Require Combination Therapy Research Articles

Effects of combining azilsartan medoxomil with amlodipine in patients with stage 2 hypertension

ObjectiveThe aim of the study was to measure the effects on blood pressure (BP) of the angiotensin receptor blocker azilsartan medoxomil, in 40 and 80 mg doses, combined with 5 mg of the calcium channel blocker amlodipine and to compare these effects with placebo plus amlodipine 5 mg.MethodsThis was a randomized, controlled, double-blind study of 6 weeks’ duration in 566 patients with stage 2 hypertension. The primary endpoint was 24-h systolic BP by ambulatory monitoring.ResultsThe mean age of the participants was 58 years; men and women were equally represented, and baseline 24-h BP (153–154/93 mmHg) and clinic BP (165–166/94–95 mmHg) were similar across the three treatment groups. After 6 weeks, 24-h BP decreased by 25/15 mmHg in both the azilsartan medoxomil/amlodipine 40/5 and 80/5 mg groups. These reductions were each greater than the 14/8 mmHg decrease with placebo plus amlodipine 5 mg (P≤0.001 for both comparisons). All treatments were well tolerated, and adverse events did not increase with the azilsartan medoxomil doses. Edema or fluid retention was less common in both combination groups (2.6 and 2.7%) than with placebo plus amlodipine (7.6%).ConclusionCoadministration of azilsartan medoxomil with amlodipine was well tolerated and led to meaningful additional BP reductions compared with placebo plus amlodipine.

A Novel Approach Utilizing Biofilm Time-Kill Curves To Assess the Bactericidal Activity of Ceftaroline Combinations against Biofilm-Producing Methicillin-Resistant Staphylococcus aureus

Medical device infections frequently require combination therapy. Beta-lactams combined with glycopeptides/lipopeptides are bactericidal against methicillin-resistant Staphylococcus aureus (MRSA). Novel macrowell kill-curve methods tested synergy between ceftaroline or cefazolin plus daptomycin, vancomycin, or rifampin against biofilm-producing MRSA. Ceftaroline combinations demonstrated the most pronounced bacterial reductions. Ceftaroline demonstrated greatest kill with daptomycin (4.02 ± 0.59 log10 CFU/cm(2)), compared to combination with vancomycin (3.36 ± 0.35 log10 CFU/cm(2)) or rifampin (2.68 ± 0.61 log10 CFU/cm(2)). These data suggest that beta-lactam combinations are useful against MRSA biofilms.

Spinal Cord Neurosarcoidosis

BackgroundSpinal cord neurosarcoidosis (SN) is problematic to diagnose because it mimics other inflammatory0020neurologic diseases. The authors report the clinical features of 29 SN cases. MethodsThey retrospectively reviewed the medical records of 29 histologically proven sarcoidosis patients with spinal cord involvement seen at 3 university medical centers. They collected clinical data including laboratory and radiological findings. Clinical outcomes were assessed retrospectively using the modified Rankin scale. ResultsThe cohort included high number of African Americans (16/29, 55%). The lung and intrathoracic lymph nodes were the most common confirmatory biopsy sites (18/29, 62%), whereas the spinal cord was a relatively uncommon one (4/29, 14%). The most common presenting symptoms were lower extremity weakness and paresthesias. Thoracic segment was most frequently involved (21/27, 78%). Lesions were mostly intramedullary (22/27, 81%), although nearly half involved the leptomeninges (13/27, 48%). The average size of a lesion spanned 3.9 spine segments (range, 1–9); 17 of 22 (77%) intramedullary patients had $3 spine segments involved. Angiotensin-converting enzyme levels in cerebrospinal fluid were elevated in only 2 of 11 (18%) patients. All patients received glucocorticosteroids. Additional immune-modulating agents were used in 24 of 29 (83%) patients. Scores on the modified Rankin scale at the final follow-up visit were improved. ConclusionsMost SN cases were diagnosed indirectly based on extraneural tissue biopsy. Extended spinal cord lesion ($3 spine segments) may be useful to distinguish SN from multiple sclerosis. Cerebrospinal fluid analysis was of limited value. Most patients experienced clinical improvement with immunosuppressive treatment, but many required combination therapy.

