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Aachen, Germany

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Aachen, Germany
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Storz E.,Vfa Die Forschenden Pharma Unternehmen | Franzen W.-H.,Takeda Pharma GmbH | Fritsch D.,Aachen und Merck Serono GmbH
Pharmazeutische Industrie | Year: 2011

Extensive proposals for strengthening pharmacovigilance in Europe were presented by the European Commission in December 2008. After two years of consultation these proposals were passed and the final versions of the Regulation and the Directive were published on December 31, 2010. The requirements of the Directive now must be implemented by the Member States by July 2012. Extensive changes can be expected in the areas of periodic safety update reports, publication of documents and information via web portals, reporting rules and performance of post-authorization safety and efficacy studies. Many of these measures will improve transparency and will lead to simplification of pharmacovigilance. Others are seen more critically by the pharmaceutical industry. This article will evaluate some of the most important changes from the pharmaceutical industry viewpoint. © ECV Editio Cantor Verlag.

Aim: To investigate the efficacy of a fixed combination of candesartan (32 mg) and hydrochlorothiazide (HCTZ, 25 mg) in previously untreated patients with severe essential hypertension. Methods: Prospective, open-label study with 105 patients with systolic blood pressure (SBP) of 150-200 mmHg and diastolic blood pressure (DBP) of 110-120 mmHg. The fixed titration schema over 9 weeks started with 16 mg Candesartan (week 1), Candesartan + HCTZ (16 mg/12.5 mg) (week 2.3), Candesartan + HCTZ (32 mg/25 mg) (week 4.9). Results: Blood pressure was lowered by 44.4±16.8 mmHg (SBP), and 32.0±11.3 mmHg (DBP) (p<0.0001). 92.4 % of patients achieved the defined goal of blood lowering below 140/90 mmHg or reduction of .20 mmHg (SBP) and 10 mmHg (DBP), respectively. The disorders were in line with the known safety profile of the study drugs. Conclusion: The maximal allowed treatment with a fixed combination of candesartan/HCTZ in Europe is effective and safe to achieve a considerable and swift blood pressure reduction in newly diagnosed severe arterial hypertension. © Verlag PERFUSION GmbH.

Background: We analyzed specific effects of an add-on therapy with pioglitazone compared to metformin and their combination in patients with basal insulin treatment on biomarkers of CV risk.Methods: In this double-blind, randomized, multicentre, active comparator controlled trial, 121 patients with type 2 diabetes were enrolled. Inclusions: treatment with basal insulin, HbA 1C6.5% - 8.5%, age 30 - 75 years. After glargine therapy over 2 weeks for titration towards FBG ≤ 7.8 mmol/L, patients received either (A) bid 850 mg metformin (n = 42), (B) bid 15 mg pioglitazone (n = 40), or (C) 30 mg pioglitazone plus 1.7 g metformin (n = 39) over 6 months. Matrix Metal Proteinase 9 (MMP-9) was primary objective, together with biomarkers of CV risk.Results: Pioglitazone (B) reduced MMP-9 versus baseline by 54.1 + 187.1 ng/mL, with metformin (A) it was increased by 49.6 + 336.2 ng/mL (p = 0.0345; B vs. A), and with the combination of both (C) it was decreased by 67.8 + 231.4 ng/mL (A vs. C: p = 0.0416; B vs. C: p = 0.8695). After logarithmic transformation due to high variances the exploratory results showed significance for A vs. B (p = 0.0043) and for A vs. C (p = 0.0289).Insulin dosage was reduced by 7.3 units in group B (p < 0.0001), by 6.0 units in C (p = 0.0004), but was increased by 2.5 units (p = 0.1539) in A at follow up. Reduction in hs-CRP was significant within treatment groups for B (p = 0.0098) and C (p < 0.0001), and between the groups for A vs. C (p = 0.0124). All three single regimens reduced PAI-1. Adiponectin was significantly elevated in B and C (p < 0.0001) and between-groups. HbA 1Cwas only significantly decreased in the combination group. No significant effects were observed for NFkB and PGFα. peripheral edema were seen in 11.9% vs. 40.0% vs. 20.5%, and weight change was -0.7 kg vs. +4.3 kg vs. +2.7 kg (A vs. B vs. C).Conclusions: Addition of pioglitazone but not of metformin reduces MMP-9, hs-CRP and increased insulin sensitivity and adiponectin in this study. The combination of both had no additional effect on inflammation. Pioglitazone is suggested to be a rational add-on therapy to basal insulin in patients with high CV risk. © 2011 Hanefeld et al; licensee BioMed Central Ltd.

