Bisoprolol versus celiprolol on dynamic hyperinflation, cardiopulmonary exercise and domiciliary safety in COPD: a single-centre, randomised, crossover study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is frequently associated with cardiovascular disease. The utility of beta-blockers for treating patients with COPD may be beneficial, but their safety remains uncertain, including worsening of dynamic hyperinflation (DH) during exercise. We hypothesised that among cardioselective beta-blockers celiprolol, due to its partial beta-2 agonist activity, may be safer than bisoprolol on exercise DH. METHODS: We measured isotime inspiratory capacity (IC) during cycle endurance testing in eleven moderate-severe COPD subjects, alongside other non-invasive cardiopulmonary exercise, bioreactance cardiac output, pulmonary function, biomarkers and daily domiciliary measures. Participants received titrated doses of either bisoprolol (maximim 5 mg) or celiprolol (maximum 400 mg) in randomised crossover fashion, each over 4 weeks. RESULTS: Clinically relevant DH occurred between resting and exercise isotime IC but showed no significant difference with either beta-blocker compared with post-run-in pooled baseline or between treatments. There were no other significant differences observed for remaining exercise ventilatory; non-invasive cardiac output; resting pulmonary function; beta-2 receptor and cardiac biomarkers; domiciliary pulmonary function, oxygen saturation and symptom outcomes, either between treatments or compared with baseline. No significant adverse effects occurred. CONCLUSIONS: Significant DH in moderate-severe COPD subjects was no different between bisoprolol or celiprolol or versus baseline. A broad spectrum of other non-invasive cardiopulmonary and domiciliary safety outcomes was equally reassuring. Bronchoprotection with a concomitant long-acting muscarinic antagonist might be an important safety measure in this context. TRIAL REGISTRATION NUMBER: NCT02380053.

Vascular Ehlers-Danlos Syndrome: Pathological Variants, Recent Discoveries, and Theoretical Approaches.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare autosomal dominant genetic disorder. It is the most fatal among all types of EDS. In addition to typical EDS characteristics, vEDS patients are at risk of blood vessel rupture due to possession of pathogenic variants of the COL3A1 gene, which encodes type III collagen. Type III collagen is a major component of humans' vascular walls. The management of this disease is possible; however, there is no cure as of present. Recently, discoveries with potential impact on the management of vEDS have been elucidated. Mice with vEDS traits treated with a beta-blocker celiprolol showed significant improvements in their thoracic aorta biomechanical strength. Moreover, it has been demonstrated that the specifically designed small interference RNAs (siRNA) can effectively silence the pathogenic variant allele. To enhance the normal allele expression, an intracellularly expressed lysyl oxidase is shown to regulate the transcription rate of the COL3A1 promoter. Similarly, an embryonic homeobox transcription factor Nanog upregulates the wild-type COL3A1 expression through activation of the transforming growth factor-beta pathway, which increases type III collagen synthesis. Despite numerous advancements, more studies are to be performed to incorporate these discoveries into clinical settings, and eventually, more personalized treatments can be created.

Celiprolol Treatment in Patients with Vascular Ehlers-Danlos Syndrome.

OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare monogenetic disease caused by pathogenic variants in procollagen 3A1. Arterial rupture is the most serious clinical manifestation. A randomised controlled trial, the Beta-Blockers in Ehlers-Danlos Syndrome Treatment (BBEST) trial, reported a significant protective effect of the beta blocker celiprolol. The aim was to study the outcome of celiprolol treatment in a cohort of Swedish patients with vEDS. METHODS: Uppsala is a national referral centre for patients with vEDS. They are assessed by vascular surgeons, angiologists, and clinical geneticists. Family history, previous and future clinical events, medication, and side effects are registered. Celiprolol was administered twice daily and titrated up to a maximum dose of 400 mg daily. Logistic regression was used to analyse predictors of vascular events. RESULTS: Forty patients with pathogenic sequence variants in COL3A1 were offered treatment with celiprolol in the period 2011-2019. The median follow up was 22 months (range 1-98 months); total follow up was 106 patient years. In two patients, uptitration of the dose is ongoing. Of the remaining 38, 26 (65%) patients reached the target dose of 400 mg daily. Dose uptitration was unsuccessful in six patients because of side effects; one died before reaching the maximum dose, and five terminated the treatment. Five major vascular events occurred; four were fatal (ruptured ascending aorta; aortic rupture after type B dissection; ruptured cerebral aneurysm; and ruptured pulmonary artery). One bled from a branch of the internal iliac artery, which was successfully coiled endovascularly. The annual risk of a major vascular event was 4.7% (n = 5/106), similar to the treatment arm of the BBEST trial (5%) and lower than in the control arm of the same trial (12%). No significant predictor of vascular events was identified. CONCLUSION: Treatment with celiprolol is tolerated in most patients with vEDS. Despite fatal vascular events, these observations suggest that celiprolol may have a protective effect in vEDS.

