Progression of Renal Impairment and Chronic Kidney Disease in Chronic Heart Failure: An Analysis From GISSI-HF.

BACKGROUND: Data on the natural change in renal function in patients with chronic heart failure (HF) are limited. METHODS AND RESULTS: Estimated glomerular filtration rate (eGFR) was assessed over 36 months in 6934 patients included in the GISSI-HF study. Associations from baseline, changes in renal function, and occurrence of cardiovascular death or HF hospitalization were assessed. Mean age was 67 years, mainly men (78%), and mean eGFR was 68 mL • min-1 • 1.73 m-2. Change in eGFR in the 1st year was -1.5 ± 16 mL • min-1 • 1.73 m-2, and over 36 months it was -3.7 ± 18 mL • min-1 • 1.73 m-2. Over the latter period, only 25% deteriorated ≥1 Kidney Disease Outcomes Quality Initiatives (KDOQI) class of chronic kidney disease (CKD). Fifteen percent of patients had >15 mL • min-1 • 1.73 m-2 decrease in eGFR in the 1st 12 months. Lower eGFR was associated with outcome: hazard ratio (HR) 1.10, 95% confidence interval (CI) 1.08-1.10 (P < .001) per 10 mL • min-1 • 1.73 m-2 decrease, as well as every 10 mL • min-1 • 1.73 m-2 decrease over the 1st year (HR 1.10, 95% CI 1.04-1.17; P < .001). A deterioration in eGFR >15 mL • min-1 • 1.73 m-2 in the 1st year showed the highest risk of events (HR 1.22, 95% CI 1.10-1.36; P < .001). CONCLUSIONS: Mean decrease in renal function over time in patients with chronic HF was modest. Only 25% deteriorated ≥1 KDOQI class of CKD after 3 years. Any decrease in eGFR over time was associated with strongly increased event rates.

Relation between weight loss and causes of death in patients with cardiovascular disease: finding from the SCOUT trial.

AIMS: Obesity is associated with an increased incidence of mortality. The Sibutramine Cardiovascular Outcomes (SCOUT) trial can provide the first evidence of the effect of intentional weight loss on mortality in an obese population at high risk. METHODS: SCOUT was a randomized, double-blind, placebo-controlled trial testing sibutramine vs. placebo. Eligibility for the trial required both men and women aged at least 55 years, with BMI of at least 27 kg/m and 45 kg/m or less. Study participants with type 2 diabetes mellitus (T2DM) only should have at least one other risk factor defined as hypertension, dyslipidaemia, smoking, or diabetic nephropathy, and/or they had a history of cardiovascular disease. Study participants were stratified in three groups: patients with T2DM, patients with a prior cardiovascular event but without diabetes, and patients with both T2DM and a prior cardiovascular event.The relationship between weight loss and mortality (all-cause, cardiovascular, and noncardiovascular) was investigated with Cox regression models. RESULTS: The main study showed that all-cause mortality was not different in patients allocated to sibutramine or placebo. This ancillary analysis demonstrates that there is a general trend showing higher mortality in patients with the greatest weight loss (weight reduction >10 kg) and in those with increasing weight (>1 kg). If integrated weight loss (area under the curve from baseline to 12 months) is used, these observations are confirmed. The impact of substantial weight loss on mortality is marked in those dying of noncardiovascular causes, specifically cancer. CONCLUSION: The relationship between weight change and mortality differs for cardiovascular and noncardiovascular mortality.

Prognostic impact of in-hospital hyperglycemia in hospitalized patients with acute heart failure: Results of the IN-HF (Italian Network on Heart Failure) Outcome registry.

