition of DHA to a therapeutic regimen in the presence of regorafenib would enhance its beneficial effects in vivo We now show that the combination of regorafenib and DHA results in a synergistic effect upon tumor invasiveness as well as p-VEGFR attenuation. In addition, this combination showed a reduction in tumor weights, greater than each agent alone, in a mouse xenograft model of human renal cell carcinoma (RCC), yielding the expected oxylipin profiles; these data were supported in several RCC cell lines that showed similar results in vitro Because DHA is the predominant component of fish oil, our data suggest that this nontoxic dietary supplement could be administered with regorafenib during therapy for advanced RCC and could be the basis of a clinical trial. Mol Cancer Ther; 15(5); 890-8. ©2016 AACR. PMID:26921392

  2. The role of chemotherapy in managing chronic lymphocytic leukemia: optimizing combinations with targeted therapy.

    PubMed

    Nastoupil, Loretta J; Sinha, Rajni; Flowers, Christopher R

    2013-09-01

    For many years, alkylating agents were the standard treatment for chronic lymphocytic leukemia (CLL). The advent of purine analogs improved response rates, but not overall survival, and although the monoclonal antibody rituximab is generally active against B-cell malignancies, it has demonstrated limited benefits as monotherapy for the treatment of CLL. However, specific combinations of chemotherapy, antibodies and targeted therapies have demonstrated additive or synergistic activity in CLL cells and deliver substantial clinical benefits. A greater understanding of the actions of chemotherapies and targeted agents on cellular pathways will advance the development of rationally designed combinations corresponding to individual patients' disease profiles. PMID:23919536

  3. Targeted therapy with propranolol and metronomic chemotherapy combination: sustained complete response of a relapsing metastatic angiosarcoma

    PubMed Central

    Banavali, Shripad; Pasquier, Eddy; Andre, Nicolas

    2015-01-01

    We report here a case of a 69-year-old woman with a relapsing metastatic angiosarcoma treated with a combination of metronomic chemotherapy and propranolol. The beta blockers were added since the tumour was positive for betaadrenergic receptor. A complete response was quickly obtained and lasted for 20 months. With this case, the combination of metronomic chemotherapy and propranolol in angiosarcoma warrants additional studies and illustrates the potential of metronomics to generate innovative yet inexpensive targeted therapies for both high-income and low-/middle-income countries. PMID:25624880

  4. Targeted therapy with propranolol and metronomic chemotherapy combination: sustained complete response of a relapsing metastatic angiosarcoma.

    PubMed

    Banavali, Shripad; Pasquier, Eddy; Andre, Nicolas

    2015-01-01

    We report here a case of a 69-year-old woman with a relapsing metastatic angiosarcoma treated with a combination of metronomic chemotherapy and propranolol. The beta blockers were added since the tumour was positive for betaadrenergic receptor. A complete response was quickly obtained and lasted for 20 months. With this case, the combination of metronomic chemotherapy and propranolol in angiosarcoma warrants additional studies and illustrates the potential of metronomics to generate innovative yet inexpensive targeted therapies for both high-income and low-/middle-income countries. PMID:25624880

  5. 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

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

    PubMed

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

    2015-01-01

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

  7. Influence of Interferon-Alpha Combined with Chemo (Radio) Therapy on Immunological Parameters in Pancreatic Adenocarcinoma

    PubMed Central

    Karakhanova, Svetlana; Mosl, Beate; Harig, Sabine; von Ahn, Katharina; Fritz, Jasmin; Schmidt, Jan; Jäger, Dirk; Werner, Jens; Bazhin, Alexandr V.

    2014-01-01

    Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combination of chemo (radio) therapies with interferon-2α. Low doses of interferon-2α led to a decrease in total leukocyte and an increase in monocyte counts. Furthermore, we observed a positive effect of interferon-2α therapy on the dendritic cells and NK (natural killer) cell activation immediately after the first injection. In addition, we recorded an increased amount of interferon-γ and IL-10 in the serum following the interferon-2α therapy. These data clearly demonstrate that pancreatic carcinoma patients also show an immunomodulatory response to interferon-2α therapy. Analysis of immunosuppressive cells in the Panc02 orthotopic mouse model of pancreatic cancer revealed an accumulation of the myeloid-derived suppressor cells in spleens and tumors of the mice treated with interferon-2α and 5-fluorouracil. The direct effect of the drugs on myeloid-derived suppressor cells was also registered in vitro. These data expose the importance of immunosuppressive mechanisms induced by combined chemo-immunotherapy. PMID:24608924

  8. Influence of interferon-alpha combined with chemo (radio) therapy on immunological parameters in pancreatic adenocarcinoma.

    PubMed

    Karakhanova, Svetlana; Mosl, Beate; Harig, Sabine; von Ahn, Katharina; Fritz, Jasmin; Schmidt, Jan; Jäger, Dirk; Werner, Jens; Bazhin, Alexandr V

    2014-01-01

    Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combination of chemo (radio) therapies with interferon-2α. Low doses of interferon-2α led to a decrease in total leukocyte and an increase in monocyte counts. Furthermore, we observed a positive effect of interferon-2α therapy on the dendritic cells and NK (natural killer) cell activation immediately after the first injection. In addition, we recorded an increased amount of interferon-γ and IL-10 in the serum following the interferon-2α therapy. These data clearly demonstrate that pancreatic carcinoma patients also show an immunomodulatory response to interferon-2α therapy. Analysis of immunosuppressive cells in the Panc02 orthotopic mouse model of pancreatic cancer revealed an accumulation of the myeloid-derived suppressor cells in spleens and tumors of the mice treated with interferon-2α and 5-fluorouracil. The direct effect of the drugs on myeloid-derived suppressor cells was also registered in vitro. These data expose the importance of immunosuppressive mechanisms induced by combined chemo-immunotherapy. PMID:24608924

  9. Hydrotherapy combined with Snoezelen multi-sensory therapy.

    PubMed

    Lavie, Efrat; Shapiro, Michele; Julius, Mona

    2005-01-01

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

  10. Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

    PubMed Central

    2011-01-01

    Background Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. Discussion In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect. As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. Summary Multitarget therapeutics like combined analgesics broaden the array of therapeutic

  11. Additives

    NASA Technical Reports Server (NTRS)

    Smalheer, C. V.

    1973-01-01

    The chemistry of lubricant additives is discussed to show what the additives are chemically and what functions they perform in the lubrication of various kinds of equipment. Current theories regarding the mode of action of lubricant additives are presented. The additive groups discussed include the following: (1) detergents and dispersants, (2) corrosion inhibitors, (3) antioxidants, (4) viscosity index improvers, (5) pour point depressants, and (6) antifouling agents.

  12. The Additive Benefit of Hypnosis and Cognitive-Behavioral Therapy in Treating Acute Stress Disorder

    ERIC Educational Resources Information Center

    Bryant, Richard A.; Moulds, Michelle L.; Guthrie, Rachel M.; Nixon, Reginald D. V.

    2005-01-01

    This research represents the first controlled treatment study of hypnosis and cognitive- behavioral therapy (CBT) of acute stress disorder (ASD). Civilian trauma survivors (N = 87) who met criteria for ASD were randomly allocated to 6 sessions of CBT, CBT combined with hypnosis (CBT-hypnosis), or supportive counseling (SC). CBT comprised exposure,…

  13. In silico analysis suggests differential response to bevacizumab and radiation combination therapy in newly diagnosed glioblastoma

    PubMed Central

    Hawkins-Daarud, Andrea; Rockne, Russell; Corwin, David; Anderson, Alexander R. A.; Kinahan, Paul; Swanson, Kristin R.

    2015-01-01

    Recently, two phase III studies of bevacizumab, an anti-angiogenic, for newly diagnosed glioblastoma (GBM) patients were released. While they were unable to statistically significantly demonstrate that bevacizumab in combination with other therapies increases the overall survival of GBM patients, there remains a question of potential benefits for subpopulations of patients. We use a mathematical model of GBM growth to investigate differential benefits of combining surgical resection, radiation and bevacizumab across observed tumour growth kinetics. The differential hypoxic burden after gross total resection (GTR) was assessed along with the change in radiation cell kill from bevacizumab-induced tissue re-normalization when starting therapy for tumours at different diagnostic sizes. Depending on the tumour size at the time of treatment, our model predicted that GTR would remove a variable portion of the hypoxic burden ranging from 11% to 99.99%. Further, our model predicted that the combination of bevacizumab with radiation resulted in an additional cell kill ranging from 2.6×107 to 1.1×1010 cells. By considering the outcomes given individual tumour kinetics, our results indicate that the subpopulation of patients who would receive the greatest benefit from bevacizumab and radiation combination therapy are those with large, aggressive tumours and who are not eligible for GTR. PMID:26202682

  14. 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

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

    PubMed

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

    2016-01-01

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

  16. Combined therapy with tiotropium and formoterol in chronic obstructive pulmonary disease: effect on the 6-minute walk test.

    PubMed

    Jayaram, Lata; Wong, Conroy; McAuley, Sue; Rea, Harry; Zeng, Irene; O'Dochartaigh, Conor

    2013-08-01

    Combined therapy with tiotropium and long-acting beta 2 agonists confers additional improvement in symptoms, lung function and aspects of health-related quality of life (QOL) compared with each drug alone in patients with COPD. However, the efficacy of combined therapy on walking distance, a surrogate measure of daily functional activity and morbidity remains unclear. The aim was, therefore, to quantify the benefit of this therapy on the six minute walk test. Secondary outcomes included change in lung function, symptoms, the BODE index and QOL. In a double-blind, crossover study, 38 participants with moderate to severe COPD on tiotropium were randomised to receive either formoterol or placebo for 6 weeks. Following a 2-week washout period, participants crossed over to the alternate arm of therapy for a further 6 weeks. Thirty-six participants, with an average age of 64.3 years and FEV1 predicted of 53%, completed the study. Combined therapy improved walking distance by a mean of 36 metres [95% CI: 2.4, 70.1; p = 0.04] compared with tiotropium. FEV1 increased in both groups (160 mL combination therapy versus 30 mL tiotropium) with a mean difference of 110 mL (95% CI: -100, 320; p = 0.07) between groups, These findings further support the emerging advantages of combined therapy in COPD. Australian New Zealand Clinical Trials. PMID:23875741

  17. Artemisinin-based combination therapies for uncomplicated malaria.

    PubMed

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

    2005-02-21

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

  18. Quantifying the pharmacology of antimalarial drug combination therapy.

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    1987-12-01

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

  20. 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

  1. [A case of HER2-positive metastatic breast cancer responding to trastuzumab plus gemcitabine combination therapy].

    PubMed

    Sugie, Tomoharu; Nagai, Toshihiro; Ohgaki, Kazuhisa

    2008-04-01

    A 60-year-old woman was admitted to the hospital with left thigh pain. She had undergone mastectomy and axillary lymph node dissection for right breast cancer (T3N2M0) five years and two months earlier. The pathological diagnosis then was invasive ductal carcinoma with axillaryly mph node metastases. Hormone receptors and HER2 status were negative and positive (3+), respectively. The patient received adjuvant chemotherapy and radiotherapy, but bone metastases appeared 18 months after surgery. Although trastuzumab-combination chemotherapy with taxane and/or capecitabine was given, bone metastases in thoracic vertebra resulted in incomplete paralysis in both legs. She underwent thoraco-lumbar vertebral fixation 10 months before admission. A PET/CT revealed multiple bone metastases in the left femur as well as vertebrae, and CEA rose markedly. She received radiotherapy and trastuzumab monotherapy in addition to bisphosphonate. Temporarily, CEA decreased, but because recurrence nests were recognized in the supraclavicle and mediastinum after the eight-month treatment, trastuzumab monotherapy was followed by trastuzumab plus vinorelbine combined therapy. This regimen markedly reduced CEA after three months, but it rose again over the following three months. As S-1-combined therapy was not effective, trastuzumab+gemcitabine (1 g/week and two weeks on/one week off) combined therapy was started. CEA decreased markedly after 4 cycles, and FDG accumulation in the recurrence region was markedly improved. The adverse event during this treatment was minor, and PS was sufficiently maintained. These results suggest that trastuzumab plus gemcitabine combination therapy is effective for HER2-positive metastatic breast cancer. PMID:18408445

  2. Additive Effect of Pronase on the Eradication Rate of First-Line Therapy for Helicobacter pylori Infection

    PubMed Central

    Bang, Chang Seok; Kim, Yeon Soo; Park, Sang Hyun; Kim, Jin Bong; Baik, Gwang Ho; Suk, Ki Tae; Yoon, Jai Hoon; Kim, Dong Joon

    2015-01-01

    Background/Aims Helicobacter pylori colonizes on the apical surface of gastric surface mucosal cells and the surface mucous gel layer. Pronase is a premedication enzyme for endoscopy that can disrupt the gastric mucus layer. We evaluated the additive effects of pronase combined with standard triple therapy for H. pylori eradication. Methods This prospective, single-blinded, randomized, controlled study was conducted between June and October 2012. A total of 116 patients with H. pylori infection were enrolled in the study (n=112 patients, excluding four patients who failed to meet the inclusion criteria) and were assigned to receive either the standard triple therapy, which consists of a proton pump inhibitor with amoxicillin and clarithromycin twice a day for 7 days (PAC), or pronase (20,000 tyrosine units) combined with the standard triple therapy twice a day for 7 days (PACE). Results In the intention-to-treat analysis, the eradication rates of PAC versus PACE were 76.4% versus 56.1% (p=0.029). In the per-protocol analysis, the eradication rates were 87.5% versus 68.1% (p=0.027). There were no significant differences concerning adverse reactions between the two groups. Conclusions According to the interim analysis of the trial, pronase does not have an additive effect on the eradication of H. pylori infection (ClinicalTrial.gov: NCT01645761). PMID:25167799

  3. Influences of BRAF Inhibitors on the Immune Microenvironment and the Rationale for Combined Molecular and Immune Targeted Therapy.

    PubMed

    Reddy, Sangeetha M; Reuben, Alexandre; Wargo, Jennifer A

    2016-07-01

    The identification of key driver mutations in melanoma has led to the development of targeted therapies aimed at BRAF and MEK, but responses are often limited in duration. There is growing evidence that MAPK pathway activation impairs antitumor immunity and that targeting this pathway may enhance responses to immunotherapies. There is also evidence that immune mechanisms of resistance to targeted therapy exist, providing the rationale for combining targeted therapy with immunotherapy. Preclinical studies have demonstrated synergy in combining these strategies, and combination clinical trials are ongoing. It is, however, becoming clear that additional translational studies are needed to better understand toxicity, proper timing, and sequence of therapy, as well as the utility of multidrug regimens and effects of other targeted agents on antitumor immunity. Insights gained through translational research in preclinical models and clinical studies will provide mechanistic insight into therapeutic response and resistance and help devise rational strategies to enhance therapeutic responses. PMID:27215436

  4. 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.

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

    PubMed

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

    2015-12-14

    In this investigation, we have designed and synthesized a novel core-shell polymer nanoparticle system for highly effective chemo-photothermal combination therapy. A nanoscale DSPE-PEG micelle encapsulating doxorubicin (Dox-M) was designed as a core, and then modified by a polydopamine (PDA) shell for photothermal therapy and bortezomib (Btz) administration (Dox-M@PDA-Btz). The facile conjugation of Btz to the catechol-containing PDA shell can form a reversible pH-sensitive boronic acid-catechol conjugate to create a stimuli-responsive drug carrier system. As expected, the micelle@PDA core-shell nanoparticles exhibited satisfactory photothermal efficiency, which has potential for thermal ablation of malignant tissues. In addition, on account of the PDA modification, both Dox and Btz release processes were pH-dependent and NIR-dependent. Both in vitro and in vivo studies illustrated that the Dox-M@PDA-Btz nanoparticles coupled with laser irradiation could enhance the cytotoxicity, and thus combinational therapy efficacy was achieved when integrating Dox, Btz, and PDA into a single nanoplatform. Altogether, our current study indicated that the micelle@polydopamine core-shell nanoparticles could be applied for NIR/pH-responsive sustained-release and synergized chemo-photothermal therapy for breast cancer. PMID:26556382

  6. 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.

  7. [Combined telaprevir plus ribavirin and pegylated interferon therapy for patients with chronic hepatitis C].

    PubMed

    Mochida, Satoshi

    2015-02-01

    Antiviral efficacy of combined Peg-IFN-α2b plus ribavirin therapy was improved by the addition of telaprevir, a first-generation NS3/4A protease inhibitor, in patients with chronic hepatitis due to HCV infection. A multicenter prospective study revealed that the triple therapy with telaprevir administered according to an algorithm based on the drug adherence, IL28B polymorphism and viral response yielded a high SVR rate through attenuation of viral relapse by prolonged ribavirin/Peg-IFN-α2b administration. Such triple therapy, however, may provoke various adverse effects potentially necessitating treatment discontinuation; dermatitis, hemolytic anemia, hyperuricemia, renal impairment and retinopathy. Thus, the role of telaprevir as a direct-acting antiviral agent used in combination with Peg-IFN and ribavirin for patients with genotype 1b HCV infection was replaced by simeprevir, a second-generation NS3/4A protease inhibitor. However, telaprevir still plays an important role in the treatment for patients with genotypes 2a and 2b HCV infection as well as those showing viral breakthrough after antiviral therapies using second-generation NS3/4A protease inhibitors. PMID:25764680

  8. Benign Prostatic Hyperplasia - An economic assessment of fixed combination therapy based on a literature review.

    PubMed

    Messina, Roberto; Mirone, Vincenzo

    2015-09-01

    FederAnziani Senior Italia and SIU - Italian Society of Urology - have decided to work together to draft a document focussing on Benign Prostatic Hyperplasia (BPH), and to stress the importance of adherence with pharmacological treatment in this setting, from both a scientific and a patient standpoint. Starting from a literature search, the two associations analysed to what extent an increase in treatment adherence amongst these patients influences hospital savings and to what extent therapy persistence levels are affected by monotherapy rather than free drug combinations. These estimates were performed only on patients taking medicinal products belonging to the 5 α-reductase inhibitors (5ARI) class that, although not indispensable, are the compounds that bring the greatest benefits, especially in the elderly and for which we know that every additional 30 days of therapy reduced the likelihood of acute urinary retention (AUR) and surgery by 14% and 11% respectively *. The results show that the use of fixed combination therapy would involve an increase in persistence due to the lower rate of patients abandoning treatment over time. Each 30 day-increment of 5ARI therapy, i.e. for an expenditure of 10.6 million euros extra per year for 5ARI medication, savings of approximately 24.3 million euros in hospital costs could be achieved. PMID:26428637

  9. Percutaneous Drainage Combined with Hyperbaric Oxygen Therapy for Pyogenic Spondylitis with Iliopsoas Abscess

    PubMed Central

    Koga, Hiroaki; Komiya, Setsuro

    2014-01-01

    Study Design A retrospective study. Purpose The purpose of this study was to evaluate outcomes in patients with pyogenic spondylitis accompanied by iliopsoas abscess who were treated by percutaneous drainage combined with hyperbaric oxygen (HBO) therapy. Overview of Literature To the best of our knowledge, there have been no previous reports of the use of percutaneous drainage combined with HBO therapy for the treatment of this condition. Methods Twenty-three patients (13 men, 10 women; mean age, 69.0 years; range, 45-85 years) were treated with percutaneous drainage combined with HBO therapy in addition to commonly used conservative therapy. Mean follow-up duration was 27.7 months (range, 12-48 months). Clinical outcomes and imaging examinations were retrospectively investigated. Results Symptoms such as low back pain, radicular pain, and hip pain resolved in all patients immediately after treatment. Mean time from the start of treatment to the return of C-reactive protein levels to normal or baseline values recorded before the onset of spondylitis was 28.3 days (range, 8-56 days). In the final set of follow-up radiographic studies, all patients were free from progressive destructive changes. Follow-up magnetic resonance images or computed tomography with contrast enhancement confirmed the disappearance or near-total resolution of the iliopsoas abscess cavity with healing of the pyogenic spondylitis in all 23 patients. No recurrences were observed during follow-up. Conclusions The present study suggests that patients with pyogenic spondylitis accompanied by iliopsoas abscess can be cured without a prolonged period of therapy or recurrence using this treatment. PMID:24967038

  10. Combination therapy of dipeptidyl peptidase-4 inhibitors and metformin in type 2 diabetes: rationale and evidence.

    PubMed

    Liu, Y; Hong, T

    2014-02-01

    The main pathogenesis of type 2 diabetes mellitus (T2DM) includes insulin resistance and pancreatic islet dysfunction. Metformin, which attenuates insulin resistance, has been recommended as the first-line antidiabetic medication. Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel oral hypoglycaemic agents that protect glucagon-like peptide-1 (GLP-1) from degradation, maintain the bioactivity of endogenous GLP-1, and thus improve islet dysfunction. Results from clinical trials have shown that the combination therapy of DPP-4 inhibitors and metformin [as an add-on, an initial combination or a fixed-dose combination (FDC)] provides excellent efficacy and safety in patients with T2DM. Moreover, recent studies have suggested that metformin enhances the biological effect of GLP-1 by increasing GLP-1 secretion, suppressing activity of DPP-4 and upregulating the expression of GLP-1 receptor in pancreatic β-cells. Conversely, DPP-4 inhibitors have a favourable effect on insulin sensitivity in patients with T2DM. Therefore, the combination of DPP-4 inhibitors and metformin provides an additive or even synergistic effect on metabolic control in patients with T2DM. This article provides an overview of clinical evidence and discusses the rationale for the combination therapy of DPP-4 inhibitors and metformin. PMID:23668534

  11. 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.

  12. Multifunctional hollow gold nanoparticles designed for triple combination therapy and CT imaging.

    PubMed

    Park, Jaesook; Park, Jin; Ju, Eun Jin; Park, Seok Soon; Choi, Jinhyang; Lee, Jae Hee; Lee, Kyoung Jin; Shin, Seol Hwa; Ko, Eun Jung; Park, Intae; Kim, Chulhee; Hwang, Jung Jin; Lee, Jung Shin; Song, Si Yeol; Jeong, Seong-Yun; Choi, Eun Kyung

    2015-06-10

    Hollow gold nanoparticles (HGNP) are a novel class of hybrid metal nanoparticles whose unique optical and morphological properties have spawned new applications including more effective cancer therapy. The shell thickness of HGNPs can tune the surface plasmon resonance to the near infrared light, resulting in photothermal ablation of tumors with optimal light penetration in tissue. The hollow cavity within a HGNP is able to accommodate a high payload of chemotherapeutic agents. They have also been used for enhancing radiosensitization in tumors during radiotherapy due to the high X-ray absorption capability of gold particles. However, no report has yet been published that utilize HGNPs for the triple combination therapy and CT imaging. In this study, we synthesized HGNPs which exhibit better response to radiation for therapy and imaging and demonstrated the effects of combined chemotherapy, thermal and radiotherapy. This combination strategy presented delayed tumor growth by 4.3-fold and reduced tumor's weight by 6.8-fold compared to control tumors. In addition, we demonstrated the feasibility of HGNP as a CT imaging agent. It is expected that translating these capabilities to human cancer patients could dramatically increase the antitumor effect and potentially overcome resistance to chemotherapeutic agents and radiation. PMID:25863273

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

    PubMed

    Ge, Yanxiu; Ma, Yakun; Li, Lingbing

    2016-10-01

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

  14. 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

  15. 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

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

    PubMed

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

    2016-05-01

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

  17. Targeted Therapy of Cancer Using Photodynamic Therapy in Combination with Multi-faceted Anti-Tumor Modalities

    PubMed Central

    Olivo, Malini; Bhuvaneswari, Ramaswamy; Lucky, Sasidharan Swarnalatha; Dendukuri, Nagamani; Thong, Patricia Soo-Ping

    2010-01-01

    Photodynamic therapy (PDT) has emerged as one of the important therapeutic options in the management of cancer and other diseases. PDT involves a tumor-localized photosensitizer (PS), which when appropriately illuminated by visible light converts oxygen into cytotoxic reactive oxygen species (ROS), that attack key structural entities within the targeted cells, ultimately resulting in necrosis or apoptosis. Though PDT is a selective modality, it can be further enhanced by combining other targeted therapeutic strategies that include the use of synthetic peptides and nanoparticles for selective delivery of photosensitizers. Another potentially promising strategy is the application of targeted therapeutics that exploit a myriad of critical pathways involved in tumorigenesis and metastasis. Vascular disrupting agents that eradicate tumor vasculature during PDT and anti-angiogenic agents that targets specific molecular pathways and prevent the formation of new blood vessels are novel therapeutic approaches that have been shown to improve treatment outcome. In addition to the well-documented mechanisms of direct cell killing and damage to the tumor vasculature, PDT can also activate the body’s immune response against tumors. Numerous pre-clinical studies and clinical observations have demonstrated the immuno-stimulatory capability of PDT. Herein, we aim to integrate the most important findings with regard to the combination of PDT and other novel targeted therapy approaches, detailing its potential in cancer photomedicine.

  18. Dual combination therapy targeting DR5 and EMMPRIN in pancreatic adenocarcinoma

    PubMed Central

    Kim, Hyunki; Zhai, Guihua; Samuel, Sharon L.; Rigell, Christopher J.; Umphrey, Heidi R.; Rana, Samir; Stockard, Cecil R.; Fineberg, Naomi S.; Zinn, Kurt R.

    2011-01-01

    The study goal was to assess the efficacy of combined EMMPRIN and DR5 targeted therapy for pancreatic adenocarcinoma in orthotopic mouse models using multi-modal imaging. Cytotoxicity of anti-EMMPRIN antibody and anti-DR5 antibody (TRA-8) in MIA PaCa-2 and PANC-1 cell lines was measured by ATPlite assay in vitro. The distributions of Cy5.5-labeled TRA-8 and Cy3-labeled anti-EMMPRIN antibody in the two cell lines were analyzed by fluorescence imaging in vitro. Groups 1–12 of SCID mice bearing orthotopic MIA PaCa-2 (groups 1–8) or PANC-1 (groups 9–12) tumors were used for in vivo studies. DCE-MRI was applied in group 1 (untreated) or group 2 (anti-EMMPRIN antibody). The tumor uptake of Tc-99m-labeled TRA-8 was measured in group 3 (untreated) and group 4 (anti-EMMPRIN antibody). PET/CT imaging with 18F-FDG was applied in groups 5–12. Groups 5–8 (or groups 9–12) were untreated or treatment with anti-EMMPRIN antibody, TRA-8, and combination, respectively. TRA-8 showed high killing efficacy for both MIA PaCa-2 and PANC-1 cells in vitro, but additional anti-EMMPRIN treatment did not improve the cytotoxicity. Cy5.5-TRA-8 formed cellular caps in both the cell lines, while the maximum signal intensity was correlated with TRA-8 cytotoxicity. Anti-EMMPRIN therapy significantly enhanced the tumor delivery of the MR contrast agent, but not Tc-99m-TRA-8. Tumor growth was significantly suppressed by the combination therapy, and the additive effect of the combination was demonstrated in both MIA PaCa-2 and PANC-1 tumor models. PMID:22203731

  19. Combination therapy with a nucleos(t)ide analogue and interferon for chronic hepatitis B: simultaneous or sequential.

    PubMed

    Enomoto, Masaru; Tamori, Akihiro; Nishiguchi, Shuhei; Kawada, Norifumi

    2013-09-01

    Currently available antiviral treatment for chronic hepatitis B virus infection can be divided into two classes of therapeutic agents: nucleos(t)ide analogues (NAs) and interferon (IFN). The major advantages of NAs are good tolerance and potent antiviral activity associated with high rates of on-treatment response to therapy; the advantages of IFN include a finite course of treatment, absence of drug resistance, and an opportunity to obtain a post-treatment durable response to therapy. The use of these two antiviral agents with different mechanisms of action in combination is theoretically an attractive approach for treatment. Here, we have reviewed previous reports of either simultaneous or sequential combination therapy with NA and IFN for chronic hepatitis B patients. In previous studies comparing the lamivudine/IFN combination and lamivudine monotherapy in a finite course, combination therapy was associated with higher rates of sustained post-treatment response and lower rates of drug resistance than lamivudine monotherapy. However, NAs such as lamivudine are generally administered indefinitely because of high rates of post-treatment relapse. In addition, concern for drug resistance has decreased significantly with newer, high-potency NAs even when administered alone. In previous studies comparing the lamivudine/IFN combination and IFN monotherapy, the combination therapy showed greater on-treatment viral suppression, but no difference was observed in the post-treatment sustained response. Thus, whether combination therapy confers an additional benefit compared to monotherapy for treating chronic hepatitis B remains unclear. The efficacy of IFN in combination with a more potent NA, such as entecavir or tenofovir, remains to be comprehensively evaluated. PMID:23338486

  20. Self-administration of cocaine-antihistamine combinations: super-additive reinforcing effects.

    PubMed

    Wang, Zhixia; Woolverton, William L

    2007-02-28

    Histamine H1 receptor antagonists have some behavioral effects that predict abuse liability. In the present study, diphenhydramine and cocaine each maintained i.v. self-administration under a progressive-ratio schedule in rhesus monkeys. When cocaine and DPH were combined in a 1:1 ratio of the ED50s, the combination was super-additive in all monkeys. The data predict that the combination of cocaine and histamine H1 receptor antagonists would have enhanced potential for abuse relative to either drug alone. PMID:17196194

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

    PubMed Central

    Cosgrove, Sara E.; Maragakis, Lisa L.

    2012-01-01

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

  2. Reduction of fatal complications from combined modality therapy in Hodgkin's disease

    SciTech Connect

    Mauch, P.M.; Canellos, G.P.; Rosenthal, D.S.; Hellman, S.

    1985-04-01

    A total of 464 pathologically staged IA through IIIB Hodgkin's disease patients were evaluated for the risk of developing acute nonlymphocytic leukemia, non-Hodgkin's lymphoma, or a fatal infection after treatment with radiation therapy (RT) alone, initial combined radiation therapy and chemotherapy (CMT), or RT with MOPP administered at relapse. Patients received a standard six cycles of MOPP, and additional maintenance chemotherapy was not administered. Patients receiving total nodal irradiation (TNI) and MOPP chemotherapy have an 11. 9% actuarial risk of developing a fatal complication at ten years, as compared to a 0.8% risk for lesser field irradiation and MOPP. The risk with RT alone is 0.6%. Patients 40 years of age or older have a greater risk for complications. These data report a low risk for fatal complication with CMT when less than TNI is administered and when maintenance chemotherapy is not used.

  3. Combination therapy in clinical and cosmetic dermatology: the marriage of device and drug.

    PubMed

    Nestor, Mark Steven

    2004-01-01

    The first generations of lasers used in clinical and cosmetic dermatology achieved their effects by means of epidermal and dermal ablation. While effective in removing some of the stigmata of photodamage including pigmentary changes and rhytides, vascular abnormalities associated with such conditions as melasma and rosacea, were not sufficiently effective. The new generation of laser and non-laser light devices (eg, intense pulsed light or IPL) offer excellent results in the management of clinical and cosmetic conditions, including significant changes in improvement in vascular conditions such as rosacea and actinic damage and stimulating dermal collagen production, without significant injury to the epidermis. The combination of light therapies and topical agents adds to the efficacy of these procedures, particularly in post-procedural maintenance. Light-based therapies have been an important addition to the anti-acne armamentarium as they are effective and do not add to the increasing bacterial resistance problem. PMID:15552594

  4. Risk assessment for the combinational effects of food color additives: neural progenitor cells and hippocampal neurogenesis.

    PubMed

    Park, Mikyung; Park, Hee Ra; Kim, So Jung; Kim, Min-Sun; Kong, Kyoung Hye; Kim, Hyun Soo; Gong, Ein Ji; Kim, Mi Eun; Kim, Hyung Sik; Lee, Byung Mu; Lee, Jaewon

    2009-01-01

    In 2006, the Korea Food and Drug Administration reported that combinations of dietary colors such as allura red AC (R40), tartrazine (Y4), sunset yellow FCF (Y5), amaranth (R2), and brilliant blue FCF (B1) are widely used in food manufacturing. Although individual tar food colors are controlled based on acceptable daily intake (ADI), there is no apparent information available for how combinations of these additives affect food safety. In the current study, the potencies of single and combination use of R40, Y4, Y5, R2, and B1 were examined on neural progenitor cell (NPC) toxicity, a biomarker for developmental stage, and neurogenesis, indicative of adult central nervous system (CNS) functions. R40 and R2 reduced NPC proliferation and viability in mouse multipotent NPC, in the developing CNS model. Among several combinations tested in mouse model, combination of Y4 and B1 at 1000-fold higher than average daily intake in Korea significantly decreased numbers of newly generated cells in adult mouse hippocampus, indicating potent adverse actions on hippocampal neurogenesis. However, other combinations including R40 and R2 did not affect adult hippocampal neurogenesis in the dentate gyrus. Evidence indicates that single and combination use of most tar food colors may be safe with respect to risk using developmental NPC and adult hippocampal neurogenesis. However, the response to excessively high dose combination of Y4 and B1 is suggestive of synergistic effects to suppress proliferation of NPC in adult hippocampus. Data indicated that combinations of tar colors may adversely affect both developmental and adult hippocampal neurogenesis; thus, further extensive studies are required to assess the safety of these additive combinations. PMID:20077213

  5. Effectiveness of a Home Exercise Program in Combination with Ultrasound Therapy for Temporomandibular Joint Disorders

    PubMed Central

    Ucar, Mehmet; Sarp, Ümit; Koca, İrfan; Eroğlu, Selma; Yetisgin, Alparslan; Tutoglu, Ahmet; Boyacı, Ahmet

    2014-01-01

    [Purpose] This study compared the effectiveness of home exercise alone versus home exercise combined with ultrasound for patients with temporomandibular joint disorders. [Subjects and Methods] This study enrolled 23 female and 15 male patients who were divided randomly into two groups. The home exercise group performed a home exercise program consisting of an exercise program and patient education, and the home exercise combined with ultrasound group received ultrasound therapy in addition to the home exercise program. Pain intensity was evaluated using a visual analogue scale. Pain free maximum mouth opening was evaluated at baseline and 2 weeks after the treatment. [Results] There was no difference between the two groups in baseline values. After the treatment, the visual analogue scale decreased and pain free maximum mouth opening scores improved significantly in each group. Additionally, both values were higher in the home exercise combined with ultrasound group than in the home exercise group. [Conclusion] The combination of home exercise combined with ultrasound appears to be more effective at providing pain relief and increasing mouth opening than does home exercise alone for patients with temporomandibular joint disorders. PMID:25540479

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

    PubMed

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

    2016-05-01

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

  7. 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

  8. Colonic exclusion and combined therapy for refractory constipation

    PubMed Central

    Peng, Hong-Yun; Xu, Ai-Zhong

    2006-01-01

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

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

    PubMed

    Kano, Shigeyuki

    2014-05-01

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

  10. Gold Nanostructures as a Platform for Combinational Therapy in Future Cancer Therapeutics

    PubMed Central

    Jelveh, Salomeh; Chithrani, Devika B.

    2011-01-01

    The field of nanotechnology is currently undergoing explosive development on many fronts. The technology is expected to generate innovations and play a critical role in cancer therapeutics. Among other nanoparticle (NP) systems, there has been tremendous progress made in the use of spherical gold NPs (GNPs), gold nanorods (GNRs), gold nanoshells (GNSs) and gold nanocages (GNCs) in cancer therapeutics. In treating cancer, radiation therapy and chemotherapy remain the most widely used treatment options and recent developments in cancer research show that the incorporation of gold nanostructures into these protocols has enhanced tumor cell killing. These nanostructures further provide strategies for better loading, targeting, and controlling the release of drugs to minimize the side effects of highly toxic anticancer drugs used in chemotherapy and photodynamic therapy. In addition, the heat generation capability of gold nanostructures upon exposure to UV or near infrared light is being used to damage tumor cells locally in photothermal therapy. Hence, gold nanostructures provide a versatile platform to integrate many therapeutic options leading to effective combinational therapy in the fight against cancer. In this review article, the recent progress in the development of gold-based NPs towards improved therapeutics will be discussed. A multifunctional platform based on gold nanostructures with targeting ligands, therapeutic molecules, and imaging contrast agents, holds an array of promising directions for cancer research. PMID:24212654

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

    PubMed

    Havlickova, Blanka; Friedrich, Markus

    2008-09-01

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

  12. 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.

