Safety Of Combination Therapy Research Articles

Results of a Phase 2 Study of MEDI-551 and Bendamustine Vs Rituximab and Bendamustine in Relapsed or Refractory Chronic Lymphocytic Leukemia

Background: In patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), novel therapies are needed to prolong disease control. MEDI-551, an afucoslylated, affinity-optimized, anti-CD19 antibody, functions by antibody-dependent cellular cytotoxicity, with a 30% monotherapy response rate in CLL. A phase 2 randomized, open-label study (NCT01466153) is evaluating the clinical activity, efficacy, and safety of combination therapy with MEDI-551 + bendamustine compared with rituximab + bendamustine in R/R CLL patients.Methods: Patients were initially randomized to receive bendamustine 70 mg/m2 intravenously (IV) on days 1, 2 with either MEDI-551 2 or 4 mg/kg on days 2, 8 of cycle 1 (on day 1 of subsequent cycles) or rituximab 375 mg/m2 IV on day 1 of cycle 1 (then 500 mg/m2 IV on day 2 of subsequent cycles), for up to six 28-day cycles. The 4-mg/kg dose of MEDI-551 was selected for the final efficacy analysis against rituximab. Safety assessments included adverse events (AEs) and laboratory parameters. Disease response was determined using 2008 International Working Group criteria. Exploratory objectives included micro RNA (miRNA) expression levels before and after treatment.Results: As of March 2014, the safety population comprised 147 patients across all treatment arms. The median age was 66 years (range 41–81), with 11% of patients with deletion (del) (17p), 20% with del (11q), 30% with del (13q), 12% with trisomy 12, and 39% with unmutated immunoglobulin heavy chains (IgVH). The median number of treatment cycles was 4 (range 1–6). Treatment-related AEs observed in ≥20% of patients included nausea, infusion-related reactions (IRRs), nausea, fatigue, pyrexia, neutropenia, and cough in the MEDI-551 arm vs nausea, fatigue, constipation, asthenia, pyrexia, and neutropenia in the rituximab arm. Grade 3/4 treatment-related AEs are listed in the table.TableTreatment-Related Grade 3/4 AEs (≥5% of patients in any treatment group)Parameter, n (%)MEDI-551 + BendamustineRituximab + Bendamustine2 mg/kg(n=32)4 mg/kg(n=56)(n=59)Patients reporting ≥1 event20 (63)25 (45)29 (49)Neutropenia8 (25)9 (16)20 (34)IRR*6 (19)4 (7)1 (2)Thrombocytopenia2 (6)1 (2)5 (9)Lymphopenia2 (6)1 (2)4 (7)Anemia1 (3)03 (5)Fatigue003 (5)*Note: After 42 patients were enrolled in the study (all treatment groups), corticosteroid prophylaxis was recommended before patients receiving the initial dose of MEDI-551.Discontinuation of study treatment because of AEs occurred in 26% of patients receiving MEDI-551/bendamustine (including neutropenia, thrombocytopenia, bradycardia, abdominal pain, asthenia, fatigue, cytokine release syndrome, hypersensitivity, pneumonia, infusion-related reactions, elevated liver function tests, dehydration, hyponatremia, headache, depression, epistaxis, hypoxia, rash, and hypotension) and in 20% of those receiving rituximab/bendamustine (including febrile neutropenia, leukopenia, neutropenia, thrombocytopenia, cardiac failure, uveitis, small intestine obstruction, upper gastrointestinal hemorrhage, asthenia, fatigue, and systemic inflammatory response syndrome). No treatment-related deaths occurred in any treatment arm. Clinical activity was observed in both the MEDI-551 and rituximab arms, and a biomarker has been identified that may predict for MEDI-551 responders. Expression of a miRNA signature is specifically elevated in NHL patient samples. Low pretreatment levels of this miRNA signature in whole blood may predict for responders to MEDI-551. Three-fold lower levels (P<.0001) in pretreatment samples from MEDI-551 responders vs nonresponders were noted, but no differences in miRNA signature expression were noted between responders and nonresponders in the rituximab arm.Conclusions: Data show evidence of clinical activity in R/R CLL patients, with comparable safety observed between the MEDI-551 and rituximab arms. Expression level of a miRNA signature is able to predict for those more likely to respond to MEDI-551, with MEDI-551 responders having low pretreatment miRNA signature expression. DisclosuresGladstone:MedImmune: Research Funding. Andre:MedImmune: Research Funding. Zaucha:MedImmune: Research Funding. Assouline:MedImmune: Research Funding. Bellam:Genentech: Research Funding; Janssen: Research Funding; MedImmune: Research Funding; Facet: Research Funding. Cascavilla:MedImmune: Research Funding. Jourdan:MedImmune: Research Funding; Roche: Research Funding. Panwalkar:MedImmune: Research Funding. Patti:MedImmune: Research Funding. Zaja:MedImmune: Research Funding. Goswami:MedImmune: Employment; MedImmune: Stock ownership, Stock ownership Other. Elgeioushi:MedImmune: Employment; MedImmune: Stock ownership, Stock ownership Other. Streicher:MedImmune: Employment; MedImmune: Stock ownership, Stock ownership Other. Bao:MedImmune: Employment; MedImmune: Stock ownership, Stock ownership Other. Spaner:MedImmune: Research Funding.

