Therapeutic Properties of Highly Selective ß-blockers With or Without Additional Vasodilator Properties: Focus on Bisoprolol and Nebivolol in Patients With Cardiovascular Disease.

Bisoprolol and nebivolol are highly selective ß1-adrenoceptor antagonists, with clinical indications in many countries within the management of heart failure with reduced left ventricular ejection fraction (HFrEF), ischaemic heart disease (IHD), and hypertension. Nebivolol has additional vasodilator actions, related to enhanced release of NO in the vascular wall. In principle, this additional mechanism compared with bisoprolol might lead to more potent vasodilatation, which in turn might influence the effectiveness of nebivolol in the management of HFrEF, IHD and hypertension. In this article, we review the therapeutic properties of bisoprolol and nebivolol, as representatives of "second generation" and "third generation" ß-blockers, respectively. Although head-to-head trials are largely lacking, there is no clear indication from published studies of an additional effect of nebivolol on clinical outcomes in patients with HFrEF or the magnitude of reductions of BP in patients with hypertension.

Cannabinoid Antagonist Drug Discrimination in Nonhuman Primates.

Despite a growing acceptance that withdrawal symptoms can emerge following discontinuation of cannabis products, especially in high-intake chronic users, there are no Food and Drug Administration (FDA)-approved treatment options. Drug development has been hampered by difficulties studying cannabis withdrawal in laboratory animals. One preclinical approach that has been effective in studying withdrawal from drugs in several pharmacological classes is antagonist drug discrimination. The present studies were designed to examine this paradigm in squirrel monkeys treated daily with the long-acting CB1 agonist AM2389 (0.01 mg/kg) and trained to discriminate the CB1 inverse agonist/antagonist rimonabant (0.3 mg/kg) from saline. The discriminative-stimulus effects of rimonabant were both dose and time dependent and, importantly, could be reproduced by discontinuation of agonist treatment. Antagonist substitution tests with the CB1 neutral antagonists AM4113 (0.03-0.3 mg/kg), AM6527 (0.03-1.0 mg/kg), and AM6545 (0.03-1.0 mg/kg) confirmed that the rimonabant discriminative stimulus also could be reproduced by CB1 antagonists lacking inverse agonist action. Agonist substitution tests with the phytocannabinoid ∆9-tetrahydrocannabinol (0.1-1.0 mg/kg), synthetic CB1 agonists nabilone (0.01-0.1 mg/kg), AM4054 (0.01-0.03 mg/kg), K2/Spice compound JWH-018 (0.03-0.3 mg/kg), FAAH-selective inhibitors AM3506 (0.3-5.6 mg/kg), URB597 (3.0-5.6 mg/kg), and nonselective FAAH/MGL inhibitor AM4302 (3.0-10.0 mg/kg) revealed that only agonists with CB1 affinity were able to reduce the rimonabant-like discriminative stimulus effects of withholding daily agonist treatment. Although the present studies did not document physiologic disturbances associated with withdrawal, the results are consistent with the view that the cannabinoid antagonist drug discrimination paradigm provides a useful screening procedure for examining the ability of candidate medications to attenuate the interoceptive stimuli provoked by cannabis discontinuation. SIGNIFICANCE STATEMENT: Despite a growing acceptance that withdrawal symptoms can emerge following the discontinuation of cannabis products, especially in high-intake chronic users, there are no FDA-approved pharmacotherapies to assist those seeking treatment. The present studies systematically examined cannabinoid antagonist drug discrimination, a preclinical animal model that is designed to appraise the ability of candidate medications to attenuate the interoceptive effects that accompany abrupt cannabis abstinence.

Statin and rottlerin small-molecule inhibitors restrict colon cancer progression and metastasis via MACC1.

MACC1 (Metastasis Associated in Colon Cancer 1) is a key driver and prognostic biomarker for cancer progression and metastasis in a large variety of solid tumor types, particularly colorectal cancer (CRC). However, no MACC1 inhibitors have been identified yet. Therefore, we aimed to target MACC1 expression using a luciferase reporter-based high-throughput screening with the ChemBioNet library of more than 30,000 compounds. The small molecules lovastatin and rottlerin emerged as the most potent MACC1 transcriptional inhibitors. They remarkably inhibited MACC1 promoter activity and expression, resulting in reduced cell motility. Lovastatin impaired the binding of the transcription factors c-Jun and Sp1 to the MACC1 promoter, thereby inhibiting MACC1 transcription. Most importantly, in CRC-xenografted mice, lovastatin and rottlerin restricted MACC1 expression and liver metastasis. This is-to the best of our knowledge-the first identification of inhibitors restricting cancer progression and metastasis via the novel target MACC1. This drug repositioning might be of therapeutic value for CRC patients.

