Hereditární angioedém (HAE) je vzácné, geneticky podmíněné onemocnění s autozomálně dominantním přenosem a variabilním spektrem klinických projevů i život ohrožujících. V širším kontextu se jedná o imunodeficitní onemocnění, klasifikované na HAE s deficiencí C1 inhibitoru (HAE-C1-INH, dříve HAE-I a HAE-II) a HAE s normální hladinou a funkcí C1 inhibitoru (HAE nC1-INH) označovaný též jako HAE-III typu, s mutacemi jiného (mnohdy ještě neznámého) typu. Klinickým projevem jsou masivní otoky podkoží a/nebo sliznic v důsledku nekontrolované aktivace komplementového a kininového systému. V důsledku lokální nadprodukce bradykininu vznikají typické angioedémy. Vzácněji může deficit C1-inhibitoru vzniknout s vazbou na jiné patologické stavy (autoimunitní, lymfoproliferace, monoklonální gamapatie) – jedná se o získaný angioedém (AAE, acquired angioedema). Za samostatný klinický syndrom, který je nutno odlišit od získaného angioedému, je považován ACE inhibitory indukovaný angioedém (AE-ACEi). Důležitá je farmakologická anamnéza, rizikové mohou být i sartany, inhibitory mTOR, gliptiny, mezi dalšími léky je uváděn aliskiren, sakubitril, tkáňový aktivátor plasminogenu. Vznik center pro diagnostiku a péči o pacienty s HAE/AAE významně zlepšil životní osudy těchto pacientů. Do center jsou konzilárně odesíláni i pacienti s atypickými angioedémy (s převahou bradykininové etiologie).
Hereditary angioedema (HAE) is a rare, genetically determined disease with autosomal dominant transmission and a variable spectrum of clinical and life-threatening manifestations. In a broader context, it is an immunodeficiency disease, classified into HAE with a deficiency of C1 inhibitor (HAE-C1-INH, formerly HAE-I and HAE-II) and HAE with a normal level and function of C1 inhibitor (HAE nC1-INH), also referred to as HAE-III type, with mutations of another (often still unknown) type. The clinical manifestation is massive swelling of the subcutaneous tissue and/or mucous membranes due to uncontrolled activation of the complement and kinin systems. Local overproduction of bradykinin results in typical angioedema. More rarely, C1-inhibitor deficiency can arise in connection with other pathological conditions (autoimmune, lymphoproliferation, monoclonal gammopathy) – this is acquired angioedema (AAE). Angioedema induced by ACE inhibitors (AE-ACEi) is considered a separate clinical syndrome that must be distinguished from acquired angioedema. The pharmacological anamnesis is important, sartans, mTOR inhibitors, gliptins can also be risky, aliskiren, sacubitril, tissue plasminogen activator are mentioned among other drugs. The emergence of centers for the diagnosis and care of patients with HAE/AAE significantly improved the lives of these patients. Patients with atypical angioedema (predominantly of bradykinin etiology) are also sent to the centers on a consular basis.
- MeSH
- bradykinin metabolismus škodlivé účinky MeSH
- diferenciální diagnóza MeSH
- hereditární angioedémy * diagnóza farmakoterapie klasifikace MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
The kinin receptors are classically involved in inflammation, pain and sepsis. The effects of the kinin B1 receptor agonist des-Arg9-bradykinin (DBK) and lipopolysaccharide (LPS) were investigated by comparing the membrane potential responses of aortic rings from transgenic rats overexpressing the kinin B1 receptor (B1R) in the endothelium (TGR(Tie2B1)) and Sprague Dawley (SD) rats. No difference in the resting membrane potential in the aorta's smooth muscle from the transgenic and SD rats was observed. The aorta rings from SD rats hyperpolarized only to LPS but not to DBK, whereas the aorta rings from TGR(Tie2B1) responded by the administration of both drugs. DBK and LPS responses were inhibited by the B1 receptor antagonist R715 and by iberiotoxin in both cases. Thapsigargin induced a hyperpolarization in the smooth muscle of SD rats that was not reversed by R715, but was reversed by iberiotoxin and this hyperpolarization was further augmented by DBK administration. These results show that the model of overexpression of vascular B1 receptors in the TGR(Tie2B1) rats represent a good model to study the role of functional B1 receptors in the absence of any pathological stimulus. The data also show that KCa channels are the final mediators of the hyperpolarizing responses to DBK and LPS. In addition, we suggest an interaction between the B1R and TLR4, since the hyperpolarization induced by LPS could be abolished in the presence of R715.
