Seratrodast

Seratrodast
Systematic (IUPAC) name
7-Phenyl-7-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)heptanoic acid
Clinical data
Trade names SeradAir (India), Seretra (India), Bronica (Japan),[1] Changnuo (China), Mai Xu Jia (China), Quan Kang Nuo (China)
AHFS/Drugs.com International Drug Names
Routes of
administration		 Oral
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Protein binding >96%
Biological half-life 22 hours
Identifiers
CAS Number 112665-43-7 YesY
ATC code R03DX06 (WHO)
PubChem CID 2449
ChemSpider 2355 N
UNII 4U58JM421N YesY
KEGG D01123 YesY
Chemical data
Formula C22H26O4
Molar mass 354.43 g/mol
 NYesY (what is this?)  (verify)

Seratrodast (INN) is a thromboxane A2 (TXA2) receptor (TP receptor) antagonist used primarily in the treatment of asthma.[2][3] It was the first TP receptor antagonist that was developed as an anti-asthmatic drug and received marketing approval in Japan in 1997.[4] Seratrodast is currently marketed in Japan,[5] China[6] and India[7] (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.[8] Seratrodast has no effect on prothrombin time and activated partial thromboplastin time, thus ruling out any action on blood coagulation cascade.[9]

Pharmacodynamics

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:

Airway smooth muscle contraction

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.[10][11][12] 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.[11][12] In studies, Seratrodast competitively inhibited the contractile response to the TXA2 mimetic (analogue), PGD2, 9α,11β-PGF2 and PGF2α.[13] 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).[13]

Vascular smooth muscle contraction

Activation of vascular TP receptors has been observed to invariably induce vasoconstriction.[14] The same has been illustrated by in vitro potency and efficacy of TXA2 in inducing constriction of internal mammary arteries.[15] Seratrodast competitively inhibited the contractile response to TXA2 mimetic (analogue) in guinea pig lung parenchymal strips and dog saphenous vein strips.[13] 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.[16]

Pathophysiological processes in asthma mediated via TP receptors

Plasma extravasation

TXA2 and PGF2α potently induce plasma exudation in airways.[17] 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.[17]

Neuromodulatory effects

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.[18] TXA2 has also been implicated in acting presynaptically to enhance the release or duration of release of acetylcholine, a potent bronchoconstrictor, from cholinergic nerves.[18]

Mucous secretion

Prostanoids such as PGF2α and PGD2 have been observed to significantly increase mucous glycoprotein release,[19][20] while TXA2 has been shown to increase tracheal mucous gel layer.[21] 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.[21]

Smooth muscle proliferation

TXA2 elicits the proliferation of human airway smooth muscle cells as well as vascular smooth muscle cells,[22][23] thus participating in airway smooth muscle hypertrophy and hyperplasia.[24]

Airway hyper-responsiveness

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.[25] The airway mucosal edema due to plasma exudation and the smooth muscle proliferation contribute to thickening of the airway wall [25] 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.[25]

In addition to inhibition of actions of prostanoids, TP receptor antagonism has been shown to prevent increased airway reactivity to allergens,[26] PAF,[27] LTC4, D4,[28][29] and B4,[30] bradykinin,[31] endothelin,[32] endotoxin,[33] and ozone.[34]

Pharmacokinetics

The pharmacokinetics of Seratrodast have been studied in Japanese and Caucasian, including Indian, healthy volunteers.[35][36][37][38] 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.[35] Steady state plasma concentrations of seratrodast are reached within 4–5 days.[37] 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.[35][37] Approximately 20% of the administered dose is recovered in the urine, with 60% of the urinary recovery being in the form of conjugates [36]

Dosage and administration

Recommended dosage

The average recommended dose of Seratrodast is 80 mg once daily.[39] 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.[39]

Pregnancy and lactation

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.[39] Seratrodast should not be used during lactation.[39]

Pediatric use

The safety and efficacy of Seratrodast has not been established in children (< 18 years of age).[39]

Clinical experience

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.

