The Combination Sorafenib-raloxifene-loratadine as a Novel Potential Therapeutic Approach Against Human Liver Cancer.

BACKGROUND/AIM: Liver cancer is one of the malignancies with the highest mortality-to-incidence ratio worldwide. Therefore, novel therapeutic approaches are urgently needed. Combination therapy and drug repurposing can improve the response of the patients to therapy in several cancers. The aim of the present study was to merge these two strategies and evaluate whether the two-drug- or three-drug- combination of sorafenib, raloxifene, and loratadine improves the antineoplastic effect on human liver cancer cells in comparison to the single-drug effect. MATERIALS AND METHODS: The human liver cancer cell lines HepG2 and HuH7 were studied. The effect of sorafenib, raloxifene, and loratadine on the metabolic activity was determined using the MTT assay. The inhibitory concentrations (IC20 and IC50) were calculated from these results and used in the drug-combination experiments. Apoptosis and cell survival were studied by flow cytometry and using the colony formation assay, respectively. RESULTS: In both cell lines, sorafenib, raloxifene, and loratadine in two-drug and three-drug combinations significantly reduced metabolic activity and significantly increased the percentage of apoptotic cells compared to the single-drug effect. In addition, all the combinations significantly reduced the colony-forming capacity in the HepG2 cell line. Surprisingly, the effect of raloxifene on apoptosis was similar to that observed using the combinations. CONCLUSION: The triple combination sorafenib-raloxifene-loratadine may be a novel promising approach in the treatment of liver cancer patients.

A novel nasal co-loaded loratadine and sulpiride nanoemulsion with improved downregulation of TNF-α, TGF-ß and IL-1 in rabbit models of ovalbumin-induced allergic rhinitis.

PURPOSE: The work aimed to develop a co-loaded loratadine and sulpiride nasal nanoemulsion for allergic rhinitis management. METHODS: Compatibility studies were conducted adopting differential scanning calorimetry and Fourier transform infrared spectroscopy. Nanoemulsion formulations were prepared using soybean lecithin, olive oil and tween 80. Sodium cholate and glycerol were employed as co-surfactants. Nanoemulsions were assessed for viscosity, pH, droplet size, polydispersity index, zeta potential, electrical conductivity, entrapment, In vitro drug release and corresponding kinetics. Stability of the selected formulation was investigated. The biological effectiveness was evaluated in rabbit models of ovalbumin-induced allergic rhinitis by measuring TNF-α, TGF-ß and IL-1. RESULTS: Compatibility studies revealed absence of drug/drug interactions. Nanoemulsions exhibited > 90% entrapment efficiency. The selected nanoemulsion demonstrated small droplet size (85.2 ± 0.2 nm), low PDI (0.35 ± 0.0) and appropriate Zeta Potential (-23.3 ± 0.2) and stability. It also displayed enhanced in vitro drug release following the Higuashi Diffusion and Baker-Lonsdale models. The mean relative mRNA expression of TNF-α, IL-1 and TGF-ß significantly decreased from 9.59 ± 1.06, 4.15 ± 0.02 and 4.15 ± 0.02 to 1.28 ± 0.02, 1.93 ± 0.06 and 1.56 ± 0.02 respectively after treatment with the selected nanoemulsion formulation. CONCLUSION: The results reflected a promising potent effect of the combined loratadine and sulpiride nasal nanoemulsion in managing the symptoms of allergic rhinitis.

Effects of loratadine, a histamine H1 receptor antagonist, on the skeletal system of young male rats.

