Individual Monotherapies Research Articles

Pregabalin and Amitriptyline as Monotherapy or as Low-Dose Combination in Patients of Neuropathic Pain: A Randomized, Controlled Trial to Evaluate Efficacy and Safety in an Eastern India Teaching Hospital.

Objectives:The main objective is to compare efficacy and safety of pregabalin and amitriptyline monotherapy with their low-dose combination in patients of neuropathic pain (NeuP).Methodology:In this parallel-group, open-label interventional study at the Neurology Outpatient Department of Bankura Sammilani Medical College, a total of 147 patients were randomly allocated into three groups and were prescribed the following drugs – Group P (n = 42) pregabalin 150 mg once daily, Group A (n = 34), amitriptyline 25 mg once daily, and Group Z (n = 37) = pregabalin (75 mg) + amitriptyline (10 mg) as combination once daily. They were followed up after 4, 8, and 12 weeks. Efficacy was assessed by NeuP symptom inventory score (NPSI) and safety was assessed by treatment-emergent adverse events.Results:Final assessment was done on 92 patients (P = 31, A = 31, Z = 30). Males were predominant (71.7%). NPSI score significantly decreased in every group from baseline (P < 0.0001). There was no difference of NPSI score between groups at any level of follow-up. Percentage of adverse drug reactions were maximum (44.9%) in amitriptyline monotherapy group and lowest in combined group. However, amitriptyline monotherapy was the cheapest treatment option among these three.Conclusion:Combining pregabalin and amitriptyline at low doses proved to be equally effective but more tolerable compared to individual higher dosage monotherapy. However, if tolerability is good, amitriptyline monotherapy can be an attractive choice in economically challenged group of patients.

Superiority of dutasteride 0.5 mg and tamsulosin 0.2 mg for the treatment of moderate‐to‐severe benign prostatic hyperplasia in Asian men

To assess the effectiveness and safety of dutasteride 0.5 mg + tamsulosin 0.2 mg combination compared with tamsulosin 0.2 mg in Asian men with moderate-to-severe benign prostatic hyperplasia. A 4-week, single-blind, placebo, run-in was followed by a 2-year double-blind randomized controlled trial in men age ≥50 years with symptomatic benign prostatic hyperplasia, International Prostate Symptom Score ≥12, prostate volume ≥30 cc, prostate-specific antigen ≥1.5 and ≤10 ng/mL, peak urinary flow >5 and ≤15 mL/s, and voided volume of ≥125 mL. Participants were randomized to oral daily dutasteride 0.5 mg + tamsulosin 0.2 mg combination or tamsulosin 0.2 mg. The primary efficacy end-point was change in International Prostate Symptom Score at year 2. Data from 607 participants showed a significant reduction in International Prostate Symptom Score (P < 0.05) at month 24, along with greater improvements (P ≤ 0.006) in peak urinary flow at every assessment and significant prostate volume reduction at months 12 and 24 (P < 0.001) in the combination group. Combination therapy was associated with a significant reduction in the risk of acute urinary retention or benign prostatic hyperplasia-related surgery (P = 0.012), primarily due to a significant reduction in the risk of acute urinary retention (P = 0.005). The safety and tolerability profile of combination therapy was consistent with the known profiles for the individual monotherapies. Dutasteride 0.5 mg + tamsulosin 0.2 mg combination therapy showed better clinical outcomes than tamsulosin 0.2 mg monotherapy, making it an effective and safe treatment option for Asian men with moderate-to-severe benign prostatic hyperplasia.

Oral diabetes medication monotherapy and short-term mortality in individuals with type 2 diabetes and coronary artery disease

ObjectiveTo determine whether sulfonylurea use, compared with non-sulfonylurea oral diabetes medication use, was associated with 2-year mortality in individuals with well-controlled diabetes and coronary artery disease (CAD).Research design and methodsWe...