Asthma

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.[40][41][42][43][44] 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).[40] With respect to the levels of various biochemical parameters of sputum, seratrodast showed significant reduction in sputum fucose,[40][45] eosinophil cationic protein (ECP) [40][46] and albumin levels.[40][45] The decrease in sputum ECP and albumin levels with seratrodast was found to be better than Montelukast [40] 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%).[41] 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.[46] 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.[45] 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).[47]

Perennial allergic rhinitis

Seratrodast has been observed to show improvement in nasal obstruction, nasal discharge and sneezing in patients with allergic rhinitis.[48][49][50][51][52][53][54][55] Improvement rates of nasal obstruction, nasal discharge and sneezing with Seratrodast (80 mg/day) were found to be better than terfenadine (120 mg/day).[48] 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.[50] Dose dependent increase in improvement rates of nasal symptoms has been observed with Seratrodast,[51] with equivalent efficacy of 80 mg/day and 120 mg/day dosage of Seratrodast.[52] Seratrodast (80 mg o.d.) administered over 4 weeks was found to significantly improve nasal volume and cross-sectional area.[54] 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.[53]

Chronic bronchitis

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.[56]

COPD

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.[57] Plasma levels of 11-dehydro-TXB2 were also observed to decrease significantly by the end of 8 weeks.[57]

Smoker's cough

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.[58][59]

Safety and tolerability

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.[39] Less than 0.1% of patients experienced vomiting, thrombocytopenia, epistaxis, bleeding tendency, insomnia, tremor, numbness, hot flushes and edema.[39] All the adverse reactions reported were of mild to moderate severity, and resolved when the drug was discontinued.[39]

In clinical studies with Seratrodast, no significant difference was observed in the incidence of adverse events when compared with Montelukast.[40] Global assessment towards the therapy with Seratrodast was deemed as “satisfactory-to-excellent” by the investigators.[40] No difference in overall drug compliance was observed with Seratrodast when compared with Montelukast (99.02% vs. 98.06%).[40]

Synthesis

Seratrodast can be prepared in five steps starting from pimelic acid monoester.[60]

