Ultrasonographic assessment of renal perfusion in bitches with mammary carcinoma treated with long-term carprofen.

The aim of this study was to evaluate renal hemodynamics, routine clinical and laboratory parameters used to estimate renal function, and clinical evolution during six months in bitches with mammary carcinomas that underwent mastectomy and were treated (TG) or not (CG) with carprofen for three months after surgery. Twenty-six bitches with mammary carcinoma were equally distributed into TG that received carprofen 4.4 mg/kg/day for 90 days and CG that did not receive anti-inflammatory medication. Renal artery Doppler flowmetry, contrast-enhanced ultrasound (CEUS) of renal parenchyma, haematological, biochemical and clinical analyses were obtained once a month. These data were compared between groups and time via analysis of variance (ANOVA) in a completely randomized design with repeated measures (P < 0.05). On B-mode ultrasound, the area of the renal artery was greater (P = 0.0003) in the TG. Regarding laboratory findings, haematocrit and haemoglobin were similar in both groups, showing a significant and gradual increase after three months of treatment; MCV, MHC, and MCHC were increased (P < 0.05) and lymphocyte and band counts decreased (P < 0.05) in the TG. Regarding biochemical tests, ALT was the only parameter with a significant difference, being higher (P = 0.0272) in the treated group. It can be concluded that the use of carprofen for 90 days causes minimal changes in renal perfusion, erythrocyte parameters and ALT activity, and reduces the proportion of blood inflammatory cells. Therefore, use of this medication can be carried out safely in patients who require auxiliary cancer treatment.

Pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol.

LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]- and S[-]-carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80-1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)- and S(-)-carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug-drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies.

Clinical status and outcome of Japanese heart failure patients with reduced or preserved ejection fraction treated with carvedilol.

The effect of beta-blockers in treating Japanese heart failure (HF) patients with preserved left ventricular (LV) ejection fraction (EF) is unclear. This prospective observational study enrolled 1,682 Japanese HF patients who received carvedilol for the first time. Patients were followed for a mean of 1.6 years. The 1,492 patients with baseline LVEF measurements were allocated to the following groups: reduced EF (LVEF < 40%; n = 724), borderline EF (LVEF 4050%; n = 355), and preserved EF (LVEF ≥ 50%; n = 413). Baseline characteristics, New York Heart Association (NYHA) class, change in B-type natriuretic peptide (BNP) level, and long-term outcome were compared among the groups. Patients with preserved EF were more likely to be older, female, and have ischemic etiology and hypertension than patients with reduced EF. Carvedilol maintenance dosage was lower in patients with preserved EF (7.9 mg/day versus 6.6 mg/ day). NYHA class and BNP level were lower in patients with preserved EF at baseline but improved to the same level in all groups at 6 months. After adjusting for baseline characteristics, the hazard ratio for death or hospitalization due to cardiovascular disease in patients with preserved EF versus those with reduced EF was 1.031 (P = 0.847). This study elucidated the characteristics of HF patients given carvedilol in "real world" clinical settings. A comparative controlled study is necessary to elucidate whether the improvements in NYHA and BNP as well as the outcome profile observed in patients with preserved EF were caused by the favorable effects of carvedilol.

Self-rated health predicts adverse events during ß-blocker treatment: the CIBIS-ELD randomised trial analysis.

BACKGROUND: Self-rated health (SRH) predicts outcome in patients with heart failure. Beta-blockers are known to improve health-related quality of life and reduce mortality in such patients. We aimed to evaluate the relation between SRH and adverse events during titration of beta-blockers in elderly patients with heart failure. METHODS: The cardiac insufficiency bisoprolol study in the elderly (CIBIS-ELD) is a multicentre, double-blind trial, in which 883 patients aged ≥ 65 years with chronic heart failure (73 ± 6 years, 38% women, left ventricular ejection fraction [LVEF] 42% ± 14%) were randomised to bisoprolol or carvedilol. SRH was assessed at baseline and after 12 weeks, using a 5-grade descriptive scale: excellent, very good, good, fair, and poor. RESULTS: Median SRH at baseline and follow-up was good, but more patients reported fair/poor SRH at baseline (36% vs. 30%, p = 0.012). Women, beta-blocker-naïve patients, patients in NYHA class III/IV and those with PHQ-9 score ≥ 12 were more likely to report fair/poor baseline SRH (p < 0.001 for all). During follow-up, SRH improved in 34% of patients and worsened in 8% (p < 0.001). Adverse events were experienced by 64% patients and 38% experienced > 1 adverse event or serious adverse event, with higher prevalence in lower SRH categories. In a multivariate logistic regression model, SRH, age, distance achieved on the 6-min walk test and LVEF >45% predicted adverse events (p < 0.05 for all). CONCLUSIONS: SRH is an independent predictor of adverse events during titration of beta-blockers and correlates with the proportion and number of adverse events per patient.

