clinical trial description

8/13/2019 Clinical Trial Description

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The novel beta-blocker, carvedilol, provides neuroprotection in transient focal stroke.

Savitz SI,Erhardt JA,Anthony JV,Gupta G,Li X,Barone FC,Rosenbaum DM.

Author information

Abstract

Increasing evidence supports a role for oxidative stress, proinflammatory cytokines, and

apoptosis in the pathophysiology of focal ischemic stroke. Previous studies have found that

the multi-action drug, carvedilol, is a mixed adrenergic antagonist, and that it behaves as an

antioxidant and inhibits apoptosis. In the current study, the authors investigated whether

carvedilol provides protection in focal cerebral ischemia and whether this protection is

associated with reduced apoptosis and the downregulation of the inflammatory cytokines,

tumor necrosis factor-alpha (TNF-alpha) and interleukin- 1beta (IL-1beta). Male Sprague-

Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) by an

intraluminal filament technique. Carvedilol (1, 3, and 10 mg/kg) was injected daily

subcutaneously 2 or 4 days before the induction of ischemia. Neurologic scores, infarct

volumes, TUNEL staining, and mRNA levels of TNF-alpha and IL-1beta were assessed at 24

hours reperfusion. The effect of carvedilol on microvascular cortical perfusion was studied

with continuous laser-Doppler flowmetry. Twenty-four hours after MCAO, carvedilol at all

three doses reduced infarct volumes by at least 40% and reduced neurologic deficits on

average by 40% compared with vehicle-treated controls when given 2 or 4 days before the

induction of ischemia. This protection was not mediated by changes in temperature or blood

flow. Treatment with all three dose regimens resulted in fewer TUNEL positive cells

compared with controls. At 24 hours reperfusion, carvedilol decreased TNF-alpha and IL-

1beta expression by 40% to 50% in the ipsilateral ischemic cortex compared with the

contralateral controls. The results of the current study indicate that carvedilol

is neuroprotective in focal cerebral ischemia and may protect the ischemic brain by inhibiting

apoptosis and attenuating the expression of TNF-alpha and IL-1beta.

Detailed Clinical Trial Description

The main objective of this trial is to assess the efficacy and safety of propranolol in middlecerebral artery stroke patients. The primary hypothesis is as follows: Early administration of
http://www.ncbi.nlm.nih.gov/pubmed?term=Savitz%20SI%5BAuthor%5D&cauthor=true&cauthor_uid=10950380http://www.ncbi.nlm.nih.gov/pubmed?term=Erhardt%20JA%5BAuthor%5D&cauthor=true&cauthor_uid=10950380http://www.ncbi.nlm.nih.gov/pubmed?term=Anthony%20JV%5BAuthor%5D&cauthor=true&cauthor_uid=10950380http://www.ncbi.nlm.nih.gov/pubmed?term=Gupta%20G%5BAuthor%5D&cauthor=true&cauthor_uid=10950380http://www.ncbi.nlm.nih.gov/pubmed?term=Li%20X%5BAuthor%5D&cauthor=true&cauthor_uid=10950380http://www.ncbi.nlm.nih.gov/pubmed?term=Barone%20FC%5BAuthor%5D&cauthor=true&cauthor_uid=10950380http://www.ncbi.nlm.nih.gov/pubmed?term=Rosenbaum%20DM%5BAuthor%5D&cauthor=true&cauthor_uid=10950380http://www.ncbi.nlm.nih.gov/pubmed/10950380http://www.ncbi.nlm.nih.gov/pubmed/10950380http://www.ncbi.nlm.nih.gov/pubmed?term=Rosenbaum%20DM%5BAuthor%5D&cauthor=true&cauthor_uid=10950380http://www.ncbi.nlm.nih.gov/pubmed?term=Barone%20FC%5BAuthor%5D&cauthor=true&cauthor_uid=10950380http://www.ncbi.nlm.nih.gov/pubmed?term=Li%20X%5BAuthor%5D&cauthor=true&cauthor_uid=10950380http://www.ncbi.nlm.nih.gov/pubmed?term=Gupta%20G%5BAuthor%5D&cauthor=true&cauthor_uid=10950380http://www.ncbi.nlm.nih.gov/pubmed?term=Anthony%20JV%5BAuthor%5D&cauthor=true&cauthor_uid=10950380http://www.ncbi.nlm.nih.gov/pubmed?term=Erhardt%20JA%5BAuthor%5D&cauthor=true&cauthor_uid=10950380http://www.ncbi.nlm.nih.gov/pubmed?term=Savitz%20SI%5BAuthor%5D&cauthor=true&cauthor_uid=10950380