Multiple-Ascending-Dose Phase 1 Clinical Study of the Safety, Tolerability, and Pharmacokinetics of CRS3123, a Narrow-Spectrum Agent with Minimal Disruption of Normal Gut Microbiota.

CRS3123 is a novel small molecule that potently inhibits methionyl-tRNA synthetase of Clostridioides difficile, inhibiting C. difficile toxin production and spore formation. CRS3123 has been evaluated in a multiple-ascending-dose placebo-controlled phase 1 trial. Thirty healthy subjects, ages 18 to 45 years, were randomized into three cohorts of 10 subjects each, receiving either 200, 400, or 600 mg of CRS3123 (8 subjects per cohort) or placebo (2 subjects per cohort) by oral administration twice daily for 10 days. CRS3123 was generally safe and well tolerated, with no serious adverse events (SAEs) or severe treatment-emergent adverse events (TEAEs) reported. All subjects completed their assigned treatment and follow-up visits, and there were no trends in systemic, vital sign, or laboratory TEAEs. There were no QTcF interval changes or any clinically significant changes in other electrocardiogram (ECG) intervals or morphology. CRS3123 showed limited but detectable systemic uptake; although absorption increased with increasing dose, the increase was less than dose proportional. Importantly, the bulk of the oral dose was not absorbed, and fecal concentrations were substantially above the MIC90 value of 1 µg/ml at all dosages tested. Subjects receiving either of the two lower doses of CRS3123 exhibited minimal disruption of normal gut microbiota after 10 days of twice-daily dosing. CRS3123 was inactive against important commensal anaerobes, including Bacteroides, bifidobacteria, and commensal clostridia. Microbiome data showed favorable differentiation compared to other CDI therapeutics. These results support further development of CRS3123 as an oral agent for the treatment of CDI. (This study has been registered at Clinicaltrials.gov under identifier NCT02106338.).

Randomized placebo-controlled double-blind phase II study of zaltoprofen for patients with diffuse-type and unresectable localized tenosynovial giant cell tumors: a study protocol.

BACKGROUND: A tenosynovial giant cell tumor (TGCT) is a locally aggressive benign neoplasm arising from intra- or extra-articular tissue. Diffuse TGCT (D-TGCT) most commonly develops in the knee, followed by the hip, ankle, elbow, and shoulder. Surgical removal is the only effective treatment option for the patients. However, a local recurrence rate as high as 47% has been reported. Recently, we revealed that zaltoprofen, a nonsteroidal anti-inflammatory drug possessing the ability to activate peroxisome proliferator-activated receptor gamma (PPARγ), can inhibit the proliferation of TGCT stromal cells via PPARγ. PPARγ is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. It plays an important role in the differentiation of adipocytes from precursor cells and exhibits antitumorigenic effects on certain malignancies. Therefore, we are conducting this investigator-initiated clinical trial to evaluate whether zaltoprofen is safe and effective for patients with D-TGCT or unresectable localized TGCT (L-TGCT). METHODS: This study is a randomized, placebo-controlled, double-blind, multicenter trial to evaluate the safety and efficacy of zaltoprofen for patients with D-TGCT or L-TGCT. For the treatment group, zaltoprofen 480 mg/day will be administered for 48 weeks; the placebo group will receive similar dosages without zaltoprofen. Twenty participants in each group are needed in this trial (40 participants total). The primary outcome is the progression-free rate at 48 weeks after treatment administration. "Progression" is defined as any serious events (1. Repetitive joint swelling due to hemorrhage, 2. Joint range of motion limitation, 3. Invasion of adjacent cartilage or bone, 4. Severe joint space narrowing, 5. Increase in tumor size) requiring surgical interventions. We hypothesize that the zaltoprofen group will have a higher progression-free rate compared to that of the placebo group at 48 weeks. DISCUSSION: This is the first study to evaluate the efficacy of zaltoprofen in patients with D-TGCT or unresectable L-TGCT. We believe that the results of this trial will validate a novel treatment option, zaltoprofen, to stabilize disease progression for TGCT patients. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( UMIN000025901 ) registered on 4/01/2017.