Single-Pill Combination of Telmisartan and Hydrochlorothiazide: Studies and Pooled Analyses of Earlier Hypertension Treatment

Lowering blood pressure (BP) in patients with high blood pressure reduces cardiovascular risk. Studies support health benefits when BP goals are achieved earlier in the course of treatment. Many patients require combination therapy to achieve BP goals; initial use of combination therapy may improve earlier BP goal attainment. This analysis reports the results of a search of the Boehringer Ingelheim clinical trial database for randomized, double-blind studies of telmisartan/hydrochlorothiazide (T/H) combination therapy compared with blood pressure monotherapies. Nine studies were identified. This report examined six separate analyses of these nine studies (three analyses of individual trials; three analyses for which two trials each were pooled). The focus of this report is the BP effects of combination T/H therapy compared with respective monotherapies at the earliest available time points (Weeks 1, 2, 3 and/or 4). These analyses included a total of 5,358 patients. During these earlier time periods, combination T/H reduced systolic BP (SBP) and diastolic BP (DBP) significantly more than placebo or respective monotherapies in most treatment comparisons for patients initiated on monotherapy. Combination T/H also allowed significantly more patients to achieve BP (<140/90 mmHg), SBP (<140 mmHg), and DBP (<90 mmHg) goal attainment rates compared with placebo (p < 0.0002), and numerically higher compared with T or H monotherapy. In patients uncontrolled by monotherapy, combination T/H significantly reduced SBP/DBP more than monotherapy (p < 0.0001). Similarly, BP, SBP and DBP goal attainment rates were significantly higher with combination T/H therapy (p < 0.0022). Reported adverse events with T/H therapy were generally similar to monotherapy, and placebo. In summary, the six separate analyses of nine different trials demonstrated that T/H significantly lowered BP as early as 1-4 weeks after initiation of therapy, with greater BP lowering, and greater BP goal attainment than with monotherapies or placebo.

Lisinopril-loaded Chitosan Nanoparticles and Indapamide in Hard Gelatine Capsules: Simultaneous HPLC Quantification

To treat hypertension around 75% of patients will require combination therapy for which administration of lisinopril and indapamide could be of practical use. Lisinopril has a low oral bioavailability (around 25%) with large intersubject variability (6-60%), due to slow absorption. In order to improve drug permeability, encapsulation of the drugs within nanoparticles (NPs) has demonstrated great potential. For this reason we have prepared hard capsules containing both drugs: indapamide and lisinopril-loaded chitosan (CS) nanoparticles. The mucoadhesive characteristics of CS-NPs will prolong the residence time of lisinopril in contact with the intestinal membrane thereby increasing its oral bioavailability. Moreover, for their quantification a reversed-phase HPLC method is developed and validated using a C18 column. The mobile phase is prepared with methanol:water (50:50, v/v) including triethylamine (0.1% of total volume) and adjusted at pH 3.1. The calibration curves are linear over the ranges 16-24 µg.mL-1 for lisinopril and 8-12 µg.mL-1 for indapamide. Intra-day precision results in %RSD ranging 0.74-1.86 for lisinopril and 0.60-1.91 for indapamide. Recovery results obtained for lisinopril and indapamide range 98.22-102.34% and 97.35-101.00%, respectively. The LOD and LOQ are 0.4 µg.mL-1 and 1.4 µg.mL-1 for lisinopril, and 0.5 µg.mL-1 and 1.5 µg.mL-1 for indapamide. The HPLC method is simple, easy to apply, rapid, with UV detection, and allows for quality control of the new formulation developed. The method can be applied for the quantification of this drug combination in medicinal products. Keywords: Lisinopril, indapamide, chitosan, nanoparticles, HPLC.

