Short-term Combination Therapy Research Articles

Carbonic Anhydrase IX Suppression Shifts Partial Response to Checkpoint Inhibitors into Complete Tumor Eradication: Model-Based Investigation.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of solid malignancies, including non-small-cell lung cancer. However, immunotherapy resistance constitutes a significant challenge. To investigate carbonic anhydrase IX (CAIX) as a driver of resistance, we built a differential equation model of tumor-immune interactions. The model considers treatment with the small molecule CAIX inhibitor SLC-0111 in combination with ICIs. Numerical simulations showed that, given an efficient immune response, CAIX KO tumors tended toward tumor elimination in contrast to their CAIX-expressing counterparts, which stabilized close to the positive equilibrium. Importantly, we demonstrated that short-term combination therapy with a CAIX inhibitor and immunotherapy could shift the asymptotic behavior of the original model from stable disease to tumor eradication. Finally, we calibrated the model with data from murine experiments on CAIX suppression and combination therapy with anti-PD-1 and anti-CTLA-4. Concluding, we have developed a model that reproduces experimental findings and enables the investigation of combination therapies. Our model suggests that transient CAIX inhibition may induce tumor regression, given a sufficient immune infiltrate in the tumor, which can be boosted with ICIs.

Therapeutic inhibition of Bmi-1 ablates chemoresistant cancer stem cells in adenoid cystic carcinoma

ObjectivesAdenoid Cystic Carcinomas (ACC) typically show modest responseto cytotoxic therapy. Cancer stem cells (CSC) have been implicated in chemoresistance and tumor relapse. However, their role in ACC remains unknown. The purpose of this work was to evaluate the impact of targeting ACC CSCs with Bmi-1 inhibitors on resistance to cytotoxic therapy and tumor relapse. Materials and methodsTherapeutic efficacy of a small molecule inhibitor of Bmi-1 (PTC596; Unesbulin) and/or Cisplatin on ACC stemness was evaluated in immunodeficient mice harboring PDX ACC tumors (UM-PDX-HACC-5) and in human ACC cell-lines (UM-HACC-2A,-14) or low passage primary human ACC cells (UM-HACC-6). The effect of therapy on stemness was examined by salisphere assays, flow cytometry for ALDH activity and CD44 expression, and Western blots for Bmi-1 (self-renewal marker) and Oct4 (embryonic stem cell marker) expression. ResultsPlatinum-based agents (Cisplatin, Carboplatin) induced Bmi-1 and Oct4 expression, increased salisphere formation and the CSC fraction in vitro and in vivo. In contrast, PTC596 inhibited expression of Bmi-1, Oct4 and pro-survival proteins Mcl-1 and Claspin; decreased the number of salispheres, and the fraction of ACC CSCs in vitro. Silencing Claspin decreased salisphere formation and CSC fraction. Both, single agent PTC596 and PTC596/Cisplatin combination decreased the CSC fraction in PDX ACC tumors. Notably, short-term combination therapy (2 weeks) with PTC596/Cisplatin prevented tumor relapse for 150 days in a preclinical trial in mice. ConclusionTherapeutic inhibition of Bmi-1 ablates chemoresistant CSCs and prevents ACC tumor relapse. Collectively, these results suggest that ACC patients might benefit from Bmi-1-targeted therapies.

Combination biologic therapy for ulcerative colitis

In The Lancet Gastroenterology & Hepatology, Brian Feagan and colleagues report the results of VEGA, the first randomised, controlled trial investigating the efficacy and safety of short-term combination therapy with biologics in patients with moderate-to-severe ulcerative colitis. 1 Feagan BG Sands BE Sandborn WJ et al. Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial. Lancet Gastroenterol Hepatol. 2023; (published online Feb 1.)https://doi.org/10.1016/S2468-1253(22)00427-7 Google Scholar Patients were randomly assigned (1:1:1) to receive anti-tumour necrosis factor (TNF) inhibitor golimumab, interleukin (IL)-23p19 inhibitor guselkumab, or combined therapy with both golimumab and guselkumab, referred to as combined therapy hereafter. The primary endpoint of the trial was clinical response at week 12. At week 12, 59 (83%) of 71 patients in the combination therapy group had achieved clinical response compared with 44 (61%) of 72 patients in the golimumab monotherapy group (adjusted treatment difference 22·1% [80% CI 12·9 to 31·3]; nominal p=0·0032) and 53 (75%) of 71 patients in the guselkumab monotherapy group (adjusted treatment difference 8·5% [–0·2 to 17·1; nominal p=0·2155). However, the prespecified criterion for significance (the superiority of combination therapy to both monotherapy groups for the primary endpoint at the two-sided significance level of 0·2) was not met. The fact that the primary endpoint of the trial was not met does not detract from the importance of the study findings: twice as many patients in the combination therapy group achieved the more stringent endpoint of clinical remission when compared with either monotherapy group. At weeks 12 and 38, the proportion of patients who met other objective endpoints, including endoscopic, histological, and composite histological-endoscopic endpoints was numerically higher in the combination therapy group than either monotherapy. Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trialData from this proof-of-concept study suggest that combination therapy with guselkumab and golimumab might be more effective for ulcerative colitis than therapy with either drug alone. These findings require confirmation in larger trials. Full-Text PDF