References

  1. ↑ Seratrodast, Kyoto Encyclopedia of Genes and Genomes drug database
  2. ↑ Endo S, Akiyama K (November 1996). "[Thromboxane A2 receptor antagonist in asthma therapy]". Nippon Rinsho (in Japanese) 54 (11): 3045–8. PMID 8950952.
  3. ↑ Hada S, Hashizume M, Nishii S, Yoshioka F, Yasunaga K (January 1993). "[Study on the inhibitory effect of AA-2414 on platelet aggregation and its clinical effect in asthmatic patients]". Arerugi (in Japanese) 42 (1): 18–25. PMID 8457165.
  4. ↑ Dogné JM, de Leval X, Benoit P, Delarge J, Masereel B (2002). "Thromboxane A2 inhibition: therapeutic potential in bronchial asthma". Am J Respir Med 1 (1): 11–7. doi:10.1007/bf03257158. PMID 14720071.
  5. ↑ Bronica tablets, Takeda Pharmaceutical Co. Ltd., Japan
  6. ↑ Changnuo granules, Chia Tai Tianqing Pharm, China
  7. ↑ Seretra tablets, Zuventus Healthcare Ltd., India
  8. ↑ Dogné JM, Hanson J, de Leval X, Kolh P, Tchana-Sato V, de Leval L, Rolin S, Ghuysen A, Segers P, Lambermont B, Masereel B, Pirotte B (2004). "Pharmacological characterization of N-tert-butyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a novel thromboxane A2 receptor antagonist and thromboxane synthase inhibitor in a rat model of arterial thrombosis and its effects on bleeding time". J Pharmacol Exp Ther 309 (2): 498–505. doi:10.1124/jpet.103.063610. PMID 14742735.
  9. ↑ Samara EE. "Seratrodast (AA-2414)—A Novel Thromboxane-A2 Receptor Antagonist". Cardiovascular Drug Reviews 14 (3): 272–85. doi:10.1111/j.1527-3466.1996.tb00231.x.
  10. ↑ Beasley R, Varley I, Robinson C, Holgate ST (1987). "Cholinergic mediated bronchoconstriction induced by prostaglandin (PG)D2 and its initial metabolite 9α,11β-PGF2 and PGF2α in asthma". Am Rev Respir Dis 136 (5): 1140–4. doi:10.1164/ajrccm/136.5.1140. PMID 2960256.
  11. 1 2 Coleman RA, Sheldrick RLG (1989). "Prostanoid-induced contraction of human bronchial smooth muscle is mediated by TP receptors". Br J Pharmacol 96 (3): 688–92. doi:10.1111/j.1476-5381.1989.tb11869.x. PMC 1854400. PMID 2720298.
  12. 1 2 Featherstone RL, Robinson C, Holgate ST, Church MK (1990). "Evidence for thromboxane receptor mediated contraction of guinea-pig and human airways in vitro by prostaglandin (PG)D2, 9α,11β-PGF2 and PGF2α". Naunyn Schmiedebergs Arch Pharmacol 341 (5): 439–43. doi:10.1007/bf00176337. PMID 2142256.
  13. 1 2 3 Beasley RC, Featherstone RL, Church MK, Rafferty P, Varley JG, Harris A, Robinson C, Holgate ST (1989). "Effect of a thromboxane receptor antagonist on PGD2- and allergen-induced bronchoconstriction". J Appl Physiol 66 (4): 1685–93. PMID 2525122.
  14. ↑ Devillier P, Bessard G (1997). "Thromboxane A2 and related prostaglandins in airways". Fundam Clin Pharmacol 11 (1): 2–18. doi:10.1111/j.1472-8206.1997.tb00163.x. PMID 9182072.
  15. ↑ He GW, Rosenfeldt FL, Buxton BF, Angus JA (1989). "Reactivity of human isolated internal mammary artery to constrictor and dilator agents". Circulation 80 (3 Pt 1): I141–50. PMID 2766521.
  16. ↑ Shirai M, Ninomiya I, Sada K (1992). "Thromboxane A2/endoperoxide receptors mediate cholinergic constriction of rabbit lung microvessels". J Appl Physiol 72 (3): 1179–85. PMID 1533210.
  17. 1 2 Lotvall J, Elwood W, Tokuyama K, Sakamoto T, Barnes PJ, Chung KF (1992). "A thromboxane mimetic, U-46619, produces plasma exudation in airways of the guinea pig". J Appl Physiol 72 (6): 2415–9. PMID 1385805.