Primary Antiphospholipid Syndrome–Associated Diffuse Alveolar Hemorrhage

Diffuse alveolar hemorrhage (DAH) is an uncommon complication of primary antiphospholipid syndrome (APS). We aimed to describe the clinical characteristics, treatment, and outcomes of primary APS-associated DAH in a single center. We conducted a retrospective review of all adults with primary APS-associated DAH evaluated at Mayo Clinic over a 15-year period. DAH was defined as bilateral pulmonary infiltrates and bronchoalveolar lavage (BAL) fluid documenting progressively bloody returns and/or the presence of >20% hemosiderin-laden macrophages. Patients with other causes of DAH were excluded. Eighteen patients were identified (median age 43 years). Capillaritis was present in surgical lung biopsy samples of 3 patients. BAL differential cell counts revealed predominantly neutrophils. All patients were treated initially with glucocorticoids. Cyclophosphamide (CYC) was used in 8 patients; complete remission was achieved in 3 patients treated with CYC alone and in 1 patient receiving combination therapy with rituximab (RTX). RTX was used in 9 patients; 2 patients achieved remission with RTX alone, whereas 3 patients required combination therapy with CYC or mycophenolate mofetil (MMF). No patient achieved complete remission while receiving single therapy with MMF, azathioprine, or plasma exchange. Intravenous gamma globulin therapy was administered in 5 patients; no patient achieved control of the disease. Six patients died, all because of complications related to uncontrolled DAH or its therapy. We present the largest case series of primary APS-associated DAH reported in the literature. DAH carries a very poor prognosis and therapeutic options are limited. Immunosuppression with either CYC or RTX is associated with the highest likelihood of remission induction and should be considered early.

Robotic nephrolithotomy and pyelolithotomy with utilization of the robotic ultrasound probe

The treatment of large renal stones in children can be challenging often requiring combination therapy and multiple procedures. The purpose of this video is to describe our technique of robotic nephrolithotomy and pyelolithotomy for complex renal stone disease in children, and to demonstrate the utility of the robotic ultrasound probe to aid with stone localization. Robotic nephrolithotomy/pyelolithotomy was carried out in four consecutive patients. A robotic ultrasound probe (Hitachi-Aloka, Tokyo, Japan) under console surgeon control was used in all cases. Two patients underwent robotic pyelolithotomy, one patient underwent robotic nephrolithotomy, whilst the fourth patient underwent robotic pyelolithotomy and nephrolithotomy along with Y-V pyeloplasty for concurrent ureteropelvic junction obstruction. Mean operative time, blood loss and hospital stay was 216 minutes, 37.5 mL and 2 days, respectively. The robotic ultrasound probe aided identification of calculi within the kidney in all cases. For nephroli¬thotomy it was helpful in planning the incision for nephrotomy. After nephrotomy or pyelotomy, stones were removed using a combination of robotic Maryland forceps, fenestrated grasper or Prograsp. Antegrade nephroscopy introduced through a laparoscopic port was used in all patients for confirmation of residual stone status. Two patients did not require a ureteral stent in the post-operative period. One patient had a minor complication (Clavien Grade 2 - dislodged malecot catheter). All patients were stone free at last follow-up. Robotic nephrolithotomy and pyelolithotomy with utilization of the robotic ultrasound probe offers a one-stop solution for complex renal stones with excellent stone-free rates.

Comparison of Baseline Characteristics of Pulmonary Arterial Hypertension Patients That Require Combination Therapy Compared to Those Maintained on Monotherapy

Comparison of Baseline Characteristics of Pulmonary Arterial Hypertension Patients That Require Combination Therapy Compared to Those Maintained on Monotherapy

The role of direct renin inhibitors in the treatment of the hypertensive diabetic patient

Hypertensive patients with diabetes exhibit an increased risk for cardiovascular complications, such as acute coronary syndrome, stroke, heart failure and chronic kidney disease (CKD). These two chronic diseases are linked to a high rate of morbidity and mortality and for this reason it is important for the clinician to recognize the need for effective treatment of hypertension, which can require combination therapy to achieve blood pressure (BP) goals. Direct renin inhibitors (DRIs) may be useful in combination with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) as they provide a more complete blockade of the renin-angiotensin-aldosterone system (RAAS), effectively suppressing residual angiotensin II production and the counter-regulatory increase in plasma renin activity observed in patients receiving monotherapy with ACEIs or ARBs. Some questions regarding the action of aliskiren in cardiovascular and renal disorders are open. In particular, the combination therapy of aliskiren and a RAAS blocker in diabetic hypertensive patients with CKD is controversial. Several published studies demonstrated that aliskiren is suitable for once-daily administration and its antihypertensive effect is comparable or superior to that of other antihypertensive agents at recommended doses, with a good tolerability profile. At the moment the association with ACEIs and ARBs is not recommended in patients with type 2 diabetes mellitus (T2DM) and renal impairment even if a recent published open-label study of low-dose aliskiren (150 mg/daily) in association with ACEIs or ARBs has demonstrated a good tolerability profile without the adverse events found in other studies. This review provides a brief overview of RAAS blocking, in particular the rationale and clinical evidence supporting the use of the DRI aliskiren, in high-risk patients with T2DM.

