Seldane

テルフェナジン

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/01/23 19:00:43」(JST)

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Terfenadine

Systematic (IUPAC) name
(RS)-1-(4-tert-butylphenyl)-4-{4-[hydroxy(diphenyl)methyl]piperidin-1-yl}-butan-1-ol
Clinical data
Trade names	Seldane, Triludan, Teldane
AHFS/Drugs.com	Multum Consumer Information
MedlinePlus	a600034
Pregnancy cat.	C (US)
Legal status	Withdrawn
Pharmacokinetic data
Protein binding	70%
Half-life	3.5 hours
Identifiers
CAS number	50679-08-8 Y
ATC code	R06AX12
PubChem	CID 5405
IUPHAR ligand	2608
DrugBank	DB00342
ChemSpider	5212 Y
UNII	7BA5G9Y06Q Y
KEGG	D00521 Y
ChEMBL	CHEMBL17157 Y
Chemical data
Formula	C32H41NO2
Mol. mass	471.673 g/mol
SMILES OC(c1ccccc1)(c2ccccc2)C4CCN(CCCC(O)c3ccc(cc3)C(C)(C)C)CC4
InChI InChI=1S/C32H41NO2/c1-31(2,3)26-18-16-25(17-19-26)30(34)15-10-22-33-23-20-29 (21-24-33)32(35,27-11-6-4-7-12-27)28-13-8-5-9-14-28/ h4-9,11-14,16-19,29-30,34-35H,10,15,20-24H2,1-3H3 N Key:GUGOEEXESWIERI-UHFFFAOYSA-N Y
N (what is this?)  (verify)

Terfenadine was an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel (now Sanofi-Aventis) and marketed under various brand names, including Seldane in the United States, Triludan in the United Kingdom, and Teldane in Australia. According to its manufacturer, terfenadine had been used by over 100 million patients worldwide as of 1990. It was superseded by fexofenadine in the 1990s due to the risk of a particular type of disruption of the electrical rhythms of the heart (specifically cardiac arrhythmia caused by QT interval prolongation).

Terfenadine is a prodrug, generally completely metabolized to the active form fexofenadine in the liver by the enzyme cytochrome P450 CYP3A4 isoform. Due to its near complete metabolism by the liver immediately after leaving the gut, terfenadine normally is not measurable in the plasma. Terfenadine itself, however, is cardiotoxic at higher doses, while its major active metabolite is not. The reason for the differences in cardiotoxicity between Terfenadine and fexofenadine is not fully understood. Toxicity is possible after years of continued use with no previous problems as a result of an interaction with other medications such as erythromycin, or foods such as grapefruit. The addition of, or dosage change in, these CYP3A4 inhibitors makes it harder for the body to metabolize and remove terfenadine. In larger plasma concentrations, it may lead to toxic effects on the heart's rhythm (e.g. ventricular tachycardia and torsades de pointes).

History

In the United States, Seldane was brought to market in 1985 as the first nonsedating antihistamine for the treatment of allergic rhinitis. In June 1990, evidence of serious ventricular arrhythmias among those taking Seldane prompted the FDA to issue a report on the risk factors associated with concomitant use of the drug with macrolide antibiotics and ketoconazole. Two months later, the FDA required the manufacturer to send a letter to all physicians, alerting them to the problem; in July 1992, the existing precautions were elevated to a black box warning and the issue attracted mass media attention in reports that people with liver disease or who took ketoconazole, an antifungal agent, or the antibiotic erythromycin, could suffer cardiac arrhythmia if they also took Seldane.

In January 1997, the same month when the U.S. Food and Drug Administration (FDA) had earlier approved a generic version of Seldane made by IVAX Corporation of Miami, the FDA recommended terfenadine-containing drugs be removed from the market and physicians consider alternative medications for their patients. Seldane (and Seldane-D, terfenadine combined with the decongestant pseudoephedrine) were removed from the U.S. market by their manufacturer in late 1997 after the FDA approval of Allegra-D (fexofenadine/pseudoephedrine). Terfenadine-containing drugs were subsequently removed from the Canadian market in 1999, and are no longer available for prescription in the UK.