Gasanin E.,Kerckhoff Klinik GmbH | Patyna W.,Kurpark Klinik | Tajdivand M.,Kerckhoff Klinik GmbH | Fuchs W.,Takeda Pharma GmbH | Mitrovic V.,Kerckhoff Klinik GmbH
Perfusion | Year: 2011

Background: During long-term therapy angiotensin converting enzyme inhibitors do not completely block the formation of angiotensin-II. Combination with angiotensin-II type 1 receptor antagonists could provide a better blockade of the RAAS system compared with monotherapy. Objectives: The aim of this study was to evaluate the hemodynamic and neurohumoral effects at rest and during exercise of angiotensin-II type 1 receptor antagonist candesartan cilexetil as add-on therapy to ACE inhibitors in patients with moderate to severe symptomatic heart failure NYHA class III-IV. Furthermore, the safety of candesartan cilexetil add-on therapy was investigated. Methods: This was a prospective, randomised, double-blind, placebo-controlled, parallel group study. 35 patients received either candesartan 8 mg/16 mg (week 1 and 2/week 3-24) or placebo as add-on therapy to their previous ACE inhibitor during a 24-weeks treatment period. The hemodynamic evaluation was performed by using right heart catheterization and and exercise capacity by ergospirometry. The ITT population comprised 14 patients in the candesartan and 15 patients in the placebo group. Results: Peak aerobic capacity remained about constant in the candesartan group (0.06 ± 1.43 mL/min/kg) and slightly decreased in the placebo group (-1.10 ± 1.51 mL/min/kg). No superiority of candesartan could be concluded (p=0.13). Exercise time showed a relevant increase in the candesartan group (31.9 ± 58.5 s) and a significant decrease in the placebo group (-25.9 ± 85.9 s) compared to baseline value. The difference between treatment groups was significant (p=0.0018). Further relevant differences between treatment groups were observed in changes of right atrial pressure at rest (candesartan: -1.9 ± 1.7 mmHg, placebo: 1.0 ± 2.7 mmHg; p=0.0045), pulmonary capillary wedge pressure at rest (candesartan: -3.1 ± 3.8 mmHg, placebo: 0.2 ± 4.6 mmHg; p=0.0497) and systemic vascular resistance at maximum exercise (candesartan: -141.9 ± 253.3 dyn·s/cm -5, placebo: 47.3 ± 221.0 dyn·s/cm -5; p=0.0296). Plasma-renin-concentration was significantly increased with candesartan (279.5 ± 901.9 ng/L; p=0.0127), but in the placebo group it remained unchanged (-29.0 ± 211.9 ng/L; p=0.6267). Conclusion: The efficacy of CHF treatment was improved by candesartan as add-on therapy to ACE inhibitors. In our patients population co-administration of candesartan did not impose an additional risk on patients treated with ACE inhibitors. © Verlag PERFUSION GmbH.