BACKGROUND: Histamine H1 receptor antagonists are widely used in the treatment of allergic diseases. H1 receptors are expressed on bone cells and histamine takes part in regulation of bone metabolism. Loratadine is often prescribed to children. PURPOSE: The aim of the present study was to investigate the effects of loratadine on the skeletal system of young rats. MATERIAL AND METHODS: Loratadine (0.5, 5, and 50 mg/kg p.o. daily) was administered for 4 weeks to male Wistar rats, 6-week-old at the start of the experiment. Bone mass, mass of bone mineral, calcium, and phosphorus content in the bone mineral of the tibia, femur, and L-4 vertebra, histomorphometric parameters of the femur, mechanical properties of the proximal tibial metaphysis, femoral diaphysis and femoral neck, and serum levels of bone turnover markers were examined. RESULTS: Loratadine at 0.5 and 5 mg/kg did not significantly affect the skeletal system of young rats. At 50 mg/kg, loratadine decreased the femoral length, increased content of calcium and phosphorus in the bone mineral of the vertebra, and tended to improve mechanical properties of the tibial metaphysis. CONCLUSION: High-dose loratadine slightly but significantly affected development of the skeletal system in rapidly growing rats.

Inhibitory effect of Phlai capsules on skin test responses among allergic rhinitis patients: a randomized, three-way crossover study.

BACKGROUND: Zingiber cassumunar Roxb., commonly known as Phlai in Thai, has been used as a traditional medicine in Thailand for the treatment of various diseases, including inflammation and chronic airway disease. OBJECTIVE: The purpose of this study was to assess the antihistaminic effect of Phlai on skin testing. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: This was a randomized, open-label, three-way crossover study. Twenty allergic rhinitis (AR) patients were enrolled. In randomized sequence, patients received a single dose of Phlai capsules (100 or 200 mg) or loratadine (10 mg) with a washout period of 1 week between each treatment. MAIN OUTCOME MEASURES: Skin prick testing for histamine and common aeroallergen (house dust mite) were performed before treatment and after 1, 2, 3, 4, 6, 8, 12 and 24 hours of treatment. The main treatment outcomes were the mean wheal and flare responses to the skin prick test after treatment. RESULTS: Both 100 mg and 200 mg Phlai doses suppressed wheal and flare responses to house dust mite allergen, but only 200 mg of Phlai capsules significantly suppressed wheal and flare responses to histamine. Repeated measures analysis of variance showed that loratadine caused more wheal and flare suppression than Phlai capsules in responses to the histamine skin prick test. However, there were no significant differences among the effects of 100 mg Phlai capsules, 200 mg Phlai capsules and loratadine in suppression of wheal and flare induced by the mite skin prick test. Both doses of Phlai were well-tolerated with no adverse events. CONCLUSION: Both 100 mg (compound D 4 mg) and 200 mg (compound D 8 mg) Phlai capsules, when taken as a single therapeutic dose, inhibited skin reactivity to histamine and mite skin prick tests in AR patients. TRIAL REGISTRATION: Thai clinical trial registry (TCTR20160510001).

[Effect of Modified Danggui Yinzi on Delayed Allergy in Model Mice with Qi-Blood Deficiency Syndrome].

OBJECTIVE: To explore the effect of Danggui Yinzi (DY) on delayed allergy in model mice with qi-blood deficiency syndrome (QBDS). METHODS: QBDS model was established in 48 Kuming mice of SPF grade by using reserpine and acetophenone hydrazine. Forty of them were then randomly divided into the model group, the loratadine group, the high dose DY group, the middle dose DY group, and the low dose DY group, 8 in each group. Another 8 in line with the same standard were recruited as a blank group. Mice in high, middle, and low dose DY groups were administered with DY concentrated solution at 60, 30, 15 g/kg by gastrogavage. Mice in the loratadine group were administered with loratadine solution at 1.66 mg/kg by gastrogavage. Equal volume of normal saline was administered to mice in the model group and the blank group by gastrogavage. All medication was given once per day for 1 successive week. Except those in the blank group, the rest mice were evenly smeared with 1% DNCB solution on the abdomen. Five days after skin allergy, 1% DNCB solution was smeared to right ear of all mice to stimulate allergic reaction. Mice in the blank group were smeared in the same way without allergenic reaction. The auricle swelling and the inhibition ratio were determined at 24 h after attack. Blood was collected from orbit and serum IgE level detected using double-antibody sandwich ELISA. RESULTS: Compared with the blank group, auricle swelling obviously increased and serum IgE level was obviously elevated in the model group (P < 0.01). Compared with the model group, auricle swelling obviously decreased and serum IgE level was obviously reduced in the 3 dose DY groups (P < 0.05, P < 0.01). Meanwhile, the auricle swelling degree was superior in high and middle dose DY groups to that in the loratadine group (P < 0.05). The inhibition ratio of auricle swelling was sequenced from high to low as 67.3% in the high dose DY group, 56.0% in the middle dose DY group, 48.1% in the low dose DY group, 47.3% in the loratadine group. CONCLUSIONS: DY could inhibit auricle swelling and lower serum IgE level. It also could inhibit delayed allergic reaction in model mice with QBDS to some extent.

