β-Adrenoceptor–blocking agents (also known as β1-adrenoceptor antagonists or β-blockers) are used to treat a variety of disorders such as arterial hypertension, systemic hypertension, angina, coronary heart disease, arrhythmias, hypertrophic cardiomyopathy, mitral valve prolapse, migraine, and glaucoma.1–3 The pharmacological classification of these agents is based on their affinity, β1-selectivity, partial agonist activity, effects on other adrenergic receptors, and physicochemical properties.1 For some conditions, the efficacy of the various β1-adrenoceptor antagonists is similar, whereas in other conditions, only certain subgroups have demonstrated therapeutic benefits. In the United States, there are currently 17 β-adrenoceptor antagonists available for the treatment of cardiovascular and other disorders, although globally there are over 30 available for clinical use (Figure 1).4 Celiprolol (3-[3-acetyl-4-(3-t-butylamino-2- hydroxypropoxy)phenyl]-2,1-diethylurea hydrochloride; Figure 2) was developed as a third-generation β1-adrenoceptor antagonist with partial β2 agonist activity and a unique pharmacological profile.5 Like β blockers, it demonstrates antihypertensive and antianginal activity; however, it lacks the typical side effects of the class, such as bronchoconstriction, depression of left ventricular function, and peripheral vasoconstriction.5 This is likely a result of its β2 agonist activity.2,6–9 Given this unique combination of pharmacologic effects, celiprolol is perhaps more accurately described as a selective adrenoceptor modulator (SAM). Furthermore, celiprolol’s ability to stimulate β2-receptors, influence vascular tone, and directly affect smooth muscle suggests its potential usefulness in patients with cardiovascular disease and concomitant lung disease.2,3,8 Recently, the unique properties of celiprolol have inspired investigation into its use in a rare connective tissue disorder—Ehlers–Danlos syndrome, vascular type (vEDS; formerly known as EDS type IV).
There are 6 major types of EDS, each defined according to signs and symptoms and thought to involve a unique connective tissue defect (Table 1).10,11 vEDS is an autosomal dominant inherited connective tissue disorder (100% phenotypic penetrance) caused by structural defects of the pro α1 (III) chain of collagen type III (COL3A1) gene.12,13 Mutations in the COL3A1 gene result in decreased thermal stability and proteolytic processing irregularities, which subsequently lead to procollagen degradation.13 Complications of vEDS include life-threatening arterial dissections and ruptures, vascular aneurysms, intestinal ruptures, and uterine ruptures.14 The average life span of patients with vEDS is approximately 50 years of age, with manifestation of the disorder often evident by 20 years of age.15,16 vEDS is suspected when a combination of clinical findings is present. The Villefranche criteria provide guidance on clinical diagnosis (Table 2).14,17 The diagnosis is confirmed by the identification of a pathogenic mutation in COL3A1 gene or the appearance of abnormal type III procollagen in cultured fibroblasts in patients with clinical features of vEDS.15 Currently, there are no Food and Drug Administration (FDA)–approved therapies for vEDS.18 Celiprolol was investigated for the treatment of vEDS because of the observed effects of reduced heart rate, mean, and pulsatile pressures in animals and in patients with hypertension and with potentially decreased continuous and pulsatile mechanical stress on collagen fibers within the arterial wall.19 On the basis of these data and on the fragile connective tissues associated with vEDS, celiprolol was investigated as a preventive therapy for the life-threatening risks, specifically arterial dissections and ruptures and intestinal and uterine ruptures associated with vEDS.