Realistic low-doses of two emerging contaminants change size distribution of an annual flowering plant population.

HHCB [1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta(g)-2-benzopyran] and 4-tert-octylphenol [4-(1,1,3,3-tetramethylbutyl)phenol] are widely used emerging contaminants that have the potential to cause adverse effects in the environment. The purpose of this study was to observe if and how environmentally realistic concentrations of these contaminants alter growth in plant populations. It was hypothesized that within an exposed Gypsophila elegans Bieb (annual baby's breath) population especially fast-growing seedlings are impaired even when the population mean is unaffected, and small doses can cause hormesis and, thus, an increase in shoot or root length. In a dose-response experiment, an experimental population of G. elegans was established (total 15.600 seeds, 50 seeds per replicate, 24 replicates per concentration, 5.2 seedlings/cm2) and exposed to 12 doses of HHCB or 4-tert-octylphenol. After five days, shoot and root length values were measured and population averages, as well as slow- and fast-growing subpopulations, were compared with unexposed controls. Growth responses were predominantly monophasic. HHCB seemed to selectively inhibit both root and shoot elongation among slow- and fast-growing individuals, while 4-tert-octylphenol selectively inhibited both root and shoot elongation of mainly fast-growing seedlings. The ED50 values (dose causing 50% inhibition) revealed that the slow-growing seedlings were more sensitive and fast-growing seedlings less sensitive than the average of all individuals. Although there was toxicant specific variation between the effects, selective toxicity was consistently found among both slow- and fast-growing plants starting already at concentrations of 0.0067 µM, that are usually considered to be harmless. This study indicates that these contaminants can change size distribution of a plant population at low concentrations in the nM/µM range.

Nonhormonal selective estrogen receptor modulator 1-(2-[4-{(3R,4S)-7-Methoxy-2, 2-dimethyl-3-phenyl-chroman-4yl}phenoxy]ethyl)pyrrolidine hydrochloride (ormeloxifene hydrochloride) for the treatment of breast cancer.

Breast cancer is the most common type of diagnosed cancers in women, difficult to treat, and has received international attention because of its aggressive nature and inherent drug resistance mechanisms. Development of a better selective estrogen receptor modulator with good therapeutic profile and less toxicity is very crucial in this scenario. This study was undertaken to evaluate and compare the in vitro and in vivo antitumor activities of ormeloxifene with other clinically used breast cancer drugs. Cytotoxic activity of ormeloxifene was compared with standard drugs, 4-hydroxytamoxifene and Adriamycin. Ormeloxifene (50 µM) concentration showed cytotoxicity of 75% and 82% in MDAMB-231 and 24% and 80% in MCF-7 cells, respectively, after 72 and 144 hr of incubation as displayed by cell viability assay. The same concentration of ormeloxifene was shown to exert 74% caspase-7 activation in MCF-7 cells after 24 hr of incubation by fluorescence resonance energy transfer assay. Cell cycle analysis proved that there was an increase in sub-G1 peak to 64.4% and 33.9% in MDAMB-231 and MCF-7 cells, respectively, after treatment using ormeloxifene (50 µM) for 48 hr. The nonobese diabetic-severe combined immunodeficiency mice bearing tumor xenografts of triple negative MDAMB-231 cells treated with ormeloxifene (3 mg/kg bw) showed significant regression in relative tumor volume compared to control. From the results obtained and as evidenced from prior literature, ormeloxifene in addition to contraceptive use, can be repositioned for the development of an efficacious anticancer drug. These data present the preclinical part of a well concerted effort to place ormeloxifene into further clinical trials.

Efficacy and safety of nebivolol and valsartan as fixed-dose combination in hypertension: a randomised, multicentre study.

