Icatibant Acetate

Angiotensin-converting enzyme inhibitors (ACEIs) are first-line antihypertensive drugs widely used in clinical practice, and are also indicated for the treatment of post-myocardial infarction, heart failure, diabetes mellitus, chronic kidney disease and other disorders. Approximately 35 to 40 million patients worldwide are currently receiving ACEI therapy. However, a potentially severe adverse reaction exists in their clinical use-angioedema. Although its incidence is low (about 0.1%~0.5%), it has an acute onset and can involve the face, lips, larynx and other parts. Laryngeal edema, in particular, can rapidly obstruct the airway, cause asphyxiation and threaten patients' lives.

The core pathogenesis of ACEI-induced angioedema is closely related to abnormal bradykinin metabolism: ACEIs inhibit the activity of angiotensin-converting enzyme, which also functions to degrade bradykinin. This inhibition leads to an abnormal elevation of bradykinin levels in the body. Excessive bradykinin binds to B₂ receptors on the surface of vascular endothelial cells, triggering increased vascular permeability and plasma extravasation, and ultimately resulting in local edema. Since this type of edema is bradykinin-mediated, conventional antihistamines and glucocorticoids have poor therapeutic effects, and there is an urgent clinical need for targeted therapeutic drugs.

As a highly selective antagonist of the bradykinin B₂ receptor, Icatibant Acetate can precisely block the binding of bradykinin to B₂ receptors and inhibit the occurrence and development of edema from the pathogenic root cause, without relying on the metabolic clearance of ACEIs. It therefore has distinct therapeutic advantages and is expected to become a first-line therapeutic agent for ACEI-induced angioedema, especially suitable for rapid intervention in emergency settings, filling the gap in the targeted treatment of this adverse reaction.In addition, its convenient subcutaneous injection route enables rapid onset of action, further enhancing its application potential in emergency treatment.

Asthma is a common chronic airway inflammatory disease with a complex pathogenesis, associated with multiple factors such as airway hyperresponsiveness, release of inflammatory mediators, and immune dysfunction. In recent years, studies have found that bradykinin, as an important inflammatory mediator, plays a key role in the pathogenesis of asthma: the level of bradykinin in bronchoalveolar lavage fluid of asthmatic patients is significantly elevated, and its concentration is positively correlated with the severity of airway inflammation.

Bradykinin binds to B₂ receptors on the surface of airway smooth muscle cells, glandular cells and inflammatory cells, triggering airway smooth muscle contraction, increased mucus secretion and inflammatory cell infiltration, which in turn lead to airway narrowing, wheezing, cough and other asthmatic symptoms. At the same time, it can enhance airway hyperresponsiveness and exacerbate disease recurrence.

Based on the above mechanism, the product can block bradykinin-mediated airway inflammatory response and airway hyperresponsiveness through specific antagonism of the bradykinin B₂ receptor, and is expected to become a novel adjuvant drug for asthma treatment.In vitro experiments and animal studies have initially confirmed its efficacy: in a guinea pig asthma model, intravenous injection of Icatibant Acetate dose-dependently inhibited bradykinin-induced bronchoconstriction, reduced pulmonary resistance and improved lung compliance.

A phase Ⅱ multicenter, double-blind, placebo-controlled clinical trial further explored the efficacy of inhaled the product in patients with moderate to severe chronic asthma. The study enrolled 300 asthmatic patients aged 18~65 years, who were randomly divided into three groups and received 900 μg, 3000 μg inhaled it or placebo three times a day for 4 weeks. The results showed that lung function indices (e.g., forced expiratory volume in 1 second [FEV1], peak expiratory flow [PEF]) in the product groups improved in a dose-dependent manner.

In the 3000 μg group, lung function indices were significantly increased by approximately 10% compared with the placebo group after 4 weeks of treatment (P<0.001). This improvement began to appear 1~2 weeks after the start of treatment, persisted until the end of treatment, and gradually declined after drug withdrawal, suggesting a definite anti-inflammatory effect of the drug.

Although the study found no significant advantages in alleviating the Asthma Control Test (ACT) score or reducing the use of rescue medications, the improvement in lung function provides an important basis for its application in asthma treatment.At present, clinical research on asthma is still ongoing, focusing on exploring its therapeutic value in refractory asthma and severe asthma, as well as the effect of combination therapy with conventional asthma medications.

Liver cirrhosis is an end-stage liver disease progressing from various chronic liver diseases, with core pathological features of hepatic fibrosis and destruction of hepatic lobule structure. It is often accompanied by a series of complications such as portal hypertension, opening of collateral circulation and hepatic insufficiency, which seriously affect the quality of life and survival time of patients.

In recent years, studies have found that abnormal metabolism of vasoactive substances such as bradykinin plays an important role in the occurrence and development of liver cirrhosis and its complications: in patients with liver cirrhosis, the degradation capacity of bradykinin decreases due to hepatic tissue damage. At the same time, portal hypertension leads to intestinal congestion and impaired intestinal barrier function, and endotoxemia activates the kallikrein-kinin system, resulting in a massive increase in bradykinin release.

Excessive bradykinin further exacerbates portal hypertension, leading to splanchnic vasodilation and increased blood flow, which raises the risk of complications such as ascites and rupture of esophagogastric varices. Meanwhile, bradykinin-mediated inflammatory response accelerates the process of hepatic fibrosis and aggravates hepatic function damage. In addition, bradykinin may also be involved in the occurrence of renal function damage in patients with liver cirrhosis, leading to severe complications such as hepatorenal syndrome.

By specifically antagonizing the bradykinin B₂ receptor, it can effectively regulate bradykinin levels in the body and block its mediated pathological reactions, thereby exerting a positive effect on the condition of patients with liver cirrhosis. At present, relevant research is mainly focused on animal experiments and preliminary clinical exploration: in animal models of liver cirrhosis, the product treatment significantly reduced portal pressure, decreased splanchnic blood flow, reduced ascites formation, and simultaneously inhibited hepatic inflammatory response and fibrogenesis, improving hepatic and renal functions.

Preliminary clinical observations found that in patients with liver cirrhosis complicated with ascites, the product treatment significantly accelerated ascites resolution, reduced ascites volume, and no obvious adverse reactions were observed.
In the future, with the deepening of research, it is expected to become an adjuvant therapeutic agent for complications of liver cirrhosis (e.g., ascites, portal hypertension), providing new ideas and methods for the treatment of liver cirrhosis, especially for patients with poor response to conventional treatment. At the same time, its inhibitory effect on hepatic fibrosis may also provide a new therapeutic target for delaying the progression of liver cirrhosis.