Forst T.,University of Mainz | Forst T.,Johannes Gutenberg University Mainz | Weber M.M.,Johannes Gutenberg University Mainz | Lobig M.,University of Mainz | And 6 more authors.
Clinical Science | Year: 2010

The aim of the present study was to compare the effect of PIO (pioglitazone) or GLIM (glimepiride) on erythrocyte deformability in T2DM (Type 2 diabetes mellitus). The study covered 23 metformin-treated T2DM patients with an HbA 1c (glycated haemoglobin) >6.5%. Patients were randomized to receive either PIO (15 mg, twice a day) or GLIM (1 mg, twice a day) in combination with metformin (850 mg, twice a day) for 6 months. Blood samples were taken for the measurement of fasting glucose, HbA 1c, fasting insulin, intact proinsulin, adiponectin and Hct (haematocrit). In addition, the erythrocyte EI (elongation index) was measured using laser diffractoscopy. Both treatments significantly improved HbA 1c levels (PIO, -0.9 ± 1.1%; GLIM, -0.6 ± 0.4%; both P < 0.05) and resulted in comparable HbA 1c levels after 6 months (PIO, 6.5 ± 1.2%; GLIM, 6.2 ± 0.4%) Treatment with PIO reduced fasting insulin levels (-8.7 ± 15.8 milli-units/l; P = 0.098), intact proinsulin levels (-11.8 ± 9.5 pmol/l; P < 0.05) and Hct (-1.3 ± 2.3%; P = 0.09), whereas adiponectin levels increased (8.2 ± 4.9 μg/ml; P < 0.05). No significant change in these parameters was observed during GLIM treatment. PIO improved the EI, resulting in a significant increase in EI at all physiological shear stress ranges (0.6 - 6.0 Pa; P < 0.05). The improvement in EI correlated with the increase in adiponectin levels (r = 0.74; P < 0.001), and inversely with intact proinsulin levels (r = -0.47; P < 0.05). This is the first study showing an improvement in EI during treatment with PIO, which was associated with an increase in adiponectin and a decrease in intact proinsulin levels, but independent of glycaemic control. © The Authors.

Pfutzner A.,Institute for Clinical Research and Development | Pfutzner A.,Bingen University of Applied Sciences | Hanefeld M.,GWT | Dekordi L.A.,Institute for Clinical Research and Development | And 4 more authors.
Journal of Diabetes Science and Technology | Year: 2011

Aims: This study investigated the effects of pioglitazone (PIO), ramipril (RAM), or their combination (PIRA) on low-grade inflammation in nondiabetic hypertensive patients with increased cardiovascular risk. Methods and Results: Patients enrolled in this placebo-controlled, double-blind, randomized, parallel trial (72 male, 77 female, aged 60 ± 9 years, body mass index 30.4 ± 4.7 kg/m2, duration of hypertension 9 ± 8 years) were treated with either 30/45 mg PIO (dose titration), 2.5/5 mg RAM, or their combination for 12 weeks. A reduction in high-sensitivity C-reactive protein was observed with PIO (-0.89 ± 1.98 mg/liter; -25%) and PIRA (-0.49 ± 2.11 mg/liter; -16%), while an increase was seen with RAM (0.58 ± 2.13 mg/liter; +20%, p < .05 vs PIO and PIRA). The 24-hour blood pressure profile showed a small increase with both monotherapies but a decrease with PIRA (p < .05 vs PIO). Improvements in biomarkers of chronic systemic inflammation and insulin resistance (IR) were observed in the PIO and PIRA arms only [PIO/RAM/PIRA: homeostasis model of assessment of IR: -0.78 ± 1.39 (-29%)/0.15 ± 1.03 (+5%)/ -1.44 ± 2.83 (-40%); adiponectin: 8.51 ± 5.91 (+104%)/ 0.09 ± 2.63 (+1%)/ 8.86 ± 6.37 mg/liter (+107%); matrix metallo-proteinase- 9: -48 ± 127 (-12%)/-1 ± 224 (0%)/-60 ± 210 ng/ml (-13%), p < .05 for RAM vs PIO or PIRA in all cases]. Conclusions: Our 3-month study in nondiabetic hypertensive patients showed a decrease in biomarkers of IR and chronic systemic inflammation with the PIO monotherapy and the PIRA combination only, which may help to explain some findings in other cardiovascular outcome trials. © Diabetes Technology Society.