Changes in antiepileptic drug-prescribing patterns in pregnant women with epilepsy

ObjectiveWe analyzed current prescribing patterns for antiepileptic drugs (AEDs) in pregnant women with epilepsy (PWWE) at 20 USA tertiary epilepsy centers. MethodsThe Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes for both mother and child, which enrolled women from December 2012 to January 2016. Inclusion criteria for PWWE included ages 14–45 years and up to 20 weeks gestational age. Exclusion criteria included history of psychogenic nonepileptic spells, expected intelligence quotient (IQ) <70, other major medical illness, progressive cerebral disease, and switching AEDs in pregnancy prior to enrollment. ResultsThree hundred fifty-one PWWE were enrolled in the MONEAD study, which included 259 (73.8%) on monotherapy, 77 (21.9%) on polytherapy, and 15 (4.3%) on no AEDs. The most common AED monotherapy regimens were lamotrigine (42.1% of monotherapies), levetiracetam (37.5%), carbamazepine (5.4%), zonisamide (5.0%), oxcarbazepine (4.6%), and topiramate (3.1%). All other individual monotherapies were each <1%. The most common AED polytherapy combination was lamotrigine + levetiracetam (42.9% of polytherapies), followed by lacosamide + levetiracetam (6.5%), lamotrigine + zonisamide (5.2%), and all other remaining combinations (each <4%); only 5.2% of polytherapy subjects were on ≥3 AEDs (1.1% of total PWWE). Only four subjects (1.1%) were on valproate (1 monotherapy, 3 polytherapy). ConclusionsThe distribution of AED use likely reflects current prescribing patterns for PWWE cared for in USA tertiary epilepsy centers. This distribution has changed markedly since the turn of the century, but changes in the general population remain uncertain.

Bioequivalence of Dapagliflozin/Metformin Extended-release Fixed-combination Drug Product and Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Russian Subjects

PurposeFixed-combination drug products (FCDPs) combining dapagliflozin and metformin extended release (XR) may provide patients with type 2 diabetes mellitus with an alternative antihyperglycemic treatment, which could improve adherence by reducing tablet burden. This study evaluated the bioequivalence of dapagliflozin/metformin XR FCDP versus the co-administration of the individual monotherapy tablets currently available for use in the Russian Federation. MethodsHealthy subjects aged 18 to 45 years were enrolled in this randomized, open-label, 2-period crossover study, conducted in a single Russian center. Pharmacokinetic parameters (AUC0–t, Cmax, and Cmax/AUC0–t) were used to assess bioequivalence of dapagliflozin/metformin XR (10/1000 mg) FCDP to the individual component tablets (dapagliflozin [10 mg] plus metformin XR [2 × 500 mg]) under standard fed conditions. Safety and tolerability were also assessed. FindingsForty healthy subjects were included (47.5% male; mean age, 30 years; and mean body mass index, 24.2 kg/m2). Dapagliflozin and metformin XR in the FCDP were bioequivalent to the individual component tablets marketed in the Russian Federation, with the 90% CIs of the geometric least-squares mean ratios for all key pharmacokinetic parameters being contained within the 80% to 125% bioequivalence limits. Both FCDP and the individual component formulations were well tolerated, with no serious adverse events. ImplicationsBioequivalence of dapagliflozin/metformin XR FCDP and the individual components was established without any new safety concerns, presenting a safe alternative for patients currently receiving regimens including each component individually. ClinicalTrials.gov identifier: NCT02722239.

Efficacy of anti-IL-23 monotherapy versus combination therapy with anti-IL-17 in estrogen deficiency induced bone loss conditions.

Recent studies have identified that Interleukin (IL)-23/IL-17 axis plays crucial role in pathogenesis of inflammation and bone destruction. IL-23 is thought to promote joint destruction in arthritis by stimulating Th17 cells. IL-23 directly mediates bone loss by inducing osteoclastogenesis and receptor activator of kappa B ligand (RANKL) expression in T cells. IL-23 also promotes tartrate-resistant acid phosphatase (TRAP) activity of osteoclast in osteoblast-osteoclast co-culture. The role of IL-23 has not been studied in estrogen deficiency induced bone loss. Here, we study the effect of IL-23 neutralization in ovariectomized (Ovx) estrogen deficient mice on various immune and skeletal parameters. We also determine whether the combination of anti-IL-23 and anti-IL17 has enhanced osteoprotective effects compared to monotherapies. Treatment of anti-IL-23 and its combination with anti-IL-17 suppressed Th17 cell differentiation and promoted development of T regulatory cells. Anti-IL-23 and its combination with anti-IL-17 prevented bone loss. However, the individual monotherapies of anti-IL-23 and anti-IL-17 were more effective than combination therapy. Treatment of IL-17 and IL-23 cytokines to bone marrow stromal cells led to increased differentiation towards osteoblast lineage. Double neutralization of IL-23 and IL-17 might be inhibiting this phenomenon thus producing less potent effects. Our studies thus support bone protective effects of anti-IL-23 and that the monotherapies of neutralizing antibodies against IL-17 and IL-23 may be a more accepted mode of treatment in management of post-menopausal bone loss rather than combination therapy.