Phase I/Ib Trial of the Efficacy and Safety of Combination Therapy with Lenalidomide/Bortezomib/Dexamethasone (RVD) and Panobinostat in Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma

Background: Induction therapy prior to consolidation with autologous stem cell transplantation (ASCT) continues to improve with the use of proteasome inhibitors and imids and combination regimens such as RVD. Bortezomib-based induction therapy has improved overall response rates (ORR) prior to transplant, which has translated to improvements in ORR and progression free survival post ASCT. However, complete remission (CR) rates with RVD remain low (10-15%) after 4 cycles of induction therapy. Panobinostat, a histone deacetylase inhibitor, in combination with bortezomib/dexamethasone, has demonstrated a significant improvement in depth of response and progression free survival in patients (pts) with relapsed myeloma as seen in PANORMA I. Preclinical data demonstrate synergy between the combination of bortezomib and panobinostat. We undertook a phase I/Ib trial in pts with newly diagnosed myeloma (NDMM) of RVD + Panobinostat to establish the safety of the combination and goal of improving the depth of response with induction therapy prior to ASCT.Methods: The primary objective was to determine the maximum tolerated dose (MTD) and safety/tolerability of RVD + panobinostat in NDMM. Secondary objectives were to determine efficacy as measured by the CR/nCR rate after 4 cycles, ORR, tolerability/toxicity, and progression free survival. Pts had to have NDMM with indication for therapy, candidates for ASCT with and had adequate organ function. Panobinostat was administered on days 1, 3, 5, 8, 10, 12; bortezomib 1.3 mg/m2 was administered subcutaneously on days 1, 4, 8, 11; lenalidomide 25 mg on days 1-14; dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 on a 21 day cycle. Dose-escalation of panobinostat used a standard 3+3 schema with dose-limiting toxicities (DLTs) assessed during cycle 1. Three dose levels were studied with Panobinostat escalated from 10 to 20 mg. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria.Results: 22 pts were enrolled; 12 pts in the completed phase 1 dose escalation portion of the study and 10/20 in the ongoing dose expansion. The median age was 61 (range 53-79); ISS stage I 12; stage II 7/20; stage III in 3/20 pts.No DLTs were observed in 3 pts dosed in cohort 1, with Panobinostat at 10 mg. In cohort 2, panobinostat was dosed at 15 mg, 2/6 pts encountered a DLT. One patient experienced Grade 4 (G4) thrombocytopenia, and the second patient had G3 diarrhea without supportive measures, for <12 hours and resolved with supportive measures. In cohort 1, 3 additional patients were enrolled and no DLTs were encountered in the remaining 3 pts. The final recommended dose was Panobinostat 10 mg in combination with RVD in NDMM.Treatment emergent SAEs related to therapy observed in 5 pts with 2 incidences of G3 diarrhea; 2 pts with atrial fibrillation; and other events included G4 thrombocytopenia; G3 bacteremia, G3 cellulitis, G3 myocardial infarction (MI), G3 pulmonary emboli; G3 pneumonia.Hematologic adverse events G3/4 included anemia 3/22; neutropenia 4/22; thrombocytopenia 7/22. G3/4 nonhematologic toxicities included ALT elevation (n=2); AST elevation (n=1); constipation (n=2); diarrhea (n=2); fatigue/muscle weakness (n=2); MI (n=1); pneumonia (n=3).Among 18/22 pts who have completed 4 cycles of therapy and are evaluable for efficacy, the ORR (≥PR) was 100%: including nCR/CR in 5/18 (28%), VGPR in 5/18 (28%), PR in 8/18 (44%).Conclusions: MTD has been established at level 1, with panobinostat 10 mg and full dose RVD in NDMM. The DLTs were diarrhea (irrespective of supportive care) and thrombocytopenia. This is the first experience with panobinostat and subcutaneous bortezomib and first experience in combination with RVD. The combination is well tolerated with limited toxicity and side effects can be managed with supportive care. The preliminary activity after 4 cycles of therapy demonstrated a high ORR of 100% and a promising depth of response with a nCR/CR of 27%. Enrollment in a dose expansion cohort is near completion and full data will be presented at ASH. DisclosuresShah:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Array: Consultancy, Research Funding. Off Label Use: Carfilzomib for use in front-line tx of multiple myeloma . Weber:OncPep: Research Funding. Thomas:Novartis, Celgene, Millenium, Idera Pharmaceuticals: Consultancy, Research Funding. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Combined use of systemic agents for psoriasis: a systematic review.

