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Medicinal Research Reviews 1990Bradykinin and its active metabolites are produced at the sites of their actions by kallikreins. They potently elicit a variety of biological effects: hypotension,... (Review)
Review
Bradykinin and its active metabolites are produced at the sites of their actions by kallikreins. They potently elicit a variety of biological effects: hypotension, bronchoconstriction, gut and uterine contraction, epithelial secretion in airway, gut, and exocrine glands, vascular permeability, pain, connective tissue proliferation, and eicosanoid formation. These effects are mediated by at least two broad classes of receptors. The most common is the B2 subtype. The Stewart and Vavrek peptides characterized by a DPhe7 substitution have provided powerful tools for study of bradykinin's actions by competitively and specifically blocking bradykinin B2 receptors. The significance of kinins in certain human diseases is being explored using these new tools and potential therapeutic agents. At present, human clinical trials are underway to test the usefulness of bradykinin receptor antagonists in the symptoms of the common cold and in the pain associated with severe burns. Trials for use in asthma will be initiated in 1990.
Topics: Animals; Bradykinin; Humans; Hyperalgesia; Inflammation; Pain; Receptors, Bradykinin; Receptors, Neurotransmitter
PubMed: 2158607
DOI: 10.1002/med.2610100204 -
BMC Nephrology May 2023Intradialytic hypotension (IDH) is a common clinical complication and is associated with increased morbidity and mortality in patients undergoing maintenance... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Intradialytic hypotension (IDH) is a common clinical complication and is associated with increased morbidity and mortality in patients undergoing maintenance hemodialysis (MHD). The pathogenesis of IDH has been attributed to the rapid reduction of plasma volume during hemodialysis and the inadequate compensatory mechanisms in response to hypovolemia, such as the lack of vasoconstriction. This may be due to the increased production of vasodilators, such as bradykinin. In this study we test the hypothesis that bradykinin B receptor blockade prevents intradialytic hypotension.
METHODS
We performed a post-hoc analysis of a double-blind, placebo-controlled, randomized, 2 × 2 crossover clinical trial comparing the continuous infusion of icatibant, a bradykinin B receptor blocker, and placebo during hemodialysis. Icatibant or placebo was infused for 30 min before and during hemodialysis in 11 patients on MHD.
RESULTS
Seven of the patients had IDH, defined as a reduction of systolic blood pressure equal to or greater than 20 mmHg during hemodialysis. Stratified analysis, based on the presence of IDH, revealed that icatibant prevented the decrease in blood pressure compared to placebo in patients with IDH [blood pressure at average nadir (2.5 h after hemodialysis): Placebo,114.3 ± 8.9 vs. icatibant, 125.6 ± 9.1 mmHg, mean ± S.E.M]. Icatibant did not affect blood pressure in the group of patients without IDH.
CONCLUSION
Bradykinin B2 receptor blocker may prevent the occurrence of IDH. Further studies should evaluate the hemodynamic effects of icatibant during hemodialysis and the symptomatology associated with IDH.
Topics: Humans; Receptors, Bradykinin; Bradykinin; Hypotension; Renal Dialysis; Blood Pressure
PubMed: 37170244
DOI: 10.1186/s12882-023-03192-4 -
Thorax Nov 1992
Review
Topics: Asthma; Bradykinin; Bronchoconstriction; Humans; Nociceptors; Respiratory Muscles
PubMed: 1465760
DOI: 10.1136/thx.47.11.979 -
Current Pharmaceutical Design 2003The nonapeptide bradykinin is an important growth factor for many cancers. Certain peptide and non-peptide bradykinin antagonists show remarkable anti-cancer activities... (Review)
Review
The nonapeptide bradykinin is an important growth factor for many cancers. Certain peptide and non-peptide bradykinin antagonists show remarkable anti-cancer activities in both in vitro and in vivo cancer models, especially of lung and prostate cancers. Bradykinin antagonists stimulate apoptosis in cancers by a novel "biased agonist" mechanism: they block intracellular increase of calcium concentration but stimulate the MAP kinase pathway. This unbalanced effect stimulates caspase activation. In nude mouse xenotransplants of lung and prostate cancers the antagonists inhibit angiogenesis and activation of membrane metalloproteases (MMP 2 and 9). In the xenotransplants certain bradykinin antagonists showed higher potency than standard anti-cancer drugs, without evident toxicity to the hosts. These compounds offer great promise for development of new anti-cancer drugs.