Novel Inducers of Fetal Globin Identified through High Throughput Screening (HTS) Are Active In Vivo in Anemic Baboons and Transgenic Mice.

High-level fetal (γ) globin expression ameliorates clinical severity of the beta (ß) hemoglobinopathies, and safe, orally-bioavailable γ-globin inducing agents would benefit many patients. We adapted a LCR-γ-globin promoter-GFP reporter assay to a high-throughput robotic system to evaluate five diverse chemical libraries for this activity. Multiple structurally- and functionally-diverse compounds were identified which activate the γ-globin gene promoter at nanomolar concentrations, including some therapeutics approved for other conditions. Three candidates with established safety profiles were further evaluated in erythroid progenitors, anemic baboons and transgenic mice, with significant induction of γ-globin expression observed in vivo. A lead candidate, Benserazide, emerged which demonstrated > 20-fold induction of γ-globin mRNA expression in anemic baboons and increased F-cell proportions by 3.5-fold in transgenic mice. Benserazide has been used chronically to inhibit amino acid decarboxylase to enhance plasma levels of L-dopa. These studies confirm the utility of high-throughput screening and identify previously unrecognized fetal globin inducing candidates which can be developed expediently for treatment of hemoglobinopathies.

Dissolution evaluation in vitro and bioavailability in vivo of self-microemulsifying drug delivery systems for pH-sensitive drug loratadine.

The aim of this study was to improve the oral absorption of loratadine, a pH-sensitive drug, by self-microemulsifying drug delivery systems (SMEDDSs). The optimal SMEDDS was analysed and evaluated after emulsification in distilled water with diameter of 26.57 ± 0.71 nm and zeta potential of -30.5 ± 4.5 mV. Dissolution experiments in vitro were carried out in different released media of pH values and the SMEDDS formulations were able to release loratadine completely in different media while market tablets just performed similarly in the media of pH 1.2. Furthermore, the oral bioavailability and the pharmacokinetic behaviour of loratadine formulations in vivo were studied after a single dose of 1 mg/kg loratadine in beagle dogs. The SMEDDS formulations displayed higher Cmax and AUC, approximately 9 and 5 times increase than those of market tablets (p < 0.01) respectively. These results demonstrated that SMEDDS formulations had significantly increased the oral absorption of loratadine in beagle dogs.

In vitro alterations in dental enamel exposed to acidic medicines.

OBJECTIVE: To evaluate the effect of acidic medicines (Klaricid(®), Claritin(®), and Dimetapp(®)) on surface enamel in vitro. METHODS: Enamel blocks (n=104) were randomly distributed into two groups: G1 (pH-cycling simulating physiological oral conditions) and G2 (erosive conditions). Each group was divided into four subgroups, three to be immersed in the medicines and the control in deionized water. Specimen surfaces were evaluated for roughness and hardness at baseline and again after the in vitro experimental phase, which included 30 min immersions in the medicines twice daily for 12 days. Scanning electron microscopy (SEM) was also performed after the in vitro experimental phase. RESULTS: All medicines produced a significant reduction in hardness in G1 after 12 days (P<0.05). The three medicines promoted greater roughness after both pH-regimens - G1 and G2 (P<0.01), except for Claritin in G1. Scanning electron microscopy analysis showed erosive patterns in all subgroups. Dimetapp(®) showed the most erosion and Klaricid(®) the least, in both groups. CONCLUSION: Dimetapp(®) (lowest pH and viscosity) and deionized water (control) showed the most pronounced erosive patterns. Klaricid(®) (highest pH and viscosity) presented an in vitro protective effect against acid attacks perhaps due to its mineral content and viscosity.