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

    PubMed

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

    2014-07-18

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

  14. 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.

  15. Combination Therapy with Cholinesterase Inhibitors and Memantine for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

    PubMed Central

    Kishi, Taro; Iwata, Nakao

    2015-01-01

    Background: We performed an updated meta-analysis of randomized controlled trials of combination therapy with cholinesterase inhibitors and memantine in patients with Alzheimer’s disease. Methods: We reviewed cognitive function, activities of daily living, behavioral disturbance, global assessment, discontinuation rate, and individual side effects. Results: Seven studies (total n=2182) were identified. Combination therapy significantly affected behavioral disturbance scores (standardized mean difference=−0.13), activity of daily living scores (standardized mean difference=−0.10), and global assessment scores (standardized mean difference=−0.15). In addition, cognitive function scores (standardized mean difference=−0.13, P=.06) exhibited favorable trends with combination therapy. The effects of combination therapy were more significant in the moderate-to-severe Alzheimer’s disease subgroup in terms of all efficacy outcome scores. The discontinuation rate was similar in both groups, and there were no significant differences in individual side effects. Conclusions: Combination therapy was beneficial for the treatment of moderate-to-severe Alzheimer’s disease in terms of cognition, behavioral disturbances, activities of daily living, and global assessment was well tolerated. PMID:25548104

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  18. Effect of combined herbal feed additives on methane, total gas production and rumen fermentation

    PubMed Central

    Chaturvedi, Indu; Dutta, Tapas Kumar; Singh, Pawan Kumar; Sharma, Ashwani

    2015-01-01

    The present study was to evaluate effect of herbal feed additives on methane and total gas production during the rumen fermentation for environment and animal health concern. Different parts of the five medicinal plants were selected such as leaf and small stems of Ocimum sanctum (Tulsi), roots of Curcuma longa (Haldi), fruits of Emblica officinalis (Amla), leaves of Azadirachta indica (Neem) and leaves and small stem of Clerodendrum phlomidis (Arni) for our study. Addition of different herbal additive combinations did not influence IVDMD and total gas production however methane production (mg/g of substrate DM) was significantly (P<0.05) reduced in Amla: Neem and Neem: Arni combinations. Total nitrogen significantly (P<0.01) increased in the combinations of Tulsi: Haldi and Amla: Neem. TCA–ppt-N is significantly (P<0.01) increased in Tulsi: Haldi, Haldi: Amla, Amla: Neem and Neem: Arni however NH3-N (mg/dl) significantly decreased in all treatments. We conclude that the screening of plant combinations, Amla: Neem and Neem: Arni have potential to decrease methane production and our herbal feed supplements have no side-effects on the ruminant in small amount. PMID:26124571

  19. Effect of combined herbal feed additives on methane, total gas production and rumen fermentation.

    PubMed

    Chaturvedi, Indu; Dutta, Tapas Kumar; Singh, Pawan Kumar; Sharma, Ashwani

    2015-01-01

    The present study was to evaluate effect of herbal feed additives on methane and total gas production during the rumen fermentation for environment and animal health concern. Different parts of the five medicinal plants were selected such as leaf and small stems of Ocimum sanctum (Tulsi), roots of Curcuma longa (Haldi), fruits of Emblica officinalis (Amla), leaves of Azadirachta indica (Neem) and leaves and small stem of Clerodendrum phlomidis (Arni) for our study. Addition of different herbal additive combinations did not influence IVDMD and total gas production however methane production (mg/g of substrate DM) was significantly (P<0.05) reduced in Amla: Neem and Neem: Arni combinations. Total nitrogen significantly (P<0.01) increased in the combinations of Tulsi: Haldi and Amla: Neem. TCA-ppt-N is significantly (P<0.01) increased in Tulsi: Haldi, Haldi: Amla, Amla: Neem and Neem: Arni however NH3-N (mg/dl) significantly decreased in all treatments. We conclude that the screening of plant combinations, Amla: Neem and Neem: Arni have potential to decrease methane production and our herbal feed supplements have no side-effects on the ruminant in small amount. PMID:26124571

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

    PubMed

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

    2016-02-01

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

  1. 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

  2. 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.

  3. Rational design and adaptive management of combination therapies for Hepatitis C virus infection

    SciTech Connect

    Ke, Ruian; Loverdo, Claude; Qi, Hangfei; Sun, Ren; Lloyd-Smith, James O.; Kouyos, Roger Dimitri

    2015-06-30

    Recent discoveries of direct acting antivirals against Hepatitis C virus (HCV) have raised hopes of effective treatment via combination therapies. Yet rapid evolution and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health concern. We develop a general model incorporating viral dynamics and pharmacokinetics/ pharmacodynamics to assess how suboptimal adherence affects resistance development and clinical outcomes. We derive design principles and adaptive treatment strategies, identifying a high-risk period when missing doses is particularly risky for de novo resistance, and quantifying the number of additional doses needed to compensate when doses are missed. Using data from large-scale resistance assays, we demonstrate that the risk of resistance can be reduced substantially by applying these principles to a combination therapy of daclatasvir and asunaprevir. By providing a mechanistic framework to link patient characteristics to the risk of resistance, these findings show the potential of rational treatment design.

  4. Rational design and adaptive management of combination therapies for Hepatitis C virus infection

    DOE PAGESBeta

    Ke, Ruian; Loverdo, Claude; Qi, Hangfei; Sun, Ren; Lloyd-Smith, James O.; Kouyos, Roger Dimitri

    2015-06-30

    Recent discoveries of direct acting antivirals against Hepatitis C virus (HCV) have raised hopes of effective treatment via combination therapies. Yet rapid evolution and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health concern. We develop a general model incorporating viral dynamics and pharmacokinetics/ pharmacodynamics to assess how suboptimal adherence affects resistance development and clinical outcomes. We derive design principles and adaptive treatment strategies, identifying a high-risk period when missing doses is particularly risky for de novo resistance, and quantifying the number of additional doses needed to compensatemore » when doses are missed. Using data from large-scale resistance assays, we demonstrate that the risk of resistance can be reduced substantially by applying these principles to a combination therapy of daclatasvir and asunaprevir. By providing a mechanistic framework to link patient characteristics to the risk of resistance, these findings show the potential of rational treatment design.« less

  5. Combination approaches to potentiate immune response after photodynamic therapy for cancer†

    PubMed Central

    St Denis, Tyler G.; Aziz, Kanza; Waheed, Anam A.; Huang, Ying-Ying; Sharma, Sulbha K.; Mroz, Pawel; Hamblin, Michael R.

    2012-01-01

    Photodynamic therapy (PDT) has been used as a cancer therapy for forty years but has not advanced to a mainstream cancer treatment. Although it has been shown to be an efficient way to destroy local tumors by a combination of non-toxic dyes and harmless visible light, it is its additional effects in mediating the stimulation of the host immune system that gives PDT great potential to become more widely used. Although the stimulation of tumor-specific cytotoxic T-cells that can destroy distant tumor deposits after PDT has been reported in some animal models, it remains the exception rather than the rule. This realization has prompted several investigators to test various combination approaches that could potentiate the immune recognition of tumor antigens that have been released after PDT. This review will cover these combination approaches using immunostimulants including various microbial preparations that activate Toll-like receptors and other receptors for pathogen-associated molecular patterns, cytokines growth factors, and approaches that target regulatory T-cells. We believe that by understanding the methods employed by tumors to evade immune response and neutralizing them, more precise ways of potentiating PDT-induced immunity can be devised. PMID:21479313

  6. 5-Aminolevulinic Acid Photodynamic Therapy combined with CO2 laser therapy in treatment of laryngeal papilloma: Case report.

    PubMed

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

    2016-06-01

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

  7. Combining Advanced Oxidation Processes: Assessment Of Process Additivity, Synergism, And Antagonism

    SciTech Connect

    Peters, Robert W.; Sharma, M.P.; Gbadebo Adewuyi, Yusuf

    2007-07-01

    This paper addresses the process interactions from combining integrated processes (such as advanced oxidation processes (AOPs), biological operations, air stripping, etc.). AOPs considered include: Fenton's reagent, ultraviolet light, titanium dioxide, ozone (O{sub 3}), hydrogen peroxide (H{sub 2}O{sub 2}), sonication/acoustic cavitation, among others. A critical review of the technical literature has been performed, and the data has been analyzed in terms of the processes being additive, synergistic, or antagonistic. Predictions based on the individual unit operations are made and compared against the behavior of the combined unit operations. The data reported in this paper focus primarily on treatment of petroleum hydrocarbons and chlorinated solvents. (authors)

  8. 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

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

    PubMed

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

    2016-04-01

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

  10. Antimicrobial combinations: Bliss independence and Loewe additivity derived from mechanistic multi-hit models.

    PubMed

    Baeder, Desiree Y; Yu, Guozhi; Hozé, Nathanaël; Rolff, Jens; Regoes, Roland R

    2016-05-26

    Antimicrobial peptides (AMPs) and antibiotics reduce the net growth rate of bacterial populations they target. It is relevant to understand if effects of multiple antimicrobials are synergistic or antagonistic, in particular for AMP responses, because naturally occurring responses involve multiple AMPs. There are several competing proposals describing how multiple types of antimicrobials add up when applied in combination, such as Loewe additivity or Bliss independence. These additivity terms are defined ad hoc from abstract principles explaining the supposed interaction between the antimicrobials. Here, we link these ad hoc combination terms to a mathematical model that represents the dynamics of antimicrobial molecules hitting targets on bacterial cells. In this multi-hit model, bacteria are killed when a certain number of targets are hit by antimicrobials. Using this bottom-up approach reveals that Bliss independence should be the model of choice if no interaction between antimicrobial molecules is expected. Loewe additivity, on the other hand, describes scenarios in which antimicrobials affect the same components of the cell, i.e. are not acting independently. While our approach idealizes the dynamics of antimicrobials, it provides a conceptual underpinning of the additivity terms. The choice of the additivity term is essential to determine synergy or antagonism of antimicrobials.This article is part of the themed issue 'Evolutionary ecology of arthropod antimicrobial peptides'. PMID:27160596

  11. Effect of combinations of additives on the performance of lithium ion batteries

    NASA Astrophysics Data System (ADS)

    Santee, Stuart; Xiao, Ang; Yang, Li; Gnanaraj, Joe; Lucht, Brett L.

    Commercial lithium-ion batteries have excellent performance at room temperature for a few years. However, the calendar life and thermal stability (>50 °C) need to be improved for many applications, including electric vehicles. We have conducted an investigation of the effect of thermal stabilizing additives, including dimethyl acetamide, vinylene carbonate, and lithium bis(oxalato) borate, on the performance of lithium ion batteries stored at 70 °C for one month. The reactions of the lithium hexafluorophosphate/carbonate electrolyte, with and without electrolyte additives, with the surface of the electrodes after initial formation cycling have been analyzed via a combination of IR-ATR and XPS.

  12. 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

  13. Remediation of metal polluted soils by phytorremediation combined with biochar addition

    NASA Astrophysics Data System (ADS)

    Méndez, Ana; Paz-Ferreiro, Jorge; Gómez-Limón, Dulce; César Arranz, Julio; Saa, Antonio; Gascó, Gabriel

    2016-04-01

    The main objective of this work is to optimize and quantify the treatment of metal polluted soils through phytoremediation techniques combined with the addition of biochar. Biochar is a carbon rich material obtained by thermal treatment of biomass in inert atmosphere. In recent years, it has been attracted considerable interest due to their positive effect after soil addition. The use of biochar also seems appropriate for the treatment of metal-contaminated soils decreasing their mobility. Biochar properties highly depend on the raw material composition and manufacturing conditions. This paper is based on the use of manure wastes, rich in nutrients and therefore interesting raw materials for biochar production, especially when combined with phytoremediation techniques since the biochar act as conditioner and slow release fertilizer. We are very grateful to Ministerio de Economia y Competitividad (Spain) for financial support under Project CGL2014-58322-R.

  14. Efficacy of stabilisation splint therapy combined with non-splint multimodal therapy for treating RDC/TMD axis I patients: a randomised controlled trial.

    PubMed

    Nagata, K; Maruyama, H; Mizuhashi, R; Morita, S; Hori, S; Yokoe, T; Sugawara, Y

    2015-12-01

    Stabilisation splint therapy has long been thought to be effective for the management of temporomandibular disorders (TMD). However, the superiority of stabilisation splint therapy compared to other TMD treatments remains controversial. The aim of this study was to determine the efficacy of stabilisation splint therapy combined with non-splint multimodal therapy for TMD. A total of 181 TMD participants were randomly allocated to a non-splint multimodal therapy (NS) group (n = 85) or a non-splint multimodal therapy plus stabilisation splint (NS+S) group (n = 96). Non-splint multimodal therapy included self-exercise of the jaw, cognitive-behavioural therapy, self-management education and additional jaw manipulation. Three outcome measurements were used to assess treatment efficacy: mouth-opening limitation, oro-facial pain and temporomandibular joint sounds. A two-factor repeated-measures analysis of variance (anova) was used to evaluate the efficacy of the two treatment modalities (NS vs. NS+S), and Scheffe's multiple comparison test was used to compare the treatment periods. Subgroup analyses were performed to disclose the splint effects for each TMD diagnostic group. All three parameters significantly decreased over time in both groups. However, there were no significant differences between the two treatment groups in the total comparison or subgroup analyses; an exception was the group with degenerative joint disease. No significant difference between the NS and NS+S treatment approaches was revealed in this study. Therefore, we conclude that the additional effects of stabilisation splint are not supported for patients with TMD during the application of multimodal therapy. PMID:26174571

  15. Combination therapy with bioengineered miR-34a prodrug and doxorubicin synergistically suppresses osteosarcoma growth.

    PubMed

    Zhao, Yong; Tu, Mei-Juan; Yu, Yi-Feng; Wang, Wei-Peng; Chen, Qiu-Xia; Qiu, Jing-Xin; Yu, Ai-Xi; Yu, Ai-Ming

    2015-12-15

    Osteosarcoma (OS) is the most common form of primary malignant bone tumor and prevalent among children and young adults. Recently we have established a novel approach to bioengineering large quantity of microRNA-34a (miR-34a) prodrug for miRNA replacement therapy. This study is to evaluate combination treatment with miR-34a prodrug and doxorubicin, which may synergistically suppress human OS cell growth via RNA interference and DNA intercalation. Synergistic effects were indeed obvious between miR-34a prodrug and doxorubicin for the suppression of OS cell proliferation, as defined by Chou-Talalay method. The strongest antiproliferative synergism was achieved when both agents were administered simultaneously to the cells at early stage, which was associated with much greater degrees of late apoptosis, necrosis, and G2 cell cycle arrest. Alteration of OS cellular processes and invasion capacity was linked to the reduction of protein levels of miR-34a targeted (proto-)oncogenes including SIRT1, c-MET, and CDK6. Moreover, orthotopic OS xenograft tumor growth was repressed to a significantly greater degree in mouse models when miR-34a prodrug and doxorubicin were co-administered intravenously. In addition, multiple doses of miR-34a prodrug and doxorubicin had no or minimal effects on mouse blood chemistry profiles. The results demonstrate that combination of doxorubicin chemotherapy and miR-34a replacement therapy produces synergistic antiproliferative effects and it is more effective than monotherapy in suppressing OS xenograft tumor growth. These findings support the development of mechanism-based combination therapy to combat OS and bioengineered miR-34a prodrug represents a new natural miRNA agent. PMID:26518752

  16. Optimal Doses of Methotrexate Combined with Anti-TNF Therapy to Maintain Clinical Remission in Inflammatory Bowel Disease

    PubMed Central

    Rubin, David T

    2015-01-01

    Background and aims: Methotrexate (MTX) is sometimes used as part of combination therapy for the treatment of inflammatory bowel disease [IBD]; however, the optimal MTX dose for combination therapy has not been established. This study compared the efficacy of lower-dose and higher-dose MTX with anti tumor necrosis factor alpha (anti-TNF) therapy among IBD patients. Methods: Retrospective chart review was performed of 88 IBD patients at our center between 2010 and 2013. Low-dose MTX was defined as ≤ 12.5mg/week and high-dose MTX as 15–25mg/week. Patients who met the criteria for clinical remission [Harvey-Bradshaw Index ≤ 4, Simple Clinical Colitis Activity Index ≤ 2] at baseline were followed for up to 42 months. Chart review occurred in 6-month intervals. The primary outcome was consecutive months in remission prior to relapse. Secondary outcomes included other indicators of worsening disease [endoscopic inflammation, steroid use, therapy escalation/addition, or surgery] and adverse events. Regression analysis and Kaplan–Meier survival analysis were completed. Results: We identified 73 [83%] dual-therapy patients, of whom 32 low-dose and 14 high-dose individuals achieved remission. When compared with high-dose patients, low-dose patients were more likely to relapse [log-rank test, p < 0.01]. Secondary indicators of worsening disease occurred during 34.4% of low-dose review periods and 31.4% of high-dose review periods [p = 0.67]; 3/52 [6%] low-dose patients and 3/21 [14%] high-dose patients [p = 0.34] discontinued MTX therapy due to adverse events. Conclusions: When combined with anti-TNF therapy, MTX at doses of >12.5mg/week was more effective at maintaining clinical remission than lower doses. These findings will guide management of combination therapy in IBD patients. PMID:25616487

  17. Can homeopathy bring additional benefits to thalassemic patients on hydroxyurea therapy? Encouraging results of a preliminary study.

    PubMed

    Banerjee, Antara; Chakrabarty, Sudipa Basu; Karmakar, Susanta Roy; Chakrabarty, Amit; Biswas, Surjyo Jyoti; Haque, Saiful; Das, Debarsi; Paul, Saili; Mandal, Biswapati; Naoual, Boujedaini; Belon, Philippe; Khuda-Bukhsh, Anisur Rahman

    2010-03-01

    Several homeopathic remedies, namely, Pulsatilla Nigricans (30th potency), Ceanothus Americanus (both mother tincture and 6th potency) and Ferrum Metallicum (30th potency) selected as per similia principles were administered to 38 thalassemic patients receiving Hydroxyurea (HU) therapy for a varying period of time. Levels of serum ferritin (SF), fetal hemoglobin (HbF), hemoglobin (Hb), platelet count (PC), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), white blood cell (WBC) count, bilirubin content, alanine amino transferase (ALT), aspartate amino transferase (AST) and serum total protein content of patients were determined before and 3 months after administration of the homeopathic remedies in combination with HU to evaluate additional benefits, if any, derived by the homeopathic remedies, by comparing the data with those of 38 subjects receiving only HU therapy. Preliminary results indicated that there was a significant decrease in the SF and increase in HbF levels in the combined, treated subjects. Although the changes in other parameters were not so significant, there was a significant decrease in size of spleen in most patients with spleenomegaly and improvement in general health conditions along with an increased gap between transfusions in most patients receiving the combined homeopathic treatment. The homeopathic remedies being inexpensive and without any known side-effects seem to have great potentials in bringing additional benefits to thalassemic patients; particularly in the developing world where blood transfusions suffer from inadequate screening and fall short of the stringent safety standards followed in the developed countries. Further independent studies are encouraged. PMID:18955271

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

    PubMed

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

    2016-03-16

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

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

    PubMed

    Thiboutot, Diane M; Gollnick, Harald P

    2006-09-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  2. Comparative Metabolomic Profiling of Hepatocellular Carcinoma Cells Treated with Sorafenib Monotherapy vs. Sorafenib-Everolimus Combination Therapy

    PubMed Central

    Zheng, Jian-feng; Lu, Juan; Wang, Xiao-zhong; Guo, Wu-hua; Zhang, Ji-xiang

    2015-01-01

    Background Sorafenib-everolimus combination therapy may be more effective than sorafenib monotherapy for hepatocellular carcinoma (HCC). To better understand this effect, we comparatively profiled the metabolite composition of HepG2 cells treated with sorafenib, everolimus, and sorafenib-everolimus combination therapy. Material/Methods A 2D HRMAS 1H-NMR metabolomic approach was applied to identify the key differential metabolites in 3 experimental groups: sorafenib (5 μM), everolimus (5 μM), and combination therapy (5 μM sorafenib +5 μM everolimus). MetaboAnalyst 3.0 was used to perform pathway analysis. Results All OPLS-DA models displayed good separation between experimental groups, high-quality goodness of fit (R2), and high-quality goodness of predication (Q2). Sorafenib and everolimus have differential effects with respect to amino acid, methane, pyruvate, pyrimidine, aminoacyl-tRNA biosynthesis, and glycerophospholipid metabolism. The addition of everolimus to sorafenib resulted in differential effects with respect to pyruvate, amino acid, methane, glyoxylate and dicarboxylate, glycolysis or gluconeogenesis, glycerophospholipid, and purine metabolism. Conclusions Sorafenib and everolimus have differential effects on HepG2 cells. Sorafenib preferentially affects glycerophospholipid and purine metabolism, while the addition of everolimus preferentially affects pyruvate, amino acid, and glucose metabolism. This phenomenon may explain (in part) the synergistic effects of sorafenib-everolimus combination therapy observed in vivo. PMID:26092946

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

    NASA Astrophysics Data System (ADS)

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

    1988-06-01

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

  4. Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer.

    PubMed

    Elgogary, Amira; Xu, Qingguo; Poore, Brad; Alt, Jesse; Zimmermann, Sarah C; Zhao, Liang; Fu, Jie; Chen, Baiwei; Xia, Shiyu; Liu, Yanfei; Neisser, Marc; Nguyen, Christopher; Lee, Ramon; Park, Joshua K; Reyes, Juvenal; Hartung, Thomas; Rojas, Camilo; Rais, Rana; Tsukamoto, Takashi; Semenza, Gregg L; Hanes, Justin; Slusher, Barbara S; Le, Anne

    2016-09-01

    Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer. PMID:27559084

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

    PubMed

    Hommer, A

    2013-02-01

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

  6. Efficacy of a feed-additive antibacterial combination for improving feedlot cattle performance and health.

    PubMed Central

    Gallo, G F; Berg, J L

    1995-01-01

    The effectiveness of a feed-additive antimicrobial combination for improving feedlot performance and health was tested using 4325 high-risk feeder calves randomly allocated to a control group or an experimental group. The experimental group received the conventional ration plus a feed additive containing 700 mg per head/day of chlortetracycline and sulfamethazine from arrival at the feedlot to day 56 of the feeding period. The inclusion of the feed additive to the ration significantly improved average daily gain for days 0-28 (P = 0.0163) and 0-56 (P = 0.0001), and the feed conversion for days 0-28 (P = 0.0061) and 0-56 (P = 0.0004). Additionally, the use of the feed additive significantly reduced the rate of bovine respiratory disease morbidity for days 0-28 (P = 0.0014) and 0-56 (P = 0.0001), the rate of relapses and mortality for days 0-56 (P = 0.0151 and P = 0.0209, respectively), and the rate of animals diagnosed with chronic respiratory disease for days 0-28 and 0-56 (P = 0.0009 and P = 0.0002, respectively). Performance and health improvements produced by the use of the feed additive were cost-effective. PMID:7600512

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

    PubMed Central

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

    2014-01-01

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

  8. Combined Ethanol Injection Therapy and Radiofrequency Ablation Therapy in Percutaneous Treatment of Hepatocellular Carcinoma Larger than 4 cm

    SciTech Connect

    Vallone, Paolo; Catalano, Orlando Izzo, Francesco; Siani, Alfredo

    2006-08-15

    Background. Optimal treatment of large-sized hepatocellular carcinoma (HCC) is still debated, because percutaneous ablation therapies alone do not always achieve complete necrosis. Objective. To report our experience in the treatment of patients with HCC larger than 4 cm in diameter by combined percutaneous ethanol injection and radiofrequency thermal ablation. Methods. In a 5-year period there were 40 consecutive patients meeting the inclusion criteria (24 men and 16 women; age range 41-72 years, mean 58 years). These subjects had a single HCC larger than 4 cm. Twelve subjects also had one or two additional nodules smaller than 4 cm (mean 1.2 nodules per patient). Patients were submitted to one to three sessions consisting of ethanol injection at two opposite tumor poles (mean 12 ml) and then of radiofrequency application through one or two electrodes placed at the tumor center (mean treatment duration 30 min). Results. Complete necrosis was obtained in all cases with one to three sessions (mean 1.3 sessions per patient). All patients experienced pain and fever but one only subject had a major complication requiring treatment (abscess development and fistulization). Overall follow-up was 7-69 months. Two patients showed local recurrence and 9 developed new etherotopic HCC nodules. Seven subjects died during follow-up while 33 were free from recurrence 8-69 months after treatment. Conclusion. A combination of ethanol injection and radiofrequency ablation is effective in the treatment of large HCC.

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

    PubMed

    Carvajal, Luis A; Steidl, Ulrich

    2016-07-01

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

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

    SciTech Connect

    Barker, Christopher A.; Postow, Michael A.

    2014-04-01

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

  11. Nonoperative Korean Medicine Combination Therapy for Lumbar Spinal Stenosis: A Retrospective Case-Series Study

    PubMed Central

    Kim, Kiok; Jeong, Yongjae; Youn, Yousuk; Choi, Jeongcheol; Kim, Jaehong; Chung, Wonseok; Kim, Tae-Hun

    2015-01-01

    This is a retrospective case series exploring the therapeutic benefits and harm of nonoperative Korean medicine combination therapy for lumbar spinal stenosis (LSS). The medical records of a total of 33 LSS patients, who were treated as inpatients at Mokhuri Neck and Back Hospital, Republic of Korea, from November 2010 to January 2012, were reviewed first and telephone survey on these patients was conducted after one year. Body acupuncture, pharmacoacupuncture, Chuna, and oral administration of herbal medicines were offered to all patients. A Visual analogue scale (VAS) of pain and the walking duration without pain were used to assess the patients during the approximately 1-month treatment period. The average VAS score of pain and the walking duration improved significantly; the VAS score decreased from 9 (SD, 1.15) to 2.75 (2.22) (p < 0.01), and the walking duration increased from 5.5 (6.66) to 16.75 (13.00) minutes (p < 0.01). No adverse event was reported during the treatment. In addition, the decreased pain level and improved function continued for over one year. Although we did not find definitive evidence, the study results suggest that KM combination therapy may be beneficial for decreasing pain and improving function in LSS patients and may produce comparatively few adverse events. PMID:26543486

  12. Combined near infrared photothermolysis and photodynamic therapy by association of gold nanoparticles and an organic dye

    NASA Astrophysics Data System (ADS)

    Tuchina, Elena S.; Ratto, Fulvio; Khlebtsov, Boris N.; Centi, Sonia; Matteini, Paolo; Rossi, Francesca; Fusi, Franco; Khlebtsov, Nikolai G.; Pini, Roberto; Tuchin, Valery V.

    2011-03-01

    We investigated the combination of near infrared (NIR) photothermolysis and photodynamic therapy against different models of bacteria (S. aureus, S. epidermidis both methicillin susceptible and resistant), in order to discover possible synergistic pathways in the fight against cancer. Photothermolysis was mediated by NIR light absorption from gold nanorods, which were coated with polyethylene glycol to gain biocompatibility and provide for a convenient interface with the bacterial cell walls. At the same time photodynamic therapy was delivered by administration of Indocyanine Green (ICG), whose spectrum of molecular excitation overlaps the plasmonic oscillations of gold nanorods (~ 800 nm). Therefore irradiation with NIR light from a low power diode laser resulted into simultaneous photothermolysis and generation of reactive oxygen species and cytotoxic byproducts of ICG. We assessed the inhibition of the bacterial colony forming ability under different NIR light exposures, and compared the performance of the combined treatment (gold nanorods plus ICG) with the projected addition of the separate treatments (either gold nanorods or ICG). Our preliminary results may originate from the interplay of synergistic and conflicting interactions, which may include e.g. the enhanced intake of cytotoxic species due to permeabilization of the bacterial cell walls, quenching of ICG and modification of the bleaching of ICG due to the noble metal surface.

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

    PubMed Central

    2014-01-01

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

  14. 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

  15. Effects of combination therapy with vildagliptin and valsartan in a mouse model of type 2 diabetes

    PubMed Central

    2013-01-01

    Background Dipeptidyl peptidase-4 (DPP-4) inhibitors modulate incretin hormones and exert anti-diabetic effects in type 2 diabetes mellitus. Treatment with angiotensin II type 1 receptor blockers (ARB) is a proven successful intervention for hypertension with type 2 diabetes. The present study investigated the combined effects of the DPP-4 inhibitor vildagliptin and the ARB valsartan in a mouse model of type 2 diabetes. Methods C57BL/6 J mice fed with high-fat diet (HFD) or db/db mice were treated with placebo, phloridzin (PHZ), vildagliptin alone (ViL), valsartan alone (VaL) or ViL with VaL (ViLVaL) for 8 weeks. Results Glucose metabolism was improved in response to PHZ, ViL and ViLVaL in both HFD and db/db mice. Upon glucose challenge, ViLVaL showed the greatest suppression of blood glucose excursions, with increased insulin secretion, in db/db mice. ViLVaL treatment also showed an improvement of insulin sensitivity in db/db mice. Serum inflammatory cytokines were significantly decreased, and adiponectin was highest, in the ViLVaL group. ViLVaL improved insulin signaling and attenuated stress signaling in liver with amelioration of hepatic steatosis due to activated fatty acid oxidation in db/db mice. Furthermore, immunohistochemical analysis of the pancreas revealed that the combination treatment resulted in an increased expression of insulin and PDX-1, and increased insulin content. Conclusions The combination therapy of ViL and VaL improves both pancreatic beta-cell function and insulin sensitivity, with a reduction of the inflammatory and cell stress milieu in mouse models of T2DM. Our results suggest that this combination therapy exerts additive or even synergistic benefits to treat T2DM. PMID:24188631

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  18. Revisiting Dosing Regimen Using Pharmacokinetic/Pharmacodynamic Mathematical Modeling: Densification and Intensification of Combination Cancer Therapy.

    PubMed

    Meille, Christophe; Barbolosi, Dominique; Ciccolini, Joseph; Freyer, Gilles; Iliadis, Athanassios

    2016-08-01

    Controlling effects of drugs administered in combination is particularly challenging with a densified regimen because of life-threatening hematological toxicities. We have developed a mathematical model to optimize drug dosing regimens and to redesign the dose intensification-dose escalation process, using densified cycles of combined anticancer drugs. A generic mathematical model was developed to describe the main components of the real process, including pharmacokinetics, safety and efficacy pharmacodynamics, and non-hematological toxicity risk. This model allowed for computing the distribution of the total drug amount of each drug in combination, for each escalation dose level, in order to minimize the average tumor mass for each cycle. This was achieved while complying with absolute neutrophil count clinical constraints and without exceeding a fixed risk of non-hematological dose-limiting toxicity. The innovative part of this work was the development of densifying and intensifying designs in a unified procedure. This model enabled us to determine the appropriate regimen in a pilot phase I/II study in metastatic breast patients for a 2-week-cycle treatment of docetaxel plus epirubicin doublet, and to propose a new dose-ranging process. In addition to the present application, this method can be further used to achieve optimization of any combination therapy, thus improving the efficacy versus toxicity balance of such a regimen. PMID:26946136

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

    PubMed

    Bobyreva, L E

    1998-01-01

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

  20. Combined sonodynamic and antimetabolite therapy for the improved treatment of pancreatic cancer using oxygen loaded microbubbles as a delivery vehicle.

    PubMed

    McEwan, Conor; Kamila, Sukanta; Owen, Joshua; Nesbitt, Heather; Callan, Bridgeen; Borden, Mark; Nomikou, Nikolitsa; Hamoudi, Rifat A; Taylor, Mark A; Stride, Eleanor; McHale, Anthony P; Callan, John F

    2016-02-01

    In this manuscript we describe the preparation of an oxygen-loaded microbubble (O2MB) platform for the targeted treatment of pancreatic cancer using both sonodynamic therapy (SDT) and antimetabolite therapy. O2MB were prepared with either the sensitiser Rose Bengal (O2MB-RB) or the antimetabolite 5-fluorouracil (O2MB-5FU) attached to the microbubble (MB) surface. The MB were characterised with respect to size, physical stability and oxygen retention. A statistically significant reduction in cell viability was observed when three different pancreatic cancer cell lines (BxPc-3, MIA PaCa-2 and PANC-1), cultured in an anaerobic cabinet, were treated with both SDT and antimetabolite therapy compared to either therapy alone. In addition, a statistically significant reduction in tumour growth was also observed when ectopic human xenograft BxPC-3 tumours in SCID mice were treated with the combined therapy compared to treatment with either therapy alone. These results illustrate not only the potential of combined SDT/antimetabolite therapy as a stand alone treatment option in pancreatic cancer, but also the capability of O2-loaded MBs to deliver O2 to the tumour microenvironment in order to enhance the efficacy of therapies that depend on O2 to mediate their therapeutic effect. Furthermore, the use of MBs to facilitate delivery of O2 as well as the sensitiser/antimetabolite, combined with the possibility to activate the sensitiser using externally applied ultrasound, provides a more targeted approach with improved efficacy and reduced side effects when compared with conventional systemic administration of antimetabolite drugs alone. PMID:26702983

  1. Individual and combined in vitro (anti)androgenic effects of certain food additives and cosmetic preservatives.

    PubMed

    Pop, Anca; Drugan, Tudor; Gutleb, Arno C; Lupu, Diana; Cherfan, Julien; Loghin, Felicia; Kiss, Béla

    2016-04-01

    The individual and combined (binary mixtures) (anti)androgenic effect of butylparaben (BuPB), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and propyl gallate (PG) was evaluated using the MDA-kb2 cell line. Exposing these cells to AR agonists results in the expression of the reporter gene (encoding for luciferase) and luminescence can be measured in order to monitor the activity of the reporter protein. In case of the evaluation of the anti-androgenic effect, the individual test compounds or binary mixtures were tested in the presence of a fixed concentration of a strong AR agonist (1000 pM 5-alpha-dihydrotestosterone; DHT). Cell viability was assessed using a resazurin based assay. For PG, this is the first report in the literature concerning its (anti)androgenic activity. In case of both individual and mixture testing none of the compounds or binary combinations showed androgenic activity. When tested in the presence of DHT, BuPB, BHA and BHT proved to be weak anti-androgens and this was confirmed during the evaluation of binary mixtures (BuPB+BHA, BuPB+BHT and BHA+BHT). Besides performing the in vitro testing of the binary combinations, two mathematical models (dose addition and response addition) were evaluated in terms of accuracy of prediction of the anti-androgenic effect of the selected binary mixtures. The dose addition model guaranteed a good correlation between the experimental and predicted data. However, no estimation was possible in case of mixtures containing PG, due to the lack of effect of the compound in case of the individual testing. PMID:26812027

  2. Iatrogenic posterior tibial nerve division during a combined anterior ankle arthroscopy with an additional posterolateral portal.

    PubMed

    Abdul-Jabar, Hani B; Bhamra, Jagmeet; Quick, Tom J; Fox, Michael

    2016-01-01

    Ankle arthroscopy is an important diagnostic and therapeutic technique in the management of ankle disorders. Nowadays ankle arthroscopy provides good to excellent results (up to 90%) in the treatment of certain intra-articular disorders. Due to the superficial location of ankle joint and the abundance of overlying neurovascular structures, complications reported in ankle arthroscopy are greater than those reported in other joints. We present the first reported case of a complete division of the posterior tibial nerve during an anterior ankle arthroscopy combined with an additional posterolateral portal. This was due to a poorly controlled use of the arthroscopic instruments. PMID:27197613

  3. Iatrogenic posterior tibial nerve division during a combined anterior ankle arthroscopy with an additional posterolateral portal

    PubMed Central

    Abdul-Jabar, Hani B; Bhamra, Jagmeet; Quick, Tom J; Fox, Michael

    2016-01-01

    Ankle arthroscopy is an important diagnostic and therapeutic technique in the management of ankle disorders. Nowadays ankle arthroscopy provides good to excellent results (up to 90%) in the treatment of certain intra-articular disorders. Due to the superficial location of ankle joint and the abundance of overlying neurovascular structures, complications reported in ankle arthroscopy are greater than those reported in other joints. We present the first reported case of a complete division of the posterior tibial nerve during an anterior ankle arthroscopy combined with an additional posterolateral portal. This was due to a poorly controlled use of the arthroscopic instruments. PMID:27197613

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

    PubMed

    Grande, Iria; Vieta, Eduard

    2015-03-01

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

  5. A double-blind comparative study of Chinese herbal medicine Jinlianqingre Effervescent Tablets in combination with conventional therapy for the treatment of uncomplicated hand, foot, and mouth disease.