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propranolol reduces the frequency of cardiovascular and/or neurological complications

including vascular death in the first 30 days after acute ischemic stroke. Secondary

hypotheses are as follows: Early administration of propranolol improves neurological and

functional outcome of patients with acute ischemic stroke. Early administration of

propranolol reduces post-stroke immunodepression and therefore lowers the rate of

pneumonia after acute ischemic stroke, without increasing the frequency of auto-aggressive,

CNS antigen-specific T cells. Early administration of propranolol influences alterations in

cardiologic, electrophysiologic phenomenons as a reaction to autonomic dysregulation after

acute ischemic stroke. Early administration of Propranolol reduces growth of infarct as

determined by MRI examinations in the first 6 days.

Beta-adrenoreceptor antagonists attenuate brain injury after transient focal ischemia in

rats.

Goyagi T,Kimura T,Nishikawa T,Tobe Y,Masaki Y

Abstract

Beta-adrenoreceptor antagonists experimentally reduce cardiac and renal injury after

ischemia and are also clinically useful for myocardial infarction and severe burns. In

addition, beta-adrenoreceptor antagonists provide neuroprotective effects after focal cerebral

ischemia in experimental settings. We conducted the present study to compare the

neuroprotective effects of several beta-adrenoreceptor antagonists in rat transient focal

cerebral ischemia. Halothane-anesthetized normothermic adult male Sprague-Dawley rats

were subjected to 2 h of middle cerebral artery occlusion using the intraluminal suture

technique confirmed by laser Doppler flowmetry. Rats received an IV infusion of saline 0.5

mL/h, propranolol 100 microg x kg(-1) x min(-1), carvedilol 4 microg x kg(-1) x min(-1),esmolol 200 microg x kg(-1) x min(-1), or landiolol 50 microg x kg(-1) x min(-1) (n = 6 in

each group). Infusion was initiated 30 min before middle cerebral artery occlusion and

continued for 24 h. Additional rats received esmolol 50 microg x kg(-1) x min(-1) or

landiolol 10 microg x kg(-1) x min(-1) intrathecally (IT) via the cisterna magna (n = 5 in each

group), according to the same experimental protocol. The neurological deficit score was

evaluated at 22 h after reperfusion, and the brains were removed and stained with

triphenyltetrazolium chloride for evaluation of infarct volume. Additional rats that received

saline, esmolol, and landiolol IV (n = 6 in each group) were allowed to survive for 7 days
http://www.ncbi.nlm.nih.gov/pubmed?term=Goyagi%20T%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Kimura%20T%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Nishikawa%20T%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Tobe%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Masaki%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Masaki%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Tobe%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Nishikawa%20T%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Kimura%20T%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Goyagi%20T%5BAuthor%5D&cauthor=true&cauthor_uid=16931677


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followed by measurement of infarct size. Neurological deficit scores were smaller in rats

treated with propranolol-IV, carvedilol-IV, esmolol-IV, landiolol-IV, esmolol-IT, and

landiolol-IT compared with saline-treated rats (P < 0.05). Cortical and striatum infarct

volumes were less in the rats receiving beta-adrenoreceptor antagonists via either IV or IT

than in saline-treated rats (P < 0.05). We conclude that beta-adrenoreceptor antagonists

improve neurological and histological outcomes after transient focal cerebral ischemia in rats

independent of administration route.

Carvedilol, a new antihypertensive drug with unique antioxidant activity: potential role

in cerebroprotection.

Yue TL,Lysko PG,Barone FC,Gu JL,Ruffolo RR Jr,Feuerstein GZ.

Author information

Abstract

The antioxidant activities of carvedilol have been demonstrated in a wide variety of test

systems, including (i) physicochemical (EPR studies), (ii) biochemical (measurement of lipid

peroxidation and endogenous antioxidant depletion), (iii) cellular, and (iv) in vivo. The

antioxidant activity of carvedilol clearly emanates from the carbazole moiety which is unique

to carvedilol. The antioxidant activity resides equally in both of the enantiomers of

carvedilol, as well as in some of its metabolites which are devoid of either the alpha 1-

adrenoceptor blocking activity or beta-adrenoceptor blocking activity. This novel antioxidant

property of carvedilol may account, at least in part, for its cerebroprotection. The data

discussed in this article suggest that carvedilol may not only provide effective and safe

antihypertensive therapy and therefore reduce a major risk factor for stroke, but will also be

better able to provide additional benefits to patients by protecting against oxygen free radicalsgenerated during cerebral ischemia and stroke.