Short-term combined therapy of yoga, ayurveda and naturopathy for dyslipidaemia: a case report

Hyperlipidemia is a condition which comprises several acquired and genetic disorders that cause elevated lipid levels in the body. The elevated lipids may further lead to various health complications such as arteriosclerosis, cardiovascular disease, cerebrovascular and peripheral vascular diseases. A 41-year-old male, non-alcoholic, non-smoking, vegetarian, and self-employed patient reported with chronic abnormally high level of lipids. The patient was assessed on day 1, day 18 and after completion of 25 days of Ayurveda and naturopathy therapy for hyperlipidemia. In spite of suffering from hyperlipidemia, the patient was not having any associated complaints; therefore he was prescribed an integrated therapy of yoga, Ayurveda and Naturopathy. The results of present case report showed substantial reduction in cholesterol and triglycerides levels with three weeks of yoga, Ayurveda, and Naturopathy treatment. The patient was not prescribed any concomitant allopathic medications during the treatment period. The case study concluded that combined alternative therapies of yoga, Ayurveda and Naturopathy have helped in substantial reduction of abnormal levels of lipids in a short duration of three weeks.

Clinical Pharmacokinetics of Gentamicin in Various Patient Populations and Consequences for Optimal Dosing for Gram-Negative Infections: An Updated Review.

Gentamicin is an aminoglycoside antibiotic with a small therapeutic window that is currently used primarily as part of short-term empirical combination therapy. Gentamicin dosing schemes still need refinement, especially for subpopulations where pharmacokinetics can differ from pharmacokinetics in the general adult population: obese patients, critically ill patients, paediatric patients, neonates, elderly patients and patients on dialysis. This review summarizes the clinical pharmacokinetics of gentamicin in these patient populations and the consequences for optimal dosing of gentamicin for infections caused by Gram-negative bacteria, highlighting new insights from the last 10 years. In this period, several new population pharmacokinetic studies have focused on these subpopulations, providing insights into the typical values of the most relevant pharmacokinetic parameters, the variability of these parameters and possible explanations for this variability, although unexplained variability often remains high. Both dosing schemes and pharmacokinetic/pharmacodynamic (PK/PD) targets varied widely between these studies. A gentamicin starting dose of 7 mg/kg based on total body weight (or on adjusted body weight in obese patients) appears to be the optimal strategy for increasing the probability of target attainment (PTA) after the first administration for the most commonly used PK/PD targets in adults and children older than 1 month, including critically ill patients. However, evidence that increasing the PTA results in higher efficacy is lacking; no studies were identified that show a correlation between estimated or predicted PK/PD target attainment and clinical success. Although it is unclear if performing therapeutic drug monitoring (TDM) for optimization of the PTA is of clinical value, it is recommended in patients with highly variable pharmacokinetics, including patients from all subpopulations that are critically ill (such as elderly, children and neonates) and patients on intermittent haemodialysis. In addition, TDM for optimization of the dosing interval, targeting a trough concentration of at least < 2 mg/L but preferably < 0.5–1 mg/L, has proven to reduce nephrotoxicity and is therefore recommended in all patients receiving more than one dose of gentamicin. The usefulness of the daily area under the plasma concentration–time curve for predicting nephrotoxicity should be further investigated. Additionally, more research is needed on the optimal PK/PD targets for efficacy in the clinical situations in which gentamicin is currently used, that is, as monotherapy for urinary tract infections or as part of short-term combination therapy.