OBJECTIVES: Although diabetes mellitus is frequently associated with heart failure (HF), the association between elevated admission glucose levels and adverse outcomes has not been well established in hospitalized patients with acute HF. METHODS: We prospectively evaluated in-hospital mortality, post-discharge 1-year mortality and 1-year re-hospitalization rates in the Italian Network on Heart Failure (IN-HF) Outcome registry cohort of 1776 patients hospitalized with acute HF and stratified by their admission glucose levels (i.e., known diabetes, newly diagnosed hyperglycemia, no diabetes). RESULTS: Compared with those without diabetes (n = 586), patients with either known diabetes (n = 749) (unadjusted-odds ratio [OR] 1.64, 95%CI 0.99­2.70) or newly diagnosed hyperglycemia (n = 441) (unadjusted-OR 2.34, 95%CI 1.39­3.94) had higher in-hospital mortality, but comparable post-discharge 1-year mortality rates. After adjustment for age, sex, systolic blood pressure, estimated glomerular filtration rate, left ventricular ejection fraction, HF etiology and HF worsening/de novo presentation, the results remained unchanged in patients with known diabetes (adjusted-OR 1.86, 95%CI 1.01­3.42), while achieved borderline significance in those with newly diagnosed hyperglycemia (adjusted-OR 1.81, 95%CI 0.95­3.45). One-year re-hospitalization rates were lower in patients with newly diagnosed hyperglycemia (adjusted-hazard ratio 0.74, 95%CI 0.56­0.96) than in other groups. CONCLUSIONS: Elevated admission blood glucose levels are associated with poorer in-hospital survival outcomes in patients with acute HF, especially in those with previously known diabetes. This finding further highlights the importance of tight glycemic control during hospital stay and address the need of dedicated intervention studies to identify customized clinical protocols to improve in-hospital survival of these high-risk patients.

Appropriateness of Prescriptions of Recommended Treatments in Organisation for Economic Co-operation and Development Health Systems: Findings Based on the Long-Term Registry of the European Society of Cardiology on Heart Failure.

OBJECTIVE: This observational study aimed to identify clinical variables and health system characteristics associated with incomplete guideline application in drug treatment of patients with chronic heart failure (HF) across 15 countries. METHODS: Three data sets were used: European Society of Cardiology Heart Failure Registry, Organisation for Economic Co-operation and Development's Health System Characteristics Survey, and Organisation for Economic Co-operation and Development Health Statistics 2013. Patient and country variables were examined by multilevel, multiple logistic regression. The study population consisted of ambulatory patients with chronic HF and reduced ejection fraction. Inappropriateness of prescription of pharmacological treatments was defined as patients not prescribed at least one of the two recommended treatments (angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers and beta-blockers) or treated with both medications but at suboptimal dosage and in absence of documented contraindication/intolerance. RESULTS: Of 4605 patients, 1097 (23.8%) received inappropriate drug prescriptions with a large variation within and across countries, with 18.5% of the total variability accounted for by between-country health structure characteristics. Patient-level characteristics such as having mitral regurgitation (odds ratio 1.4; 95% confidence interval 1.1-1.7) was significantly associated with inappropriate prescription of recommended drugs, whereas chronic obstructive pulmonary disease (odds ratio 0.7; 95% confidence interval 0.5-0.9) was associated with more appropriate prescriptions. Among the country-level variables, incentives or obligation to comply with guidelines increased the probability of prescription appropriateness. CONCLUSIONS: Combining clinical variables with health system characteristics is a promising exercise to explain the appropriateness of recommended drug prescriptions. Such an understanding can help decision makers to design more effective policies to improve adherence to guidelines, improve health care outcomes, and potentially reduce costs.

Clinical and biochemical effects of a 3-week program of diet combined with spa therapy in obese and diabetic patients: a pilot open study.

Obesity is a major risk factor for arterial hypertension, coronary artery disease, dyslipidemias, and type 2 diabetes. Spa therapy has long been used for treating obesity and its comorbidities. Enlargement of adipose tissue has been linked to a dysregulation of adipokine secretion and adipose tissue inflammation. Adipokines are currently investigated as potential drug targets in these conditions. Our primary aim was to assess the clinical efficacy of a 3-week program of diet combined with spa therapy in obese patients with and without type 2 diabetes. The secondary aim was to examine whether this combined program influences the response of serum levels of leptin, adiponectin, visfatin, and high-sensitivity C-reactive protein. Fifty obese males were enrolled and 21 of these featured a type 2 diabetes. During the 3-week period of the study, the patients were on a 1,000-kcal diet and were involved in mineral bath and total body's mud-pack applications (15 procedures). Patients were assessed at baseline and at the end of the therapy for clinical and biochemical parameters (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, glycemia, and adipokines). We showed that a 3-week program of spa therapy in obese patients induced significant decrease of body weight, body mass index, triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, glycemia, and serum levels of leptin and high-sensitivity C-reactive protein. So, a cycle of mud-bath therapy associated with a controlled diet may be a promising treatment for obesity and type 2 diabetes decreasing body weight and many risk factors for atherosclerosis and metabolic syndrome.

Treatment with inotropes and related prognosis in acute heart failure: contemporary data from the Italian Network on Heart Failure (IN-HF) Outcome registry.