An assessment of the association between carvedilol exposure and severe hypersensitivity reactions, angioedema, and anaphylactic reactions: a retrospective nested case-control analysis.

BACKGROUND: There is limited information in the literature regarding the risk of severe hypersensitivity reactions due to different ß-blocking agents. Most of the available information addresses the potential for increased severity of anaphylaxis or poor response to treatments among patients receiving ß-blocking agents. OBJECTIVE: The objective of this study was to estimate the incidence rates of severe hypersensitivity reactions (angioedema and anaphylactic reactions) for various ß-blockers and to examine the risk of severe hypersensitivity reactions in patients exposed to carvedilol extended-release compared with carvedilol and compared with other ß-blockers. METHODS: A case-control analysis nested within a cohort of ß-blocker users in the LabRx Database was conducted. A case was defined as an incident hypersensitivity reaction of either anaphylactic shock (International Classification of Diseases, 9th Revision [ICD-9] code 995.0) or angioneurotic edema (ICD-9 code 995.1). Three controls were matched to each case. Patients were classified according to their ß-blocker exposure in the 30 day-period before the index date. Conditional logistic regression was used to calculate odds ratios and 95% CIs. RESULTS: A total of 1,810,487 ß-blocker users were identified; 7811 hypersensitivity cases and 23,433 controls were included in this analysis. The mean (SD) age of the cohort was 53 (14) years, and 49% were men. The overall incidence rates of severe hypersensitivity reactions among various ß-blockers categories were similar to that in the overall ß-blocker users cohort (2.40 per 1000 person-years [95% CI, 2.35-2.45]). The odds ratios of severe hypersensitivity reaction for carvedilol extended-release compared with carvedilol and with other long-acting ß-blockers were 0.86 (95% CI, 0.48-1.53) and 1.10 (95% CI, 0.90-1.35), respectively. CONCLUSIONS: This retrospective database analysis of mostly middle-aged patients detected no statistically significant differences in the likelihood of severe hypersensitivity reactions among patients who received carvedilol extended-release versus carvedilol or other long-acting ß-blockers.

Persistence with nebivolol in the treatment of hypertension: a retrospective claims analysis.

OBJECTIVE: Examine drug persistence by evaluating the hazard of discontinuation and of switching to different antihypertensive drugs in patients initiating treatment with a recently approved ß-blocker, nebivolol, versus other ß-blockers. METHODS: This retrospective analysis included all patients diagnosed with hypertension in the MarketScan Database (January 2007 - December 2008) with at least two medical claims and no prior ß-blocker prescriptions within 6 months of the initial prescription date. Multivariate Cox proportional hazard models (adjusted for baseline differences in demographics, previous use of other antihypertensive medications, initial doses and supply of medication, and number of distinct prescriptions at baseline) were used to assess the hazard of discontinuation, defined as the first prescription gap of ≥30 days, and to assess the hazard of switching to another antihypertensive drug, defined as a prescription fill for another antihypertensive drug within 15 days before and 30 days after discontinuation of the initial ß-blocker. RESULTS: Of the 173,200 patients included in the study population, the adjusted hazard of discontinuation for nebivolol-initiated patients was 8-20% lower than that of patients who initiated treatment with atenolol (hazard ratio [HR] 0.82, p < 0.001), metoprolol (HR 0.91, p < 0.001), carvedilol (HR 0.92, p < 0.001), or other ß-blockers (HR 0.80, p < 0.001). The adjusted hazard of nebivolol-treated patients switching to a different antihypertensive medication was 12-22% lower than that of the other four ß-blocker cohorts (atenolol: HR 0.80, p < 0.001; metoprolol: HR 0.86, p < 0.001; carvedilol: HR 0.88, p < 0.001; other ß-blockers: HR 0.78, p < 0.001). Sensitivity analyses defined discontinuation as prescription gaps of ≥45 days and ≥60 days and showed a lower hazard of discontinuation among patients initiating nebivolol than among patients initiating all other drug cohorts (p < 0.001). LIMITATIONS: Comparisons of non-randomized treatment groups may be confounded by unobserved differences in patients' baseline characteristics. CONCLUSIONS: Initiation with nebivolol was associated with greater persistence than initiation with atenolol, carvedilol, metoprolol, or other ß-blockers.