Correlation between N-Acetyltransferase 2 (NAT2) Polymorphism Genotype with Plasma Isoniazid (INH) Concentration in MDR TB Patients Receiving Short Regimen in West Sumatera

Background: Isoniazid (INH) is one of the most potent TB drug. High dose INH is used in short regimen MDR TB drugs. The genetic polymorphism of NAT2 affects the acetylation status. Awareness of the patients’ acetylator status is important to determine the risk of toxicity, treatment failure and drug resistance. The aim of this study was to demonstrate NAT2 genotype association with INH plasma concentration after 2 hours of oral INH therapy. Methods: This was a cross sectional study of MDR TB patients who received short term combination therapy at RSUP Dr. M.Djamil Padang, Achmad Muchtar Hospital Bukittinggiand West Sumatra Pulmonary Hospital from September 2019 to February 2020. Patients were examined for NAT2 genotype and plasma INH concentration. The results of the plasma INH concentrations obtained were evaluated based on the NAT2 acetylator phenotype group.Results: The majority of the subjects weremen (62.5%), aged 40-64 years (50%), had the most common comorbid of diabetes mellitus (31.25%), were normoweight (75%) and had negative HIV status (93.8%). A total of 7 alleles consisting of 7 SNPs and 7 variations of the NAT2 genotype were found in MDR TB patients who received short-term therapy. The NAT2*12A alleles (56.25%) was the most common allele and was a fast acetylator. Based on the bimodal distribution, the median concentration of INH in the fast and slow acetylator were 1.25 µg/ml and 5.24 µg/ml, respectively. The median values of INH concentration based on the trimodal distribution for fast, intermediate, and slow acetylators were 1.25 µg/ml, 2.17 µg/ml and 5.24 µg/ml. Conclusion: There were no correlations between the type of NAT2 acetylator phenotype and plasma INH concentrations.

The efficacy and safety of the short-term combination therapy with ticagrelor and PPIs or H2RA in patients with acute STEMI who underwent emergency PCI.

Combination therapy with platelet inhibitors and acid‐suppressive agents is recommended for patients with acute ST‐segment elevation myocardial infarction (STEMI) who underwent percutaneous coronary intervention (PCI), but there remains a paucity of data to evaluate both the efficacy and safety of these combinations. In this prospective study, a total of 170 patients with acute STEMI who underwent PCI were divided into four groups: pantoprazole + ticagrelor, omeprazole + ticagrelor, ranitidine + ticagrelor, and ticagrelor only. The risk of PCI, antithrombotic efficacy, cardiac function, and main end points were evaluated and compared. No significant differences were found in infarction‐related artery perfusion indexes (thrombolysis in myocardial infarction [TIMI], corrected TIMI frame count), the incidence of stent thrombosis after PCI, platelet indicators (platelet count, mean platelet volume, and platelet distribution width), platelet activation (P‐selectin and glycoprotein IIb/IIIa levels), platelet aggregation (thrombelastography indicators, such as ADP% and MAADP), myocardial necrosis biomarker (creatine kinase isoenzyme‐MB and cardiac troponin I) levels, brain natriuretic peptide levels, the incidence of ischemic end point events, and the incidence of other tissue and organ bleeding events among the four groups. The incidence of gastrointestinal (GI) bleeding events in the proton pump‐inhibitor (PPI) group was significantly lower than that in the control group, whereas in the H2 receptor antagonist (H2RA) group it was not significantly different from the control group. The short‐term combination therapy with ticagrelor and PPIs or H2RA is safe and effective in patients with acute STEMI after PCI. In addition, the PPIs combined with ticagrelor could reduce the incidence of GI bleeding events without increasing the incidence of ischemic events.