Combined use of systemic agents may be necessary to achieve disease control in therapy-resistant patients. However, to our knowledge, an overview of evidence, including quality assessments, is not yet available, and no guidance on monitoring, contraindications, and interactions exists. To summarize and critically appraise the evidence on efficacy and safety of combination therapy with systemic agents in plaque-type psoriasis. Through March 2013, an electronic search limited to randomized clinical trials was performed in MEDLINE, EMBASE, The Cochrane Library, and ongoing trial registers. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. The initial search retrieved 2583 records, of which 17 met the inclusion criteria. Most studies favored combination therapy, albeit with low significance and low quality of evidence. Etanercept plus methotrexate was the only combination therapy investigated with an adequate sample size (n = 478). In the short term, this combination had superior efficacy with a moderate quality of evidence compared with etanercept monotherapy (Psoriasis Area and Severity Index, 75; relative risk, 1.28; 95% CI, 1.14-1.45). Although this finding coincided with an increase in adverse events (relative risk, 1.25; 95% CI, 1.10-1.42), the overall safety profile remained acceptable. This systematic review provides a comprehensive overview on the validity of different systemic combination therapies. For most combinations, insufficient evidence is available. Initial results indicate that combined therapy with etanercept plus methotrexate may be beneficial in patients that are therapy resistant under intensive follow-up. Dose reductions should be taken into account to minimize adverse effects.

Эффективность и безопасность комбинированной терапии на основе хлорталидона и атенолола в одной таблетке (тенорик) у пациентов с гипертонической болезнью: первые результаты Всеукраинского научно-исследовательского проекта TRUST

Целью настоящей работы является оценка эффективности и безопасности комбинированной терапии на основе хлорталидона и атенолола в одной таблетке (тенорик) у пациентов с гипертонической болезнью.В исследовании принимали участие 330 врачей первичного контакта из различных регионов Украины. Всего в исследование было включено 3000 больных с уровнем артериального давления (АД) 140/90 мм рт.ст. и выше. В основе настоящей статьи лежит анализ первых 1798 пациентов, включенных в исследование. Первичной конечной точкой исследования было снижение АД у включенных в исследование пациентов.Шестинедельная терапия тенориком обеспечивала эффективное снижение уровня артериального давления у 97,7 % больных гипертонической болезнью I–II стадии с 1–3-й степенью повышения артериального давления. При этом целевой уровень артериального давления (менее 140/90 мм рт.ст.) был достигнут у 53,9 % пациентов. На фоне лечения наблюдалось прогрессирующее (возрастающее по мере длительности приема препарата) достоверное снижение уровня как САД, так и ДАД с достижением уровня 135/80 мм рт.ст. на 4-м визите через 6 недель. Таким образом, снижение АД составило 31/19 мм рт.ст. Кроме этого, отмечалось снижение частоты сердечных сокращений на 17 уд/мин, которая на последнем визите достигла в среднем 71 уд/мин. Наиболее частым побочным эффектом была головная боль (17,7 %), а также покраснение кожных покровов (8 %). Оба побочных эффекта не требовали отмены препарата. Число пациентов, у которых исходно наблюдалась гипокалиемия (уровень калия в сыворотке ниже 3,5 ммоль/л), составило 8,3 % (21 пациент). На фоне лечения снижение уровня сывороточного калия ниже указанного предела наблюдалось еще у 6 больных, что составило 11,7 % (27 пациентов). Особого внимания требует оценка частоты брадикардии (5,2 %) и блокад сердца (0,5 %). Это наиболее серьезные побочные эффекты, которые требовали пересмотра дозировок или даже отмены препарата. Препарат был отменен всего у 51 больного (3,1 %).Таким образом, терапия тенориком по указанной схеме в течение 6 недель обеспечивала эффективное снижение уровня АД у 97,7 % больных гипертонической болезнью I–II стадии с 1–3-й степенью повышения АД.

Phase || Study of Pemetrexed + Carboplatin + Bevacizumab As First-Line Therapy for Nonsquamous Non-Small Cell Lung Cancer with Egfr Mutation, Result of Induction Therapy: Central Japan Lung Study Group (Cjlsg) 0910 Trial