Pirlindole in the treatment of depression and fibromyalgia syndrome.

Depression and fibromyalgia syndrome are debilitating chronic conditions that impose a significant burden on individuals, families and society. Both depression and fibromyalgia have many overlapping symptoms, and antidepressants of several classes are among recommended treatment options for patients with fibromyalgia syndrome. Pirlindole is a selective and reversible inhibitor of monoamine oxidase (MAO) subtype A (MAO-A) that is approved in some European and non-European countries for the treatment of depression. The antidepressant efficacy and safety of pirlindole have been demonstrated in a number of placebo- and active comparator-controlled studies and are supported by many years of clinical experience in the treatment of depression. The drug's efficacy and safety have also been demonstrated, more recently, in the treatment of fibromyalgia syndrome. Pirlindole has a favourable tolerability profile, with no deleterious effect on cardiovascular dynamics. The effect of pirlindole on sensorimotor performance relevant to driving a motor vehicle is similar to that of placebo, as pirlindole appears to have an activating rather than a sedating antidepressant profile. Because of its specific and reversible inhibition of MAO-A and relatively short elimination half-life, no tyramine or 'cheese' effect is likely after short- or long-term administration. The available evidence supports pirlindole as a safe and effective treatment option for the management of depression and fibromyalgia syndrome.

Use and risk management of carvedilol for the treatment of heart failure in the community in England: results from a modified prescription-event monitoring study.

BACKGROUND: In the UK, the licence for carvedilol was extended in 1998 to include symptomatic heart failure (New York Heart Association [NYHA] class II and III heart failure) with the recommendation that initiation and up-titration should be under the supervision of a hospital physician. A post-marketing surveillance study was conducted to address the UK regulatory authority's request for monitoring the use and safety of carvedilol prescribed for heart failure in clinical practice. AIM: To investigate adherence to risk management recommendations for the use of carvedilol for heart failure, monitor how patients' subsequent care was managed and collect event data to evaluate the safety profile of carvedilol used for the treatment of heart failure. METHODS: An observational cohort study using a modified prescription-event monitoring technique identified patients from dispensed primary care prescriptions in England (August 1999 to June 2001). An eligibility questionnaire was used to identify patients who had been prescribed carvedilol for heart failure for the first time after 31 July 1999. Up to three follow-up questionnaires were sent to the prescribers of eligible patients, requesting demographic information, dosage, supervision of treatment, status of cardiac failure and event information. RESULTS: 2311 patients met the eligibility criteria. For 1666 patients, one or more valid follow-up questionnaires were returned: 68.5% were male; male median age 66 years; female median age 72 years; the observation period was up to 3 years. Hospital physicians supervised initiation of treatment and first up-titration in 85.6% and 61.4% of patients, respectively. 49.2% of patients were prescribed the recommended starting dosage of carvedilol (6.25 mg/day). Approximately 25% of patients started on a lower dose than recommended, and the same proportion were prescribed a higher dose. NYHA status of cardiac failure between starting treatment and the third questionnaire improved for 39.5% of patients, deteriorated for 10.9%, and 11.7% of those for whom NYHA status was given died. Adverse drug reactions (ADRs) were reported for 2.4% of patients; the most commonly reported ADR was malaise/lassitude. Overall, 27.1% of patients stopped taking carvedilol. None of the 163 deaths were attributed to carvedilol. CONCLUSIONS: Regulatory guidelines for the use and risk management of carvedilol in heart failure were mostly followed, and most patients appeared to benefit from treatment with carvedilol for heart failure. Malaise/lassitude was the main reason for discontinuing treatment. Further investigations may be warranted to examine the prescribing of carvedilol at lower than recommended doses.