    PubMed

    He, L-Y; Zhang, G-L; Yan, S-Y; Liu, Y; Zhao, C-S; Wang, X-L; Li, Y; Mi, Y-Q; Liu, Y-M; Li, C-P; Kou, Y-H; Li, Y; Chang, K; Meng, X-L; Sun, X-J; Zhao, T; Li, J; Wang, Y-Y; Liu, B-Y

    2014-08-01

    Chinese herbal medicine Jinlianqingre Effervescent Tablets (JET) are the recommended control measure for uncomplicated hand, foot, and mouth disease (HFMD) by the Ministry of Health of China. However, high-quality evidence to support this recommendation is limited. A total of 288 patients ranging in age from 1 to 13 years were randomly assigned to JET in combination with conventional therapy (mainly including the reduction of temperature by applying physical cooling paste or warm bathing), or conventional therapy with placebo group for 7 days. The objective was to test the hypothesis that JET combination therapy is more effective than conventional therapy for uncomplicated HFMD. A randomized, double-blind, placebo-controlled trial was designed. Our study showed that, compared with conventional therapy, the median time to fever resolution was significantly shorter in the JET combination therapy (8 vs. 80 h; p < 0.0001); the risk of fever resolution increased in the JET combination therapy [hazard ratio, 19.8; 95% confidence interval (CI), 12.8 to 30.7]; the median healing time of rash or oral ulcer was significantly shorter in the JET combination therapy (14 vs. 74 h; p < 0.0001); and the median symptom score for skin or oral mucosa lesions improved more rapidly in the JET combination therapy during the follow-up period. The median duration of hospital stay was 6 days in the JET combination therapy and 7 days in the conventional therapy (p < 0.0001). No significant adverse events and complications were found in both groups. The addition of JET to conventional therapy reduced fever clearance time, healing time of skin or oral mucosa lesions, and duration of hospital stay in children with uncomplicated HFMD. PMID:24643639

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

    PubMed

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

    2016-01-01

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

  7. Aliskiren: a review of its use as monotherapy and as combination therapy in the management of hypertension.

    PubMed

    Duggan, Sean T; Chwieduk, Claudine M; Curran, Monique P

    2010-10-22

    Aliskiren is an orally administered, nonpeptide direct renin inhibitor indicated for the management of hypertension. Aliskiren was effective in controlling blood pressure (BP) as monotherapy and in combination with other antihypertensives, in large, randomized trials. Aliskiren 150-300 mg/day as monotherapy was effective in lowering BP across short- (≤12 weeks) and longer-term (up to 54 weeks) periods, providing sustained and consistent effects with 24-hour BP control. Compared with other antihypertensives, aliskiren was generally as effective as hydrochlorothiazide (HCTZ), valsartan, losartan, irbesartan and lisinopril in reducing BP. Furthermore, short-term aliskiren was noninferior to ramipril in reducing BP, but with a longer treatment duration, a greater efficacy of aliskiren-based therapy over ramipril-based therapy was demonstrated. Additional BP-lowering effects occurred when aliskiren was coadministered (as a fixed-dose combination or separate tablets) with other antihypertensives, including HCTZ, valsartan and amlodipine, according to large, randomized trials of short- (≤12 weeks) and longer-term (up to 54 weeks) duration. Combination therapy with aliskiren plus HCTZ was effective in hypertensive patients when administered as initial therapy or to patients previously treated with HCTZ or aliskiren monotherapy. Aliskiren-based therapy was also effective in lowering BP in obese patients, patients with type 1 or 2 diabetes mellitus, patients with metabolic syndrome and the elderly. Aliskiren efficacy was observed irrespective of patient age, sex or ethnicity. Aliskiren monotherapy or combination therapy was generally well tolerated over short- and longer-term study durations in large, randomized clinical trials. Clinical trials to evaluate the effects of aliskiren on clinical outcomes, including renoprotective and cardioprotective effects, are currently ongoing. Thus, aliskiren is a useful option for the treatment of patients with stage 1 to stage 2

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

    PubMed

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

    2016-07-01

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

  9. Aromatase inhibiting and combined estrogenic effects of parabens and estrogenic effects of other additives in cosmetics

    SciTech Connect

    Meeuwen, J.A. van Son, O. van; Piersma, A.H.; Jong, P.C. de; Berg, M. van den

    2008-08-01

    There is concern widely on the increase in human exposure to exogenous (anti)estrogenic compounds. Typical are certain ingredients in cosmetic consumer products such as musks, phthalates and parabens. Monitoring a variety of human samples revealed that these ingredients, including the ones that generally are considered to undergo rapid metabolism, are present at low levels. In this in vitro research individual compounds and combinations of parabens and endogenous estradiol (E{sub 2}) were investigated in the MCF-7 cell proliferation assay. The experimental design applied a concentration addition model (CA). Data were analyzed with the estrogen equivalency (EEQ) and method of isoboles approach. In addition, the catalytic inhibitory properties of parabens on an enzyme involved in a rate limiting step in steroid genesis (aromatase) were studied in human placental microsomes. Our results point to an additive estrogenic effect in a CA model for parabens. In addition, it was found that parabens inhibit aromatase. Noticeably, the effective levels in both our in vitro systems were far higher than the levels detected in human samples. However, estrogenic compounds may contribute in a cumulative way to the circulating estrogen burden. Our calculation for the extra estrogen burden due to exposure to parabens, phthalates and polycyclic musks indicates an insignificant estrogenic load relative to the endogenous or therapeutic estrogen burden.

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

    PubMed

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

    2006-02-01

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

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

    PubMed

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

    2016-09-01

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

  12. Inhaled corticosteroids as combination therapy with beta-adrenergic agonists in airways disease: present and future.

    PubMed

    Chung, Kian Fan; Caramori, Gaetano; Adcock, Ian M

    2009-09-01

    Inhaled corticosteroid (ICS) therapy in combination with long-acting beta-adrenergic agonists represents the most important treatment for chronic airways diseases such as asthma and chronic obstructive pulmonary disease (COPD). ICS therapy forms the basis for treatment of asthma of all severities, improving asthma control, lung function and preventing exacerbations of disease. Use of ICS has also been established in the treatment of COPD, particularly symptomatic patients, who experience useful gains in quality of life, likely from an improvement in symptoms such as breathlessness and in reduction in exacerbations, and an attenuation of the yearly rate of deterioration in lung function. The addition of long-acting beta-agonist (LABA) therapy with ICS increases the efficacy of ICS effects in moderate-to-severe asthma. Thus, a 800 mug daily dose of the ICS budesonide reduced severe exacerbation rates by 49% compared to a low dose of 200 mug daily, and addition of the LABA formoterol to budesonide (800 mug) led to a 63% reduction. In COPD, the effects of ICS are less prominent but there are beneficial effects on the decline in FEV(1) and the rate of exacerbations. A reduction in the rate of decline in FEV(1) of 16 ml/year with a 25% reduction in exacerbation rate has been reported with the salmeterol and fluticasone combination. A non-significant 17.5% reduction in all-cause mortality rate with ICS and LABA is reported. Chronic inflammation is a feature of both asthma and COPD, although there are site and characteristic differences. ICS targets this inflammation although this effect of ICS is less effective in patients with severe asthma and with COPD; however, addition of LABA may potentiate the anti-inflammatory effects of ICS. An important consideration is the presence of corticosteroid insensitivity in these patients. Currently available ICS have variably potent binding activities to specific glucocorticoid receptors, leading to inhibition of gene expression by

  13. Combination therapy with tamoxifen and amphotericin B in experimental cutaneous leishmaniasis.

    PubMed

    Trinconi, Cristiana T; Reimão, Juliana Q; Yokoyama-Yasunaka, Jenicer K U; Miguel, Danilo C; Uliana, Silvia R B

    2014-05-01

    Leishmaniasis chemotherapy remains very challenging. The high cost of active drugs, along with the severity of their side effects and the increasing failure rate of the current therapeutic schemes, calls for the discovery of new active drugs and schemes of treatment. The use of combination therapy has gained much attention in recent years as a possible strategy for overcoming the various shortcomings in the present arsenal. We recently described the effectiveness of tamoxifen in murine models of leishmaniasis, and here, we investigated the interactions between tamoxifen and amphotericin B, one of the most potent drugs used in leishmaniasis treatment. The in vitro interactions were indifferent for the association of tamoxifen and amphotericin B. The association was also assayed in vivo in Leishmania amazonensis-infected BALB/c mice and was found to yield at least additive effects at low doses of both drugs. PMID:24550333

  14. Combined Therapeutic and Monitoring Ultrasonic Catheter for Cardiac Ablation Therapies.

    PubMed

    Carias, Mathew; Hynynen, Kullervo

    2016-01-01

    This study evaluated the feasibility of a combined therapeutic and diagnostic ultrasonic catheter for cardiac ablation therapies. Ultrasound can be used to determine when diseased cardiac tissues have become fully coagulated through a method known as local harmonic motion imaging (LHMI). LHMI is an imaging modality for treatment monitoring that uses acoustic radiation force, displacement tracking and the different mechanical properties of viable and ablated tissues. In this study, we developed catheters that are capable of LHMI measurements. Experiments were conducted in phantoms, ex vivo cardiac samples and the in vivo beating hearts of healthy porcine subjects. In vivo experiments revealed that four of four epicardial sonications revealed a decrease in measured displacements from LHMI experiments and that when lower power was used, no lesions formed and there was no corresponding decrease in measured displacement amplitudes. In addition, two of three endocardial lesions were confirmed and corresponded to a decrease in the measured displacement amplitude. PMID:26431798

  15. Single-Agent Therapies After Standard Combination Regimens.

    PubMed

    Chokshi, Saurin; Hochster, Howard S

    2016-01-01

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

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

    ERIC Educational Resources Information Center

    Wadden, Thomas A; Stunkard, Albert J.

    1986-01-01

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

  17. Second neoplasms in patients with Hodgkin's disease following combined modality therapy--the Yale experience

    SciTech Connect

    Koletsky, A.J.; Bertino, J.R.; Farber, L.R.; Prosnitz, L.R.; Kapp, D.S.; Fischer, D.; Portlock, C.S.

    1986-03-01

    From 1969 to 1982, 183 patients with previously untreated stages IIIB and IV Hodgkin's disease and relapsing Hodgkin's disease after radiation therapy were treated with combination chemotherapy plus low-dose irradiation (CRT). One hundred fifty patients who achieved a complete response (CR) were analyzed for risk of developing a second neoplasm. Median follow-up has been 8.3 years. Actuarial survival of all patients is 74% at 10 years with a relapse-free survival of 68%. An additional 24 patients with stage IIIA disease were also treated with CRT. There were 22 CRs at risk who were analyzed. Median follow-up has been 3+ years with an actuarial survival of 90% at five years and a relapse-free survival of 83%. Second neoplasms have developed in 14 of 172 patients at risk: acute nonlymphocytic leukemia (ANLL; five patients); aggressive histology non-Hodgkin's lymphoma (NHL; three patients); and a variety of solid neoplasms (six patients). Time to second neoplasm diagnosis after initial treatment ranged from 12 to 141 months. Five patients were older than 40 years. At the time of diagnosis of the second malignancy, 11 patients were free of Hodgkin's disease (for 36 to 141 months) and three were receiving therapy for recurrent Hodgkin's disease. The 10-year actuarial risk (%) of developing ANLL was 5.9 +/- 2.8; for NHL, the risk was 3.5 +/- 2.4, and for solid neoplasms, 5.8 +/- 3.0. Our results suggest that combination chemotherapy plus low-dose irradiation does not appear to significantly increase the risk of developing second neoplasms above that already reported for combination chemotherapy when administered as either initial or salvage treatment of Hodgkin's disease.

  18. Combined inhaled salbutamol and mannitol therapy for mucus hyper-secretion in pulmonary diseases.

    PubMed

    Ong, Hui Xin; Traini, Daniela; Ballerin, Giulia; Morgan, Lucy; Buddle, Lachlan; Scalia, Santo; Young, Paul M

    2014-03-01

    This study focuses on the co-engineering of salbutamol sulphate (SS), a common bronchodilator, and mannitol (MA), a mucolytic, as a potential combination therapy for mucus hypersecretion. This combination was chosen to have a synergic effect on the airways: the SS will act on the β2-receptor for relaxation of smooth muscle and enhancement of ciliary beat frequency, whilst mannitol will improve the fluidity of mucus, consequently enhancing its clearance from the lung. A series of co-spray-dried samples, containing therapeutically relevant doses of SS and MA, were prepared. The physico-chemical characteristics of the formulations were evaluated in terms of size distribution, morphology, thermal and moisture response and aerosol performance. Additionally, the formulations were evaluated for their effects on cell viability and transport across air interface Calu-3 bronchial epithelial cells, contractibility effects on bronchial smooth muscle cells and cilia beat activity using ciliated nasal epithelial cells in vitro. The formulations demonstrated size distributions and aerosol performance suitable for inhalation therapy. Transport studies revealed that the MA component of the formulation enhanced penetration of SS across the complex mucus layer and the lung epithelia cells. Furthermore, the formulation in the ratios of SS 10(-6) and MA 10(-3) M gave a significant increase in cilia beat frequency whilst simultaneously preventing smooth muscle contraction associated with mannitol administration. These studies have established that co-spray dried combination formulations of MA and SS can be successfully prepared with limited toxicity, good aerosol performance and the ability to increase ciliary beat frequency for improving the mucociliary clearance in patients suffering from hyper-secretory diseases, whilst simultaneously acting on the underlying smooth muscle. PMID:24431080

  19. Combining T-cell immunotherapy and anti-androgen therapy for prostate cancer

    PubMed Central

    Sanchez, C; Chan, R; Bajgain, P; Rambally, S; Palapattu, G; Mims, M; Rooney, CM; Leen, AM; Brenner, MK; Vera, JF

    2013-01-01

    BACKGROUND Prostate cancer remains a significant health problem for men in the Western world. Although treatment modalities are available, these do not confer long-term benefit and are accompanied by substantial side effects. Adoptive immunotherapy represents an attractive alternative to conventional treatments as a means to control tumor growth. METHODS To selectively target the tumor-expressed form of Muc1 we constructed a retroviral vector encoding a chimeric antigen receptor (CAR) directed against the aberrantly-expressed extracellular portion of Muc1 called the ‘variable number of tandem repeats’. RESULTS We now demonstrate that T cells can be genetically engineered to express a CAR targeting the tumor-associated antigen Muc1. CAR-Muc1 T cells were able to selectively kill Muc1-expressing human prostate cancer cells. However, we noted that heterogeneous expression of the Muc1 antigen on tumor cells facilitated immune escape and the outgrowth of target-antigen loss variants of the tumor. Given the importance of androgen ablation therapy in the management of metastatic prostate cancer, we therefore also tested the value of combining conventional (anti-androgen) and experimental (CAR-Muc1 T cells) approaches. We show that CAR-Muc1 T cells were not adversely impacted by anti-androgen therapy and subsequently demonstrate the feasibility of combining the approaches to produce additive anti-tumor effects in vitro. CONCLUSIONS Adoptive transfer of CAR-Muc1 T cells alone or in combination with other luteinizing hormone-releasing hormone analogs or antagonists should be tested in human clinical trials. PMID:23295316

  20. [Subcutaneous stimulation as additional therapy to spinal cord stimulation in a post-laminectomy syndrome patient].

    PubMed

    Akbaş, Mert; Yeğin, Mehmet Arif; Özdemir, İrem; Göksu, Ethem; Akyüz, Mahmut

    2016-01-01

    Spinal cord stimulation as treatment of chronic low back pain via neuromodulation has been frequently performed in recent years. The dorsal column is stimulated by an electrode placed at the epidural region. In the case presently described, subcutaneous lead was implanted in a patient with failed back syndrome after spinal cord stimulation was inadequate to treat back and gluteal pain. A 65-year-old male had undergone surgery to treat lumbar disc herniation, after which he received physical therapy and multiple steroid injections due to unrelieved pain. He was admitted to the pain clinic with pain radiating to right gluteal muscle and leg. Spinal cord stimulation was performed and, as pain was not relieved, subcutaneous lead was applied to the right cluneal nerve distribution. Following treatment, the patient scored 1-2 on visual analog scale. Pain had been reduced by over 80%. Octad electrode was placed between T8 and T10 vertebrae after Tuohy needle was introduced to intervertebral area between L1 and L2. Paresthesia occurred in the right extremity. Boundaries were determined by area of right gluteal region in which paresthesia did not occur. Octad electrode was placed subcutaneously after vertical line was drawn from center point. Paresthesia occurred throughout the region. Pulse wave was 390-450 msec; frequency was 10-30 Hz. Subcutaneous electrode replacement is effective additional therapy when pain is not relieved by spinal cord stimulation. PMID:27225614

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

    PubMed

    Millichap, J Gordon; Yee, Michelle M

    2016-01-01

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

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

    PubMed

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

    2011-01-01

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

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

    PubMed

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

    2016-02-11

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

  4. 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

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

    PubMed

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

    1990-03-01

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

  6. A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin

    PubMed Central

    Xia, Yifeng; Liu, Yi-Liang; Xie, Yonghua; Zhu, Wei; Guerra, Francisco; Shen, Shen; Yeddula, Narayana; Fischer, Wolfgang; Low, William; Zhou, Xiaoying; Zhang, Yonghui; Oldfield, Eric; Verma, Inder M.

    2015-01-01

    Lung cancer is the most common human malignancy and leads to about one-third of all cancer-related deaths. Lung adenocarcinomas harboring KRAS mutations, in contrast to those with EGFR and EML4-ALK mutations, have not yet been successfully targeted. Here, we describe a combination therapy for treating these malignancies using two agents: a lipophilic bisphosphonate and rapamycin. This drug combination is much more effective than either agent acting alone in the KRAS G12D induced mouse lung model. Lipophilic bisphosphonates inhibit both farnesyl and geranylgeranyldiphosphate synthases, effectively blocking prenylation of the KRAS and other small G-proteins critical for tumor growth and cell survival. Bisphosphonate treatment of cells initiated autophagy but was ultimately unsuccessful and led to p62 accumulation and concomitant NF-κB activation, resulting in dampened efficacy in vivo. However, we found that rapamycin, in addition to inhibiting the mTOR pathway, facilitated autophagy and prevented p62 accumulation-induced NF-κB activation and tumor cell proliferation. Overall, these results suggest that using lipophilic bisphosphonates in combination with rapamycin may provide an effective strategy for targeting lung adenocarcinomas harboring KRAS mutations. PMID:25411474

  7. Mesoporous silica coated gold nanorods loaded doxorubicin for combined chemo-photothermal therapy.

    PubMed

    Monem, A Soltan; Elbialy, Nihal; Mohamed, Noha

    2014-08-15

    The efficacy of the combined chemo-photothermal therapy, using a mesoporous silica-coated gold nanorods loaded DOX (pGNRs@mSiO2-DOX), was consistently tested both in vitro and in vivo. The prepared nanoparticles that were characterized using transmission electron microscopy (TEM), UV-vis absorption spectroscopy and zeta potential showed high doxorubicin loading capacity in addition to its pH-responsive release. The pGNRs@mSiO2-DOX photo-heat conversion characteristic found to be stable for several repeated NIR irradiated doses was tested in simulated body fluid. In vitro results showed that pGNRs@mSiO2-DOX causes a significant damage in breast cancer cell line MCF-7 compared to free DOX. Contrary to this, it showed low toxicity to human amnion wish cells compared to CTAB coated GNRs and free DOX. In vivo results showed that intravenous administration of pGNRs@mSiO2-DOX (1.7 mg/kg) markedly suppresses the growth of subcutaneous Ehrlich carcinoma in female Balb mice (p<0.0001). Consistently, histopathological examination revealed a complete loss of tumor cellular details for mice that received the combined treatment. Based on the obtained results, this passively targeted pGNRs@mSiO2-DOX could specifically deliver drug and excessive local heat to tumor sites achieving high combined therapeutic efficacy. PMID:24792973

  8. Immune activation by combination human lymphokine-activated killer and dendritic cell therapy

    PubMed Central

    West, E J; Scott, K J; Jennings, V A; Melcher, A A

    2011-01-01

    Background: Optimal cellular immunotherapy for cancer should ideally harness both the innate and adaptive arms of the immune response. Lymphokine-activated killer cells (LAKs) can trigger early innate killing of tumour targets, whereas long-term adaptive-specific tumour control requires priming of CD8+ cytotoxic lymphocytes (CTLs) following acquisition of tumour-associated antigens (TAAs) by antigen-presenting cells such as dendritic cells (DCs). As DCs stimulate both innate and adaptive effectors, combination cell therapy using LAKs and DCs has the potential to maximise anti-tumour immune priming. Methods: Reciprocal activation between human clinical grade LAKs and DCs on co-culture, and its immune consequences, was monitored by cell phenotype, cytokine release and priming of both innate and adaptive cytotoxicity against melanoma targets. Results: Co-culture of DCs and LAKs led to phenotypic activation of natural killer (NK) cells within the LAK population, which was associated with increased production of inflammatory cytokines and enhanced innate cytotoxicity against tumour cell targets. The LAKs reciprocally matured DCs, and the combination of LAKs and DCs, on addition of melanoma cells, supported priming of specific anti-tumour CTLs better than DCs alone. Conclusion: Clinical-grade LAKs/DCs represents a practical, effective combination cell immunotherapy for stimulation of both innate and adaptive anti-tumour immunity in cancer patients. PMID:21847125

  9. Antibody therapy alone and in combination with targeted drugs in chronic lymphocytic leukemia.

    PubMed

    Robak, Tadeusz; Blonski, Jerzy Z; Robak, Pawel

    2016-04-01

    The development of non-chemotherapeutic agents, including monoclonal antibodies (mAbs) and other targeted drugs, makes chemotherapy-free treatment an attractive option for chronic lymphocytic leukemia (CLL). The classical mAb, rituximab, has been authorized for use in both first-line and second-line therapy for CLL. New mAbs directed against CD20, ofatumumab, and obinutuzumab (GA-101) have also been approved for the treatment of this disease. Recently, several new mAbs with potential benefits over the approved anti-CD20 antibodies have been developed for use in CLL. Anti-CD37, anti-CD19, and anti-CD40 mAbs are in early clinical trials and show promise in treating CLL. In addition, the combination of mAbs with B-cell receptor signaling pathway inhibitors and immunomodulatory drugs makes the chemotherapy-free option a reality today. Combinations of antibodies with targeted drugs like ibrutinib, idelalisib, or lenalidomide are expected to replace chemotherapy-based combinations for treating CLL in the near future. However, phase III trials should confirm the benefit of these new treatment strategies and establish their exact place in the therapeutic armamentarium for CLL. PMID:27040707

  10. Strategies for combining immunotherapy with radiation for anticancer therapy

    PubMed Central

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

    2016-01-01

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

  11. Survival Advantage With the Addition of Radiation Therapy to Chemotherapy in Early Stage Peripheral T-Cell Lymphoma, Not Otherwise Specified

    SciTech Connect

    Zhang, Xi-Mei; Li, Ye-Xiong; Wang, Wei-Hu; Jin, Jing; Wang, Shu-Lian; Liu, Yue-Ping; Song, Yong-Wen; Fang, Hui; Ren, Hua; Zhou, Li-Qiang; Liu, Xin-Fan; Yu, Zi-Hao

    2013-03-15

    Purpose: Early stage peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is rare. The purpose of this study was to evaluate the outcome of treatment as well as the potential role of radiation therapy in PTCL-NOS. Methods and Materials: Thirty-five patients with early stage PTCL-NOS were included. There were 13 patients with stage I disease and 22 with stage II. All patients except 1 received doxorubicin-based chemotherapy alone (n=13) or a combination of chemotherapy and radiation therapy (CMT) (n=21). Results: The 3-year overall survival (OS) and progression-free survival (PFS) rates for the entire group were 41.3% and 25.7%, respectively. The addition of radiation therapy to chemotherapy significantly improved OS and PFS in early stage PTCL-NOS. The 3-year OS and PFS rates were 49.7% and 33.3% for CMT, compared with 23.1% (P=.042) and 15.4% (P=.035) for chemotherapy alone, respectively. The prognosis for patients who achieved a complete response (CR) was significantly better than that observed in those who did not achieve a CR. Conclusions: Despite the aggressive clinical course of early stage PTCL-NOS, additional radiation therapy has a significant impact on outcome. The integration of local radiation therapy into more effective systemic therapies may further improve survival.

  12. In vitro and in vivo antimicrobial activity of combined therapy of silver nanoparticles and visible blue light against Pseudomonas aeruginosa.

    PubMed

    Nour El Din, Suzanne; El-Tayeb, Tarek A; Abou-Aisha, Khaled; El-Azizi, Mohamed

    2016-01-01

    Silver nanoparticles (AgNPs) have been used as potential antimicrobial agents against resistant pathogens. We investigated the possible therapeutic use of AgNPs in combination with visible blue light against a multidrug resistant clinical isolate of Pseudomonas aeruginosa in vitro and in vivo. The antibacterial activity of AgNPs against P. aeruginosa (1×10(5) colony forming unit/mL) was investigated at its minimal inhibitory concentration (MIC) and sub-MIC, alone and in combination with blue light at 460 nm and 250 mW for 2 hours. The effect of this combined therapy on the treated bacteria was then visualized using transmission electron microscope. The therapy was also assessed in the prevention of biofilm formation by P. aeruginosa on AgNP-impregnated gelatin biopolymer discs. Further, in vivo investigations were performed to evaluate the efficacy of the combined therapy to prevent burn-wound colonization and sepsis in mice and, finally, to treat a real infected horse with antibiotic-unresponsive chronic wound. The antimicrobial activity of AgNPs and visible blue light was significantly enhanced (P<0.001) when both agents were combined compared to each agent alone when AgNPs were tested at MIC, 1/2, or 1/4 MIC. Transmission electron microscope showed significant damage to the cells that were treated with the combined therapy compared to other cells that received either the AgNPs or blue light. In addition, the combined treatment significantly (P<0.001) inhibited biofilm formation by P. aeruginosa on gelatin discs compared to each agent individually. Finally, the combined therapy effectively treated a horse suffering from a chronic wound caused by mixed infection, where signs of improvement were observed after 1 week, and the wound completely healed after 4 weeks. To our knowledge, this combinatorial therapy has not been investigated before. It was proved efficient and promising in managing infections caused by multidrug resistant bacteria and could be used as an

  13. In vitro and in vivo antimicrobial activity of combined therapy of silver nanoparticles and visible blue light against Pseudomonas aeruginosa

    PubMed Central

    Nour El Din, Suzanne; El-Tayeb, Tarek A; Abou-Aisha, Khaled; El-Azizi, Mohamed

    2016-01-01

    Silver nanoparticles (AgNPs) have been used as potential antimicrobial agents against resistant pathogens. We investigated the possible therapeutic use of AgNPs in combination with visible blue light against a multidrug resistant clinical isolate of Pseudomonas aeruginosa in vitro and in vivo. The antibacterial activity of AgNPs against P. aeruginosa (1×105 colony forming unit/mL) was investigated at its minimal inhibitory concentration (MIC) and sub-MIC, alone and in combination with blue light at 460 nm and 250 mW for 2 hours. The effect of this combined therapy on the treated bacteria was then visualized using transmission electron microscope. The therapy was also assessed in the prevention of biofilm formation by P. aeruginosa on AgNP-impregnated gelatin biopolymer discs. Further, in vivo investigations were performed to evaluate the efficacy of the combined therapy to prevent burn-wound colonization and sepsis in mice and, finally, to treat a real infected horse with antibiotic-unresponsive chronic wound. The antimicrobial activity of AgNPs and visible blue light was significantly enhanced (P<0.001) when both agents were combined compared to each agent alone when AgNPs were tested at MIC, 1/2, or 1/4 MIC. Transmission electron microscope showed significant damage to the cells that were treated with the combined therapy compared to other cells that received either the AgNPs or blue light. In addition, the combined treatment significantly (P<0.001) inhibited biofilm formation by P. aeruginosa on gelatin discs compared to each agent individually. Finally, the combined therapy effectively treated a horse suffering from a chronic wound caused by mixed infection, where signs of improvement were observed after 1 week, and the wound completely healed after 4 weeks. To our knowledge, this combinatorial therapy has not been investigated before. It was proved efficient and promising in managing infections caused by multidrug resistant bacteria and could be used as an

  14. 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

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

    PubMed

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

    2012-11-15

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

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

    PubMed

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

    2014-02-01

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

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

    PubMed Central

    Simone, Charles B.; Burri, Stuart H.

    2015-01-01

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

  18. Inactivation of Bacillus subtilis spores using various combinations of ultraviolet treatment with addition of hydrogen peroxide.

    PubMed

    Zhang, Yiqing; Zhou, Lingling; Zhang, Yongji; Tan, Chaoqun

    2014-01-01

    This study aims at comparing the inactivation of Bacillus subtilis spores by various combinations of UV treatment and hydrogen peroxide (H2O2) addition. The combinations included sequential (UV-H2O2, H2O2-UV) and simultaneous (UV/H2O2) processes. Results showed that B. subtilis spores achieved a certain inactivation effect through UV treatment. However, hardly any inactivation effect by H2O2 alone was observed. H2O2 had a significant synergetic effect when combined with UV treatment, while high irradiance and H2O2 concentration both favored the reaction. When treated with 0.60 mm H2O2 and 113.0 μW/cm(2) UV irradiance for 6 min, the simultaneous UV/H2O2 treatment showed significantly improved disinfection effect (4.13 log) compared to that of UV-H2O2 (3.03 log) and H2O2-UV (2.88 log). The relationship between the inactivation effect and the exposure time followed a typical pseudo-first-order kinetics model. The pseudo-first-order rate constants were 0.478, 0.447 and 0.634 min(-1), for the UV-H2O2, H2O2-UV and UV/H2O2 processes, respectively, further confirming the optimal disinfection effect of the UV/H2O2 process. The disinfection could be ascribed to the OH radicals, as verified by the level of para-chlorobenzoic acid (pCBA). PMID:24447294

  19. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial

    PubMed Central

    Warde, Padraig; Mason, Malcolm; Ding, Keyue; Kirkbride, Peter; Brundage, Michael; Cowan, Richard; Gospodarowicz, Mary; Sanders, Karen; Kostashuk, Edmund; Swanson, Greg; Barber, Jim; Hiltz, Andrea; Parmar, Mahesh KB; Sathya, Jinka; Anderson, John; Hayter, Charles; Hetherington, John; Sydes, Matthew R; Parulekar, Wendy

    2011-01-01

    Summary Background Whether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer. Methods Patients with: locally advanced (T3 or T4) prostate cancer (n=1057); or organ-confined disease (T2) with either a prostate-specific antigen (PSA) concentration more than 40 ng/mL (n=119) or PSA concentration more than 20 ng/mL and a Gleason score of 8 or higher (n=25), were randomly assigned (done centrally with stratification and dynamic minimisation, not masked) to receive lifelong ADT and RT (65–69 Gy to the prostate and seminal vesicles, 45 Gy to the pelvic nodes). The primary endpoint was overall survival. The results presented here are of an interim analysis planned for when two-thirds of the events for the final analysis were recorded. All efficacy analyses were done by intention to treat and were based on data from all patients. This trial is registered at controlledtrials.com as ISRCTN24991896 and Clinicaltrials.gov as NCT00002633. Results Between 1995 and 2005, 1205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6·0 years (IQR 4·4–8·0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70–78 vs 66%, 60–70; hazard ratio [HR] 0·77, 95% CI 0·61–0·98, p=0·033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0·5%) in the ADT only group, two (0·3%) in the ADT and RT group; diarrhoea grade >3, four patients (0·7%) vs eight (1·3%); urinary toxicity grade >3, 14 patients (2·3%) in both groups). Interpretation The benefits of combined

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

    PubMed Central

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

    2008-01-01

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

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

    PubMed

    Cui, Liwang; Su, Xin-zhuan

    2009-10-01

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

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

    PubMed

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

    2012-03-01

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

  3. 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

  4. Optimum population-level use of artemisinin combination therapies: a modelling study

    PubMed Central

    Nguyen, Tran Dang; Olliaro, Piero; Dondorp, Arjen M; Baird, J Kevin; Lam, Ha Minh; Farrar, Jeremy; Thwaites, Guy E; White, Nicholas J; Boni, Maciej F

    2015-01-01

    Summary Background Artemisinin combination therapies (ACTs) are used worldwide as first-line treatment against confirmed or suspected Plasmodium falciparum malaria. Despite the success of ACTs at reducing the global burden of malaria, emerging resistance to artemisinin threatens these gains. Countering onset of resistance might need deliberate tactics aimed at slowing the reduction in ACT effectiveness. We assessed optimum use of ACTs at the population level, specifically focusing on a strategy of multiple first-line therapies (MFT), and comparing it with strategies of cycling or sequential use of single first-line ACTs. Methods With an individual-based microsimulation of regional malaria transmission, we looked at how to apply a therapy as widely as possible without accelerating reduction of efficacy by drug resistance. We compared simultaneous distribution of artemether–lumefantrine, artesunate–amodiaquine, and dihydroartemisinin–piperaquine (ie, MFT) against strategies in which these ACTs would be cycled or used sequentially, either on a fixed schedule or when population-level efficacy reaches the WHO threshold of 10% treatment failure. The main assessment criterion was total number of treatment failures per 100 people per year. Additionally, we analysed the benefits of including a single non-ACT therapy in an MFT strategy, and did sensitivity analyses in which we varied transmission setting, treatment coverage, partner-drug half-life, fitness cost of drug resistance, and the relation between drug concentration and resistance evolution. Findings Use of MFT was predicted to reduce the long-term number of treatment failures compared with strategies in which a single first-line ACT is recommended. This result was robust to various epidemiological, pharmacological, and evolutionary features of malaria transmission. Inclusion of a single non-ACT therapy in an MFT strategy would have substantial benefits in reduction of pressure on artemisinin resistance

  5. Morphine and clonidine combination therapy improves therapeutic window in mice: synergy in antinociceptive but not in sedative or cardiovascular effects.