  18. 1 2 Barnes PI (1986). "Am Rev Respir Dis". The American review of respiratory disease 134 (6): 1289–314. PMID 3538958.
  19. ↑ Marom Z, Shelhamer JH, Kaliner M (1981). "Effects of arachidonic acid, monohydroxyeicosatetraenoic acid and prostaglandins on the release of mucous glycoproteins from human airways in vitro". J Clin Invest 67 (6): 1695–702. doi:10.1172/JCI110207. PMC 370746. PMID 6787082.
  20. ↑ Rich B, Peatfield AC, Williams IP, Richardson PS (1984). "Effects of prostaglandins E1, E2 and F2 alpha on mucin secretion from human bronchi in vitro". Thorax 39 (6): 420–3. doi:10.1136/thx.39.6.420. PMC 459823. PMID 6589806.
  21. 1 2 Yanni JM, Smith WL, Foxwell MH (1988). "U46619 and carbocyclic thromboxane A2-induced increases in tracheal mucous gel layer thickness". Prostaglandins Leukot Essent Fatty Acids 32 (1): 45–9. doi:10.1016/0952-3278(88)90093-2. PMID 3387452.
  22. ↑ Morinelli TA, Zhang LM, Newman WH, Meier KE (1994). "Thromboxane A/Prostaglandin H2-stimulated mitogenesis of coronary artery smooth muscle cells involves activation of mitogen-activated protein kinase and S6 kinase". J Biol Chem 269 (8): 5693–8. PMID 8119906.
  23. ↑ Tomlinson PR, Wilson JW, Stewart AG (1994). "Inhibition by salbutamol of the proliferation of human airway smooth muscle cells grown in culture". Br J Pharmacol 111 (2): 641–7. doi:10.1111/j.1476-5381.1994.tb14784.x. PMC 1909958. PMID 7911722.
  24. ↑ Stewart AG, Tomlinson PR, Wilson J (1993). "Airway wall remodeling in asthma: a novel target for the development of antiasthma drugs". Trends Pharmacol Sci 14 (7): 275–9. doi:10.1016/0165-6147(93)90130-c. PMID 8105598.
  25. 1 2 3 O'Byrne PM, Fuller RW (1989). "The role of thromboxane A2 in the pathogenesis of airway hyperresponsiveness". Eur Respir J 2 (8): 782–6. PMID 2680585.
  26. ↑ Minoguchi K, Adachi M, Tokunaga H, Gonogami Y, Kouno Y, Kobayashi H, Inoue K, Sakai Y, Honma I, Takahashi T (1993). "Change in responsiveness of airway and beta-adrenoceptor in guinea pigs". Arerugi 42 (4): 556–63. PMID 8391794.
  27. ↑ Chung KF, Aizawa H, Leikauf GD, Ueki IF, Evans TW, Nadel JA (1986). "Airway hyperresponsiveness induced by platelet-activating factor: role of thromboxane generation". J Pharmacol Exp Ther 236 (3): 580–4. PMID 3005546.
  28. ↑ Muccitelli RM, Osborn RR, Weichman BM (1983). "Effect of inhibition of thromboxane production on the leukotriene D4-mediated bronchoconstriction in the guinea pig". Prostaglandins 26 (2): 197–206. doi:10.1016/0090-6980(83)90088-6. PMID 6689082.
  29. ↑ Kurosawa M, Tsukagoshi H (1993). "Inhibitory effect of a thromboxane A2 synthetase inhibitor OKY-046 on bronchial hyperresponsiveness to histamine, but not on airway wall thickening, induced by intravenous administration of leukotriene C4 in guinea-pigs". Pulm Pharmacol 6 (4): 247–53. doi:10.1006/pulp.1993.1033. PMID 8148578.
  30. ↑ O'Byrne PM, Leikauf GD, Aizawa H, Bethel RA, Ueki IF, Holtzman MJ, Nadel JA (1985). "Leukotriene B4 induces airway hyperresponsiveness in dogs". J Appl Physiol 59 (6): 1941–6. PMID 3001017.
  31. ↑ Ueno A, Tanaka K, Katori M (1982). "Possible involvement of thromboxane in bronchoconstrictive and hypertensive effects of LTC4 and LTD4 in guinea pigs". Prostaglandins 23 (6): 865–80. doi:10.1016/0090-6980(82)90130-7. PMID 7122910.