Oral diabetes medication monotherapy and short-term mortality in individuals with type 2 diabetes and coronary artery disease

Oral diabetes medication monotherapy and short-term mortality in individuals with type 2 diabetes and coronary artery disease

Everolimus Plus Ku0063794 Regimen Promotes Anticancer Effects against Hepatocellular Carcinoma Cells through the Paradoxical Inhibition of Autophagy.

PurposeEverolimus only inhibits mammalian target of rapamycin complex 1 (mTORC1), whereas Ku0063794 inhibits both mTORC1 and mTORC2. Although they have similar anticancer effects, their combination has a synergistic effect against hepatocellular carcinoma (HCC) cells. We aimed to determine the mechanism underlying the synergistic effects of everolimus and Ku0063794 associated with autophagy in HCC cells.Materials and MethodsWe compared the effects of everolimus and Ku0063794, individually or in combination, on both the in vitro and in vivo models of HCCs.ResultsHepG2 cells treated with both agents had significantly lower rates of cell proliferation and higher apoptosis than the individual monotherapies (p < 0.05). Autophagic studies consistently indicated that, unlike the monotherapies, the combination therapy significantly reduced autophagy (p < 0.05). Autophagic blockage directly promoted the pro-apoptotic effects of combination therapy, suggesting autophagy as the survival mechanism of HCC cells. Unlike the monotherapies, combination therapy showed the potential to inhibit sirtuin 1 (SIRT1), the positive regulator of autophagy. SIRT1 overexpression abrogated the autophagy-inhibiting and pro-apoptotic effects of combination therapy. In a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with combination therapy than in mice treated with the respective monotherapies (p < 0.05). The immunohistochemical and immunofluorescence stains of the tumor obtained from the xenograft model showed that combination therapy had the potential of reducing autophagy and promoting apoptosis.ConclusionThe combination of everolimus and Ku0063794 potentiates anticancer effects on HCCs through a decrease in autophagy, which is prompted by SIRT1 downregulation.

Abstract 5617: Combined intratumoral electroporation and allogeneic vaccination of Gp96-Ig/Fc-OX40L stimulates CD8 T cell cross-priming to tumor specific neoantigens and enhanced anti-tumor response

Abstract Growing clinical evidence has unequivocally proven that combination approaches are leading the way in increasing the overall response rates in cancer immunotherapy (IT), compared to single agent therapies. Most cancer ITs have a higher likelihood of succeeding if the targeted tumor has a preexisting state of inflammation elicited by the combined presentation of shared- and neo-antigens from tumor cells. Certain cancers have been deemed to be non-immunogenic due to tumor intrinsic strategies that evade immune recognition. Thus, novel combination treatment modalities are needed to convert non-immunogenic, ‘cold’ tumors into inflamed ‘hot’ tumors that are amenable to IT. Gp96-Ig/Fc-OX40L is a re-engineered molecular chaperone, designed to export and deliver MHC I-associated antigens to APCs in context of the immune costimulator, OX40L. Allogeneic cancer vaccine cell lines designed to co-secrete Gp96-Ig and Fc-OX40L, generate antigen-specific CD4+/CD8+ anti-tumor responses in both highly immunogenic (CT26) and less immunogenic (B16) mouse tumors (Fromm et al., Cancer Immunol Res, 2016). Such a strategy allows for Gp96-Ig-mediated chaperoning of antigens from the allogeneic vaccine cell line (shared antigens), which could benefit further from increased presentation of tumor-derived peptides (neo-antigens) that are only accessible if Gp96-Ig/Fc-OX40L is expressed from within the tumor. To achieve this, we have employed an in vivo electroporation-based strategy (EP) to deliver Gp96-Ig/Fc-OX40L expressing DNA to tumor cells in situ. Herein we set out to test whether a combination approach of intratumoral EP of Gp96-Ig/Fc-OX40L DNA and vaccination with allogeneic cells co-secreting the same effector molecules would lead to enhanced CD4+/CD8+ T cell cross-priming to tumor neo-antigens and superior anti-tumor activity over the individual monotherapies in a non-immunogenic B16 tumor model. To assess antigen-specific CD8+ T cell expansion, mice were adoptively transferred with OT-I cells after B16-ovalbumin cells were injected to generate primary and contralateral melanotic tumors. Contralateral tumors were monitored to assess whether a systemic CD8+ T cell response could be elicited following vaccination and primary tumor EP. The combination approach lead to a significant synergistic expansion of OT-I cells in tumors and in the peripheral blood compared to the individual monotherapies. A synergistic increase in SIINFEKL-positive CD8+ TIL cells was also observed in treated tumors, which was associated with superior anti-tumor response in both the EP-treated primary and untreated contralateral tumors. These findings suggest that a combination approach of allogeneic vaccination and in situ tumor EP of Gp96-Ig/Fc-OX40L may have significant benefit in eliciting a potent immune response in less-immunogenic tumors. Citation Format: Suresh de Silva, George Fromm, Anandaroop Mukhopadhyay, Jean Campbell, Robert Pierce, Taylor Schreiber. Combined intratumoral electroporation and allogeneic vaccination of Gp96-Ig/Fc-OX40L stimulates CD8 T cell cross-priming to tumor specific neoantigens and enhanced anti-tumor response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5617. doi:10.1158/1538-7445.AM2017-5617