    PubMed

    Stone, Laura S; German, Jonathan P; Kitto, Kelly F; Fairbanks, Carolyn A; Wilcox, George L

    2014-01-01

    Opioids are used to manage all types of pain including acute, cancer, chronic neuropathic and inflammatory pain. Unfortunately, opioid-related adverse effects such as respiratory depression, tolerance, physical dependence and addiction have led to an underutilization of these compounds for adequate pain relief. One strategy to improve the therapeutic utility of opioids is to co-administer them with other analgesic agents such as agonists acting at α2-adrenergic receptors (α2ARs). Analgesics acting at α2ARs and opioid receptors (ORs) frequently synergize when co-administered in vivo. Multimodal analgesic techniques offer advantages over single drug treatments as synergistic combination therapies produce analgesia at lower doses, thus reducing undesired side effects. This inference presumes, however, that the synergistic interaction is limited to the analgesic effects. In order to test this hypothesis, we examined the effects of α2AR/OR combination therapy in acute antinociception and in the often-undesired side effects of sedation and cardiovascular depression in awake unrestrained mice. Morphine, clonidine or their combination was administered by spinal or systemic injection in awake mice. Antinociception was determined using the warm water tail flick assay (52.5°C). Sedation/motor impairment was evaluated using the accelerating rotarod assay and cardiovascular function was monitored by pulse oximetry. Data were converted to percent maximum possible effect and isobolographic analysis was performed to determine if an interaction was subadditive, additive or synergistic. Synergistic interactions between morphine and clonidine were observed in the antinociceptive but not in the sedative/motor or cardiovascular effects. As a result, the therapeutic window was improved ∼200-fold and antinociception was achieved at non-sedating doses with little to no cardiovascular depression. In addition, combination therapy resulted in greater maximum analgesic efficacy over

  6. COMBINATION THERAPY EFFECTIVENESS OF EZETIMIBE AND ATORVASTATIN IN PATIENTS WITH ACUTE CORONARY SYNDROME.

    PubMed

    Japaridze, L; Sadunishvili, M; Megreladze, I

    2016-03-01

    Atorvastatin reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe (EZE) , a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known. We conducted a 16-week one-center, prospective, randomized, and open-label clinical trial, involving 323 patients who had been hospitalized for an acute coronary syndrome within the preceding 14 days. They were received atorvastatin 20 mg during 28 days and after that 292 patients, who had LDL cholesterol levels≥1.81 mmol/L, were randomized to ezetimibe 10 mg/day co-administered with atorvastatin therapy (EZE+Statin) or doubling their current atorvastatin dose. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. At 16 weeks, the mean LDL cholesterol level during the study was 1.60 mmol per liter in the atorvastatine-ezetimibe group, as compared with 1.91 mmol per liter in the atorvastatin-monotherapy group (p<0.001). The Kaplan-Meier survival rate at 16 weeks were 88 .1 % in the atorvastatin-ezetimibe group and 77.0 % in the atorvastatin monotherapy group (absolute risk reduction, 11.1 percentage points; hazard ratio, 2.099 ; 95% confidence interval, 1.165 to 3.781; p=0.014). Patients receiving ezetimibe and statin were more likely to achieve target LDL-C after 16 weeks compared to patients doubling their statin dose. When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Ezetimibe/statin combination therapy was well tolerated among this patients, without safety concerns. PMID:27119829

  7. Estimating additive and dominance variances for complex traits in pigs combining genomic and pedigree information.

    PubMed

    Costa, E V; Diniz, D B; Veroneze, R; Resende, M D V; Azevedo, C F; Guimaraes, S E F; Silva, F F; Lopes, P S

    2015-01-01

    Knowledge of dominance effects should improve ge-netic evaluations, provide the accurate selection of purebred animals, and enable better breeding strategies, including the exploitation of het-erosis in crossbreeds. In this study, we combined genomic and pedi-gree data to study the relative importance of additive and dominance genetic variation in growth and carcass traits in an F2 pig population. Two GBLUP models were used, a model without a polygenic effect (ADM) and a model with a polygenic effect (ADMP). Additive effects played a greater role in the control of growth and carcass traits than did dominance effects. However, dominance effects were important for all traits, particularly in backfat thickness. The narrow-sense and broad-sense heritability estimates for growth (0.06 to 0.42, and 0.10 to 0.51, respectively) and carcass traits (0.07 to 0.37, and 0.10 to 0.76, respec-tively) exhibited a wide variation. The inclusion of a polygenic effect in the ADMP model changed the broad-sense heritability estimates only for birth weight and weight at 21 days of age. PMID:26125833

  8. Evaluation of the local dose enhancement in the combination of proton therapy and nanoparticles

    SciTech Connect

    Martínez-Rovira, I. Prezado, Y.

    2015-11-15

    Purpose: The outcome of radiotherapy can be further improved by combining irradiation with dose enhancers such as high-Z nanoparticles. Since 2004, spectacular results have been obtained when low-energy x-ray irradiations have been combined with nanoparticles. Recently, the same combination has been explored in hadron therapy. In vitro studies have shown a significant amplification of the biological damage in tumor cells charged with nanoparticles and irradiated with fast ions. This has been attributed to the increase in the ionizations and electron emissions induced by the incident ions or the electrons in the secondary tracks on the high-Z atoms, resulting in a local energy deposition enhancement. However, this subject is still a matter of controversy. Within this context, the main goal of the authors’ work was to provide new insights into the dose enhancement effects of nanoparticles in proton therapy. Methods: For this purpose, Monte Carlo calculations (GATE/GEANT4 code) were performed. In particular, the GEANT4-DNA toolkit, which allows the modeling of early biological damages induced by ionizing radiation at the DNA scale, was used. The nanometric radial energy distributions around the nanoparticle were studied, and the processes (such as Auger deexcitation or dissociative electron attachment) participating in the dose deposition of proton therapy treatments in the presence of nanoparticles were evaluated. It has been reported that the architecture of Monte Carlo calculations plays a crucial role in the assessment of nanoparticle dose enhancement and that it may introduce a bias in the results or amplify the possible final dose enhancement. Thus, a dosimetric study of different cases was performed, considering Au and Gd nanoparticles, several nanoparticle sizes (from 4 to 50 nm), and several beam configurations (source-nanoparticle distances and source sizes). Results: This Monte Carlo study shows the influence of the simulations’ parameters on the local

  9. A combined toxicity study of zinc oxide nanoparticles and vitamin C in food additives

    NASA Astrophysics Data System (ADS)

    Wang, Yanli; Yuan, Lulu; Yao, Chenjie; Ding, Lin; Li, Chenchen; Fang, Jie; Sui, Keke; Liu, Yuanfang; Wu, Minghong

    2014-11-01

    At present, safety evaluation standards for nanofood additives are made based on the toxic effects of a single additive. Since the size, surface properties and chemical nature influence the toxicity of nanomaterials, the toxicity may have dramatically changed when nanomaterials are used as food additives in a complex system. Herein, we investigated the combined toxicity of zinc oxide nanoparticles (ZnO NPs) and vitamin C (Vc, ascorbic acid). The results showed that Vc increased the cytotoxicity significantly compared with that of the ZnO only NPs. When the cells were exposed to ZnO NPs at a concentration less than 15 mg L-1, or to Vc at a concentration less than 300 mg L-1, there was no significant cytotoxicity, both in the case of gastric epithelial cell line (GES-1) and neural stem cells (NSCs). However, when 15 mg L-1 of ZnO NPs and 300 mg L-1 of Vc were introduced to cells together, the cell viability decreased sharply indicating significant cytotoxicity. Moreover, the significant increase in toxicity was also shown in the in vivo experiments. The dose of the ZnO NPs and Vc used in the in vivo study was calculated according to the state of food and nutrition enhancer standard. After repeated oral exposure to ZnO NPs plus Vc, the injury of the liver and kidneys in mice has been indicated by the change of these indices. These findings demonstrate that the synergistic toxicity presented in a complex system is essential for the toxicological evaluation and safety assessment of nanofood.At present, safety evaluation standards for nanofood additives are made based on the toxic effects of a single additive. Since the size, surface properties and chemical nature influence the toxicity of nanomaterials, the toxicity may have dramatically changed when nanomaterials are used as food additives in a complex system. Herein, we investigated the combined toxicity of zinc oxide nanoparticles (ZnO NPs) and vitamin C (Vc, ascorbic acid). The results showed that Vc increased the

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

    PubMed Central

    Jiang, Jhih-Hang; Peleg, Anton Y.

    2015-01-01

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

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

    PubMed

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

    2011-12-01

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

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

    PubMed

    Macauley, Shannon L

    2016-06-01

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

  13. Addition of Propolis to Irinotecan Therapy Prolongs Survival in Ehrlich Ascites Tumor-Bearing Mice

    PubMed Central

    Lisičić, Duje; Đikić, Domagoj; Blažević, Ana Sofia; Mihaljević, Josipa; Oršolić, Nada; Knežević, Anica Horvat

    2014-01-01

    Abstract We investigated possible synergistic action of anticancer drug Irinotecan (IRI) combined with ethanolic (EEP) and water-soluble (WSDP) derivate of propolis on Swiss albino mice injected with Ehrlich ascites tumor (EAT). For survival analysis mice were administered WSDP and EEP (100 mg/kg) daily for 3 consecutive days, beginning on 3rd day after EAT cell (1×106) injection. IRI was administered at a dose of 50 mg/kg on days 1, 13, and 19. We simultaneously studied peripheral white blood cell count, cell types washed from the peritoneal cavity, functional activity of macrophages from peritoneal cavity, and the level of primary DNA damage in leukocytes, kidney, and liver cells using the alkaline comet assay. Three out of 9 mice per group survived the entire duration of the experiment (90 days) in groups treated with IRI combined with WSDP and EEP. All test components increased survival of mice by 7.53% to 231.54%. Combined treatment with IRI and/or WSDP and EEP significantly decreased percentage of tumor cells in the peritoneal cavity as compared to nontreated EAT-injected mice. All treated animals had significantly higher percentage of neutrophils in the peritoneal cavity in comparison to nontreated EAT-injected mice. We observed significantly higher value of DNA damage in leukocytes of mice treated with IRI and combination of IRI and/or WSDP and EEP as compared to nontreated EAT-injected mice, while the same treatment decreased DNA damage in kidney. Our results showed that addition of propolis to IRI treatment enhanced antitumor activity of IRI and prolongs survival in EAT-bearing mice, which definitely deserve further studies to clarify the possible mechanisms of antitumor actions of combined herb–drug treatments. PMID:24383762

  14. Combination therapy with cystic fibrosis transmembrane conductance regulator modulators augment the airway functional microanatomy.

    PubMed

    Birket, Susan E; Chu, Kengyeh K; Houser, Grace H; Liu, Linbo; Fernandez, Courtney M; Solomon, George M; Lin, Vivian; Shastry, Suresh; Mazur, Marina; Sloane, Peter A; Hanes, Justin; Grizzle, William E; Sorscher, Eric J; Tearney, Guillermo J; Rowe, Steven M

    2016-05-15

    Recently approved therapies that modulate CFTR function have shown significant clinical benefit, but recent investigations regarding their molecular mechanism when used in combination have not been consistent with clinical results. We employed micro-optical coherence tomography as a novel means to assess the mechanism of action of CFTR modulators, focusing on the effects on mucociliary clearance. Primary human airway monolayers from patients with a G551D mutation responded to ivacaftor treatment with increased ion transport, airway surface liquid depth, ciliary beat frequency, and mucociliary transport rate, in addition to decreased effective viscosity of the mucus layer, a unique mechanism established by our findings. These endpoints are consistent with the benefit observed in G551D patients treated with ivacaftor, and identify a novel mechanism involving mucus viscosity. In monolayers derived from F508del patients, the situation is more complicated, compounded by disparate effects on CFTR expression and function. However, by combining ion transport measurements with functional imaging, we establish a crucial link between in vitro data and clinical benefit, a finding not explained by ion transport studies alone. We establish that F508del cells exhibit increased mucociliary transport and decreased mucus effective viscosity, but only when ivacaftor is added to the regimen. We further show that improvement in the functional microanatomy in vitro corresponds with lung function benefit observed in the clinical trials, whereas ion transport in vitro corresponds to changes in sweat chloride. Functional imaging reveals insights into clinical efficacy and CFTR biology that significantly impact our understanding of novel therapies. PMID:26968770

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

    NASA Astrophysics Data System (ADS)

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

    2016-02-01

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

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

    PubMed

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

    2015-12-16

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

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

    PubMed

    Shimodozono, Megumi

    2013-01-01

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

  18. Perspectives on the Design of Clinical Trials Combining Transarterial Chemoembolization and Molecular Targeted Therapy

    PubMed Central

    Hsu, Chiun; Po-Ching-Liang; Morita, Satoshi; Hu, Fu-Chang; Cheng, Ann-Lii

    2012-01-01

    Transarterial chemoembolization (TACE) moderately prolongs the survival of patients with intermediate-stage hepatocellular carcinoma. Molecular targeted therapy (MTT) may improve the efficacy of TACE. However, the findings of clinical trials evaluating the efficacy of a combination of TACE and MTT are conflicting. We hypothesized that this disparity can be prevented using alternative study designs. In this review, we classify the pertinent issues of study designs into five domains: primary endpoints, patients, TACE procedures, timing of randomization, and drug administration. Furthermore, we discuss the methods for increasing the success rate by minimizing potentially confounding factors within these five domains. Transarterial chemoembolization (TACE) is the current standard therapy for patients with Barcelona Clinic Liver Cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC) [1, 2, 3]. The survival benefit of TACE is supported by the results of meta-analysis of clinical trials comparing TACE with other conservative treatments in patients with inoperable HCC [4]. The results showed that the median survival of patients improved from approximately 16 to 20 months following TACE [4, 5]. Although advances in TACE techniques and the use of new embolization agents may improve the efficacy of TACE [6, 7], other approaches are needed to further improve the outcome in HCC patients treated using TACE. Molecular targeted therapy (MTT) has improved the survival of patients with advanced-stage HCC [5, 8]. Therefore, combining MTT and TACE may additionally improve the survival in patients with intermediate-stage HCC. Many molecular targeted agents (MTA) are currently undergoing evaluation in randomized trials (table 1). However, the designs of these trials differ significantly. The results of two trials combining sorafenib and TACE were recently reported. Both trials failed to demonstrate a therapeutic benefit of the combination therapy for time to tumor progression

  19. Fixed-dose combination therapy of nebivolol and valsartan for the treatment of hypertension.

    PubMed

    Sander, Gary E; Fernandez, Camilo; Giles, Thomas D

    2016-01-01

    Recent large clinical trials have refuted earlier suggestions from the Joint National Committee 8 committee that less aggressive targets for blood pressure control were all that could be justified in most hypertensive patients. It now does appear that in fact "lower is better," with blood pressure targets < 120/80 mm Hg appropriate for many hypertensive patients. Two drug combinations are often indicated as initial therapy if a 20/10 mm Hg or greater blood pressure reduction is necessary to reach target. Combinations consisting of β-blockers and renin-angiotensin-aldosterone system inhibitors have previously been deemed "less effective," based on partially overlapping mechanisms of action and limited clinical trial evidence. Nebivolol is a vasodilating β1-selective blocker and β3- adrenoceptor agonist; β3-adrenoceptor activation increases nitric oxide concentrations and thus explains the vasodilatory effect. A recent 8-week randomized trial (N=4,161) in individuals with stage 1-2 hypertension demonstrated that single-pill fixed dose combinations (FDC) of nebivolol and valsartan, an angiotensin II subtype 1 receptor blocker, were more effective in reducing blood pressure than the corresponding monotherapies, with comparable tolerability. In addition, an ABPM-biomarkers substudy from that trial (n=805) demonstrated that the FDC prevented a valsartan-induced increase in plasma renin activity, and that the nebivolol/valsartan 20/320 mg/day dose reduced plasma aldosterone concentration significantly more than valsartan 320 mg/day. This article will describe the properties of nebivolol that make it unique and separate it from other β-blockers, and will further support the pharmacological advantages of this particular combination. PMID:26986445

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

    PubMed

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

    2016-06-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

    Yazici, Cenk Murat; Kurt, Omer

    2015-01-01

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

  4. Efficacy and safety of irbesartan/HCTZ combination therapy as initial treatment for rapid control of severe hypertension.

    PubMed

    Neutel, Joel M; Franklin, Stanley S; Oparil, Suzanne; Bhaumik, Amitabha; Ptaszynska, Agata; Lapuerta, Pablo

    2006-12-01

    Severe hypertension is difficult to control. This prospective, randomized, double-blind, active-controlled, multicenter trial compared efficacy and safety of once-daily irbesartan/hydrochlorothiazide (HCTZ) combination therapy with irbesartan monotherapy in severe hypertension. Patients who were untreated or uncontrolled on monotherapy (seated diastolic blood pressure [BP] > or =110 mm Hg) received fixed-dose irbesartan 150 mg/HCTZ 12.5 mg combination therapy for 7 weeks, force-titrated to irbesartan 300 mg/HCTZ 25 mg at week 1 (n=468); or irbesartan 150 mg monotherapy, force-titrated to 300 mg at week 1 (n=269). Significantly more patients on combination therapy achieved seated diastolic BP <90 mm Hg at week 5 (primary end point) compared with monotherapy recipients (47.2% vs 33.2%; P=.0005). Likewise, significantly more patients attained goals per the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) (<140/90 mm Hg) at week 5 (34.6% vs 19.2%, respectively; P<.0001), while the mean difference between combination and monotherapy in seated diastolic BP and seated systolic BP was 4.7 mm Hg and 9.7 mm Hg (P<.0001). Greater and more rapid BP reduction with irbesartan/HCTZ was achieved without additional side effects. PMID:17170610

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

    PubMed

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

    2014-01-01

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

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

    PubMed

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

    2002-06-28

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

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

    PubMed Central

    Radcliffe, Nathan M

    2014-01-01

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

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

    NASA Astrophysics Data System (ADS)

    Halasa, Salaheldin; Dickinson, Eva

    2014-02-01

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

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

    PubMed

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

    2016-10-01

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

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

    PubMed

    Boyapati, Ann; Sinclair, Rodney

    2013-02-01

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

  11. Anti-tumor effects on the combination of photodynamic therapy with arsenic compound in TC-1 cells implanted C57BL/6 mice

    NASA Astrophysics Data System (ADS)

    Lee, Kyu Wan; Wen, Lan Ying; Bae, Su Mi; Park, Choong Hak; Jeon, Woo Kyu; Lee, Doo Yun; Ahn, Woong Shick

    2009-06-01

    The effects of As4O6 were studied as adjuvant on photodynamic therapy. As4O6 is considered to have anticancer activity via several biological actions such as free radical producing and inhibition of VEGF expression. In vitro experiments, cell proliferation and morphology were determined by MTT assay. Also, quantitative PCR array was performed to study the synergetic mechanism. Additionally, this study was supported by the finding that combination of photodynamic therapy and As4O6 shows an inhibition effect of tumor growth in C57BL/6 mice with TC-1 cells xenographs in vivo. Radachlorin and As4O6 significantly inhibited TC-1 cell proliferation in a dose-dependent manner (P < 0.05). Antiproliferative effect of combination treatment was significantly higher than those of TC-1 cells treated with either photodynamic therapy or As4O6 (62.4 and 52.5% decrease, respectively, compared to photodynamic therapy or As4O6 alone, P < 0.05). In addition, cell proliferation in combination of photodynamic therapy and As4O6 treatment significantly decreased by 77.4% compared to vehicle-only treated TC-1 cells (P < 0.05). Cell survival pathway (Naip1, Tert and Aip1) and p53-dependent pathway (Bax, p21Cip1, Fas, Gadd45, IGFBP-3 and Mdm-2) were markedly increased by combination treatment of photodynamic therapy and As4O6. Besides, the immunology response NEAT pathway (Ly- 12, CD178 and IL-2) also modulated after combination treatment of photodynamic therapy and As4O6. This combination effect apparently shows a same pattern in vivo model. These findings suggest the benefit of the combination treatment of photodynamic therapy and As4O6 for the inhibition of cervical cancer growth.

  12. Phosphorus availability from rock phosphate: Combined effect of green waste composting and sulfur addition.

    PubMed

    Bustamante, M A; Ceglie, F G; Aly, A; Mihreteab, H T; Ciaccia, C; Tittarelli, F

    2016-11-01

    Rock phosphate constitutes a natural phosphorus (P) source for organic farming systems, but with a limiting direct agricultural use due to its poor inherent reactivity. Thus, this work studies the effect of the co-composting of rock phosphate with green wastes and elemental sulfur on phosphorus availability. Six composts were prepared combining different green wastes and rock phosphate in three different proportions (0%, 0.27% and 0.54% P fresh mass basis) and elemental sulfur in two proportions (0% and 0.5% S fresh mass basis). During composting, the temperature of the mixtures was monitored, as were physico-chemical and chemical parameters, especially those related to phosphorus. The co-composting of green wastes with rock phosphate improved phosphorus mobilization and also constituted a viable method to manage green wastes, obtaining P-enriched compost for organic farming systems. Sulfur addition favored the composting process and also phosphorus solubilization, especially in the mixture with the lowest proportion of rock phosphate. PMID:27543750

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

    PubMed

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

    2014-06-01

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

  14. Treatment-resistant depression in adolescents: is the addition of cognitive behavioral therapy of benefit?

    PubMed Central

    Hetrick, Sarah E; Cox, Georgina R; Merry, Sally N

    2011-01-01

    Background Many young people with major depression fail first-line treatments. Treatment-resistant depression has various definitions in the literature but typically assumes nonresponse to medication. In young people, cognitive behavioral therapy (CBT) is the recommended first-line intervention, thus the definition of treatment resistance should be expanded. Therefore, our aim was to synthesize the existing evidence of any interventions for treatment-resistant depression, broadly defined, in children and adolescents and to investigate the effectiveness of CBT in this context. Methods We used Cochrane Collaboration methodology, with electronic searches of Medline, PsycINFO, Embase, and the Cochrane Depression Anxiety and Neurosis Group trials registers. Only randomized controlled trials were included, and were assessed for risk of bias. Meta- analysis was undertaken where possible and appropriate. Results Of 953 articles retrieved, four trials were eligible for inclusion. For one study, only the trial registration document was available, because the study was never completed. All other studies were well conducted with a low risk of bias, although one study had a high dropout rate. Two studies assessed the effect of adding CBT to medication. While an assertive trial of antidepressants does appear to lead to benefit, when compared with placebo, there was no significant advantage, in either study, or in a meta-analysis of data from these trials, that clearly demonstrated an additional benefit of CBT. The third trial showed little advantage of a tricyclic antidepressant over placebo in the context of an inpatient admission. Conclusion Few randomized controlled trials have investigated interventions for treatment-resistant depression in young people, and results from these show modest benefit from antidepressants with no additional benefit over medication from CBT. Overall, there is a lack of evidence about effective interventions to treat young people who have failed to

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

    PubMed

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

    2016-08-01

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

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

    PubMed Central

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

    2013-01-01

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

  17. 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

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

    PubMed

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

    2016-04-11

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

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

    PubMed

    Chen, Lumin; Sun, Jihong; Yang, Xiaoming

    2016-01-01

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

  20. Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia.

    PubMed

    Chen, Jing; Pise-Masison, Cynthia A; Shih, Joanna H; Morris, John C; Janik, John E; Conlon, Kevin C; Keating, Anne; Waldmann, Thomas A

    2013-03-14

    Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4(+)CD25(+) lymphocytes caused by human T-cell lymphotropic virus type 1. Currently, there is no accepted curative therapy for ATL. In gene expression profiling, the antiapoptotic protein survivin (BIRC5) demonstrated a striking increase in ATL, and its expression was increased in patient ATL cells resistant to the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H). In this study, we investigated the antitumor activity of a small-molecule survivin suppressant YM155 alone and in combination with alemtuzumab in a murine model of human ATL (MET-1). Both YM155 alone and its combination with alemtuzumab demonstrated therapeutic efficacy by lowering serum soluble IL-2Rα (sIL-2Rα) levels (P < .001) and prolonged the survival of tumor-bearing mice (P < .0001). Moreover, the combination of YM155 with alemtuzumab demonstrated markedly additive antitumor activity by significantly lowering serum sIL-2Rα levels and improving the survival of leukemia-bearing mice compared with monotherapy with either YM155 (P < .001) or alemtuzumab (P < .05). More significantly, all mice that received the combination therapy survived and were tumor free >6 months after treatment. Our data support a clinical trial of the combination of YM155 with alemtuzumab in ATL. This trial was registered at www.clinicaltrials.gov as #NCT00061048. PMID:23321252

  1. Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia

    PubMed Central

    Chen, Jing; Pise-Masison, Cynthia A.; Shih, Joanna H.; Morris, John C.; Janik, John E.; Conlon, Kevin C.; Keating, Anne

    2013-01-01

    Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4+CD25+ lymphocytes caused by human T-cell lymphotropic virus type 1. Currently, there is no accepted curative therapy for ATL. In gene expression profiling, the antiapoptotic protein survivin (BIRC5) demonstrated a striking increase in ATL, and its expression was increased in patient ATL cells resistant to the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H). In this study, we investigated the antitumor activity of a small-molecule survivin suppressant YM155 alone and in combination with alemtuzumab in a murine model of human ATL (MET-1). Both YM155 alone and its combination with alemtuzumab demonstrated therapeutic efficacy by lowering serum soluble IL-2Rα (sIL-2Rα) levels (P < .001) and prolonged the survival of tumor-bearing mice (P < .0001). Moreover, the combination of YM155 with alemtuzumab demonstrated markedly additive antitumor activity by significantly lowering serum sIL-2Rα levels and improving the survival of leukemia-bearing mice compared with monotherapy with either YM155 (P < .001) or alemtuzumab (P < .05). More significantly, all mice that received the combination therapy survived and were tumor free >6 months after treatment. Our data support a clinical trial of the combination of YM155 with alemtuzumab in ATL. This trial was registered at www.clinicaltrials.gov as #NCT00061048. PMID:23321252

  2. Combination gene therapy targeting on interleukin-1β and RANKL for wear debris-induced aseptic loosening.

    PubMed

    Wang, H; Jia, T-H; Zacharias, N; Gong, W; Du, H-X; Wooley, P H; Yang, S-Y

    2013-02-01

    This study investigated the efficacy of a combination gene therapy to repress interleukin-1 (IL-1) and receptor activator of nuclear factor NF-kappa B ligand (RANKL) for the treatment of particulate debris-induced aseptic loosening, and tried to explore the molecular mechanism of the exogenous gene modifications on osteoclastogenesis. RAW cells activated by titanium particles were transduced with DFG-IL-1Ra (retroviral vector encoding IL-1 receptor antagonist) and AAV-OPG (adeno-associated viral vectors-osteoprotegerin) individually or in combination for 4 weeks. Pro-inflammatory cytokines in culture media were determined by enzyme-linked immunosorbent assay, and gene expressions of RANK, IL-1β, c-Fos, TRAF6, JNK1 and CPK were examined using real-time PCR. An established knee-implant-failure mouse model was employed to evaluate the efficacy of the in vivo double-gene therapy. The surgical implantation of a titanium alloy pin into the proximal tibia was followed by monthly challenge with titanium debris. Peri-implant gene transfers of IL-1Ra and OPG (respectively or in combination) were given 3 weeks after surgery. The combination of OPG and IL-1Ra gene transfer exhibited strong synergetic effects in blockage of inflammation and osteoclastogenesis at 8 weeks after gene modification. The combination therapy reversed peri-implant bone resorption and restored implant stability when compared with either single gene transduction. Real-time PCR data indicated that the action of IL-1Ra gene therapy may be mediated via the JNK1 pathway, while the reduction of osteoclastogenesis by OPG gene modification may be regulated by c-Fos expression. In addition, both gene modifications resulted in significant diminishment of TRAF6 expression. PMID:22318091

  3. Clinical investigation of combined therapy influence over Keratitis Herpetica Dendritica with He-Ne laser, Pandavir, and Acycovir

    NASA Astrophysics Data System (ADS)

    Koev, K.; Tanev, V.; Avramov, L.; Borisova, E.

    2007-03-01

    The main goal of this study is to investigate the treatment effect of combined therapy over Keratitis Herpetica Dendritica applying drugs Pandavir and Acycovir in combination with He-Ne laser irradiation. The current survey includes 75 patients with Keratitis Herpetica Dendritica that are divided in three groups. The first group of 25 patients is treated with Acycovir. The second group, which includes 24 patients, is treated with Pandavir and Acycovir. In the third group that consists from 26 patients, besides the abovementioned combination of drugs is applied low-level laser therapy using He-Ne laser, emitted at 632,8 nm wavelength, with power density 0,3 mW/cm2 and light exposure used - 3 minutes. The flourescein reaction was monitored every day to detect the eye recovery. We observe earliest answer reaction to the treatment applied in the group of He-Ne laser& Pandavir&Acycovir, revealing as inflammation suppression and perifocal edema disappearance in the group treated. Eyes treated only with Acycovir present mean time of improvement (MTI), as the flourescein colorization disappearance and epithelization setting in for 9,3+/-1,2 days is observed. Similar results were obtained on the eyes treated in double combination, Pandavir and Acycovir, with MTI - 8,2+/-1,1 days. The best effect was obtained by the triple combination: Pandavir, Acycovir and He-Ne laser (statistically proved), with the mean time of improvement 6,2+/-1,3 days. The combined laser treatment shows significant additional effect on the recovery rate. The combined treatment with He-Ne laser, Pandavir and Acycovir is revealed as an efficient method for eye therapy of Keratitis Herpetica Dendritica.

  4. Successful up-front combination therapy in a patient with idiopathic pulmonary hypertension and patent foramen ovale: an alternative to epoprostenol therapy?

    PubMed

    Pitsiou, Georgia G; Chavouzis, Nikolaos; Nakou, Chrysanthi; Boutou, Afroditi K; Argyropoulou, Paraskevi; Stanopoulos, Ioannis

    2009-06-01

    Pulmonary arterial hypertension (PAH) is a life-threatening disease of the pulmonary arterioles, which, in the absence of effective therapy, progresses rapidly to right heart failure and death. Opening of a patent foramen ovale (PFO) is common in patients with severe pulmonary hypertension (PH), resulting in resistive hypoxemia. We report the case of a 40-year-old woman with idiopathic pulmonary hypertension (iPAH) in New York Heart Association (NYHA) class III to IV, who was admitted in the intensive care unit with hemodynamic compromise and severe hypoxemia due to right-to-left shunt throughout a PFO. Combination therapy initially with inhaled iloprost and sildenafil, and then addition of an endothelin A receptor-selective antagonist (sitaxsentan), resulted in impressive improvement in oxygenation with reversal of the right-to-left shunt and marked improvement in functional class of the patient. PMID:19481029

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

    PubMed Central

    Lee, Deborah; Oh, Doo Jin; Kim, Jung Wook; Park, Sung Wook; Oh, Min Kyung; Sung, Ho Suk

    2008-01-01

    Background Combination therapy using cyclosporine A (CsA) together with low-dose corticosteroids has adequate efficacy with little toxicity for the treatment of severe alopecia areata (AA). Objective We wanted to evaluate the clinical efficacy of combination therapy using CsA with low-dose corticosteroid for the treatment of severe AA and we also wanted to determine the safe therapeutic concentration of CsA in the peripheral blood. Methods We treated 34 cases of severe AA with combination therapy for 24 weeks and we evaluated the efficacy at 12 and 24 weeks. We monitored the peripheral blood concentration of CsA to determine the therapeutic range of CsA that has the fewest side effects. Results Of the patients, 77.4% (n=24) and 22.6% (n=10) were classified in the responder and poor-responder groups, respectively. The mean trough concentration of CsA was 95.1 and 101.2 ng/ml in the responder and poor-responder groups, respectively. For the patients with side effects associated with CsA, the mean CsA concentration was 195.8 ng/ml. Conclusion We found that combination therapy with systemic CsA and low-dose corticosteroids effectively treats severe AA and this therapy results in a safe, therapeutic concentration of CsA in the peripheral blood. PMID:27303186

  6. Mono- and combination drug therapies in hospitalized patients with bipolar depression. Data from the European drug surveillance program AMSP

    PubMed Central

    2012-01-01

    Background For the pharmacological treatment of bipolar depression several guidelines exist. It is largely unknown, to what extent the prescriptions in daily clinical routine correspond to these evidence based recommendations and which combinations of psychotropic drugs are frequently used. Methods The prescriptions of psychotropic drugs were investigated of all in-patients with bipolar depression (n = 2246; time period 1994–2009) from hospitals participating in the drug surveillance program AMSP. For the drug use in 2010, 221 cases were analysed additionally. Results From 1994 to 2009, 85% of all patients received more than one class of psychotropic substances: 74% received antidepressants in combination therapy, 55% antipsychotics, 48% anticonvulsants and 33% lithium. When given in combination, lithium is the most often prescribed substance for bipolar depression (33%), followed by valproic acid (23%), mirtazapine and venlafaxine (16% each), quetiapine (15%), lamotrigine (14%) and olanzapine (13%). Both, lithium and valproic acid are often combined with selective serotonin reuptake inhibitors (SSRI), but also with mirtazapine und venlafaxine. Combinations of more than one antidepressant occur quite often, whereby combinations with bupropion, paroxetine, fluoxetine or fluvoxamine are very rare. In 2010, quetiapine (alone and combined) was the most frequently prescribed drug (39%); aripiprazole was administered in 10%. Conclusion Combinations of antidepressants (SSRI, mirtazapine, venlafaxine) with mood stabilizers (lithium, valproic acid, lamotrigine) and / or atypical antipsychotics (quetiapine, olanzapine) are common. Of most of those combinations the efficacy has not been studied. The use of aripiprazole and the concomitant use of two or three antidepressants contrast the guidelines. PMID:22998655

  7. Substitution of Nickel by Combined Addition of Cobalt and Zirconium in Alloy A 332

    NASA Astrophysics Data System (ADS)

    Wüstenhagen, Andreas; Tonn, Babette

    2011-01-01

    Due to the increasing international competition and the resulting pricing pressure it is imperative to avoid the use of expensive alloying elements during the production of aluminium castings. The piston alloy A 332 shows an optimum combination of mechanical and casting properties and an attractive cost-performance ratio whereas nickel is the most expensive alloying element. A substitution of nickel by a combined addition of low contents of cobalt and zirconium has the potential capacitiy to increase the mechanical properties and reduce the costs of the alloy. At Clausthal University of Technology Thermo-Calc simulations and casting experiments were carried out to investigate the effect of the nickel subtitution. Thermo-Calc-simulations were made to analyze the intermetallic phases in these alloys. These simulations were evaluated by observations under optical microscope and SEM of specimens poured into permanent moulds. The size and morphology of the intermetallic phases and the primary silicon was analyzed by the use of image analysis software. The mechanical properties of the alloys were determined by tensile tests at room temperature, 250° C and 350° C. The tensile specimens were tested in as-cast and pre-aged condition. The effect on the castability was characterized by determining the flow length and the susceptibility to form shrinkages and hot cracks. The standard alloy A 332 and the new piston alloy with cobalt and zirconium were compared. The new alloy AlSi12,6Cu1Mg1CoZr exhibits a yield strength of 115 MPa and a tensile strength of 171 MPa at 250° C in pre-aged condition (250° C/100 h). At 350° C the new alloy displays a yield strength of 57 MPa and a tensile strength of 85 MPa in pre-aged condition (350° C/100h). Compared to the reference alloy AlSi12,6Cu1Ni1Mg1 the yield strength at 250° C was improved about 25% and the yield strength at 350° C about 7%. The favorable castability of the reference alloy is not affected by the substitution of

  8. 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

  9. 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

  10. Three-Year Follow-Up of the Treatment of Obesity by Very Low Calorie Diet, Behavior Therapy, and Their Combination.

    ERIC Educational Resources Information Center

    Wadden, Thomas A.; And Others

    1988-01-01

    Treated obesity by very low calorie diet, behavior therapy, and combination. Mean weight loss for three conditions was 14.09, 14.26, and 19.25 kilograms, respectively. Three years later, and correcting for additional therapy in interim, mean weight losses for 45 of original 50 subjects declined to 2.20, 3.54, and 5.11 kilograms, respectively.…

  11. Benefits and risks of combining anti-tumor necrosis factor with immunomodulator therapy in pediatric inflammatory bowel disease.

    PubMed

    Cozijnsen, Martinus A; Escher, Johanna C; Griffiths, Anne; Turner, Dan; de Ridder, Lissy

    2015-04-01

    Since the introduction of anti-tumor necrosis factor (TNF) therapy as treatment of inflammatory bowel disease (IBD), care of pediatric and adult patients with IBD has significantly improved. To further improve treatment efficacy and durability, multiple trials have compared the efficacy of combination therapy, using anti-TNF therapy combined with an immunomodulator (a thiopurine or methotrexate), with that of anti-TNF monotherapy with contradicting results. The safety of combined therapy has been questioned after several reported cases of hepatosplenic T-cell lymphoma in young patients with IBD so treated. Physicians prescribing anti-TNF therapy to patients with IBD are required to weigh the benefits of combined therapy with its risks. To inform physicians treating children with IBD of these benefits and risks, we reviewed studies in pediatric and adult patients with IBD comparing efficacy, durability, and/or safety of combined therapy with anti-TNF monotherapy. PMID:25723615

  12. 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

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

    PubMed

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

    2015-01-01

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

  14. Exhaust emissions reduction from diesel engine using combined Annona-Eucalyptus oil blends and antioxidant additive

    NASA Astrophysics Data System (ADS)

    Senthil, R.; Silambarasan, R.; Pranesh, G.

