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Pharmaceuticals (Basel, Switzerland) Aug 2020Kinins, bradykinin and kallidin are vasoactive peptides that signal through the bradykinin B1 and B2 receptors (B1R and B2R). B2R is constitutively expressed in healthy... (Review)
Review
Kinins, bradykinin and kallidin are vasoactive peptides that signal through the bradykinin B1 and B2 receptors (B1R and B2R). B2R is constitutively expressed in healthy tissues and mediates responses such as vasodilation, fluid balance and retention, smooth muscle contraction, and algesia, while B1R is absent in normal tissues and is induced by tissue trauma or inflammation. B2R is activated by kinins, while B1R is activated by kinins that lack the C-terminal arginine residue. Perturbations of the kinin system have been implicated in inflammation, chronic pain, vasculopathy, neuropathy, obesity, diabetes, and cancer. In general, excess activation and signaling of the kinin system lead to a pro-inflammatory state. Depending on the disease context, agonism or antagonism of the bradykinin receptors have been considered as therapeutic options. In this review, we summarize molecular imaging agents targeting these G protein-coupled receptors, including optical and radioactive probes that have been used to interrogate B1R/B2R expression at the cellular and anatomical levels, respectively. Several of these preclinical agents, described herein, have the potential to guide therapeutic interventions for these receptors.
PubMed: 32824565
DOI: 10.3390/ph13080199 -
Clinical Reviews in Allergy & Immunology Jun 2018Non-hereditary angioedema (AE) with normal C1 esterase inhibitor (C1INH) can be presumably bradykinin- or mast cell-mediated, or of unknown cause. In this systematic... (Review)
Review
Non-hereditary angioedema (AE) with normal C1 esterase inhibitor (C1INH) can be presumably bradykinin- or mast cell-mediated, or of unknown cause. In this systematic review, we searched PubMed, EMBASE, and Scopus to provide an overview of the efficacy of different treatment options for the abovementioned subtypes of refractory non-hereditary AE with or without wheals and with normal C1INH. After study selection and risk of bias assessment, 61 articles were included for data extraction and analysis. Therapies were described for angiotensin-converting enzyme inhibitor-induced AE (ACEi-AE), for idiopathic AE, and for AE with wheals. Described treatments consisted of ecallantide, icatibant, C1INH, fresh frozen plasma (FFP), tranexamic acid (TA), and omalizumab. Additionally, individual studies for anti-vitamin K, progestin, and methotrexate were found. Safety information was available in 26 articles. Most therapies were used off-label and in few patients. There is a need for additional studies with a high level of evidence. In conclusion, in acute attacks of ACEi-AE and idiopathic AE, treatment with icatibant, C1INH, TA, and FFP often leads to symptom relief within 2 h, with limited side effects. For prophylactic treatment of idiopathic AE and AE with wheals, omalizumab, TA, and C1INH were effective and safe in the majority of patients.
Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Humans; Omalizumab; Progestins; Tranexamic Acid; Treatment Outcome
PubMed: 27672078
DOI: 10.1007/s12016-016-8585-0 -
Laryngoscope Investigative... Jun 2021This study systematically reviews the existing literature on the management of hereditary angioedema (HAE) and provides an update on the clinical presentation and... (Review)
Review
OBJECTIVE
This study systematically reviews the existing literature on the management of hereditary angioedema (HAE) and provides an update on the clinical presentation and specific therapies.
METHODS
A literature search of PubMed and Embase databases was conducted from start of the database to February 2021. Inclusion criteria included relevant systematic reviews, randomized control clinical trials, prospective and retrospective cohort studies, and outcomes research published in English and available in full-text. Out of 310 candidate articles, a total of 55 articles were included in our study.
RESULTS
The most common genetic form of HAE in up to 85% of cases is caused by low levels of C1 esterase inhibitor (C1-INH) protein, leading to a bradykinin-mediated increase in vascular permeability. During an attack of HAE, abortive treatment with C1-INH replacement is most commonly described, however, icatibant, ecallantide, or fresh frozen plasma are also used. Long-term prophylaxis in the form of C1-INH replacement (subcutaneous or intravenous), monoclonal antibodies targeting plasma kallikrein, attenuated androgens, and transexemic acid should be considered for those who suffer from frequent, severe attacks.
CONCLUSION
Progressively distal involvement of the upper airway, especially the larynx, has been shown to pose an increased risk of asphyxiation and death in the acute presentation of HAE. Evaluation by an otolaryngologist is often sought during the emergent clinical management of HAE; therefore, it is prudent that the consulting physician is well-versed in the prompt recognition, triage of patients, and appropriate treatment modalities.