Concomitant activity of histamine and cysteinyl leukotrienes on porcine nasal mucosal vessels and nasal inflammation in the rat.

BACKGROUND: Histamine and cysteinyl leukotrienes are pivotal mast cell mediators which contribute considerably and likely complementary to the symptoms of allergic rhinitis. Currently, we sought to explore the direct actions of histamine and leukotriene D(4) (LTD(4)), a cysteinyl leukotriene, on porcine nasal arteries and veins. We also studied combined blocks of histamine and cysteinyl leukotrienes using loratadine and montelukast in an in vivo model of allergy-mediated nasal inflammation. METHODS: For the evaluation of the action of histamine and LTD(4) on arteries and veins, porcine nasal mucosa was isolated and cut into slices (100-300 microm thick). Real-time images of the nasal arteries and veins were recorded and vessel activities estimated by changes in cross-sectional area before and after the tested drugs. For the in vivo studies, the effect of loratadine and montelukast given alone and in combination was examined on upper airway inflammation in ovalbumin-sensitized and -challenged Brown Norway rats. RESULTS: Both histamine (0.001-10 micromol/l) and LTD(4) (0.001-10 micromol/l) produced a concentration-dependent increase in the lumen area of nasal mucosa arteries and veins. Histamine (0.01 micromol/l) alone produced a 24 and 12% increase in cross-sectional areas of arteries and veins, respectively. LTD(4) (0.001 micromol/l) alone increased artery and vein dilation by about 17 and 9%, respectively. Combination treatment with histamine (0.01 micromol/l) and LTD(4) (0.001 micromol/l) increased vessel dilation by 65% (arteries) and 26% (veins). In our in vivo Brown Norway rat studies, oral loratadine (0.01-10 mg/kg) and montelukast (0.01-10 mg/kg) significantly reduced antigen-induced total nasal inflammatory cell infiltration in a dose-dependent manner. The antiinflammatory dose-response curve of loratadine was shifted to the left when studied in combination with montelukast (0.01 mg/kg). Similarly, the dose-response characteristics of montelukast (0.01-10 mg/kg) was shifted in the presence of loratadine (0.01 mg/kg). CONCLUSION: Our studies support the position that histamine and cysteinyl leukotrienes may act collaboratively to elicit allergic nasal pathologies such as upper airway inflammation and nasal vessel dilation (which may translate into increased nasal mucosal engorgement). Furthermore, the current results are supportive of the hypothesis that combined treatment of allergic rhinitis with an H(1) receptor antagonist and a CysLT(1) receptor antagonist may have greater benefit than sole treatment with these agents alone.

Hybrid approach for the design of highly affine and selective dopamine D(3) receptor ligands using privileged scaffolds of biogenic amine GPCR ligands.

A series of compounds containing privileged scaffolds of the known histamine H(1) receptor antagonists cetirizine, mianserin, ketotifen, loratadine, and bamipine were synthesized for further optimization as ligands for the related biogenic amine binding dopamine D(3) receptor. A pharmacological screening was carried out at dopamine D(2) and D(3) receptors. In the preliminary testing various ligands have shown moderate to high affinities for dopamine D(3)receptors, for example, N-(4-{4-[benzyl(phenyl)amino]piperidin-1-yl}butylnaphthalen-2-carboxamide (19a) (hD(3)K(i)=0.3 nM; hD(2)K(i)=703 nM), leading to a selectivity ratio of 2343.

Eosinophil recruiting chemokines are down-regulated in peripheral blood mononuclear cells of allergic patients treated with deflazacort or desloratadine.

