Disease relevance of Seldane

• Two of the nonsedating antihistaminic drugs, terfenadine and astemizole, have recently been recognized in rare cases to induce the syndrome of torsades de pointes, i.e. QT interval prolongation and life-threatening ventricular tachycardia [1].
• Torsades de pointes occurring in association with terfenadine use [2].
• The Kd value for HERG block is relevant to the toxicity of the antihistamine, since the clinical terfenadine concentrations in human plasma may reach the 100 nmol/L range [3].
• BACKGROUND: Administration of the antihistamine terfenadine (Seldane) to patients may result in acquired long QT syndrome and ventricular arrhythmias [3].
• The high-affinity interaction of terfenadine with the inactivated state of L-type Ca2+ channels may play an important role in its cardiotoxicity under pathophysiological conditions, such as ischemia [4].

Psychiatry related information on Seldane

• Hydroxyzine, but not terfenadine, significantly prolonged both simple and choice reaction time (p less than or equal to 0.0001) [5].
• Patients were given a brief neuropsychological test battery before and after double-blind treatment with terfenadine or placebo and completed a daily mood rating scale (Positive and Negative Affect Schedule) during the study [6].
• No therapeutic benefit from terfenadine could be detected in terms of symptom amelioration, improved physical or social functioning, health perceptions, or mental health [7].
• Terfenadine neither impairs psychomotor performance nor adversely affects subjective feelings, nor enhances the depressant effects of concomitantly administered alcohol or benzodiazepines [8].
• These effects appear to be caused by different mechanisms, but both may have potentially dangerous consequences. while several of the newer antihistamines, such as terfenadine, have overcome the problem of sedation, it is also important to establish their propensity to cause psychomotor impairment [9].

High impact information on Seldane

• OBJECTIVES AND METHODS--To gain insight into possible mechanisms of and predisposing factors for torsades de pointes during terfenadine therapy, spontaneous reports in the US Food and Drug Administration's Spontaneous Reporting System database were examined [10].
• OBJECTIVE--To examine prospectively the effects of ketoconazole on the pharmacokinetics and electrocardiographic repolarization pharmacodynamics (corrected QT intervals) of terfenadine in men and women [11].
• In vitro studies found that terfenadine is equipotent to quinidine as a blocker of the delayed rectifier potassium current in isolated feline myocytes [10].
• Dosage restriction and awareness of the clinical conditions and drug interactions capable of inhibiting the metabolism of terfenadine are essential for prevention of this serious reaction [10].
• An H1-receptor antagonist, terfenadine (60 mg), protected against the bronchoconstrictor effect but had no significant influence on the increase in permeability [12].

Chemical compound and disease context of Seldane

• CONCLUSION: After oral administration, fexofenadine provided better protection than terfenadine against the immediate allergic reaction [13].
• Terfenadine is a nonsedating H1-antagonist that when overdosed, used with hepatic compromise, or when given with ketoconazole results in accumulation of parent terfenadine, prolongation of the QT interval, and torsades de pointes in susceptible patients [14].
• Patients entered a single-blind placebo period, and if hives of moderate severity were present for at least 3 days during the week, they were randomly assigned in a double-blind fashion to take terfenadine, 60 mg twice daily, chlorpheniramine, 4 mg three times a day, or placebo for 6 weeks [15].
• Prolongation of simple and choice reaction times in a double-blind comparison of twice-daily hydroxyzine versus terfenadine [5].
• Regarding local reactions, significantly fewer patients treated with a combination of terfenadine and ranitidine and with terfenadine alone as compared with placebo had severe local symptoms of erythema (29%, 29%, and 49%), edema (24%, 18%, and 41%), and pruritus (13%, 11%, and 31%) at week 1 (p < 0.05) [16].