Antioxidant action of the antihypertensive drug, carvedilol, against lipid peroxidation.

Noguchi N,Nishino K,Niki E.
http://www.ncbi.nlm.nih.gov/pubmed?term=Yue%20TL%5BAuthor%5D&cauthor=true&cauthor_uid=7832432http://www.ncbi.nlm.nih.gov/pubmed?term=Lysko%20PG%5BAuthor%5D&cauthor=true&cauthor_uid=7832432http://www.ncbi.nlm.nih.gov/pubmed?term=Barone%20FC%5BAuthor%5D&cauthor=true&cauthor_uid=7832432http://www.ncbi.nlm.nih.gov/pubmed?term=Gu%20JL%5BAuthor%5D&cauthor=true&cauthor_uid=7832432http://www.ncbi.nlm.nih.gov/pubmed?term=Ruffolo%20RR%20Jr%5BAuthor%5D&cauthor=true&cauthor_uid=7832432http://www.ncbi.nlm.nih.gov/pubmed?term=Feuerstein%20GZ%5BAuthor%5D&cauthor=true&cauthor_uid=7832432http://www.ncbi.nlm.nih.gov/pubmed/7832432http://www.ncbi.nlm.nih.gov/pubmed?term=Noguchi%20N%5BAuthor%5D&cauthor=true&cauthor_uid=10704936http://www.ncbi.nlm.nih.gov/pubmed?term=Nishino%20K%5BAuthor%5D&cauthor=true&cauthor_uid=10704936http://www.ncbi.nlm.nih.gov/pubmed?term=Niki%20E%5BAuthor%5D&cauthor=true&cauthor_uid=10704936http://www.ncbi.nlm.nih.gov/pubmed?term=Niki%20E%5BAuthor%5D&cauthor=true&cauthor_uid=10704936http://www.ncbi.nlm.nih.gov/pubmed?term=Nishino%20K%5BAuthor%5D&cauthor=true&cauthor_uid=10704936http://www.ncbi.nlm.nih.gov/pubmed?term=Noguchi%20N%5BAuthor%5D&cauthor=true&cauthor_uid=10704936http://www.ncbi.nlm.nih.gov/pubmed/7832432http://www.ncbi.nlm.nih.gov/pubmed?term=Feuerstein%20GZ%5BAuthor%5D&cauthor=true&cauthor_uid=7832432http://www.ncbi.nlm.nih.gov/pubmed?term=Ruffolo%20RR%20Jr%5BAuthor%5D&cauthor=true&cauthor_uid=7832432http://www.ncbi.nlm.nih.gov/pubmed?term=Gu%20JL%5BAuthor%5D&cauthor=true&cauthor_uid=7832432http://www.ncbi.nlm.nih.gov/pubmed?term=Barone%20FC%5BAuthor%5D&cauthor=true&cauthor_uid=7832432http://www.ncbi.nlm.nih.gov/pubmed?term=Lysko%20PG%5BAuthor%5D&cauthor=true&cauthor_uid=7832432http://www.ncbi.nlm.nih.gov/pubmed?term=Yue%20TL%5BAuthor%5D&cauthor=true&cauthor_uid=7832432


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Author information

Abstract

The action of carvedilol, a vasodilating, beta-adrenoceptor blocking agent, against lipid

peroxidation has been the subject of many studies, but the results reported thus far are

contradictory. In an attempt to define the antioxidant mechanism of carvedilol against lipid

peroxidation, the dynamics of the action of carvedilol were studied in several oxidation

systems. We investigated the reactivity of carvedilol toward radicals and its inhibitory effect

on lipid peroxidation induced by several kinds of initiating species such as azo compounds

and metal ions in solution, micelles, membranes, and low-density lipoprotein. Carvedilol

exerted poor reactivity toward phenoxyl, alkoxyl, and peroxyl radicals in acetonitrile solution

nor did it show an appreciable antioxidant effect against either the peroxyl radical-inducedoxidation of methyl linoleate in acetonitrile or against phosphatidylcholine liposomal

membranes in aqueous suspension. Carvedilol completely inhibited the ferric ion-induced

oxidation of methyl linoleate micelles by sequestering ferric ions, but not by reducing

hydroperoxide. It was shown that carvedilol enhanced the oxidation of micelles induced by

either methemoglobin or peroxyl radical. Carvedilol, which was added exogenously, did not

suppress the oxidation of isolated low-density lipoprotein induced by peroxyl radical or

cupric ion. These results show that carvedilol does not act as a radical-scavenging

antioxidant, but that it does act most efficiently as an antioxidant against ferric ion-induced

oxidation by sequestering ferric ion.