BACKGROUND: In the recent Italian Network on Heart Failure (IN-HF) Outcome registry, including 1,855 patients with acute heart failure (AHF), we reviewed the use of inotropes and their prognostic implication on in-hospital and 12-month mortality. METHODS: IN-HF Outcome is a prospective, multicenter, observational, study involving 61 Italian cardiology centers. AHF patients have been enrolled over a 2-year period and followed-up for 1 year. Inotropes were used in 360 patients (19.4%). RESULTS: Patients who received inotropes had a more severe clinical and hemodynamic profile than those who did not and exhibited a significantly higher rate of in-hospital (21.4% vs 2.7%, p < 0.01) and 1-year (50.6% vs 17.7%, p < 0.01) mortality. At entry, systolic blood pressure (SBP) was ≤ 110 mm Hg in 58%, 111 to 130 mm Hg in 24.5%, and > 130 mm Hg in 17.5%. Multivariable analyses showed use of inotropes was the strongest predictor of all-cause death. These data were confirmed by propensity score analyses. According to SBP at entry, the 2 groups with SBP > 110 mm Hg who took inotropes, despite a more favorable clinical profile, exhibited a similar worse prognosis, particularly at 1 year: 56.3% (≤ 110 mm Hg), 43.7% (111-130 mm Hg), and 40.3% (>130 mm Hg) vs 17.7%. CONCLUSIONS: Inotropes were used in nearly 20% of the patient admitted for AHF, and this treatment was associated with a short-term to medium-term poor prognosis. An inappropriate use of inotropes in patients with normal to high SBP, and presumably preserved cardiac output, may have significantly contributed to affect the all-group outcome.

In-hospital and 1-year outcomes of acute heart failure patients according to presentation (de novo vs. worsening) and ejection fraction. Results from IN-HF Outcome Registry.

BACKGROUND: To investigate the outcomes of hospitalized patients with both de-novo and worsening heart failure (HF) with preserved left ventricular ejection fraction (LVEF) (HFpEF) (LVEF ≥ 50%), compared to those with reduced LVEF (HFrEF). METHODS AND RESULTS: We studied 1669 patients (22.6% HFpEF) hospitalized for acute HF in the prospective multi-center nationwide Italian Network on Heart Failure (IN-HF) Outcome Registry. In all patients LVEF was assessed during hospitalization. De-novo HF presentations constituted 49.6% of HFpEF and 43.1% of HFrEF hospitalizations. All-cause mortality during hospitalization was lower in HFpEF than HFrEF (2.9% vs 6.5%, p=0.01), but this mortality difference was not significant at 1 year (19.6% vs 24.4%, p=0.06), even after adjusting for clinical covariates. Similarly, there were no differences in 1-year mortality between HFpEF and HFrEF when compared by cause of death (cardiovascular vs non-cardiovascular) or mode of presentation (worsening HF vs de novo). Rehospitalization rates (all-cause, non-cardiovascular, cardiovascular, HF-related) at 90 days and 1 year were also similar. Mode of presentation influenced rehospitalizations in HFpEF, where those presenting with worsening HFpEF had higher all-cause (36.8% vs 21.6%, p=0.001), cardiovascular (28.1% vs 14.9%, p=0.002), and HF-related (21.1% vs 7.7%, p=0.0003) rehospitalization rates at 1 year compared to those with de novo presentations. CONCLUSIONS: Outcomes at 1 year following hospitalization for HFpEF are as poor as that of HFrEF. A prior history of HF decompensation or hospitalization identifies patients with HFpEF at particularly high risk of recurrent events. These findings may have implications for clinical practice, quality and process improvements and trial design.

Co-morbidities in patients with heart failure: an analysis of the European Heart Failure Pilot Survey.