BACKGROUND: The fixed-dose combination of any two antihypertensive drugs from different drug classes is typically more effective in reducing blood pressure than a dose increase of component monotherapy. We assessed the efficacy and safety of a fixed-dose combination of a vasodilating ß blocker (nebivolol) and an angiotensin II receptor blocker (valsartan) in adults with hypertension. METHODS: We did an 8-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial at 401 US sites. Participants (age ≥18 years) with hypertension but with blood pressure less than 180/110 mm Hg were randomly assigned (2:2:2:2:2:2:2:1) by a 24-h interactive web response system in blocks of 15 to 4 weeks of double-blind treatment with nebivolol and valsartan fixed-dose combination (5 and 80 mg/day, 5 and 160 mg/day, or 10 and 160 mg/day), nebivolol (5 mg/day or 20 mg/day), valsartan (80 mg/day or 160 mg/day), or placebo. Doses were doubled in weeks 5-8; results are reported according to the final dose. Participants and research staff were masked to treatment allocation. The primary and key secondary endpoints were changes from baseline to week 8 in diastolic and systolic blood pressure, respectively. The primary statistical comparison was between the highest fixed-dose combination dose and the highest monotherapy doses; lower doses were then compared if this comparison was positive (Hochberg method for multiple testing). Efficacy analyses were by intention to treat. Safety assessments included monitoring of adverse events. Continuous efficacy parameters were analysed using an ANCOVA model; binary outcomes were analysed using a logistic regression model. This study is registered with ClinicalTrials.gov, NCT01508026. FINDINGS: Between Jan 6, 2012, and March 15, 2013, 4161 patients were randomly assigned (277 to placebo and 554-555 to each active comparator group), 4118 of whom were included in the primary analysis. At week 8, the fixed-dose combination 20 and 320 mg/day group had significantly greater reductions in diastolic blood pressure from baseline than both nebivolol 40 mg/day (least-squares mean difference -1·2 mm Hg, 95% CI -2·3 to -0·1; p=0·030) and valsartan 320 mg/day (-4·4 mm Hg, -5·4 to -3·3; p<0·0001); all other comparisons were also significant, favouring the fixed-dose combinations (all p<0·0001). All systolic blood pressure comparisons were also significant (all p<0·01). At least one treatment-emergent adverse event was experienced by 30-36% of participants in each group. INTERPRETATION: Nebivolol and valsartan fixed-dose combination is an effective and well-tolerated treatment option for patients with hypertension. FUNDING: Forest Research Institute.

A first-in-human dose-escalation study of ME-143, a second generation NADH oxidase inhibitor, in patients with advanced solid tumors.

BACKGROUND: ME-143, a second-generation tumor-specific NADH oxidase inhibitor, is broadly active against human cancers in vitro and in vivo. This first-in-human dose-escalation study evaluated the dose-limiting toxicities (DLTs), pharmacokinetics, safety, tolerability, and preliminary anti-tumor activity of ME-143 in patients with advanced solid tumors. METHODS: Patients with advanced solid tumors were treated in a 3 + 3 escalation design. ME-143 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle, and weekly thereafter; the final cohort received twice-weekly treatment. Samples for pharmacokinetic analysis were collected during cycle 1. Treatment continued until disease progression or unacceptable toxicity. RESULTS: Eighteen patients were treated: 2.5 mg/kg (n = 3); 5 mg/kg (n = 3); 10 mg/kg (n = 3); 20 mg/kg (n = 6); 20 mg/kg twice-weekly (n = 3). There were no DLTs observed. Nearly all treatment-related toxicities were grade 1/2, specifically (all grades) nausea (22 %) and fatigue (17 %). Two patients experienced infusion reactions at the 20 mg/kg dose level, one of which was grade 4. Stable disease was documented in three patients with colorectal cancer, cholangiocarcinoma, and anal cancer. Pharmacokinetic exposures were linear and dose-dependent, with a half-life of approximately 5 h. CONCLUSIONS: ME-143 was well-tolerated when administered intravenously at the maximally administered/recommended phase 2 dose of 20 mg/kg once weekly to patients with advanced solid tumors. Though limited clinical activity was observed with monotherapy, inhibitors of tumor-specific NADH oxidase such as ME-143 may derive their greatest benefit in combination with cytotoxic chemotherapy.

[Postregistration study of comparative assessment efficacy of the use of fixed combination of nebivolol and amlodipine for the treatment of patients with moderate and high degree of arterial hypertension].