The impact of baseline HR and BP on the tolerability of carvedilol in the elderly: the COLA (Carvedilol Open Label Assessment) II Study.

BACKGROUND: The COLA (Carvedilol Open Label Assessment) II Study prospectively evaluated the tolerability of carvedilol in 1030 patients >70 years of age with chronic heart failure (CHF). Tolerability, defined as patients receiving > or =3 months of carvedilol and achieving a maintenance dosage > or =12.5 mg/day, was 80%. In a multivariate analysis, advanced age, low DBP, left ventricular ejection fraction, obstructive airways disease, and a presence of diabetes mellitus were predictors of tolerability. The aim of this analysis was to evaluate further the relationship between baseline HR, SBP, DBP and tolerability in COLA II. METHODS: Baseline HR, SBP and DBP data were available in 1009 patients (98%). These data were analyzed as both continuous and categorical variables. For the latter analysis, the following categories were created: HR <70, 70 < or = HR <90, HR > or =90 bpm; SBP <120, 120 < or = SBP <160, SBP > or =160 mm Hg; DBP <70, 70 < or = DBP <90, DBP > or =90 mm Hg. RESULTS: Baseline HR did not differ between patients who tolerated carvedilol (T) and those who did not (non-T) [81 +/- 16 vs 79 +/- 16 bpm]. However, SBP and DBP were significantly lower in the non-T versus the T group (131 +/- 20 vs 139 +/- 22 mm Hg for SBP [p < 0.001] and 77 +/- 11 vs 81 +/- 12 mm Hg for DBP [p < 0.001]). Seventy-four percent of patients in the lowest category for baseline HR (<70 bpm tolerated carvedilol versus 82% and 79% of those in the higher categories (p = not significant). Seventy percent of patients in the lowest category of baseline SBP (<120 mm Hg) tolerated carvedilol versus 80% and 89% of those in the upper categories (p < 0.001). Similarly, 73% of patients in the lowest category for DBP (<70 mm Hg) tolerated carvedilol versus 78% and 87% of those in the upper categories (p < 0.005). CONCLUSIONS: Carvedilol is generally well tolerated by elderly patients with CHF, even in those with low baseline BP or HR. However, a low baseline SBP or DBP does identify patients who are less likely to tolerate the drug. Baseline HR does not appear to significantly affect tolerability in this population.

A risk-benefit assessment of carvedilol in the treatment of cardiovascular disorders.

Carvedilol is a nonselective beta-adrenoceptor blocking vasodilator drug that may be a promising new agent in the management of cardiovascular disease. The rationale for the development of agents of this type is that the alpha-blocking component may overcome the direct vasoconstrictor consequence of beta 2-blockade, whilst the beta-blocker component may inhibit the reflex tachycardia that occurs following alpha-blockade. In clinical trials published to date, carvedilol has been demonstrated to be effective as an antihypertensive agent as monotherapy and also as additional therapy in those patients whose blood pressure cannot be controlled on other standard agents. It is also effective in the management of angina. Carvedilol has beneficial haemodynamic effects in patients with congestive heart failure. beta-Blocker vasodilator drugs of this type may be particularly useful in this condition as the vasodilator component of the drug may overcome the initial negative inotropy of the beta-blocker. In addition, carvedilol possess potentially useful pharmacological actions. In particular, the drug has antimitogenic and free radical scavenging effects that may make it a useful therapy in the long term management of atherosclerotic vascular disease. Its metabolic profile is also favourable, presumably on the basis of its alpha-blocking properties. Thus, beta 2-mediated adverse effects on peripheral vascular tone, glycaemic control and lipid status appear to be offset by the alpha-blocking property of the drug. Carvedilol thus far appears to be well tolerated, with postural dizziness the major adverse effect, especially in the elderly. As with nonselective beta-blockers, carvedilol is contraindicated in patients with asthma.