An old drug for a rare disease: The example of celiprolol for vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome (OMIM 130050, 1/150,000 birth) is caused by mutations in collagen 3A1 gene. It is associated with severe phenotype associating early arterial dissection and rupture, digestive and uterine perforations, and skin and joints fragility. Until recently, no treatment was available. Celiprolol, a beta1 antagonist with beta2 partial antagonist properties betablocker was tested in a randomized, controlled trial. We could show that this compound was associated with a 3-fold decrease in major events related to the disease. This effect was similar in molecular-proven patients. Administration of celiprolol in a cohort of patients followed routinely in France was accompanied to similar benefit. Celiprolol is unavailable in the USA. The ACER Therapeutics company applied for new drug application (NDA) to the Food and Drug Administration.

Vascular Ehlers-Danlos Syndrome: Long-Term Observational Study.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is a rare genetic connective tissue disorder secondary to pathogenic variants within the COL3A1 gene, resulting in exceptional arterial and organ fragility and premature death. The only published clinical trial to date demonstrated the benefit of celiprolol on arterial morbimortality. OBJECTIVES: The authors herein describe the outcomes of a large cohort of vEDS patients followed ≤17 years in a single national referral center. METHODS: All patients with molecularly confirmed vEDS were included in a retrospective cohort study. After an initial work-up, patients were treated or recommended for treatment with celiprolol (≤400 mg/day) in addition to usual care and scheduled for yearly follow-up. vEDS-related events and deaths were collected and recorded for each patient. RESULTS: Between 2000 and 2017, 144 patients (median age at diagnosis 34.5 years, 91 probands) were included in this study. After a median follow-up of 5.3 years, overall patient survival was high (71.6%; 95% confidence interval: 50% to 90%) and dependent on the type of COL3A1 variant, age at diagnosis, and medical treatment. At the end of the study period, almost all patients (90.3%) were treated with celiprolol alone or in combination. More than two-thirds of patients remained clinically silent, despite a large number (51%) with previous arterial events or arterial lesions at molecular diagnosis. Patients treated with celiprolol had a better survival than others (p = 0.0004). The observed reduction in mortality was dose-dependent: the best protection was observed at the dose of 400 mg/day versus <400 mg/day (p = 0.003). During the period surveyed, the authors observed a statistically significant difference in the ratio of hospitalizations for acute arterial events/hospitalizations for regular follow-up before and after 2011. CONCLUSIONS: In this long-term survey, vEDS patients exhibited a low annual occurrence of arterial complications and a high survival rate, on which the overall medical care seems to have a positive influence.

Non-antipsychotic catecholaminergic drugs for antipsychotic-induced tardive dyskinesia.