LEVEL OF EVIDENCE
1A.
PubMed: 34195359
DOI: 10.1002/lio2.555 -
Neurology Jan 2013We conducted a systematic review of the literature with meta-analysis to determine whether complex regional pain syndrome (CRPS) is associated with a specific... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
We conducted a systematic review of the literature with meta-analysis to determine whether complex regional pain syndrome (CRPS) is associated with a specific inflammatory profile and whether this is dependent on the duration of the condition.
METHODS
Comprehensive searches of the literature using MEDLINE, Embase, Scopus, Web of Science, and reference lists from published reviews identified articles that measured inflammatory factors in CRPS. Two independent investigators screened titles and abstracts, and performed data extraction and risk of bias assessments. Studies were subgrouped by medium (blood, blister fluid, and CSF) and duration (acute and chronic CRPS). Where possible, meta-analyses of inflammatory factor concentrations were performed and pooled effect sizes were calculated using random-effects models.
RESULTS
Twenty-two studies were included in the systematic review and 15 in the meta-analysis. In acute CRPS, the concentrations of interleukin (IL)-8 and soluble tumor necrosis factor receptors I (sTNF-RI) and II (sTNF-RII) were significantly increased in blood. In chronic CRPS, significant increases were found in 1) TNFα, bradykinin, sIL-1RI, IL-1Ra, IL-2, sIL-2Ra, IL-4, IL-7, interferon-γ, monocyte chemoattractant protein-1 (MCP-1), and sRAGE (soluble receptor for advanced glycation end products) in blood; 2) IL-1Ra, MCP-1, MIP-1β, and IL-6 in blister fluid; and 3) IL-1β and IL-6 in CSF. Chronic CRPS was also associated with significantly decreased 1) substance P, sE-selectin, sL-selectin, sP-selectin, and sGP130 in blood; and 2) soluble intercellular adhesion molecule-1 (sICAM-1) in CSF. Most studies failed to meet 3 or more of our quality criteria.
CONCLUSION
CRPS is associated with the presence of a proinflammatory state in the blood, blister fluid, and CSF. Different inflammatory profiles were found for acute and chronic cases.
Topics: Acute Pain; Blister; Chronic Pain; Complex Regional Pain Syndromes; Humans; Inflammation Mediators
PubMed: 23267031
DOI: 10.1212/WNL.0b013e31827b1aa1 -
Frontiers in Pharmacology 2020The Kinin B2 receptor (B2R) is classically involved in vasodilation and inflammatory responses. However, through the observation of hypoglycemic effects of...
The Kinin B2 receptor (B2R) is classically involved in vasodilation and inflammatory responses. However, through the observation of hypoglycemic effects of Angiotensin-I-Converting Enzyme (ACE) inhibitors, this protein has been related to metabolic glucose modulation in physiological and pathophysiological contexts. Although several studies have evaluated this matter, the different methodologies and models employed, combined with the distinct target organs, results in a challenge to summarize and apply the knowledge in this field. Therefore, this review aims to compile human and animal data in order to provide a big picture about what is already known regarding B2R and glucose metabolism, as well to suggest pending investigation issues aiming at evaluating the role of B2R in relation to glucose metabolism in homeostatic situations and metabolic disturbances. The data indicate that B2R signaling is involved mainly in glucose uptake in skeletal muscle and adipose tissue, acting as a synergic player beside insulin. However, most data indicate that B2R induces increased glucose oxidation, instead of storage, activation of a broad signaling cascade involving Nitric Oxide (NO) and cyclic-GMP dependent protein kinase (PKG). Additionally, we highlight that this modulation is impaired in metabolic disturbances such as diabetes and obesity, and we provide a hypothetic mechanism to explain this blockade in light of literature data provided for this review, as well as other authors.