    2016-07-01

    The limited resources, rising petroleum prices and depletion of fossil fuel have now become a matter of great concern. Hence, there is an urgent need for researchers to find some alternate fuels which are capable of substituting partly or wholly the higher demanded conventional diesel fuel. Lot of research work has been conducted on diesel engine using biodiesel and its blends with diesel as an alternate fuel. Very few works have been done with combination of biodiesel-Eucalypts oil without neat diesel and this leads to lots of scope in this area. The aim of the present study is to analyze the performance and emission characteristics of a single cylinder, direct injection, compression ignition engine using eucalyptus oil-biodiesel as fuel. The presence of eucalyptus oil in the blend reduces the viscosity and improves the volatility of the blends. The methyl ester of Annona oil is blended with eucalypts oil in 10, 20, 30, 40 and 50 %. The performance and emission characteristics are evaluated by operating the engine at different loads. The performance characteristics such as brake thermal efficiency, brake specific fuel consumption and exhaust gas temperature are evaluated. The emission constituents measured are Carbon monoxide (CO), unburned hydrocarbons (HC), Oxides of nitrogen (NOx) and Smoke. It is found that A50-Eu50 (50 Annona + 50 % Eucalyptus oil) blend showed better performance and reduction in exhaust emissions. But, it showed a very marginal increase in NOx emission when compared to that of diesel. Therefore, in order to reduce the NOx emission, antioxidant additive (A-tocopherol acetate) is mixed with Annona-Eucalyptus oil blends in various proportions by which NOx emission is reduced. Hence, A50-Eu50 blend can be used as an alternate fuel for diesel engine without any modifications.

  15. Elevated CO2 promotes long-term nitrogen accumulation only in combination with nitrogen addition.

    PubMed

    Pastore, Melissa A; Megonigal, J Patrick; Langley, J Adam

    2016-01-01

    Biogeochemical models that incorporate nitrogen (N) limitation indicate that N availability will control the magnitude of ecosystem carbon uptake in response to rising CO2 . Some models, however, suggest that elevated CO2 may promote ecosystem N accumulation, a feedback that in the long term could circumvent N limitation of the CO2 response while mitigating N pollution. We tested this prediction using a nine-year CO2 xN experiment in a tidal marsh. Although the effects of CO2 are similar between uplands and wetlands in many respects, this experiment offers a greater likelihood of detecting CO2 effects on N retention on a decadal timescale because tidal marshes have a relatively open N cycle and can accrue soil organic matter rapidly. To determine how elevated CO2 affects N dynamics, we assessed the three primary fates of N in a tidal marsh: (1) retention in plants and soil, (2) denitrification to the atmosphere, and (3) tidal export. We assessed changes in N pools and tracked the fate of a (15) N tracer added to each plot in 2006 to quantify the fraction of added N retained in vegetation and soil, and to estimate lateral N movement. Elevated CO2 alone did not increase plant N mass, soil N mass, or (15) N label retention. Unexpectedly, CO2 and N interacted such that the combined N+CO2 treatment increased ecosystem N accumulation despite the stimulation in N losses indicated by reduced (15) N label retention. These findings suggest that in N-limited ecosystems, elevated CO2 is unlikely to increase long-term N accumulation and circumvent progressive N limitation without additional N inputs, which may relieve plant-microbe competition and allow for increased plant N uptake. PMID:26577708

  16. Micafungin alone and in combination therapy with deferasirox against Pythium insidiosum.

    PubMed

    Zanette, R A; Jesus, F P K; Pilotto, M B; Weiblen, C; Pötter, L; Ferreiro, L; Alves, S H; Santurio, J M

    2015-03-01

    This study evaluated the in vitro and in vivo activity of micafungin alone and in combination with the iron chelator deferasirox against Pythium insidiosum. Micafungin showed a poor in vitro activity when it was used alone, but synergistic interactions were observed for 88.2% of the strains when the drug was combined with deferasirox. Smaller lesions were observed in infected rabbits receiving the combination therapy, although it favored disease dissemination to the lungs. The present results show that micafungin alone is ineffective against P. insidiosum, and the combination micafungin-deferasirox might have deleterious effects for the host. PMID:25459680

  17. Combining Antiangiogenic Therapy with Adoptive Cell Immunotherapy Exerts Better Antitumor Effects in Non-Small Cell Lung Cancer Models

    PubMed Central

    Shi, Shujing; Wang, Rui; Chen, Yitian; Song, Haizhu; Chen, Longbang; Huang, Guichun

    2013-01-01

    Introduction Cytokine-induced killer cells (CIK cells) are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. Methods We combined recombinant human endostatin (rh-endostatin) and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. Results Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. Conclusions Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells therapy against lung

  18. Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy

    PubMed Central

    Blanchard, Miran; Shim, Kevin G.; Grams, Michael P.; Rajani, Karishma; Diaz, Rosa M.; Furutani, Keith M.; Thompson, Jill; Olivier, Kenneth R.; Park, Sean S.; Markovic, Svetomir N.; Pandha, Hardev; Melcher, Alan; Harrington, Kevin; Zaidi, Shane; Vile, Richard

    2016-01-01

    Purpose The oligometastatic state is an intermediate state between a malignancy that can be completely eradicated with conventional modalities and one in which a palliative approach is undertaken. Clinically, high rates of local tumor control are possible with stereotactic ablative radiation therapy (SABR), using precisely targeted, high-dose, low-fraction radiation therapy. However, in oligometastatic melanoma, virtually all patients develop progression systemically at sites not initially treated with ablative radiation therapy that cannot be managed with conventional chemotherapy and immunotherapy. We have demonstrated in mice that intravenous administration of vesicular stomatitis virus (VSV) expressing defined tumor-associated antigens (TAAs) generates systemic immune responses capable of clearing established tumors. Therefore, in the present preclinical study, we tested whether the combination of systemic VSV-mediated antigen delivery and SABR would be effective against oligometastatic disease. Methods and Materials We generated a model of oligometastatic melanoma in C57BL/6 immunocompetent mice and then used a combination of SABR and systemically administered VSV-TAA viral immunotherapy to treat both local and systemic disease. Results Our data showed that SABR generates excellent control or cure of local, clinically detectable, and accessible tumor through direct cell ablation. Also, the immunotherapeutic activity of systemically administered VSV-TAA generated T-cell responses that cleared subclinical metastatic tumors. We also showed that SABR induced weak T-cell-mediated tumor responses, which, particularly if boosted by VSV−TAA, might contribute to control of local and systemic disease. In addition, VSV−TAA therapy alone had significant effects on control of both local and metastatic tumors. Conclusions We have shown in the present preliminary murine study using a single tumor model that this approach represents an effective, complementary combination

  19. Efficacy and safety of antiplatelet-combination therapy after drug-eluting stent implantation

    PubMed Central

    Cho, Yun-Kyeong; Park, Hyoung-Seob; Yoon, Hyuck-Jun; Kim, Hyungseop; Hur, Seung-Ho; Kim, Yoon-Nyun; Lee, Jang-Hoon; Yang, Dong-Heon; Lee, Bong-Ryeol; Jung, Byung-Chun; Kim, Woong; Park, Jong-Seon; Lee, Jin-Bae; Kim, Kee-Sik; Kim, Kwon-Bae

    2014-01-01

    Background/Aims Combination single-pill therapy can improve cost-effectiveness in a typical medical therapy. However, there is a little evidence about the efficacy and tolerability of combination single-pill antiplatelet therapy after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). Methods From June to November 2012, in total, 142 patients who met the following criteria were enrolled: at least 18 years old; successful PCI with DES at least 3 months earlier; and regular medication of aspirin and clopidogrel with no side effects. After VerifyNow P2Y12 and aspirin assays, the combination single pill of aspirin and clopidogrel was given and laboratory tests were repeated 6 weeks later. Results At baseline, the incidence of aspirin resistance, defined as aspirin reaction unit (ARU) ≥ 550, was 9.2%, that of clopidogrel resistance, defined as P2Y12 reaction unit (PRU) ≥ 230, was 46.5%, and that of percent inhibition of PRU < 20% was 32.4%. At follow-up, the incidence of resistance by ARU value was 7.0%, 50.0% by PRU value, and 35.9% by percentage inhibition of PRU, respectively. The mean values of ARU (431.5 ± 63.6 vs. 439.8 ± 55.2; p = 0.216) and PRU (227.5 ± 71.4 vs. 223.3 ± 76.0; p = 0.350) were not significantly different before versus after antiplatelet-combination single-pill therapy. Five adverse events (3.5%) were observed during the study period. Conclusions Combination single-pill antiplatelet therapy, which may reduce daily pill burden for patients after PCI with DES, demonstrated similar efficacy to separate dual-pill antiplatelet therapy. PMID:24648804

  20. Addition of Bevacizumab to Standard Radiation Therapy and Daily Temozolomide Is Associated With Minimal Toxicity in Newly Diagnosed Glioblastoma Multiforme

    SciTech Connect

    Vredenburgh, James J.; Desjardins, Annick; Kirkpatrick, John P.; Reardon, David A.; Peters, Katherine B.; Herndon, James E.; Marcello, Jennifer; Bailey, Leighann; Threatt, Stevie; Sampson, John; Friedman, Allan; Friedman, Henry S.

    2012-01-01

    Purpose: To determine the safety of the addition of bevacizumab to standard radiation therapy and daily temozolomide for newly diagnosed glioblastoma multiforme (GBM). Methods and Materials: A total of 125 patients with newly diagnosed GBM were enrolled in the study, and received standard radiation therapy and daily temozolomide. All patients underwent a craniotomy and were at least 2 weeks postoperative. Radiation therapy was administered in 1.8-Gy fractions, with the clinical target volume for the primary course treated to a dose of 45 to 50.4 Gy, followed by a boost of 9 to 14.4 Gy, to a total dose of 59.4 Gy. Patients received temozolomide at 75 mg/m{sup 2} daily throughout the course of radiation therapy. Bevacizumab was given at 10 mg/kg intravenously every 14 days, beginning a minimum of 4 weeks postoperatively. Results: Of the 125 patients, 120 (96%) completed the protocol-specified radiation therapy. Five patients had to stop the protocol therapy, 2 patients with pulmonary emboli, and 1 patient each with a Grade 2 central nervous system hemorrhage, Grade 4 pancytopenia, and wound dehiscence requiring surgical intervention. All 5 patients ultimately finished the radiation therapy. After radiation therapy, 3 patients had progressive disease, 2 had severe fatigue and decreased performance status, 1 patient had a colonic perforation, and 1 had a rectal fissure; these 7 patients therefore did not proceed with the protocol-specified adjuvant temozolomide, bevacizumab, and irinotecan. However, 113 patients (90%) were able to continue on study. Conclusions: The addition of bevacizumab to standard radiation therapy and daily temozolomide was found to be associated with minimal toxicity in patients newly diagnosed with GBM.

  1. Spatiotemporally photoradiation-controlled intratumoral depot for combination of brachytherapy and photodynamic therapy for solid tumor.

    PubMed

    Mukerji, Ratul; Schaal, Jeffrey; Li, Xinghai; Bhattacharyya, Jayanta; Asai, Daisuke; Zalutsky, Michael R; Chilkoti, Ashutosh; Liu, Wenge

    2016-02-01

    In an attempt to spatiotemporally control both tumor retention and the coverage of anticancer agents, we developed a photoradiation-controlled intratumoral depot (PRCITD) driven by convection enhanced delivery (CED). This intratumoral depot consists of recombinant elastin-like polypeptide (ELP) containing periodic cysteine residues and is conjugated with a photosensitizer, chlorin-e6 (Ce6) at the N-terminus of the ELP. We hypothesized that this cysteine-containing ELP (cELP) can be readily crosslinked through disulfide bonds upon exposure to oxidative agents, specifically the singlet oxygen produced during photodynamic stimulation. Upon intratumoral injection, CED drives the distribution of the soluble polypeptide freely throughout the tumor interstitium. Formation and retention of the depot was monitored using fluorescence molecular tomography imaging. When imaging shows that the polypeptide has distributed throughout the entire tumor, 660-nm light is applied externally at the tumor site. This photo-radiation wavelength excites Ce6 and generates reactive oxygen species (ROS) in the presence of oxygen. The ROS induce in situ disulfide crosslinking of the cysteine thiols, stabilizing the ELP biopolymer into a stable therapeutic depot. Our results demonstrate that this ELP design effectively forms a hydrogel both in vitro and in vivo. These depots exhibit high stability in subcutaneous tumor xenografts in nude mice and significantly improved intratumoral retention compared to controls without crosslinking, as seen by fluorescent imaging and iodine-125 radiotracer studies. The photodynamic therapy provided by the PRCITD was found to cause significant tumor inhibition in a Ce6 dose dependent manner. Additionally, the combination of PDT and intratumoral radionuclide therapy co-delivered by PRCITD provided a greater antitumor effect than either monotherapy alone. These results suggest that the PRCITD could provide a stable platform for delivering synergistic, anti

  2. A Novel Mechanism of PPAR Gamma Induction via EGFR Signalling Constitutes Rational for Combination Therapy in Bladder Cancer

    PubMed Central

    Mansure, Jose Joao; Nassim, Roland; Chevalier, Simone; Szymanski, Konrad; Rocha, Joice; Aldousari, Saad; Kassouf, Wassim

    2013-01-01

    Background Two signalling molecules that are attractive for targeted therapy are the epidermal growth factor receptor (EGFR) and the peroxisome proliferator-activated receptor gamma (PPARγ). We investigated possible crosstalk between these 2 pathways, particularly in light of the recent evidence implicating PPARγ for anticancer therapy. Principal Findings As evaluated by MTT assays, gefitinib (EGFR inhibitor) and DIM-C (PPARγ agonist) inhibited growth of 9 bladder cancer cell lines in a dose-dependent manner but with variable sensitivity. In addition, combination of gefitinib and DIM-C demonstrated maximal inhibition of cell proliferation compared to each drug alone. These findings were confirmed in vivo, where combination therapy maximally inhibited tumor growth in contrast to each treatment alone when compared to control (p<0.04). Induction of PPARγ expression along with nuclear accumulation was observed in response to increasing concentrations of gefitinib via activation of the transcription factor CCAT/enhancer-binding protein-β (CEBP-β). In these cell lines, DIM-C significantly sensitized bladder cancer cell lines that were resistant to EGFR inhibition in a schedule-specific manner. Conclusion These results suggest that PPARγ agonist DIM-C can be an excellent alternative to bladder tumors resistant to EGFR inhibition and combination efficacy might be achieved in a schedule-specific manner. PMID:23409107

  3. [Apparative aversive therapy in combination with verbal suggestions in special obsessional syndromes (initial investigation)].

    PubMed

    Dummer, W

    1977-12-01

    The author restricts the use of aversion therapy by means of deliberate production of pain to obsessional, especially therapy-resistant disturbances of a permanent nature, with consideration being, of course, given to ethical factors. Experiences worthy of generalization are derived from methodically varied courses of treatment, bringing out suggestive moments subliminally involved in any therapeutical situation and also specifically used by the therapist. In addition, the author emphasizes the need for simultaneously developing, besides aversion therapy, positive attitudes and behavior patterns. PMID:609650

  4. WS2 nanosheet as a new photosensitizer carrier for combined photodynamic and photothermal therapy of cancer cells

    NASA Astrophysics Data System (ADS)

    Yong, Yuan; Zhou, Liangjun; Gu, Zhanjun; Yan, Liang; Tian, Gan; Zheng, Xiaopeng; Liu, Xiaodong; Zhang, Xiao; Shi, Junxin; Cong, Wenshu; Yin, Wenyan; Zhao, Yuliang

    2014-08-01

    We have developed a simple and efficient strategy to fabricate WS2 nanosheets with low toxicity and good water solubility via a liquid exfoliation method by using H2SO4 intercalation and ultrasonication. The as-prepared WS2 nanosheets were employed not only as an NIR absorbing agent for photothermal therapy (PTT) but also as a photosensitizer (PS) carrier for photodynamic therapy (PDT) due to their sheet like structure that offers large surface area to load PS molecules. Moreover, singlet-oxygen generation of the PSs-WS2 complex could be finely controlled by NIR irradiation that could manipulate the PSs release behavior from WS2 nanosheets. The synergistic anti-tumor effect of WS2 nanosheets mediated PDT-PTT was also evaluated carefully and the results clearly showed that the efficacy of combined PDT-PTT treatment of cancer cells is significantly higher than those of PDT-only and PTT-only treatment, indicating enhanced efficiency of the combined therapeutic system. In addition, the WS2 could be used as a computed tomography (CT) contrast agent for bio-imaging since W atoms have strong X-ray attenuation ability, making them a multifunctional theranostic platform for simultaneous imaging-guided diagnosis and therapy.We have developed a simple and efficient strategy to fabricate WS2 nanosheets with low toxicity and good water solubility via a liquid exfoliation method by using H2SO4 intercalation and ultrasonication. The as-prepared WS2 nanosheets were employed not only as an NIR absorbing agent for photothermal therapy (PTT) but also as a photosensitizer (PS) carrier for photodynamic therapy (PDT) due to their sheet like structure that offers large surface area to load PS molecules. Moreover, singlet-oxygen generation of the PSs-WS2 complex could be finely controlled by NIR irradiation that could manipulate the PSs release behavior from WS2 nanosheets. The synergistic anti-tumor effect of WS2 nanosheets mediated PDT-PTT was also evaluated carefully and the results

  5. Combination therapies in the management of type 2 diabetes: the use of insulin degludec/liraglutide

    PubMed Central

    Minze, Molly G; Chastain, Lisa M

    2016-01-01

    The global burden of type 2 diabetes is estimated to currently affect over 350 million people worldwide and is anticipated to continue increasing over the next 20 years. Current treatment guidelines recommend the choice of pharmacotherapy based upon patient-specific parameters, with combination therapy for patients with a hemoglobin A1c level ≥9%. A new combination therapy of insulin degludec + liraglutide provides a long-acting basal insulin with a glucagon-like peptide agonist. In clinical trials, this combination product has reduced hemoglobin A1c and fasting plasma glucose more than the individual agents alone. Further advantages observed with this combination include weight loss and decrease in hypoglycemia compared to basal insulin alone. PMID:27099505

  6. [Photodynamic therapy in combined treatment of stage III non-small cell lung carcinoma].

    PubMed

    Akopov, A L; Rusanov, A A; Molodtsova, V P; Chistiakov, I V; Kazakov, N V; Urtenova, M A; Rait, Makhmud; Papaian, G V

    2013-01-01

    The aim of the study was to evaluate the effectiveness of combined treatment of locally advanced lung cancer with the use of neoadjuvant chemotherapy and surgery with the use of pre- and intraoperative photodynamic therapy. 20 patients with IIIa (n=7) and IIIb (n=13) stage of non-small cell lung carcinoma were included. At the time of diagnosis the surgical treatment was decided to abstain because of the trachea invasion in 9 patients, wide mediastinal invasion in 2 patients and contralateral mediastinal lymph nodes metastases in 2 patients; pneumonectomy was not possible due to the poor respiratory function in 7 patients. Neoadjuvant therapy included 3 courses of chemotherapy and endobronchial photodynamic therapy. During the operation, along with the lung resection (pneumonectomy - 15, lobectomy - 5), photodynamic therapy of the resection margins were carried out. No adjuvant treatment was done. Preoperative treatment led to partial regress of the disease in all cases; the goal of surgery was the complete tumor removal. No complications of the photodynamic therapy were observed. 18 surgical interventions were radical and two non-complete microscopically (R1). Postoperative morbidity was 20%, one patient died due to massive gastrointestinal bleeding. The average follow-up period was 18 months: 19 patients were alive, of them 18 with no signs of the disease recurrence. The first experience of the combined use of neoadjuvant chemotherapy and surgery with pre- and intraoperative photodynamic therapy demonstrates safety and efficacy of the suggested treatment tactics. PMID:23612332

  7. The outcome of combining home based and clinic based amblyopia therapy among preschool children.

    PubMed

    Rokiah, O; Knight, V F; Duratul, A H

    2013-06-01

    This study determined the outcome of combining home based and clinic based amblyopia therapy among preschool children. A total of 479 preschool children were randomly selected for vision screening. Amblyopic therapy was prescribed to children whose visual acuity (VA) could not be improved to <0.1 LogMAR after a 6 week adaptation period with glasses. Intensive near work activities were conducted daily at home for 12 weeks, monitored by parents while weekly therapy was conducted at the optometry clinic by an optometrist. Six preschool children were diagnosed with refractive amblyopia, spherical equivalent (SE) was -11.25D to +0.75D. Significant improvement was found in the VA of right eye, t(6) = 3.07, left eye t(6) = 3.07 and both eyes t(6) = 3.42) p<0.05, at the end of the 12 week therapy. Combining home based and clinic based amblyopia therapy among preschool children showed a positive improvement in VA after 12 weeks of therapy. PMID:23749015

  8. Stability of vitamins C and E in topical microemulsions for combined antioxidant therapy.

    PubMed

    Rozman, Branka; Gasperlin, Mirjana

    2007-04-01

    An interesting strategy for protecting skin from excessive exposure to free radicals is to support the skin endogenous antioxidant system. As the balance between different skin antioxidants is very important, a combined therapy using at least two antioxidants is desirable. In the present work, o/w, w/o, and gel-like microemulsions (ME), all composed of the same ingredients, were selected as carrier systems for dermal delivery of vitamins C and E. Gel-like ME was found to offer the best protection for both vitamins, although other ME also significantly increased their stability compared with that solution. In the presence of vitamin C no decrease in vitamin E content occurred. To obtain ME appropriate for dermal use, their viscosity was increased by adding thickening agents. On the basis of visual examination of viscosity and physical stability of thickened systems, several thickeners were selected. The addition of thickener significantly increased the viscosity of ME and changed the behavior of systems from ideal Newtonian to thixotropic. Finally, the stability of both vitamins was examined as a function of thickening agent and of the location of vitamins in the ME. The addition of thickeners changed the stability of at least one vitamin, but the systems generally still protected vitamins better than solutions. It is likely that the changes in internal organization of ME resulting from the addition of thickener, confirmed by thermal analysis and changes in solubility of oxygen in the outer phase, were the most important factors that influenced the stability of vitamins in thickened systems. PMID:17497356

  9. Combination formoterol and budesonide as maintenance and reliever therapy versus inhaled steroid maintenance for chronic asthma in adults and children

    PubMed Central

    Cates, Christopher J; Lasserson, Toby J

    2014-01-01

    Background Traditionally inhaled treatment for asthma has been considered as preventer and reliever therapy. The combination of formoterol and budesonide in a single inhaler introduces the possibility of using a single inhaler for both prevention and relief of symptoms (single inhaler therapy). Objectives The aim of this review is to compare formoterol and corticosteroid in single inhaler for maintenance and relief of symptoms with inhaled corticosteroids for maintenance and a separate reliever inhaler. Search methods We last searched the Cochrane Airways Group trials register in September 2008. Selection criteria Randomised controlled trials in adults and children with chronic asthma. Data collection and analysis Two review authors independently assessed studies for inclusion and extracted the characteristics and results of each study. Authors or manufacturers were asked to supply unpublished data in relation to primary outcomes. Main results Five studies on 5,378 adults compared single inhaler therapy with current best practice, and did not show a significant reduction in participants with exacerbations causing hospitalisation (Peto OR 0.59; 95% CI 0.24 to 1.45) or treated with oral steroids (OR 0.83; 95% CI 0.66 to 1.03). Three of these studies on 4281 adults did not show a significant reduction in time to first severe exacerbation needing medical intervention (HR 0.96; 95% CI 0.85 to 1.07). These trials demonstrated a reduction in the mean total daily dose of inhaled corticosteroids with single inhaler therapy (mean reduction ranged from 107 to 267 micrograms/day, but the trial results were not combined due to heterogeneity). The full results from four further studies on 4,600 adults comparing single inhaler therapy with current best practice are awaited. Three studies including 4,209 adults compared single inhaler therapy with higher dose budesonide maintenance and terbutaline for symptom relief. No significant reduction was found with single inhaler therapy

  10. Sitagliptin/metformin fixed-dose combination in type 2 diabetes mellitus: an evidence-based review of its place in therapy.

    PubMed

    Hayes, Jennifer; Anderson, Rosie; Stephens, Jeffrey W

    2016-01-01

    Type 2 diabetes mellitus is a progressive disease associated with significant morbidity and mortality. There is good evidence showing that intensive glycemic control reduces the development and progression of complications. In order to achieve glycemic targets, patients often require a combination of oral therapy and/or insulin in addition to lifestyle modification. Unfortunately, many of the traditional therapies for type 2 diabetes are associated with weight gain and hypoglycemia, resulting in poor compliance and subsequent worsening of glycemic control. The dipeptidyl peptidase-4 inhibitor sitagliptin is a therapy for type 2 diabetes and is available as a fixed-dose combination with metformin. Phase III clinical trials have demonstrated beneficial effects on glycemic control and minimal untoward effects with this combination. In this article, we provide an overview of the pharmacology, efficacy, and safety and examine the role of this combination within current practice. PMID:27486305

  11. Sitagliptin/metformin fixed-dose combination in type 2 diabetes mellitus: an evidence-based review of its place in therapy

    PubMed Central

    Hayes, Jennifer; Anderson, Rosie; Stephens, Jeffrey W

    2016-01-01

    Type 2 diabetes mellitus is a progressive disease associated with significant morbidity and mortality. There is good evidence showing that intensive glycemic control reduces the development and progression of complications. In order to achieve glycemic targets, patients often require a combination of oral therapy and/or insulin in addition to lifestyle modification. Unfortunately, many of the traditional therapies for type 2 diabetes are associated with weight gain and hypoglycemia, resulting in poor compliance and subsequent worsening of glycemic control. The dipeptidyl peptidase-4 inhibitor sitagliptin is a therapy for type 2 diabetes and is available as a fixed-dose combination with metformin. Phase III clinical trials have demonstrated beneficial effects on glycemic control and minimal untoward effects with this combination. In this article, we provide an overview of the pharmacology, efficacy, and safety and examine the role of this combination within current practice. PMID:27486305

  12. Newcastle disease virus, rituximab, and doxorubicin combination as anti-hematological malignancy therapy

    PubMed Central

    Al-Shammari, Ahmed Majeed; Rameez, Huda; Al-Taee, Maha F

    2016-01-01

    Hematological malignancies are important diseases that need more powerful therapeutics. Even with current targeting therapies, such as rituximab and other chemotherapeutic agents, there is a need to develop new treatment strategies. Combination therapy seems the best option to target the tumor cells by different mechanisms. Virotherapy is a very promising treatment modality, as it is selective, safe, and causes cancer destruction. The Iraqi strain of Newcastle disease virus (NDV) has proved to be effective both in vitro and in vivo. In the current work, we tested its ability on anti-hematological tumors and enhanced current treatments with combination therapy, and studied this combination using Chou–Talalay analysis. p53 concentration was measured to evaluate the mechanism of this proposed synergism. The results showed that NDV was synergistic with doxorubicin in low doses on plasmacytoma cells, with no involvement of p53 pathways, but involved p53 when the combination was used on non-Hodgkin lymphoma cells. NDV in combination with rituximab showed enhanced cytotoxicity that was p53-independent. In conclusion, this work proposes a novel combination modality for treatment of some hematological malignancies. PMID:27579294

  13. Newcastle disease virus, rituximab, and doxorubicin combination as anti-hematological malignancy therapy.

    PubMed

    Al-Shammari, Ahmed Majeed; Rameez, Huda; Al-Taee, Maha F

    2016-01-01

    Hematological malignancies are important diseases that need more powerful therapeutics. Even with current targeting therapies, such as rituximab and other chemotherapeutic agents, there is a need to develop new treatment strategies. Combination therapy seems the best option to target the tumor cells by different mechanisms. Virotherapy is a very promising treatment modality, as it is selective, safe, and causes cancer destruction. The Iraqi strain of Newcastle disease virus (NDV) has proved to be effective both in vitro and in vivo. In the current work, we tested its ability on anti-hematological tumors and enhanced current treatments with combination therapy, and studied this combination using Chou-Talalay analysis. p53 concentration was measured to evaluate the mechanism of this proposed synergism. The results showed that NDV was synergistic with doxorubicin in low doses on plasmacytoma cells, with no involvement of p53 pathways, but involved p53 when the combination was used on non-Hodgkin lymphoma cells. NDV in combination with rituximab showed enhanced cytotoxicity that was p53-independent. In conclusion, this work proposes a novel combination modality for treatment of some hematological malignancies. PMID:27579294

  14. [Combined radiation therapy and androgen deprivation in the management of prostate cancer: Where do we stand?].

    PubMed

    Bellefqih, S; Hadadi, K; Mezouri, I; Maghous, A; Marnouche, E; Andaloussi, K; Elmarjany, M; Sifat, H; Mansouri, H; Benjaafar, N

    2016-04-01

    Radiotherapy and androgen deprivation therapy play a major role in the management of prostate cancer. Indeed, radiotherapy and hormone therapy are combined in a neoadjuvant and concomitant setting for intermediate risk cancers but also in an adjuvant setting in high risk or locally advanced prostate cancer. The benefice of this association was suggested by preclinical studies and demonstrated later by several randomized trials. However, as these trials were conducted before the era of dose escalation the role of androgen deprivation therapy in this case is less clear. Moreover, as hormonal therapy can lead to a significant morbidity and a decrement in quality of life its indications must be carefully weighed especially in case of intermediate risk cancer witch represent a heterogeneous group with distinct prognostic subgroups. PMID:26969245

  15. Clinical efficacy of the Nd:YAG laser for combination periodontitis therapy.

    PubMed

    Neill, M E; Mellonig, J T

    1997-08-01

    Recent results of a limited clinical trial suggest that mechanical root scaling and root planing therapy alone may not be the most effective mode of treatment for patients affected by moderate to severe adult periodontitis. However, scaling and planing combined with laser therapy utilizing a low-powered pulsed Nd:YAG laser have been shown to be successful in the elimination of the bacteria commonly associated with the development of this oral condition. The double-blind, split mouth design study involved 10 human subjects randomly assigned to one of three treatments: 1) scaling and root planing alone, 2) dental laser plus scaling and root planing, and 3) control only. This article presents the clinical results of the trial, which suggest that laser therapy is a viable adjunct to local, nonsurgical therapy such as scaling and planing. PMID:9573831

  16. 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

  17. Internal ribosome entry site-based vectors for combined gene therapy

    PubMed Central

    Renaud-Gabardos, Edith; Hantelys, Fransky; Morfoisse, Florent; Chaufour, Xavier; Garmy-Susini, Barbara; Prats, Anne-Catherine

    2015-01-01

    Gene therapy appears as a promising strategy to treat incurable diseases. In particular, combined gene therapy has shown improved therapeutic efficiency. Internal ribosome entry sites (IRESs), RNA elements naturally present in the 5’ untranslated regions of a few mRNAs, constitute a powerful tool to co-express several genes of interest. IRESs are translational enhancers allowing the translational machinery to start protein synthesis by internal initiation. This feature allowed the design of multi-cistronic vectors expressing several genes from a single mRNA. IRESs exhibit tissue specificity, and drive translation in stress conditions when the global cell translation is blocked, which renders them useful for gene transfer in hypoxic conditions occurring in ischemic diseases and cancer. IRES-based viral and non viral vectors have been used successfully in preclinical and clinical assays of combined gene therapy and resulted in therapeutic benefits for various pathologies including cancers, cardiovascular diseases and degenerative diseases. PMID:25699230

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

    PubMed

    Shin, Yoon-Kyum; Cho, Sung-Rae

    2016-01-01

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

  19. 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…

  20. 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...

  1. Use of combined liothyronine and thyroxine therapy for consumptive hypothyroidism associated with hepatic haemangiomas in infancy.

    PubMed

    Peters, Catherine; Langham, Shirley; Mullis, Primus E; Dattani, Mehul T

    2010-01-01

    Hepatic haemiangiomas in infancy are rare. An association with hypothyroidism has been previously reported and is believed to be secondary to the conversion of thyroxine (fT4) to biologically inactive reverse triiodothyronine (rT3) by type 3 iodothyronine deiodinase (D3). We report a case that responded well to the combined use of liothyronine and thyroxine therapy. PMID:20516650

  2. [Postoperatively conformed effectiveness of preoperative radio therapy, combined with chemotherapy - cysplatin].

    PubMed

    Lazarov, N; Lazarov, L; Lazarov, S

    2012-01-01

    The authors present a case of a 35 years old female patient with spinocellular carcinoma of the cervix, diagnosed after byopsy and treated with radiotherapy 30 Gray, combined with Cisplatin 50 mg. per square meter, per week, 6 months before radical histerectomy and lymphonodulectomy was performed. The postoperative histology shows only traces of dysplastic epithelia, which proves preoperative therapy effective. PMID:22639781

  3. 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.

  4. 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

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

    PubMed

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

    2015-07-15

    Millions of persons every year are affected by traumatic brain injury (TBI), and currently no therapies have shown efficacy in improving outcomes clinically. Recent research has suggested that enriched environments (EE), embryonic neural stem cells (eNSC), and progesterone (PROG) improve functional outcomes after TBI, and further, several investigators have suggested that a polytherapuetic approach may have greater efficacy than a single therapy. The purpose of the current study was to determine if varying combinations of post-injury EE, progesterone therapy, or eNSC transplantation would improve functional outcomes over just a single therapy. A controlled cortical impact was performed in rats to create a lesion in the medial frontal cortex. The rats were then placed in either EE or standard environments and administered 10 mg/kg progesterone or vehicle injections 4 h post-injury and every 12 h for 72 h after the initial injection. Seven days after the surgery, rats were transplanted with either eNSCs or media. Rats were then tested on the open field test, Barnes maze, Morris water maze, and Rotor-Rod tasks. Improved functional outcomes were shown on a majority of the behavioral tasks in animals that received a combination of therapies. This effect was especially prominent with therapies that were combined with EE. Immunohistochemistry showed that the transplanted eNSCs survived, migrated, and displayed neural phenotypes. These data suggest that a poly-therapeutic approach after TBI improves functional recovery to a greater magnitude. Moreover, when polytherapies are combined with EE, the effects on recovery are enhanced, leading to greater recovery of function. PMID:25268854

  6. Combined Nurr1 and Foxa2 roles in the therapy of Parkinson's disease

    PubMed Central

    Oh, Sang-Min; Chang, Mi-Yoon; Song, Jae-Jin; Rhee, Yong-Hee; Joe, Eun-Hye; Lee, Hyun-Seob; Yi, Sang-Hoon; Lee, Sang-Hun

    2015-01-01

    Use of the physiological mechanisms promoting midbrain DA (mDA) neuron survival seems an appropriate option for developing treatments for Parkinson's disease (PD). mDA neurons are specifically marked by expression of the transcription factors Nurr1 and Foxa2. We show herein that Nurr1 and Foxa2 interact to protect mDA neurons against various toxic insults, but their expression is lost during aging and degenerative processes. In addition to their proposed cell-autonomous actions in mDA neurons, forced expression of these factors in neighboring glia synergistically protects degenerating mDA neurons in a paracrine mode. As a consequence of these bimodal actions, adeno-associated virus (AAV)-mediated gene delivery of Nurr1 and Foxa2 in a PD mouse model markedly protected mDA neurons and motor behaviors associated with nigrostriatal DA neurotransmission. The effects of the combined gene delivery were dramatic, highly reproducible, and sustained for at least 1 year, suggesting that expression of these factors is a promising approach in PD therapy. PMID:25759364

  7. Primaquine plus artemisinin combination therapy for reduction of malaria transmission: promise and risk.

    PubMed

    John, Chandy C

    2016-01-01

    Reduction of gametocyte transmission from humans to mosquitoes is a key component of malaria elimination. The study by Gonçalves and colleagues provides valuable new data on how the addition of low-dose primaquine to artemether-lumefantrine affects reduction of gametocytemia and transmission of gametocytes to mosquitoes in asymptomatically Plasmodium falciparum-infected children without G6PD deficiency, and on the degree to which low-dose primaquine affects hemoglobin levels in these children. The study sets the stage for future research required for consideration of an artemisinin combination therapy (ACT)-primaquine regimen in mass drug administration campaigns. Future studies will need to evaluate toxicity in adults and G6PD deficient persons, assess gametocyte transmission from adults, evaluate different ACT drugs with primaquine, and assess the implications of "rare" toxicities in large treatment populations, such as hemolysis requiring blood transfusion. The study highlights both the promise and the potential risk of ACT-primaquine treatment in malaria elimination campaigns.Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0581-y . PMID:27039396

  8. Efficacy and Safety Assessment of the Addition of Bevacizumab to Adjuvant Therapy Agents in Cancer Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Ahmadizar, Fariba; Onland-Moret, N. Charlotte; de Boer, Anthonius; Liu, Geoffrey; Maitland-van der Zee, Anke H.