  32. ↑ Ninomiya H, Yu XY, Hasegawa S, Spannhake EW (1992). "Endothelin-1 induces stimulation of prostaglandin synthesis in cells obtained from canine airways by bronchoalveolar lavage". Prostaglandins 43 (5): 401–11. doi:10.1016/0090-6980(92)90124-c. PMID 1584994.
  33. ↑ Held HD, Uhlig S (2000). "Mechanisms of endotoxin-induced airway and pulmonary vascular hyperreactivity in mice". Am J Respir Crit Care Med 162 (=4 Pt 1): 1547–52. doi:10.1164/ajrccm.162.4.9912079. PMID 11029375.
  34. ↑ Aizawa H, Chung KF, Leikauf GD, Ueki I, Bethel RA, O'Byrne PM, Hirose T, Nadel JA (1985). "Significance of thromboxane generation in ozone-induced airway hyperresponsiveness in dogs". J Appl Physiol 59 (6 pages=1918–23): 1918–23. PMID 3935642.
  35. 1 2 3 An open-labeled, randomized, cross-over bioequivalence study of Seratrodast 80mg under fasting condition. Data on file (appears on website on Seretra)
  36. 1 2 Hiraga K, Tateno M (1993). "The clinical phase I study of AA-2414, a thromboxane A, receptor antagonist – repeated-dose study at 160 mg once daily for 7 days". Clin Pharmacol 9 (Suppl. 8): 41–55.
  37. 1 2 3 Hussein Z, Samara E, Locke CS, Orchard MA, Ringham GL, Granneman GR (1994). "Characterization of the pharmacokinetics and pharmacodynamics of a new oral thromboxane A2-receptor antagonist AA-2414 in normal subjects: population analysis". Clin Pharmacol Ther 55 (4): 441–50. doi:10.1038/clpt.1994.54. PMID 8162671.
  38. ↑ Samara E, Qian J, Locke CS, Granneman R, Dean R, Killian A (1996). "Single-dose and steady-state pharmacokinetics of seratrodast in healthy male and female volunteers". Pharmac Res 13 (Suppl. 9).
  39. 1 2 3 4 5 6 7 8 Prescribing information of Bronica, Takeda Pharmaceuticals Co. Ltd., Japan
  40. 1 2 3 4 5 6 7 8 9 A Multi-centric, Double blind, Randomized, Comparative Clinical trial to Evaluate the Efficacy and Safety of Seratrodast 80 mg as compared to Montelukast 10 mg in the treatment of Asthma. Data on file (appears on website on Seretra).
  41. 1 2 Yin K, Cay Y, Xia X, Chen G, Sun T (2004). "A Double-Blind Randomized Clinical Study in Multiple-Centre Comparing The Effect Of Seratrodast On Asthma With Zafirlukast". J Jiangsu Clin Med (2).
  42. ↑ Li X, Zhao J, Lou Y, Chen H, Zhu D, Tu J (2006). "Seratrodast in treatment of 107 patients with asthma". Chin J New Drugs Clin Rem 25 (10): 729–733.
  43. ↑ Tanaka H, Igarashi T, Saitoh T, Teramoto S, Miyazaki N, Kaneko S, Ohmichi M, Abe S (1999). "Can urinary eicosanoids be a potential predictive marker of clinical response to thromboxane A2 receptor antagonist in asthmatic patients?". Respir Med 93 (12): 891–7. doi:10.1016/s0954-6111(99)90055-0. PMID 10653051.
  44. ↑ Samara E, Cao G, Locke C, Granneman GR, Dean R, Killian A (1997). "Population analysis of the pharmacokinetics and pharmacodynamics of seratrodast in patients with mild to moderate asthma". Clin Pharmacol Ther 62 (4): 426–35. doi:10.1016/S0009-9236(97)90121-1. PMID 9357394.
  45. 1 2 3 Tamaoki J, Kondo M, Nakata J, Nagano Y, Isono K, Nagai A (2000). "Effect of a thromboxane A2 antagonist on sputum production and its physicochemical properties in patients with mild to moderate asthma". Chest 118 (1): 73–9. doi:10.1378/chest.118.1.73. PMID 10893362.
  46. 1 2 Fukuoka T, Miyake S, Umino T, Inase N, Tojo N, Yoshizawa Y (2003). "The effect of Seratrodast on eosinophil cationic protein and symptoms in asthmatics". J Asthma 40 (3): 257–64. doi:10.1081/jas-120018322. PMID 12807169.