PubMed: 32848770
DOI: 10.3389/fphar.2020.01162 -
The Cochrane Database of Systematic... 2000Oligo-astheno-teratospermia (sperm of low concentration, reduced motility and increased abnormal morphology) of unknown cause is common and the need for treatment is... (Review)
Review
BACKGROUND
Oligo-astheno-teratospermia (sperm of low concentration, reduced motility and increased abnormal morphology) of unknown cause is common and the need for treatment is felt by patients and doctors alike. As a result, a variety of empirical, non-specific treatments have been used in an attempt to improve semen characteristics and fertility. One suggested treatment for idiopathic oligo- and/or asthenospermia is the administration of kallikrein (kallidinogenase), a kinin-releasing enzyme (or kininogenase). The kinin biological system is complex and involves kininogen (the substrate), kininogenases (the activating enzymes), kinins (the effectors) and kininases (the inactivating enzymes). All four components of the kinin system have been found in the genitalia and in semen. Kallikrein releases 2 major kinins, kallidin and bradykinin, from seminal plasma kininogens. Activated kinins in semen affect sperm motility and metabolism. In vitro addition of kallikrein to semen has been shown to have a positive effect on sperm motility, sperm velocity, cervical mucus penetration, penetration of zona-free hamster eggs and post-thaw survival and motility rate after semen cryopreservation. The latter observation, however, was not confirmed in a more recent comparison of motility stimulants for cryopreserved semen using computerised sperm motion analysis. In vitro treatment of semen with kallikrein has been employed in a clinical context during sperm preparation prior to insemination. Although the kinin system may also be involved in the regulation of spermatogenesis in vivo, a clear mechanism of action is missing. Multiple suggestions on how an increase in kinin levels in the genital tract influences spermatogenesis at the testicular levels have been made by various authors.
OBJECTIVES
To determine whether treatment of the male with drugs enhancing kinin levles increases pregnancy rates among couples where failure to conceive has been attributed to idiopathic oligo- and/or asthenospermia. Effects on sperm parameters and sex hormones were studied as secondary outcomes.
SEARCH STRATEGY
The Cochrane Subfertility Review Group specialised register of controlled trials was searched".
SELECTION CRITERIA
SIxteen RCTs on the therapeutic use of androgens (clomiphene citrate or tamoxifen) in subfertile men were identified. Six trials were excluded.
DATA COLLECTION AND ANALYSIS
Methodological characteristics of trials Baseline characteristics of the studied groups Outcomes: Pregnancy rates, semen parameters (sperm concentration, motility and morphology), endocrinology (serum FSH, testosterone and oestradiol)
Topics: Fertility Agents, Male; Humans; Infertility, Male; Kallikreins; Male
PubMed: 10796695
DOI: 10.1002/14651858.CD000153 -
Endocrine Reviews May 2024Carcinoid syndrome (CS) is a debilitating disease that affects approximately 20% of patients with neuroendocrine neoplasms (NEN). Due to the increasing incidence and... (Review)
Review
Carcinoid syndrome (CS) is a debilitating disease that affects approximately 20% of patients with neuroendocrine neoplasms (NEN). Due to the increasing incidence and improved overall survival of patients with NEN over recent decades, patients are increasingly suffering from chronic and refractory CS symptoms. At present, symptom control is hampered by an incomplete understanding of the pathophysiology of this syndrome. This systematic review is the first to critically appraise the available evidence for the various hormonal mediators considered to play a causative role in CS. Overall, evidence for the putative mediators of CS was scarce and often of poor quality. Based on the available literature, data are only sufficient to agree on the role of serotonin as a mediator of CS-associated diarrhea and fibrosis. A direct role for tachykinins and an indirect role of catecholamines in the pathogenesis of CS is suggested by several studies. Currently, there is insufficient evidence to link histamine, bradykinin, kallikrein, prostaglandins, or motilin to CS. To summarize, available literature only sufficiently appoints serotonin and suggests a role for tachykinins and catecholamines as mediators of CS, with insufficient evidence for other putative mediators. Descriptions of CS should be revised to focus on these proven hormonal associations to be more accurate, and further research is needed into other potential mediators.
Topics: Humans; Malignant Carcinoid Syndrome; Serotonin; Catecholamines; Tachykinins
PubMed: 38038364
DOI: 10.1210/endrev/bnad035 -
Orphanet Journal of Rare Diseases May 2018Bradykinin-mediated angioedema (Bk-AE) can be life-threatening and requires specific targeted therapies. Knowledge of its epidemiology may help optimize its management.
BACKGROUND
Bradykinin-mediated angioedema (Bk-AE) can be life-threatening and requires specific targeted therapies. Knowledge of its epidemiology may help optimize its management.
METHODS
We systematically searched the medical literature to identify abstracts of interest indexed between 1948 and March, 2016. We used published national survey data on the proportion of the population treated with angiotensin-converting enzyme inhibitors (ACEI) to derive estimates of the population prevalence of ACEI-AE in the USA, Germany and France. For hereditary angioedema (C1-INH-HAE) and C1-inhibitor related acquired angioedema (C1-INH-AAE), publications had to contain original epidemiologic data collection within a defined geographical area. Hereditary angioedema with normal C1-INH was not included in the analysis due to lack of clearly defined criteria.