Chemokines are cytokines with chemotactic properties on leukocyte subsets whose modulation plays a key role in allergic inflammatory processes. To better understand the possible anti-inflammatory effects of histamine-1 receptor antagonists in allergic asthma, we studied the mRNA expression of a set of chemokines known to be involved in the eosinophils-basophils activation as well as recruitment and T-cell signaling events, before and after corticosteroid or antihistamine treatment in PBMCs from allergic-asthmatic patients ex vivo. Twelve patients were enrolled, all of whom were allergic to Parietaria judaica and suffering for mild persistent asthma: six were treated with desloratadine (10 mg/day), and six with deflazacort (12 mg/day). Before and after the treatment, PBMC samples were collected from each patient and analyzed for the expression of encoding mRNAs for several chemokines, I-309 (CCL1), MCP-1 (CCL2), MIP1-alpha (CCL3), MIP1-beta (CCL4), RANTES (CCL5), IL-8 (CXCL8), IP-10 (CXCL10), Lymphotactin (XCL1). Clinical and functional improvements were seen after 3 weeks of therapy; this was associated with a reduced expression in the mRNA levels for the chemokines RANTES, MIP1-alpha and MIP1-beta with either the corticosteroid or the antihistamine, compared to the pre-treatment levels. Chemokine downregulation was statistically significant in both groups of patients. These findings suggest that certain antihistamines may act as down-modulators of allergic inflammation, possibly through a negative regulation of the chemokines involved in activation and attraction of eosinophils. Our results suggest that clinical trials with long follow-ups may be useful in evaluating histamine-1 receptor antagonists as add-on therapy to steroids in the treatment of asthma.

Effect of a Chinese herbal formula, Shi-Bi-Lin, on an experimental model of allergic rhinitis.

BACKGROUND: Jia Wei Cang Er Zi San, a traditional Chinese herbal formula, has been used to treat allergic rhinitis (AR) for several centuries. However, its effect on experimental animal models and its therapeutic mechanism remain unclear. OBJECTIVE: To study the effect of Shu-Bi-Lin, a modified Jia Wei Cang Er Zi San, on an animal model of AR. METHODS: Shu-Bi-Lin was administered to the guinea pig model of AR. Meanwhile, an antihistamine-treated group for the treatment control, an ovalbumin-sensitized and untreated group for the positive control, and a sham-sensitized, sham-challenged group for the sham control were studied in parallel. Symptomatic and some pathophysiologic variables were evaluated. RESULTS: Sneezing and nasal scratching after challenges were significantly ameliorated in the Shu-Bi-Lin-treated group compared with the ovalbumin-sensitized and untreated group, but rhinorrhea volume was not reduced. Shu-Bi-Lin significantly suppressed the production of IgG1 in the passive cutaneous anaphylaxis test. The thromboxane B2 level in nasal lavage fluid was significantly deceased in the Shu-Bi-Lin-treated group; however, the reduction in histamine and peptide leukotriene levels did not reach statistical significance. In addition, eosinophil infiltration and endothelial nitric oxide synthase immunoreactivity in the nasal tissues were reduced in the Shu-Bi-Lin-treated group. CONCLUSIONS: Shu-Bi-Lin could alleviate the nasal symptoms of AR, and its mechanism might be related to its inhibitory effect on type I anaphylaxis reactions and eosinophil infiltration in the nasal tissues, as well as the inhibition of some mediators related to AR.

The effect of desloratadine on eosinophil/basophil progenitors and other inflammatory markers in seasonal allergic rhinitis: a placebo-controlled randomized study.