PHARMACOKINETIC PROPERTIES OF CELIPROLOL
As a whole, β1-adrenoceptor antagonists have similar therapeutic effects; however, their pharmacokinetic properties differ.19 This is attributed to the distinct aromatic ring structure of these compounds, which results in differences in absorption, metabolism, first-pass hepatic metabolism, lipid solubility, protein binding, and renal clearance among the drugs. Specifically, configuration of the asymmetric β-carbon of the side chain determines activation or blockade effect.20 Celiprolol’s aromatic ring structure (benzene) is similar to other β1-adrenoceptor antagonists and is most closely related to acebutolol (Figure 2).21,22
β1-Adrenoceptor antagonists are either considered lipophilic or hydrophilic. Celiprolol is a hydrophilic agent, freely soluble in water.23 Most β1-adrenoceptor antagonists (except atenolol) are absorbed in the small intestine.1 Mean peak plasma concentrations after oral doses of 100–600 mg of celiprolol range from 300 to 3000 µg/L.23,24 The bioavailability of celiprolol is dose-dependent: 30% at 100 mg and 70% over the range 300–400 mg.24,25 Food may impair this bioavailability; however, the effect is not clinically relevant with long-term therapy.23 Grapefruit juice and orange juice, both inhibitors of the organic anion–transporting polypeptide 1A2 (OATP1A2), have been shown to cause a significant decrease in the oral absorption of celiprolol.26 Although the clinical relevance of this interaction has not been fully assessed, studies have suggested that the effects of celiprolol on blood pressure and heart rate are not affected. Nevertheless, the marked reduction in celiprolol bioavailability in the presence of grapefruit or orange juice suggests that this interaction may be of clinical significance in some patients.26,27 In addition, concomitant administration of drugs such as chlorthalidone, hydrochlorothiazide, theophylline, or digoxin may have an effect on its bioavailability.23 As a class, β1-adrenoceptor antagonists are known to interact with several drugs, particularly with agents that affect cardiovascular function. A list of select drug interactions with celiprolol is found in Table 3.2,25–28
Distribution of β1-adrenoceptor antagonists occurs rapidly from the blood to other tissues.29 The distribution of celiprolol has been studied in animals and humans. Celiprolol was found to be a water-soluble substance that is widely distributed in all tissues, with the exception of the brain, after absorption.24 This is likely due to its hydrophilic properties.23,25,29 In vitro studies indicate that the rate of diffusion across the human placenta is 3–4 times lower than that of comparative β-blockers (propranolol, timolol, and labetalol) with approximately 25% plasma protein binding (Table 4).24 It is unclear whether this translates to a lower risk of fetal complications with celiprolol.
Celiprolol is minimally metabolized, with only a very low percentage of a dose being excreted.8 Similar to other β1-adrenoceptor antagonists, celiprolol displays first-pass metabolism. However, the concentration of celiprolol is greatly reduced before it reaches the systemic circulation. A small study in healthy volunteers demonstrated no drug accumulation with chronic dosing over a 7-day period.8
According to their pharmacokinetic properties, β1-adrenoceptor drugs are divided into 2 categories: those eliminated via hepatic metabolism and those eliminated (unchanged) via the kidney.30 The pharmacokinetics of celiprolol have been studied in animals and patients with primary hypertension and chronic stable angina pectoris.24 Investigations have found that celiprolol is minimally metabolized and excreted unchanged via the urine and feces, with a half-life of approximately 4–5 hours (10–15% observed dose excreted in the urine).23,24 One study also reports the possible urinary excretion of a celiprolol metabolite.7
A summary of celiprolol’s pharmacokinetic properties is found in Table 4.8,23
PHARMACODYNAMIC PROPERTIES OF CELIPROLOL
Celiprolol was developed as a third-generation β-adrenoceptor antagonist with selective β1-antagonist, partial β2-agonist, and mild α2-antagonist actions. The α2 antagonism is weak and ineffective in blocking the effects of the α2 agonist clonidine. The α2 agonist effects of celiprolol are, therefore, believed to contribute little to its overall pharmacologic effect.23 Its blockade of β1-adrenoreceptors reduces sympathoadrenal stimulation of the heart during physiological stress.23 In addition, celiprolol’s blockade of β1-adrenoreceptors reduces heart rate (negative chronotropic effect) in the sinoatrial node and decreases cardiac contractility (negative inotropic effect) in the myocardium.23 Furthermore, studies indicate that celiprolol improves vasodilation through β2 agonism and may also act on β3 receptors as evidenced by a 2013 study of porcine coronary arteries, which demonstrated that celiprolol exerts β3-adrenoceptor agonistic activity with resulting vasorelaxation.2,5,6 In addition, celiprolol may induce coronary vasodilation due to stimulation of the release of nitric oxide.31 As a result of this activity profile, celiprolol may offer advantages over other β-adrenergic antagonists due to its bronchosparing properties, mild lipid effects, and minor cardiac conduction effects.2
Studies support the idea that celiprolol reduces arteriolar resistance and improves blood flow without depressing cardiac function.23 In healthy adults, a single 400-mg oral dose reduced standing diastolic blood pressure by approximately 10% with no change in systolic blood pressure.32 In patients with hypertension, celiprolol moderated the positive chronotropic effects of sympathetic arousal, did not depress resting cardiac output, and reduced resting total peripheral resistance.23 Regarding celiprolol’s effect on cardiac conduction, in vivo animal studies demonstrated that treatment did not accelerate the ventricular rate during electrically induced atrial fibrillation despite stimulation of cardiac β2-adrenoceptors.33 Furthermore, celiprolol had no membrane stabilizing or local anesthetic activity.25,33 In a small study of patients with stable atrial fibrillation, the normalized maximum rate of left ventricular pressure reduction immediately after systole (dP/dtip) increased by 24%, and the left ventricular relaxation time constant declined by 20% after celiprolol administration.23 In addition, Vyssoulis et al34 found, in patients with left ventricular hypertrophy, that celiprolol lowered blood pressure to normal levels and reduced left ventricular size estimated from end-systolic and diastolic diameters, interventricular septal thickness, and posterior wall thickness at end diastole and end systole.