Approaches for the prevention and treatment of venous thromboembolism in a patient with anaplastic astrocytoma: a case report

Venous thromboembolism occurs in 48–200 out of 1,000 patients with brain cancer per year, which is significantly more frequent than in general population.Case report. A female patient had surgical treatment of anaplastic astrocytoma following radiotherapy and chemotherapy (temozolomide, irinotecan, bevacizumab) at the age of 17 years old. She also received dexamethasone. At the age of 20 years, she developed cancer recurrence, that required chemotherapy. After chemotherapy had been initiated, the patient developed deep vein thrombosis of the legs. Rivaroxaban 20 mg/d for 2.5 months with the subsequent switch to enoxaparin 60 mg/d showed no recanalization. Enoxaparin dose increasing up to 160 mg/d demonstrated incomplete recanalization, however, superficial venous thrombosis of the legs developed. Combination therapy with enoxaparin plus warfarin resulted in further deep and superficial veins recanalization.Discussion. In cancer-associated venous thromboembolism that is resistant to low molecular weight heparin monotherapy, short-term combination therapy with low molecular weight heparin and vitamin K antagonists can be considered. However, in recurrent cancer standard treatment protocols can be ineffective.

The Safety Profile of the Short-Term Combination Therapy of Ticagrelor With PPI or H2RA in Patients With Acute STEMI Underwent PCI

Background: The combination therapy of anti-platelet medication and PPI/H2RA was recommended but yet being controversial due to the safety issue. To evaluate the efficacy and safety of the combination therapy of ticagrelor and PPI/H2RA on patients with acute STEMI receiving PCI. Methods: A total of 170 patients were hospitalized for PCI due to acute STEMI. The patients were divided into 4 groups receiving pantoprazole+ ticagrelor, omeprazole+ ticagrelor, ranitidine+ ticagrelor and ticagrelor only, respectively. The the prognosis of the therapy was evaluated and compared to verify the efficacy and safety of the combination therapy. Findings: No significant differences were found in IRA perfusion indexes (TIMI, CTFC), incidence of stent thrombosis after PCI, platelets indicators (PLT, MPV, PDW), platelets activation (P-selectin and GPIIb/IIIa levels), TEG indicators (ADP%, MAADP), myocardial necrosis biomarker (CK-MB, cTnI) and BNP levels between the 4 groups of patients after 7 days of follow-up. Patients receiving PPI+tecagrelor had significantly better safety profile than those who were given ticagrelor only. Interpretation: Based on our findings, the combinational application of tecagrelor and PPI yielded a satisfying safety profile in patients with acute STEMI after PCI. Funding Statement: None. Declaration of Interests: The authors declare that they had no competing interests. Ethics Approval Statement: This work was approved by the Ethics Committee of The First Affiliated Hospital with Nanjing Medical University. Written informed consent was obtained from all patients.

Short-term intensive combined therapy with metformin, sagliptin and dapagliflozin for newly diagnosed type 2 diabetes: efficacy, weight control and safety

To assess the efficacy and safety of short- term intensive hypoglycemic therapy with a triple regimen consisting of metformin, sagliptin and dapagliflozin in patients with newly diagnosed type 2 diabetes mellitus with hemoglobin Alc (HbA1c) of 9%-12%. We prospectively enrolled 58 patients with newly diagnosed type 2 diabetes, who were treated with metformin combined with sagliptin and dapagliflozin for 12 weeks on the basis of diabetic diet and regular exercise. Blood glucose was monitored during the treatment and the changes in HbA1c, fasting blood glucose (FBG), 2-hour postprandial blood glucose (2 hPBG), fasting insulin (FINS), 2-hour postprandial insulin (2 hPINS), fasting C-peptide (F-CP), 2-hour postprandial C-peptide (2 hP-CP), and body weight after treatment as well as the incidence of hypoglycemia and adverse events associated with the treatment were recorded. Two patients withdrew from the study for intolerance of gastrointestinal reactions, and another 2 withdrew for inconvenience of access to the medicines. Fifty-four of the patients finally completed the study, including 34 male and 20 female patients. After 12 weeks of therapy, all the patients showed significant improvements in FBG, 2 hPBG, HbA1c, HOMA-beta and HOMA-IR (P < 0.001) with a mean reduction of HbA1c level by (4.19 ± 1.07)%, and the goal of HbA1c control to below 7.0% was achieved in 83.33% of the patients. The reduction of HbA1c was correlated with FBG (r=0.487, P=0.000), 2 hPBG (r=0.310, P=0.023), and HOMA-β (r=-0.398, P=0.003). The patients had a mean body weight loss by 2.47±3.38 kg (P < 0.001) and a mean decrease of body mass index (BMI) by 0.90± 1.18 kg/m2 (P < 0.001) after the therapy. The body weight-reducing effect was associated with the patients' baseline body weight (r=0.678, P=0.000), BMI (r=0.818, P=0.000), F-CP (r=0.282, P=0.039) and HOMA-IR (r=0.297, P=0.029). During the therapy 8 patients experienced hypoglycemic symptoms (10 times, 14.81%); 3 patients were diagnosed with hypoglycemia (blood glucose ≤3.9 mmol/L, 3 times), and the overall incidence of hypoglycemia was 5.56%. No serious hypoglycemia or infections of the urinary and reproductive systems occurred in these patients. Short-term intensive oral hypoglycemic therapy with metformin combined with sagliptin and dapagliflozin is effective for treatment of patients with newly diagnosed type 2 diabetes with HbA1c of 9%-12% and shows a good weight-reducing effect with a low risk of hypoglycemia. The combined therapy can effectively improve β-cell insulin secretion function, and is suitable for treatment of newly diagnosed type 2 diabetic patients with high blood glucose.