Biological context of Seldane

• Astemizole and terfenadine potently blocked the rapidly activating component of the delayed rectifier, IKr, with IC50 values of 1.5 and 50 nmol/L, respectively [17].
• Astemizole and terfenadine significantly increased action potential duration of guinea pig myocytes [17].
• Compared with placebo, all antihistamines provided significant protection against histamine-induced bronchoconstriction when measured as the provocation concentration required to cause a 20% fall in FEV1; terfenadine and cetirizine provided significantly greater protection than other antihistamines [18].
• CONCLUSIONS: Administration of grapefruit juice concomitantly with terfenadine may lead to an increase in systemic terfenadine bioavailability and result in increases in QT interval [19].
• We used a nonsedating, selective histamine H1-receptor antagonist, terfenadine, to investigate the effects of antihistamines on the microcirculatory changes and vascular permeability induced by topical histamine provocation challenge [20].

Anatomical context of Seldane

• METHODS AND RESULTS: We therefore heterologously expressed Kv1.5 and HERG in Xenopus oocytes to compare the sensitivity of each to terfenadine [3].
• A greater percentage of fluticasone-treated patients compared with either terfenadine- or placebo-treated patients experienced reductions in intranasal eosinophil and basophil counts after 2 weeks of therapy [21].
• Cetirizine passed into the central nervous system only half as readily as terfenadine [22].
• Hydroxyzine and dexchlorpheniramine and, to a lesser extent, terfenadine crossed the blood-brain barrier in significant amounts [22].
• We also compared terfenadine blockade of fHK (Kv1.5a) currents stably expressed in a human embryonic kidney cell line with terfenadine blockade of IKur in human atrial myocytes [23].

Associations of Seldane with other chemical compounds

• Both astemizole and terfenadine suppressed the IK1 channel by 17% to 50% in a voltage-dependent manner in rat and guinea pig myocytes [24].
• CONCLUSIONS: Terfenadine carboxylate, the major metabolite of terfenadine, does not block either HERG or Kv1.5, which agrees with the hypothesis that the buildup of parent terfenadine is the likely explanation for its cardiotoxicity [3].
• More tachyphylaxis to histamine was shown by the subjects taking terfenadine, as demonstrated by a larger increase in skin sensitivity over the study period [25].
• Pharmacokinetics and pharmacodynamics of terfenadine and chlorpheniramine in the elderly [26].
• Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin [14].

Gene context of Seldane

• Surprisingly, with expressed CYP3A4, terfenadine (20 microM) inhibited MDZ 1'-OH formation [27].
• Based on this substrate structure-activity relationship, computer modeling studies were undertaken to explore the likely interactions of terfenadine with CYP2D6 [28].
• There was no notable inhibition of terfenadine metabolism or of any of the isoforms of cytochrome P450 (CYP1A1/2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4) by Z-338 in in vitro studies using human liver microsomes [29].
• Drug-drug interactions of Z-338, a novel gastroprokinetic agent, with terfenadine, comparison with cisapride, and involvement of UGT1A9 and 1A8 in the human metabolism of Z-338 [29].
• Human cytochrome P450 3A (CYP3A) mediated midazolam metabolism: the effect of assay conditions and regioselective stimulation by alpha-naphthoflavone, terfenadine and testosterone [27].

Analytical, diagnostic and therapeutic context of Seldane

• To elucidate possible mechanisms underlying the cardiotoxicity of terfenadine, the effect of this antihistamine on L-type Ca2+ channel current (ICa,L) was studied in adult rat ventricular myocytes using the whole-cell patch-clamp technique [4].
• Patients were then included into a double-blind, randomized, 2-way crossover study to receive terfenadine or fexofenadine 120 mg 2 hours before provocation [13].
• In a separate randomized double-blind study we have also examined the effect of an orally administered antihistamine, terfenadine, on kinin-induced wheal and flare responses and their repeatability in a group of nine volunteers [30].
• The incidence of ECG rhythm abnormalities was not significantly higher in any treatment group; however, the incidence of prolongation of QTc > 10% above baseline was significantly higher in the groups treated with terfenadine [31].
• The 300 mg bid terfenadine regimen produced significantly greater skin test suppression (p less than 0.05) than the currently recommended 60 mg bid dose [32].

References