Preclinical Pharmacology of Desloratadine, a Selective and Nonsedating Histamine H1 Receptor Antagonist

Kreutner, William; Hey, John A.; Anthes, John C.; Barnett, Allen; Young, Simon S.; Tozzi, Salvatore

doi:10.1055/s-0031-1300213

Cited by 31 publications

(3 citation statements)

References 10 publications

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“…The dose of antagonists was 0.1 mg/kg bw for Naloxone, 26 0.26 mg/kg bw for Desloratadine, 27 0.05 mg/kg bw for Atropine, 28 0.15 mg/kg bw for Acebutolol, 29 and 0.075 mg/kg bw for Risperidone 30 …”

Section: Methodsmentioning

confidence: 99%

Evaluation of antinociceptive effect and pharmacological mechanisms of thiocyanoacetamide in rats

et al. 2023

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ObjectiveAcute pain is the most common type of pain. The aim of the present work was carried out to study the antinociceptive effect and pharmacological mechanisms of thiocyanoacetamide (Thm) in rats exposed to thermal pain stimulus.Materials and MethodsThe anti‐nociceptive effect of the newly synthesized compound, Thm was studied in comparison to that of paracetamol (Para), dexamethasone (Dex), and morphine (Morph) at different doses using a hot plate test at a constant temperature of 48.0 ± 0.5°C. During this test, the latency time (LT) was measured when rats express pain behavior. Then, the pharmacological mechanisms were determined using receptor‐antagonist drugs.ResultsFirstly, the obtained result showed pain modulation of the pretreated rats with Thm at 10 mg/kg dose proved by the delay of latency time during the thermal test. This significant antinociceptive activity of the thiocyanoacetamide was more effective than that of paracetamol or dexamethasone and less than that of morphine. Second, the pretreatment with acebutolol or risperidone antagonist drugs of, respectively, adrenergic and serotonin receptors demonstrated the elimination of pain modulation with Thm 10 mg/kg dose proved by a short latency time of rat's response in hot plate test. In this case, the pharmacological mechanism of Thm was characterized by the involvement of adrenergic and serotoninergic systems.ConclusionsIt may be concluded that Thm constitutes a promising antinociceptive drug including beta‐adrenergic and serotoninergic targets. The present study warrants further investigation to determine the side effects of this compound.

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Section: Methodsmentioning

confidence: 99%

Evaluation of antinociceptive effect and pharmacological mechanisms of thiocyanoacetamide in rats

et al. 2023

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“…Transformation of desloratadine- N -glucuronide to 3-hydroxydesloratadine- N -glucuronide by CYP2C8 exemplifies the interaction of N -glucuronide conjugates with this enzyme (Figure ). Desloratadine, a second generation nonsedating long-lasting antihistamine, is widely used in the treatment of seasonal allergic rhinitis and chronic idiopathic urticarcia and nasal congestion. , In humans, desloratadine is extensively metabolized to an active metabolite 3-hydroxydesloratadine, which is subsequently converted to 3-hydroxydesloratadine- O -glucuronide. Approximately 13% of the dose is eliminated in the urine as 3-hydroxydesloratadine- O -glucuronide, while 3-hydroxydesloratadine is the major fecal metabolite accounting for 17% of the dose …”

Section: Glucuronide Conjugates As Substrates Of Cyp2c8mentioning

confidence: 99%

Glucuronides as Potential Anionic Substrates of Human Cytochrome P450 2C8 (CYP2C8)

Ma¹,

Fu²,

Khojasteh³

et al. 2017

J. Med. Chem.

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Glucuronidation is in general considered as a terminal metabolic step that leads to direct elimination of drugs and generally abolishes their biological activity. However, there is growing evidence to suggest that glucuronides can be ligands of human CYP2C8, making CYP2C8 distinct from the other CYP isoforms. Several classes of glucuronide conjugates, which include acyl glucuronides, ether glucuronides, N-glucuronides, and carbamoyl glucuronides, have been shown to be substrates or time-dependent inhibitors of CYP2C8. Although the structures of CYP2C8-glucuronide complexes have not been determined, the structural features of CYP2C8 active site support its binding to anionic and bulky ligands like glucuronides. As interaction perpetrators with CYP2C8, glucuronides of gemfibrozil and clopidogrel showed marked clinical drug-drug interactions (e.g., with cerivastatin and repaglinide), which are more than expected from the parent drug. This review summarizes glucuronides as CYP2C8 ligands and the active-site structural features of CYP2C8 that allow potential binding to glucuronides.

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“…Desloratadine has a higher H1 receptor affinity and avidity than other second-generation antihistamines [23]. It is 15-20 times more potent than loratadine and terfenadine, and has 50-194 times greater affinity than cetirizine, loratadine and fexofenadine [24,25].…”

Section: Introductionmentioning

confidence: 99%

Bioequivalence of a Fixed Dose Combination of Desloratadine/Betamethasone Tablets (Oradus Beta) in Healthy Human Volunteers

Bustami¹,

S²

2016

J Bioequiv Availab

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A fixed dose combination of desloratadine, a long-acting tricyclic antihistamine with selective peripheral histamine H1 receptor antagonistic activity, and betamethasone, a glucocorticoid, can potentially provide synergistic effect in the treatment of severe allergic conditions and improve clinical outcomes. Co-administration of an anti-allergy medication and a corticosteroid is extensively used in clinical practice, either as single drug tablets or as a fixed dose combination tablet. The current study was conducted to compare the pharmacokinetics of fixed combination tablets of desloratadine and betamethasone in 40 healthy human volunteers after a single oral dose in a randomized two-period, two-treatment, and two-sequence cross-over study. The study protocol was prepared in accordance to the requirements set in the EMA guidance for conducting bioequivalence studies. Reference (Frenaler Cort 5 mg desloratadine/0.6 mg betamethasone film coated tablet, Roemmers S.A.I.C.F., Argentina) and test (Oradus β 5 mg desloratadine/0.6 mg betamethasone film coated tablet, Pharmaline, Lebanon) drugs were administered to fasted volunteers and blood samples were collected up to 72 h and assayed for desloratadine, hydroxydesloratadine metabolite and betamethasone using a validated LC-MS/MS method. The pharmacokinetic parameters AUC 0-t , C max , Tmax, T1/2, Ke, in addition to (for betamethasone only) AUC 0-∞ , MRTinf, and residual area (%) were determined from plasma concentration-time profile by non-compartmental analysis method using thermos Scientific Kinetica (version 5.1). The analysis of variance did not show any significant difference between the two formulations and 90% confidence intervals fell within the acceptable range for bioequivalence (80-125%). The resulting data demonstrated that when administered as fixed dose combination, the pharmacokinetics of desloratadine and betamethasone were bioequivalent and were well-tolerated.

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Preclinical Pharmacology of Desloratadine, a Selective and Nonsedating Histamine H1 Receptor Antagonist

Cited by 31 publications

References 10 publications

Evaluation of antinociceptive effect and pharmacological mechanisms of thiocyanoacetamide in rats

Evaluation of antinociceptive effect and pharmacological mechanisms of thiocyanoacetamide in rats

Glucuronides as Potential Anionic Substrates of Human Cytochrome P450 2C8 (CYP2C8)

Bioequivalence of a Fixed Dose Combination of Desloratadine/Betamethasone Tablets (Oradus Beta) in Healthy Human Volunteers

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