Phase 1b/2, open label, multicenter, study of intratumoral SD-101 in combination with pembrolizumab in anti-PD1 naïve &amp; experienced metastatic melanoma patients.

9550 Background: SD-101 is a synthetic CpG-ODN agonist of TLR 9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells to activate T cell anti-tumor responses. Pembro is a PD-1 inhibitor approved for the treatment of metastatic melanoma. This study, MEL-01 (NCT02521870), assesses the safety and preliminary efficacy of SD-101 in combination with pembro in stage IIIC-IV melanoma. Methods: A modified 3+3 design was used for SD-101 dose escalation of 1, 2, 4, and 8 mg injected in a single tumor lesion Q1W x 4 then Q3W x 7 in combination with pembro (200 mg IV Q3W). Tumor responses were assessed per investigator using RECIST v1.1. Results: In phase Ib, 22 pts were enrolled: median age 64 y/o, male 68%, white 82%, Stage IV/IIIc 86%/14%, LDH &gt; 1 ULN 27%, ≥ 3 prior lines therapy 36%, anti-PD-1 naïve (n = 9) and experienced (n = 13). There has been no dose limiting toxicity (DLT) to date. The most common (≥20%) treatment-related AEs (TRAEs) were transient low-grade fatigue, myalgia, headache, chills and injection site reactions. Grade ≥ 3 TRAEs were observed in 59.1% pts (most common: myalgia 13.6% and injection site pain 13.6%). Immune-related AEs occurred in 2 pts. One had a G2 pneumonitis on Day 23 resulting in drug withdrawal and the other G3 hypophysitis (85 days after last treatment). No deaths occurred. Responses were observed at all doses in PD-1 inhibitor naïve pts, both at the injected and non-injected lesions. A response was seen at the 8 mg dose in PD-1 inhibitor experienced pts. With median f/u of 97 days (max 382), the ORR was 66.7% in the PD-1 inhibitor naïve patients with best overall response of CR 22.2% (n = 2), PR 44.4% (n = 4), SD 11.1% (n = 1), PD 11.1% (n = 1), and NE 11.1% (n = 1). In the PD-1 inhibitor experienced pts: PR 7.7% (n = 1) and SD 38.5% (n = 5). Conclusions: The combination of SD-101 and pembro was well tolerated and demonstrates no worsening of the expected toxicities of each of the individual monotherapies. These interim data support enhanced activity of adding SD-101 to pembro in anti-PD-1 naive metastatic melanoma as well as potential activity in anti-PD-1 experienced pts. Additional follow up data through May 15, 2017 will be presented. Clinical trial information: NCT02521870.

Benefit of Ezetimibe Added to Simvastatin in Reduced Kidney Function.