- MeSH
- aorta MeSH
- bradykinin * farmakologie MeSH
- cévní endotel MeSH
- krysa rodu rattus MeSH
- lipopolysacharidy farmakologie MeSH
- membránové potenciály MeSH
- potkani Sprague-Dawley MeSH
- potkani transgenní MeSH
- receptor bradykininu B1 * genetika MeSH
- techniky in vitro MeSH
- thapsigargin farmakologie MeSH
- toll-like receptor 4 MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Hereditární angioedém je vzácné onemocnění, jehož projevem jsou rekurentní angioedémy v různých lokalitách. Nejčastěji bývá podmíněn deficitem C1 inhibitoru. Za hlavní mediátor otoků považujeme u této diagnózy bradykinin. Lanadelumab je plně humánní monoklonální protilátka namířená proti plazmatickému kalikreinu, který z vysokomolekulárního kininogenu bradykinin vyštěpuje. Aktuálně je lanadelumab registrován pro dlouhodobou profylaktickou terapii hereditárního angioedému a představuje velmi účinnou a dobře tolerovanou léčebnou alternativu pro pacienty s častými a závažnými otoky.
Hereditary angioedema is a rare disorder associated with recurrent episodes of swellings in different body areas. C1 inhibitor deficiency is the most common cause of this disease. Bradykinin is considered to be the main mediator responsible for angioedema formation. Fully human monoclonal antibody lanadelumab targets plasma kalikrein, which is responsible for bradykinin formation. It is currently registered for long term prophylaxis in hereditary angioedema and represents a highly effective and well tolerated treatment option in patients with frequent and severe swellings.
- Klíčová slova
- lanadelumab,
- MeSH
- bradykinin škodlivé účinky MeSH
- hereditární angioedémy * etiologie farmakoterapie patologie MeSH
- humanizované monoklonální protilátky * aplikace a dávkování farmakologie terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- nežádoucí účinky léčiv MeSH
- plazmatický kalikrein antagonisté a inhibitory MeSH
- Check Tag
- lidé MeSH
Deoxynivalenol (DON), the most naturally-occurring trichothecenes, may affect animal and human health by causing vomiting as a hallmark of food poisoning. Deoxynivalenol-3-glucoside (D3G) usually co-occurs with DON as its glucosylated form and is another emerging food safety issue in recent years. However, the toxicity of D3G is not fully understood compared to DON, especially in emetic potency. The goals of this research were to (1) compare emetic effects to D3G by oral and intraperitoneal (IP) routes and relate emetic effects to brain-gut peptides glucose-dependent insulinotropic polypeptide (GIP) and substance P (SP) in mink; (2) determine the roles of calcium-sensing receptor (CaSR) and transient receptor potential (TRP) channel in D3G's emetic effect. Both oral and IP exposure to D3G elicited marked emetic events. This emetic response corresponded to an elevation of GIP and SP. Blocking the GIP receptor (GIPR) diminished emetic response induction by GIP and D3G. The neurokinin 1 receptor (NK-1R) inhibitor Emend® restrained the induction of emesis by SP and D3G. Importantly, CaSR antagonist NPS-2143 or TRP channel antagonist ruthenium red dose-dependently inhibited both D3G-induced emesis and brain-gut peptides GIP and SP release; cotreatment with both antagonists additively suppressed both emetic and brain-gut peptide responses to D3G. To summarize, our findings demonstrate that activation of CaSR and TRP channels contributes to D3G-induced emesis by mediating brain-gut peptide exocytosis in mink.
- MeSH
- emetika * toxicita MeSH
- glukosa MeSH
- glukosidy MeSH
- norek MeSH
- receptory gastrointestinálních hormonů MeSH
- receptory spřažené s G-proteiny MeSH
- substance P MeSH
- trichotheceny * chemie toxicita MeSH
- zvířata MeSH
- zvracení chemicky indukované MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Hereditárny angioedém (HAE) je zriedkavé geneticky podmienené ochorenie charakterizované rekurentnými epizódami lokalizovaného, bradykinínom sprostredkovaného opuchu hlbokých tkanív kože, dýchacieho a gastrointestinálneho traktu, ktorý môže ohroziť pacientov život. Vo väčšine prípadov je HAE spôsobený nedostatkom inhibítora C1-esterázy (C1-inhibítora), najčastejšie vplyvom mutácie v géne SERPING1. Symptómy sa obvykle začínajú v detstve alebo adolescencii a smerom k dospelosti sa zhoršujú. Diagnostiku komplikuje značná variabilita klinických príznakov a/alebo prítomnosť sprievodných najmä alergických ochorení. V článku uvádzame súbor 6 pacientov z 3 rodín s geneticky potvrdeným HAE a ich klinický fenotyp.
Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of localized, bradykinin-mediated swelling of the deep tissues of the skin, respiratory and gastrointestinal tract, which can be life-threatening. In most cases, HAE is caused by C1-esterase inhibitor (C1-inhibitor) deficiency, most commonly due to a mutation in the SERPING1 gene. Symptoms usually begin in childhood or adolescence and worsen towards adulthood. Diagnosis is complicated by the considerable variability of clinical symptoms and/or the presence of concomitant, mainly allergic diseases. In this article, we describe a series of 6 patients from 3 families with genetically confirmed HAE and their clinical phenotype.