ABSTRACT Aim: In advanced non-squamous (sq) non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation (MT), EGFR-tyrosine kinase inhibitor (TKI) showed better response rate (RR) and longer progression-free survival (PFS) than standard chemotherapy, but showed almost the same overall survival (OS). Recently, chemotherapy with bevacizumab (Bev) showed higher RR, and maintenance therapy with Bev or pemetrexed (Pem) showed longer PFS. But, there have been few reports of chemotherapy with Pem and Bev including maintenance therapy in patients(pts) with EGFR-MT. According to the result of IPASS study, response to standard chemotherapy in pts with EGFR-MT is also better than in pts without EGFR mutation. Therefore, we thought chemotherapy containing Pem and Bev may be more effective in EGFR-MT pts. This study was designed to evaluate the efficacy and safety of combination therapy with Pem, carboplatin (Cb) and Bev followed by Pem plus Bev maintenance therapy for non-sq NSCLC pts with EGFR-MT. Methods: Patients receive Pem 500mg/m2 day1 + Cb AUC 6 day1 + Bev 15mg/kg day1, every 3 weeks, 4-6 cycles (induction therapy. Patients who achieved disease control receive Pem 500mg/m2 day1 + Bev 15mg/kg day1, every 3 weeks until disease progression (maintenance therapy). Key inclusion criteria are as follows: histologically or cytologically proven non-sq NSCLC, EGFR mutation (exon 19 deletion or L858R), stage IIIB or IV, or recurrent disease after surgery (rec), no prior chemotherapy, age: 20-74. Results: Thirty-two eligible pts were enrolled between July 2010 and July 2012, two pts refused after enrollment . The median age was 65.5 years (range, 47–74); 13/17 males/females; 1/27/2 with IIIB/IV/rec; 29/1/ with adenocarcinoma/large cell carcinoma. In the induction therapy, the median number of cycles was 6. In 29 pts, there were 15 partial responses with an RR of 51.7% . SD was observed in 14 pts and DCR was 100% and 24 pts (82.7%) followed by maintenance therapy. Major adverse events were grade 3-4 neutropenia in 14 pts (46.7%), grade 3 anemia in 6 pts (20.0%), grade 3-4 thrombocytopenia in 6 pts (20.0%), grade 3 diarrhea in 2 pts(6.7%), grade 3 nausea and grade 3 anorexia in 1 pt (3.3%). There was no treatment-related death. Conclusions: This study suggested that chemotherapy, including maintenance therapy is also useful in patients with EGFR-MT. Disclosure: All authors have declared no conflicts of interest.

Efficacy of entecavir-tenofovir combination therapy for chronic hepatitis B patients with multidrug-resistant strains.

The emergence of multidrug-resistant (MDR) strains of hepatitis B virus (HBV) is a major concern. This study aimed to investigate the efficacy and safety of combination therapy with entecavir (ETV) plus tenofovir disoproxil fumarate (TDF) against MDR HBV. To adjust for differences in baseline characteristics, inverse probability weighting (IPW) using propensity scores for the entire cohort and weighted Cox proportional hazards models were applied. Ninety-three consecutive patients who were treated with ETV-TDF combination therapy for >6 months were included; at baseline, 45 were infected with HBV strains with genotypic resistance to lamivudine (LAM) and ETV (the LAM/ETV-R group), 28 with strains resistant to LAM and adefovir (ADV) (the LAM/ADV-R group), and 20 with strains resistant to LAM, ETV, and ADV (the LAM/ETV/ADV-R group). The median duration of rescue therapy was 13.0 (range, 6.7 to 31.7) months. Seventy-four of 93 patients (79.6%) achieved complete virologic suppression, after a median of 4.5 (95% confidence interval, 3.0 to 6.0) months. The cumulative probability of complete virologic suppression at month 6 was 63.6% (55.7%, 75.0%, and 65.0% in the LAM/ETV-R, LAM/ADV-R, and LAM/ETV/ADV-R groups, respectively). During the treatment period, these probabilities were not significantly different across the resistance profiles before and after IPW (P = 0.072 and P = 0.510, respectively). In multivariate analysis, a lower baseline HBV DNA level, but not resistance profiles, was an independent predictor of complete virologic suppression. Renal dysfunction was not observed during the treatment period. In conclusion, rescue therapy with ETV-TDF combination is efficient and safe in patients infected with MDR HBV strains regardless of the antiviral drug resistance profiles.

Long-term Safety and Efficacy of Single-tablet Combinations of Solifenacin and Tamsulosin Oral Controlled Absorption System in Men with Storage and Voiding Lower Urinary Tract Symptoms: Results from the NEPTUNE Study and NEPTUNE II Open-label Extension

