Quantification of Hydrochlorothiazide and Ramipril/Ramiprilate in Blood Serum and Cerebrospinal Fluid: A Pharmacokinetic Assessment of Central Nervous System Adverse Effects.

BACKGROUND: A drug must reach the central nervous system (CNS) in order to directly cause CNS adverse effects (AEs). Our current study addressed the pharmacokinetic (PK) background of the assumption that CNS concentrations of hydrochlorothiazide (HCT) and ramiprilate may directly cause CNS AEs such as headache and drowsiness. METHODS: In neurological patients, paired serum and cerebrospinal fluid (CSF) samples were withdrawn simultaneously. Some of them were treated with HCT (n = 15, daily chronic doses 7.5-25 mg) or ramipril (n = 9, 2.5-10 mg). Total concentrations of HCT and ramiprilate were quantified in these samples. To this end, sensitive liquid chromatography/tandem mass spectrometry methods were developed. RESULTS: CSF reached 4.1% (interquartile ranges 2.5-5%) of total serum concentrations for HCT and 2.3% (1.7-5.7%) for ramiprilate, corresponding to about 11.3% and 5.5% of respective unbound serum concentrations. CONCLUSION: The PK/Pharmacodynamic characteristics of HCT and ramiprilate in the CNS are unknown. However, since the CSF levels of these agents, both free and bound, were much lower than the corresponding concentrations in serum, it is unlikely that the observed CNS AEs are mediated primarily via direct effects in the brain.

Fixed-dose vs free-dose combinations for the management of hypertension-An analysis of 81 958 patients.

Fixed-dose combinations (FDC) have been developed to reduce the pill burden for hypertensive patients. Data on fixed-dose or free-dose (freeDC) ramipril/amlodipine (R/A) or candesartan/amlodipine (C/A) combination treatment initiation were assessed. 71 463 patients were prescribed R/A and 10 495 C/A. For both R/A and C/A, FDC patients were younger (both P < .001) and less comorbid. Prior MI (OR: 0.61 and 0.60), prior stroke (OR: 0.68 and 0.70) and CHD (OR: 0.68 and 0.64) were negatively associated with FDC use, whereas hyperlipidemia was positively associated (OR: 1.26 and 1.19). Use of antihypertensive comedication (OR: 0.78; OR: 0.55) and treatment discontinuation within 12 months (HR: 0.65 and 0.82) were less likely in FDC patients, who also showed superior adherence (mean MPR; both P < .001). Cost of the combination was higher for FDCs (both P < .001). FDCs improve persistence and adherence, although they are more commonly prescribed in patients with less cardiovascular disease.

The Fuster-CNIC-Ferrer Cardiovascular Polypill: a polypill for secondary cardiovascular prevention.

During the last decade, there has been a tremendous effort to develop different cardiovascular polypills in response to the upsurge in global cardiovascular disease worldwide. The pharmacological development of such a strategy has proven to be extremely complex from a formulation standpoint. Not all drugs are suitable for use in a polypill because of potential drug incompatibilities between them. Candidate agents must be safe, well tolerated, effective, guideline recommended and physiochemically compatible with the other components of the pill. The Fuster-CNIC-Ferrer cardiovascular (CV) polypill has been found to be the first-in-class polypill to be approved and commercialized in Europe and Latinamerican Countries. In this article, we review the pharmacological properties of its three components, including the clinical evidence supporting their use in patients with established cardiovascular disease, their pharmacokinetic properties, adverse effects, drug interactions and contraindications.

Telmisartan for the management of patients at high cardiovascular risk.

BACKGROUND: Cardiovascular disease (CVD) places a significant burden on healthcare providers. High blood pressure (BP) is the single most prevalent risk factor for CVD worldwide and is responsible for more deaths than any other risk factor. 'Cardiovascular (CV) high-risk patients' make up the broad cross-section of patients in the middle of the risk spectrum for CVD progression that is referred to as the CV continuum and includes those with atherothrombotic disease, those with target organ damage associated with type 2 diabetes and those with multiple risk factors. Angiotensin II is involved in CVD progression at every stage of the CV continuum, making the renin-angiotensin system a rational target for pharmacologic intervention. Angiotensin II receptor blockers (ARBs) offer a better tolerated alternative to angiotensin converting enzyme inhibitors, with greater long-term adherence. The ARB telmisartan recently received an indication for CV prevention. SCOPE: A PubMed literature search was conducted to identify evidence on the use of telmisartan for preventing CV events. FINDINGS: Telmisartan has a favourable safety and tolerability profile, and has demonstrated efficacious and long-lasting 24-hour BP reductions, whether as monotherapy or in combination with hydrochlorothiazide or amlodipine. In the largest CV prevention trial program undertaken with an ARB (the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial; ONTARGET), telmisartan 80 mg/day alone was as effective as ramipril in reducing the composite primary endpoint of CV mortality, non-fatal myocardial infarction, non-fatal stroke and hospitalization for heart failure in CV high-risk patients. However, patients were significantly more likely to adhere to treatment with telmisartan than ramipril due to its better tolerability. CONCLUSION: To date, telmisartan is the only ARB indicated to reduce CV morbidity in a broad CV high-risk population.

Cost-effectiveness of the treatment of heart failure with ramipril: a Spanish analysis of the AIRE study.

AIMS: To estimate the cost-effectiveness of adding ramipril to conventional treatment in patients with heart failure after myocardial infarction from the perspective of the Spanish National Health System. METHODS AND RESULTS: A retrospective analysis of the AIRE study was made, using previously published data from the clinical trial combined with local Spanish resource and cost data. A typical rehospitalisation for a heart failure episode would last an average of 11.6 days with an average cost of 350.80 per day. The incremental cost of ramipril per life-year gained in the baseline case was 1550.10 after 3.8 years of follow-up. Sensitivity analysis showed that the basic conclusions were robust in spite of extreme variations in the values of the key parameters of the model. CONCLUSION: The use of ramipril in addition to conventional treatment in heart failure patients after myocardial infarction is cost-effective both according to currently accepted international standards of what constitutes a cost-effective intervention and also indirectly by comparing the results with similar pharmaceutical products financed under the Spanish National Health System.