Topics: Antineoplastic Agents; Bradykinin; Humans; Lung Neoplasms; Male; Prostatic Neoplasms
PubMed: 14529414
DOI: 10.2174/1381612033454171 -
Annals of the New York Academy of... 1991
Review
Topics: Amino Acid Sequence; Animals; Bradykinin; Humans; Kinetics; Molecular Sequence Data; Muscle, Smooth; Receptors, Bradykinin; Receptors, Neurotransmitter; Respiratory Physiological Phenomena; Respiratory System
PubMed: 1659280
DOI: 10.1111/j.1749-6632.1991.tb37980.x -
Peptides Mar 2004Practical bradykinin antagonists were discovered in 1984 by Vavrek and Stewart and reported in "Peptides." At that time there was already much evidence for involvement... (Review)
Review
Practical bradykinin antagonists were discovered in 1984 by Vavrek and Stewart and reported in "Peptides." At that time there was already much evidence for involvement of bradykinin in inflammation and pain, so the specific, competitive antagonists were widely accepted and applied. The key to conversion of bradykinin into an antagonist was replacement of the proline residue at position 7 with a D-aromatic amino acid. Other modifications converted the initial weak antagonists into modern peptides which are totally resistant to all degrading enzymes, are orally available, and have been used in clinical trials. Non-peptide bradykinin antagonists have also been developed.
Topics: Amino Acids; Animals; Bradykinin; Humans; Inflammation; Neoplasms
PubMed: 15134872
DOI: 10.1016/j.peptides.2003.10.016 -
Agents and Actions. Supplements 1992The availability of practical bradykinin antagonists has revolutionized research in the kinin field. Development of the first antagonists and progress to the present... (Review)
Review
The availability of practical bradykinin antagonists has revolutionized research in the kinin field. Development of the first antagonists and progress to the present time are reviewed.
Topics: Amino Acid Sequence; Animals; Binding, Competitive; Bradykinin; Humans; Molecular Sequence Data; Structure-Activity Relationship
PubMed: 1466295
DOI: 10.1007/978-3-0348-7321-5_66 -
Expert Opinion on Therapeutic Patents Jul 2009For > 20 years, pharmaceutical companies and academic centers have been developing bradykinin antagonists. The patent literature on these molecules (up to and including... (Review)
Review
BACKGROUND
For > 20 years, pharmaceutical companies and academic centers have been developing bradykinin antagonists. The patent literature on these molecules (up to and including 2004) has been analyzed previously in this journal in two review articles.
OBJECTIVE
The aim of this review is to provide an update (from 2005 to early 2009) on the patenting activity in the field of bradykinin antagonists (including patents on their formulation). Where possible, the information from the patents has been supplemented with that from the primary literature, clinical trial databases and company websites in an attempt to give a more complete picture.
CONCLUSIONS
In the past 4 years, nearly 50 new patents have been filed on bradykinin antagonists--in the case of several filings, only the original source has been considered in this analysis--the vast majority of these (> 93%) on B1 antagonists. However, despite this large amount of work, only one compound, icatibant--a hydrophilic decapeptide selective for the B2 receptor--has reached the market, although it needs to be administered parenterally.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B1 Receptor Antagonists; Bradykinin B2 Receptor Antagonists; Clinical Trials as Topic; Drug Design; Humans; Patents as Topic
PubMed: 19552510
DOI: 10.1517/13543770902994389 -
Canadian Journal of Physiology and... Jul 1995The present brief review summarizes the evidence for the possibility that endogenously released bradykinin plays a major role in protecting the heart against the... (Review)
Review
The present brief review summarizes the evidence for the possibility that endogenously released bradykinin plays a major role in protecting the heart against the consequences of acute myocardial injury. This evidence includes the facts that kinins are generated under myocardial ischemia; that when they are administered, they are cardioprotective (e.g., antiarrhythmic); that drugs that enhance the release of bradykinin from the ischemic heart reduce the ischemic injury and, conversely, drugs that block bradykinin receptors attenuate the reduction in ischemic injury resulting from the release of, or administration of, bradykinin. The possible mechanism of bradykinin in the cardioprotection afforded by ischemic preconditioning is summarized. Ischemic preconditioning can be defined as the marked reduction in the severity of ischemic changes that result from coronary artery occlusion when that occlusion is preceded by brief periods of myocardial ischemia, either regional or global, induced, for example, by complete or partial coronary artery occlusion or by rapid ventricular pacing. The possible mechanisms of cardioprotection elicited by bradykinin (and ischemic preconditioning) are summarized. The most likely is the generation of cyclic GMP within the ischemic myocardium following bradykinin-stimulated nitric oxide generation and release from endothelial cells.
Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Cyclic GMP; Heart; Humans; Myocardial Ischemia; Nitric Oxide
PubMed: 8846418
DOI: 10.1139/y95-114 -
Biopolymers 1995Bradykinin (BK) is involved in regulation of every major physiological system and is an initiator or mediator of many pathophysiological conditions. Rapid progress in... (Review)
Review
Bradykinin (BK) is involved in regulation of every major physiological system and is an initiator or mediator of many pathophysiological conditions. Rapid progress in understanding these aspects of BK biology has come since the discovery of BK antagonists. This article reviews principal points in the history of the kallikrein-kinin field and of kinin biology. The chemistry and development of antagonists for B1 and B2 kinin receptors is discussed. Uses of the antagonists in biomedical research and potential clinical applications are presented.
Topics: Amino Acid Sequence; Animals; Bradykinin; Humans; Inflammation; Kallikreins; Kinins; Mammals; Molecular Sequence Data; Second Messenger Systems
PubMed: 7893946
DOI: 10.1002/bip.360370208