AIM: of the study was to assess efficacy of the use of fixed combination of nebivolol and amlodipine in patients with moderate and high degree of arterial hypertension (AH). MATERIAL AND METHODS: Patients with diagnosis of primary AH (n=124) were divided into 2 groups by random sample method. Patients of group 1 (n=62) received of fixed combination of nebivolol and amlodipine, while those of group 2 (n=62) received free combination of nebivolol and amlodipine. Study drugs were administered both as initial therapy and replacement of preceding treatment. Duration of observation was 3 months with visits after first 2 weeks and in 1, 2, and 3 months after enrollment. RESULTS: Starting from 2nd week visit of fixed combination of nebivolol and amlodipine treated patients had significantly lower levels of systolic and diastolic AP. Already after 2 weeks of combined two-component therapy 60% of group 1 and 52% of group 2 patients achieved target AP. Target AP was achieved by the end of month 1 by 86 and 71%, of month 2 - by 93 and 78% of patients in groups 1 and 2, respectively. In 3 months almost all patients had target AP, but in 1.6% of group 1 and 2.3% of group 2 patients this level was achieved after addition of a thiazide diuretic. Patients receiving of fixed combination of nebivolol and amlodipine achieved noromosyslolia more quickly compared with patients who received free combination of nebivolol and amlodipine. CONCLUSION: Combined therapy with fixed combination of nebivolol and amlodipine appears to be one of effective approaches to treatment of patients with moderate and high degree AH.

[Effect of monotherapy with nebivolol, bisoprolol, carvedilol on the state of vegetative nervous system and sexual function in men with arterial hypertension].

Aim of the study was to assess effect of monotherapy with nebivolol, bisoprolol, carvedilol for 2 months on sexual function in men with arterial hypertension (AH). Men with 1-2 degree of AH (n=75, age 35-55 years, mean age 48+/-3,5 years) received monotherapy with these drugs for 2 months. Registration of parameters of heart rate variability (HRV), Dopplerography of penile arteries, and the Vasilchenko questionnaire were implemented at the end of 4 months of placebo period and after 2 months of therapy with a study drug. Therapy with bisoprolol, carvedilol, and nebivolol was associated with significant elevation of parasympathetic part of vegetative nervous system tone, improvement of systolic blood flow in cavernous and dorsal arteries. Analysis of data obtained by Vasilchenko questionnaire demonstrated improvement of psychic and erectile components of sexual function. Thus bisoprolol, carvedilol, and nebivolol did not worsen sexual function of men with AH, improved spectral parameters of HRV and vascular blood flow in arteries of cavernous bodies.

Mutagenicity and oral toxicity studies of Terminalia chebula.

The fruit of Terminalia chebula Retz. (T. chebula), which is a member of the Combfreetaceae family, is used widely in Asian countries as a traditional folk medicine, and its extract has been reported to be an anticancer, antidiabetic and anticaries agent. In our previous study, chebulic acid isolated from T. chebula extract was confirmed to show antioxidant activity and protective action against endothelial cell dysfunction. In order to support the safety-in-use of the ethyl acetate (EtOAc)-soluble portion of a T. chebula ethanol extract containing 29.4% chebulic acid content, the prepared portion was tested in an in vitro mutagenicity assay, and a single- and 14-day repeated dose oral toxicity study. In the bacterial mutation assay, up to 5000 µg/mL concentration of the EtOAc-soluble portion, the numbers of colonies did not increase whether with or without metabolic activation. In the oral toxicity study, the single oral dose of the extract at 2000 mg/kg did not produce mortality or abnormal lesions in the internal organs of rats. The results of a 14-day orally repeated dose showed that the EtOAc-soluble portion of T. chebula ethanol extracts gave no adverse effects at dosages of 2000 mg/kg in rats in the study.

Resolution of nebivolol-induced coronary vasospasm by intracoronary nitroglycerin during a coronary angiogram.

Nebivolol is a novel beta1-selective beta-blocker with vasodilator properties mediated through activation of the l-arginine-nitric oxide pathway. There is no published report of coronary artery spasm associated with nebivolol. We describe a 64-year-old female patient who developed unstable angina secondary to nebivolol-induced vasospastic angina which was also visible during coronary angiography.

[Use of nebivolol in patients with idiopathic pulmonary hypertension: results of the pilot study].