Small studies with celiprolol in patients with heart failure have shown variable results. In 1 study of 16 patients with reduced left ventricular ejection fraction (LVEF), 3 months of celiprolol therapy showed hemodynamic benefits and improved LVEF in patients with nonischemic cardiomyopathy, but the benefits in those with ischemic cardiomyopathy were mixed.35 A larger study of 132 patients with reduced LVEF showed no difference between celiprolol and placebo in the primary end point of change in functional status (measured by the Goldman score) after 1 year of treatment.36 Some of the secondary efficacy measures showed an advantage with celiprolol (heart rate was reduced more and DiBianco heart failure score, which is a composite of exertional and decubitus dyspnea, asthenia, and leg edema was reduced more), but other efficacy measures showed no significant differences compared to placebo (LVEF, end-diastolic diameter, fractional shortening, and exercise duration).36 In aggregate, although these small trials did not show consistent efficacy with celiprolol for treating heart failure, they did suggest that the drug was safe in this population.
The effects of celiprolol on the respiratory function of healthy patients and asthmatic patients have been studied.36 Although respiratory function in patients with asthma was not changed with single doses of celiprolol (200 or 400 mg), bronchospasm and asthma have been reported in nonasthmatic patients with ischemic heart disease and hypertension being treated with celiprolol.23,37,38 Monitoring for respiratory symptoms is, therefore, still recommended with the use of celiprolol in both asthmatic and nonasthmatic patients.38
Similar to α-adrenoceptor antagonists, but unlike many other β1-adrenoceptor antagonists, celiprolol has no harmful effects on lipid and lipoprotein profiles but may have mild beneficial effects.39 In a study of 100 patients with hypertension, celiprolol 200 mg once daily reduced low-density lipoprotein cholesterol (LDL-C) levels in hyperlipidemic patients (baseline LDL-C >160 mg/dL) by 16.9% and total cholesterol by 12.8%. No significant changes were observed in patients with baseline LDL-C levels lower than 160 mg/dL.39
In a small placebo-controlled, crossover study, celiprolol 100–400 mg once daily did not induce significant changes in glomerular filtration rate, renal plasma blood flow, plasma renin activity, filtration fraction, serum creatinine, aldosterone, or urinary enzymes.40
Four trials demonstrated the role of celiprolol in improving hypertension and vascular elasticity. In 1988, Donaldson et al41 evaluated the hemodynamic effects of celiprolol in a small group (n = 10) of patients diagnosed with ischemic heart disease. Cardiac catheterization was performed, and left ventricular pressure and aortic pressure were recorded for 30 minutes post celiprolol treatment (intravenous infusion of 10 mg over 5 minutes). The measurements were taken at rest, in sinus rhythm, and during atrial pacing at a rate of 100 bpm. Results of the study demonstrated that celiprolol exerted a vasodilatory effect without depressing cardiac function.41
A randomized, double-blind study was conducted in 2 centers over 9 months to understand the pathogenesis of the vascular lesions of vEDS. Ninety-eight patients with essential hypertension were treated with either 200-mg celiprolol or 10-mg enalapril.19 The efficacy was similar in both groups and indicated that the decrease in carotid artery internal diameter was significantly related to the reduction in pulse pressure rather than mean blood pressure.19
Roman et al42 utilized duplex echo Doppler techniques to determine the site of celiprolol’s vasodilating effect. Thirty-five hypertensive patients were treated with increasing doses of celiprolol, 200 and 400 mg, over 15 days. Duplex echo Doppler was used to measure forearm (brachial artery) arterial and arteriolar vasodilation, before and during each celiprolol dose period. Celiprolol significantly (P < 0.05) increased brachial artery diameter and blood flow velocity compared to baseline. Statistically significant (P < 0.05) changes were also seen in forearm vascular measures: resistance decreased and compliance increased in response to celiprolol. These changes, except for blood flow velocity, occurred in a dose-dependent manner.42
These trials formed the backdrop for a study of celiprolol in vEDS, a condition in which reduction of arterial wall stress and increased vascular elasticity would likely be beneficial.