    2015-01-01

    Aim To evaluate the efficacy and safety of bevacizumab in the adjuvant cancer therapy setting within different subset of patients. Methods & Design/ Results PubMed, EMBASE, Cochrane and Clinical trials.gov databases were searched for English language studies of randomized controlled trials comparing bevacizumab and adjuvant therapy with adjuvant therapy alone published from January 1966 to 7th of May 2014. Progression free survival, overall survival, overall response rate, safety and quality of life were analyzed using random- or fixed-effects models according to the PRISMA guidelines. We obtained data from 44 randomized controlled trials (30,828 patients). Combining bevacizumab with different adjuvant therapies resulted in significant improvement of progression free survival (log hazard ratio, 0.87; 95% confidence interval (CI), 0.84–0.89), overall survival (log hazard ratio, 0.96; 95% CI, 0.94–0.98) and overall response rate (relative risk, 1.46; 95% CI: 1.33–1.59) compared to adjuvant therapy alone in all studied tumor types. In subgroup analyses, there were no interactions of bevacizumab with baseline characteristics on progression free survival and overall survival, while overall response rate was influenced by tumor type and bevacizumab dose (p-value: 0.02). Although bevacizumab use resulted in additional expected adverse drug reactions except anemia and fatigue, it was not associated with a significant decline in quality of life. There was a trend towards a higher risk of several side effects in patients treated by high-dose bevacizumab compared to the low-dose e.g. all grade proteinuria (9.24; 95% CI: 6.60–12.94 vs. 2.64; 95% CI: 1.29–5.40). Conclusions Combining bevacizumab with different adjuvant therapies provides a survival benefit across all major subsets of patients, including by tumor type, type of adjuvant therapy, and duration and dose of bevacizumab therapy. Though bevacizumab was associated with increased risks of some adverse drug

  9. Recent advances in COPD disease management with fixed-dose long-acting combination therapies.

    PubMed

    Bateman, Eric D; Mahler, Donald A; Vogelmeier, Claus F; Wedzicha, Jadwiga A; Patalano, Francesco; Banerji, Donald

    2014-06-01

    Combinations of two long-acting bronchodilators and long-acting bronchodilators with inhaled corticosteroids (ICS) are recommended therapies in the management of chronic obstructive pulmonary disease (COPD). Three fixed-dose combination products have recently been approved for the treatment of COPD (the long-acting β2-agonist plus long-acting muscarinic antagonist [LABA/LAMA] combinations glycopyrronium/indacaterol [QVA149] and umeclidinium/vilanterol, and the LABA/ICS fluticasone furoate/vilanterol), with others currently in late-stage development. LABA/LAMA and LABA/ICS combination therapies demonstrate positive effects on both lung function and patient-reported outcomes, with significant improvements observed with LABA/LAMA combinations compared with placebo, each component alone and other comparators in current use. No new safety concerns have been observed with combinations of long-acting bronchodilators. Combinations of two long-acting bronchodilators represent a new and convenient treatment option in COPD. This review summarizes published efficacy and safety data from clinical trials of both LABA/LAMA and novel LABA/ICS combinations in patients with COPD. PMID:24802656

  10. Step-down therapy in well-controlled asthmatic patients using salmeterol xinafoate/fluticasone propionate combination therapy

    PubMed Central

    Horiuchi, Kazuya; Kasahara, Keita; Kuroda, Yusuke; Morohoshi, Haruna; Hagiwara, Yosuke; Ishii, Gen

    2016-01-01

    Purpose A combination therapy with inhaled corticosteroid (ICS) and a long-acting β agonist (LABA) is the standard treatment for asthmatic patients, and step-down treatment is recommended once control has been achieved. However, little data exist that evaluate the long-term outcomes after step-down treatment. Objective To compare the long-term outcomes of step-down therapy with ICS/LABA or ICS alone for asthmatic patients who have achieved well-controlled asthma by the ICS (250 µg fluticasone)/LABA (50 µg salmeterol) combination (SFC, two puffs per day). Patients and methods We randomized 40 well-controlled patients with asthma receiving SFC (250 µg) to two groups; one group of patients received step-down therapy with low-dose SFC (100 µg, two puffs daily) and another group of patients received step-down therapy with high-dose fluticasone propionate (FP) alone (500 µg, daily). The two groups were monitored over 12 months for changes in asthma control test scores, respiratory function (percent forced expiratory volume in 1 second, maximal expiratory flow rate at 50% of the vital capacity [%FEF50], and maximal expiratory flow rate at 25% of the vital capacity [%FEF25]), and the concentration of fractional exhaled nitric oxide. Results There was no significant difference in the dropout rate between the SFC and FP groups. Low-dose SFC maintained the stability of all parameters over 12 months, whereas the FP group exhibited a rapid 5% decrease in forced expiratory volume in 1 second within 2 months after discontinuation of salmeterol; furthermore, after 10 months, there was a gradual decrease in %FEF50 and %FEF25. Conclusion This study suggests that a balanced step-down protocol, including both ICS and LABA, is essential in providing long-term stability to patients with mild-to-moderate well-controlled asthma. PMID:27051309

  11. Ranibizumab in monotherapy and combined with photodynamic therapy for retinal angiomatous proliferation

    PubMed Central

    Arias, Luis; Gómez-Ulla, Francisco; Ruiz-Moreno, José M

    2016-01-01

    Purpose To compare the effects of intravitreal ranibizumab in monotherapy (group A) and combined with photodynamic therapy (PDT) with verteporfin (group B) in retinal angiomatous proliferation (RAP) treatment. Methods This was a multicentric, prospective, randomized clinical study conducted with parallel groups. The study eye in both groups received ranibizumab on days 1, 30, and 60 (loading dose); group B received PDT additionally on day 1. Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) testing and optical coherence tomography were performed monthly, and fluorescein angiography and indocyanine green angiography were performed quarterly. Retreatment criteria were leakage in fluorescein angiography or indocyanine green angiography, mean foveal thickness increase ≥100 µm, or VA decrease ≥5 letters. Results Twenty patients were recruited (ten patients in each group). Six eyes had previous treatment (three eyes in group A and three eyes in group B), so only 14 eyes were naïve. At 12-month follow-up, mean VA improved +1.5 letters in group A and +5.6 letters in group B (analysis of variance test; P>0.05). Two patients (20%) in both groups gained ≥15 letters (chi-square test; P>0.05). Mean changes in greatest linear dimension and in foveal thickness were not statistically significant between groups of treatment (analysis of variance test; P>0.05). Mean retreatments per patient were 1.8 (group A) and 0.9 (group B) (Mann–Whitney U-test; P>0.05). One patient died due to underlying disease not related to study medication. Conclusion Intravitreal ranibizumab administered in monotherapy or combined with PDT was efficacious in terms of VA stabilization in patients with RAP. PMID:27274190

  12. Graphitic carbon nitride nanosheet@metal-organic framework core-shell nanoparticles for photo-chemo combination therapy

    NASA Astrophysics Data System (ADS)

    Chen, Rui; Zhang, Jinfeng; Wang, Yu; Chen, Xianfeng; Zapien, J. Antonio; Lee, Chun-Sing

    2015-10-01

    Recently, nanoscale metal-organic frameworks (NMOFs) have started to be developed as a promising platform for bioimaging and drug delivery. On the other hand, combination therapies using multiple approaches are demonstrated to achieve much enhanced efficacy. Herein, we report, for the first time, core-shell nanoparticles consisting of a photodynamic therapeutic (PDT) agent and a MOF shell while simultaneously carrying a chemotherapeutic drug for effective combination therapy. In this work, core-shell nanoparticles of zeolitic-imadazolate framework-8 (ZIF-8) as shell embedded with graphitic carbon nitride (g-C3N4) nanosheets as core are fabricated by growing ZIF-8 in the presence of g-C3N4 nanosheets. Doxorubicin hydrochloride (DOX) is then loaded into the ZIF-8 shell of the core-shell nanoparticles. The combination of the chemotherapeutic effects of DOX and the PDT effect of g-C3N4 nanosheets can lead to considerably enhanced efficacy. Furthermore, the red fluorescence of DOX and the blue fluorescence of g-C3N4 nanosheets provide the additional function of dual-color imaging for monitoring the drug release process.Recently, nanoscale metal-organic frameworks (NMOFs) have started to be developed as a promising platform for bioimaging and drug delivery. On the other hand, combination therapies using multiple approaches are demonstrated to achieve much enhanced efficacy. Herein, we report, for the first time, core-shell nanoparticles consisting of a photodynamic therapeutic (PDT) agent and a MOF shell while simultaneously carrying a chemotherapeutic drug for effective combination therapy. In this work, core-shell nanoparticles of zeolitic-imadazolate framework-8 (ZIF-8) as shell embedded with graphitic carbon nitride (g-C3N4) nanosheets as core are fabricated by growing ZIF-8 in the presence of g-C3N4 nanosheets. Doxorubicin hydrochloride (DOX) is then loaded into the ZIF-8 shell of the core-shell nanoparticles. The combination of the chemotherapeutic effects of DOX

  13. Hyperactivity--Drug Therapy/Food Additives/Allergies. A Selective Bibliography. Exceptional Child Bibliography Series No. 602.

    ERIC Educational Resources Information Center

    ERIC Clearinghouse on Handicapped and Gifted Children, Reston, VA.

    The annotated bibliography on Hyperactivity--Drug Therapy/Food Additives/Allergies contains approximately 65 abstracts and associated indexing information for documents or journal articles published from 1968 to 1975 and selected from the computer files of the Council for Exceptional Children's Information Services and the Education Resources…

  14. Nanotechnology-based combination therapy improves treatment response in cancer models

    NASA Astrophysics Data System (ADS)

    Rai, Prakash; Chang, Sung K.; Mai, Zhiming; Neuman, Daniel; Hasan, Tayyaba

    2009-06-01

    Pancreatic cancer (PanCa) has a poor prognosis with a 5-year survival rate of only 5%. Photodynamic therapy (PDT) has shown promising results in treating PanCa. Mechanism-based combinations with PDT have enhanced treatment outcome. Agents tested with PDT include Avastin, an antibody against vascular endothelial growth factor (VEGF) which is approved for treating various cancers. Simultaneous delivery of drugs in nano-constructs could improve the treatment response of mechanism based combination therapies. Here, we investigate the effect of neutralizing VEGF using nanotechnology for the delivery of Avastin in combination with PDT. For this we used a construct called "nanocells" in which the photosensitizer was trapped inside polymer nanoparticles and these, with Avastin, were then encapsulated inside liposomes. In vitro, nanocells containing Avastin (NCA) significantly enhanced cytotoxicity in PanCa cells. NCA based PDT also significantly improved treatment response in mice that were orthotopically implanted with PanCa. Avastin delivered extracellularly in combination with PDT did not show any improvement. Here we propose a new paradigm for Avastin-based therapy by combining intracellular delivery of the antibody and PDT using nanotechnology for treating PanCa.

  15. Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer

    PubMed Central

    Chow, L W-C; Xu, B; Gupta, S; Freyman, A; Zhao, Y; Abbas, R; Vo Van, M-L; Bondarenko, I

    2013-01-01

    Introduction: Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours. Methods: This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer. Results: Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m−2 on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1–147.3 weeks). Common treatment-emergent adverse events (all grades/grade ⩾3) included diarrhoea (92%/29% none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9–81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan–Meier median progression-free survival was 57

  16. Combination of anti-VEGF therapy and temozolomide in two experimental human glioma models.

    PubMed

    Grossman, Rachel; Brastianos, Harry; Blakeley, Jaishri O; Mangraviti, Antonella; Lal, Bachchu; Zadnik, Patti; Hwang, Lee; Wicks, Robert T; Goodwin, Rory C; Brem, Henry; Tyler, Betty

    2014-01-01

    Anti-angiogenic agents, such as bevacizumab (BEV), can induce normalization of the blood brain barrier, which may influence the penetration and activity of a co-administered cytotoxic drug. However, it is unknown whether this effect is associated with a benefit in overall survival. This study employed intracranial human glioma models to evaluate the effect of BEV alone and in combination with temozolomide (TMZ) and/or radiation therapy (XRT) on overall survival. One hundred eight male athymic rats were intracranially injected with either U251 or U87 human glioma. Ten or eleven days after tumor inoculation, animals bearing U251 and U87, respectively, were treated with: TMZ alone (50 mg/kg for 5 consecutive days, P.O.), BEV alone (15 mg/kg, I.V.), a combination of TMZ and BEV, or a combination of TMZ, BEV, and a single fraction of XRT (20 Gy). Controls received no treatment. The U87 experiment was repeated and the relationship between survival and the extent of anti-angiogenesis via anti-laminin antibodies for the detection of blood vessels was assessed. In both U87 glioma experiments, all of the treatment groups had a statistically significant increase in survival as compared to the control groups. Also, for both U87 experiments the combination groups of TMZ and BEV had significantly better survival when compared to either treatment administered alone, with 75% of animals demonstrating long-term survival (LTS) (defined as animals alive 120 days after tumor implantation) in one experiment and 25% LTS in the repeat experiment. In the U251 glioma experiment, all treated groups (except BEV alone) had significantly improved survival as compared to controls with minimal statistical variance among groups. The percent vessel area was lowest in the group of animals treated with BEV alone. The addition of BEV to TMZ and/or XRT had variable effect on prolonging survival in the two human glioma models tested with reduced tumor vascularity in groups treated with BEV. These

  17. Effects of candesartan and propranolol combination therapy versus propranolol monotherapy in reducing portal hypertension

    PubMed Central

    Kim, Jae Hyun; Kim, Jung Min; Cho, Youn Zoo; Na, Ji Hoon; Kim, Hyun Sik; Kim, Hyoun A; Kang, Hye Won; Baik, Soon Koo; Kwon, Sang Ok; Cha, Seung Hwan; Kim, Young Ju

    2014-01-01

    Background/Aims Angiotensin receptor blockers (ARBs) inhibit activated hepatic stellate cell contraction and are thought to reduce the dynamic portion of intrahepatic resistance. This study compared the effects of combined treatment using the ARB candesartan and propranolol versus propranolol monotherapy on portal pressure in patients with cirrhosis in a prospective, randomized controlled trial. Methods Between January 2008 and July 2009, 53 cirrhotic patients with clinically significant portal hypertension were randomized to receive either candesartan and propranolol combination therapy (26 patients) or propranolol monotherapy (27 patients). Before and 3 months after the administration of the planned medication, the hepatic venous pressure gradient (HVPG) was assessed in both groups. The dose of propranolol was subsequently increased from 20 mg bid until the target heart rate was reached, and the candesartan dose was fixed at 8 mg qd. The primary endpoint was the HVPG response rate; patients with an HVPG reduction of >20% of the baseline value or to <12 mmHg were defined as responders. Results The mean portal pressure declined significantly in both groups, from 16 mmHg (range, 12-28 mmHg) to 13.5 mmHg (range, 6-20 mmHg) in the combination group (P<0.05), and from 17 mmHg (range, 12-27 mmHg) to 14 mmHg (range, 7-25 mmHg) in the propranolol monotherapy group (P<0.05). However, the medication-induced pressure reduction did not differ significantly between the two groups [3.5 mmHg (range, -3-11 mmHg) vs. 3 mmHg (range, -8-10 mmHg), P=0.674]. The response rate (55.6% vs. 61.5%, P=0.435) and the reductions in mean blood pressure or heart rate also did not differ significantly between the combination and monotherapy groups. Conclusions The addition of candesartan (an ARB) to propranolol confers no benefit relative to classical propranolol monotherapy for the treatment of portal hypertension, and is thus not recommended. PMID:25548744

  18. MEK inhibitors and their potential in the treatment of advanced melanoma: the advantages of combination therapy

    PubMed Central

    Tran, Khiem A; Cheng, Michelle Y; Mitra, Anupam; Ogawa, Hiromi; Shi, Vivian Y; Olney, Laura P; Kloxin, April M; Maverakis, Emanual

    2016-01-01

    The treatment of melanoma has improved markedly over the last several years with the advent of more targeted therapies. Unfortunately, complex compensation mechanisms, such as those of the mitogen-activated protein kinase (MAPK) pathway, have limited the clinical benefit of these treatments. Recently, a better understanding of melanoma resistance mechanisms has given way to intelligently designed multidrug regimes. Herein, we review the extensive pathways of BRAF inhibitor (vemurafenib and dabrafenib) resistance. We also review the advantages of dual therapy, including the addition of an MEK inhibitor (cobimetinib or trametinib), which has proven to increase progression-free survival when compared to BRAF inhibitor monotherapy. Finally, this review touches on future treatment strategies that are being developed for advanced melanoma, including the possibility of triple therapy with immune checkpoint inhibitors and the work on optimizing sequential therapy. PMID:26730180

  19. Combination therapy for portopulmonary hypertension with intravenous iloprost and oral bosentan.

    PubMed

    Halank, Michael; Kolditz, Martin; Miehlke, Stephan; Schiemanck, Steffen; Schmeisser, Alexander; Hoeffken, Gert

    2005-08-01

    Severe portopulmonary hypertension (PPHTN) is a rare complication of liver cirrhosis and carries a poor prognosis. In the last years, intravenous (IV) epoprostenol has been suggested to be the optimal medical treatment for PPHTN, and recently oral bosentan has been shown to be efficacious and safe in selected patients with PPHTN. We report a case of PPHTN suffering from recurrent right heart failure while on treatment with IV iloprost, which was successfully managed by combination therapy with IV iloprost plus oral bosentan, providing sustained cardiopulmonary stabilization for at least two years. This report documents the first case of a patient with PPHTN successfully treated with the combination of IV iloprost and oral bosentan over an extended period. Thus, combination therapy with IV iloprost and oral bosentan might be a promising new option for selected patients suffering from PPHTN and recurrent right heart failure. PMID:16160926

  20. Colistin combination therapy improves microbiologic cure in critically ill patients with multi-drug resistant gram-negative pneumonia.

    PubMed

    Parchem, N L; Bauer, K A; Cook, C H; Mangino, J E; Jones, C D; Porter, K; Murphy, C V

    2016-09-01

    Currently, in vitro synergy with colistin has not translated into improved clinical outcomes. This study aimed to compare colistin combination therapy to colistin monotherapy in critically ill patients with multi-drug resistant gram-negative (MDR-GN) pneumonia. This was a retrospective analysis of critically ill adult patients receiving intravenous colistin for MDR-GN pneumonia comparing colistin combination therapy to colistin monotherapy with a primary endpoint of clinical cure. Combination therapy was defined by administration of another antibiotic to which the MDR-GN pathogen was reported as susceptible or intermediate. Ninety patients were included for evaluation (41 combination therapy and 49 monotherapy). Baseline characteristics were similar between groups. No difference in clinical cure was observed between combination therapy and monotherapy in univariate analysis, nor when adjusted for APACHE II score and time to appropriate antibiotic therapy (57.1 vs. 63.4 %, adjusted OR 1.15, p = 0.78). Microbiological cure was significantly higher for combination therapy (87 vs. 35.5 %, p < 0.001). Colistin combination therapy was associated with a significant improvement in microbiological cure, without improvement in clinical cure. Based on the in vitro synergy and improvement in microbiological clearance, colistin combination therapy should be prescribed for MDR-GN pneumonia. Further research is warranted to determine if in vitro synergy with colistin translates into improved clinical outcomes. PMID:27230510

  1. Combining Dopaminergic Facilitation with Robot-Assisted Upper Limb Therapy in Stroke Survivors: A Focused Review.

    PubMed

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

    2016-06-01

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

  2. 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

  3. Addition of clidinium-C to the 14-day proton-pump inhibitor-based triple therapy for Helicobacter pylori eradication

    PubMed Central

    Seyyedmajidi, Mohammadreza; Homapoor, Saba; Zanganeh, Elahe; Dadjou, Mohammad; Eskandari Nejad, Shahab; Tajik Galayeri, Mohammad Hadi; Vafaeimanesh, Jamshid

    2016-01-01

    Background: Triple therapy with a proton pump inhibitor and two antibiotics in Helicobacter pylori (HP) eradication is widely accepted, but this combination fails in a considerable number of cases. The aim of this study was to assess the effect of clidinium-C addition on HP eradication and to investigate the efficacy and safety of clidinium-C in prevention of drugs' side effects. Methods: A total of 200 histopathologically confirmed HP positive peptic ulcer enrolled in this study which were randomly assigned to two treatment groups: OAC (20 mg omeprazole bid, 1000 mg amoxicillin bid and 500 mg clarithromycin bid) and OAC + clidinium-C. The effect of treatment and adverse effects were compared 6 weeks after completion of treatment. A13C-urea breath test was performed to confirm HP eradication. Results: A total of 184 patients (90 in group A and 94 in group B) completed the treatment protocols. HP eradication was achieved in 71.1% in OAC versus 72.3% in OCA+clidinium-C, (P=0.73). The frequencies of abdominal pain and stool abnormality, among the side effects recorded during the therapy period, were significantly lower in group B (OCA+clidinium-C) (P=0.01 and P=0.001, respectively). Conclusion: Addition of clidinium-C to OCA triple therapy decreases abdominal pain and frequency of stool abnormalities without affecting HP eradication rate. Based on these findings addition of clidinium-C may increase patient's compliance. PMID:27386057

  4. Options for empagliflozin in combination therapy in type 2 diabetes mellitus

    PubMed Central

    Hershon, Kenneth S

    2016-01-01

    Objective To update clinicians with an overview of empagliflozin for the treatment of type 2 diabetes mellitus (T2DM), with focus on use in combination regimens. Methods Keyword searches were conducted in the Medline database to identify literature reporting clinical trials of at least 12 weeks’ duration using empagliflozin treatment in patients with T2DM. Results When given as monotherapy or in combination therapy (as add-on or single-pill therapy) with metformin, pioglitazone, sulfonylurea, linagliptin, and insulin, empagliflozin produced clinically meaningful reductions in glycated hemoglobin levels, plasma glucose concentrations, bodyweight, and blood pressure. These changes were sustained during long-term treatment. In a dedicated cardiovascular event trial, empagliflozin on top of standard of care demonstrated a significant reduction in the risk of cardiovascular mortality and all-cause mortality. Across the clinical trials, empagliflozin combination therapies were well tolerated, and empagliflozin used alone was not associated with increased risk of hypoglycemia versus placebo. Indeed, the combination of empagliflozin and metformin had a significantly reduced rate of hypoglycemia compared with the combination of metformin and a sulfonylurea. On the other hand, empagliflozin treatment did have increased risk of genital infections compared with placebo. In clinical trials to date, diabetic ketoacidosis was not seen more frequently with empagliflozin than with placebo, but physicians should be alert to the possibility of this rare event. Conclusion Empagliflozin has the potential to make an important contribution to the treatment of patients with T2DM. In some patients, empagliflozin may be used as monotherapy, but it is most likely to be used in combination with other therapies. Given the reduced risk of mortality seen when empagliflozin was added to standard care in patients at high cardiovascular risk, as well as the lack of alternative options for

  5. Initial combination therapy for type 2 diabetes mellitus: is it ready for prime time?

    PubMed

    Zinman, Bernard

    2011-01-01

    The increased prevalence of type 2 diabetes mellitus is primarily being driven by the increasing global rates of overweight/obesity. Given the magnitude of this epidemic, we can expect these metabolic abnormalities to play an increasing role in the development of cardiovascular disease. In a pathophysiologic sense, type 2 diabetes is a multiorgan, multifactorial condition, characterized by β-cell dysfunction, insulin resistance in peripheral tissues and the liver, defective incretin activity, and elevated levels of free fatty acids and proinflammatory mediators. Despite the considerable burden of disease associated with type 2 diabetes, most patients are not at, or are unable to achieve, recommended glycemic control guideline targets. In part, this is because of the relentlessly progressive nature of the disease, but it may also be attributable to the current diabetes treatment paradigm, which is characterized by ineffective lifestyle interventions, followed by monotherapy and frequent early treatment failure with prolonged periods of elevated glucose as a consequence of clinical inertia. Thus, it is most appropriate to rethink the current treatment paradigm for type 2 diabetes in the context of a more aggressive initial therapy; specifically with early initiation of combination therapy. Our current understanding of the complex pathophysiology of the disease and the progressive deterioration in glycemic control over time supports the philosophy of earlier intervention with a more comprehensive initial therapy. Thus, while control of hyperglycemia remains the paramount goal, focusing on the underlying pathophysiology of type 2 diabetes is increasingly becoming the therapeutic strategy, with the aim of potentially providing disease modification. Although this is a logical approach, it remains to be demonstrated that early combination therapy will result in disease modification in a clinical setting. Not surprisingly, the incretin-based therapies have gained a great

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

    PubMed

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

    2016-01-01

    Tinnitus is a phantom perception of sound in the absence of overt acoustic stimulation. The focus of our attention is a combined therapy of tinnitus. In this prospective study (2013-2014) we evaluated the data of normal-hearing patients with tinnitus treated with various treatment modalities. In Group 1 we evaluated the data of 84 patients/124 ears after six weeks of treatment with betahistine dihydrochloride (72 mg). In Group 2, we evaluated the data of 36 patients/ 55 ears unimproved from Group 1 who were then treated for six weeks with hyperbaric oxygen (HBO₂) therapy combined with gingko biloba extract (120 mg). In Group 1, tinnitus disappeared in 9.7%, alleviated in 18.5% and improved overall in 28.2%. Average intensity of tinnitus before/after treatment was 37 decibels (dB)/33 dB. Tinnitus intensities after treatment are statistically significantly lower (p = 0.001) than the values before treatment. In Group 2 tinnitus disappeared in 5.4%, 36.4% achieved alleviation, and 41.8% showed overall improvement. The average intensity of tinnitus before/after treatment was 41dB/ 38dB. The values of tinnitus intensity after combined therapy are statistically significantly lower (p = 0.046). We have shown that both methods treatment of tinnitus are statistically significant. HBO₂therapy was recommended for the general public. PMID:27416687

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

    PubMed Central

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

    2016-01-01

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

  8. Dynamics of tumor growth and combination of anti-angiogenic and cytotoxic therapies

    NASA Astrophysics Data System (ADS)

    Kohandel, M.; Kardar, M.; Milosevic, M.; Sivaloganathan, S.

    2007-07-01

    Tumors cannot grow beyond a certain size (about 1-2 mm in diameter) through simple diffusion of oxygen and other essential nutrients into the tumor. Angiogenesis, the formation of blood vessels from pre-existing vessels, is a crucial and observed step, through which a tumor obtains its own blood supply. Thus, strategies that interfere with the development of this tumor vasculature, known as anti-angiogenic therapy, represent a novel approach to controlling tumor growth. Several pre-clinical studies have suggested that currently available angiogenesis inhibitors are unlikely to yield significant sustained improvements in tumor control on their own, but rather will need to be used in combination with conventional treatments to achieve maximal benefit. Optimal sequencing of anti-angiogenic treatment and radiotherapy or chemotherapy is essential to the success of these combined treatment strategies. Hence, a major challenge to mathematical modeling and computer simulations is to find appropriate dosages, schedules and sequencing of combination therapies to control or eliminate tumor growth. Here, we present a mathematical model that incorporates tumor cells and the vascular network, as well as their interplay. We can then include the effects of two different treatments, conventional cytotoxic therapy and anti-angiogenic therapy. The results are compared with available experimental and clinical data.

  9. HSP90 Inhibitor Encapsulated Photo-Theranostic Nanoparticles for Synergistic Combination Cancer Therapy

    PubMed Central

    Lin, Tzu-yin; Guo, Wenchang; Long, Qilai; Ma, Aihong; Liu, Qiangqiang; Zhang, Hongyong; Huang, Yee; Chandrasekaran, Siddarth; Pan, Chongxian; Lam, Kit S.; Li, Yuanpei

    2016-01-01

    Photodynamic therapy (PDT) is a promising non-invasive therapeutic modality that has been proposed for treating prostate cancer, but the procedure is associated with limited efficacy, tumor recurrence and photo-toxicity. In the present study, we proposed to develop a novel multifunctional nano-platform for targeted delivery of heat, reactive oxygen species (ROS) and heat shock protein 90 (Hsp90) inhibitor simultaneously for combination therapy against prostate cancer. This new nano-platform combines two newly developed entities: 1) a unique organic and biocompatible nanoporphyrin-based drug delivery system that can generate efficient heat and ROS simultaneously with light activation at the tumor sites for dual-modal photothermal- and photodynamic- therapy (PTT/PDT), and 2) new nano-formulations of Hsp90 inhibitors that can decrease the levels of pro-survival and angiogenic signaling molecules induced by phototherapy, therefore, further sensitizing cancer cells to phototherapy. Furthermore, the nanoparticles have activatable near infrared (NIR) fluorescence for optical imaging to conveniently monitor the real-time drug delivery in both subcutaneous and orthotopic mouse models bearing prostate cancer xenograft. This novel multifunctional nano-platform has great potential to improve the care of prostate cancer patients through targeted combination therapy. PMID:27375782

  10. Anti-CD3/Anti-CXCL10 Antibody Combination Therapy Induces a Persistent Remission of Type 1 Diabetes in Two Mouse Models.

    PubMed

    Lasch, Stanley; Müller, Peter; Bayer, Monika; Pfeilschifter, Josef M; Luster, Andrew D; Hintermann, Edith; Christen, Urs

    2015-12-01

    Anti-CD3 therapy of type 1 diabetes results in a temporary halt of its pathogenesis but does not constitute a permanent cure. One problem is the reinfiltration of islets of Langerhans with regenerated, autoaggressive lymphocytes. We aimed at blocking such a reentry by neutralizing the key chemokine CXCL10. Combination therapy of diabetic RIP-LCMV and NOD mice with anti-CD3 and anti-CXCL10 antibodies caused a substantial remission of diabetes and was superior to monotherapy with anti-CD3 or anti-CXCL10 alone. The combination therapy prevented islet-specific T cells from reentering the islets of Langerhans and thereby blocked the autodestructive process. In addition, the local immune balance in the pancreas was shifted toward a regulatory phenotype. A sequential temporal inactivation of T cells and blockade of T-cell migration might constitute a novel therapy for patients with type 1 diabetes. PMID:26293506

  11. Incremental Cost-effectiveness of Combined Therapy vs Medication Only for Youth With Selective Serotonin Reuptake Inhibitor–Resistant Depression

    PubMed Central

    Lynch, Frances L.; Dickerson, John F.; Clarke, Greg; Vitiello, Benedetto; Porta, Giovanna; Wagner, Karen D.; Emslie, Graham; Asarnow, Joan Rosenbaum; Keller, Martin B.; Birmaher, Boris; Ryan, Neal D.; Kennard, Betsy; Mayes, Taryn; DeBar, Lynn; McCracken, James T.; Strober, Michael; Suddath, Robert L.; Spirito, Anthony; Onorato, Matthew; Zelazny, Jamie; Iyengar, Satish; Brent, David

    2013-01-01

    Context Many youth with depression do not respond to initial treatment with selective serotonin reuptake inhibitors (SSRIs), and this is associated with higher costs. More effective treatment for these youth may be cost-effective. Objective To evaluate the incremental cost-effectiveness over 24 weeks of combined cognitive behavior therapy plus switch to a different antidepressant medication vs medication switch only in adolescents who continued to have depression despite adequate initial treatment with an SSRI. Design Randomized controlled trial. Setting Six US academic and community clinics. Patients Three hundred thirty-four patients aged 12 to 18 years with SSRI-resistant depression. Intervention Participants were randomly assigned to (1) switch to a different medication only or (2) switch to a different medication plus cognitive behavior therapy. Main Outcome Measures Clinical outcomes were depression-free days (DFDs), depression-improvement days (DIDs), and quality-adjusted life-years based on DFDs (DFD-QALYs). Costs of intervention, nonprotocol services, and families were included. Results Combined treatment achieved 8.3 additional DFDs (P=.03), 0.020 more DFD-QALYs (P=.03), and 11.0 more DIDs (P=.04). Combined therapy cost $1633 more (P=.01). Cost per DFD was $188 (incremental cost-effectiveness ratio [ICER]=$188; 95% confidence interval [CI], −$22 to $1613), $142 per DID (ICER=$142; 95% CI, −$14 to $2529), and $78 948 per DFD-QALY (ICER=$78 948; 95% CI, −$9261 to $677 448). Cost-effectiveness acceptability curve analyses suggest a 61% probability that combined treatment is more cost-effective at a willingness to pay $100 000 per QALY. Combined treatment had a higher net benefit for subgroups of youth without a history of abuse, with lower levels of hopelessness, and with comorbid conditions. Conclusions For youth with SSRI-resistant depression, combined treatment decreases the number of days with depression and is more costly. Depending on a decision

  12. Combination of Aflibercept and Bromfenac Therapy in Age-Related Macular Degeneration: A Pilot Study Aflibercept and Bromfenac in AMD

    PubMed Central

    Wyględowska-Promieńska, Dorota; Piotrowska-Gwóźdź, Anna; Piotrowska-Seweryn, Agnieszka; Mazur-Piotrowska, Grażyna

    2015-01-01

    Background Among many protocols for treatment of exudative AMD, combined therapy of anti-VEGF agents and non-steroidal anti-inflammatory drugs (NSAIDs) seems to be an ideal alternative to monotherapy based on ranibizumab or bevacizumab. The aim of this study was to evaluate the effectiveness of aflibercept and bromfenac in the treatment of exudative AMD. Material/Methods The study was conducted on a group of 27 patients with exudative AMD who were administered intravitreal aflibercept and topical bromfenac (study group) once a month. Additional injections were administered up to 3 months after the third administration, depending on response to treatment. The control group consisted of subjects treated with aflibercept only. Visual acuity and anatomical outcomes in optical coherence tomography (OCT) were assessed at baseline visit, 4 months after the first dose, and 6 months after the start of the treatment. Results Visual acuity improved over time in the study group and the differences between the groups were statistically significant. No statistically significant differences were found in OCT parameters. Conclusions Combined therapy of aflibercept and bromfenac in the treatment of wet AMD is more effective than single aflibercept therapy. PMID:26667262

  13. Generalized Granuloma Annulare Treated with Monthly Rifampicin, Ofloxacin, and Minocycline Combination Therapy

    PubMed Central

    Garg, Shilpa; Baveja, Sukriti

    2013-01-01

    Granuloma annulare (GA) is a disease characterized by granulomatous inflammation of the dermis. A variant form of the disease, generalized granuloma annulare (GGA), can be observed in 15% of affected patients. Localized GA is likely to resolve spontaneously within months or a few years, whereas GGA can persist for decades. There are various therapies for treating GGA. Monthly combination therapy of rifampicin 600 mg, ofloxacin 400 mg, and minocycline 100 mg (ROM) is used for treating paucibacillary leprosy which shares both clinical and histopathologic similarities with GA. Therefore, we decided to evaluate the possible efficacy of monthly ROM in a patient with GGA. PMID:23723470

  14. CD20-targeting in B-cell malignancies: novel prospects for antibodies and combination therapies.

    PubMed

    Safdari, Yaghoub; Ahmadzadeh, Vahideh; Farajnia, Safar

    2016-08-01

    Expression of CD20 antigen by the most of transformed B cells is believed to be the driving force for targeting this molecule by using anti-CD20 monoclonal antibodies. While it is true that most lymphoma/leukemia patients can be cured, these regimens are limited by the emergence of treatment resistance. Based on these observations, development of anti-CD20 monoclonal antibodies and combination therapies have been recently proposed, in particular with the aim to optimize the cytotoxic activity. Here we outline a range of new experimental agents concerning the CD20 positive B-cell tumors which provide high benefit from conventional therapy. PMID:27075017

  15. 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

  16. Berberine in Combination with Insulin Has Additive Effects on Titanium Implants Osseointegration in Diabetes Mellitus Rats

    PubMed Central

    Lu, Li; Zhijian, Huang; Lei, Li; Wenchuan, Chen; Zhimin, Zhu

    2015-01-01

    This study evaluated the effects of berberine in combination with insulin on early osseointegration of implants in diabetic rats. Fifty male Sprague-Dawley rats were randomly divided into 5 groups: healthy rats were used as control (HC), and streptozotocin-induced diabetic rats were treated with insulin, berberine, berberine + insulin (IB), or no treatment. Each rat received one machined-surface cp-Ti implant into the right tibia and was given insulin injection and/or gavage feeding with berberine daily for 8 weeks until being sacrificed. Serum levels of alkaline phosphatase (ALP) and bone gamma-carboxyglutamic acid-containing protein (BGP) were analyzed in each group. Peri-implant mineral apposition was marked by fluorochrome double-labeling and osseointegration was histomorphologically examined. The ALP and BGP levels decreased in diabetic rats but were successfully corrected by insulin and berberine combined treatment. Moreover, untreated diabetic rats had less labeled mineral apposition and impaired osseointegration. In contrast, Groups I, B, and IB were observed with increased peri-implant bone formation. The combination treatment of insulin and berberine was more effective than each administrated as a monotherapy. These results suggest that berberine combined with insulin could promote osseointegration in diabetic rats, thereby highlighting its potential application to patients, though further studies are needed. PMID:26783411

  17. Additive Antinociceptive Effects of a Combination of Vitamin C and Vitamin E after Peripheral Nerve Injury

    PubMed Central

    Lu, Ruirui; Kallenborn-Gerhardt, Wiebke; Geisslinger, Gerd; Schmidtko, Achim

    2011-01-01

    Accumulating evidence indicates that increased generation of reactive oxygen species (ROS) contributes to the development of exaggerated pain hypersensitivity during persistent pain. In the present study, we investigated the antinociceptive efficacy of the antioxidants vitamin C and vitamin E in mouse models of inflammatory and neuropathic pain. We show that systemic administration of a combination of vitamins C and E inhibited the early behavioral responses to formalin injection and the neuropathic pain behavior after peripheral nerve injury, but not the inflammatory pain behavior induced by Complete Freund's Adjuvant. In contrast, vitamin C or vitamin E given alone failed to affect the nociceptive behavior in all tested models. The attenuated neuropathic pain behavior induced by the vitamin C and E combination was paralleled by a reduced p38 phosphorylation in the spinal cord and in dorsal root ganglia, and was also observed after intrathecal injection of the vitamins. Moreover, the vitamin C and E combination ameliorated the allodynia induced by an intrathecally delivered ROS donor. Our results suggest that administration of vitamins C and E in combination may exert synergistic antinociceptive effects, and further indicate that ROS essentially contribute to nociceptive processing in special pain states. PMID:22195029

  18. Genotype-Selective Combination Therapies for Melanoma Identified by High Throughput Drug Screening

    PubMed Central

    Held, Matthew A.; Langdon, Casey G.; Platt, James T.; Graham-Steed, Tisheeka; Liu, Zongzhi; Chakraborty, Ashok; Bacchiocchi, Antonella; Koo, Andrew; Bosenberg, Marcus W.; Stern, David F.