AIMS: Co-morbidities frequently accompany heart failure (HF), contributing to increased morbidity and mortality, and an impairment of quality of life. We assessed the prevalence, determinants, regional variation, and prognostic implications of co-morbidities in patients with chronic HF in Europe. METHODS AND RESULTS: A total of 3226 European outpatients with chronic HF were included in this analysis of the European Society of Cardiology (ESC) Heart Failure Pilot Survey. The following co-morbidities were considered: diabetes, hyper- and hypothyroidism, stroke, COPD, sleep apnoea, chronic kidney disease (CKD), and anaemia. Prognostic implications of co-morbidities were evaluated using population attributable risks (PARs), and patients were divided into geographic regions. Clinical endpoints were all-cause mortality and HF hospitalization. The majority of patients (74%) had a least one co-morbidity, the most prevalent being CKD (41%), anaemia (29%), and diabetes (29%). Co-morbidities were independently associated with higher age (P < 0.001), higher NYHA functional class (P < 0.001), ischaemic aetiology of HF (P < 0.001), higher heart rate (P = 0.011), history of hypertension (P < 0.001), and AF (P < 0.001). Only diabetes, CKD, and anaemia were independently associated with a higher risk of mortality and/or HF hospitalization. There were marked regional differences in prevalence and prognostic implications of co-morbidities. Prognostic implications of co-morbidities (PARs) were: CKD = 41%, anaemia = 37%, diabetes = 14%, COPD = 10%, and <10% for all other co-morbidities. CONCLUSION: In this pilot survey, co-morbidities are prevalent in patients with chronic HF and are related to the severity of the disease. The presence of diabetes, CKD, and anaemia was independently related to increased mortality and HF hospitalization, with the highest PAR for CKD and anaemia.

EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot).

AIMS: The ESC-HF Pilot survey was aimed to describe clinical epidemiology and 1-year outcomes of outpatients and inpatients with heart failure (HF). The pilot phase was also specifically aimed at validating structure, performance, and quality of the data set for continuing the survey into a permanent Registry. METHODS: The ESC-HF Pilot study is a prospective, multicentre, observational survey conducted in 136 Cardiology Centres in 12 European countries selected to represent the different health systems across Europe. All outpatients with HF and patients admitted for acute HF on 1 day per week for eight consecutive months were included. From October 2009 to May 2010, 5118 patients were included: 1892 (37%) admitted for acute HF and 3226 (63%) patients with chronic HF. The all-cause mortality rate at 1 year was 17.4% in acute HF and 7.2% in chronic stable HF. One-year hospitalization rates were 43.9% and 31.9%, respectively, in hospitalized acute and chronic HF patients. Major regional differences in 1-year mortality were observed that could be explained by differences in characteristics and treatment of the patients. CONCLUSION: The ESC-HF Pilot survey confirmed that acute HF is still associated with a very poor medium-term prognosis, while the widespread adoption of evidence-based treatments in patients with chronic HF seems to have improved their outcome profile. Differences across countries may be due to different local medical practice as well to differences in healthcare systems. This pilot study also offered the opportunity to refine the organizational structure for a long-term extended European network.

Predictors of mortality in 6975 patients with chronic heart failure in the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico-Heart Failure trial: proposal for a nomogram.

BACKGROUND: We developed a prognostic model to assess the risk of all-cause mortality in patients with chronic heart failure. METHODS AND RESULTS: We examined 6975 patients with chronic heart failure enrolled in the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico-Heart Failure (GISSI-HF) trial (3.9 years follow-up). Multivariable Cox regression models were developed to predict mortality (1969 deaths). By stepwise selection, the full final model included 25 predictors. A reduced model, considering the most significant variables ranked according to the Wald χ(2) (P<0.0001) accounted for most of the prognostic information. Internal validation of the model was performed with bootstrap techniques. The discrimination ability of the reduced model constituted by 12 factors (concordance probability estimate, 0.693) was as good as the full final model (concordance probability estimate, 0.70). Among the first 12 independent risk factors emerging in the reduced model, the 3 most powerful predictors were older age, higher New York Heart Association class, and lower estimated glomerular filtration rate. Other independent predictors that increased risk included lower left ventricular ejection fraction, chronic obstructive pulmonary disease, lower systolic blood pressure, diabetes mellitus, male sex, higher uricemia, lower body mass index, lower hemoglobin, and aortic stenosis. The reduced model was used to build a nomogram to estimate the risk of death in individual patients. In a subgroup of patients, the 2 well-known biomarkers (high-sensitivity cardiac troponin T and N-terminal pro-brain natriuretic peptide) emerged as the most powerful predictors of outcome. CONCLUSIONS: In a large contemporary population with chronic heart failure, this model offers good ability to assess the risk of death, confirming most of the risk factors that have emerged in recent trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00336336.

Effects of Candesartan on Left Ventricular Function, Aldosterone and BNP in Chronic Heart Failure.