AIM: To study the impact of 24-week therapy with nebivolol in a dose of 5 mg/day on the clinical and functional status of patients with idiopathic pulmonary hypertension (IPH), echocardiographic parameters, and blood levels of vasoactive mediators and nitric oxide (NO) metabolite. SUBJECTS AND METHODS: During continuous standard therapy comprising dihydropyridine calcium antagonists, warfarin, and diuretics, 12 patients with IPH and functional class (FC) II-III received nebivolol in a dose of 5 mg/day for 24 weeks. According to the data of right heart catheterization, all the patients had a positive acute pharmacological test with a vasodilator (NO). Six-minute walk test (6'WT), estimation of the Borg dyspnea index (BDI) and FC, transthoracic echocardiography (EchoCG), and measurements of the levels of NO metabolites, endothelin-1, (ET-1), thromboxane B2 (TxB2), and 6-keto-prostaglandin F1alpha (6-ketoPG F1alpha) were done at baseline and after 12 and 24 weeks of the therapy. RESULTS: Following 24-week nebivolol treatment, there was a statistically significant increase in 6'WT distance (from 473 +/- 47.6 to 516.7 +/- 58.4 m; p < 0.0001) and a drop in BDI (from 3.4 +/- 2.2 to 1.1 +/- 0.7; p < 0.05) and FC (from 2.9 +/- 0.4 to 1.7 +/- 0.2; p < 0.05). Doppler EchoCG showed that pulmonary artery systolic pressure statistically significantly decreased (91.6 +/- 30 to 78.3 +/- 39 mm Hg; p = 0.05) at 12 weeks and slightly increased up to 83.2 +/- 32.4 mm Hg at 24 weeks. After 24-week treatment, the anteroposterior dimensions of the right ventricle (RV) statistically significantly reduced (from 4.4 +/- 0.6 to 3.8 +/- 1.2 cm; p < 0.05). The other EchoCG parameters remained substantially unchanged. There was a statistically reduction in the level of ET-1 (from 2.99 +/- 1.1 to 2.17 +/- 0.8 micromol/l; p < 0.05). The concentrations of 6-ketoPG Fla, TxB2, and NO metabolite remained substantially unchanged at 24 weeks of treatment with nebivolol. There were no adverse reactions requiring that the dose of the drug be discontinued or reduced. Heart rate tended to be lower at a 24-week follow-up. All the patients continued taking nebivolol after completion of the study. CONCLUSION: Therapy with nebivolol in a dose of 5 mg/day for 24 weeks led to a significant functional improvement in the patients with IPH and reductions in RV dimensions and blood ET-1 levels. The therapy did not cause adverse reactions.

Antipyretic and analgesic effects of zaltoprofen for the treatment of acute upper respiratory tract infection: verification of a noninferiority hypothesis using loxoprofen sodium.

A multicenter, placebo-controlled, double-dummy, randomized, parallel-group, double-blind study was conducted to verify the hypothesis of noninferiority for single-dose administration of zaltoprofen 160 mg, a nonsteroidal anti-inflammatory drug, compared with loxoprofen sodium 60 mg (loxoprofen), in terms of antipyretic and analgesic effects in patients with acute upper respiratory tract infection. The eligible 330 patients were assigned to one of 3 groups: zaltoprofen 160 mg, loxoprofen 60 mg and placebo. The analysis set consisted of 322 patients. Antipyretic effects were assessed by measuring body temperature, and analgesic effects were evaluated using a visual analog scale (VAS) for 4 h under the control of study staff. A detection kit for influenza virus A and B antigens was used to determine the presence of influenza virus infection. Compared with immediately before administration and with the placebo group, significant decreases in body temperature and summary VAS pain scores were noted in both the zaltoprofen and loxoprofen groups at 4 h after drug administration. Based on the degree of decrease in body temperature and the summary VAS pain scores up to 4 h after administration, noninferiority in terms of antipyretic and analgesic effects of zaltoprofen compared with those of loxoprofen was confirmed after single administration. Similar antipyretic and analgesic effects were also confirmed in influenza virus antigen-positive patients (73 patients). No clinical concerns were identified regarding safety. Zaltoprofen and loxoprofen are confirmed to be safe and useful for patients with acute upper respiratory tract infection, including those with influenza infection.

NEbivolol inhibition of coronary artery smooth muscle cell proliferation after percutaneous coronary artery intervention. Results of the NESCIO Study, a randomized, double blind trial.