Efficacy of statin-based therapies in reducing cardiovascular mortality in individuals with CKD seems to diminish as eGFR declines. The strongest evidence supporting the cardiovascular benefit of statins in individuals with CKD was shown with ezetimibe plus simvastatin versus placebo. However, whether combination therapy or statin alone resulted in cardiovascular benefit is uncertain. Therefore, we estimated GFR in 18,015 individuals from the IMPROVE-IT (ezetimibe plus simvastatin versus simvastatin alone in individuals with cardiovascular disease and creatinine clearance >30 ml/min) and examined post hoc the relationship of eGFR with end points across treatment arms. For the primary end point of cardiovascular death, major coronary event, or nonfatal stroke, the relative risk reduction of combination therapy compared with monotherapy differed by eGFR (P=0.04). The difference in treatment effect was observed at eGFR≤75 ml/min per 1.73 m2 and most apparent at levels ≤60 ml/min per 1.73 m2 Compared with individuals receiving monotherapy, individuals receiving combination therapy with a baseline eGFR of 60 ml/min per 1.73 m2 experienced a 12% risk reduction (hazard ratio [HR], 0.88; 95% confidence interval [95% CI], 0.82 to 0.95); those with a baseline eGFR of 45 ml/min per 1.73 m2 had a 13% risk reduction (HR, 0.87; 95% CI, 0.78 to 0.98). In stabilized individuals within 10 days of acute coronary syndrome, combination therapy seemed to be more effective than monotherapy in individuals with moderately reduced eGFR (30-60 ml/min per 1.73 m2). Further studies examining potential benefits of combination lipid-lowering therapy in individuals with CKD are needed.

Potentiation of the anticancer effects of everolimus using a dual mTORC1/2 inhibitor in hepatocellular carcinoma cells.

There is lots of evidence to support the critical involvement of mTOR signaling in the carcinogenesis of hepatocellular carcinoma (HCC). However, it has not been determined how the roles of individual mTORC1 and mTORC2 inhibitors played in the HCC therapeutics. We thus compared the effects of everolimus, Ku0063794, and a combination of the two therapies on HCC cells, using various in vitro studies (HepG2, Hep3B, and Huh7 cells), ex vivo culturing of HCC tissues obtained from patients, and the in vivo mouse xenograft model of HCC cells. Our in vitro, ex vivo, and in vivo experiments consistently demonstrated that everolimus and Ku0063794 combination therapy was superior to individual monotherapies, as manifested by higher reduction of proliferation, migration, and invasion of HCC cells, and the higher inhibition of EMT process as well. Although individual monotherapies could not inhibit SIRT1 (positive regulator of EMT) expression, the combination therapy significantly inhibited SIRT1 expression. However, overexpression of SIRT1 mitigated the EMT-inhibiting effect of the combination therapy, suggesting that the combination therapy inhibits the EMT by way of suppressing SIRT1 expression. Therefore, when considering everolimus as an anti-HCC agent, the improved anticancer effects provided by combining it with an inhibitor of both mTORC1 and mTORC2 should be recognized.

Nanoparticles for Effective Combination Therapy of Cancer

Cancer continues to remains a major healthcare problem across the world despite strong translational research efforts towards tackling the disease. Surgery, when possible, along with radiation and chemotherapy continue to remain the mainstay of cancer treatment. Novel targeted therapies or biologics and immunotherapies have recently been approved to improve treatment efficacies while reducing collateral damage to normal, non-cancerous tissues. Combination therapies have shown better results than individual monotherapies in the clinic but often the improvements in therapeutic indices remain marginal, at best. Several combinations treatments have been clinically approved for different types of cancer. Nanomedicine, the application of nanotechnology for medicine, has already made some positive impacts on the clinical care in this fight against cancer. Several nano-sized formulations of conventional chemotherapies have been clinically approved. Nanotechnology provides a novel way to deliver combination therapies with spatiotemporal control over drug release. This review explores the recent advances in nanotechnology-mediated combination treatments against cancer. Multifunctional nanomedicines for mechanism-based combination therapies are likely to deliver the right drugs to the right place at the right time for optimal treatment responses with reduced morbidity. No nanomedicine that combines two or more drugs in a single platform has been approved for clinical use yet. This is because several challenges still remain in the development of nano-combinations including but not limited to - the optimal drug ratios in these nanomedicines, control over these drug ratios over multiple batches, large scale, reproducible manufacturing of these nanomedicines and cost of these nano-combinations among others. These challenges need to be addressed soon using a multidisciplinary approach with collaborations between academia, the pharmaceutical industry and the regulatory bodies involved to ensure that nano-combination therapy delivers on its promise of better treatment outcomes while severely reducing morbidity thus improving the quality of life in cancer patients.