In 2010, Ong et al43 demonstrated the reduction of arterial and organ complications in patients with vEDS after treatment with celiprolol. The Beta-Blockers in Ehlers-Danlos Syndrome (BBEST) study was a prospective, multicenter, randomized, open trial with blinded assessment of clinical events that evaluated 53 patients who received either celiprolol or no treatment over a planned 5 years. The inclusion/exclusion criteria for this study were adapted from the Villefranche diagnostic criteria as shown in Table 2.43 Patients treated with celiprolol demonstrated a reduction in arterial events 3-fold greater than untreated patients (Figures 3 and 4).43 These results were achieved without significant changes in heart rate or blood pressure; the reduction in events was statistically significantly different from controls in the subset of vEDS patients with COL3A1 mutations.43,44 In addition, celiprolol demonstrated mild vasodilating effects in the hypertensive vEDS patients.42
Pooled data from clinical trials of patients with primary hypertension and/or angina pectoris reported no difference in adverse events between celiprolol and placebo (Figure 5).3 Additional analyses have found celiprolol to not induce clinically significant bradycardia compared to propranolol and to produce less dizziness, fatigue, and tiredness compared to atenolol—signifying an advantageous tolerability profile.23 Nonetheless, as with other β-blockers, celiprolol should not be used in patients with cardiogenic shock, decompensated heart failure, sick sinus syndrome, second- or third-degree heart block, or severe bradycardia.45 Celiprolol, unlike other β-blockers, may relax bronchial smooth muscle, rendering it theoretically safe for use in patients with pulmonary disease.45 In fact, several studies have shown celiprolol to not significantly affect respiratory function in patients with chronic obstructive lung disease46,47 or asthma.48,49 However, there have been reports of asthma and bronchospasm occurring in patients receiving celiprolol23,38 and a case of hypersensitivity pneumonitis occurring with celiprolol, which recurred upon rechallenge of the drug.50 Therefore, caution should still be exercised in patients with lung disease who are taking celiprolol, and monitoring for respiratory symptoms is still recommended even in patients without lung disease.38
USE IN VASCULAR EHLERS–DANLOS SYNDROME
Celiprolol is approved in many countries for the treatment of cardiovascular disorders; however, it is not yet approved in the United States for any indication. In 2015, the FDA granted celiprolol orphan drug status for the treatment of vEDS.51
Due to mutations in COL3A1 and abnormal vascular smooth muscle cell signaling, patients with vEDS have high carotid wall stress (steady or pulsatile) and are at high risk for arterial dissection and rupture.52 A reduction in the amplitude of carotid wall stress, along with the reduction of heart rate, and dP/dt have been suggested as potential benefits of celiprolol as preventive therapy for vEDS.52 The clinical use of celiprolol as a preventative measure for the life-threatening arterial dissections and ruptures and organ ruptures associated with vEDS has been suggested based on the agent’s capacity to reduce heart rate, mean pressure, and pulsatile pressure. Thus, celiprolol can decrease the continuous and pulsatile mechanical stress on collagen fibers within the arterial wall.43,51 In addition, celiprolol is thought to strengthen the arterial wall potentially via the upregulation of collagen synthesis. Given the strong associations between β-adrenoceptors and transforming growth factor-β (TGFβ) pathways, Ong et al43 suggested that β2 stimulation by celiprolol could enhance collagen synthesis via the TGFβ pathway. Moreover, Brooke44 suggested that β-adrenoceptor blockers suppress TGFβ expression, which could result in decreased matrix turnover, which ultimately reduces the continuous mechanical stress on collagen fibers within the vascular wall and increases the elasticity of the radial artery.
