Antihistamine activity, central nervous system and cardiovascular profiles of histamine H<sub>1</sub> antagonists: comparative studies with loratadine, terfenadine and sedating antihistamines in guinea‐pigs

Hey, John A.; Prado, M. del; Cuss, Francis M.; Egan, Robert W.; Sherwood, J; Lin, Chin‐Chung; Kreutner, William

doi:10.1111/j.1365-2222.1995.tb00400.x

Cited by 29 publications

(13 citation statements)

References 25 publications

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“…For example, Hey et al. demonstrated in anaesthetized guinea pigs that 10 mg kg −1 or 30 mg kg −1 loratadine had no effects on QTc, while terfenadine 10 mg kg −1 significantly increased the QTc and produced torsades de pointes in some animals [22].…”

Section: Discussionmentioning

confidence: 99%

“…Second, in animal models high concentrations of loratadine resulting from either greater than normal dosing or from competitive inhibition of cytochrome P450 metabolism did not result in any cardiac rhythm disturbances, including repolarization abnormalities. For example, Hey et al demonstrated in anaesthetized guinea pigs that 10 mg kg x1 or 30 mg kg x1 loratadine had no effects on QTc, while terfenadine 10 mg kg x1 signi®cantly increased the QTc and produced torsades de pointes in some animals [22].…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine

Kosoglou¹,

Salfi²,

Lim³

et al. 2000

Brit J Clinical Pharma

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Aims To evaluate whether ketoconazole or cimetidine alter the pharmacokinetics of loratadine, or its major metabolite, desloratadine (DCL), or alter the effects of loratadine or DCL on electrocardiographic repolarization in healthy adult volunteers. Methods Two randomized, evaluator-blind, multiple-dose, three-way crossover drug interaction studies were performed. In each study, subjects received three 10 day treatments in random sequence, separated by a 14 day washout period. The treatments were loratadine alone, cimetidine or ketoconazole alone, or loratadine plus cimetidine or ketoconazole. The primary study endpoint was the difference in mean QTc intervals from baseline to day 10. In addition, plasma concentrations of loratadine, DCL, and ketoconazole or cimetidine were obtained on day 10. Results Concomitant administration of loratadine and ketoconazole signi®cantly increased the loratadine plasma concentrations (307%; 90% CI 205-428%) and DCL concentrations (73%; 62-85%) compared with administration of loratadine alone. Concomitant administration of loratadine and cimetidine signi®cantly increased the loratadine plasma concentrations (103% increase; 70-142%) but not DCL concentrations (6% increase; 1-11%) compared with administration of loratadine alone. Cimetidine or ketoconazole plasma concentrations were unaffected by coadministration with loratadine. Despite increased concentrations of loratadine and DCL, there were no statistically signi®cant differences for the primary electrocardiographic repolarization parameter (QTc) among any of the treatment groups. No other clinically relevant changes in the safety pro®le of loratadine were observed as assessed by electrocardiographic parameters (mean (90% CI) QTc changes: loratadine vs loratadine + ketoconazole = 3.6 ms (-2.2, 9.4); loratadine vs loratadine + cimetidine = 3.2 ms (-1.6, 7.9)), clinical laboratory tests, vital signs, and adverse events. Conclusions Loratadine 10 mg daily was devoid of any effects on electrocardiographic parameters when coadministered for 10 days with therapeutic doses of ketoconazole or cimetidine in healthy volunteers. It is concluded that, although there was a signi®cant pharmacokinetic drug interaction between ketoconazole or cimetidine and loratadine, this effect was not accompanied by a change in the QTc interval in healthy adult volunteers.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine

Kosoglou¹,

Salfi²,

Lim³

et al. 2000

Brit J Clinical Pharma

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“…An in vivo study in guinea‐pigs [11] showed intravenous loratadine to be free of adverse cardiovascular effects at doses >170 times its peripheral anti‐H 1 ED 50 in this species while intravenous terfenadine was observed to be highly cardiotoxic at therapeutic concentrations. In this model, drugs are administered intravenously in order to assess directly the activity of the parent drug.…”

Section: In Vivo Studiesmentioning

confidence: 99%

Cardiovascular profile of loratadine

Hey¹,

Affrime²,

Cobert³

et al. 1999

Clin Experimental Allergy

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“…No substantial influence on the prolongation of QT intervals or ventricular arrhythmia was shown [3, 30]. Taglialatela et al .…”

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confidence: 99%

Cardiovascular safety of antihistamines

Olasińska-Wiśniewska¹,

Olasiński²,

Grajek³

2014

pdia

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Histamine is a mediator, which increases the permeability of capillaries during the early phase of allergic reaction, causes smooth muscle contraction of bronchi and stimulates mucous glands in the nasal cavity. Antihistamines are the basis of symptomatic treatment in the majority of allergic diseases, especially allergic rhinitis, allergic conjunctivitis, urticaria and anaphylaxis. The cardiotoxic effects of the two withdrawn drugs, terfenadine and astemizole, were manifested by prolonged QT intervals and triggering torsades de pointes (TdP) caused by blockade of the ‘rapid’ IKr potassium channels. These phenomena, however, are not a class effect. This review deals with a new generation of antihistamine drugs in the context of QT interval prolongation risk.

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Antihistamine activity, central nervous system and cardiovascular profiles of histamine H₁ antagonists: comparative studies with loratadine, terfenadine and sedating antihistamines in guinea‐pigs

Cited by 29 publications

References 25 publications

Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine

Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine

Cardiovascular profile of loratadine

Cardiovascular safety of antihistamines

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Antihistamine activity, central nervous system and cardiovascular profiles of histamine H1 antagonists: comparative studies with loratadine, terfenadine and sedating antihistamines in guinea‐pigs

Cited by 29 publications

References 25 publications

Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine

Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine

Cardiovascular profile of loratadine

Cardiovascular safety of antihistamines

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Antihistamine activity, central nervous system and cardiovascular profiles of histamine H₁ antagonists: comparative studies with loratadine, terfenadine and sedating antihistamines in guinea‐pigs