Long-term glucose lowering effects of sitagliptin monotherapy and dietary contents in Japanese individuals with type 2 diabetes

Long-term glucose lowering effects of sitagliptin monotherapy and dietary contents in Japanese individuals with type 2 diabetes

The antifibrotic effects of alveolar macrophages 5-HT2C receptors blockade on bleomycin-induced pulmonary fibrosis in rats.

The most widespread chronic fibrosing lung disease is idiopathic pulmonary fibrosis. Lung serotonin (5-HT) content is increased during pulmonary fibrosis with the implication of 5-HT2 receptors in the pathogenesis. Serotonin plays important roles in alveolar macrophages function through 5-HT2C receptors activation. Numerous studies described the important role of 5-HT2A/B receptor blockers in suppressing different types of fibrosis as idiopathic pulmonary fibrosis. The current study pointed to examine the antifibrotic effects of RS-102221 and/or terguride through in vivo model of pulmonary fibrosis. Induction of pulmonary fibrosis was through a single dose of intra-tracheal bleomycin instillation (5mg/kg dissolved in phosphate buffer saline) in adult male albino Wistar rats. Next day of bleomycin instillation, intraperitoneal injection of RS-102221 (0.5mg/kg/d) and/or terguride (1.2mg/kg/d) were administered and continued for 14 days. Noticeable increase in 5-HT2C receptors expression was observed in fibrotic lung tissues with marked allocation belonging to alveolar macrophages. Either RS-102221 or terguride reduced the increments in lung water contents, grading of lung fibrosis, lung tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta1 (TGF-β1) and vascular endothelial growth factor (VEGF) levels in lung injury and fibrosis-induced by bleomycin. Moreover, collagen content and myofibroblasts-alpha smooth muscle actin (α-SМA) were significantly decreased. Additionally, the simultaneous administration of RS-102221 with terguride had a synergistic outcome compared to that obtained by individual monotherapy. These findings suggested the potential use of 5-HT2A/B/C antagonists as anti-fibrotic agents in lung fibrosis.

PD22-10 IMPACT OF COMBINATION THERAPY 5 - ARI + ALPHA - BLOCKERS ON ERECTILE DYSFUNCTION AND ALTERATION OF LIBIDO IN PATIENTS WITH LUTS / BPH: A SYSTEMATIC REVIEW WITH META-ANALYSIS

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Medical & Non-surgical Therapy1 Apr 2016PD22-10 IMPACT OF COMBINATION THERAPY 5 - ARI + ALPHA - BLOCKERS ON ERECTILE DYSFUNCTION AND ALTERATION OF LIBIDO IN PATIENTS WITH LUTS / BPH: A SYSTEMATIC REVIEW WITH META-ANALYSIS Giorgio Ivan Russo, Vincenzo Favilla, Tommaso Castelli, Salvatore Privitera, Sebastiano Cimino, and Giuseppe Morgia Giorgio Ivan RussoGiorgio Ivan Russo More articles by this author , Vincenzo FavillaVincenzo Favilla More articles by this author , Tommaso CastelliTommaso Castelli More articles by this author , Salvatore PriviteraSalvatore Privitera More articles by this author , Sebastiano CiminoSebastiano Cimino More articles by this author , and Giuseppe MorgiaGiuseppe Morgia More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1503AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Combination therapy with of 5-alpha reductase inhibitors (5-ARI) and alpha-blockers (AB) is the gold standard for the treatment of moderate-severe secondary to benign prostatic hyperplasia (BPH). Several clinical trials have already analyzed the overall impact of the medical treatment of LUTS/BPH on sexual sphere, but any one investigated the overall impact on erectile dysfunction (ED) and libido alterations (LA). The aim of this this systematic review and meta-analysis was to evaluate the impact of combination therapy on ED and LA from randomized clinical trial (RCT) METHODS We performed a search of the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, Cochrane Database of Systematic Review, and Web of Science, until December 2014. We conducted a meta-analysis to determine the impact of combination therapy (5ARI + AB) in determining the onset of ED or LA. A p value < 0.10 was used to denote the presence of heterogeneity. RESULTS Of the 103 studies reviewed, only five RCT were included, involving 6131 participants. The overall prevalence of erectile dysfunction was of 7.93%, 6.47% and4.66%in patients treated with combination therapy, 5ARI and AB respectively. The overall prevalence of altered libido was of 3.69%, 3.37% and 2.37% in patients treated with combination therapy, 5ARI and AB respectively. Combination therapy 5ARI + AB was found to be associated with increased risk of ED (OR = 1.81; p <0.00001) and LA (OR = 1:58; p = 0.03) compared to monotherapy with AB. The combination therapy was found to increase the risk of ED (OR = 1.25; p = 0.04) compared to monotherapy with 5ARI, but not the risk of LA (OR = 1:03; p = 0.84). Analyzing the individual monotherapies, therapy with alpha-blockers significantly reduces the risk of ED (OR = 0.70; p <0.01) and LA (OR = 0.67; p = 0.0.1) compared to treatment with 5ARI. CONCLUSIONS Combination therapy 5ARI + ABis associated with a higher risk of ED. In addition, 5ARI monotherapy has the same risk of the combination of having LA. These results could be taken into account during the counseling therapy in patients with LUTS/BPH. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e465 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Giorgio Ivan Russo More articles by this author Vincenzo Favilla More articles by this author Tommaso Castelli More articles by this author Salvatore Privitera More articles by this author Sebastiano Cimino More articles by this author Giuseppe Morgia More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Traitements comparés de la néovascularisation cornéenne : injections sous-conjonctivales de bévacizumab et/ou photothérapie dynamique