References

External links

• Hoechst Marion Roussel Committed to Education Regarding Seldane Usage, an April 30, 1996 press release

English Journal

• Allosteric effects of erythromycin pretreatment on thioridazine block of hERG potassium channels.

• Crumb WJ Jr.Author information Zenas Technologies LLC, New Orleans, LA, USA.AbstractBACKGROUND AND PURPOSE: The prevalence of concurrent use of two or more drugs that block human ether-a-go-go-related gene product (hERG) K(+) channels is not uncommon, but is not well characterized. This study defined the effects of concurrent exposure of two hERG-blocking drugs on hERG current amplitude. Experiments were conducted to determine if concomitant exposure to two potent pore hERG blockers, thioridazine and terfenadine and a weak hERG blocker, erythromycin, would result in an additive, synergistic or inhibitory effect.
• British journal of pharmacology.Br J Pharmacol.2014 Apr;171(7):1668-75. doi: 10.1111/bph.12575.
• BACKGROUND AND PURPOSE: The prevalence of concurrent use of two or more drugs that block human ether-a-go-go-related gene product (hERG) K(+) channels is not uncommon, but is not well characterized. This study defined the effects of concurrent exposure of two hERG-blocking drugs on hERG current ampl
• PMID 24417241

• Surfactant-induced Chronic Pruritus: Role of L-histidine Decarboxylase Expression and Histamine Production in Epidermis.

• Inami Y1, Sasaki A, Andoh T, Kuraishi Y.Author information 1Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.AbstractShampoo and cleansers containing anionic surfactants including sodium dodecyl sulphate (SDS) often cause pruritus in humans. Daily application of 1-10% SDS for 4 days induced hind-paw scratching (an itch-related behaviour) in a concentration-dependent manner, and 10% SDS also caused dermatitis, skin dryness, barrier disruption, and an increase in skin surface pH in mice. SDS-induced scratching was inhibited by the opioid receptor antagonist naloxone and the H histamine receptor antagonist terfenadine. Mast-cell deficiency did not inhibit SDS-induced scratching, although it almost completely depleted histamine in the dermis. Treatment with SDS increased the histamine content of the epidermis, but not that of the dermis. SDS treatment increased the gene expression and post-translation processing of L-histidine decarboxylase in the epidermis. The present results suggest that repeated application of SDS induces itch through increased production of epidermal histamine, which results from an increase in the gene expression and post-translation processing of L-histidine decarboxylase.
• Acta dermato-venereologica.Acta Derm Venereol.2014 Mar 7. doi: 10.2340/00015555-1834. [Epub ahead of print]
• Shampoo and cleansers containing anionic surfactants including sodium dodecyl sulphate (SDS) often cause pruritus in humans. Daily application of 1-10% SDS for 4 days induced hind-paw scratching (an itch-related behaviour) in a concentration-dependent manner, and 10% SDS also caused dermatitis, skin
• PMID 24603881

• Expression and characterization of cynomolgus monkey cytochrome CYP3A4 in a novel human embryonic kidney cell-based mammalian system.