BACKGROUND: Eosinophil/basophil (Eo/B) progenitors fluctuate in the peripheral circulation during seasonal allergen exposure in atopic subjects. Several drugs have been shown to modulate Eo/B progenitor levels in the peripheral blood but, to date, the possible effect of antihistamines on Eo/B progenitors has not been explored. Our objective was to evaluate whether the antihistamine desloratadine (DL) can modulate peripheral blood Eo/B progenitors or other markers of allergic inflammation. METHODS: We performed a randomized double-blind placebo-controlled study on the effects of DL on peripheral blood Eo/B progenitors in subjects with symptomatic, seasonal allergic rhinitis during a ragweed pollen season. Forty-five subjects were randomized to treatment for 4 weeks with DL 20 mg daily or placebo. RESULTS: The expected fall in the number of Eo/B progenitors from baseline to 2 weeks of treatment was seen in the placebo group [median drop of 1.0 colony-forming unit (CFU)/10(6) cells], and was greater than in the DL group (median drop of 0.0 CFU/10(6) cells) (p = 0.013). The change in histamine concentration per colony from baseline to 2 weeks of treatment was lower in the DL group (median decrease of 6.1 pg/colony) compared to placebo (median increase of 1.8 pg/colony) (p = 0.01). An increase in the nasal lavage eotaxin concentration from baseline to 4 weeks of treatment was statistically significant in the placebo group but not in the DL group. Eo/B CFU were not affected by varying in vitro concentrations of DL. CONCLUSION: These results suggest that DL can modulate aspects of allergic inflammation in vivo through mechanisms other than simple blockade of H1 histamine receptors.

Comparative pharmacology of guinea pig cardiac myocyte and cloned hERG (I(Kr)) channel.

INTRODUCTION: This study used whole-cell, patch clamp techniques on isolated guinea pig ventricular myocytes and HEK293 cells expressing cloned human ether-a-go-go-related gene (hERG) to examine the action of drugs causing QT interval prolongation and torsades de pointes (TdP) in man. Similarities and important differences in drug actions on cardiac myocytes and cloned hERG I(Kr) channels were established. Qualitative actions of the drugs on cardiac myocytes corresponded with results obtained from Purkinje fibers and measurement of QT interval prolongation in animal and human telemetry studies. METHODS AND RESULTS: Adult guinea pig ventricular myocytes were isolated by enzymatic digestion. Cells were continuously perfused with Tyrode's solution at 33-35 degrees C. Recordings were made using the whole-cell, patch clamp technique. Action potentials (APs) were elicited under current clamp. Voltage clamp was used to study the effect of drugs on I(Kr) (rapidly activating delayed rectifier potassium current), I(Na) (sodium current), and I(Ca) (L-type calcium current). Dofetilide increased the myocyte action potential duration (APD) in a concentration-dependent manner, with a pIC50 of 7.3. Dofetilide 1 microM elicited early afterdepolarizations (EADs) but had little affect on I(Ca) or I(Na). E-4031 increased APD in a concentration-dependent manner, with a pIC50 of 7.2. In contrast, 10 microM loratadine, desloratadine, and cetirizine had little effect on APD or I(Kr). Interestingly, cisapride displayed a biphasic effect on myocyte APD and inhibited I(Ca) at 1 microM. Even at this high concentration, cisapride did not elicit EADs. A number of AstraZeneca compounds were tested on cardiac myocytes, revealing a mixture of drug actions that were not observed in hERG currents in HEK293 cells. One compound, particularly AR-C0X, was a potent blocker of myocyte AP (pIC50 of 8.4). AR-C0X also elicited EADs in cardiac myocytes. The potencies of the same set of drugs on the cloned hERG channel also were assessed. The pIC50 values for dofetilide, E-4031, terfenadine, loratadine, desloratadine, and cetirizine were 6.8, 7.1, 7.3, 5.1, 5.2, and <4, respectively. Elevation of temperature from 22 to 35 degrees C significantly enhanced the current kinetics and amplitudes of hERG currents and resulted in approximately fivefold increase in E-4031 potency. CONCLUSION: Our study demonstrates the advantages of cardiac myocytes over heterologously expressed hERG channels in predicting QT interval prolongation and TdP in man. The potencies of some drugs in cardiac myocytes were similar to hERG, but only myocytes were able to detect important changes in APD characteristics and display EADs predictive of arrhythmia development. We observed similar qualitative drug profiles in cardiac myocytes, dog Purkinje fibers, and animal and human telemetry studies. Therefore, isolated native cardiac myocytes are a better predictor of drug-induced QT prolongation and TdP than heterologously expressed hERG channels. Isolated cardiac myocytes, when used with high-throughput patch clamp instruments, may have an important role in screening potential cardiotoxic compounds in the early phase of drug discovery. This would significantly reduce the attrition rate of drugs entering preclinical and/or clinical development. The current kinetics and amplitudes of the cloned hERG channel were profoundly affected by temperature, significantly altering the potency of one drug (E-4031). This finding cautions against routine drug testing at room temperature compared to physiologic temperature when using the cloned hERG channel.