RESULTS
We identified 4 relevant publications on the prevalence of ACEI-AE, 6 on the prevalence of C1-INH-HAE, and 1 on the prevalence of C1-INH-AAE. The 1st year cumulative incidence of ACEI-AE was estimated to vary between 0.12 (population-based analyses) and 0.30 (meta-analyses of clinical trials) per 100 patient-years. The population prevalence of ACEI-AE was modeled to vary between 7 and 26 in 100,000. The prevalence of C1-INH-HAE was estimated to vary between 1.1 and 1.6 per 100,000. The prevalence of C1-INH-AAE was estimated to be 0.15 per 100,000 in one epidemiological investigation of AAE in Denmark.
CONCLUSIONS
Epidemiological evidence on Bk-AE is limited to North America and Europe. ACEI-AE is more common than C1-INH-HAE (~ 10:1), which is more common than C1-INH-AAE (~ 10:1). More studies are needed to comprehensively assess the epidemiological burden of Bk-AE.
Topics: Angioedema; Angioedemas, Hereditary; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Epidemiologic Studies; Humans
PubMed: 29728119
DOI: 10.1186/s13023-018-0815-5 -
The Cochrane Database of Systematic... May 2018Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood. The psychostimulant methylphenidate is the most frequently used... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood. The psychostimulant methylphenidate is the most frequently used medication to treat it. Several studies have investigated the benefits of methylphenidate, showing possible favourable effects on ADHD symptoms, but the true magnitude of the effect is unknown. Concerning adverse events associated with the treatment, our systematic review of randomised clinical trials (RCTs) demonstrated no increase in serious adverse events, but a high proportion of participants suffered a range of non-serious adverse events.
OBJECTIVES
To assess the adverse events associated with methylphenidate treatment for children and adolescents with ADHD in non-randomised studies.
SEARCH METHODS
In January 2016, we searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, 12 other databases and two trials registers. We also checked reference lists and contacted authors and pharmaceutical companies to identify additional studies.
SELECTION CRITERIA
We included non-randomised study designs. These comprised comparative and non-comparative cohort studies, patient-control studies, patient reports/series and cross-sectional studies of methylphenidate administered at any dosage or formulation. We also included methylphenidate groups from RCTs assessing methylphenidate versus other interventions for ADHD as well as data from follow-up periods in RCTs. Participants had to have an ADHD diagnosis (from the 3rd to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders or the 9th or 10th edition of theInternational Classification of Diseases, with or without comorbid diagnoses. We required that at least 75% of participants had a normal intellectual capacity (intelligence quotient of more than 70 points) and were aged below 20 years. We excluded studies that used another ADHD drug as a co-intervention.
DATA COLLECTION AND ANALYSIS
Fourteen review authors selected studies independently. Two review authors assessed risk of bias independently using the ROBINS-I tool for assessing risk of bias in non-randomised studies of interventions. All review authors extracted data. We defined serious adverse events according to the International Committee of Harmonization as any lethal, life-threatening or life-changing event. We considered all other adverse events to be non-serious adverse events and conducted meta-analyses of data from comparative studies. We calculated meta-analytic estimates of prevalence from non-comparative cohorts studies and synthesised data from patient reports/series qualitatively. We investigated heterogeneity by conducting subgroup analyses, and we also conducted sensitivity analyses.