- Klíčová slova
- C1 inhibitor,
- MeSH
- bradykinin MeSH
- dítě MeSH
- hereditární angioedémy * diagnóza genetika terapie MeSH
- lidé MeSH
- mladiství MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Obstructed blood flow and erratic blood supply in the tumor region attenuate the distribution and accumulation of nanomedicines in the tumor. Therefore, improvement of these conditions is crucial for efficient drug delivery. In this study, we designed and synthesized a novel N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymer conjugate of BK, which possessed adequate systemic stability and tumor-selective action required to improve the accumulation of nanomedicines in the tumor. Levulinoyl-BK (Lev-BK) was conjugated to an HPMA-based polymer via an acid-cleavable hydrazone bond (P-BK). An acid-responsive release of Lev-BK from P-BK was observed, and P-BK alone after intradermal application showed below 10% of the BK activity, thus proving a reduction in the vascular permeability activity of BK when attached to the polymer carrier. P-BK pre-treatment improved blood flow in the tumor tissue by 1.4-1.7-fold, which was maintained for more than 4 h. In addition, P-BK pre-treatment increased the tumor accumulation of pegylated liposomal doxorubicin (PLD) by approximately 3-fold. Furthermore, P-BK pre-treatment led to superior antitumor activity of PLD and significantly improved the survival of tumor-bearing mice. The release of BK from P-BK in the acidic milieu of the tumor was a prerequisite for P-BK to exert its effect, as the vascular permeability enhancing activity of P-BK was negligible. Collectively, P-BK pre-treatment improved intratumoral blood flow and augmented tumor accumulation of nanomedicine, thereby resulting in a significant suppression of tumor growth. Therefore, these findings demonstrate that P-BK is a potential concomitant drug for improving the tumor delivery of nanomedicines.
- MeSH
- bradykinin terapeutické užití MeSH
- doxorubicin terapeutické užití MeSH
- methakryláty MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory * farmakoterapie MeSH
- nanomedicína MeSH
- nosiče léků terapeutické užití MeSH
- polymery terapeutické užití MeSH
- protinádorové látky * terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Transient receptor potential vanilloid 1 (TRPV1) channels contribute to the development of several chronic pain states and represent a possible therapeutic target in many painful disease treatment. Proinflammatory mediator bradykinin (BK) sensitizes TRPV1, whereas noxious peripheral stimulation increases BK level in the spinal cord. Here, we investigated the involvement of spinal TRPV1 in thermal and mechanical hypersensitivity, evoked by intrathecal (i.t.) administration of BK and an endogenous agonist of TRPV1, N-oleoyldopamine (OLDA), using behavioral tests and i.t. catheter implantation, and administration of BK-induced transient thermal and mechanical hyperalgesia and mechanical allodynia. All these hypersensitive states were enhanced by co-administration of a low dose of OLDA (0.42 µg i.t.), which was ineffective only under the control conditions. Intrathecal pretreatment with TRPV1 selective antagonist SB366791 prevented hypersensitivity induced by i.t. co-administration of BK and OLDA. Our results demonstrate that both thermal and mechanical hypersensitivity evoked by co-administration of BK and OLDA is mediated by the activation of spinal TRPV1 channels.
Některé teorie naznačují, že bradykinin by mohl hrát roli v patogenezi tkáňového postižení u pacientů s infekcí COVID-19. Protože se současně jedná o hlavní mediátor vzniku angioedému u pacientů s hereditárním angioedémem, nabízí se možnost závažnějšího průběhu infekce COVID-19 u pacientů s touto diagnózou. V současnosti ovšem máme k dispozici jen omezené údaje o průběhu infekce COVID-19 u pacientů s tímto onemocněním. Výskyt angioedémů bez kopřivky u pacientů s infekcí COVID-19 i bez přítomnosti diagnózy hereditárního angioedému a účinnost preparátů určených k jeho terapii u pacientů s covidovou pneumonií by však význam bradykininu v patogenezi tkáňového postižení při infekci COVID-19 mohly podpořit.
Some theories suggest, that bradykinin may play a role in pathogenesis of tissue damage in COVID-19 infection. It is also a main mediator responsible for angioedema attacks in patients with hereditary angioedema. Therefore we may assume COVID-19 infection can be more severe for these patients. Unfortunately we have only limited data about course of COVID-19 disease in hereditarian angioedema patients so far. However, angioedema without wheals has been described in patients with COVID-19 infection and some trials showed improvement of COVID-19 pneumonia after administration of drugs, commonly used for angioedema treatment. These findings may support bradykinin involvement in COVID-19 tissue damage.