Desloratadine: an update of its efficacy in the management of allergic disorders.

UNLABELLED: Desloratadine (Clarinex, Neoclarityn, Aerius, Azomyr, Opulis, Allex), the principal metabolite of loratadine, is itself an orally active, nonsedating, peripheral histamine H(1)-receptor antagonist. It is indicated in the US and Europe for the treatment of seasonal allergic rhinitis (SAR), perennial allergic rhinitis (PAR) and chronic idiopathic urticaria (CIU). It has a rapid onset of effect, efficacy throughout a 24-hour dosage interval, and sustained efficacy in these allergic conditions, as demonstrated in placebo-controlled trials of up to 6 weeks' duration in adult and adolescent patients. At present, there are no published direct comparisons of desloratadine and other H(1)-antihistamines; however, the principal, potential clinical advantages of desloratadine over late-generation H(1)-antihistamines are the drug's decongestant activity, which has been corroborated in several studies of patients with allergic rhinitis, and its anti-inflammatory effects. Indeed, the decongestant activity of desloratadine did not differ from that of pseudoephedrine in a trial in patients with SAR, and in patients with SAR and coexisting asthma, desloratadine reduced asthma symptoms and beta(2)-agonist use, and improved forced expiratory flow in 1 second. However, these issues warrant further study. Desloratadine is generally well tolerated. The overall incidence of adverse events in adults, adolescents and children was not significantly different to that with placebo, and similar proportions of desloratadine or placebo recipients reported events such as pharyngitis, dry mouth, myalgia, somnolence, dysmenorrhoea or fatigue. Desloratadine does not cause sedation or prolong the corrected QT (QTc) interval, can be administered without regard to concurrent intake of food and grapefruit juice, and appears to have negligible potential for drug interactions mediated by several metabolic systems. CONCLUSION: Although comparative studies with second-generation and other recently developed H(1)-antihistamines are needed to define the drug's clinical profile more clearly, desloratadine can be expected to claim a prominent place in the management of allergic disorders in general, and in the amelioration of specific symptoms of allergy (e.g. nasal congestion) in patients with such disorders.

Pharmacology and clinical efficacy of desloratadine as an anti-allergic and anti-inflammatory drug.

Desloratadine is a biologically active metabolite of the second-generation antihistamine loratadine. Desloratadine is a highly selective peripheral H1 receptor antagonist that is significantly more potent than loratadine. Results of in vitro and in vivo studies have suggested that desloratadine has anti-allergic effects that are unrelated to its ability to antagonise the effects of histamine. Desloratadine inhibits the expression of cell adhesion molecules, inhibits the generation and release of inflammatory mediators and cytokines, attenuates eosinophil chemotaxis, adhesion and superoxide generation. Studies in animals indicate that desloratadine does not cross the blood-brain barrier and therefore does not cause sedation and does not impair cognition or psychomotor performance. Desloratadine has an excellent overall safety profile. It has no effect on QRS and QTc intervals and does not cause arrhythmias. Desloratadine is not associated with any significant changes in gastrointestinal function. In clinical studies, oral desloratadine is rapidly absorbed and bioavailability is not affected by ingestion with food or grapefruit juice. The half-life of desloratadine in humans is 27 h; the linear kinetic profile is unaltered by race or gender. Desloratadine is not a substrate for P-glycoprotein or organic anion transport polypeptide and the drug does not appear to be metabolised to a significant extent by the cytochrome P450 CYP3A4 pathway. It therefore may be safely administered with ketoconazole, erythromycin, fluoxetine, or azithromycin. Clinically, desloratadine effectively controls both nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR), including nasal congestion. Desloratadine also provides significant relief of SAR symptoms in patients with co-existing asthma and is effective in the treatment of chronic idiopathic urticaria. Desloratadine improves quality of life and is well-tolerated.

