|Systematic (IUPAC) name|
|Trade names||SeradAir (India), Seretra (India), Bronica (Japan), Changnuo (China), Mai Xu Jia (China), Quan Kang Nuo (China)|
|AHFS/Drugs.com||International Drug Names|
|Biological half-life||22 hours|
|CAS Number||112665-43-7 Y|
|ATC code||R03DX06 (WHO)|
|Molar mass||354.43 g/mol|
|NY (what is this?)|
Seratrodast (INN) is a thromboxane A2 (TXA2) receptor (TP receptor) antagonist used primarily in the treatment of asthma. It was the first TP receptor antagonist that was developed as an anti-asthmatic drug and received marketing approval in Japan in 1997. Seratrodast is currently marketed in Japan, China and India (approved in Dec 2012) as an add-on controller therapy in the management of asthma.
Unlike thromboxane synthase inhibitors such as ozagrel, seratrodast does not affect thrombus formation, time to occlusion and bleeding time. Seratrodast has no effect on prothrombin time and activated partial thromboplastin time, thus ruling out any action on blood coagulation cascade.
TXA2 and other bronchoconstrictor prostanoids, like PGD2 and PGF2α, are generated in asthma and participate in acute and chronic inflammatory processes. Seratrodast, being a TP receptor antagonist, inhibits the following pathophysiological processes in asthma:
Ligand binding studies on TP receptors have shown the existence of TP receptors on airway smooth muscle. Experimental studies have indicated that the contractile potency of TXA2 is about two times more potent than other prostaglandins. Experiments utilizing several TP receptor antagonists have further supported the view that not only TXA2 but even PGF2α, PGD2 and its metabolite 9α,11β-PGF2 contract airway smooth muscle via direct stimulation of TP receptors, indicating the involvement of TP receptors in airway smooth muscle contractions. In studies, Seratrodast competitively inhibited the contractile response to the TXA2 mimetic (analogue), PGD2, 9α,11β-PGF2 and PGF2α. Other than inhibition of actions of prostanoids, Seratrodast, when given orally, inhibited bronchoconstriction in guinea pigs induced by leukotriene D4 (LTD4) and platelet activating factor (PAF).
Activation of vascular TP receptors has been observed to invariably induce vasoconstriction. The same has been illustrated by in vitro potency and efficacy of TXA2 in inducing constriction of internal mammary arteries. Seratrodast competitively inhibited the contractile response to TXA2 mimetic (analogue) in guinea pig lung parenchymal strips and dog saphenous vein strips. In anesthetized rabbits, Seratrodast abolished the decrease in internal diameter of small pulmonary arteries in response to TXA2 mimetic (analogue), indicating direct role of activation of TP receptors in vascular smooth muscle contraction.
TXA2 and PGF2α potently induce plasma exudation in airways. Studies have indicated inhibition of PAF- or leukotriene D4 (LTD4)-induced plasma exudation by TP receptor antagonists, suggesting that TXA2 is endogenously released in response to inflammatory mediators other than prostanoids resulting in airway microvascular leakage.
Prostanoids have potent neuromodulatory effects. Experimental studies on isolated arterial preparation have suggested that TXA2 and related prostaglandins may have some vascular effects on adrenergic fibres that have been found to be in close association with bronchial vessels. TXA2 has also been implicated in acting presynaptically to enhance the release or duration of release of acetylcholine, a potent bronchoconstrictor, from cholinergic nerves.
Prostanoids such as PGF2α and PGD2 have been observed to significantly increase mucous glycoprotein release, while TXA2 has been shown to increase tracheal mucous gel layer. Antagonism of TP receptor was not only observed to inhibit the tracheal mucous gel layer response of TXA2, but was also found to attenuate the mucous gel layer response caused by leukotrienes, indicating an indirect link between leukotrienes and TP receptors.
TXA2 elicits the proliferation of human airway smooth muscle cells as well as vascular smooth muscle cells, thus participating in airway smooth muscle hypertrophy and hyperplasia.
The effects of TXA2 and related prostaglandins on plasma exudation, acetylcholine release and smooth muscle proliferation support the potential role of TP receptor stimulation in the pathogenesis of airway hyper-responsiveness. The airway mucosal edema due to plasma exudation and the smooth muscle proliferation contribute to thickening of the airway wall  Plasma exudation leads to liquid filling of the airway interstices formed between luminal epithelial projections, which amplify the luminal narrowing due to airway smooth muscle contraction.
In addition to inhibition of actions of prostanoids, TP receptor antagonism has been shown to prevent increased airway reactivity to allergens, PAF, LTC4, D4, and B4, bradykinin, endothelin, endotoxin, and ozone.