Mengden T.,Kerckhoff Klinik GmbH | Hubner R.,Takeda Pharma GmbH | Bramlage P.,Institute For Kardiovaskulare Pharmakologie Und Epidemiologie
Vascular Health and Risk Management | Year: 2011

Background: Fixed-dose combinations of candesartan 32 mg and hydrochlorothiazide (HCTZ) have been shown to be effective in clinical trials. Upon market entry we conducted a noninterventional study to document the safety and effectiveness of this fixed-dose combination in an unselected population in primary care and to compare blood pressure (BP) values obtained during office measurement (OBPM) with ambulatory blood pressure measurement (ABPM). Methods: CHILI CU Soon was a prospective, noninterventional, noncontrolled, open-label, multicenter study with a follow-up of at least 10 weeks. High-risk patients aged $18 years with previously uncontrolled hypertension were started on candesartan 32 mg in a fixed-dose combination with either 12.5 mg or 25 mg HCTZ. OBPM and ABPM reduction and adverse events were documented. Results: A total of 4131 patients (52.8% male) with a mean age of 63.0 ± 11.0 years were included. BP was 162.1 ± 14.8/94.7 ± 9.2 mmHg during office visits at baseline. After 10 weeks of candesartan 32 mg/12.5 mg or 25 mg HCTZ, mean BP had lowered to 131.7 ± 10.5/80.0 ± 6.6 mmHg (P, 0.0001 for both comparisons). BP reduction was comparable irrespective of prior or concomitant medication. In patients for whom physicians regarded an ABPM to be necessary (because of suspected noncontrol over 24 hours), ABP at baseline was 158.2/93.7 mmHg during the day and 141.8/85.2 mmHg during the night. At the last visit, BP had significantly reduced to 133.6/80.0 mmHg and 121.0/72.3 mmHg, respectively, resulting in 20.8% being normotensive over 24 hours (,130/80 mmHg). The correlation between OBPM and ABPM was good (r = 0.589 for systolic BP and r = 0.389 for diastolic BP during the day). Of those who were normotensive upon OBPM, 35.1% had high ABPM during the day, 49.3% were nondippers, and 3.4% were inverted dippers. Forty-nine adverse events (1.19%) were reported, of which seven (0.17%) were regarded as serious. Conclusion: Candesartan 32 mg in a fixed-dose combination with either 12.5 mg or 25 mg HCTZ is safe and effective for further BP lowering irrespective of prior antihypertensive drug class not being able to control BP.© 2011 Mengden et al, publisher and licensee Dove Medical Press Ltd.

Samyshkin Y.,IMS Health | Schlunegger M.,Takeda Pharma AG | Haefliger S.,Takeda Pharma AG | Ledderhose S.,Takeda Pharma AG | Radford M.,IMS Health
International Journal of COPD | Year: 2013

