OBJECTIVETo investigate the effects and the mechanisms of the first-generation histamine H(1)-antagonist diphenhydramine and the second-generation histamine H(1)- antagonist fexofenadine on seizure development of pentylenetetrazole (PTZ)-induced kindling in rats.

METHODSThe first-or second-generation histamine H(1)-antagonists and/or histidine were ip injected in rats every 48 h, followed by a subconvulsive dose of PTZ (35 mg/kg). Then the behavioral changes were observed for 30 min after every injection of PTZ. The histamine content of brain was measured spectrofluorometrically.

RESULTCompared with the control group, diphenhydramine (5 mg/kg) significantly augmented the severity of seizure development of PTZ-induced kindling, whereas fexofenadine (5 mg/kg) had no marked influence. The effects of diphenhydramine were antagonized by histidine, the precursor of histamine.

CONCLUSIONSeizure development of PTZ-induced kindling is promoted by the first-but not the second generation histamine H(1)-antagonists via the blockade of brain histamine H(1)-receptor.

Animals ; Histamine ; physiology ; Histamine H1 Antagonists ; pharmacology ; Histamine H1 Antagonists, Non-Sedating ; pharmacology ; Histidine ; pharmacology ; Kindling, Neurologic ; drug effects ; Male ; Pentylenetetrazole ; Rats ; Rats, Sprague-Dawley ; Seizures ; chemically induced

Torsade de pointes (TdP) is a form of polymorphic ventricular tachycardia that is associated with prolongation of the QT interval. Although it occurs in many clinical settings, torsade de pointes is most commonly caused by drugs. The second generation antihistamines, including terfenadine and astemizole, have little sedation or other adverse effects on the CNS. They have been used widely to treat various allergic diseases, but it has been reported that overdoses or combinations with antifungal agents or macrolide antibiotics may lead to TdP. We report a case of TdP that occured during com-bination therapy of terfenadine and ketoconazole.
Anti-Bacterial Agents ; Antifungal Agents ; Astemizole ; Histamine H1 Antagonists, Non-Sedating ; Ketoconazole* ; Tachycardia, Ventricular ; Terfenadine* ; Torsades de Pointes*

H1-antihistamines have been prescribed widely for the treatment of allergic diseases, such as rhinitis, atopic dermatitis, and urticaria besides common colds since the 1940s. H1-antihistamines are classified by chemical structures (akylamine, piperazine, piperidine, ethanolamine, ethylendiamine, and phenothiazine) or functionally by permeability through blood brain barrier (first or second generation). The first generation antihistamines have been prescribed up to now with several adverse effects such as central nervous system dysfunction, anticholinergic and antiserotonic action and cardiotoxicity with overdose. Hence second generation antihistamines are recommended for the treatment of allergic rhinitis and urticaria. Physicians should consider concomitant diseases or medications when prescribing first generation antihistamines.
Blood-Brain Barrier ; Central Nervous System ; Common Cold ; Dermatitis, Atopic ; Ethanolamine ; Histamine Antagonists ; Histamine H1 Antagonists, Non-Sedating ; Permeability ; Piperazines ; Piperidines ; Rhinitis ; Rhinitis, Allergic, Perennial ; Urticaria

Chronic urticaria is a well-known disease entity, characterized by the rapid appearance of frequently occurring, short-lived wheals, surrounded by a bright-red flare, and often accompanied by angioedema. Any pattern of recurrent urticaria occurring at least twice a week for 6 weeks is called chronic. The cause of chronic urticaria is undefined and its diagnosis requires exclusion of other conditions with somewhat similar symptoms. Degranulation of mast cells with release of histamine is central to the development of wheals. About 26~50% of patients with idiopathic urticaria have histamine-releasing autoantibodies in their blood. Urticaria has a profound impact on the quality of life. It is essential to avoid substances likely to trigger or intensify episodes. Treatment is directed at eliminating or at least substantially reducing symptoms. The most important pharmacotherapy is non-sedating H1 antihistamines. They have proved to be effective in double-blind controlled studies. However, alternative therapies may be required because of different urticaria subtypes and individual variations. Immunosuppressive drugs such as cyclosporin A and corticosteroids should not be used as a longterm management due to undesirable side effects.
Adrenal Cortex Hormones ; Angioedema ; Autoantibodies ; Complementary Therapies ; Cyclosporine ; Diagnosis ; Drug Therapy ; Histamine ; Histamine H1 Antagonists, Non-Sedating ; Humans ; Mast Cells ; Quality of Life ; Urticaria*

OBJECTIVETo study the determination of desloratadine in human serum and its pharmacokinetics in healthy volunteers.