The extent of surgery for stage III melanoma: how much is appropriate?

Since the first documented lymph node dissection in 1892, many trials have investigated the potential effect of this surgical procedure on survival in patients with melanoma. Two randomised controlled trials were unable to demonstrate improved survival with completion lymph node dissection versus nodal observation in patients with sentinel node-positive disease, although patients with larger sentinel node metastases (>1 mm) might benefit more from observation than from dissection, and could potentially be considered for adjuvant systemic therapy instead of complete dissection. Adjuvant immunotherapy with high-dose ipilimumab has led to improvements in overall survival, whereas therapy with nivolumab and pembrolizumab has improved relapse-free survival with greater safety. Furthermore, adjuvant-targeted therapy with dabrafenib and trametinib has improved survival outcomes in BRAFV600E and BRAFV600K-mutated melanomas. Three neoadjuvant trials have all shown high response rates, including complete responses, after short-term combination therapy with ipilimumab and nivolumab with no recurrences so far, although follow-up is still short. Despite the absence of a survival benefit with completion lymph node dissection in patients with sentinel node-positive or negative disease, the use of sentinel node staging will increase because of the introduction of effective adjuvant therapies. However, routine completion lymph node dissection for sentinel node-positive disease should be reconsidered. Accordingly, existing clinical guidelines are currently being revised. For palpable (macroscopic) nodal disease, the type and extent of surgery could be reduced if the index node can accurately predict the response and if studies show that lymph node dissection can be safely foregone in patients with a complete response. Overall, the appropriate type and extent of surgery for stage III melanoma is changing and becoming more personalised.

Effects of short-term combination therapy with insulin on glycoregulation and insulin secretory function in patients with type 2 diabetes mellitus and secondary failure to treatment with oral antidiabetic agents

&amp;lt;p&amp;gt;Introduction. Secondary failure to treatment with oral antidiabetic agents is defined as the absence of a favorable reaction to the oral therapy which had proved effective in the previous course of the treatment. The aim of the study is to investigate the residual effects of the short-term combination therapy with insulin on glycoregulation and insulin secretory function. Methods. The sample comprised 53 patients with type 2 diabetes mellitus (DM2) and secondary failure to treatment with oral antidiabetic agents who had been receiving combination therapy (basal insulin plus metformin) for three months. Following the evaluation of acute effects of insulin therapy, the patients had been receiving oral antihyperglycemic medications, used at the time of secondary failure, for three months, after which the residual effects of insulin therapy were estimated. Results. Three-month combination therapy significantly improved glycoregulation (fasting glycemia: 9.4 mmol/l vs. 6.1 mmol/l; postpransial glycemia: 11.5 mmol/l vs. 7.3mmol/l; daily glycemic profile: 10.0 mmol/l vs. 7.2 mmol/l) and insulin secretory parameters (insulinemia: 16.63 mU/l vs. 10.8 mU/l; C-peptid: 1.53 mg/ml vs. 1.81 mg/ml) compared with the period when secondary failure to oral therapy was observed (acute effects). Three months after the insuline therapy, glycoregulation and insulin secretory function were slightly poorerresidual effects (glycemia: 7.1mmol/l; postpransial glycemia: 8.3 mmol/l; daily glycemic profile: 8.4mmol/l; insulinemia: 13.3mU/l; C-peptid: 1.72 mg /ml). Conclusion. The reinclusion of oral antidiabetic agents after short-term insulin therapy led to mild deterioration in insulin secretory function. Nevertheless, all observed parameters of metabolic status were significantly better compared with the period prior to short-term use of insulin.&amp;lt;/p&amp;gt;

Sirolimus for the treatment of progressive kaposiform hemangioendothelioma: A multicenter retrospective study.