    2012-01-01

    Resistance and partial responses to targeted monotherapy are major obstacles in cancer treatment. Systematic approaches to identify efficacious drug combinations for cancer are not well established, especially in the context of genotype. To address this, we have tested pairwise combinations of an array of small molecule inhibitors on early passage melanoma cultures using combinatorial drug screening. Results reveal several inhibitor combinations effective for melanomas with activating RAS or BRAF mutations, including mutant BRAF melanomas with intrinsic or acquired resistance to vemurafenib. Inhibition of both EGFR and AKT sensitized treatment-resistant BRAF-mutant melanoma cultures to vemurafenib. Melanomas with RAS mutations were more resistant to combination therapies relative to BRAF mutants, but were sensitive to combinations of statins and cyclin-dependent kinase inhibitors in vitro and in vivo. These results demonstrate the utility of combinatorial drug screening for discovering unique treatment regimens that overcome resistance phenotypes of mutant BRAF and RAS driven melanomas. PMID:23239741

  19. Radiobiological Optimization of Combination Radiopharmaceutical Therapy Applied to Myeloablative Treatment of Non-Hodgkin’s Lymphoma

    PubMed Central

    Hobbs, Robert F; Wahl, Richard L; Frey, Eric C; Kasamon, Yvette; Song, Hong; Huang, Peng; Jones, Richard J; Sgouros, George

    2014-01-01

    Combination treatment is a hallmark of cancer therapy. Although the rationale for combination radiopharmaceutical therapy was described in the mid ‘90s, such treatment strategies have only been implemented clinically recently, and without a rigorous methodology for treatment optimization. Radiobiological and quantitative imaging-based dosimetry tools are now available that enable rational implementation of combined targeted radiopharmaceutical therapy. Optimal implementation should simultaneously account for radiobiological normal organ tolerance while optimizing the ratio of two different radiopharmaceuticals required to maximize tumor control. We have developed such a methodology and applied it to hypothetical myeloablative treatment of non-hodgkin’s lymphoma (NHL) patients using 131I-tositumomab and 90Y-ibritumomab tiuxetan. Methods The range of potential administered activities (AA) is limited by the normal organ maximum tolerated biologic effective doses (MTBEDs) arising from the combined radiopharmaceuticals. Dose limiting normal organs are expected to be the lungs for 131I-tositumomab and the liver for 90Y-ibritumomab tiuxetan in myeloablative NHL treatment regimens. By plotting the limiting normal organ constraints as a function of the AAs and calculating tumor biological effective dose (BED) along the normal organ MTBED limits, the optimal combination of activities is obtained. The model was tested using previously acquired patient normal organ and tumor kinetic data and MTBED values taken from the literature. Results The average AA values based solely on normal organ constraints was (19.0 ± 8.2) GBq with a range of 3.9 – 36.9 GBq for 131I-tositumomab, and (2.77 ± 1.64) GBq with a range of 0.42 – 7.54 GBq for 90Y-ibritumomab tiuxetan. Tumor BED optimization results were calculated and plotted as a function of AA for 5 different cases, established using patient normal organ kinetics for the two radiopharmaceuticals. Results included AA ranges

  20. Preliminary In Vivo Evaluation of a Hybrid Armored Vascular Graft Combining Electrospinning and Additive Manufacturing Techniques

    PubMed Central

    Spadaccio, Cristiano; Nappi, Francesco; De Marco, Federico; Sedati, Pietro; Sutherland, Fraser W.H.; Chello, Massimo; Trombetta, Marcella; Rainer, Alberto

    2016-01-01

    In this study, we tested in vivo effectiveness of a previously developed poly-l-lactide/poly-ε-caprolactone armored vascular graft releasing heparin. This bioprosthesis was designed in order to overcome the main drawbacks of tissue-engineered vascular grafts, mainly concerning poor mechanical properties, thrombogenicity, and endothelialization. The bioprosthesis was successfully implanted in an aortic vascular reconstruction model in rabbits. All grafts implanted were patent at four weeks postoperatively and have been adequately populated by endogenous cells without signs of thrombosis or structural failure and with no need of antiplatelet therapy. The results of this preliminary study might warrant for further larger controlled in vivo studies to further confirm these findings. PMID:26949333

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

    PubMed Central

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

    2014-01-01

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

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

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen

    2000-06-01

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

  3. Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance

    PubMed Central

    Khdair, Ayman; Chen, Di; Patil, Yogesh; Ma, Linan; Dou, Q. Ping; Shekhar, Malathy P.V.; Panyam, Jayanth

    2013-01-01

    Tumor drug resistance significantly limits the success of chemotherapy in the clinic. Tumor cells utilize multiple mechanisms to prevent the accumulation of anticancer drugs at their intracellular site of action. In this study, we investigated the anticancer efficacy of doxorubicin in combination with photodynamic therapy using methylene blue in a drug-resistant mouse tumor model. Surfactant-polymer hybrid nanoparticles formulated using an anionic surfactant, Aerosol-OT™ (AOT), and a naturally occurring polysaccharide polymer, sodium alginate, were used for synchronized delivery of the two drugs. Balb/c mice bearing syngeneic JC tumors (mammary adenocarcinoma) were used as a drug-resistant tumor model. Nanoparticle-mediated combination therapy significantly inhibited tumor growth and improved animal survival. Nanoparticle-mediated combination treatment resulted in enhanced tumor accumulation of both doxorubicin and methylene blue, significant inhibition of tumor cell proliferation, and increased induction of apoptosis. These data suggest that nanoparticle-mediated combination chemotherapy and photodynamic therapy using doxorubicin and methylene blue has significant therapeutic potential against drug-resistant tumors. PMID:19751777

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

    PubMed

    Bukowska, Barbara; Rogalska, Aneta; Marczak, Agnieszka

    2016-04-15

    Despite more modern therapeutics approaches and the use of new drugs for chemotherapy, patients with ovarian cancer still have poor prognosis and therefore, new strategies for its cure are highly needed. One of the promising ways is combined therapy, which has many advantages as minimizing drug resistance, enhancing efficacy of treatment, and reducing toxicity. Combined therapy has rich and successful history in the field of ovarian cancer treatment. Currently use therapy is usually based on platinum-containing agent (carboplatin or cisplatin) and a member of taxanes (paclitaxel or docetaxel). In the mid-2000s this standard regimen has been expanded with bevacizumab, monoclonal antibody directed to Vascular Endothelial Growth Factor (VEGF). Another drug combination with promising perspectives is WP 631 given together with epothilone B (Epo B). WP 631 is a bisanthracycline composed of two molecules of daunorubicin linked with a p-xylenyl linker. Epo B is a 16-membered macrolide manifesting similar mechanism of action to taxanes. Their effectiveness against ovarian cancer as single agents is well established. However, the combination of WP 631 and Epo B appeared to act synergistically, meaning that it is much more potent than the single drugs. The mechanism lying under its efficacy includes disturbing essential cell cycle-regulating proteins leading to mitotic slippage and following apoptosis, as well as affecting EpCAM and HMGB1 expression. In this article, we summarized the current state of knowledge regarding combined therapy based on WP 631 and Epo B as a potential way of ovarian cancer treatment. PMID:26944437

  5. 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

  6. Cost-Effectiveness Analysis of Combination Therapies for Visceral Leishmaniasis in the Indian Subcontinent

    PubMed Central

    Meheus, Filip; Balasegaram, Manica; Olliaro, Piero; Sundar, Shyam; Rijal, Suman; Faiz, Md. Abul; Boelaert, Marleen

    2010-01-01

    Background Visceral leishmaniasis is a systemic parasitic disease that is fatal unless treated. We assessed the cost and cost-effectiveness of alternative strategies for the treatment of visceral leishmaniasis in the Indian subcontinent. In particular we examined whether combination therapies are a cost-effective alternative compared to monotherapies. Methods and Findings We assessed the cost-effectiveness of all possible mono- and combination therapies for the treatment of visceral leishmaniasis in the Indian subcontinent (India, Nepal and Bangladesh) from a societal perspective using a decision analytical model based on a decision tree. Primary data collected in each country was combined with data from the literature and an expert poll (Delphi method). The cost per patient treated and average and incremental cost-effectiveness ratios expressed as cost per death averted were calculated. Extensive sensitivity analysis was done to evaluate the robustness of our estimations and conclusions. With a cost of US$92 per death averted, the combination miltefosine-paromomycin was the most cost-effective treatment strategy. The next best alternative was a combination of liposomal amphotericin B with paromomycin with an incremental cost-effectiveness of $652 per death averted. All other strategies were dominated with the exception of a single dose of 10mg per kg of liposomal amphotericin B. While strategies based on liposomal amphotericin B (AmBisome) were found to be the most effective, its current drug cost of US$20 per vial resulted in a higher average cost-effectiveness. Sensitivity analysis showed the conclusion to be robust to variations in the input parameters over their plausible range. Conclusions Combination treatments are a cost-effective alternative to current monotherapy for VL. Given their expected impact on the emergence of drug resistance, a switch to combination therapy should be considered once final results from clinical trials are available. PMID:20838649

  7. Fixed-dose combination therapy with dutasteride and tamsulosin in the management of benign prostatic hyperplasia.

    PubMed

    Dimitropoulos, Konstantinos; Gravas, Stavros

    2016-02-01

    Despite their multifactorial etiology, male lower urinary tract symptoms (LUTS) have been traditionally associated with benign prostatic enlargement (BPE) because of benign prostatic hyperplasia (BPH). Several pharmaceutical therapies have been used to manage LUTS, with α1-adrenergic receptor antagonists (α1-blockers) and inhibitors of 5α-reductase (5α-RIs) representing the most commonly prescribed agents currently in use for LUTS treatment. Due to their different modes of action, combined use of α1-blockers and 5α-RIs has been proven to offer more optimal control of symptoms and better associated quality of life, even though higher rates of adverse events have been shown. Following previous studies on the separate administration of dutasteride and tamsulosin, a fixed-dose combination capsule of tamsulosin 0.4 mg and dutasteride 0.5 mg has been approved and released for clinical use in men with BPH. The present review aims to discuss the rationale behind the combined use of tamsulosin and dutasteride for treating male LUTS, and to present the available data on the role of combination therapy in the management of BPH-related symptoms in terms of efficacy and safety. Special attention is given to the impact of combination treatment on the prevention of clinical progression of BPH. Cost-effectiveness of fixed-dose combination and patients' adherence to treatment are also discussed. PMID:26834837

  8. Fixed-dose combination therapy with dutasteride and tamsulosin in the management of benign prostatic hyperplasia

    PubMed Central

    Dimitropoulos, Konstantinos; Gravas, Stavros

    2016-01-01

    Despite their multifactorial etiology, male lower urinary tract symptoms (LUTS) have been traditionally associated with benign prostatic enlargement (BPE) because of benign prostatic hyperplasia (BPH). Several pharmaceutical therapies have been used to manage LUTS, with α1-adrenergic receptor antagonists (α1-blockers) and inhibitors of 5α-reductase (5α-RIs) representing the most commonly prescribed agents currently in use for LUTS treatment. Due to their different modes of action, combined use of α1-blockers and 5α-RIs has been proven to offer more optimal control of symptoms and better associated quality of life, even though higher rates of adverse events have been shown. Following previous studies on the separate administration of dutasteride and tamsulosin, a fixed-dose combination capsule of tamsulosin 0.4 mg and dutasteride 0.5 mg has been approved and released for clinical use in men with BPH. The present review aims to discuss the rationale behind the combined use of tamsulosin and dutasteride for treating male LUTS, and to present the available data on the role of combination therapy in the management of BPH-related symptoms in terms of efficacy and safety. Special attention is given to the impact of combination treatment on the prevention of clinical progression of BPH. Cost-effectiveness of fixed-dose combination and patients’ adherence to treatment are also discussed. PMID:26834837

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

    PubMed

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

    2014-01-01

    SUMMARY Eradikacion therapy at patients with chronic pancreatitis and combined with Helicobacter associated erosive gastropathy in a month after treatment appeared successful at 75% patients which accepted therapy of the first line--pantoprazol, amoksicillin, klaritromicin. Inclusion in antihelicobakter therapy of seknidazol in place of klaritromicin rendered a positive antihelicobakter effect at 85% patients with a chronic pancreatitis. Therapy with the use of seknidazole was better tolerated. Application of synbiotik laktiale on a background antihelicobakter therapy helped normalizations of chair and was comfortable in application, which is important in the treatment of patients. Application of synbiotika laktiale on a background antigelikobakter therapy is helped in the improvement of clinical effect. PMID:25796863

  10. Combination therapy with monoamine oxidase inhibitors and other antidepressants or stimulants: strategies for the management of treatment-resistant depression.

    PubMed

    Thomas, Samantha J; Shin, Mirae; McInnis, Melvin G; Bostwick, Jolene R

    2015-04-01

    combination treatment certainly exist with selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, or clomipramine, the current literature supports cautious use of combining MAOIs with other antidepressants in patients with TRD who have failed multiple treatment modalities. In addition, the data from the 29 patients receiving combination therapy with an MAOI and another antidepressant or stimulant medication revealed that 21% improved significantly, with no complications. This case series and literature review suggest that when used under close supervision and under the care of an experienced clinician in psychiatry, combination therapy may be a consideration for the management of TRD in patients not responding to monotherapy or other combinations of antidepressants. PMID:25884531

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

    PubMed Central

    El-Azizi, Mohamed

    2016-01-01

    An in vitro microdilution method was developed to assess double and triple combinations of antibiotics. Five antibiotics including ciprofloxacin, amikacin, ceftazidime, piperacillin, and imipenem were tested against 10 clinical isolates of Pseudomonas aeruginosa. Each isolate was tested against ten double and nine triple combinations of the antibiotics. A 96-well plate was used to test three antibiotics, each one alone and in double and triple combinations against each isolate. The minimum bacteriostatic and bactericidal concentrations in combination were determined with respect to the most potent antibiotic. An Interaction Code (IC) was generated for each combination, where a numerical value was designated based on the 2-fold increase or decrease in the MICs with respect to the most potent antibiotic. The results of the combinations were verified by time-kill assay at constant concentrations of the antibiotics and in a chemostat. Only 13% of the double combinations were synergistic, whereas 5% showed antagonism. Forty-three percent of the triple combinations were synergistic with no antagonism observed, and 100% synergism was observed in combination of ciprofloxacin, amikacin, and ceftazidime. The presented protocol is simple and fast and can help the clinicians in the early selection of the effective antibiotic therapy for treatment of severe infections. PMID:27195009

  12. Choroidal Neovascularization Associated with Punctate Inner Choroidopathy: Combination of Intravitreal Anti-VEGF and Systemic Immunosuppressive Therapy

    PubMed Central

    Hohberger, Bettina; Rudolph, Michael; Bergua, Antonio

    2015-01-01

    Purpose Choroidal neovascularization (CNV) associated with punctate inner choroidopathy (PIC) is a rare clinical entity, yet still a challenge for medical treatment. A case of a young myopic woman developing CNV secondary to unilateral PIC is presented. Clinical morphology, diagnostic procedure and follow-up are reported. Case Report A 29-year-old woman presented with multiple yellowish dots at the posterior pole. No other signs of inflammation could be seen. Angiography with fluorescein yielded hyperfluorescent signals in the affected areas with a diffuse leak, and SD-OCT showed a slightly elevated retinal pigment epithelial layer, consistent with the diagnosis of PIC. Additionally a classic CNV was observed. Results Anti-inflammatory therapy with local prednisolone acetate eye drops in combination with intravitreal injection of anti-vascular endothelial growth factor (VEGF, bevacizumab) yielded an increased best-corrected visual acuity. As CNV reappeared, systemic medication with prednisone and azathioprine in combination with two further intravitreal injections of anti-VEGF stabilized CNV and increased visual acuity again. Conclusion Combined therapy of immunosuppression with intravitreal anti-VEGF injections can be considered as therapeutic strategy in the management of recurrent CNV associated with PIC. PMID:26955337

  13. 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.

  14. "Smart" nickel oxide based core-shell nanoparticles for combined chemo and photodynamic cancer therapy.

    PubMed

    Bano, Shazia; Nazir, Samina; Munir, Saeeda; AlAjmi, Mohamed Fahad; Afzal, Muhammad; Mazhar, Kehkashan

    2016-01-01

    We report "smart" nickel oxide nanoparticles (NOPs) as multimodal cancer therapy agent. Water-dispersible and light-sensitive NiO core was synthesized with folic acid (FA) connected bovine serum albumin (BSA) shell on entrapped doxorubicin (DOX). The entrapped drug from NOP-DOX@BSA-FA was released in a sustained way (64 hours, pH=5.5, dark conditions) while a robust release was found under red light exposure (in 1/2 hour under λmax=655 nm, 50 mW/cm(2), at pH=5.5). The cell viability, thiobarbituric acid reactive substances and diphenylisobenzofuran assays conducted under light and dark conditions revealed a high photodynamic therapy potential of our construct. Furthermore, we found that the combined effect of DOX and NOPs from NOP-DOX@BSA-FA resulted in cell death approximately eightfold high compared to free DOX. We propose that NOP-DOX@BSA-FA is a potential photodynamic therapy agent and a collective drug delivery system for the systemic administration of cancer chemotherapeutics resulting in combination therapy. PMID:27471383

  15. 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

  16. Effect of hyperbaric oxygen therapy combined with autologous platelet concentrate applied in rabbit fibula fraction healing

    PubMed Central

    Neves, Paulo César Fagundes; de Campos Vieira Abib, Simone; Neves, Rogério Fagundes; Pircchio, Oronzo; Saad, Karen Ruggeri; Saad, Paulo Fernandes; Simões, Ricardo Santos; Moreira, Marcia Bento; de Souza Laurino, Cristiano Frota

    2013-01-01

    OBJECTIVES: The purpose is to study the effects of hyperbaric oxygen therapy and autologous platelet concentrates in healing the fibula bone of rabbits after induced fractures. METHODS: A total of 128 male New Zealand albino rabbits, between 6–8 months old, were subjected to a total osteotomy of the proximal portion of the right fibula. After surgery, the animals were divided into four groups (n = 32 each): control group, in which animals were subjected to osteotomy; autologous platelet concentrate group, in which animals were subjected to osteotomy and autologous platelet concentrate applied at the fracture site; hyperbaric oxygen group, in which animals were subjected to osteotomy and 9 consecutive daily hyperbaric oxygen therapy sessions; and autologous platelet concentrate and hyperbaric oxygen group, in which animals were subjected to osteotomy, autologous platelet concentrate applied at the fracture site, and 9 consecutive daily hyperbaric oxygen therapy sessions. Each group was divided into 4 subgroups according to a pre-determined euthanasia time points: 2, 4, 6, and 8 weeks postoperative. After euthanasia at a specific time point, the fibula containing the osseous callus was prepared histologically and stained with hematoxylin and eosin or picrosirius red. RESULTS: Autologous platelet concentrates and hyperbaric oxygen therapy, applied together or separately, increased the rate of bone healing compared with the control group. CONCLUSION: Hyperbaric oxygen therapy and autologous platelet concentrate combined increased the rate of bone healing in this experimental model. PMID:24141841

  17. Mediated Moderation in Combined Cognitive Behavioral Therapy Versus Component Treatments for Generalized Anxiety Disorder

    PubMed Central

    Newman, Michelle G.; Fisher, Aaron J.

    2015-01-01

    Objective This study examined (a) duration of generalized anxiety disorder (GAD) as a moderator of cognitive behavioral therapy (CBT) versus its components (cognitive therapy and self-control desensitization) and (b) increases in dynamic flexibility of anxious symptoms during the course of psychotherapy as a mediator of this moderation. Degree of dynamic flexibility in daily symptoms was quantified as the inverse of spectral power due to daily to intradaily oscillations in four-times-daily diary data (Fisher, Newman, & Molenaar, 2011). Method This was a secondary analysis of the data of Borkovec, Newman, Pincus, and Lytle (2002). Seventy-six participants with a principle diagnosis of GAD were assigned randomly to combined CBT (n = 24), cognitive therapy (n = 25), or self-control desensitization (n = 27). Results Duration of GAD moderated outcome such that those with longer duration showed greater reliable change from component treatments than they showed from CBT, whereas those with shorter duration fared better in response to CBT. Decreasing predictability in daily and intradaily oscillations of anxiety symptoms during therapy reflected less rigidity and more flexible responding. Increases in flexibility over the course of therapy fully mediated the moderating effect of GAD duration on condition, indicating a mediated moderation process. Conclusions Individuals with longer duration of GAD may respond better to more focused treatments, whereas those with shorter duration of GAD may respond better to a treatment that offers more coping strategies. Importantly, the mechanism by which this moderation occurs appears to be the establishment of flexible responding during treatment. PMID:23398493

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

    PubMed

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

    2016-07-01

    We managed 6 cases of severe liver atrophy and failure associated with paclitaxel and bevacizumab combination therapy (PB therapy)for HER2-negative metastatic breast cancer. In this case-controlstudy, we examined the records of these 6 patients to investigate past treatment, medication history, and degree of atrophy, and compared their data with that of 67 patients without liver atrophy. The degree of the liver atrophy used SYNAPSE VINCENT®of the image analysis software. The results showed that patients with liver atrophy had a longer pretreatment period than those without liver atrophy(33.5 months vs 15.5 months), and they also experienced a longer median time to treatment failure with PB therapy than other patients(11 months vs 6 months). The ratio of individuals presenting with diffuse liver metastasis among patients with liver metastasis was 80% with liver atrophy, compared to 8% without liver atrophy. The degree of liver atrophy was an average of 67%in terms of volume ratio before/after PB therapy(57-82%). The individualwith the greatest extent of liver atrophy died of liver failure, not as a result of breast cancer progression. The direct causal link between bevacizumab and liver atrophy and failure is unclear, but the individuals in this study had a long previous history of treatment, and diffuse liver metastases may develop in patients undergoing long periods of PB therapy, which may also cause liver atrophy; therefore, the possibility of liver failure should be considered in such cases. PMID:27431631

  19. [Helium-neon laser therapy in the combined treatment of unstable stenocardia].

    PubMed

    Korochkin, I M; Kapustina, G M; Babenko, E V; Zhuravleva, N Iu

    1990-01-01

    He-Ne laser therapy included in complex of therapeutic methods for patients with unstable angina pectoris is a highly effective treatment modality; it helps essentially reduce the risk of acute myocardial infarction in these patients. Clinical efficacy of laser therapy is confirmed by its favorable action on hemostasis plasma factors, consisting in reduction of fibrinogen level, normalization of antithrombin-III (AT-III), decrease of the level of soluble fibrinomonomer complexes, this indicating a lowering of the blood coagulation potential. Absence of significant changes in plasminogen level may be an indicator of the nonenzymic route of fibrinogen system activation. Sessions of intravenous laser therapy should be administered 2-3 times a week to unstable angina pectoris patients with low AT-III levels, whereas for patients with initially high or normal AT-III levels combined laser therapy is advisable (4-5 daily invasive procedures and 6-8 skin surface ones on the Zakharyin-Head's zones). Measurements of endogenic anticoagulants is an effective means for monitoring laser therapy in this patient population. PMID:1973307

  20. Role of targeted therapy in combination with surgery in renal cell carcinoma.

    PubMed

    Bex, Axel; Powles, Thomas; Karam, Jose A

    2016-01-01

    Surgical complete resection is the only curative treatment of renal cell carcinoma including patients with locally advanced disease and those with limited metastatic disease. Patients at high risk of recurrence after complete resection might theoretically benefit from adjuvant and neoadjuvant systemic treatment strategies to prolong disease-free survival and ultimately overall survival. Another rationale for using targeted therapy includes downsizing/downstaging of surgically complex locally advanced renal cell carcinoma to facilitate complete resection or primary tumors to allow for nephron-sparing strategies. Unfortunately, a considerable percentage of patients are diagnosed with metastatic disease at first presentation. Although large population-based studies consistently show a survival benefit after cytoreductive nephrectomy in the targeted therapy era, confounding factors preclude definite conclusions for this heterogeneous patient group until ongoing phase III trials are published. Presurgical targeted therapy has been proposed to identify patients with clinical benefit and potentially long-term survival after cytoreductive nephrectomy. Recently, the use of targeted therapy before or after local treatment of metastases has been reported in small retrospective series. The present review revisits the current evidence base of targeted therapy in combination with surgery for the various disease stages in renal cell carcinoma. PMID:26238981

  1. 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.

  2. Apremilast and Secukinumab Combined Therapy in a Patient With Recalcitrant Plaque Psoriasis.

    PubMed

    Rothstein, Brooke E; McQuade, Brianna; Greb, Jacqueline E; Goldminz, Ari M; Gottlieb, Alice B

    2016-05-01

    We report a 67-year-old Caucasian man with a long-term history of recalcitrant plaque psoriasis and psoriatic arthritis who was initiated on a treatment regimen of apremilast and secukinumab after failing multiple topical, photo, and systemic therapies. This combination provided significant skin improvement with minimal drug side effects.

    J Drugs Dermatol. 2016;15(5):648-649. PMID:27168275

  3. 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.

  4. Complications of combined radical hysterectomy-postoperative radiation therapy in women with early stage cervical cancer

    SciTech Connect

    Barter, J.F.; Soong, S.J.; Shingleton, H.M.; Hatch, K.D.; Orr, J.W. Jr.

    1989-03-01

    Fifty patients with cervical cancer were treated with radical hysterectomy and lymphadenectomy followed by postoperative radiation therapy for high risk factors (nodal metastases, lymphvascular space invasion, close or involved margins) at the University of Alabama at Birmingham Medical Center from 1969 to 1984. Fifteen (30%) of the patients treated had serious complications, 8 (16%) requiring an operation, and 1 (2%) dying as a result of treatment-related problems. This combined modality approach is associated with significant complications.

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

    PubMed Central

    Campbell, Anita; Cooper, Celia; Davis, Stephen

    2014-01-01

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

  6. Rainfall estimation by rain gauge-radar combination: A concurrent multiplicative-additive approach

    NASA Astrophysics Data System (ADS)

    GarcíA-Pintado, Javier; Barberá, Gonzalo G.; Erena, Manuel; Castillo, Victor M.

    2009-01-01

    A procedure (concurrent multiplicative-additive objective analysis scheme [CMA-OAS]) is proposed for operational rainfall estimation using rain gauges and radar data. On the basis of a concurrent multiplicative-additive (CMA) decomposition of the spatially nonuniform radar bias, within-storm variability of rainfall and fractional coverage of rainfall are taken into account. Thus both spatially nonuniform radar bias, given that rainfall is detected, and bias in radar detection of rainfall are handled. The interpolation procedure of CMA-OAS is built on Barnes' objective analysis scheme (OAS), whose purpose is to estimate a filtered spatial field of the variable of interest through a successive correction of residuals resulting from a Gaussian kernel smoother applied on spatial samples. The CMA-OAS, first, poses an optimization problem at each gauge-radar support point to obtain both a local multiplicative-additive radar bias decomposition and a regionalization parameter. Second, local biases and regionalization parameters are integrated into an OAS to estimate the multisensor rainfall at the ground level. The procedure is suited to relatively sparse rain gauge networks. To show the procedure, six storms are analyzed at hourly steps over 10,663 km2. Results generally indicated an improved quality with respect to other methods evaluated: a standard mean-field bias adjustment, a spatially variable adjustment with multiplicative factors, and ordinary cokriging.

  7. Combining phytoextraction and biochar addition improves soil biochemical properties in a soil contaminated with Cd.

    PubMed

    Lu, Huanping; Li, Zhian; Fu, Shenglei; Méndez, Ana; Gascó, Gabriel; Paz-Ferreiro, Jorge

    2015-01-01

    The main goal of phytoremediation is to improve ecosystem functioning. Soil biochemical properties are considered as effective indicators of soil quality and are sensitive to various environmental stresses, including heavy metal contamination. The biochemical response in a soil contaminated with cadmium was tested after several treatments aimed to reduce heavy metal availability including liming, biochar addition and phytoextraction using Amaranthus tricolor L. Two biochars were added to the soil: eucalyptus pyrolysed at 600 °C (EB) and poultry litter at 400 °C (PLB). Two liming treatments were chosen with the aim of bringing soil pH to the same values as in the treatments EB and PLB. The properties studied included soil microbial biomass C, soil respiration and the activities of invertase, β-glucosidase, β-glucosaminidase, urease and phosphomonoesterase. Both phytoremediation and biochar addition improved soil biochemical properties, although results were enzyme specific. For biochar addition these changes were partly, but not exclusively, mediated by alterations in soil pH. A careful choice of biochar must be undertaken to optimize the remediation process from the point of view of metal phytoextraction and soil biological activity. PMID:25010741

  8. [Monotherapy vs. combined therapy in the treatment of multi-drug resistance gramnegative bacteria].

    PubMed

    Martínez-Sagasti, F; González-Gallego, M A; Moneo-González, A

    2016-09-01

    The increasing number of multidrug resistant gram negative bacteria, particularly in patients with risk factors, but in those who suffer community infections as well, is doing more and more difficult to choose the appropriate treatment. The most challenging cases are due to the production of extended-spectrum-β-lactamases (ESBL) and carbapenemases. This mini-review will discuss the adequacy of administering carbapenems when suspecting infections due to ESBL that could be modified after knowing the MIC of the isolated bacteria and the combined therapy in cases of carbapenemases, being particularly important to include a carbapenem and/or colistine at high dosages in this combination. PMID:27608313

  9. 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.

  10. Neuroprotective Effect of Combination Therapy of Glatiramer Acetate and Epigallocatechin-3-Gallate in Neuroinflammation

    PubMed Central

    Hentschel, Nicole; Infante-Duarte, Carmen; Aktas, Orhan; Zipp, Frauke

    2011-01-01

    Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system. However, studies of MS and the animal model, experimental autoimmune encephalomyelitis (EAE), indicate that neuronal pathology is the principle cause of clinical disability. Thus, there is need to develop new therapeutic strategies that not only address immunomodulation but also neuroprotection. Here we show that the combination therapy of Glatiramer acetate (GA), an immunomodulatory MS therapeutic, and the neuroprotectant epigallocatechin-3-gallate (EGCG), the main phenol in green tea, have synergistic protective effects in vitro and in the EAE model. EGCG and GA together led to increased protection from glutamate- and TRAIL-induced neuronal cell death in vitro. EGCG combined with GA induced regeneration of hippocampal axons in an outgrowth assay. The combined application of EGCG and GA did not result in unexpected adverse events in vivo. Neuroprotective and neuroregenerative effects could be translated in the in vivo model, where combination treatment with EGCG and GA significantly delayed disease onset, strongly reduced clinical severity, even after onset of symptoms and reduced inflammatory infiltrates. These results illustrate the promise of combining neuroprotective and anti-inflammatory treatments and strengthen the prospects of EGCG as an adjunct therapy for neuroinflammatory and neurodegenerative diseases. PMID:22022398

  11. 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.

  12. Combination of vascular endothelial growth factor inhibitors and laser therapy for diabetic macular oedema: a review.