Desloratadine: A new, nonsedating, oral antihistamine.

Desloratadine is a new, selective, H(1)-receptor antagonist that also has anti-inflammatory activity. In vitro studies have shown that desloratadine inhibits the release or generation of multiple inflammatory mediators, including IL-4, IL-6, IL-8, IL-13, PGD(2), leukotriene C(4), tryptase, histamine, and the TNF-alpha-induced chemokine RANTES. Desloratadine also inhibits the induction of cell adhesion molecules, plateletactivating factor-induced eosinophil chemotaxis, TNF-alpha-induced eosinophil adhesion, and spontaneous and phorbol myristate acetate-induced superoxide generation in vitro. In animals desloratadine had no effect on the central nervous, cardiovascular, renal, or gastrointestinal systems. Desloratadine is rapidly absorbed, has dose-proportional pharmacokinetics, and has a half-life of 27 hours. The absorption of desloratadine is not affected by food, and the metabolism and elimination are not significantly affected by the subject's age, race, or sex. There are no clinically relevant interactions between desloratadine and erythromycin, ketoconazole, or grapefruit juice. Desloratadine is not a significant substrate of the P-glycoprotein transport system. Once daily administration of desloratadine rapidly reduces the nasal and nonnasal symptoms of seasonal allergic rhinitis, including congestion. In patients with seasonal allergic rhinitis and concomitant asthma, desloratadine treatment was also associated with significant reductions in total asthma symptom score and use of inhaled beta(2)-agonists. Use of desloratadine in patients with chronic idiopathic urticaria was associated with significant reductions in pruritus, number of hives, size of the largest hive, and interference with sleep and daily activities. Clinical experience in over 2300 patients has shown that the adverse event profile of desloratadine is similar to that of placebo; desloratadine has no clinically relevant effects on electrocardiographic parameters, does not impair wakefulness or psychomotor performance, and does not exacerbate the psychomotor impairment associated with alcohol use.

Effects of methysergide and loratadine on food intake, mood, and performance of humans living in a residential laboratory.

The effects of loratadine, a peripherally acting histamine (H1) antagonist, and methysergide, a serotonin (5-HT) antagonist, were evaluated in seven normal-weight, male research volunteers, participating in a placebo-controlled, double-blind, 17-day residential study. Participants received oral loratadine (10 or 20 mg), methysergide (4 or 8 mg), or placebo at 1000 and 1700 hours daily. Active drug was administered on Days 4, 5, 7, 8, 11, 12, 15, and 16; placebo was administered on all other days. Drug and dose order were counterbalanced across participants. Food intake, performance, and subjective ratings were measured repeatedly throughout the day. Loratadine had no effect on food intake, performance, or subjective ratings. In contrast, total caloric intake significantly decreased from approximately 3500 kcal during placebo administration to 3065 kcal on the first but not the second day of methysergide administration. Consumption of carbohydrate (p < 0.055), protein, and fat decreased on the first day of methysergide administration. This decrease in food intake was due to a decrease in meal size; the number of meals consumed was not affected. The proportion of calories derived from carbohydrates significantly increased on the first day of methysergide administration. Methysergide also significantly impaired performance of a psychomotor task on the first day of high-dose administration and increased ratings of several subjective measures, including "Vomiting," "Stomach Pain," and "Miserable." These results suggest that the anorectic effect occurred as a result of the somatic and mood changes produced by methysergide. In addition, the inability of loratadine to affect food intake indicates that antagonism of central histamine receptors may be responsible for the increases in food intake produced by other antihistamines (e.g., diphenhydramine).