PURPOSE: Heart failure (HF) is characterized by activation of neurohormonal systems such as aldosterone and natriuretic peptides. In the absence of published data, CandHeart trial was designed to assess the effects on left ventricular (LV) function, aldosterone and brain natriuretic peptide (BNP) of candesartan in patients with HF and preserved (LVEF ≥ 40%) or depressed (LVEF <40%) LV systolic function. METHODS: A total of 514 patients with stable symptomatic NYHA II-IV HF and any left ventricular ejection fraction (LVEF)were randomized to candesartan (target dose 32 mg once daily) as add-on therapy or standard medical therapy alone. Standardized echocardiographic exams were performed locally under central quality control, whereas biomarkers were assayed in a core laboratory. RESULTS: The majority of patients (73.3%) were NYHA II and on ACE inhibitors (91.8%) and beta-blockers (85.4%). Mean age was 66 ± 11 years. Mean LVEF was 36.2 ± 9.7% and 24.9% of patients had LVEF ≥ 40%. LVEF increased significantly more in the candesartan group (p = 0.09 at 12 weeks and p = 0.01 at 48 weeks) and left ventricular end-diastolic diameter decreased in candesartan group (p = 0.05 at 12 weeks). Candesartan significantly reduced aldosterone at 48 weeks (p = 0.009). BNP was reduced similarly over time in both study groups (p = 0.35 and p = 0.98 at 12 and 48 weeks, respectively). There were 6.6% of discontinuations of candesartan for adverse events. CONCLUSIONS: In CandHeart, the addition of candesartan to standard medical treatment did not reduce circulating BNP more than standard therapy (primary endpoint), but it significantly improved LV function and produced a marked decrease in aldosterone levels at study end.

Relation between serum sodium levels and prognosis in outpatients with chronic heart failure: neutral effect of treatment with beta-blockers and angiotensin-converting enzyme inhibitors: data from the Italian Network on Congestive Heart Failure (IN-CHF database).

INTRODUCTION: The predictive role of hyponatremia has been tested in acute and chronic heart failure. Sodium level is inversely related with renin-angiotensin-aldersterone system (RAAS) and sympathetic nervous activity but important issues remain unresolved. Our aim was to define the level of hyponatremia able to predict 1-year outcomes and investigate the relation between sodium levels and mortality and the effect of beta-blockers and angiotensin-converting enzyme (ACE) inhibitors on this relation. METHODS: We analyzed 4670 patients enrolled in the IN-CHF Italian Registry. We controlled the predictivity of hyponatremia, testing it either as a continuous variable and dividing the study sample into three severity groups: group 1 (≥136  mEq/l; n = 4207), group 2 (131-135  mEq/l; n = 389) and group 3 (≤130  mEq/l; n = 74). The linearity of the relationship between sodium levels and mortality was also tested. RESULTS: Mild-to-moderate and severe hyponatremia (groups 2 and 3) independently predicted the 1-year mortality. The relation between sodium concentration and death was not linear and a decrease of 1  mEq/l of sodium increased death rate only for values of sodium 142.9  mEq/l or less. This relationship was not modified by beta-blocker and ACE inhibitor therapies. CONCLUSION: Our data confirm the negative prognostic value of hyponatremia, even of moderate degree, independently of the use of recommended treatments for heart failure.

5-fluorouracil-based chemotherapy enhances the antitumor activity of a thymidylate synthase-directed polyepitopic peptide vaccine.

BACKGROUND: Thymidylate synthase (TS), a key enzyme in DNA synthesis, is often overexpressed in cancer cells. Some chemotherapeutic agents, such as 5-fluorouracil (5-FU), act by inhibiting TS expression. We evaluated whether a novel 28-amino acid multiepitope peptide, TS/PP, that contains the sequences of three TS-derived epitopes with binding motifs for HLA-A(*)02.01 could induce a TS-directed cytotoxic T-lymphocyte (CTL) response with antitumor activity. METHODS: TS/PP peptide immunologic activity in CTL lines derived from human leukocyte antigen (HLA)-A(*)02.01+ peripheral blood mononuclear cells (PBMCs) was tested in the presence of interleukin-2 and autologous TS/PP peptide-loaded dendritic cells. Immunologic and antitumor activities of TS/PP and its toxicity were also evaluated in vivo in HLA-A(*)02.01 transgenic (HHD) mice that were vaccinated with TS/PP, control, or TS-peptide cocktail and treated with or without 5-FU chemotherapy. The mice were also inoculated subcutaneously with TS-expressing EL-4/HHD lymphoma cells to assess immune response against these tumor cells. RESULTS: TS/PP-specific CTL lines showed a TS-multiepitopic specificity and were able to kill TS+/HLA-A(*)02.01+ breast and colon carcinoma cells. The killing ability against target cells previously exposed to sublethal doses of 5-FU was statistically significantly greater than against untreated target cells (43.5% versus 26.5% at 25/1 effector to target ratio [Difference {diff} = 17.0]; 95% confidence interval [CI] = 12.6 to 20.4) for MDA-MB-231 breast carcinoma cells and 73.5 versus 48.5 (diff = 25.0; 95% CI = 16.2 to 33.8) for the SW-1463 colon carcinoma cells. HHD mice vaccinated with TS/PP manifested a TS-peptide-specific CTL response with no sign of autoimmunity or toxicity. Furthermore, treatment of these mice with 5-FU delayed or prevented the occurrence of tumors formed by inoculation with autologous (TS+)EL-4/HHD lymphoma cells. CONCLUSIONS: The multiepitopic TS/PP vaccine induces a tumor-specific immune response in mice and is especially potent when used in combination with 5-FU-based chemotherapy.