BACKGROUND: Tardive dyskinesia (TD) is a disabling movement disorder associated with the prolonged use of antipsychotic medication. Several strategies have been examined in the treatment of TD. Currently, however, there is no clear evidence of the effectiveness of these drugs in TD and they have been associated with many side effects. One particular strategy would be to use pharmaceutical agents which are known to influence the catecholaminergic system at various junctures. OBJECTIVES: 1. To determine the effects of any of the following drugs for antipsychotic-induced TD in people with schizophrenia or other chronic mental illnesses.i. Drugs which influence the noradrenergic system.ii. Dopamine receptor agonists.iii. Dopamine receptor antagonists.iv. Dopamine-depletor drugs.v. Drugs that increase the production or release of dopamine.2. To examine whether any improvement occurred with short periods of intervention (less than 6 weeks) and, if this did occur, whether this effect was maintained at longer periods of follow-up.3. To examine if there was a differential effect for the various compounds.4. To examine whether the use of non-antipsychotic catecholaminergic drugs are most effective in those with more recent onset TD (less than five years). SEARCH METHODS: We retrieved 712 references from searching the Cochrane Schizophrenia Group Trials Register (July 2015 and April 2017). We also inspected references of all identified studies for further trials and contacted authors of trials for additional information. SELECTION CRITERIA: We selected studies if they were randomised controlled trials focusing on people with schizophrenia or other chronic mental illnesses and antipsychotic-induced tardive dyskinesia. We compared the use of catecholaminergic interventions versus placebo, no intervention, or any other intervention for the treatment of antipsychotic-induced tardive dyskinesia. DATA COLLECTION AND ANALYSIS: We independently extracted data from these trials and we estimated risk ratios (RRs) with 95% confidence intervals (CIs). We assumed that people who left the studies early had no improvement. MAIN RESULTS: There are 10 included trials (N = 261) published between 1973 and 2010; eight are new from the 2015 and 2017 update searches. Forty-eight studies are excluded. Participants were mostly chronically mentally ill inpatients in their 50s, and studies were primarily of short (2 to 6 weeks) duration. The overall risk of bias in these studies was unclear, mainly due to poor reporting of allocation concealment and generation of the sequence. Studies were also not clearly blinded and we are unsure if data are incomplete or selectively reported, or if other biases were operating.One small, three-arm trial found that both alpha-methyldopa (N = 20; RR 0.33, 95% CI 0.14 to 0.80; low-quality evidence) and reserpine (N = 20; RR 0.52 95% CI 0.29 to 0.96; low-quality evidence) may lead to a clinically important improvement in tardive dyskinesia symptoms compared with placebo after 2 weeks' treatment, but found no evidence of a difference between alpha-methyldopa and reserpine (N = 20; RR 0.60, 95% CI 0.19 to 1.86; very low quality evidence). Another small trial compared tetrabenazine and haloperidol after 18 weeks' treatment and found no evidence of a difference on clinically important improvement in tardive dyskinesia symptoms (N = 13; RR 0.93, 95% CI 0.45 to 1.95; very low quality evidence). No study reported on adverse events.For remaining outcomes there was no evidence of a difference between any of the interventions: alpha-methyldopa versus placebo for deterioration of tardive dyskinesia symptoms (1 RCT; N = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence), celiprolol versus placebo for leaving the study early (1 RCT; N = 35; RR 5.28, 95% CI 0.27 to 102.58; very low quality evidence) and quality of life (1 RCT; N = 35; RR 0.87, 95% CI 0.68 to 1.12; very low quality evidence), alpha-methyldopa versus reserpine for deterioration of tardive dyskinesia symptoms (1 RCT; N = 20; not estimable, no reported events; very low quality evidence), reserpine or carbidopa/levodopa versus placebo for deterioration of tardive dyskinesia symptoms (2 RCTs; N = 37; RR 1.18, 95% CI 0.35 to 3.99; very low quality evidence), oxypertine versus placebo for deterioration of mental state (1 RCT; N = 42; RR 2.20, 95% CI 0.22 to 22.45; very low quality evidence), dopaminergic drugs (amantadine, bromocriptine, tiapride, oxypertine, carbidopa/levodopa) versus placebo for leaving the study early (6 RCTs; N = 163; RR 1.29, 95% CI 0.65 to 2.54; very low quality evidence), and tetrabenazine versus haloperidol for deterioration of tardive dyskinesia symptoms (1 RCT; N = 13; RR 1.17, 95% CI 0.09 to 14.92) and leaving the study early (1 RCT; N = 13; RR 0.23, 95% CI 0.01 to 4.00). AUTHORS' CONCLUSIONS: Although there has been a large amount of research in this area, many studies were excluded due to inherent problems in the nature of their cross-over designs. Usually data are not reported before the cross-over and the nature of TD and its likely response to treatments make it imprudent to use this data. The review provides little usable information for service users or providers and more well-designed and well-reported studies are indicated.

Effects of Celiprolol and Bisoprolol on Blood Pressure, Vascular Stiffness, and Baroreflex Sensitivity.