Kaposiform hemangioendothelioma (KHE) is an aggressive disease with high morbidity and mortality. The aim of this study was to retrospectively evaluate the efficacy and safety of sirolimus for the treatment of progressive KHE. A multicenter, retrospective cohort study was conducted in patients with progressive KHE treated with sirolimus. A total of 52 patients were analyzed. Thirty-seven (71%) patients exhibited Kasabach-Merritt phenomenon (KMP) and were significantly younger than the patients without KMP [95% confidence interval (CI), 14.39-41.61; p < 0.001]. Patients without KMP were all treated with sirolimus alone, whereas 21 KMP patients with severe symptoms received short-term combination therapy with prednisolone. Overall, 96% and 98% of patients showed improved relief of notable symptoms and/or improved complications at 6 and 12 months after treatment, respectively. After sirolimus treatment, significant decreases in mean severity scores occurred at 6 months (95% CI, 2.23-2.54, p < 0.001) and 12 months (95% CI, 1.53-1.90, p < 0.001). Compared to KMP patients, patients without KMP showed a response that was similar to but less pronounced during the 12 months of treatment (95% CI, 40.87-53.80; p < 0.001). For subgroup analysis of KMP patients, there were no significant differences in tumor shrinkage between those treated with combination therapy and those receiving sirolimus alone (95% CI, 18.11-25.02; p > 0.05). No patients permanently discontinued treatment due to toxicity-related events, and no drug-related deaths occurred. Sirolimus was effective and safe for the treatment of progressive KHE. Sirolimus may be considered as a first-line therapy or as part of a multidisciplinary approach for the treatment of KHE.

Comment: TIA response to antiplatelets stratified by glycated albumin.

In the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) study of TIA, short-term combination therapy with clopidogrel and aspirin reduced recurrent stroke.1 Whether all TIAs benefit equally from this treatment remains unclear. Given that dual antiplatelet therapy also promotes hemorrhage, identifying which TIAs derive the greatest benefit would be clinically useful.

Aspirin plus Clopidogrel as Secondary Prevention after Stroke or Transient Ischemic Attack: A Systematic Review and Meta-Analysis

Background: Antiplatelet agents are the mainstay for secondary prevention of non-cardioembolic stroke. This systematic review examined the safety and efficacy of short-, middle-, and long-term aspirin in combination with clopidogrel as secondary prevention of stroke or transient ischemic attack (TIA) of presumed arterial origin. Methods: PubMed, EmBase, and CENTRAL were searched up to May 2014. Randomized controlled trials (RCTs) that compared aspirin plus clopidogrel versus aspirin or clopidogrel as secondary prevention of stroke or TIA of arterial origin were included. The analyses were stratified into short-term (≤3 months), middle-term (>3 months and <1 year), and long-term (≥1 year). Outcomes were compared using risk ratio (RR) and 95% confidence interval (95% CI). Results: Eight RCTs (20,728 patients) were included in the overall analysis. Compared with aspirin or clopidogrel alone, the complete analysis of all the data indicated that the combination therapy significantly reduced the risk of stroke recurrence (RR, 0.82; 95% CI 0.70-0.96, p = 0.01) and major vascular events (RR, 0.84; 95% CI 0.73-0.96, p < 0.01). But the risk of hemorrhagic stroke (RR, 1.59; 95% CI 1.08-2.33, p = 0.02) and major bleeding (RR, 1.83; 95% CI 1.37-2.45, p < 0.01) was increased. No RCT studied middle-term combination therapy. The analyses were therefore stratified into only two subgroups, short- and long-term treatment. Stratified analysis of short-term treatment showed that relative to monotherapy, the drug combination reduced the risk of stroke recurrence (RR, 0.69; 95% CI 0.59-0.81, p < 0.01) and did not increase the risk of hemorrhagic stroke (RR, 1.23; 95% CI 0.50-3.04, p = 0.65) and major bleeding events (RR, 2.17; 95% CI 0.18-25.71, p = 0.54). Short-term combination therapy was associated with a significantly lower risk of major vascular events (RR, 0.70; 95% CI 0.69 to 0.82, p < 0.01). Stratified analysis of long-term treatment revealed that the combination treatment did not decrease the risk of stroke recurrence (RR, 0.92; 95% CI 0.83-1.03, p = 0.15), but was associated with a significantly higher risk of hemorrhagic stroke (RR, 1.67; 95% CI 1.10-2.56, p = 0.02) and major bleeding events (RR, 1.90; 95% CI 1.46-2.48, p < 0.01). Long-term combination therapy failed to reduce the risk of major vascular events (RR, 0.92; 95% CI 0.84-1.03, p = 0.09). Conclusions: Compared with monotherapy, short-term aspirin in combination with clopidogrel is more effective as secondary prevention of stroke or TIA without increasing the risk of hemorrhagic stroke and major bleeding events. Long-term combination therapy does not reduce the risk of stroke recurrence, and is associated with increased major bleeding events. The clinical applicability of the findings of this systematic review, however, needs to be confirmed in future clinical trials.