BackgroundShort-term trials have demonstrated the efficacy and safety of combination therapy using antimuscarinics and α-blockers in men with lower urinary tract symptoms (LUTS). The Study of Solifenacin Succinate and Tamsulosin Hydrochloride OCAS (oral controlled absorption system) in Males with Lower Urinary Tract Symptoms (NEPTUNE) II is the first long-term study using solifenacin (Soli) and the oral controlled absorption system formulation of tamsulosin (TOCAS). ObjectiveTo evaluate long-term (up to 52 wk) safety and efficacy of flexible dosing of two fixed-dose combinations (FDC) of Soli plus TOCAS in men with moderate to severe storage symptoms and voiding symptoms. Design, setting, and participantsPatients with both storage and voiding LUTS, maximum urinary flow rate of 4.0–12.0ml/s, prostate size <75ml, and postvoid residuals ≤150ml, who completed the 12-wk, double-blind NEPTUNE study could continue in the 40-wk, open-label NEPTUNE II study. InterventionFDC of Soli 6mg plus TOCAS 0.4mg, or Soli 9mg plus TOCAS 0.4mg; patients could switch between doses in NEPTUNE II. Outcome measurements and statistical analysisSafety and efficacy data from NEPTUNE and NEPTUNE II were combined to cover a 52-wk period. Primary efficacy end points were total International Prostate Symptom Score (IPSS) and total urgency and frequency score (TUFS); secondary end points included IPSS storage and voiding subscores, micturition diary variables, and quality of life parameters. ResultsIn all, 1066 men completed NEPTUNE and received one dose or more of study medication in NEPTUNE II. Treatment-emergent adverse events were reported in 499 (46.8%) patients who participated in NEPTUNE II; most were mild or moderate. Urinary retention occurred in 13 of 1208 (1.1%) patients receiving one or more FDCs in NEPTUNE and/or NEPTUNE II; 8 (0.7%) required catheterisation (acute urinary retention [AUR]). Reductions in total IPSS and TUFS during NEPTUNE were maintained for up to 52 wk of FDC treatment, with mean reductions of 9.0 (standard deviation [SD]: 5.7) and 10.1 (SD: 9.2), respectively, from baseline to end of treatment. Clinically relevant improvements were also observed for secondary efficacy end points. ConclusionsLong-term treatment with FDC Soli plus TOCAS was well tolerated and efficacious in men with storage and voiding LUTS, with a low incidence of AUR. Patient summaryTreatment with solifenacin plus tamsulosin in a fixed-dose combination tablet was well tolerated by men with lower urinary tract symptoms. Improvements in symptoms were achieved after 4 wk of treatment, with further improvements at week 16 maintained for up to 52 wk throughout the study.

Efficacy and Safety of Combination Therapy With Tacrolimus and Sirolimus in Immunological High Risk Kidney Transplant Recipients.

Objective: The aim of this study was to evaluate the efficacy and safety of combination therapy with tacrolimus and sirolimus in immunological high risk recipients. Methods: From January 2010 to December 2011, 28 immunological high risk patients were enrolled according to the following criteria: 1) retransplantation, 2) Class I or II PRA >50%, 3) 5 or 6 HLA mismatches The efficacy endpoints were incidence of biopsy-proven acute rejection reaction, graft loss, patient death and renal function. The safety was evaluated by analyzing the adverse effects. Results: Among 28 total patients, 8 (28.6%) were dropped due to acute rejection, infection, pneumonitis, or postoperative hemorrhage. One patient death occurred due to fungal infection. Acute rejection developed in 6 (21.4%) patients. The mean eGFR (MDRD) for the 1st year after transplantation was 52.0 ± 4.0 mL/min/1.73m2. Fifteen (53.6%) patients had infections and 3 (10.7%) patients experienced pneumonitis. Lymphocele developed in 4 (14.3%) patients. Conclusion: The combination therapy with tacrolimus and sirolimus must be considered with caution for immunological high risk recipients due to high incidence of adverse events. Special attention should be given to the target blood concentration levels of the two drugs in order to minimize adverse events.

Safety of eptifibatide when added to bivalirudin during ST-segment elevation myocardial infarction

Patients presenting with ST-segment elevation myocardial infarction (STEMI) represent a high-risk group for in-hospital adverse events and bleeding. The safety and outcomes of eptifibatide in addition to bivalirudin in this population have not been determined. Over an 11-year period, we identified 1849 STEMI patients undergoing primary percutaneous coronary intervention (PCI), of which 1639 received bivalirudin monotherapy compared with 210 patients who received both bivalirudin and provisional eptifibatide. Safety of combination therapy was assessed by the occurrence of thrombolysis in myocardial infarction (TIMI) major bleeding. In-hospital event rates of death, Q-wave myocardial infarction (MI), and acute stent thrombosis were evaluated for efficacy. Multivariate analysis was used to adjust for significant differences between groups. Patients treated with bivalirudin plus eptifibatide, when compared with patients with bivalirudin monotherapy, had increased rates of cardiogenic shock (15.7% vs. 9.4%), aspiration thrombectomy (48.5% vs. 23.7%), pre-TIMI flow ≤1 (63.5% vs. 40%), and higher peak troponin I (93.65±92.7 vs. 49.16±81.59; all p <0.01). These, however, were not associated with differences in the primary end point after adjusting for significant baseline and procedural characteristics (OR: 1.63; 95% CI, 0.90-2.96, p=0.12). Importantly, TIMI major bleeding was not significantly different between groups (OR 1.78; 95% CI, 0.79-2.95, p=0.20). The addition of eptifibatide to bivalirudin during primary PCI reflects a high-risk STEMI population. This therapy results in similar in-hospital outcomes without an increase in major bleeding. Therefore, when required, combination therapy may be considered in this population.

