Viewed the Existence of Multiple Muscarinic CNS Penetration May Occur When the Blood-Brain Barrier Receptors in the Mammalian Myocardium and Have Is Compromised
Total Page:16
File Type:pdf, Size:1020Kb
BMC Pharmacology BioMed Central Research article Open Access In vivo antimuscarinic actions of the third generation antihistaminergic agent, desloratadine G Howell III†1, L West†1, C Jenkins2, B Lineberry1, D Yokum1 and R Rockhold*1 Address: 1Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA and 2Tougaloo College, Tougaloo, MS, USA Email: G Howell - [email protected]; L West - [email protected]; C Jenkins - [email protected]; B Lineberry - [email protected]; D Yokum - [email protected]; R Rockhold* - [email protected] * Corresponding author †Equal contributors Published: 18 August 2005 Received: 06 October 2004 Accepted: 18 August 2005 BMC Pharmacology 2005, 5:13 doi:10.1186/1471-2210-5-13 This article is available from: http://www.biomedcentral.com/1471-2210/5/13 © 2005 Howell et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Muscarinic receptor mediated adverse effects, such as sedation and xerostomia, significantly hinder the therapeutic usefulness of first generation antihistamines. Therefore, second and third generation antihistamines which effectively antagonize the H1 receptor without significant affinity for muscarinic receptors have been developed. However, both in vitro and in vivo experimentation indicates that the third generation antihistamine, desloratadine, antagonizes muscarinic receptors. To fully examine the in vivo antimuscarinic efficacy of desloratadine, two murine and two rat models were utilized. The murine models sought to determine the efficacy of desloratadine to antagonize muscarinic agonist induced salivation, lacrimation, and tremor. Desloratadine's effect on the cardiovascular system was explored in both rodent models. Results: In the pithed rat, both desloratadine (1.0 mg/kg, i.v.) and the muscarinic M2 selective antagonist, methoctramine (0.5 mg/kg, i.v.), inhibited negative inotropic (left ventricular dP/dt) effects caused by oxotremorine, a nonselective muscarinic agonist (p < 0.05). Negative chronotropic effects caused by oxotremorine were inhibited by desloratadine, methoctramine, and the muscarinic M3 selective antagonist, 4- DAMP (1.0 mg/kg, i.v.). A late positive inotropic event observed after the initial decrease was inhibited by all three test compounds with desloratadine and 4-DAMP being the most efficacious. In the conscious animal, inhibition of baroreflex-mediated bradycardia was evaluated. Unlike atropine (0.5 mg/kg, i.v.), desloratadine did not alter this bradycardia. The antimuscarinic action of desloratadine on salivation, lacrimation, and tremor was also explored. In urethane-anesthetized (1.5 g/kg, i.p.) male ICR mice (25–35 g) desloratadine (1.0, 5.0 mg/kg) did not inhibit oxotremorine-induced (0.5 mg/kg, s.c.) salivation, unlike atropine (0.5 mg/kg) and 4-DAMP (1.0 mg/kg). In conscious mice, desloratadine failed to inhibit oxotremorine-induced (0.5 mg/kg, s.c.) salivation, lacrimation, and tremor. However, desloratadine did inhibit oxotremorine-induced tremor in phenylephrine pretreated animals. Conclusion: The presented data demonstrate that the third generation antihistamine, desloratadine, does not significantly antagonize peripheral muscarinic receptors mediating salivation and lacrimation, therefore, xerostomia and dry eyes should not be observed with therapeutic use of desloratadine. Our data also indicate when administered to a patient with a compromised blood-brain barrier, desloratadine may cause sedation. Patients with compromised cardiovascular systems should be closely monitored when administered desloratadine based on our results that desloratadine has the ability to interfere with normal cardiovascular function mediated by muscarinic receptors. Page 1 of 12 (page number not for citation purposes) BMC Pharmacology 2005, 5:13 http://www.biomedcentral.com/1471-2210/5/13 Background Antihistaminergic drugs are commonly classified into 10 three generations. First generation antihistamines, such as diphenhydramine, effectively block the H receptor sub- 1 8 (15) (12) type but their use is limited due to significant central (12) (sedation) and peripheral (tachycardia, xerostomia) (12) (12) * 6 * * antimuscarinic side effects. Second generation antihista- * (12) (12) (12) mines, such as loratadine, retain a high selectivity for the (12) H1 receptor and have fewer centrally mediated side effects 4 than the first generation compounds because second gen- eration compounds do not readily enter the central nerv- Total Tremor Score * 2 ous system (CNS) [1]. However, two second generation (12) antihistamines, astemizole and terfenadine, cause prolon- gation of the QT interval resulting in torsades de pointes. 