Overactive bladder (OAB) is a syndrome characterized by symptoms of urinary urgency, often accompanied by urinary frequency and nocturia, with or without urge incontinence. This disease not only seriously affects the quality of life of patients but also imposes a huge economic burden on the country, and its treatment is aimed at relieving the symptoms of the urinary storage phase of patients. Currently, conservative treatment is still the first line of treatment for OAB, of which pharmacotherapy is the most commonly used and easily accepted by patients, and antimuscarinic drugs are the first-line drugs approved by the Food and Drug Administration (FDA) for the treatment of OAB. However, antimuscarinic drugs are not effective in some cases of OAB, and their side effects of dry mouth, constipation, drowsiness, and blurred vision limit their widespread use to some extent.
In addition to muscarinic acetylcholine receptors, normal bladder function is also regulated by adrenergic receptors, of which the beta3-adrenoceptor (beta-3AR) is the most important factor regulating human bladder detrusor diastole, which provides a new target for pharmacological treatment of overactive bladder. In recent years, a large number of basic and clinical studies have confirmed that β-3AR agonists are expected to be the first-line drugs for the treatment of OAB. This paper reviews the progress of research on β-3AR agonists in the treatment of overactive bladder.
1. β-3AR and agonists β-adrenoceptors were initially divided into β-1 and β-2 subtypes according to their physiological effects. in the 1980s, an atypical subtype of β-AR was discovered that was insensitive to typical β-AR antagonists. In 1989, Emorine et al. isolated and cloned the first atypical adrenergic receptor gene in human adipocytes, which is called β-3AR.
The β-3AR is widely present in human tissues, including adipose group, cardiovascular system, bladder, gastrointestinal tract and many others, but its distribution is highly dependent on the species class. Otsuka further showed that β-3AR was expressed in various tissues of the human bladder, including the detrusor muscle, interstitial cells and uroepithelium.
The β-3AR agonists are compounds containing hydroxyl groups and can be divided into four major classes: aryl ethanolamines, aryloxypropanolamines, benzopyrans and tetrahydroisoquinolines, of which the first two are the most studied. The β-3AR agonists for OAB that have entered clinical trials include mirabegron, ritobegron and solabegron, while TRK-380 has not yet been tested in clinical trials, and ritobegron has not passed Phase III clinical trials. Mirabegron was first recommended for approval in Japan in July 2011 and approved by the FDA in June 2012. It is the first β-3AR agonist approved for the treatment of OAB.
2, Mechanism of action There are two types of contractions of bladder detrusor muscles, detrusor contraction and storage autonomic contraction. Detrusor contraction is a coordinated contraction mediated by contractile transmitters (acetylcholine and ATP) released from cholinergic nerves, while storage autonomic contraction is mediated by mechanosensitive afferent nerves. Elevated bladder muscle tone excites mechanosensitive Aδ afferent nerves and initiates the voiding reflex when the strength of the nerve impulse reaches a threshold. It is currently believed that β-3AR agonists inhibit autonomic contraction primarily by acting on β-3AR on the detrusor muscle in the storage phase, thereby mediating increased bladder compliance and delayed voiding reflexes. Traditionally, the molecular mechanism by which β-3AR agonists inhibit voluntary contraction is through activation of the second messenger cAMP, which in turn activates protein kinase A, which phosphorylates key intracellular target proteins and ultimately leads to smooth muscle relaxation. However, Petkov and Frazier found that the role of cAMP in mediating bladder diastole is much less than that of K+ channels, and the specific molecular mechanisms downstream of it need to be further investigated. Also β-3AR agonists act directly on β-3AR in the urinary epithelium and afferent nerves, thereby inhibiting the voluntary contraction of the detrusor muscle during the storage phase, thereby delaying the initiation of the voiding reflex and ultimately relieving overactive bladder syndrome. michel and Hicks et al. found that unlike antimuscarinic agents, β-3AR agonists increased bladder volume and decreased the number of voiding sessions without affecting pressure and residual urine volume during voiding.
3, adverse reactions Since β-3AR is widely present in tissues other than the bladder, including adipose tissue, cardiovascular system, prostate, gastrointestinal tract, etc., β-3AR agonists can produce adverse reactions such as hypertension, nasopharyngitis, urinary tract infection, headache, etc. while treating OAB, the most important concern is cardiovascular adverse reactions.
β-3AR mRNA can be detected in human myocardium, but whether the corresponding protein is expressed in myocardium has not been unanimously recognized, so the exact physiological effects of β-3AR agonists on the heart are more controversial. protective effect. the RCT study found that mirabellum at doses less than 100 mg per day did not prolong the QT interval [26]; in a clinical study in healthy volunteers, the new β-3AR agonist mirabellum was found to accelerate the heart rate with increasing dosage, and compared to the placebo group, the mean maximum heart rate accelerated by mirabellum at 50 mg, 100 mg and 200 mg per day, respectively This side effect was reversible after discontinuation of the drug.
Early animal studies found that the vasodilatory effects induced by the β-3AR agonists BRL37344 and CGP12177 were mediated by nitric oxide (NO), and the diastolic effects induced by the β-3AR agonists were significantly reduced if the endothelium was removed or the NO synthase inhibitor L2NMMA was preadministered. It is currently believed that β-3AR agonists can directly cause vasodilation, which theoretically leads to a decrease in blood pressure. However, clinical studies have found that the result is an increase in blood pressure in both healthy people and OAB patients, with an approximate increase of 0.5 – 1 mmHg for therapeutic doses of mirabellum, and this side effect is also reversible after discontinuation of the drug.