A randomized controlled trial of combination treatment with ketoconazole 2% cream and adapalene 0.1% gel in pityriasis versicolor

Background: Ketoconazole cream and adapalene gel are effective drugs against pityriasis versicolor. However, there are no reports on combination treatment with both compounds in pityriasis versicolor. Objective: To evaluate the efficacy and safety of combination therapy with adapalene 0.1% gel and ketoconazole 2% cream against pityriasis versicolor. Methods: Participants with pityriasis versicolor were randomly assigned to two groups: the combination group was treated with adapalene 0.1% gel and ketoconazole 2% cream once daily, and the monotherapy group received ketoconazole 2% cream twice daily. The treatment lasted 2 weeks in both groups. Outcomes were assessed at baseline and 1, 2 and 4 weeks after the initiation of treatment. Results: We noted clinically significant differences in total improvement rates between groups Weeks 1 and 2. A statistically significant difference was obtained Week 4. The treatment was well tolerated by all participants. Conclusions: The combination of adapalene 0.1% gel and ketoconazole 2% cream is effective and safe in the treatment of pityriasis versicolor. This therapeutic regimen was rapid, providing a valuable option for patients with pityriasis versicolor.

Outcomes of combination therapy with dexamethasone implant and bevacizumab in macular edema related to vascular occlusions

AimTo evaluate the anatomical and visual outcomes as well as the safety of combination therapy with dexamethasone intravitreal implant (0.7 mg) and bevacizumab in macular edema secondary to vascular occlusions. MethodsIn this interventional, prospective case series all patients received dexamethasone implant and bevacizumab in a single sitting. Patients diagnosed with retinal venous occlusion were monitored for changes in visual acuity and macular thickness. All patients underwent detailed ocular examination, best corrected visual acuity (BCVA), and optical coherence tomography examination at baseline and at Week 1, Month 1, and monthly thereafter for 6 months. ResultsTwenty four eyes of 24 treatment-naïve patients (central retinal venous occlusion, n = 9; branch retinal venous occlusion, n = 15) were identified. BCVA improved in 23 patients (95.83%) during the study period. Mean BCVA gained was 0.313 ± 0.26 (85.3% of final gain) and 0.367 ± 0.34 at Week 1 and Month 6, respectively. The percentage of patients who gained ≥2 lines were 52% at Week 1 and 68% at Month 6. The mean macular thickness reduced by 350.9 μm at Week 1 and the maximum treatment effect was seen at Month 2 (379.1 μm). Recurrence of macular edema was seen in 37.5% (9/24) of the eyes. Reinjection was needed, on average, at approximately 3.7 months from the first injection. ConclusionThis study demonstrates that the combination therapy of bevacizumab and dexamethasone implant given simultaneously is safe and synergistic resulting in significantly early and sustained visual recovery and decreased macular edema in patients having retinal vein occlusions.

Peginterferon alfa-2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 2 receiving haemodialysis: a randomised trial

ObjectiveData comparing the efficacy and safety of combination therapy with peginterferon plus low-dose ribavirin and peginterferon monotherapy in treatment-naive haemodialysis patients with hepatitis C virus genotype 2 (HCV-2) infection are...

80. Tolerability and Safety of Combination Therapy with Methotrexate and Leflunomide in Rheumatoid Arthritis

80. Tolerability and Safety of Combination Therapy with Methotrexate and Leflunomide in Rheumatoid Arthritis

Safety of regular formoterol or salmeterol in adults with asthma: an overview of Cochrane reviews

Background Two large surveillance studies in adults with asthma have found an increased risk of asthma-related mortality in those who took regular salmeterol as monotherapy in comparison to placebo or regular salbutamol. No similar sized surveillance studies have been carried out in children with asthma, and we remain uncertain about the comparative safety of regular combination therapy with either formoterol or salmeterol in children with asthma.

Efficacy and Safety of Combination Therapy With Everolimus and Sorafenib for Recurrence of Hepatocellular Carcinoma After Liver Transplantation

BackgroundRecurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin/protein kinase B pathways in the pathogenesis of HCC and is being investigated in clinical practice. MethodsThis was a single-center retrospective analysis on LT recipients with unresectable HCC recurrence and undergoing combination therapy with EVL and SORA. Patients were included if they were switched to EVL+SORA at any time after surgery. Primary endpoint was overall survival (OS) after both LT and recurrence, and response to treatment based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in the intention-to-treat (ITT) population. Secondary analysis was safety of combination therapy with EVL and SORA in the population of patients who received ≥1 dose of the study drug. ResultsSeven patients (100% male; median age 53 years [interquartile range (IQR) 9 years]) were considered for analysis. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVL+SORA at a median interval since LT of 11 (126) months. Baseline immunosuppression was with tacrolimus (TAC) in 2 patients (28.6%), cyclosporine (CsA) in 2 (28.6%), and EVL monotherapy in 3 (42.8%). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4%) were alive, 4 of them (57.1%) with tumor progression according to the mRECIST criteria. Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months owing to tumor progression in 1 patient (14.3%) and sepsis in the other (14.3%). EVL monotherapy was achieved in 6 patients (85.7%), whereas 1patient (14.3%) could not withdraw from calcineurin inhibitor owing to acute rejection. Treatment complications were: hand-foot syndrome in 5 patients (71.4%), hypertension in 1 (14.3%), alopecia in 1 (14.3%), hypothyroidism in 1 (14.3%), diarrhea in 2 (28.6%), pruritus in 1 (14.3%), abdominal pain in 1 (14.3%), rash in 1 (14.3%), asthenia in 3 (42.8%), anorexia in 3 (42.8%), and hoarseness in 2 (28.6%). Adverse events led to temporary SORA discontinuation in 2 patients (28.6%) and to SORA dose reduction in 3 (42.8%). ConclusionsTreatment of HCC recurrence after LT with a combination regimen of EVL+ SORA is challenging because of SORA-related complications. Longer follow-up periods and larger series are needed to better capture the impact of such combination treatment on tumor progression and patient survival.

Pegylated Interferon-α2a With or Without Low-Dose Ribavirin for Treatment-Naive Patients With Hepatitis C Virus Genotype 1 Receiving Hemodialysis

Data are limited on the efficacy and safety of pegylated interferon plus ribavirin for patients with hepatitis C virus genotype 1 (HCV-1) receiving hemodialysis. To compare the efficacy and safety of combination therapy with pegylated interferon plus low-dose ribavirin and pegylated interferon monotherapy for treatment-naive patients with HCV-1 receiving hemodialysis. Open-label, randomized, controlled trial. (ClinicalTrials.gov: NCT00491244). 8 centers in Taiwan. 205 treatment-naive patients with HCV-1 receiving hemodialysis. 48 weeks of pegylated interferon-α2a, 135 µg weekly, plus ribavirin, 200 mg daily (n = 103), or pegylated interferon-α2a, 135 µg weekly (n = 102). Sustained virologic response rate and adverse event-related withdrawal rate. Compared with monotherapy, combination therapy had a greater sustained virologic response rate (64% vs. 33%; relative risk, 1.92 [95% CI, 1.41 to 2.62]; P < 0.001). More patients receiving combination therapy had hemoglobin levels less than 8.5 g/dL than those receiving monotherapy (72% vs. 6%; risk difference, 66% [CI, 56% to 76%]; P < 0.001). Patients receiving combination therapy required a higher dosage (mean, 13 946 IU per week [SD, 6449] vs. 5833 IU per week [SD, 1169]; P = 0.006) and longer duration (mean, 29 weeks [SD, 9] vs. 18 weeks [SD, 7]; P = 0.004) of epoetin-β than patients receiving monotherapy. The adverse event-related withdrawal rates were 7% in the combination therapy group and 4% in the monotherapy group (risk difference, 3% [CI, -3% to 9%]). Open-label trial; results may not be generalizable to patients on peritoneal dialysis. In treatment-naive patients with HCV-1 receiving hemodialysis, combination therapy with pegylated interferon plus low-dose ribavirin achieved a greater sustained virologic response rate than pegylated interferon monotherapy. National Center of Excellence for Clinical Trial and Research.

Clinical effectiveness and safety of combined therapy with solifenacin and tamsulosin for patients with type III prostatitis

Objective To evaluate the efficacy and safety of the combined therapy of tamsulosin and solifenacin for type Ⅲ prostatitis patients.Methods From May 2010 to September 2011,160 patients diagnosed as type Ⅲ prostatitis were included in this prospective study.All the 160 patients were randomly divided into 2 groups:combined therapy group (n =80) in which patients were treated with tamsulosin 0.2 mg once daily and solifenacin 5 mg once daily for 12 weeks,and tamsulosin group (n =80) in which patients were treated with tamsulosin 0.2 mg once daily for 12 weeks.NIH chronic prostatitis symptom index (NIH-CPSI),overactive bladder symptom score (OABSS) and white blood cell (WBC) counts in expressed prostate secretion (EPS) were evaluated before and after treatment.Results At baseline there was no significant difference between the 2 groups.The NIH-CPSI (32.29±5.58 versus 16.03±4.41),OABSS (9.56± 1.91 versus 5.03± 1.16) and EPS WBC count (9.75±2.24 versus 9.08±2.26) significantly decreased in the combined therapy group after 12 weeks treatment (P＜0.01).The NIH-CPSI (32.31 ±5.61 versus 24.28±4.75) (P＜0.01) also significantly decreased in tamsulosin group after 12 weeks treatment.There was no significant decrease for OABSS (9.46± 1.89 versus 9.28±2.20) and EPS WBC count (9.71±2.14 versus 9.12± 1.99) in tamsulosin group after treatment (P＞0.05).The NIH-CPSI and OABSS in combination group after treatment were significantly lower than those in tamsulosin group (P＜ 0.01).Conclusion Combined therapy with solifenacin and tamsulosin can improve the symptoms for patients with type Ⅲ prostatitis better than tamsulosin monotherapy. Key words: Prostatitis; Solifenacin; Adrenergic alpha-antagonists; Drug therapy, combination; Prospective studies