To evaluate and compare the efficacy of subconjunctival bevacizumab injections alone, photodynamic therapy alone and combined treatments for reduction of corneal neovascularization. This study was conducted as a prospective case series. A total of seven eyes of 7 patients with corneal neovascularization caused by ocular surface disorders including fungal infectious keratitis and penetrating keratoplasty were included in the study. Patients were randomized into the three following groups: patients in group A received a single subconjunctival injection of 10mg (0.4mL) of bevacizumab, patients in group B were treated with photodynamic therapy with verteporfin (6mg/m(2)) to the neovascularized area and those in group C received a subconjunctival injection of bevacizumab and photodynamic therapy 7 days later. Morphological changes in neovascularization were evaluated over 6 months using slit-lamp biomicroscopy and digital corneal photography. A computer-assisted semi-automatic analysis of the area of corneal neovascularization was performed with Image J software. Recession of corneal vessels was observed in all eyes at 1 month post-treatment. The neovascularized surface area in all groups combined showed a decrease in the first month after treatment and this decrease continued up to the 6th month. The surface area of corneal neovascularization decreased by 34.05±8.28% in group A (subconjunctival injection of bevacizumab), by 42.06±28.36% in group B (photodynamic therapy with verteporfin) and by 51.67±18.93% in group C (combined subconjunctival injection of bevacizumab and photodynamic therapy). A combined treatment consisting of a subconjunctival injection followed by a PDT session 7 days later might be more effective for the treatment of corneal neovascularisation. No serious local or systemic adverse events were observed. Our medium-term results suggest that combined subconjunctival injection of bevacizumab and photodynamic therapy with verteporfin might be used safely and effectively to reduce corneal neovascularization surface. This combined therapy may show a tendency toward greater efficacy than the individual monotherapies. Controlled prospective randomized multicentric trials with a larger sample size are necessary to assess long-term efficacy and to confirm these results.

A bi-functional antibody-receptor domain fusion protein simultaneously targeting IGF-IR and VEGF for degradation

Bi-specific antibodies (BsAbs), which can simultaneously block 2 tumor targets, have emerged as promising therapeutic alternatives to combinations of individual monoclonal antibodies. Here, we describe the engineering and development of a novel, human bi-functional antibody-receptor domain fusion molecule with ligand capture (bi-AbCap) through the fusion of the domain 2 of human vascular endothelial growth factor receptor 1 (VEGFR1) to an antibody directed against insulin-like growth factor – type I receptor (IGF-IR). The bi-AbCap possesses excellent stability and developability, and is the result of minimal engineering. Beyond potent neutralizing activities against IGF-IR and VEGF, the bi-AbCap is capable of cross-linking VEGF to IGF-IR, leading to co-internalization and degradation of both targets by tumor cells. In multiple mouse xenograft tumor models, the bi-AbCap improves anti-tumor activity over individual monotherapies. More importantly, it exhibits superior inhibition of tumor growth, compared with the combination of anti-IGF-IR and anti-VEGF therapies, via powerful blockade of both direct tumor cell growth and tumor angiogenesis. The unique “capture-for-degradation” mechanism of the bi-AbCap is informative for the design of next-generation bi-functional anti-cancer therapies directed against independent signaling pathways. The bi-AbCap design represents an alternative approach to the creation of dual-targeting antibody fusion molecules by taking advantage of natural receptor-ligand interactions.