BACKGROUND: We tested the hypothesis that celiprolol and bisoprolol have differential effects on blood pressure (BP), flow-mediated dilation (FMD), and vascular stiffness. METHODS: We analyzed 102 hypertensives (mean age: 59±14 years) who were being treated other than beta-blockers. They were randomized to receive add-on treatment with either celiprolol 100-200mg (C group) or bisoprolol 2.5-5mg (B group), and followed up for 3 months. In addition to clinic, home, and ambulatory BP monitoring, the FMD, radial augmentation index (AI), brachial-ankle pulse wave velocity (baPWV), urine albumin-to-creatinine ratio, and baroreflex sensitivity (BRS) were measured at baseline and at the end of the study. RESULTS: Compared to the baseline values, home and 24-hour BP were significantly lowered in the third month in both groups (all Ps < 0.05). Pulse rate (PR) and baPWV were reduced (P < 0.001), and BRS was increased significantly only in the B group (P = 0.02). Radial AI was unchanged in the C group but was significantly increased in the B group (P < 0.001). Central BP was significantly reduced in the C group (P = 0.003) but was unchanged in the B group. FMD was significantly increased in both groups (both P < 0.01). CONCLUSION: Bisoprolol achieved the greater reduction of PR and improved BRS and vascular stiffness, whereas, celiprolol reduced the central BP level. In treated hypertensive patients, add-on use of celiprolol may be favorable in uncomplicated stage of hypertension. On the other hand, bisoprolol may be useful in hypertensives with cardiac or vascular diseases who have advanced atherosclerotic changes and sympathetic nervous system activation.

Celiprolol reduces oxidative stress and attenuates left ventricular remodeling induced by hypoxic stress in mice.

We have previously reported that intermittent hypoxic stress, which is relevant to sleep apnea syndrome (SAS), increases oxidative stress and induces left ventricular (LV) remodeling. Celiprolol, a ß1-selective adrenoreceptor blocker, is known to have not only an antihypertensive effect but also an antioxidant effect through releasing nitric oxide. The aim of this study was to examine the hypothesis that celiprolol might ameliorate the LV remodeling induced by intermittent hypoxia through its antioxidant effect. Male C57BL/6J mice (8 weeks old) were exposed to intermittent hypoxia (30 s of 5% oxygen followed by 30 s of 21% oxygen) for 8 h day(-1) during the daytime for 10 consecutive days or were maintained under normoxic conditions. Animals were treated with either celiprolol (100 mg kg(-1) day(-1) by gavage) or vehicle. Hypoxic stress caused fluctuations in blood pressure (BP), an increase in the mean cardiomyocyte diameter, perivascular fibrosis and a decrease in endothelial nitric oxide synthase (eNOS) expression. These changes were associated with increased levels of 4-hydroxy-2-nonenal protein, superoxide, tumor necrosis factor-α mRNA and brain natriuretic peptide mRNA in the LV myocardium. Celiprolol significantly suppressed BP fluctuation, restored eNOS expression and reduced oxidative stress and superoxide production, thus ameliorating hypoxia-induced LV remodeling in mice. These findings suggest that treatment with celiprolol might prevent cardiovascular events in borderline hypertensive patients with SAS.

A vasodilating ß1 blocker celiprolol inhibits muscular release of uric acid precursor in patients with essential hypertension.

Although nonvasodilating ß1 blockers increase the levels of uric acid in serum, it is not known whether vasodilating ß1 blockers have a similar effect. In the present study, we evaluated the effect of celiprolol on the release of hypoxanthine, a uric acid precursor, from muscles after an exercise. We used the semi-ischemic forearm test to examine the release of lactate (ΔLAC), ammonia (ΔAmm), and hypoxanthine (ΔHX) before and 4, 10, and 60 min after an exercise in 18 hypertensive patients as well as 4 normotensive subjects. Before celiprolol treatment, all the levels of ΔHX and ΔAmm, and ΔLAC were increased by semi-ischemic exercise in hypertensive patients, and the increases were remarkably larger than those in normotensive subjects. Celiprolol decreased both systolic and diastolic pressure. It also decreased the levels of ΔHX and ΔAmm without changes in ΔLAC after an exercise. These findings also were confirmed by summation of each metabolite (ΣΔMetabolites). Celiprolol caused a marginal decrease of serum uric acid, but the difference was not statistically significant. On the other hand, nonvasodilating ß1 blockers did not suppress the levels of ΔHX and ΔAmm, whereas they significantly increased ΔLAC after an exercise. Celiprolol improved energy metabolism in skeletal muscles. It suppressed HX production and consequently did not adversely affect serum uric acid levels.