In a recent publication, Thanawala et al53 recommend against grouping all β-adrenoceptor antagonists into 1 class. The authors discussed a 3-state model of receptor activation that correlated with biased signaling of ligands. This was best represented when reviewing clinical data that demonstrated that not all β-adrenoceptor antagonists were effective in treating congestive heart failure.53 This further confirms the idea that classification of β-adrenoceptor antagonists should be founded on several factors: affinity, β1-selectivity, partial agonist activity, and physicochemical properties.1 On the basis of celiprolol’s unique pharmacologic profile, a β1 adrenergic antagonist with partial β2 agonist activity, reported β3-agonism, mild α2-antagonism, lack of membrane-stabilizing or local anesthetic activity, vasodilator properties, and the minimal occurrence of typical side effects of the β-adrenergic antagonist class (eg, bronchoconstriction, depression of left ventricular function, and peripheral vasoconstriction), one may consider labeling celiprolol as a SAM rather than as a β-blocker. Moreover, in light of the associations reported between β-adrenergic receptors and the TGFβ signaling cascade, investigation into celiprolol’s therapeutic efficacy via this mechanism is likely to further contribute to management of patients with vEDS and perhaps other rare cardiovascular diseases such as Loeys–Dietz syndrome and Marfan syndrome, in which TGFβ is believed to play a significant role in disease pathogenesis.43,54
vEDS is a rare genetic connective tissue disorder with life-threatening complications that include arterial dissections and ruptures, and intestinal and uterine ruptures.14 Currently, there are no FDA-approved therapies for vEDS in the United States, and physicians face the challenge of establishing an effective preventative treatment plan for their patients.18,55 Given its good tolerability and efficacy in a controlled, randomized clinical trial in preventing catastrophic vascular events and solid-organ ruptures, celiprolol may represent an agent with the ability to preemptively reduce the morbidity and mortality associated with vEDS. As such, it would represent a unique and innovative use of an agent from a class of drugs with a well-established track record of efficacy in treating other cardiovascular conditions.
1. Borchard UPharmacological properties of β-adrenoceptor blocking drugs. J Clin Bas Cardiol. 1998;1:5–9.
2. Frishman WHClinical perspective on celiprolol
: cardioprotective potential. Am Heart J. 1991;121(2 Pt 2):724–729.
3. Lamon KDClinical safety and efficacy of celiprolol
. Am Heart J. 1991;121(2 Pt 2):683–687.
4. Frishman WHFrishman WH, Sica DAAlpha- and beta-adrenergic blocking drugs. In: Cardiovascular Pharmacotherapeutics. 3rd ed. Abridged and Updated. 2012;Minneapolis, MN: Cardiotext Publishing; 57–85.
5. Perrone MH, Barrett JAPreclinical pharmacology of celiprolol
: a cardioselective beta-adrenergic antagonist and mild vasodilator. Am Heart J. 1991;121(2 Pt 2):677–683.
6. Abdelkrim MA, Martignat L, Gogny M, et alCeliprolol induces β(3)-adrenoceptors-dependent relaxation in isolated porcine coronary arteries. Can J Physiol Pharmacol. 2013;91:791–796.
7. Buskin JN, Upton RA, Sörgel F, et alSpecific and sensitive assay of celiprolol
in blood, plasma and urine using high-performance liquid chromatography. J Chromatogr. 1982;230:454–460.
8. Caruso FS, Doshan HD, Hernandez PH, et alCeliprolol: pharmacokinetics and duration of pharmacodynamic activity. Br J Clin Pract Suppl. 1985;40:12–16.
9. Louis WJ, Drummer OH, Tung LHPharmacology of celiprolol
. Cardiovasc Drugs Ther. 1991;4(suppl 6):1281–1285.