Activity of citalopram on adenosine and serotonin circulating levels in depressed patients.

Citalopram is a selective serotonin reuptake inhibitor used in the treatment of depression. Recent investigations have shown that it reduces in rat brain the release of excitatory amino neurotransmitters acid glutamate and aspartate by the involvement of the inhibitory neuromodulator adenosine. In this study, we described citalopram and serotonin levels in plasma and platelets, as well as plasma adenosine levels, in depressive patients during acute and chronic administration of citalopram. Twelve patients affected by Major Depression (DSM-IV) received a single oral dose of citalopram in the morning, 5 mg in the first 5 days, 10 mg from the 6th to the 10th day, and 20 mg from the 11th to the 40th day. Blood samples for citalopram, serotonin, and adenosine were collected at Time 0 and 4, 12 and 24 hours after drug administration on the first day of citalopram 5 mg, and on the first and the last day of citalopram 20 mg. Citalopram, serotonin, and adenosine concentrations in plasma increased after citalopram administration, and the highest levels were observed on the last day of treatment. Citalopram was detectable in platelets with concentrations showing a time variation similar to plasma values. Serotonin levels in platelets decreased after drug administration, reaching the lowest values on the last day of treatment.

Nimodipine: drug pharmacokinetics and plasma adenosine levels in patients affected by cerebral ischemia.

BACKGROUND AND OBJECTIVE: Nimodipine is a dihydropyridine calcium channel blocker used in the treatment of ischemic damage in subarachnoid hemorrhage. Recent investigations have shown that it is able to inhibit adenosine transport in human red blood cells and parietal cortex neurons. In this study we investigated the pharmacokinetics of nimodipine and the effect on plasma adenosine levels in patients affected by cerebral ischemia. METHODS: Twelve patients with cerebral ischemia (9 men and 3 women; mean age, 68.8 +/- 11.2 years; mean weight, 67.9 +/- 9.3 kg) were admitted to the study. They received nimodipine intravenously (a bolus of 0.03 mg/kg) and orally (single doses of 30, 60, and 90 mg) during different sessions. Blood samples for adenosine and nimodipine were collected at fixed intervals up to 480 minutes. Adenosine and nimodipine plasma levels were detected by HPLC methods. RESULTS: Both the intravenous and oral administrations induced a statistically significant increase in plasma adenosine levels (P <.001), which appeared to be related to the dose and route of drug administration. In particular, a 67.8% increase was observed after intravenous administration, and increases of 28.9%, 43.6%, and 60.2% were observed after 30 mg, 60 mg, and 90 mg of nimodipine, respectively. The pharmacokinetic parameters of nimodipine after intravenous administration were as follows: peak concentration (C(max)), 319.6 +/- 38.9 ng/mL at the first sampling time; area under the curve (AUC), 239 +/- 25 ng. h/mL; and terminal half-life, 3.12 +/- 0.97 hours. After oral administration, the drug kinetics was linear in the administered dose range and the pharmacokinetic parameters were as follows: C(max)(30 mg), 46.1 +/- 5.8 ng/mL; C(max)(60 mg), 81.7 +/- 14.6 ng/mL; C(max)(90 mg), 131.6 +/- 16.3 ng/mL; AUC(30 mg), 119 +/- 25 ng. h/mL; AUC(60 mg), 256 +/- 48 ng. h/mL; and AUC(90 mg), 389 +/- 54 ng. h/mL. The half-life was similar to the values observed after intravenous administration, whereas the bioavailability ranged between 2% and 5.9%. CONCLUSIONS: Our data indicate that the administration of nimodipine induces an increase in plasma adenosine levels, and we hypothesize that the drug activity could be associated, at least partially, with adenosine mediation.