Objective: Chronic obstructive pulmonary disease (COPD) represents a burden on patients and health systems. Roflumilast, an oral, selective phosphodiesterase-4-inhibitor reduces exacerbations and improves lung function in severe/very severe COPD patients with a history of exacerbations. This study aimed to estimate the lifetime cost and outcomes of roflumilast added-on to commonly used COPD regimens in Switzerland. Methods: A Markov cohort model was developed to simulate COPD progression in patients with disease states of severe, very severe COPD, and death. The exacerbation rate was assumed to be two per year in severe COPD. COPD progression rates were drawn from the published literature. Efficacy was expressed as relative ratios of exacerbation rates associated with roflumilast, derived from a mixed-treatment comparison. A cost-effectiveness analysis was conducted for roflumilast added to long-acting muscarinic antagonists (LAMA), long-acting β2-agonist/inhaled corticosteroids (LABA/ICS), and LAMA + LABA/ICS. The analysis was conducted from the Swiss payer perspective, with costs and outcomes discounted at 2.5% annually. Parameter uncertainties were explored in one-way and probabilistic sensitivity analyses. Results: In each of the comparator regimens mean life expectancy was 9.28 years and quality-adjusted life years (QALYs) gained were 6.19. Mean estimated lifetime costs per patient in the comparator arms were CHF 83,364 (LAMA), CHF 88,161 (LABA/ICS), and CHF 95,564 (LAMA + LABA/ICS) respectively. Adding roflumilast resulted in a mean cost per patient per lifetime of CHF 86,754 (LAMA + roflumilast), CHF 91,470 (LABA/ICS + roflumilast), and CHF 99,364 (LAMA + LABA/ICS + roflumilast), respectively. Life-expectancy and quality-adjusted life-expectancy were 9.63 years and 6.47 QALYs (LAMA + roflumilast), 9.64 years and 6.48 QALYs (LABA/ICS + roflumilast), and 9.63 years and 6.47 QALYs (LAMA + LABA/ICS + roflumilast). Incremental cost-effectiveness ratios were CHF 12,313, CHF 11,456, and CHF 13,671 per QALY when roflumilast was added to the three regimens. Conclusion: Treatment with roflumilast is estimated to reduce the health and economic burden of COPD exacerbations and represent a cost-effective treatment option for patients with frequent exacerbations in Switzerland. © 2013 Samyshkin et al, publisher and licensee Dove Medical Press Ltd.

PubMed | General practitioner, Takeda Pharma GmbH and University of Munster
Type: | Journal: Pragmatic and observational research | Year: 2016

To investigate the efficacy of candesartan 32 mg and hydrochlorothiazide (HCTZ) 25 mg combination in patients with severe essential hypertension.In this prospective, open-label, single-group study, 106 previously untreated patients with a baseline systolic blood pressure (SBP) of 150-200 mmHg, and a diastolic blood pressure (DBP) of 110 to 120 mmHg, started with candesartan 16 mg during the first week. HCTZ 12.5 mg was added at week 2 and from fourth week onwards candesartan 32 mg plus HCTZ 25 mg was given over 6 weeks. The primary efficacy endpoint was mean reduction in SBP and DBP after 9 weeks. Response was defined as a decrease in SBP to <140 mmHg and/or by 20 mmHg and in DBP to <90 mmHg and/or by 10 mmHg. A second response criterion defined blood pressure reduction below 140/90 mmHg.Blood pressure was lowered from 180.0 11.7/114.7 3.1 mmHg by SBP 44.4 16.8 and DBP 32.0 11.3 mmHg (A stepped treatment approach with candesartan/HCTZ combinations is effective and safe to achieve a swift blood pressure reduction in newly diagnosed, severe hypertension. The target of <140/90 mmHg was reached by >50% of the patients only after taking the full dose of candesartan 32 mg and HCTZ 25 mg.

Hanefeld M.,TU Dresden | Schaper F.,TU Dresden | Appelt D.,TU Dresden | Fuchs W.,Takeda Pharma GmbH
Hormone and Metabolic Research | Year: 2011

High levels of fetuin-A has been linked to cardiovascular disease, possibly via modulating low-grade systemic inflammation. We performed a subanalysis from the PIOSTAT study to investigate a possible link between fetuin-A and the inflammatory biomarker hs-CRP. 66 nondiabetic individuals at cardiovascular risk were randomized to either pioglitazone, simvastatin, or the combination of both, and followed for 12 weeks. At study endpoint, correlations between serum fetuin-A, hs-CRP, blood lipids, PAI-1, MMP-9, HOMA-IR, and liver transaminases were investigated by Spearman rank correlation. Changes in fetuin-A concentration did not correlate to changes in hs-CRP (r=0.19, p=0.16). A positive correlation was found for change of HOMA-IR value (r=0.33, p=0.01) and for the AST/ALT ratio (p<0.05). Our data suggest that the previously observed correlation between elevated circulating fetuin-A and hs-CRP in epidemiological studies may not reflect a causal relationship in nondiabetic patients on high cardiovascular risk. © Georg Thieme Verlag KG.

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