Treatment algorithms for hypertension: a practical approach

SUMMARY Renin–angiotensin system inhibitors, calcium channel blockers and diuretics are the mainstay of current antihypertensive therapy. Patient characteristics are likely to influence the individual response to these agents, although the majority of patients require dual therapy to meet blood pressure goals and some require triple therapy. Combination therapies offer effective blood pressure reductions, particularly when combining therapies with complementary modes of action, and may reduce side-effect burden. Typically, patients who require combination therapy will have comorbidities that influence the preferred antihypertensive class for their treatment. Single-pill combinations can offer practical benefits, but lack dose flexibility and may not comprise drug classes that are optimal for a specific patient. The management of patients who require multiple therapies, therefore, involves weighing the benefits of convenience against the need to select therapies based on a consideration of therapeutic indi...

Bioequivalence of Saxagliptin/Metformin Immediate Release (IR) Fixed-Dose Combination Tablets and Single-Component Saxagliptin and Metformin IR Tablets in Healthy Adult Subjects

As compared with individual tablets, saxagliptin/metformin immediate release (IR) fixed-dose combination (FDC) tablets offer the potential for increased convenience, compliance, and adherence for patients requiring combination therapy. Two bioequivalence studies assessed the fed-state and the fasted-state bioequivalence of saxagliptin/metformin IR 2.5 mg/500 mg FDC (study 1) and saxagliptin/metformin IR 2.5 mg/1,000 mg FDC (study 2) relative to the same dosage strengths of the individual component tablets [saxagliptin (Onglyza™) and metformin IR (Glucophage(®))] administered concurrently. These were randomized, open-label, single-dose, four-period, four-treatment, crossover studies in healthy subjects (n = 24 in each study). The treatments in study 1 were a saxagliptin/metformin IR 2.5 mg/500 mg FDC tablet in the fed and fasted states on separate occasions, and saxagliptin 2.5 mg and metformin IR 500 mg tablets co-administered in the fed state and fasted states on separate occasions. The treatments in study 2 were a saxagliptin/metformin IR 2.5 mg/1,000 mg FDC tablet in the fed and fasted states on separate occasions, and saxagliptin 2.5 mg and metformin IR 1,000 mg co-administered in the fed state and fasted states on separate occasions. The pharmacokinetics, safety, and tolerability of each treatment were evaluated. For both studies, saxagliptin and metformin in the FDCs were bioequivalent to the individual components in both the fed and the fasted states as the limits of the 90 % confidence interval of the ratio of adjusted geometric means for all key pharmacokinetic parameters were contained within the predefined 0.800 to 1.250 bioequivalence criteria. Co-administration of saxagliptin and metformin IR was generally safe and well tolerated as the FDCs or as individual tablets. Saxagliptin/metformin IR 2.5 mg/500 mg and saxagliptin/metformin IR 2.5 mg/1,000 mg FDCs were bioequivalent to individual tablets of saxagliptin and metformin of the same strengths in both the fed and the fasted states. No unexpected safety findings were observed with saxagliptin/metformin IR administration. The tolerability of the FDC of saxagliptin/metformin IR was comparable to that of the co-administered individual components. These results indicate that the safety and efficacy profile of co-administration of saxagliptin and metformin can be extended to the saxagliptin/metformin IR FDC tablets.

Educational Exhibit Abstract No. 289 - Palliative care procedures for interventional oncologist