10. National Institutes of Health, U.S. National Library of Medicine. Ehlers-Danlos Syndrome. Available at: https://ghr.nlm.nih.gov/condition/ehlers-danlos-syndrome
. Accessed June 21, 2017.
11. Ehlers Danlos Society. EDS Types. Available at: https://ehlers-danlos.com/eds-types/
. Accessed June 21, 2017.
12. Byers PH, Holbrook KAMolecular basis of clinical heterogeneity in the Ehlers-Danlos syndrome. Ann NY Acad Sci. 1985;460:298–310.
13. Superti-Furga A, Gugler E, Gitzelmann R, et alEhlers-Danlos syndrome type IV: a multi-exon deletion in one of the two COL3A1 alleles affecting structure, stability, and processing of type III procollagen. J Biol Chem. 1988;263:6226–6232.
14. Beighton P, De Paepe A, Steinmann B, et alEhlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet. 1998;77:31–37.
15. Pepin M, Schwarze U, Superti-Furga A, et alClinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med. 2000;342:673–680.
16. Oderich GS, Panneton JM, Bower TC, et alThe spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: a 30-year experience. J Vasc Surg. 2005;42:98–106.
17. Beridze N, Frishman WHVascular Ehlers-Danlos syndrome: pathophysiology, diagnosis, and prevention and treatment of its complications. Cardiol Rev. 2012;20:4–7.
18. Lum YW, Brooke BS, Black JH 3rdContemporary management of vascular Ehlers-Danlos syndrome. Curr Opin Cardiol. 2011;26:494–501.
19. Boutouyrie P, Bussy C, Hayoz D, et alLocal pulse pressure and regression of arterial wall hypertrophy during long-term antihypertensive treatment. Circulation. 2000;101:2601–2606.
20. Frishman WClinical pharmacology of the new beta-adrenergic blocking drugs. Part 1. Pharmacodynamic and pharmacokinetic properties. Am Heart J. 1979;97:663–670.
21. PubChem National Institute for Health. Celiprolol
Resources Page. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/celiprolol
. Accessed April 5, 2017.
22. PubChem National Institute for Health. Acebutolol Resources Page. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/acebutolol
. Accessed April 5, 2017.
23. Milne RJ, Buckley MMCeliprolol. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in cardiovascular disease. Drugs. 1991;41:941–969.
24. Smith RD, Wolf PSCeliprolol. New Drugs Annu Cardiovasc Drugs. 1984;2:19–35.
25. Riddell JG, Shanks RG, Brogden RNCeliprolol. A preliminary review of its pharmacodynamic and pharmacokinetic properties and its therapeutic use in hypertension and angina pectoris. Drugs. 1987;34:438–458.
26. Lilja JJ, Backman JT, Laitila J, et alItraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol
. Clin Pharmacol Ther. 2003;73:192–198.
27. Lilja JJ, Juntti-Patinen L, Neuvonen PJOrange juice substantially reduces the bioavailability of the beta-adrenergic-blocking agent celiprolol
. Clin Pharmacol Ther. 2004;75:184–190.
28. Lilja JJ, Niemi M, Neuvonen PJRifampicin reduces plasma concentrations of celiprolol
. Eur J Clin Pharmacol. 2004;59:819–824.
29. Riddell JG, Harron DW, Shanks RGClinical pharmacokinetics of beta-adrenoceptor antagonists. An update. Clin Pharmacokinet. 1987;12:305–320.
30. Frishman WHBeta-adrenoceptor antagonists: new drugs and new indications. N Engl J Med. 1981;305:500–506.
31. Asanuma H, Node K, Minamino T, et alCeliprolol increases coronary blood flow and reduces severity of myocardial ischemia via nitric oxide release. J Cardiovasc Pharmacol. 2003;41:499–505.
32. Busst CM, Bush AComparison of the cardiovascular and pulmonary effects of oral celiprolol
, propranolol and placebo in normal volunteers. Br J Clin Pharmacol. 1989;27:405–410.
33. Pruss TPCeliprolol: its profile as a potential antiarrhythmic agent. Am Heart J. 1988;116(5 Pt 2):1412–1415.
34. Vyssoulis GP, Karpanou EA, Pitsavos CE, et alRegression of left ventricular hypertrophy in systemic hypertension with beta blockers (propranolol, atenolol, metoprolol, pindolol and celiprolol
). Am J Cardiol. 1992;70:1209–1211.