OBJECTIVES: This study compared the efficacy of metoprolol and nebivolol in reducing the frequency of in-stent restenosis (ISR) after a percutaneous coronary intervention (PCI). BACKGROUND: ISR results from excessive neointimal proliferation. Nebivolol inhibits proliferation of human coronary endothelial and smooth muscle cells in vitro. Its efficacy has not been studied in clinical trials. MATERIAL AND METHODS: In a single-centre double-blind study, 79 subjects with de novo lesions were randomly assigned to receive either nebivolol (n=37) or metoprolol (n=42) 3 to 7 days before elective PCI with bare metal stents. The study medication was continued for 6 months. Nebivolol was administered at 5 mg/day for 3 weeks, then at 10 mg/day. Metoprolol was administered at 100 mg/day. The endpoints were the difference in fractional flow reserve (deltaFFR) between values immediately after PCI and those at 6 months and ISR during the 6 months following PCI The study was powered to detect a deltaFFR of 6% with 30 subjects per treatment group. RESULTS: Among subjects who underwent angiography at 6 months, mean deltaFFR was--0.08 for the nebivolol group (n=25) and -0.12 in the metoprolol group (n=26; p = 0.367). ISR occurred in 11 subjects (26.2%) on metoprolol and in 3 (8.1%) on nebivolol during treatment, and in 7 subjects on metoprolol and in 3 on nebivolol at 6 months (p = 0.014) CONCLUSION: There was a non-significant trend toward less decline in detaFFR at 6 months with nebivolol. Nebivolol should be investigated further in larger trials. Nebivolol significantly reduced the frequency of ISR as compared to metoprolol.

[Comparative analysis of antioxidant activity of nebivolol in patients with chronic heart failure with and without concomitant type 2 diabetes].

UNLABELLED: Consistent neurohormonal activation of sympatho-adrenal system in patients with chronic heart failure (CHF) and hyperglycemia contributes to development of oxidative stress--one of the most important pathogenetic mechanisms of endothelial dysfunction. PURPOSE: To study the impact of nebivolol concerning modification of clinical and hemodynamic indicators and parameters of oxidative stress in patients with CHF and with or without concomitant diabetes mellitus type 2 (DM2). MATERIAL: Nebivolol was used in complex therapy of CHF in 82 patients, suffering from NYHA class I - III CHF (EF < 50%) of ischemic genesis with or without comorbid DM2, average age 63.2 +/- 8.2 years. RESULTS: After 8 months of therapy significant improvement of clinical status was observed in both groups, tolerance to physical activity increased (significant reduction of average class of CHF in the group with DM2 from 2.5 +/- 0.58 to 2.125 +/- 0.71, p = 0.001, and in the second group from 2.3 +/- 0.5 to 1.9 +/- 0.4, p = 0.01). We also noted in both groups increase of plasma oxidative resistance (reduction of intensity of fast flash in lipid peroxidation h from 7 to 6 mm, p = 0.016, and from 8 to 6 mm, p = 0.03, respectively) and increase of antioxidant plasma protection (increase of SH-groups from 154.19 to 182.4 mmol/1, p = 0.00035, and from 176 to 205, p = 0.004, respectively). CONCLUSION: Nebivolol is a modern neurohormonal modulator, which contributes to reverse evolution of oxidative changes in patients with CHF and hyperglycemia.

Nebivolol lowers blood pressure and increases weight loss in patients with hypertension and diabetes in regard to age.

BACKGROUND: In patients with diabetes mellitus type 2 and arterial hypertension, the control of systolic and diastolic blood pressure is essential to reduce the risk of adverse events. The present study investigates the effect of treatment with the third-generation beta-blocker nebivolol, in female and male patients of different ages. METHODS: Five thousand thirty-one male and female patients with mild to moderate hypertension and type 2 diabetes were treated with a daily dose of 5-mg nebivolol for 12 weeks. Before and after therapy, each patient's blood pressure, heart rate, and body weight were measured and blood samples were obtained to study metabolic parameters. RESULTS: Nebivolol reduced systolic blood pressure, in both sexes, to a similar extent. In regard to age, the most significant reduction in blood pressure over the 12-week treatment period was observed in the group of patients below the age of 40. With advancing age, there was a decline in the reduction of systolic blood pressure induced by nebivolol. This effect was more evident among the decennial age groups in respect to diastolic blood pressure. In addition, we found weight reduction to be age dependent. Body weight was significantly more reduced in men compared with women. CONCLUSIONS: Nebivolol is effective in treating patients with diabetes suffering from high blood pressure and metabolic syndrome. The significantly decreased effect on blood pressure found in elderly patients may be attributed to increased endothelial dysfunction with advancing age.