Learning Objectives The purpose of this exhibit is to 1) describe available procedures for palliation in the setting of cancer, 2) demonstrate the applicability of these procedures across several clinical scenarios, and 3) describe the role and efficacy of interventional palliation in various settings. Background Image-guided percutaneous ablative therapies are emerging as an efficacious option for the palliation of cancer-related pain. This exhibit will describe the utilization and efficacy of radiofrequency ablation (RFA), cryoablation, microwave ablation, plasma-mediated RFA (coblation), embolization, and combination therapies for management of pain across a spectrum of neoplastic abnormalities. Following IRB approval, a retrospective one year analysis of documented pain relief parameters and complications as part of the medical record were obtained pre and post image-guided palliative procedures. Clinical Findings/Procedure Details For purposes of this presentation, we chose two cases from each of the following categories in order to demonstrate the scope and efficacy of this service: head and neck neoplasms, palliative nerve ablations, osseous metastases, soft tissue masses, painful primary bone tumors, thoracic masses, vertebral body neoplasms and lesions requiring combination therapies. Patient selection, procedure details, efficacy, and complications are discussed. Conclusion and/or Teaching Points The application of interventional radiological techniques, including ablation, embolization and combination therapies, are powerful emerging tools for palliation in the setting of cancer-related pain. One should understand the variety of ablative modalities and image guidance systems available to the interventional radiologist and their respective advantages and limitations for the management of cancer-related pain. The adoption of any of these techniques for palliation is a critical and complementary component to a successful interventional oncology service.

The new concept of total cardiovascular risk management

Introduction: Cardiovascular risk factors, such as hypertension, hypercholesterolemia, and diabetes mellitus, often cluster together and can also be seen with other pathophysiological conditions that greatly increase an individual’s risk for cardiovascular morbidity and death. Aim of the study: This article emphasizes the importance of assessing and managing the total cardiovascular risk in an individual patient. Materials and methods: Suggestions and recommendations from the most current hypertension management guidelines have been integrated with results from the major clinical trials published in the last decade. Results: Based on a review of the epidemiological data on cardiovascular disease, this paper expands the concept of stratification of hypertensive patients according to the approximate added risk of major cardiovascular events in the next 10 years and stresses the importance of subclinical target-organ damage. Conclusions: Although common in clinical practice, high-risk patients are often undiagnosed. Intensive hypertensive therapy is recommended for high-risk patients, and this treatment strategy will require combination therapy to control or reverse subclinical organ damage and prevent the progression of cardiovascular risk in subjects at low risk or medium risk.

Efficacy and safety of sitagliptin added to ongoing metformin and rosiglitazone combination therapy in a randomized placebo‐controlled 54‐week trial in patients with type 2 diabetes (一项为期54周的对持续使用二甲双胍与罗格列酮联合治疗的2型糖尿病患者加用西格列汀治疗的有效性与安全性的随机安慰剂对照研究)*

AbstractBackground: New therapeutic approaches are needed to improve glycemic control in patients with type 2 diabetes (T2D), a progressive disorder that often requires combination therapy. The present study assessed the efficacy and safety of sitagliptin as add‐on therapy to metformin and rosiglitazone in patients with T2D.Methods: The present study was a randomized double‐blind placebo‐controlled parallel‐group 54‐week study conducted at 41 sites across North and South America, Europe, and Asia in 278 patients with HbA1c ranging from ≥7.5% to ≤11.0% despite ongoing combination therapy with metformin (≥1500 mg/day) and rosiglitazone (≥4 mg/day). Patients were randomized (2:1) to receive sitagliptin 100 mg or placebo once daily. The main outcome measure was change from baseline in HbA1c at Week 18.Results: Mean baseline HbA1c was 8.8%. The mean placebo‐adjusted change from baseline in HbA1c with sitagliptin treatment was −0.7% (P &lt; 0.001) at Week 18 and −0.8% (P &lt; 0.001) at Week 54. There were also significant (P &lt; 0.001) reductions in 2‐h post‐meal glucose and fasting plasma glucose compared with placebo at Weeks 18 and 54. Significantly higher proportions of sitagliptin‐ than placebo‐treated patients had HbA1c&lt;7.0% at Weeks 18 (22% vs 9%; P = 0.003) and 54 (26% vs 14%; P = 0.015). Changes in body weight and the rates of adverse events overall, hypoglycemia, and gastrointestinal adverse events were similar in the sitagliptin and placebo groups during the 54‐week study.Conclusions: In patients with T2D, the addition of sitagliptin for 54 weeks to ongoing therapy with metformin and rosiglitazone improved glycemic control and was generally well tolerated compared with placebo.