4. Pharmacokinetics Among the beta-3 AR agonists, the most studied and FDA-approved is mirabellone, which is a once-daily oral extended-release tablet available in 25 mg and 50 mg sizes and manufactured by Astellas Japan. Bioavailability varies between 20-30% and is influenced by factors such as gender, dose and diet [29]. A study conducted in four healthy young male subjects showed that a solution of carbon 14-labeled mirabellum ( 160 mg) was rapidly absorbed after a single oral dose in subjects on an empty stomach with a tmax of 1.0 h. The product is present in the circulation mainly in its original form and excreted mainly as a prototype in urine (55%) and feces (34%), with various metabolites present in urine, including amide hydrolysis products Various metabolites are present in urine, including amide hydrolysis products (48%), glucosylation products (34%), and N-dealkylation or oxidation products of secoamines (18%).
Mirabellum is highly lipophilic and is primarily metabolized by the hepatic cytochrome P450 and CYP2D6 pathways, so pharmacokinetic interactions should be noted when combining this product with other CYP2D6 substrate drugs. In addition, the CYP2D6 gene is polymorphic, and the enzyme activity varies greatly among individuals, so the dose should be adjusted according to the patient’s specific conditions.
Clinical studies The β-3AR agonists for OAB that have entered clinical trials include mirabellone, ritobellone and solabellone, among which ritobellone has not passed the phase III clinical trial, while mirabellone has been approved in Japan and the United States.
Chapple et al. conducted a phase IIA clinical trial of mirabellone in 31 regions of six European countries, enrolling 262 patients with OAB, who were randomly divided into four groups: placebo group, tolterodine group, mirabellone 100 mg group and 150 m mg group. In addition, there was a significant improvement in the number of urinary incontinence, the number of voids and the volume of urine voided per voiding in both mirabellone groups, and a slight increase in heart rate (5 beats per minute) in the mirabellone 150 mg group, but no serious adverse events. A subsequent phase IIB clinical trial also demonstrated the effectiveness of mirabellone in treating OAB, with a non-significant difference in the incidence of adverse reactions between the placebo group and the different dose treatment groups, with a mean of 45.2% (43.2% in the placebo group and 43.8-47.9% in the mirabellone group); the total rate of forced discontinuation due to adverse drug reactions was 3.2% (3.0% in the placebo group and (2.4-5.3%).
Phase III clinical trials of mirabegron have confirmed its safe and effective treatment of OAB. a multicenter, randomized, double-blind, parallel-group, placebo-controlled phase III clinical trial conducted in North America by Nitti et al. confirmed the effectiveness of mirabegron at 50 or 100 mg for the treatment of OAB [35]. The population included 1329 patients with OAB aged 60.1 years (74.3% women) with a history of at least 3 months (urination at least 8 times every 24 hours and urinary urgency at least 3 times every 72 h before treatment, of whom 29.7% had symptoms of urinary incontinence, 32.2% had urinary frequency without symptoms of incontinence, and 38.1% had both urinary urgency and incontinence). Subjects were randomized to receive mirabellum 50 mg (n= 443) or 100 mg (n= 433) or placebo (n= 453) once daily for 12 weeks to study the degree of improvement in incontinence and frequency of urination per 24 h at the final follow-up. The results showed a significant improvement in the primary indicators for both dose groups compared to the placebo group, i.e. a mean reduction of 1.47 and 1.63 urinary incontinence and 1.66 and 1.75 urinary voids per 24 h in the 50 and 100 mg dose groups, respectively, compared to 1.13 and 1.05 in the placebo group (p<0.05); and a significant reduction in urinary output in the 50 and 100 mg dose groups. There was also a significant improvement in urinary output in the 50 and 100 mg dose groups, with a mean increase of 18.2 and 18.0 mL, respectively, compared to 7.0 mL in the placebo group (p < 0.05). The incidence of adverse reactions was similar in the two dose groups (51.6%, 46.9%, and 50.1%), with hypertension (6.1%, 4.9%, and 6.6%), urinary tract infection (2.7%, 3.7%, and 1.8%), headache (3.2%, 3.0%, and 2.0%), and nasopharyngitis (3.4%, 2.5%, and 2.9%), mouth Similar results were obtained in another similar phase III clinical trial done by Khullar et al. in Europe and Australia, and that study also established 4 mg of tolterodine extended-release tablets as a control group, which showed superior improvement in the mirabellum group compared to the tolterodine group and no adverse effects of dry mouth, and no significant differences in the incidence of hypertension and urinary tract infections. Van et al. found that 25 mg of mirabellum was also effective in improving OAB symptoms in patients. Ohlstein et al. used a multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of sorabelone in the treatment of 258 female patients with moderate to severe OAB (mean of 4.5 episodes of urinary incontinence per day) [38]. After 8 weeks of treatment, patients in the 125 mg sorabelon treatment group showed significant improvements in the number of incontinences, frequency and volume of urination per voiding, with no cases of urinary retention. The most common adverse effects included headache and nasopharyngitis. No significant changes in parameters of the cardiovascular system were observed by 24-hour monitoring of patients’ ambulatory blood pressure, blood chemistry, hematology, and electrocardiogram parameters. 6.Conclusion As a new drug for the treatment of OAB, β-3AR agonist is not only effective, but also safe and well tolerated, and has a broad application prospect. With the in-depth research on β-3AR agonists, more novel and efficient β-3AR agonists will be used for the treatment of OAB, which will become a major breakthrough in the treatment of OAB. However, the specific mechanism of β3AR agonist-mediated detrusor diastole has not been fully elucidated; the efficacy and safety of β-3AR agonists are yet to be studied in larger and long-term studies, especially cardiovascular adverse effects; the interactions that occur when combined with drugs that treat relatively narrow index CYP2D6 substrates; the efficacy of combining β-3AR agonists with antimuscarinic drugs, etc.