The pharmacokinetics of Seratrodast have been studied in Japanese and Caucasian, including Indian, healthy volunteers. The plasma concentrations of Seratrodast increase with increasing doses. The absorption of Seratrodast is relatively rapid with maximum plasma concentrations of 4.6-6 µg/ml obtained in 3 to 4 hours. Steady state plasma concentrations of seratrodast are reached within 4–5 days. Seratrodast is slowly cleared, mainly by hepatic biotransformation. The drug shows biexponential decay in plasma profiles with a mean elimination half-life of 22 hours. Approximately 20% of the administered dose is recovered in the urine, with 60% of the urinary recovery being in the form of conjugates 
The average recommended dose of Seratrodast is 80 mg once daily. Seratrodast has been well tolerated following repeated once daily oral doses of up to a maximum of 320 mg. In elderly patients it is recommended that the treatment should be started with a lower dose of 40 mg/day.
There are no adequate and well controlled studies of Seratrodast in pregnant women. The drug should be used in pregnancy only if the potential benefits justify the risk to the fetus. Seratrodast should not be used during lactation.
The safety and efficacy of Seratrodast has not been established in children (< 18 years of age).
The efficacy and safety of seratrodast has been established through various clinical studies conducted on over 5000 patients in indications like asthma, perennial allergic rhinitis, chronic bronchitis and chronic pulmonary emphysema.
In various clinical studies, seratrodast improved lung function parameters such as FEV1, FVC and PEF, and clinical symptoms of asthma such as wheezing, shortness of breath, cough, expectoration and chest tightness. The improvement in PEF with seratrodast (80 mg o.d. for 28 days) was found to be significantly greater than Montelukast (10 mg o.d. for 28 days). With respect to the levels of various biochemical parameters of sputum, seratrodast showed significant reduction in sputum fucose, eosinophil cationic protein (ECP)  and albumin levels. The decrease in sputum ECP and albumin levels with seratrodast was found to be better than Montelukast  In a 6-week comparative clinical study with zafirlukast 20 mg, seratrodast was observed to have a better control over asthma compared to zafirlukast (71.68% vs. 62.62%). Seratrodast (80 mg o.d.) administered over 12 weeks was found to decrease airway hyper-responsiveness to acetylcholine with significant improvement in PEF, clinical symptoms of asthma and sputum ECP levels. In a 6-week clinical study with seratrodast (40 mg o.d.), significant decrease in the amount and dynamic viscosity of sputum, and reduction in nasal clearance time of saccharin particle were observed. Long term administration of seratrodast (80 mg o.d.) over 2 years was observed to lessen exacerbation rate of asthma in patient after first 12 months of therapy and reduce the average dose of inhaled beclomethasone dipropionate (iBDP).
Seratrodast has been observed to show improvement in nasal obstruction, nasal discharge and sneezing in patients with allergic rhinitis. Improvement rates of nasal obstruction, nasal discharge and sneezing with Seratrodast (80 mg/day) were found to be better than terfenadine (120 mg/day). Concomitant use with Mequitazine was found to have better impact on nasal symptoms than using Mequitazine alone, though there was no significant difference in improvement rate between concomitant group and Seratrodast group. Dose dependent increase in improvement rates of nasal symptoms has been observed with Seratrodast, with equivalent efficacy of 80 mg/day and 120 mg/day dosage of Seratrodast. Seratrodast (80 mg o.d.) administered over 4 weeks was found to significantly improve nasal volume and cross-sectional area. Long term administration of Seratrodast (80 mg o.d.) over 24 weeks was found to be highly effective in treating allergic rhinitis with significant reduction in nasal obstruction, nasal discharge and sneezing.
In patients with chronic bronchitis, Seratrodast (80 mg o.d. for 4 weeks) was observed to significantly increase the cough threshold compared to placebo, while pranlukast (112.5 mg o.d. for 4 weeks) did not have any impact on the same.
Seratrodast (80 mg o.d.), administered over 8 weeks in patients with chronic pulmonary emphysema, was shown to significantly improve respiratory distress, evaluated on both the Hugh-Jones classification and the Borg scale, with significant improvement in FVC. Plasma levels of 11-dehydro-TXB2 were also observed to decrease significantly by the end of 8 weeks.
There are anecdotal evidences of improvement of cough with once daily dosage of seratrodast. Various experimental studies have been conducted providing fresh evidence for reducing the incidence of smokers cough.
In post-marketing study conducted in over 4000 patients by the innovator, the most frequently observed (0.1 to 5%) adverse reactions were elevated levels of liver enzymes such as ALT, AST, ALP, LDH and γ-GTP, nausea, loss of appetite, stomach discomfort, abdominal pain, diarrhea, constipation, dry mouth, taste disturbance, drowsiness, headache, dizziness, palpitations and malaise. Less than 0.1% of patients experienced vomiting, thrombocytopenia, epistaxis, bleeding tendency, insomnia, tremor, numbness, hot flushes and edema. All the adverse reactions reported were of mild to moderate severity, and resolved when the drug was discontinued.
In clinical studies with Seratrodast, no significant difference was observed in the incidence of adverse events when compared with Montelukast. Global assessment towards the therapy with Seratrodast was deemed as “satisfactory-to-excellent” by the investigators. No difference in overall drug compliance was observed with Seratrodast when compared with Montelukast (99.02% vs. 98.06%).
Seratrodast can be prepared in five steps starting from pimelic acid monoester.