MAIN RESULTS
We included a total of 260 studies: 7 comparative cohort studies, 6 of which compared 968 patients who were exposed to methylphenidate to 166 controls, and 1 which assessed 1224 patients that were exposed or not exposed to methylphenidate during different time periods; 4 patient-control studies (53,192 exposed to methylphenidate and 19,906 controls); 177 non-comparative cohort studies (2,207,751 participants); 2 cross-sectional studies (96 participants) and 70 patient reports/series (206 participants). Participants' ages ranged from 3 years to 20 years. Risk of bias in the included comparative studies ranged from moderate to critical, with most studies showing critical risk of bias. We evaluated all non-comparative studies at critical risk of bias. The GRADE quality rating of the evidence was very low.Primary outcomesIn the comparative studies, methylphenidate increased the risk ratio (RR) of serious adverse events (RR 1.36, 95% confidence interval (CI) 1.17 to 1.57; 2 studies, 72,005 participants); any psychotic disorder (RR 1.36, 95% CI 1.17 to 1.57; 1 study, 71,771 participants); and arrhythmia (RR 1.61, 95% CI 1.48 to 1.74; 1 study, 1224 participants) compared to no intervention.In the non-comparative cohort studies, the proportion of participants on methylphenidate experiencing any serious adverse event was 1.20% (95% CI 0.70% to 2.00%; 50 studies, 162,422 participants). Withdrawal from methylphenidate due to any serious adverse events occurred in 1.20% (95% CI 0.60% to 2.30%; 7 studies, 1173 participants) and adverse events of unknown severity led to withdrawal in 7.30% of participants (95% CI 5.30% to 10.0%; 22 studies, 3708 participants).Secondary outcomesIn the comparative studies, methylphenidate, compared to no intervention, increased the RR of insomnia and sleep problems (RR 2.58, 95% CI 1.24 to 5.34; 3 studies, 425 participants) and decreased appetite (RR 15.06, 95% CI 2.12 to 106.83; 1 study, 335 participants).With non-comparative cohort studies, the proportion of participants on methylphenidate with any non-serious adverse events was 51.2% (95% CI 41.2% to 61.1%; 49 studies, 13,978 participants). These included difficulty falling asleep, 17.9% (95% CI 14.7% to 21.6%; 82 studies, 11,507 participants); headache, 14.4% (95% CI 11.3% to 18.3%; 90 studies, 13,469 participants); abdominal pain, 10.7% (95% CI 8.60% to 13.3%; 79 studies, 11,750 participants); and decreased appetite, 31.1% (95% CI 26.5% to 36.2%; 84 studies, 11,594 participants). Withdrawal of methylphenidate due to non-serious adverse events occurred in 6.20% (95% CI 4.80% to 7.90%; 37 studies, 7142 participants), and 16.2% were withdrawn for unknown reasons (95% CI 13.0% to 19.9%; 57 studies, 8340 participants).
AUTHORS' CONCLUSIONS
Our findings suggest that methylphenidate may be associated with a number of serious adverse events as well as a large number of non-serious adverse events in children and adolescents, which often lead to withdrawal of methylphenidate. Our certainty in the evidence is very low, and accordingly, it is not possible to accurately estimate the actual risk of adverse events. It might be higher than reported here.Given the possible association between methylphenidate and the adverse events identified, it may be important to identify people who are most susceptible to adverse events. To do this we must undertake large-scale, high-quality RCTs, along with studies aimed at identifying responders and non-responders.
Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Child, Preschool; Humans; Methylphenidate; Non-Randomized Controlled Trials as Topic; Patient Dropouts; Young Adult
PubMed: 29744873
DOI: 10.1002/14651858.CD012069.pub2 -
Pneumonologia I Alergologia Polska 2013Hereditary angioedema (HAE) is a genetic disease caused by C1-esterase inhibitor deficiency, characterized by recurrent attacks of intense, massive, localized... (Comparative Study)
Comparative Study Review
[Administration of conestat alfa, human C1 esterase inhibitor and icatibant in the treatment of acute angioedema attacks in adults with hereditary angioedema due to C1 esterase inhibitor deficiency. Treatment comparison based on systematic review results].
INTRODUCTION
Hereditary angioedema (HAE) is a genetic disease caused by C1-esterase inhibitor deficiency, characterized by recurrent attacks of intense, massive, localized subcutaneous oedema that can involve all parts of the body. The aim of this study is a comparison of the clinical effectiveness of conestat alfa, human C1 esterase inhibitor (C1INH), and icatibant in the treatment of acute angioedema attacks in adults with HAE.
MATERIALS AND METHODS
A systematic review of literature published up to May 2012 was performed to assess the efficacy and safety of conestat alfa, C1INH, and icatibant in the treatment of acute angioedema attacks in adults with HAE. Databases were searched at MEDLINE (PubMed), EMBASE, and Cochrane. The general search structure was designed as a combination of keywords or synonyms: (hereditary angioedema) AND (conestat alfa OR human C1 esterase inhibitor concentrate OR synonyms OR icatibant). Only randomized clinical studies were selected.
RESULTS
Systematic review yielded no clinical trials directly comparing the therapeutic options mentioned. Two randomized clinical trials were found which compared each of the following: conestat alfa, C1INH, and icatibant with placebo. Based on the gathered evidence it was demonstrated that taking any of the medicinal substances mentioned in the treatment of acute angioedema attack results in shorter time to beginning of relief of symptoms, time to minimal symptoms, the probability of the treatment response after 4 hours is increased, and the safety profile is comparable to placebo.
CONCLUSIONS
Due to significant heterogeneity of identified trials, the scientific evidence available was insufficient to point out the most effective therapeutic option in the treatment of acute oedemas in HAE.
Topics: Adult; Aged; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Humans; Middle Aged; Randomized Controlled Trials as Topic; Recombinant Proteins; Secondary Prevention; Treatment Outcome
PubMed: 23420425
DOI: No ID Found