Beta-adrenoreceptor antagonists attenuate brain injury after transient focal ischemia in

rats.

Goyagi T,Kimura T,Nishikawa T,Tobe Y,Masaki Y.

Author information

Abstract

Beta-adrenoreceptor antagonists experimentally reduce cardiac and renal injury after

ischemia and are also clinically useful for myocardial infarction and severe burns. In

addition, beta-adrenoreceptor antagonists provide neuroprotective effects after focal cerebral

ischemia in experimental settings. We conducted the present study to compare the

neuroprotective effects of several beta-adrenoreceptor antagonists in rat transient focal
http://www.ncbi.nlm.nih.gov/pubmed/10704936http://www.ncbi.nlm.nih.gov/pubmed?term=Goyagi%20T%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Kimura%20T%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Nishikawa%20T%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Tobe%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Masaki%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed/16931677http://www.ncbi.nlm.nih.gov/pubmed/16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Masaki%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Tobe%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Nishikawa%20T%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Kimura%20T%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed?term=Goyagi%20T%5BAuthor%5D&cauthor=true&cauthor_uid=16931677http://www.ncbi.nlm.nih.gov/pubmed/10704936


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cerebral ischemia. Halothane-anesthetized normothermic adult male Sprague-Dawley rats

were subjected to 2 h of middle cerebral artery occlusion using the intraluminal suture

technique confirmed by laser Doppler flowmetry. Rats received an IV infusion of saline 0.5

mL/h, propranolol 100 microg x kg(-1) x min(-1), carvedilol 4 microg x kg(-1) x min(-1),

esmolol 200 microg x kg(-1) x min(-1), or landiolol 50 microg x kg(-1) x min(-1) (n = 6 in

each group). Infusion was initiated 30 min before middle cerebral artery occlusion and

continued for 24 h. Additional rats received esmolol 50 microg x kg(-1) x min(-1) or

landiolol 10 microg x kg(-1) x min(-1) intrathecally (IT) via the cisterna magna (n = 5 in each

group), according to the same experimental protocol. The neurological deficit score was

evaluated at 22 h after reperfusion, and the brains were removed and stained with

triphenyltetrazolium chloride for evaluation of infarct volume. Additional rats that received

saline, esmolol, and landiolol IV (n = 6 in each group) were allowed to survive for 7 days

followed by measurement of infarct size. Neurological deficit scores were smaller in rats

treated with propranolol-IV, carvedilol-IV, esmolol-IV, landiolol-IV, esmolol-IT, and

landiolol-IT compared with saline-treated rats (P < 0.05). Cortical and striatum infarct

volumes were less in the rats receiving beta-adrenoreceptor antagonists via either IV or IT

than in saline-treated rats (P < 0.05). We conclude that beta-adrenoreceptor antagonists

improve neurological and histological outcomes after transient focal cerebral ischemia in rats

independent of administration route.

Poor protective effect of beta blockers confined to ischemic stroke

By Eleanor McDermid

22 December 2008

J Hypertens 2009; 27: 174180

MedWire News: The weaker protection against stroke seen with beta blockers relative to

other antihypertensive agents is confined to ischemic stroke, a study suggests.

We also found that poor compliance with antihypertensive pharmacotherapy was an

important risk factor in stroke development, for both ischemic and hemorrhagic type, say

Jung-Der Wang (National Taiwan University, Taipei) and colleagues.


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The researchers studied a cohort of 29,759 patients with newly diagnosed uncomplicated

hypertension, 1078 of whom suffered stroke during an average follow-up of 38.8 months.

Overall, and in contrast to previous studies, the risk for stroke did not differ according to the

type of antihypertensive patients were taking. The increased stroke risk with beta blockers

(by 27% relative to other antihypertensives) emerged only when the analysis was restricted to

ischemic stroke.

Our findings indicated that outcomes research might provide additional evidence for

improving clinical guidelines, as the processes in randomized clinical trials might not be able

to take care of all conditions in the daily practices of clinicians, Wanget alcomment in

theJournal of Hypertension.

For all types of stroke among these low-risk, uncomplicated hypertensive patients in our

study, the control of their hypertension seemed to be a more important factor than the choice

of antihypertensive agent.

Based on prescription claim rates, patients were compliant with their medication regimen

42.1% of the time, on average. The risk for stroke increased with decreasing medication

compliance, by 1.5, 1.8, and 1.9 fold for compliance of 4069%, 2039%, and less than 20%,

compared with at least 70%.

Male gender, older age, and the presence of diabetes or heart disease also raised stroke risk,

after accounting for confounders.

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