Acute effects of beta-blocker with intrinsic sympathomimetic activity on stress-induced cardiac dysfunction in rats.

BACKGROUND: We have reported that α and ß adrenergic blockers could protect against emotional stress-induced cardiac dysfunction but those protective effects of ß adrenergic blockers with intrinsic sympathomimetic activity (ISA), such as celiprolol, are unknown. The purpose of this study is to evaluate whether ISA could relate with this protective effect. METHODS AND RESULTS: Rats medicated with celiprolol (8 mg/kg), metoprolol (4 mg/kg), or vehicle, were restrained for 30 min (immobilization stress: IMO) to reproduce emotional stress, and anesthetized to release stress. We measured the fractional area change (FAC) using an echocardiography (SONOS5500) with s12 probe (frequency: 5-12 MHz, frame rate: 120 Hz) at the end of IMO and every 10 min for 1h. During IMO, FAC in rats with a premedication of metoprolol was lower than in those with a premedication of vehicle or celiprolol. At 20 min after IMO, FAC in rats with a premedication of celiprolol was significantly higher than that with a premedication of metoprolol or vehicle (84 ± 9% vs. 65 ± 3% or 60 ± 7%, p<0.05). At 60 min after IMO, FAC in rats with a premedication of vehicle or celiprolol recovered, but FAC in rats with a premedication of metoprolol did not. CONCLUSION: Acute premedication with celiprolol could prevent a sudden drop of cardiac function after acute stress such as IMO. ISA might have an important role in preventing stress-induced cardiac dysfunction.

[Vascular Ehlers-Danlos syndrome and pregnancy: an obstetrical specific support]. / Syndrome d'Ehlers-Danlos de type vasculaire et grossesse : une prise en charge obstétricale spécifique.

The Ehlers-Danlos syndrome (EDS) is a rare inheritable disease, characterised by a defect in collagen synthesis. Various types have been described and the type IV or vascular type is the most severe characterised by vascular, gastrointestinal and gynaecologic complications. We describe in a case report the specific obstetrical support we applied to avoid the most frequent complications such as early spontaneous abortions, pre-term delivery, tearing of perineum, uterine and vascular rupture and hard healing. Pregnancy is very risky in women with vascular EDS. Combination of multidisciplinary support and advice of the rare vascular disease national reference centre may reduce the morbi-mortality rate, including celiprolol long-term treatment.

Contemporary management of vascular Ehlers-Danlos syndrome.

PURPOSE OF REVIEW: Vascular Ehlers-Danlos syndrome (EDS) results from mutations in the formation of type III collagen. This leads to various potentially lethal complications including rupture of the arterial vessels, intestinal organs, and the uterus. This review summarizes recent cohort studies that have improved our medical and surgical management of complications associated with vascular EDS. RECENT FINDINGS: Vascular EDS is associated with a shortened overall survival due to potential complications, namely loss of connective tissue integrity in blood vessels and increased risk of arterial rupture. The traditional approach has been to treat such complications conservatively unless they are life threatening. There have been challenges to this treatment paradigm based on recent reports. Treatment with the beta blocker Celiprolol was shown in a randomized study to be associated with a three-fold decrease in arterial rupture in vascular EDS patients. Furthermore, it was shown by observational studies that elective surgical repair of blood vessels at risk of rupture may be safely undertaken at tertiary referral centers that have expertise in managing connective tissue disorders. Novel approaches using endovascular therapy with coil embolization have also been attempted with good results in the treatment of ruptured pseudoaneurysms, visceral aneurysms, and carotid-cavernous fistulas. SUMMARY: New evidence-based treatments have greatly expanded the medical and surgical management options for patients with EDS. These patients are best managed by multidisciplinary teams of interventionalists, cardiologists, and geneticists in tertiary centers with expertise in managing connective tissue disorders.

Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial.