From new findings in acne pathogenesis to new approaches in treatment.

Acne is a chronic disease of the pilosebaceous unit which is most common during adolescence. Four factors are believed to play a key role in the development of acne lesions: excess sebum production, disturbed keratinization within the follicle, colonization of the pilosebaceous duct by Propionibacterium acnes, and the release of inflammatory mediators into the skin. Consequently, in order to effectively and rapidly reduce acne lesions, treatments need to address as many of these underlying factors as possible. Currently, about half of patients have poor adherence to acne treatments. To overcome this limitation, treatments need to be developed which are well tolerated by patients, and easy for them to use, handle and apply. Topical monotherapies for acne such as retinoids and antimicrobials by themselves have a restricted range of actions against the pathogenic factors of acne. Instead, the Global Alliance to Improve Outcomes in Acne Group recommends combination therapy with a topical retinoid and an antimicrobial agent as the preferred approach for almost all acne patients. The principal advantage of such combinations is that they target more of the underlying pathogenic factors of acne than individual monotherapies and this results in faster and more complete clearing of acne lesions. Fixed-dose combinations are also more convenient than applying two medications separately, which leads to improved adherence with the regimen. By normalizing desquamation, the retinoid component of these combinations allows entry of the antimicrobial agent into the pilosebaceous unit resulting in faster clearance of P.acnes. In conclusion, topical retinoid/antimicrobial fixed-dose combinations represent a rational approach for the treatment of acne. They should be considered as the cornerstone of acne management and should be used much more in the future.

Cumulative, additive benefits of memantine-donepezil combination over component monotherapies in moderate to severe Alzheimer's dementia: a pooled area under the curve analysis.

IntroductionTreatment in moderate or severe Alzheimer’s disease (AD) often involves adding memantine to a cholinesterase-inhibitor (ChEI: donepezil, galantamine, rivastigmine). Evidence from six-month randomized trials and long-term observational studies supports superiority of memantine-ChEI combination to ChEI monotherapy. We utilized area-under-the-curve (AUC) analysis to assess six-month cumulative treatment efficacy of memantine-donepezil combination versus component monotherapies on individual clinical domains and on a composite index.MethodsData were pooled from 1,408 individuals with moderate to severe AD from four six-month randomized trials of memantine monotherapy (n = 570) or add-on therapy (donepezil-only subset: n = 847). AUC changes from baseline on measures of cognition (SIB), function (ADCS-ADL19), behavior (NPI), global status (CIBIC-Plus), and a composite index (4D-CI: equally weighted composite of four domain measures) were calculated using the trapezoidal rule and evaluated via analysis of covariance (ANCOVA) (2-sided-α = 0.05). AUC results were contrasted with visit-by-visit changes from baseline (“snapshot analysis”), performed using a mixed-effects model with repeated measures (MMRM).ResultsOver the entire six-month period, placebo-only treatment was associated with significant cumulative worsening on all outcomes. Memantine-donepezil combination showed significantly greater AUC improvements (point x week) on the SIB, NPI, and CIBIC-Plus than placebo-donepezil (SIB: 68.4 versus 32.0, P = 0.019; NPI: −74.3 versus −28.2, P = 0.003; CIBIC-Plus: −2.5 versus 1.4, P = 0.006) and memantine-only monotherapies (SIB: 68.4 versus 12.0, P <0.001; NPI: −74.3 versus −7.4, P <0.001; CIBIC-Plus: −2.5 versus 2.7, P <0.001), whereas these comparisons were not significant for the ADCS-ADL19 (memantine-donepezil (1.4) versus placebo-donepezil (−0.9), P = 0.407; versus memantine-only (−12.2), P = 0.310). Composite index analysis demonstrated significant cumulative advantages of memantine-donepezil combination (630.0) over placebo-donepezil (344.7, P <0.001) and memantine-only (152.1, P <0.001) treatments. Combining memantine and donepezil had an additive effect. Compared with AUC analysis, baseline-to-endpoint change-score analysis underestimated effects of combination therapy, monotherapies, or both.ConclusionsThis large pooled area-under-the-curve analysis of randomized-trial data in moderate to severe AD provides ecologically valid support that adding memantine to stable donepezil results in overall clinical benefits that are additive compared with individual monotherapies, continue to accumulate through six-month treatment, and are at least 50% greater than those of monotherapies.