• Selvakumar S1, Bhutani P, Ghosh K, Krishnamurthy P, Kallipatti S, Selvam S, Ramarao M, Mandlekar S, Sinz MW, Rodrigues AD, Subramanian M.Author information 1Pharmaceutical Candidate Optimization (P.B., M.S.) and Applied Biotechnology (Si.S., K.G., P.K., S.K., Sa.S.), Biocon Bristol-Myers Squibb Research and Development Center (BBRC), Syngene International Limited, Plot No. 2 & 3, Bommasandra IV Phase, Bangalore, India; Bristol-Myers Squibb, Wallingford, Connecticut (M.W.S.); Bristol-Myers Squibb, Pennington, New Jersey (A.D.R.); and Bristol-Myers Squibb India Ltd. BBRC, Bangalore, India (M.R., S.M.).AbstractCynomolgus monkeys are a commonly used species in preclinical drug discovery, and have high genetic similarity to humans, especially for the drug-metabolizing cytochrome P450s. However, species differences are frequently observed in the metabolism of drugs between cynomolgus monkeys and humans, and delineating these differences requires expressed CYPs. Toward this end, cynomolgus monkey CYP3A4 (c3A4) was cloned and expressed in a novel human embryonic kidney 293-6E cell suspension system. Following the preparation of microsomes, the kinetic profiles of five known human CYP3A4 (h3A4) substrates (midazolam, testosterone, terfenadine, nifedipine, and triazolam) were determined. All five substrates were found to be good substrates of c3A4, although some differences were observed in the Km values. Overall, the data suggest a strong substrate similarity between c3A4 and h3A4. Additionally, c3A4 exhibited no activity against non-h3A4 probe substrates, except for a known human CYP2D6 substrate (bufuralol), which suggests potential metabolism of human cytochrome CYP2D6-substrates by c3A4. Ketoconazole and troleandomycin showed similar inhibitory potencies toward c3A4 and h3A4, whereas non-h3A4 inhibitors did not inhibit c3A4 activity. The availability of a c3A4 preparation, in conjunction with commercially available monkey liver microsomes, will support further characterization of the cynomolgus monkey as a model to assess CYP3A-dependent clearance and drug-drug interactions.
• Drug metabolism and disposition: the biological fate of chemicals.Drug Metab Dispos.2014 Mar;42(3):369-76. doi: 10.1124/dmd.113.055491. Epub 2013 Dec 13.
• Cynomolgus monkeys are a commonly used species in preclinical drug discovery, and have high genetic similarity to humans, especially for the drug-metabolizing cytochrome P450s. However, species differences are frequently observed in the metabolism of drugs between cynomolgus monkeys and humans, and
• PMID 24335510

Japanese Journal

• Dose-response relation between terfenadine (Seldane) and the QTc interval on the scalar electrocardiogram : distinguishing a drug effect from spontaneous variability

• PRATT CM
• Am Heart J 131, 472-480, 1996
• NAID 30016726106

Related Links

• Terfenadine - Wikipedia, the free encyclopedia

In the United States, Seldane was brought to market in 1985 as the first nonsedating antihistamine for the treatment of ... In June 1990, evidence of serious ventricular arrhythmias among those taking Seldane prompted the FDA to issue a ...

• Seldane (Terfenadine (Removed from market 1998)) Drug ... - RxList

Learn about the prescription medication Seldane (Terfenadine (Removed from market 1998)), drug uses, dosage, side effects, drug interactions, warnings, reviews and patient labeling.

Related Pictures

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★リンクテーブル★

リンク元

「テルフェナジン」

「テルフェナジン」

　　[★]

英

terfenadine

商

トリルダン, Seldane

関

抗ヒスタミン薬

• 第二世代ヒスタミン薬
• 抗アレルギー薬

• 抗ヒスタミン薬

• ピペリジン系

• ヒスタミンH₁受容体拮抗作用
• 化学伝達物質遊離抑制作用
• ロイコトリエン拮抗作用
• 販売停止

副作用

• QT延長、心房性不整脈(torsades de pointes)を起こし、心停止を起こしうる
• テルフェナジンはプロドラッグであり、99.5%がすぐ代謝されフェキソフェナジンとなる
• 代謝が滞るとテルフェナジンは電位依存性Kチャネルを抑制するので危険。
• テルフェナジン代謝酵素はCYP3A4で代謝されるので、これを阻害する薬物(CYP3A4と親和性の高い薬物)との併用は危険

• イトコナゾール、ミコナゾール、抗真菌剤、マクロライド抗生物質、ドセタキセル、パクリタキセル
• 肝障害、グレープフルーツ

• 服用に注意を要するのはQT延長をおこしやすい人

• 低K血症
• 低Mg血症
• 先天性QT延長症候群