METHODSA single oral dose of 10 mg desloratadine was given to 18 healthy volunteers. The serum concentrations of desloratadine were determined by HPLC-MS assay. The pharmacokinetics parameters of desloratadine tablets were calculated with program 3P97.

RESULTThe main pharmacokinetics parameters of desloratadine tablets were as followsút(max)(1.611 +/-0.366)h, C(max) (4.455+/-1.990)microg x L(-1), AUC(0-t) (58.50+/-21.34)microg x L(-1) x h(-1), AUC(0-infinity) (60.59+/-22.32)microg x L(-1) x h(-1), t(1/2(ke)) (20.303+/-5.833)h, Ke (0.0372+/-0.0116)h(-1) and CL(0.1838+/-0.0563)L x h(-1).

CONCLUSIONDesloratadine tablet is absorbed quicker in the 18 healthy volunteers than the reports and its peak blood concentration reached at 1.5 h after oral administration with t(1/2) 20 h.

Chromatography, High Pressure Liquid ; methods ; Histamine H1 Antagonists, Non-Sedating ; blood ; pharmacokinetics ; Humans ; Loratadine ; analogs & derivatives ; blood ; pharmacokinetics ; Mass Spectrometry ; methods

AIMTo study the chromatographic behavior of cetirizine dihydrochloride on the proteinate- and amylose- based chiral stationary phases so as to optimizate the chromatographic condition of its enantiomers separation.

METHODSWhen using amylose-based, alpha1-acid glycoprotein and ovomucoid protein chiral stationary phase, the mobile phase was hexane-isopropyl alcohol-alcohol-trifluoroacetic acid (430:45:25:1), acetonitrile-10 mmol x L(-1) phosphate buffer solution (adjusted to pH 7.0 with sodium hydroxide) (4:96) and acetonitrile-20 mmol x L(-1) KH, PO4 solution (adjusted to pH 7.0 with triethylamine) (12.7:87.3), respectively. The temperature of proteinate column was 25 degrees C. The detective wavelength was 230 nm.

RESULTSThe two enantiomers could be separated on the two kinds of chiral stationary phases without derivatization and the resolution was above 2.0. The methods developed on the two kinds of chiral stationary phases are accurate, sensitive and specific.

CONCLUSIONBoth the proteinate- and amylose-based chiral stationary phases can be used to separate the enantiomers of cetirizine.

Amylose ; analogs & derivatives ; Cetirizine ; chemistry ; isolation & purification ; Chromatography, High Pressure Liquid ; Histamine H1 Antagonists, Non-Sedating ; chemistry ; isolation & purification ; Molecular Structure ; Orosomucoid ; Stereoisomerism

AIMTo establish an HPLC-fluorescence method for determination of loratadine in human plasma and evaluate its relative bioavailability.

METHODSAn Alltech-C18 column and a mobile phase of acetonitrile-water-glacial acetic acid-triethylamine (90:100:6:0.15) were used. The fluorescence detector was set at Ex 274 nm, Em 450 nm. The flow rate was 1 mL.min-1.

RESULTSThe calibration curve was linear over a concentration range of 0.2-30 micrograms.L-1. The limit of quantification was 0.2 microgram.L-1. The average method recoveries varied from 96% to 98%. The results showed AUC, Tmax, Cmax and T1/2 beta between the testing tablets, testing capsules and reference tablets had no significant difference (P > 0.05). Relative bioavailabilities were 107% +/- 17% and 100% +/- 14% respectively.

CONCLUSIONThe three formulations were bioequivalent.

Area Under Curve ; Biological Availability ; Chromatography, High Pressure Liquid ; methods ; Fluorescence ; Histamine H1 Antagonists, Non-Sedating ; blood ; pharmacokinetics ; Humans ; Loratadine ; blood ; pharmacokinetics ; Male

AIMTo study the intervention of cetirizine on monocyte chemoattractant protein-1 (MCP-1) in different cutaneous inflammation models.