A retrospective analysis of combination methotrexate–cyclosporine therapy in moderate–severe psoriasis

Background: Methotrexate–cyclosprine combination therapy has traditionally been discouraged in the treatment of moderate–severe psoriasis. However, recent reports indicate that the two may be used in combination in psoriasis. Aim: The retrospective study was undertaken to study the adverse effects and efficacy of the combination in Indian patients of psoriasis. Methods: The records of all patients who received combination therapy between 2005 and 2010 were extracted. Demographic details, disease profile, presence of coexistent arthropathy, prior therapy, duration of combination therapy, body surface area involvement, Psoriasis Area and Severity Index (PASI), and adverse effects were recorded. Descriptive statistics were used to analyze the data. Results: Eighteen patients received combination therapy during the study period. Fourteen patients received short-term combination therapy and four patients received long-term combination therapy. Twelve patients in the first group and all patients of the second group achieved the primary end point of PASI by 50% from baseline (PASI 50). Nine patients in the first group and all patients in the second group suffered from significant adverse effects; they were however reversible. Conclusion: Methotrexate–cyclosporine combination therapy can be used with adequate monitoring in the treatment of moderate–severe psoriasis. Adverse effects seen are usually reversible with reduction in dose and cessation of therapy. Adverse effects related to cyclosporine are a common problem.

Disease control with glucocorticoid therapy in rheumatoid arthritis

DMARDs aim to improve long-term prognosis of RA, as indicated by reduced progression of radiographic damage and maintenance of function. However, it may be more appropriate to consider disease-modifying strategies rather than drugs alone. Despite the challenges (e.g. lack of standard outcome measures, poor reporting of dose levels), a systematic review of 15 studies involving more than 1400 patients showed that glucocorticoid treatment for 1-2 years slowed radiographic progression compared with control treatment. Evidence for longer term disease-modifying benefits of glucocorticoids comes from individual studies with extended follow-up. In the Utrecht study, patients with early RA originally assigned to prednisone 10 mg/day for 2 years and then tapered off the therapy showed significantly less radiographic progression at follow-up after a further 3 years than patients originally assigned placebo, with no significant difference in the use of synthetic DMARD therapy. In the combination therapy in early RA (COBRA) study, patients with newly diagnosed RA treated with glucocorticoid (starting with 60 mg/day, quickly reduced to 7.5 mg/day for weeks 7-28 and subsequently stopped), MTX up to week 40 and SSZ showed significantly decreased radiographic progression compared with those treated with SSZ alone. The benefits of short-term combination therapy on disease progression were still apparent at 5-year and 11-year follow-up. In conclusion, there is clear evidence that treatment regimens including low-dose glucocorticoids given early in RA slow radiographic progression, meeting the definition of a DMARD. Furthermore, the evidence suggests that such treatment strategies favourably alter the disease course even after glucocorticoid discontinuation.