BACKGROUND: Vascular Ehlers-Danlos syndrome is a rare severe disease that causes arterial dissections and ruptures that can lead to early death. No preventive treatment has yet been validated. Our aim was to assess the ability of celiprolol, a ß(1)-adrenoceptor antagonist with a ß(2)-adrenoceptor agonist action, to prevent arterial dissections and ruptures in vascular Ehlers-Danlos syndrome. METHODS: Our study was a multicentre, randomised, open trial with blinded assessment of clinical events in eight centres in France and one in Belgium. Patients with clinical vascular Ehlers-Danlos syndrome were randomly assigned to 5 years of treatment with celiprolol or to no treatment. Randomisation was done from a centralised, previously established list of sealed envelopes with stratification by patients' age (≤32 years or >32 years). 33 patients were positive for mutation of collagen 3A1 (COL3A1). Celiprolol was administered twice daily and uptritrated by 100 mg steps every 6 months to a maximum of 400 mg per day. [DOSAGE ERROR CORRECTED]. The primary endpoints were arterial events (rupture or dissection, fatal or not). This study is registered with ClinicalTrials.gov, number NCT00190411. FINDINGS: 53 patients were randomly assigned to celiprolol (25 patients) or control groups (28). Mean duration of follow-up was 47 (SD 5) months, with the trial stopped early for treatment benefit. The primary endpoints were reached by five (20%) in the celiprolol group and by 14 (50%) controls (hazard ratio [HR] 0·36; 95% CI 0·15-0·88; p=0·040). Adverse events were severe fatigue in one patient after starting 100 mg celiprolol and mild fatigue in two patients related to dose uptitration. INTERPRETATION: We suggest that celiprolol might be the treatment of choice for physicians aiming to prevent major complications in patients with vascular Ehlers-Danlos syndrome. Whether patients with similar clinical presentations and no mutation are also protected remains to be established. FUNDING: French Ministry of Health, Programme Hospitalier de Recherche Clinique 2001.

Celiprolol, a selective beta1-blocker, reduces the infarct size through production of nitric oxide in a rabbit model of myocardial infarction.

BACKGROUND: It is still unclear whether celiprolol, a beta(1)-selective blocker, reduces myocardial infarct size. This study will examine whether celiprolol reduces myocardial infarct size, as well as investigate the mechanisms for its infarct size-reducing effect in rabbits. METHODS AND RESULTS: Japanese white rabbits underwent 30 min of ischemia and 48 h of reperfusion. Celiprolol (1 or 10 mg x kg (-1) x h(-1) for 60 min, iv) was administered 20 min before ischemia with or without pretreatment with N(omega)-nitro-L-arginine methylester (L-NAME, 10 mg/kg, iv, a nitric oxide synthase inhibitor) or 5-hydroxydecanoic acid sodium salt (5-HD, 5 mg/kg, iv, a mitochondrial K(ATP) channel blocker). The area at risk as a percentage of the left ventricle was determined by using Evans blue dye, and the infarct size was determined as a percentage of the area at risk by triphenyl tetrazolium chloride staining. Celiprolol 1 and 10 mg x kg(-1) x h(-1) significantly reduced the infarct size in a dose-dependent manner (36.4+/-1.7%, n=7 and 25.4+/-2.9%, n=7, respectively) compared with the control (46.2+/-3.1%, n=8). The infarct size-reducing effect of celiprolol was completely blocked by L-NAME (40.4 +/-2.8%, n=8) but not by 5-HD (27.3+/-1.0%, n=8). Celiprolol 1 mg x kg(-1) x h (-1) increased the myocardial interstitial levels of NOx, an indicator of nitric oxide, and reduced the intensity of dihydro-ethidium staining of myocardium, an indicator of superoxide, during reperfusion after 30 min of ischemia. CONCLUSION: Celiprolol reduces myocardial infarct size and also increases nitric oxide production and reduces superoxide levels but not mitochondrial K(ATP) channels in rabbits.

beta1 antagonist and beta2 agonist, celiprolol, restores the impaired endothelial dependent and independent responses and decreased TNFalpha in rat with type II diabetes.