  47. ↑ Baba K, Sakakibara A, Yagi T, Niwa S, Wakayama H, Takagi K (2002). "Long-term observations of the clinical course after step down of corticosteroid inhalation therapy in adult chronic asthmatics: correlation with serum levels of eosinophil cationic protein". Respirology 7 (3): 255–66. doi:10.1046/j.1440-1843.2002.00389.x. PMID 12153692.
  48. 1 2 Sakakura Y, Unno T, Tasaka T, Baba K, Oyama M, Ogawa N (1991). "Clinical Evaluation of Seratrodast, a Thromboxane A2 Antagonist, in Patients with Perennial Allergic Rhinitis. Multi-center Comparative Double-blind Test with Terfenadine". J Clin Ther Med 15 (2): 267–307.
  49. ↑ Ishikawa T, Unno T, Baba K, Sakakura Y, Oyama M (1991). "A Study on Efficacy and Safety of 20 mg/day, 40 mg/day, 80 mg/day of Seratrodast, a Thromboxane A2 Receptor Antagonist on Perennial Allergic Rhinitis Patients. An Early Phase II Study". J Clin Ther Med 15 (2): 147–82.
  50. 1 2 Unno T, Kawabori S, Kaga K, Ichimura K, Sakakura Y, Ukai K, Mogi G (1991). "Effect of Combination Therapy with Seratrodast and Mequitazine on Perennial Allergic Rhinitis". J Clin Ther Med 15 (2): 309–37.
  51. 1 2 Sakakura Y, Unno T, Takasaka T, Baba K, Oyama M, Ogawa N (1991). "Dose Finding Study of Seratrodast, a Thromboxane A2 Antagonist, in Patients with Perennial Allergic Rhinitis. A Multi-center, Double-blind Comparative Study". J Clin Ther Med 15 (2): 213–45.
  52. 1 2 Unno T, Kawabori S, Kaga K, Ichimura K (1991). "Study on Administration of 80 mg/day and 120 mg/day of Seratrodast in Perennial Allergic Rhinitis Patients". J Clin Ther Med 15 (2): 247–66.
  53. 1 2 Yajin K, Hirakawa K, Takebayashi S, Omura R, Yamashita T, Watanabe H, Tada W, Nikaido M, Nagasawa A (1991). "Clinical Evaluation on 12-week Administration of Seratrodast, a Thromboxane A2 Antagonist, in Perennial Allergic Rhinitis". J Clin Ther Med 15 (2): 373–88.
  54. 1 2 Sakakura Y, Unno T, Ichimura K, Kase Y, Ukai K, Yamagiwa M, Nonaka S, Fujita T, Fujita K (1991). "J Clin Ther Med" 15 (2): 183–211.
  55. ↑ Masuda Y, Ogawara T, Akagi S, Saito C, Takehisa T, Sasaki O, Iguchi I, Aochi K, Nagano T (1991). "Efficacy and Safety on 12-week Administration of Seratrodast, a Thromboxane A2 Antagonist, in Patients with Perennial Allergic Rhinitis". J Clin Ther Med 15 (2): 355–71.
  56. ↑ Ishiura Y, Fujimura M, Yamamori C, Nobata K, Myou S, Kurashima K, Takegoshi T (2003). "Thromboxane antagonism and cough in chronic bronchitis". Annals of Medicine 35 (2): 135–9. doi:10.1080/07853890310010032. PMID 12795341.
  57. 1 2 Horiguchi T, Tachikawa S, Kondo R, Shiga M, Hirose M, Fukumoto K (2002). "Study on the usefulness of Seratrodast in the treatment of chronic pulmonary emphysema". Arzneimittelforschung 52 (10): 764–8. doi:10.1055/s-0031-1299963. PMID 12442639.
  58. ↑ An J, Li JQ, Wang T, Li XO, Guo LL, Wan C, Liao ZL, Dong JJ, Xu D, Wen FQ. (2013). "Blocking of thromboxane A(2) receptor attenuates airway mucus hyperproduction induced by cigarette smoke". Eur J Pharmacol 703 (1–3): 11–7. doi:10.1016/j.ejphar.2013.01.042. PMID 23399768.
  59. ↑ Wordpress Seretra Blog
  60. ↑ Shiraishi M, Kato K, Terao S, Ashida Y, Terashita Z, Kito G (September 1989). "Quinones. 4. Novel eicosanoid antagonists: synthesis and pharmacological evaluation". Journal of Medicinal Chemistry 32 (9): 2214–21. doi:10.1021/jm00129a030. PMID 2769691.
This article is issued from Wikipedia - version of the Saturday, April 02, 2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.