Fatal DisseminatedFusariumInfection in a Human Immunodeficiency Virus Positive Patient

Systemic mycotic infections have been increasing in incidence in immunocompromised patients. Although yeasts are most often isolated, opportunistic fungal infections may also be caused by filamentous fungi, including Aspergillus and Fusarium. Like Aspergillus, Fusarium is angioinvasive with an ability to disseminate widely. Disseminated fusariosis is most commonly linked to prolonged neutropenia. Disseminated infections due to Fusarium are rare in Human Immunodeficiency Virus (HIV) positive patients but have been reported in HIV positive patients with neutropenia and lymphoma. We describe an HIV positive patient without neutropenia, skin lesions, or concomitant malignancy, who developed fatal disseminated infection with possible endocarditis due to Fusarium solani. Early identification of Fusarium is important because of its high level of resistance to several antifungal drugs, with response often requiring combination therapy.

Cardiovascular outcomes in hypertensive patients

To determine whether blood pressure (BP) control in hypertensive patients achieved with combination drug therapy provides the same cardiovascular benefits as with single-agent therapy. Drug combinations, most often including hydrochlorothiazide (HCTZ), are now recommended for routine BP management, but their effects on cardiovascular event rates have not been compared with effective monotherapy. We conducted retrospective analyses of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) data. VALUE compared cardiovascular event rates of valsartan and amlodipine. Patients with BPs not controlled (<140/90 mmHg) by the single agents had HCTZ and, if required, additional drugs of different classes, added. Using data pooled from the two treatment arms, we have now divided patients into those controlled on monotherapy and those controlled or not controlled by combination therapy. The primary study endpoint was first occurrence of cardiovascular death or nonfatal myocardial infarction or stroke. Comparisons between groups were by Cox regression, adjusted for on-treatment BP, age, prior cardiovascular events and left ventricular hypertrophy; the comparison between the monotherapy and combination therapy controlled groups was based on events occurring after 3 months by when the decision to use monotherapy or combination therapy was made. The primary endpoint occurred in 505 of 5924 (8.5%) monotherapy and 511 of 4621 (11.1%) combination therapy controlled patients: hazard ratio was 0.80 [95% confidence interval (CI) 0.70-0.90]. If these two groups were matched for baseline BPs and all events included from study baseline, the hazard ratio was 0.76 (95% CI 0.67-0.86). The difference between combination controlled and uncontrolled [434 of 3390 (12.8%)] groups was not significant [hazard ratio 0.90 (95% CI 0.80-1.03], nor when they were matched for baseline BPs [hazard ratio 0.95 (95% CI 0.81-1.11)]. Independent of prior cardiovascular history or baseline BP, hypertensive patients requiring combination therapy, which includes a thiazide diuretic for BP control, have a poorer cardiovascular prognosis than those controlled by monotherapy and only a nonsignificantly lower event rate than noncontrolled patients.

A Ten-Year Retrospective Study on Livedo Vasculopathy in Asian Patients

This study aims to analyse the clinico-epidemiological characteristics of Asian patients diagnosed with livedo vasculopathy (LV). We performed a retrospective analysis of all patients diagnosed with LV from 1997 to 2007 at our centre. Seventy patients were diagnosed with LV with a mean age of 39 years, female: male ratio of 3:1 and no racial predilection. Most cases remained purely cutaneous, presenting with painful leg ulcers and atrophie blanche. Peripheral neuropathy was the only extra-cutaneous complication (9%). In patients who were screened, associations included hepatitis B (7%) and hepatitis C (4%), positive anti-nuclear antibody (14%), positive anti-myeloperoxidase antibody (5%), positive anti-cardiolipin antibodies (7%) and positive lupus anticoagulant (2%). In 49 patients who achieved remission, 55% required combination therapy, most commonly with colchicine, pentoxifylline and prednisolone. In those treated successfully with monotherapy, colchicine was effective in 59% followed by prednisolone (17.5%), pentoxifylline (17.5%) and aspirin (6%). Mean follow-up period was 50 months. LV in Asian patients is a high morbidity, chronic relapsing ulcerative skin condition. Most patients require induction combination therapy for remission. As further evidence emerges to support a procoagulant pathogenesis, a standardised protocol is needed to investigate for prothrombotic disorders during diagnosis.