UNLABELLED: The effect of beta antagonists in the diabetic vascular lesion is controversial. We investigated the effect of celiprolol hydrochloride, a beta1 antagonist and mild beta2 agonist, on the lesions and function in type II male Otsuka Long-Evans Tokushima Fatty (OLETF) diabetic rats. OLETF rats were fed regular chow with or without atenolol (25 mg/kg/day) or celiprolol (100 mg/kg/day) treatment (group DM, no treatment; group DM-a, atenolol treatment; group DM-c, celiprolol treatment), and treatment was continued for 31 days. Separately, normoglycemic control rats, LETO, were prepared as group C. On day 3, endothelial cells of the right internal carotid artery were removed by balloon injury, and the rats were evaluated 4 weeks after balloon injury. The plasma glucose and lipid levels were unchanged throughout the treatment period. Intimal thickening was observed in the right carotid artery in the DM and DM-a groups; however, little thickening was observed in those of DM-c rats. Acetylcholine-induced NO-dependent relaxation in arteries was improved in DM-c rats compared with DM and DM-a rats (maximum relaxation DM 30.8+/-4.5, DM-a 37.4+/-3.9, DM-c 48.8+/-4.6%, *P<0.05 vs. DM for DM-c rats). Tone-related basal NO release and acetylcholine-induced NO-dependent relaxation in the arteries and plasma NO(x) (sum of NO(2)(-) and NO(3)(-)) were greater in DM-c and C groups than in DM and DM-a groups. The serum TNFalpha levels did not increase in DM-c rats compared with those of the DM or DM-a groups, and were comparable with those of group C. CONCLUSION: In conclusion, Celiprolol improves endothelial function in the arteries of OLETF rats, and further restore it 4 weeks after endothelial denudation in the arteries of OLETF rats. NO and O(2)(-) may have a role in the important underlying mechanisms by reducing the TNFalpha levels.

[Vascular Ehlers-Danlos syndrome]. / Syndrome d'Ehlers-Danlos vasculaire.

The vascular type of Ehlers-Danlos syndrome (EDS) is a rare genetic disease transmitted as an autosomal dominant trait. It is distinguished from other forms of EDS by its unstable acrogeric morphotype and by vascular, gastrointestinal, and obstetrical complications. Diagnosis is based on various clinical signs, noninvasive imaging, and on the identification of a mutation of the COL3A1 gene, which provides diagnostic certainty but has a sensitivity of only 61%. When two major diagnostic criteria are present, a genetic test should be proposed, performed and its result presented in a multidisciplinary group. The precautionary principle requires that preventive measures be implemented when the diagnosis is suspected. All artery puncture, surgery, and gastrointestinal and uterine endoscopy are contraindicated, permissible only in life-threatening emergencies. Straining against a closed glottis and all other situations or drugs likely to raise blood pressure must be avoided. Contraception must be discussed to avoid pregnancy during the diagnostic period. Arterial lesions suggestive of the disease include dissecting aneurysms of the internal carotid and iliac arteries and of the anterior visceral branches of the abdominal aorta, fusiform aneurysms of the splenic artery, and early onset nontraumatic direct carotid-cavernous fistulae. Early-onset varicose veins, spontaneous peritonitis or unusually important perineal lesions after giving birth should also attract the physician's attention. Psychological treatment and support of patients and their families is essential, to help them both to live with their disease and to deal with the information and screening issues. The prognosis of Ehlers-Danlos syndrome, vascular type, is grim but there is wide interindividual variability and life expectancy is best among patients receiving regular follow-up. Management by an experienced multidisciplinary team, implementation of drastic prevention measures and, depending on the results of the BBEST study, the possible prescription of beta-blockers should help to reduce the risk of complications and justify hope for a real improvement in prognosis in the near future.

Effects of celiprolol and simvastatin on the calculated risk of coronary heart disease (the Celisimva study).

OBJECTIVES: The most important risk factors for coronary heart disease are hypercholesterolemia, smoking and hypertension. To find out which treatment is more effective in modifying the total risk--lowering cholesterol concentration or using antihypertensive treatment--we conducted a parallel group placebo-controlled study. The goal of the study was to assess the effect of two drugs on the calculated CHD Framingham risk score in subjects with both moderate hypertension and moderate hypercholesterolemia. DESIGN: Celiprolol for hypertension and simvastatin for cholesterol-lowering were given as monotherapy or as combination treatment. The effects of the treatments on the CHD risk scores were calculated after 3 months. A total of 112 patients were randomized. RESULTS: The total CHD risk decreased in simvastatin and combination groups from 26% to 19% and from 26% to 17%, respectively. Celiprolol alone decreased the risk from 25% to 21%, which was not statistically different from placebo. CONCLUSIONS: It can be concluded that subjects with moderate hypercholesterolemia and hypertension benefit more from lipid-lowering treatment with simvastatin than from blood pressure-lowering with beta blocker celiprolol.