Elimination of hepatitis C virus by short term NS3-4A and NS5B inhibitor combination therapy in human hepatocyte chimeric mice

The current treatment regimen for chronic hepatitis C virus (HCV) infection is peg-interferon plus ribavirin combination therapy. The majority of developing therapeutic strategies also contain peg-interferon with or without ribavirin. However, interferon is expensive and sometimes intolerable for some patients because of severe side effects. Using human hepatocyte chimeric mice, we examined whether a short term combination therapy with the HCV NS3-4A protease inhibitor telaprevir and the RNA polymerase inhibitor MK-0608 with or without interferon eradicates the HCV from infected mice. The effect of telaprevir and MK-0608 combination therapy was examined using subgenomic HCV replicon cells. Combination therapy with the two drugs enhanced inhibition of HCV replication compared with either drug alone. In in vivo experiments, early emergence of drug resistance was seen in mice treated with either telaprevir or MK-0608 alone. However, emergence was prevented by the combination of these drugs. Mice treated with a triple combination therapy of telaprevir, MK-0608, and interferon became negative for HCV RNA soon after commencement of the therapy, and HCV RNA was not detected in serum of these mice 12 weeks after cessation of the therapy. Furthermore, all mice treated with a high dose telaprevir and MK-0608 combination therapy for 4 weeks became negative for HCV RNA 1 week after the beginning of the therapy and remained negative after 18 weeks. Eradication of HCV from mice with only 4 weeks of therapy without interferon points the way to future combination therapies for chronic hepatitis C patients.

The successful treatment of rapidly progressive idiopathic membranoproliferative glomerulo-nephritis Type 1 in a 4-year-old male pediatric patient

A multivariate analysis [4] revealed that the presence of crescent formation on initial biopsy irrespective of type of membranoproliferative glomerulonephritis (MPGN) was independently associated not only with end-stage renal disease but also with post-transplantation recurrence. In this study, we reported on a 4-year-old male pediatric patient requiring hemodialysis due to rapidly progressive idiopathic MPGN Type 1 with severe nephrotic syndrome and extensive cellular crescent formation on initial biopsy. The patient had been treated intravenously (i.v.) with 9 pulses of methylprednisolone, followed by daily prednisolone, resulting in the withdrawal of dialysis within 1 month. However, since active lesions in the second renal biopsy such as cellular crescents still remained and nephrotic range proteinuria had persisted for more than 2 months, the patient received additional 3 i.v. pulses of methylprednisolone, followed by combinations of alternate-day prednisolone, mizoribine, dipyridamole and warfarin, which lead to complete remission in a short-period of time. The patient has been off the combination therapy for 10 months because the third biopsy prior to the termination of this regimen showed decreased inflammatory activity. There is currently no established protocol for children with crescentic MPGN due to a rarity of its clinicopathological presentation. This case report indicates that early treatment with multiple pulses of methylprednisolone followed by the short-term combination therapy may be of benefit for children with rapidly progressive idiopathic MPGN Type 1, even when both diffuse crescentic changes and nephrotic syndrome are present at onset.

Impact of Short-Term Combined Antiretroviral Therapy on Brain Virus Burden in Simian Immunodeficiency Virus-Infected and CD8 + Lymphocyte-Depleted Rhesus Macaques

Antiretroviral drugs suppress virus burden in the cerebrospinal fluid of HIV-infected individuals; however, the direct effect of antiretrovirals on virus replication in brain parenchyma is poorly understood. We investigated the effect of short-term combined antiretroviral therapy (CART) on brain virus burden in rhesus monkeys using the CD8-depletion model of accelerated simian immunodeficiency virus (SIV) encephalitis. Four monkeys received CART (consisting of the nonpenetrating agents PMPA and RCV) for four weeks, beginning 28 days after SIV inoculation. Lower virus burdens were measured by real-time RT-PCR in four of four regions of brain from monkeys that received CART as compared with four SIV-infected, untreated controls; however, the difference was only significant for the frontal cortex (P < 0.05). In contrast, significantly lower virus burdens were measured in plasma and four of five lymphoid compartments from animals that received CART. Surprisingly, despite normalization of neuronal function in treated animals, the numbers of activated macrophages/microglia and the magnitude of TNF-alpha mRNA expression in brain were similar between treated animals and controls. These results suggest that short-term therapy with antiretrovirals that fail to penetrate the blood-cerebrospinal fluid barrier can reduce brain virus burden provided systemic virus burden is suppressed; however, longer treatment may be required to completely resolve encephalitic lesions and microglial activation, which may reflect the longer half-life of the principal target cells of HIV/SIV in the brain (macrophages) versus lymphoid tissues (T lymphocytes).