Nebivolol/hydrochlorothiazide (HCTZ) combination in patients with essential hypertension: a pooled analysis from five non-interventional studies with a focus on diabetic and elderly patients.

BACKGROUND AND OBJECTIVES: Nebivolol is a third-generation beta-blocker, characterized by unique pharmacological properties. The combination of nebivolol and hydrochlorothiazide (HCTZ) has been evaluated in large-scale clinical trials. This post-marketing surveillance analysis evaluated the effectiveness of the nebivolol/HCTZ combination in a "real-life" setting that included diabetic and elderly patients. PATIENTS AND METHODS: The analysis was based on data from five non-interventional studies conducted in Germany, which lasted up to 12 weeks. Data from patients treated with nebivolol/HCTZ 5/12.5 mg/day in combination were pooled. The following parameters were calculated at the final visit, in the whole population and in elderly (>70 years) and diabetic subgroups: (1) difference from baseline in diastolic blood pressure (DBP) and in systolic blood pressure (SBP); (2) percentage of responder patients (reduction in DBP or SBP of 10 or 20 mmHg, respectively). Alterations in laboratory parameters were also monitored. RESULTS: In total, 86 patients (mean age 58.9 +/- 10.8 years) were included in the analysis. Nebivolol/HCTZ significantly reduced both DBP (-11.8 +/- 7.9 mmHg; p<0.0001 vs baseline) and SBP (-22.5 +/- 13.5 mmHg; p<0.0001 vs baseline). In total, 81.4% of patients were responders (75% and 83.3% in elderly and diabetic patients, respectively). No clinically significant alterations in laboratory parameters were observed. DISCUSSION: This study confirms that nebivolol/HCTZ is an effective and well tolerated therapeutic strategy in a real-life setting as well as in clinical trials. Therefore, this combination may represent a first-choice therapy in the management of hypertension.

Efficacy, tolerability and safety of nebivolol in patients with hypertension and diabetes: a post-marketing surveillance study.

BACKGROUND AND OBJECTIVES: Hypertension is a widely prevalent condition of elevated blood pressure (BP) and is the leading risk factor for the development of cardiovascular disease (CVD). Many patients have additional risk factors such as diabetes mellitus (DM) or previous history of CVD. Nebivolol is a third-generation beta (beta)-blockers which has been shown not to influence metabolic parameters in patients with DM. This postmarketing surveillance study aimed to collect information on the efficacy, safety and tolerability of nebivolol in hypertensive patients with concomitant DM. PATIENTS AND METHODS: Hypertensive patients with DM followed by 52 cardiologists, internal medicine specialists and general practitioners, between 24 August 2003 and 9 January 2007 in The Netherlands were included in this study. Physicians were asked to survey nebivolol treatment for 6 months. RESULTS: A total of 510 patients were enrolled. Overall, 93.3% of patients were diagnosed with essential hypertension and 6.7% with secondary hypertension. All patients were co-diagnosed with DM. Nebivolol therapy was associated with a significant reduction in both systolic blood pressure (BP) and diastolic BP versus baseline (p < 0.001 for both). These reductions were seen regardless of reason for initiation of nebivolol (i.e. first diagnosis of hypertension, resistance or intolerance to previous antihypertensive medication, or other reasons). A significant improvement in blood glucose was seen at 4 months (-0.6 mmol/L; p = 0.021). Significant reductions in total cholesterol (-1.45 mmol/L; p = 0.006), low density lipoprotein (LDL) cholesterol (-1.32 mmol/L; p = 0.003) and LDL/high density lipoprotein (HDL) cholesterol ratio (-0.77; p = 0.011) were observed at 2 months. No significant changes were seen in HDL cholesterol and triglycerides. CONCLUSION: Nebivolol treatment was associated with a significantly reduced BP, improved blood glucose and LDL cholesterol levels and was well tolerated in hypertensive patients with concomitant DM.