    PubMed

    Mehta, Hemal; Gillies, Mark C; Fraser-Bell, Samantha

    2016-05-01

    This review provides a perspective on published and ongoing clinical trials of vascular endothelial growth factor inhibitors (anti-VEGF agents) combined with laser therapy for diabetic macular oedema (DMO). Although there was little short-term benefit in combining prompt macular laser with anti-VEGF therapy for centre-involving DMO in the Diabetic Retinopathy Clinical Research Network (DRCRnet) Protocol I study, deferred macular laser was still required in over 40% of study eyes in DRCRnet Protocol T. Macular laser was applied in more than 30% of eyes with centre-involving DMO receiving ranibizumab in the RISE and RIDE studies. For non centre-involving DMO the evidence-base still supports use of focal macular laser alone, although clinicians should be cautious about applying laser too close to the foveal avascular zone with the availability of pharmacotherapy. Ongoing clinical trials are assessing whether selectively targeting areas of peripheral retinal ischaemia with laser reduces the number of anti-VEGF injections to stabilise DMO and whether combining macular micropulse laser with anti-VEGF therapy is beneficial in DMO. PMID:27061760

  13. L-dopa-carbidopa: combined therapy for the treatment of Parkinson's disease.

    PubMed

    Celesia, G G; Wanamaker, W M

    1976-03-01

    It is now generally acknowledged that L-Dopa is the therapy of choice for Parkinson's Disease. However, L-Dopa has some short comings: It requires large daily dosage, the therapeutic benefits are achieved only after a delayed onset of 1-2 months, and it has a number of side effects both central and peripheral. In the last few years there has been an intense search for agents that are less toxic, more efficient and more rapidly acting that L-Dopa. The ideal agent has not yet been found. However, a combination therapy with L-Dopa and dopa decarboxylase inhibitors has shown promise. The decarboxylase inhibitors used have a large molecule which does not cross the blood brain barrier. Thus when L-Dopa and the decarboxylase inhibitor are given togehher, peripheral production of dopamine from L-Dopa is inhibited, therefore, rendering L-Dopa more readily and rapidly available for brain metabolism. In the present paper we present the results of the treatment of 50 patients on combined therapy using L-Dopa combined with Carbidopa. PMID:1253661

  14. Atazanavir/ritonavir-based combination antiretroviral therapy for treatment of HIV-1 infection in adults.

    PubMed

    Achenbach, Chad J; Darin, Kristin M; Murphy, Robert L; Katlama, Christine

    2011-02-01

    In the past 15 years, improvements in the management of HIV infection have dramatically reduced morbidity and mortality. Similarly, rapid advances in antiretroviral medications have resulted in the possibility of life-long therapy with simple and tolerable regimens. Protease inhibitors have been important medications in regimens of combination antiretroviral therapy for the treatment of HIV. One of the recommended and commonly used therapies in this class is once-daily-administered atazanavir, pharmacologically boosted with ritonavir (atazanavir/r). Clinical studies and practice have shown these drugs, in combination with other antiretroviral agents, to be potent, safe and easy to use in a variety of settings. Atazanavir/r has minimal short-term toxicity, including benign bilirubin elevation, and has less potential for long-term complications of hyperlipidemia and insulin resistance compared with other protease inhibitors. A high genetic barrier to resistance and a favorable resistance profile make it an excellent option for initial HIV treatment or as the first drug utilized in the protease inhibitors class. Atazanavir/r is also currently being studied in novel treatment strategies, including combinations with new classes of antiretrovirals to assess nucleoside reverse transcriptase inhibitor-sparing regimens. In this article we review atazanavir/r as a treatment for HIV infection and discuss the latest information on its pharmacology, efficacy and toxicity. PMID:21731578

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

    PubMed

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

    2016-10-01

    Treatment failures in patients suffering from giardiasis are not uncommon feature. The most frequent approach in these cases is to treat these patients with longer repeated courses and/or higher doses of the primary therapy, or using drugs from a different class to avoid potential cross-resistance. However, a higher rate of adverse events may limit this strategy. In this context, combination therapy (CT) is emerging as a valuable option against refractory giardiasis. In the attempt to evaluate the benefits of CT, a number of experimental studies, clinical series, and randomized clinical trials (RCTs), as well as several veterinary studies have been performed, with varying results. Here, we present a critical analysis of the available information regarding CT for the treatment of Giardia infection, as well as the authors' opinion with respect to its use. RCTs of combination therapy are limited and the optimal combinations and administration strategies need yet to be clarified. Analyses of the cost-effectiveness and RCTs of CTs for Giardia infection are required to assess the role of these drugs for the control of giardiasis, mainly in the case of treatment failures linked to suspected drug tolerance are the case. PMID:27349189

  16. Azithromycin plus chloroquine: combination therapy for protection against malaria and sexually transmitted infections in pregnancy

    PubMed Central

    Chico, R Matthew; Chandramohan, Daniel

    2011-01-01

    Introduction: The first-line therapy for the intermittent preventive treatment of malaria in pregnancy (IPTp) is sulphadoxine-pyrimethamine (SP). There is an urgent need to identify safe, well-tolerated and efficacious alternatives to SP due to widespread Plasmodium falciparum resistance. Combination therapy using azithromycin and chloroquine is one possibility that has demonstrated adequate parasitological response > 95% in clinical trials of non-pregnant adults in sub-Saharan Africa and where IPTp is a government policy in 33 countries. Areas covered: Key safety, tolerability and efficacy data are presented for azithromycin and chloroquine, alone and/or in combination, when used to prevent and/or treat P. falciparum, P. vivax, and several curable sexually transmitted and reproductive tract infections (STI/RTI). Pharmacokinetic evidence from pregnant women is also summarized for both compounds. Expert opinion: The azithromycin-chloroquine regimen that has demonstrated consistent efficacy in non-pregnant adults has been a 3-day course containing daily doses of 1 g of azithromycin and 600 mg base of chloroquine. The pharmacokinetic evidence of these compounds individually suggests that dose adjustments may not be necessary when used in combination for treatment efficacy against P. falciparum, P. vivax, as well as several curable STI/ RTI among pregnant women, although clinical confirmation will be necessary. Mass trachoma-treatment campaigns have shown that azithromycin selects for macrolide resistance in the pneumococcus, which reverses following the completion of therapy. Most importantly, no evidence to date suggests that azithromycin induces pneumococcal resistance to penicillin. PMID:21736423

  17. 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.

  18. Atazanavir/ritonavir-based combination antiretroviral therapy for treatment of HIV-1 infection in adults

    PubMed Central

    Achenbach, Chad J; Darin, Kristin M; Murphy, Robert L; Katlama, Christine

    2011-01-01

    In the past 15 years, improvements in the management of HIV infection have dramatically reduced morbidity and mortality. Similarly, rapid advances in antiretroviral medications have resulted in the possibility of life-long therapy with simple and tolerable regimens. Protease inhibitors have been important medications in regimens of combination antiretroviral therapy for the treatment of HIV. One of the recommended and commonly used therapies in this class is once-daily-administered atazanavir, pharmacologically boosted with ritonavir (atazanavir/r). Clinical studies and practice have shown these drugs, in combination with other antiretroviral agents, to be potent, safe and easy to use in a variety of settings. Atazanavir/r has minimal short-term toxicity, including benign bilirubin elevation, and has less potential for long-term complications of hyperlipidemia and insulin resistance compared with other protease inhibitors. A high genetic barrier to resistance and a favorable resistance profile make it an excellent option for initial HIV treatment or as the first drug utilized in the protease inhibitors class. Atazanavir/r is also currently being studied in novel treatment strategies, including combinations with new classes of antiretrovirals to assess nucleoside reverse transcriptase inhibitor-sparing regimens. In this article we review atazanavir/r as a treatment for HIV infection and discuss the latest information on its pharmacology, efficacy and toxicity. PMID:21731578

  19. Potential of Hazardous Waste Encapsulation in Concrete Compound Combination with Coal Ash and Quarry Fine Additives.

    PubMed

    Lieberman, Roy Nir; Anker, Yaakov; Font, Oriol; Querol, Xavier; Mastai, Yitzhak; Knop, Yaniv; Cohen, Haim

    2015-12-15

    Coal power plants are producing huge amounts of coal ash that may be applied to a variety of secondary uses. Class F fly ash may act as an excellent scrubber and fixation reagent for highly acidic wastes, which might also contain several toxic trace elements. This paper evaluates the potential of using Class F fly ashes (<20% CaO), in combination with excessive fines from the limestone quarry industry as a fixation reagent. The analysis included leaching experiments (EN12457-2) and several analytical techniques (ICP, SEM, XRD, etc.), which were used in order to investigate the fixation procedure. The fine sludge is used as a partial substitute in concrete that can be used in civil engineering projects, as it an environmentally safe product. PMID:26510011

  20. Activation of HER3 Interferes with Antitumor Effects of Axl Receptor Tyrosine Kinase Inhibitors: Suggestion of Combination Therapy1

    PubMed Central

    Torka, Robert; Pénzes, Kinga; Gusenbauer, Simone; Baumann, Christine; Szabadkai, István; Őrfi, Lászlȯ; Kéri, György; Ullrich, Axel

    2014-01-01

    The Axl receptor tyrosine kinase (RTK) has been established as a strong candidate for targeted therapy of cancer. However, the benefits of targeted therapies are limited due to acquired resistance and activation of alternative RTKs. Therefore, we asked if cancer cells are able to overcome targeted Axl therapies. Here, we demonstrate that inhibition of Axl by short interfering RNA or the tyrosine kinase inhibitor (TKI) BMS777607 induces the expression of human epidermal growth factor receptor 3 (HER3) and the neuregulin 1(NRG1)–dependent phosphorylation of HER3 in MDA-MB231 and Ovcar8 cells. Moreover, analysis of 20 Axl-expressing cancer cell lines of different tissue origin indicates a low basal phosphorylation of RAC-α serine/threonine-protein kinase (AKT) as a general requirement for HER3 activation on Axl inhibition. Consequently, phosphorylation of AKT arises as an independent biomarker for Axl treatment. Additionally, we introduce phosphorylation of HER3 as an independent pharmacodynamic biomarker for monitoring of anti-Axl therapy response. Inhibition of cell viability by BMS777607 could be rescued by NRG1-dependent activation of HER3, suggesting an escape mechanism by tumor microenvironment. The Axl-TKI MPCD84111 simultaneously blocked Axl and HER2/3 signaling and thereby prohibited HER3 feedback activation. Furthermore, dual inhibition of Axl and HER2/3 using BMS777607 and lapatinib led to a significant inhibition of cell viability in Axl-expressing MDA-MB231 and Ovcar8 cells. Therefore, we conclude that, in patient cohorts with expression of Axl and low basal activity of AKT, a combined inhibition of Axl and HER2/3 kinase would be beneficial to overcome acquired resistance to Axl-targeted therapies. PMID:24862757

  1. 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

  2. Likely Additive Ergogenic Effects of Combined Preexercise Dietary Nitrate and Caffeine Ingestion in Trained Cyclists

    PubMed Central

    Handzlik, Michal K.

    2013-01-01

    Aims. To evaluate the possible additive effects of beetroot juice plus caffeine on exercise performance. Methods. In a randomized, double-blinded study design, fourteen healthy well-trained men aged 22 ± 3 years performed four trials on different occasions following preexercise ingestion of placebo (PLA), PLA plus 5 mg/kg caffeine (PLA+C), beetroot juice providing 8 mmol of nitrate (BR), and beetroot juice plus caffeine (BR+C). Participants cycled at 60% maximal oxygen uptake (V˙O2max) for 30 min followed by a time to exhaustion (TTE) trial at 80% V˙O2max. Saliva was collected before supplement ingestion, before exercise, and after the TTE trial for salivary nitrate, nitrite, and cortisol analysis. Results. In beetroot trials, saliva nitrate and nitrite increased >10-fold before exercise compared with preingestion (P ≤ 0.002). TTE in BR+C was 46% higher than in PLA (P = 0.096) and 18% and 27% nonsignificant TTE improvements were observed on BR+C compared with BR and PLA+C alone, respectively. Lower ratings of perceived exertion during TTE were found during 80% V˙O2max on BR+C compared with PLA and PLA+C (P < 0.05 for both). Conclusions. Acute preexercise beetroot juice coingestion with caffeine likely has additive effects on exercise performance compared with either beetroot or caffeine alone. PMID:24967257

  3. THE COMBINED CARCINOGENIC RISK FOR EXPOSURE TO MIXTURES OF DRINKING WATER DISINFECTION BY-PRODUCTS MAY BE LESS THAN ADDITIVE

    EPA Science Inventory

    The Combined Carcinogenic Risk for Exposure to Mixtures of Drinking Water Disinfection By-Products May be Less Than Additive

    Risk assessment methods for chemical mixtures in drinking water are not well defined. Current default risk assessments for chemical mixtures assume...

  4. What’s next after metformin? focus on sulphonylurea: add-on or combination therapy

    PubMed Central

    Lim, Phei C.; Chong, Chee P.

    2015-01-01

    Introduction: The pathophysiology of type 2 diabetes (T2DM) mainly focused on insulin resistance and insulin deficiency over the past decades. Currently, the pathophysiologies expanded to ominous octet and guidelines were updated with newer generation of antidiabetic drug classes. However, many patients had yet to achieve their target glycaemic control. Although all the guidelines suggested metformin as first line, there was no definite consensus on the second line drug agents as variety of drug classes were recommended. Objectives: The aim of this review was to evaluate the drug class after metformin especially sulphonylurea and issues around add-on or fixed dose combination therapy. Methods: Extensive literature search for English language articles, clinical practice guidelines and references was performed using electronic databases. Results: Adding sulphonylurea to metformin targeted both insulin resistance and insulin deficiency. Sulphonylurea was efficacious and cheaper than thiazolidinedione, dipeptidyl peptidase-4 inhibitor, glucagon-like peptide 1 analogue and insulin. The main side effect of sulphonylurea was hypoglycaemia but there was no effect on the body weight when combining with metformin. Fixed dose sulphonylurea/metformin was more efficacious at lower dose and reported to have fewer side effects with better adherence. Furthermore, fixed dose combination was cheaper than add-on therapy. In conclusion, sulphonylurea was feasible as the second line agent after metformin as the combination targeted on two pathways, efficacious, cost-effective and had long safety history. Fixed dose combination tablet could improve patient’s adherence and offered an inexpensive and more efficacious option regardless of original or generic product as compared to add-on therapy. PMID:26445623

  5. Combination Therapy of Sorafenib and TACE for Unresectable HCC: A Systematic Review and Meta-Analysis

    PubMed Central

    Zhao, Yan; Cai, Guohong; Qi, Xingshun; Han, Guohong

    2014-01-01

    Background and Aim A large number of studies have tried to combine sorafenib with TACE for patients with unresectable hepatocellular carcinoma (HCC) and the results were controversial. We conducted this systematic review and meta-analysis to evaluate the safety and efficacy of combination therapy of sorafenib and TACE in the management of unresectable HCC. Methods MEDLINE, PsycINFO, Scopus, EMBASE, and the Cochrane Library were searched from January 1990 to October 2013 and these databases were searched for appropriate studies combining TACE and sorafenib in treatment of HCC. Two authors independently reviewed the databases and extracted the data and disagreements were resolved by discussion. Effective value and safety were analyzed. Effective value included disease control rate (DCR), time to progression (TTP) and overall survival (OS). Results 17 studies were included in the study. In the 10 noncomparative studies, DCR ranged from 18.4 to 91.2%. Median TTP ranged from 7.1 to 9.0 months, and median OS ranged from 12 to 27 months. In the 7 comparative studies, the hazard ratio (HR) for TTP was found to be 0.76 (95% CI 0.66–0.89; P<0.001) with low heterogeneity among studies (P = 0.243; I2 = 25.5%). However, the HR for OS was found to be 0.81 (95% CI 0.65–1.01; P = 0.061) with low heterogeneity among studies (P = 0.259; I2 = 25.4%). The common toxicities included fatigue, diarrhea, nausea, hand foot skin reaction (HFSR), hematological events, hepatotoxicity, alopecia, hepatotoxicity, hypertension and rash/desquamation. AEs are generally manageable with dose reductions. Conclusions Combination therapy may bring benefits for unresectable HCC patients in terms of TTP but not OS. Further well-designed randomized controlled studies are needed to confirm the efficacy of combination therapy. PMID:24651044

  6. Combination therapy with molecular hydrogen and hyperoxia in a murine model of polymicrobial sepsis.

    PubMed

    Xie, Keliang; Fu, Wenzheng; Xing, Weibin; Li, Ailin; Chen, Hongguang; Han, Huanzhi; Yu, Yonghao; Wang, Guolin

    2012-12-01

    Sepsis is the most common cause of death in intensive care units. Some studies have found that hyperoxia may be beneficial to sepsis. However, the clinical use of hyperoxia is hindered by concerns that it could exacerbate organ injury by increasing free radical formation. Recently, it has been suggested that molecular hydrogen (H2) at low concentration can exert a therapeutic antioxidant activity and effectively protect against sepsis by reducing oxidative stress. Therefore, we hypothesized that combination therapy with H2 and hyperoxia might afford more potent therapeutic strategies for sepsis. In the present study, we found that inhalation of H2 (2%) or hyperoxia (98%) alone improved the 14-day survival rate of septic mice with moderate cecal ligation and puncture (CLP) from 40% to 80% or 70%, respectively. However, combination therapy with H2 and hyperoxia could increase the 14-day survival rate of moderate CLP mice to 100% and improve the 7-day survival rate of severe CLP mice from 0% to 70%. Moreover, moderate CLP mice showed significant organ damage characterized by the increases in lung myeloperoxidase activity, lung wet-to-dry weight ratio, protein concentration in bronchoalveolar lavage, serum biochemical parameters (alanine aminotransferase, aspartate aminotransferase, creatinine, and blood urea nitrogen), and organ histopathological scores (lung, liver, and kidney), as well as the decrease in PaO2/FIO2 ratio at 24 h, which was attenuated by either H2 or hyperoxia alone. However, combination therapy with H2 and hyperoxia had a more beneficial effect against lung, liver, and kidney damage of moderate or severe CLP mice. Furthermore, we found that the beneficial effect of this combination therapy was associated with the decreased levels of oxidative product (8-iso-prostaglandin F2α), increased activities of antioxidant enzymes (superoxide dismutase and catalase) and anti-inflammatory cytokine (interleukin 10), and reduced levels of proinflammatory

  7. Is the Combination of Insecticide and Mating Disruption Synergistic or Additive in Lightbrown Apple Moth, Epiphyas postvittana?

    PubMed

    Suckling, David M; Baker, Greg; Salehi, Latif; Woods, Bill

    2016-01-01

    Pest suppression from combinations of tactics is fundamental to pest management and eradication. Interactions may occur among tactical combinations and affect suppression. The best case is synergistic, where suppression from a combination is greater than the sum of effects from single tactics (AB > A+B). We explored how mating disruption and insecticide interacted at field scale, additively or synergistically. Use of a pheromone delivery formulation (SPLAT™) as either a mating disruption treatment (i.e. a two-component pheromone alone) or as a lure and kill treatment (i.e. the two-component pheromone plus a permethrin insecticide) was compared for efficacy against the lightbrown apple moth Epiphyas postvittana. Next, four point-source densities of the SPLAT™ formulations were compared for communication disruption. Finally, the mating disruption and lure and kill treatments were applied with a broadcast insecticide. Population assessment used virgin female traps and synthetic pheromone in replicated 9-ha vineyard plots compared with untreated controls and insecticide-treated plots, to investigate interactions. Lure and kill and mating disruption provided equivalent suppression; no additional benefit accrued from including permethrin with the pheromone suggesting lack of contact. The highest point-source density tested (625/ha) was most effective. The insect growth regulator methoxyfenoxide applied by broadcast application lowered pest prevalence by 70% for the first ten weeks compared to pre-trial. Pheromone addition suppressed the pest further by an estimated 92.5%, for overall suppression of 97.7% from the treatment combination of insecticide plus mating disruption. This was close to that expected for an additive model of interactivity between insecticide and mating disruption (AB = A+B) estimated from plots with single tactics as 98% suppression in a combination. The results indicate the need to examine other tactical combinations to achieve the potential

  8. Is the Combination of Insecticide and Mating Disruption Synergistic or Additive in Lightbrown Apple Moth, Epiphyas postvittana?

    PubMed Central

    Baker, Greg; Salehi, Latif; Woods, Bill

    2016-01-01

    Pest suppression from combinations of tactics is fundamental to pest management and eradication. Interactions may occur among tactical combinations and affect suppression. The best case is synergistic, where suppression from a combination is greater than the sum of effects from single tactics (AB >> A+B). We explored how mating disruption and insecticide interacted at field scale, additively or synergistically. Use of a pheromone delivery formulation (SPLAT™) as either a mating disruption treatment (i.e. a two-component pheromone alone) or as a lure and kill treatment (i.e. the two-component pheromone plus a permethrin insecticide) was compared for efficacy against the lightbrown apple moth Epiphyas postvittana. Next, four point-source densities of the SPLAT™ formulations were compared for communication disruption. Finally, the mating disruption and lure and kill treatments were applied with a broadcast insecticide. Population assessment used virgin female traps and synthetic pheromone in replicated 9-ha vineyard plots compared with untreated controls and insecticide-treated plots, to investigate interactions. Lure and kill and mating disruption provided equivalent suppression; no additional benefit accrued from including permethrin with the pheromone suggesting lack of contact. The highest point-source density tested (625/ha) was most effective. The insect growth regulator methoxyfenoxide applied by broadcast application lowered pest prevalence by 70% for the first ten weeks compared to pre-trial. Pheromone addition suppressed the pest further by an estimated 92.5%, for overall suppression of 97.7% from the treatment combination of insecticide plus mating disruption. This was close to that expected for an additive model of interactivity between insecticide and mating disruption (AB = A+B) estimated from plots with single tactics as 98% suppression in a combination. The results indicate the need to examine other tactical combinations to achieve the potential

  9. Dose combinations of exendin-4 and salmon calcitonin produce additive and synergistic reductions in food intake in nonhuman primates

    PubMed Central

    Kemm, Matthew H.; Ofeldt, Erica M.; Moran, Timothy H.

    2010-01-01

    Glucagon-like peptide-1 (GLP-1) and amylin mediate the feedback control of eating by seemingly separate, but overlapping mechanisms. This study examined the effects of combined doses of the GLP-1 agonist, exendin-4 (Ex-4), and the amylin analog, salmon calcitonin (sCT), on food intake and meal patterns in adult male rhesus monkeys. Monkeys received intramuscular injections of Ex-4 (0, 0.1, 0.32, or 0.56 μg/kg), sCT (0, 0.1, or 0.32 μg/kg), or combinations thereof before a 6-h daily access to food. Dose combinations produced reductions in food intake that were significantly greater than those produced by the individual doses. Surface plots of the hourly intake indicated a synergistic interaction at lower doses of Ex-4 and sCT during the first 4 h of feeding and additive effects at hours 5 and 6. Meal pattern analysis revealed the combinational doses reduced average meal size and meal frequency by additive interactions, whereas infra-additive effects were apparent at lower doses for first meal size. Combinational doses were further characterized by administration of repeated daily injections of 0.56 μg/kg Ex-4 + 0.32 μg/kg sCT for 5 days. This resulted in sustained reductions in daily food intake (>70% from saline baseline) for 5 days with residual reductions (∼48% from saline baseline) persisting on day 1 following the injections. In contrast, when pair-fed an identical amount of daily food, there was a compensatory food intake increase on day 1 following the pair-feeding (∼132% of saline baseline). Such data suggest Ex-4 and sCT interact in an overall additive fashion to reduce food intake and further the understanding of how GLP-1 and amylin agonist combinations influence feeding behavior. PMID:20554932

  10. 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

  11. Facing the challenges of new melanoma-targeted therapies: Treatment of severe fevers associated with dabrafenib/trametinib combination therapy.

    PubMed

    Lindsay, Julian N; Barras, Michael

    2015-08-01

    With the emergence of new oral therapies for metastatic melanoma to the market, as well as ongoing pre-marketing trials and special access schemes, it is important to keep up to date with the side effect profiles of these medications. A common side effect associated with the BRAF inhibitor dabrafenib is severe fever symptoms such as pyrexia and rigors/chills; however, treatment options are limited. We report a patient who was debilitated by severe pyrexia and rigors caused by dabrafenib used in combination with trametinib to treat metastatic melanoma, who was treated with low-dose steroids. To our knowledge, the use of prednisolone for the treatment and prevention of further dabrafenib-associated pyrexia is not published; however, it is a low risk and low cost option that was very effective in this case. PMID:24664475

  12. Antihypertensive combination therapy in primary care offices: results of a cross-sectional survey in Switzerland

    PubMed Central

    Roas, Susanne; Bernhart, Felix; Schwarz, Michael; Kaiser, Walter; Noll, Georg

    2014-01-01

    Background Most hypertensive patients need more than one substance to reach their target blood pressure (BP). Several clinical studies indicate the high efficacy of antihypertensive combinations, and recent guidelines recommend them in some situations even as initial therapies. In general practice they seem widespread, but only limited data are available on their effectiveness under the conditions of everyday life. The objectives of this survey among Swiss primary care physicians treating hypertensive patients were: to know the frequency of application of different treatment modalities (monotherapies, free individual combinations, single-pill combinations); to see whether there are relationships between prescribed treatment modalities and patient characteristics, especially age, treatment duration, and comorbidities; and to determine the response rate (percentage of patients reaching target BP) of different treatment modalities under the conditions of daily practice. Methods This cross-sectional, observational survey among 228 randomly chosen Swiss primary care physicians analyzed data for 3,888 consecutive hypertensive patients collected at one single consultation. Results In this survey, 31.9% of patients received monotherapy, 41.2% two substances, 20.9% three substances, and 4.7% more than three substances. By combination mode, 34.9% took free individual combinations and 30.0% took fixed-dose single-pill combinations. Combinations were more frequently given to older patients with a long history of hypertension and/or comorbidities. In total, 67.8% of patients achieved their BP target according to their physician’s judgment. When compared, single-pill combinations were associated with a higher percentage of patients achieving target BP than free individual combinations and monotherapies for the total sample and for patients with comorbidity. Conclusion Antihypertensive combination therapy was widely used in Swiss primary care practices. The number of prescribed

  13. Efficacy and safety of combination therapy for preventing bone damage in rheumatoid arthritis.

    PubMed

    Iannone, Florenzo; Lopalco, Giuseppe; Cantarini, Luca; Galeazzi, Mauro; Lapadula, Giovanni

    2016-01-01

    The main outcomes of the therapies for rheumatoid arthritis (RA) must be preventing, or at least lessening, the development of structural damage. Biological disease-modifying anti-rheumatic drugs (bDMARDs), targeting tumour necrosis factor-α (TNF-α) or other key steps (IL-1, IL-6, T cells, B cells) in the pathogenesis of RA, have given clues to be effective and safe as treatments for RA, being capable of improving disease activity, ameliorating functional ability and halting joint damage. A large body of evidence, stemming from randomized clinical trials, observational studies, and registries, has shown that the beneficial effects of the bDMARDs become optimal when combined with synthetic (s)-DMARDs, mainly methotrexate (MTX). Despite combination therapy is advocated by the international guidelines for the management of RA, data from the daily standard of care indicate that almost one third of RA patients are treated with bDMARDs as monotherapy. Many reasons may be taken into account to explain this gap from official recommendations, among which the fact that in real-life settings, the assessment of clinical outcomes is exclusively based on clinical indices, disregarding the evolution of bone damage. Furthermore, some bDMARDs have been launched in the market with the official approval to be used as monotherapy. But even for the latter, there is no conclusive proof that monotherapy regimen is comparable to co-therapy with MTX in preventing articular damage. In conclusion, the most recent published data show that combination therapy with bDMARDs and MTX represents the best therapeutic option for the treatment of RA since it can stop or at least slow the progression of disabling structural damage. PMID:26581205

  14. Effect of combined psycho-physiological stretching and breathing therapy on sexual satisfaction

    PubMed Central

    2013-01-01

    Background During the last few decades, marital tensions and stresses have influenced various dimensions of life. The objective of the current study was to examine the effects of combined psycho-physiological therapy (stretching therapy combined with breathing exercise) on sexual satisfaction among heterosexual men. Methods For this research, we used “convenience sampling” to select 80 males, who were then split equally into two groups, the intervention group and the control group, both groups containing men who had voiced a desire to be in the experimental group. For collection of data, we used an identical quasi-experimental design called the “nonequivalent control group.” Therapy sessions, each lasting 90 to 120 min, were carried out on the same 3 days of the week (Sunday, Tuesday, and Thursday) for a total of 20 sessions. The volunteers were selected from heterosexual men with stable relationships, who had been married a minimum of 6 months and were ages 20 to 55 years of age. Pre-tests, post-tests, and follow-up tests were conducted in a clinic at the Hospital Universiti Sains Malaysia (HUSM [1] ). For assessment, we used the sexual satisfaction subscale of the ENRICH [2] questionnaire. Results The intervention group had better post-test scores than the control group. Also, follow-up test scores for the intervention group were marginally better than those for the control group, but the difference did not reach statistical significance. Conclusions Combined psycho-physiological therapy including stretching and breathing exercise leads to improved sexual satisfaction. PMID:23522405

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

    PubMed

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

    2016-01-01

    Recently, microRNA (miRNA or miR) has emerged as a new cancer biomarker because of its high expression level in various cancer types and its role in the control of tumor suppressor genes. In cancer studies, molecular imaging and treatment based on target cancer markers have been combined to facilitate simultaneous cancer diagnosis and therapy. In this study, for combined therapy with diagnosis of cancer, we developed a doxorubicin-conjugated miR-221 molecular beacon (miR-221 DOXO MB) in a single platform composed of three different nucleotides: miR-221 binding sequence, black hole quencher 1 (BHQ1), and doxorubicin binding site. Imaging of endogenous miR-221 was achieved by specific hybridization between miR-221 and the miR-221 binding site in miR-221 DOXO MB. The presence of miR-221 triggered detachment of the quencher oligo and subsequent activation of a fluorescent signal of miR-221 DOXO MB. Simultaneous cancer therapy in C6 astrocytoma cells and nude mice was achieved by inhibition of miRNA-221 function that downregulates tumor suppressor genes. The detection of miR-221 expression and inhibition of miR-221 function by miR-221 DOXO MB provide the feasibility as a cancer theragnostic probe. Furthermore, a cytotoxic effect was induced by unloading of doxorubicin intercalated into miR-221 DOXO MB inside cells. Loss of miR-221 function and cytotoxicity induced by the miR-221 DOXO MB provides combined therapeutic efficacy against cancers. This method could be used as a new theragnostic probe with enhanced therapy to detect and inhibit many cancer-related miRNAs. PMID:26454049

  16. Increased generation of intracellular reactive oxygen species initiates selective cytotoxicity against the MCF-7 cell line resultant from redox active combination therapy using copper-thiosemicarbazone complexes.

    PubMed

    Akladios, Fady N; Andrew, Scott D; Parkinson, Christopher J

    2016-06-01

    The combination of cytotoxic copper-thiosemicarbazone complexes with phenoxazines results in an up to 50-fold enhancement in the cytotoxic potential of the thiosemicarbazone against the MCF-7 human breast adenocarcinoma cell line over the effect attributable to drug additivity-allowing minimization of the more toxic copper-thiosemicarbazone component of the therapy. The combination of a benzophenoxazine with all classes of copper complex examined in this study proved more effective than combinations of the copper complexes with related isoelectronic azines. The combination approach results in rapid elevation of intracellular reactive oxygen levels followed by apoptotic cell death. Normal fibroblasts representative of non-cancerous cells (MRC-5) did not display a similar elevation of reactive oxygen levels when exposed to similar drug levels. The minimization of the copper-thiosemicarbazone component of the therapy results in an enhanced safety profile against normal fibroblasts. PMID:26951232

  17. 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

  18. 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

  19. 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

  20. Acneiform eruption in a patient with metastatic melanoma after ceasing combination dabrafenib/trametinib therapy.

    PubMed

    Uribe, Pablo; Anforth, Rachael M; Kefford, Richard F; Fernandez-Peñas, Pablo

    2014-10-01

    BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) increase survival in BRAF mutant metastatic melanoma patients; however, they induce a well-known spectrum of cutaneous side effects during treatment. Whereas the BRAFi dabrafenib induces cutaneous squamous cell carcinomas and verrucal keratosis, the MEKi trametinib frequently induces acneiform eruptions that are reversible after drug discontinuation. Furthermore, when dabrafenib and trametinib are used in combination, there are fewer cutaneous toxicities. We report a patient with BRAF mutant metastatic melanoma treated with the BRAFi/MEKi combination therapy who developed an acneiform eruption after treatment discontinuation rather than during active therapy. Moreover, the eruption resolved when the combination treatment was reintroduced and recurred after increasing the dose of trametinib. The eruption may be explained by the longer half-life of trametinib (4.5 days) compared with dabrafenib (5.2 h). This is the first case reported with this particular side effect induced after stopping the treatment and could become more frequent as the BRAFi/MEKi combination of drugs is more frequently prescribed. PMID:24922191

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

    PubMed

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

    2016-01-01

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

  2. 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

  3. 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.

  4. Austenite Grain Growth and Precipitate Evolution in a Carburizing Steel with Combined Niobium and Molybdenum Additions

    NASA Astrophysics Data System (ADS)

    Enloe, Charles M.; Findley, Kip O.; Speer, John G.

    2015-11-01

    Austenite grain growth and microalloy precipitate size and composition evolution during thermal processing were investigated in a carburizing steel containing various additions of niobium and molybdenum. Molybdenum delayed the onset of abnormal austenite grain growth and reduced the coarsening of niobium-rich precipitates during isothermal soaking at 1323 K, 1373 K, and 1423 K (1050 °C, 1100 °C, and 1150 °C). Possible mechanisms for the retardation of niobium-rich precipitate coarsening in austenite due to molybdenum are considered. The amount of Nb in solution and in precipitates at 1373 K (1100 °C) did not vary over the holding times evaluated. In contrast, the amount of molybdenum in (Nb,Mo)C precipitates decreased with time, due to rejection of Mo into austenite and/or dissolution of fine Mo-rich precipitates. In hot-rolled alloys, soaking in the austenite regime resulted in coarsening of the niobium-rich precipitates at a rate that exceeded that predicted by the Lifshitz-Slyozov-Wagner relation for volume-diffusion-controlled coarsening. This behavior is attributed to an initial bimodal precipitate size distribution in hot-rolled alloys that results in accelerated coarsening rates during soaking. Modification of the initial precipitate size distribution by thermal processing significantly lowered precipitate coarsening rates during soaking and delayed the associated onset of abnormal austenite grain growth.

  5. Dephenolization, dearomatization and detoxification of olive mill wastewater with sonication combined with additives and radical scavengers.

    PubMed

    Sponza, Delia Teresa; Oztekin, Rukiye

    2014-05-01

    In this study, the effects of some additives [manganese (III) oxide (Mn3O4), Cu(+2), Fe(0) and potassium iodate (KIO3)] and some radical scavengers [sodium carbonate (Na2CO3), perfluorohexane (C6F14) and t-butyl alcohol (C4H10O)] on the sonication of olive mill effluent wastewater (OMW) were investigated since the wastewaters of this industry are removed with low efficiencies. The maximum total phenol and total aromatic amines (TAAs) removal efficiencies were 88% and 79%, respectively, at 60°C with only 150 min sonication. The maximum phenol removal was found as 98% with 19 mg L(-1) perfluorohexane and 5 mg L(-1) Fe(0) while the maximum TAAs removal was 99% with 16 mg L(-1) KIO3. Catechol, tyrosol, quercetin, caffeic acid, 4-methyl catechol, 2-phenylphenol (2-PHE) and 3-phenyl phenol (3-PHE) were detected as phenol intermediates while trimethlyaniline, aniline, o-toluidine, o-anisidine, dimethylaniline, ethylbenzene and durene were identified as TAAs in the OMW. The maximum acute toxicity removals were 96% and 99% in Vibrio fischeri and Daphnia magna, respectively. Total phenol, TAAs and the toxicity in an OMW were removed efficiently and cost-effectively through sonication. PMID:24315030

  6. 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

  7. Combined methotrexate and high-dose vincristine chemotherapy with radiation therapy for small cell bronchogenic carcinoma

    SciTech Connect

    Holoye, P.Y.; Libnoch, J.A.; Anderson, T.; Cox, J.D.; Byhardt, R.W.; Hoffmann, R.G.

    1985-04-01

    The addition of methotrexate to a previously described regimen of cyclophosphamide, Adriamycin (doxorubicin), and high-dose vincristine (VAC) was tested in 50 evaluable patients with small cell bronchogenic carcinoma. Prophylactic whole brain radiation therapy was given during the first chemotherapy course and consolidation radiation therapy was given to the mediastinum and primary site after achieving partial or complete remission. The addition of methotrexate did not improve the incidence of complete remission as compared to a previous regimen without it. The addition of radiation therapy improved the local control rate. The high-dose vincristine in this and a previous CAV study improved the incidence of complete remission in both limited and extensive disease presentation as compared with the authors previous experience and induced an acceptable and reversible neurotoxicity. Moderate dose consolidation radiotherapy to the lung primary and mediastinum was effective in improving local control. The distinction between limited and extensive disease was found to be vague, as 22% of the patients could be shifted from one group to the other depending on definition. The evaluation of the various staging procedures indicates that bone scan gave a small number of truly abnormal tests. Isotopic brain and liver-spleen scan could be duplicated by computerized axial tomography (CAT). CAT scan of abdomen disclosed unexpected extension to the retroperitoneal nodes and adrenals.

  8. Initial Experience of Sorafenib Neoadjuvant Therapy Combined with Retroperitoneoscopy in Treating T2 Large Renal Carcinoma

    PubMed Central

    Lin, Chun-hua; Yuan, He-jia; Wang, Ke; Wu, Ji-tao; Liu, Qing-zuo; Yu, Sheng-qiang; Men, Chang-ping; Gao, Zhen-li; Wang, Jiahui

    2015-01-01

    Objectives. To investigate the safety and feasibility of sorafenib neoadjuvant therapy combined with retroperitoneoscopic radical nephrectomy (RRN) in treating T2 large renal cell carcinoma (RCC). Methods. Retrospectively analyzed 5 cases (2 males and 3 females, aged 52–73 years) of T2 stage large RCC who receive preoperative sorafenib targeted treatment (400 mg bid f