METHODSHistamine and IFN-gamma stimulated dermal fibroblast cells and HaCaT cells to mimic cutaneous inflammation. Expression of MCP-1 was assessed by means of RT-PCR and ELISA.

RESULTSCompared with the control group of dermal fibroblast (DF) cells and HaCaT cells, MCP-1 mRNA was significantly upregulated by histamine (10 micromol x L(-1)) and IFN-gamma (20 ng x mL(-1)). The protein secretions of MCP-1 were increased 3.5 fold and 8.4 fold in DF cells, respectively. The similar tendency was observed in HaCaT cells. The enhancing effects of histamine and IFN-gamma on MCP-1 protein production were significantly inhibited by cetirizine (1 and 10 micromol x L(-1)) in DF and HaCaT cells.

CONCLUSIONCetirizine may exert the anti-inflammatory effect of skin via inhibiting MCP-1 expression.

Cell Line ; Cells, Cultured ; Cetirizine ; pharmacology ; Chemokine CCL2 ; biosynthesis ; genetics ; Dermatitis ; metabolism ; Dermis ; cytology ; Fibroblasts ; cytology ; metabolism ; Histamine ; pharmacology ; Histamine H1 Antagonists, Non-Sedating ; pharmacology ; Humans ; Interferon-gamma ; pharmacology ; Keratinocytes ; cytology ; metabolism ; RNA, Messenger ; biosynthesis ; genetics

Levocetirizine is a second-generation nonsedative antihistaminic agent that has been demonstrated to be safe and effective for treating allergic disease. There was only one case report of levocetirizine-induced liver toxicity, but a liver biopsy was not performed. In this article, we present the first case of levocetirizine-induced liver injury with histologic findings. A 48-year-old man was hospitalized with jaundice and generalized pruritus that had developed after 2 months of therapy with levocetirizine for prurigo nodularis. Laboratory findings revealed acute hepatitis with cholestasis. A liver biopsy demonstrated portal inflammation and hepatitis with apoptotic hepatocytes. The patient fully recovered 3 weeks after withdrawing levocetirizine. Although levocetirizine is safe and effective, physicians should be aware of its potential hepatotoxicity.
Cetirizine/*adverse effects/therapeutic use ; Chemical and Drug Induced Liver Injury/*diagnosis/pathology ; Histamine H1 Antagonists, Non-Sedating/*adverse effects/therapeutic use ; Humans ; Hypersensitivity/drug therapy ; Jaundice/etiology ; Liver/pathology ; Male ; Middle Aged ; Pruritus/etiology

To investigate the effect of cetirizine hydrochloride on the expression of neurokinin 1 receptor (NK-1R) and cytokines production induced by substance P (SP) in HaCaT cells (a human epidermal keratinocyte cell line) and dermal fibroblasts. The effect of cetirizine on the expression of NK-1R protein was detected by flow cytometry and Western blotting analysis. The modulation of cetirizine on the production of interferon (IFN)-gamma, interleukin (IL)-1beta, IL-6 and IL-8 in HaCaT cells and fibroblasts was measured by ELISA. The results showed that cetirizine significantly inhibited the expression of NK-1R in HaCaT cells and fibroblasts. SP induced the production of IFN-gamma, IL-1beta and IL-8 in both cell types. Cetirizine 1-100 micromol x L(-1) inhibited SP-induced IL-1beta and IL-8 production in HaCaT cells and fibroblasts, while had no effect on the production of IFN-gamma in both cells. Both SP and cetirizine had no effect on the secretion of IL-6 in HaCaT cells and fibroblasts. These findings suggest that cetirizine may be involved in the treatment of SP-induced skin inflammation by inhibiting the expression of substance P receptor and regulation the production of IL-1beta and IL-8 in epidermal keratinocyte and dermal fibroblasts.
Anti-Allergic Agents ; pharmacology ; Cell Line ; Cetirizine ; pharmacology ; Fibroblasts ; cytology ; metabolism ; Histamine H1 Antagonists, Non-Sedating ; pharmacology ; Humans ; Interferon-gamma ; metabolism ; Interleukin-1beta ; metabolism ; Interleukin-8 ; metabolism ; Keratinocytes ; cytology ; metabolism ; Receptors, Neurokinin-1 ; metabolism ; Substance P ; pharmacology