35. Hennersdorf MG, Perings C, Vester EGHemodynamic effects of celiprolol
in patients with ischemic and non-ischemic cardiomyopathy. Int J Cardiol. 1999;68:289–295.
36. Witchitz S, Cohen-Solal A, Dartois N, et alTreatment of heart failure with celiprolol
, a cardioselective beta blocker with beta-2 agonist vasodilatory properties. The CELICARD Group. Am J Cardiol. 2000;85:1467–1471.
37. Bruschi C, Casali L, Cerveri I, et alEffects of celiprolol
on the bronchial reactivity in asthma. Am J Cardiol. 1988;61:53C–54C.
38. Ahmed R, Branley HReversible bronchospasm with the cardio-selective beta-blocker celiprolol
in a non-asthmatic subject. Respir Med CME. 2009;2:141–143.
39. Vyssoulis GP, Karpanou EA, Pitsavos CE, et alDifferentiation of beta-blocker effects on serum lipids and apolipoproteins in hypertensive patients with normolipidaemic or dyslipidaemic profiles. Eur Heart J. 1992;13:1506–1513.
40. Lucarini AR, Salvetti ASystemic and renal hemodynamic effects of celiprolol
in essential hypertensives. Am J Cardiol. 1988;61:45C–48C.
41. Donaldson RM, Williams LA, Lee EHAcute hemodynamic effects of celiprolol
. Am J Cardiol. 1988;61:49C–51C.
42. Roman O, Meza N, Klenner CEffect of celiprolol
on large and small arteries of the forearm circulation in hypertensive patients. Cardiovasc Drugs Ther. 1990;4:745–749.
43. Ong KT, Perdu J, De Backer J, et alEffect of celiprolol
on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet. 2010;376:1476–1484.
44. Brooke BSCeliprolol therapy for vascular Ehlers-Danlos syndrome. Lancet. 2010;376:1443–1444.
45. Pruss TP, Khandwala A, Wolf PS, et alCeliprolol: a new beta adrenoceptor antagonist with novel ancillary properties. J Cardiovasc Pharmacol. 1986;8(suppl 4):S29–S32.
46. Fogari R, Zoppi A, Tettamanti F, et alComparative effects of celiprolol
, propranolol, oxprenolol, and atenolol on respiratory function in hypertensive patients with chronic obstructive lung disease. Cardiovasc Drugs Ther. 1990;4:1145–1149.
47. Chahuán M, Corradi L, Román O, et al[Safety and efficacy of celiprolol
in hypertensive patients with chronic obstructive lung disease]. Rev Med Chil. 2000;128:59–63.
48. Clauzel AM, Jean T, Etienne R, et alEffect of long-term treatment with celiprolol
on pulmonary function in a group of mild hypertensive asthmatics. J Int Med Res. 1988;16(suppl 1):27A–33A.
49. Szmidt M, Minc P, Wasiak W[Comparison of the influence of celiprolol
, metoprolol and atenolol on pulmonary ventilation in patients with asthma]. Pneumonol Alergol Pol. 1999;67:452–461.
50. Lombard JN, Bonnotte B, Maynadie M, et alCeliprolol pneumonitis. Eur Respir J. 1993;6:588–591.
51. US Food and Drug Administration. Search Orphan Drug Designations and Approvals. Available at: https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=456714
. Accessed April 5, 2017.
52. Boutouyrie P, Germain DP, Fiessinger JN, et alIncreased carotid wall stress in vascular Ehlers-Danlos syndrome. Circulation. 2004;109:1530–1535.
53. Thanawala VJ, Forkuo GS, Stallaert W, et alLigand bias prevents class equality among beta-blockers. Curr Opin Pharmacol. 2014;16:50–57.
54. MacCarrick G, Black JH 3rd, Bowdin S, et alLoeys-Dietz syndrome: a primer for diagnosis and management. Genet Med. 2014;16:576–587.
55. De Paepe A, Malfait FBleeding and bruising in patients with Ehlers-Danlos syndrome and other collagen vascular disorders. Br J Haematol. 2004;127:491–500.