A luteinizing hormone-releasing hormone agonist plus an aromatase inhibitor as second-line endocrine therapy in premenopausal females with hormone receptor-positive metastatic breast cancer

The aim of the current study was to explore the efficacy and safety of combination therapy using a luteinizing hormone-releasing hormone (LHRH) agonist plus an aromatase inhibitor (AI) as second-line therapy in premenopausal females with hormone receptor (HR)-positive recurrent or metastatic breast cancer (MBC). A retrospective analysis was conducted in patients registered in the breast cancer database of our institution between January 2001 and December 2012. The breast cancer database identified 14 premenopausal patients who had been treated with an LHRH agonist plus AI for HR-positive recurrent or MBC. Fourteen patients with recurrent breast cancer (N = 10) or metastatic disease at primary diagnosis (N = 4) were included in the present study. All patients had previously been treated with an LHRH agonist plus tamoxifen. The clinical benefit rate was 71.4% and the median TTP was 11 months (95% confidence interval 1.7-20.3 months). One patient discontinued treatment because of liver dysfunction (grade 3). The combination of an LHRH agonist plus an AI is a treatment option for premenopausal females with HR-positive MBC that can prolong the chemotherapy-free interval and yield effective disease stabilization.

Clinical Improvement of Striae Distensae in Korean Patients Using a Combination of Fractionated Microneedle Radiofrequency and Fractional Carbon Dioxide Laser

Striae distensae are dermal scars with flattening and atrophy of the epidermis. To evaluate the efficacy and safety of combination therapy with fractionated microneedle radiofrequency (RF) and fractional carbon dioxide (CO2) laser in the treatment of striae distensae. Thirty patients (30 female; mean age 33, range 21-51, Fitzpatrick skin type IV) with moderate to severe striae distensae were enrolled in this study. Patients were divided into three groups: fractional CO2 laser only (n = 10), microneedle RF only (n = 10), and combination (n = 10). Improvement was evaluated using a visual analogue scale (range 1-4). Mean clinical improvement score of the dermatologist was 2.2 in the fractional CO2 laser-treated group, 1.8 in the microneedle RF-treated group, and 3.4 in the combination group. Through skin biopsy, we observed thickened epidermis and a clear increase in the number of collagen fibers in the microneedle RF- and fractional CO2 combination-treated sites. Consistent with these results, greater expression of transforming growth factor-β1 and stratifin was observed in treated sites. Combination therapy of fractionated microneedle RF and fractional CO2 laser is a safe treatment protocol with a positive therapeutic effect on striae distensae.

The efficacy and safety of aspirin plus dipyridamole versus aspirin in secondary prevention following TIA or stroke: A meta-analysis of randomized controlled trials

ObjectiveStroke is becoming a common disease worldwide, and has an increased rate of recurrence yearly after a transient ischemic attack (TIA) or stroke. Aspirin, dipyridamole, clopidogrel and aspirin plus dipyridamole combination therapy have been recommended for the secondary prevention of stroke in Americans. DesignWe performed meta-analyses to assess the effectiveness and safety of combination therapy with aspirin and dipyridamole (A+D) versus aspirin (A) alone in secondary prevention after transient ischemic attack (TIA) or stroke of presumed arterial origin within one week and six months. Data sourcesMedline, Embase, and the Cochrane Library. Selection of studiesEligible studies were completed randomized controlled trials investigating the effect of aspirin plus dipyridamole versus aspirin in patients with previous TIA or stroke. ResultsFive trials involving the use of aspirin and dipyridamole were included, 4318 allocated to A+D and 4304 to A alone. Meta-analysis of trials showed a significant protective effect of reducing or preventing recurrence of stroke (P=0.01), and ischemic event (P=0.003). The statistics showed no significant difference in vascular event, death from all cause and myocardial infarction (P>0.05). There were similarities with all bleeding events, major bleeding and intracranial hemorrhage was significant (P>0.05) between two groups. ConclusionsAspirin plus dipyridamole combination therapy was beneficial in reducing the recurrence of stroke, and did not increase the bleeding event. Hence, aspirin plus dipyridamole combination therapy is effective and safe for the secondary prevention of stroke.