Differential effects of clinically used derivatives and metabolites of artemisinin in the activation of constitutive androstane receptor isoforms

Widespread resistance to antimalarial drugs requires combination therapies with increasing risk of pharmacokinetic drug-drug interactions. Here, we explore the capacity of antimalarial drugs to induce drug metabolism via activation of constitutive androstane receptors (CAR) by ligand binding. A total of 21 selected antimalarials and 11 major metabolites were screened for binding to CAR isoforms using cellular and in vitro CAR-coactivator interaction assays, combined with in silico molecular docking. Identified ligands were further characterized by cell-based assays and primary human hepatocytes were used to elucidate induction of gene expression. Only two artemisinin derivatives arteether and artemether, the metabolite deoxyartemisinin and artemisinin itself demonstrated agonist binding to the major isoforms CAR1 and CAR3, while arteether and artemether were also inverse agonists of CAR2. Dihydroartemisinin and artesunate acted as weak inverse agonists of CAR1. While arteether showed the highest activities in vitro, it was less active than artemisinin in inducing hepatic CYP3A4 gene expression in hepatocytes. Artemisinin derivatives and metabolites differentially affect the activities of CAR isoforms and of the pregnane X receptor (PXR). This negates a common effect of these drugs on CAR/PXR-dependent induction of drug metabolism and further provides an explanation for artemisinin consistently inducing cytochrome P450 genes in vivo, whereas arteether and artemether do not. All these drugs are metabolized very rapidly, but only artemisinin is converted to an enzyme-inducing metabolite. For better understanding of pharmacokinetic drug-drug interaction possibilities, the inducing properties of artemisinin metabolites should be considered.

579 Single-pill combination of telmisartan 80 mg/amlodipine 5 mg provides sustainable 24 hours blood pressure reduction

Objectives: The majority of patients with hypertension may require combination therapy to achieve BP targets. This study was conducted to evaluate the 24 hours antihypertensive efficacy of telmisartan 80 mg (T80) plus amlopipine 5 mg (A5) as a single-pill combination (SPC) by 24 h ambulatory blood pressure monitoring (ABPM). Methods: In an open-label, single center, phase III trial, 40 chinese adult patients with mean seated trough cuff diastolic blood pressure [DBP] ≥ 100 mmHg or 24 hour mean DBP ≥ 85 mmHg at baseline were screened to be treated with T80/A5 SPC for 8 weeks. Primary efficacy measures were the changes from baseline in the 24-hour ABPM mean (relative to dose time) for both DBP and SBP after 8 weeks of treatment with T80/A5 SPC. Results: 27 patients (mean age, 52 years; male, 66.8%; mean SBP and DBP in baseline by ABPM, 150.24 ± 17.30mmHg and 95.79 ± 7.74 mmHg repectively) received treatment;. 24 hours mean BP reductions (mmHg) with T80/A5 from baseline to Week 8 were -23.8 ± 14.5 for SBP and -12.8 ± 7.4 for DBP. The median trough-to-peak(T/P) ratios for SBP and DBP using 24-hour ABPM were 0.98 and 1.13, respectively. T80/A5 SPC had a low rate of patients with overall adverse events (AEs) (14.8% and AEs leading to discontinuation (3.7%). Conclusions: In Chinese patients with hypertension, 8 weeks treatment with T80/A5 SPC resulted in a clinically meaningful decrease in both SBP and DBP with a low T/P ratio of about 1. T80/A5 SPC was safe and well tolerated in this population. Appendix

Heterogeneity of breast cancer stem cells as evidenced with Notch‐dependent and Notch‐independent populations

Studies have suggested the potential importance of Notch signaling to the cancer stem cell population in some tumors, but it is not known whether all cells in the cancer stem cell fraction require Notch activity. To address this issue, we blocked Notch activity in MCF-7 cells by expressing a dominant-negative MAML-GFP (dnMAML) construct, which inhibits signaling through all Notch receptors, and quantified the effect on tumor-initiating activity. Inhibition of Notch signaling reduced primary tumor sphere formation and side population. Functional quantification of tumor-initiating cell numbers in vivo showed a significant decrease, but not a complete abrogation, of these cells in dnMAML-expressing cells. Interestingly, when assessed in secondary assays in vitro or in vivo, there was no difference in tumor-initiating activity between the dnMAML-expressing cells and control cells. The fact that a subpopulation of dnMAML-expressing cells was capable of forming primary and secondary tumors indicates that there are Notch-independent tumor-initiating cells in the breast cancer cell line MCF-7. Our findings thus provide direct evidence for a heterogeneous cancer stem cell pool, which will require combination therapies against multiple oncogenic pathways to eliminate the tumor-initiating cell population.