Seratrodast (development name, AA-2414; marketed originally as Bronica) is a thromboxane A₂ (TXA₂) receptor (TP receptor) antagonist used primarily in the treatment of

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, c ...

. It was the first TP receptor antagonist that was developed as an anti-asthmatic drug and received marketing approval in Japan in 1997. As of 2017 seratrodast was marketed as Bronica in Japan, and as Changnuo, Mai Xu Jia, Quan Kang Nuo in China. Unlike

thromboxane synthase Thromboxane A synthase 1 (, platelet, cytochrome P450, family 5, subfamily A), also known as TBXAS1, is a cytochrome P450 enzyme that, in humans, is encoded by the ''TBXAS1'' gene. Function This gene encodes a member of the cytochrome P450 supe ...

inhibitors such as

ozagrel Ozagrel (INN) is an antiplatelet agent working as a thromboxane A2 Thromboxane A2 (TXA2) is a type of thromboxane that is produced by activated platelets during hemostasis and has prothrombotic properties: it stimulates activation of new platel ...

, seratrodast does not affect

thrombus A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cr ...

formation, time to occlusion and

bleeding time Bleeding time is a medical test done on someone to assess their platelets function. It involves making a patient bleed, then timing how long it takes for them to stop bleeding using a stopwatch or other suitable devices. The term template bleed ...

. Seratrodast has no effect on

prothrombin time The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the ''extrinsic'' pathway and common pathway of coagulation. This blood test is al ...

and

activated partial thromboplastin time The partial thromboplastin time (PTT), also known as the activated partial thromboplastin time (aPTT or APTT), is a blood test that characterizes coagulation of the blood. A historical name for this measure is the kaolin-cephalin clotting time ( ...

, thus ruling out any action on

blood coagulation Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechani ...

cascade.

Medical uses

Seratrodast is used to treat asthma. 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).

Contraindications and interactions

Seratrodast should not be used in people with liver disease. Use with

paracetamol Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol. At a standard dose, paracetamol only slightly decreases body temperature; it is inferi ...

or with

cephem Cephems are a sub-group of β-lactam antibiotics including cephalosporin The cephalosporins (sg. ) are a class of β-lactam antibiotics originally derived from the fungus '' Acremonium'', which was previously known as ''Cephalosporium''. T ...

antibiotics increases the risk of liver damage. Use with

aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat in ...

increases the bioavailability of seratrodast.

Adverse effects

The most frequently observed (0.1 to 5%) adverse reactions include

elevated transaminases In medicine, the presence of elevated transaminases, commonly the transaminases alanine transaminase (ALT) and aspartate transaminase (AST), may be an indicator of liver dysfunction. Other terms include transaminasemia, transaminitis, and elevat ...

, 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.

Pharmacology

Thromboxane A2 Thromboxane A2 (TXA2) is a type of thromboxane that is produced by activated platelets during hemostasis and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by act ...

(TXA₂) is generated in the lungs of people with asthma, and when it signals through the

thromboxane receptor The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the ''TBXA2R'' gene, The thromboxane receptor is one among the five classes of prostanoid receptors and was the first eicosanoid re ...

it causes

bronchoconstriction Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath. Causes The condition has a number of causes, the most common bei ...

vasoconstriction Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood ve ...

mucous Mucus ( ) is a slippery aqueous secretion produced by, and covering, mucous membranes. It is typically produced from cells found in mucous glands, although it may also originate from mixed glands, which contain both serous and mucous cells. It ...

secretion, and

airway hyper-responsiveness Bronchial hyperresponsiveness (or other combinations with airway or hyperreactivity, BH used as a general abbreviation) is a state characterised by easily triggered bronchospasm (contraction of the bronchioles or small airways). Bronchial hyperresp ...

. Seratrodast inhibits the activity of the

, blocking the effects of TXA₂.

Pharmacokinetics

The pharmacokinetics of seratrodast have been studied in Japanese and Caucasian, including Indian, healthy volunteers.An open-labeled, randomized, cross-over bioequivalence study of Seratrodast 80mg under fasting condition. Data on file (appears on website o
Seretra
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

Chemistry

Seratrodast can be prepared in five steps starting from

pimelic acid Pimelic acid is the organic compound with the formula HO2C(CH2)5CO2H. Pimelic acid is one unit longer than a related dicarboxylic acid, adipic acid, a precursor to many polyesters and polyamides. However compared to adipic acid, pimelic acid i ...

monoester.

History

Seratrodast was the first

thromboxane receptor antagonist The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the ''TBXA2R'' gene, The thromboxane receptor is one among the five classes of prostanoid receptors and was the first eicosanoid rec ...

to reach the market as a treatment for asthma; it was approved in Japan in 1997.

Society and culture

As of 2017 seratrodast was marketed as Bronica in Japan, Changnuo, Mai Xu Jia, Quan Kang Nuo in China and as Seretra & Seradair in India.

Research

Seratrodast was studied in

perennial allergic rhinitis Rhinitis, also known as coryza, is irritation and inflammation of the mucous membrane inside the nose. Common symptoms are a stuffy nose, runny nose, sneezing, and post-nasal drip. The inflammation is caused by viruses, bacteria, irritants o ...

chronic bronchitis Bronchitis is inflammation of the bronchi (large and medium-sized airways) in the lungs that causes coughing. Bronchitis usually begins as an infection in the nose, ears, throat, or sinuses. The infection then makes its way down to the bronchi. ...

and chronic pulmonary emphysema but efforts to bring the drug to market in those indications was abandoned around 2000.

References

{{Prostanoidergics 1,4-Benzoquinones Carboxylic acids