0 CT AT AM DP MO 4-D DL DL DL DL RL N H T A 5. 1. 0. 0. This adverse effect prompted the removal of terfenadine MP 0 0 1 01 from the drug market [2]. The most recent, third genera- tion compounds, include fexofenadine and desloratadine. InhibitionFigure 1 of oxotremorine-induced tremors These compounds are active metabolites of the second Inhibition of oxotremorine-induced tremors. Mice generation antihistamines, terfenadine and loratadine, were treated with a single i.p. injection of one of the test respectively, and generally retain or surpass the H1 recep- agents (atropine sulfate, AT; atropine methyl nitrate, AMN; tor selectivity of their parent compounds. For instance, diphenhydramine, DPH; methoctramine, MOT; 1,1-dimethyl- 4-diphenylacetoxypiperidinium iodide, 4-DAMP; deslorata- desloratadine displays a higher affinity for the H1 receptor than does loratadine and antagonizes the human H dine, DL) and placed in individual shoebox cages for observa- 1 tion. Fifteen minutes later, each mouse received a single s.c. receptor in a pseudoirreversible manner [3,4]. injection of oxotremorine sesquifumarate (0.5 mg/kg) at the nape of the neck. At 5, 10 and 15 minutes following the Questions remain concerning the potential for antimus- oxotremorine injection, mice were observed for severity of carinic adverse effects with desloratadine since both in tremor and for the presence of salivation and lacrimation. vitro and in vivo experimentation indicates that deslorata- The sum of the scores for the three time points for tremor is dine has the ability to block muscarinic receptors. presented as Total Tremor Score. Numbers in parenthesis Desloratadine demonstrated in vitro IC50 values of 48 nM represent the number of animals in each group and asterisk and 125 nM against cloned human M1 and M3 muscarinic denotes statistical significance (P < 0.05) vs. control. receptor subtypes, respectively [4]. In vivo muscarinic receptor blockade has been demonstrated in that deslorat- adine has been shown to inhibit pilocarpine induced sal- ivation in mice and inhibit contractions of isolated rabbit and guinea pig iris smooth muscle [5,6]. Therefore, these data present the need to more definitively ascertain the potential antimuscarinic activity of desloratadine, in vivo. as did administration of both 4-DAMP (1.0 mg/kg) and In the present study, several in vivo models were used to methoctramine (0.5 mg/kg) prior to administration of further assess antimuscarinic activity of desloratadine as oxotremorine. well as the potential for penetration of the blood-brain barrier. Oxotremorine-induced tremor with phenylephrine pretreatment Results Pretreatment with the vasopressor agent, phenylephrine Oxotremorine-induced tremor (10 µg/kg; PE), functions to disrupt the blood-brain bar- Intraperitoneal injection of oxotremorine (0.5 mg/kg) rier by inducing acute hypertension [7,8]. Blood-brain induced tremor in conscious mice. The only dose of barrier disruption resulted in significant inhibition of desloratadine causing inhibition of oxotremorine- oxotremorine-induced tremors by desloratadine (1.0 mg/ induced tremor was 5.0 mg/kg (Figure 1). Desloratadine kg) compared to the 1% DMSO vehicle as reflected by (1.0, 0.1, and 0.01 mg/kg) did not significantly inhibit their respective total tremor scores (Figure 2). Pretreat- generation of tremor. Unlike atropine sulfate (0.5 mg/kg), ment with PE followed by administration of deslorata- atropine methyl nitrate (0.5 mg/kg) did not inhibit trem- dine (1.0 mg/kg; i.p.) elicited an oxotremorine-induced ors which confirms the central locus for oxotremorine- total tremor score of 2.0 ± 0.7 (mean ± SD) whereas PE induced tremors. Diphenhydramine (1.0 mg/kg) signifi- pretreatment followed by vehicle elicited an oxotremo- cantly inhibited the generation of tremor by oxotremorine rine-induced total tremor score of 5.2 ± 1.3 (mean ± SD). Page 2 of 12 (page number not for citation purposes) BMC Pharmacology 2005, 5:13 http://www.biomedcentral.com/1471-2210/5/13 4 7 (15) 6 3 (12) (12) 5 (15) (12) (12) 2 (12) (12) 4 * 3 (12) Total Lacrimation Score Total Tremor Score 1 * * * 2 (12) (12) (12) 1 0 C A A D M 4 D D D D TR T MN PH OT -DA L 5 L 1 L 0 L 0 0 L MP .0 .0 .1 .01 DL Control InhibitiontremorsFigure 3 of lacrimation during oxotremorine-induced Inhibition of lacrimation during oxotremorine- InhibitionphrineFigure pretreatment 2 of oxotremorine-induced tremors with phenyle- induced tremors. Mice were treated with a single i.p. injec- Inhibition of oxotremorine-induced tremors with tion of one