Reduction of side-effects from ultrarush immunotherapy with honeybee venom by pretreatment with fexofenadine: a double-blind, placebo-controlled trial

BACKGROUND: Immunotherapy with Hymenoptera venoms is highly effective but causes allergic side-effects frequently, especially when honeybee venom is used. Therefore, our objective was to investigate the effect of pretreatment with the antihistamine fexofenadine on the incidence of allergic side-effects during ultrarush immunotherapy with bee venom. METHODS: In a double-blind, placebo-controlled trial, 57 patients with a history of systemic allergic reactions to honeybee stings and positive diagnostic tests (skin tests, serum specific IgE to honeybee venom) were investigated. Bee venom immunotherapy was started with an ultrarush protocol and patients were randomized to pretreatment with either fexofenadine 180 mg or placebo on days 1, 8, 22, and 50 of the protocol. Local and systemic allergic side-effects were registered. RESULTS: Fifty-four patients completed the study, 28 on fexofenadine and 26 on placebo pretreatment. On day 1, large local reactions were significantly reduced in both extension and duration by fexofenadine pretreatment (P<0.025). Systemic allergic side-effects on the whole were not reduced. However, the symptoms pruritus, urticaria, and angioedema occurred less frequently with fexofenadine (P<0.05). CONCLUSIONS: Pretreatment with fexofenadine during venom immunotherapy reduces local allergic reactions and generalized symptoms of the urticaria and angioedema type.     

Fexofenadine, an H1-receptor antagonist, partially but rapidly inhibits the itch of contact dermatitis induced by diphenylcyclopropenone in patients with alopecia areata

Antihistamines have been used for the treatment of not only allergic diseases such as allergic urticaria and rhinitis, but also of eczematous skin diseases because of their anti-pruritic effects. Moreover, the pruritus associated with eczematous diseases is considered to be induced, in part, by histamine. However, it is unclear whether antihistamines inhibit the itch of eczematous diseases in the absence of topical corticosteroids. In this study, we investigated the anti-pruritic effect of the antihistamine, fexofenadine, on the itch of contact dermatitis that was induced by topical application of diphenylcyclopropenone for the treatment for alopecia areata. Thirteen patients with alopecia areata, who had been treated weekly with topical immunotherapy with diphenylcyclopropenone for 3 months to 2 years, recorded the severity of their itching on a visual analog scale before and 3, 6, 12, 24, 48 and 72 h after application of diphenylcyclopropenone for 4 consecutive weeks. Seven patients took fexofenadine during the first and third weeks, and six patients took fexofenadine during the second and fourth weeks. The severity of itching reached a maximum 6-12 h after the induction of the contact dermatitis in most of the patients. However, fexofenadine partially but rapidly reduced the severity of itching for 72 h during the entire period of treatment in the absence of topical corticosteroids. Our results suggest that fexofenadine can be beneficial in the daily management of patients with itching due to eczematous disease.     

新型镇痛药——盐酸他喷他朵

盐酸他喷他朵是一种新型的具有双重功效的中枢止痛剂,它既是μ型阿片受体激动剂同时又抑制中枢去甲肾上腺素再摄取,是迄今为止研发的第一个同时具有上述两种药理作用的单一分子药物。该药镇痛谱广,包括各种急性和慢性疼痛。对各种疼痛模型中包括神经病理性痛在内的多种大鼠疼痛模型有效,镇痛作用是吗啡的1/2～1/3。临床应用副反应轻微,耐受良好。     

Transport Characteristics of Fexofenadine in the Caco-2 Cell Model

PURPOSE: To investigate the membrane transport mechanisms of fexofenadine in the Caco-2 model. METHODS: Transport studies were performed in Caco-2 cell monolayers 21-25 days after seeding. The apparent permeability (Papp) of fexofenadine was determined in the concentration range 10-1000 microM in the basolateral-to-apical (b-a) and 50-1000 microM in the apical-to-basolateral (a-b) direction. The concentration-dependent effects of various inhibitors of P-glycoprotein (P-gp) (GF120918, ketoconazole, verapamil, erythromycin), multidrug resistant associated protein (MRP) (indomethacin, probenecid), and organic anion transporting polypeptide (OATP) (rifamycin SV) on the bidirectional transport of 150 microM fexofenadine were also examined. RESULTS: Fexofenadine displayed polarized transport, with the Pappb-a being 28- to 85-fold higher than the Papp(a-b). The Papp(a-b) was independent of the concentration applied, whereas Pappb-a decreased with increasing concentration (Vmax = 5.21 nmol cm(-2)s(-1) and K(M) = 150 microM), suggesting saturation of an apical efflux transporter. All four P-gp inhibitors had a strong, concentration-dependent effect on the Papp of fexofenadine in both directions, with GF 120918 being the most specific among them. The IC50 of verapamil was 8.44 microM on the P-gp-mediated secretion of fexofenadine. The inhibitors of OATP or MRP appeared not to affect the Papp(a-b) of fexofenadine in the Caco-2 model. CONCLUSIONS: This study clearly indicates that P-gp was the main transport protein of fexofenadine in the Caco-2 model. Even though P-gp was completely inhibited, fexofenadine was predicted to have a low fraction dose absorbed in humans due to poor intestinal permeability, and low passive diffusion seems to be the major absorption mechanism.     

Brain delivery of intranasal in situ gel of nanoparticulated polymeric carriers containing antidepressant drug: behavioral and biochemical assessment

This study was aimed for brain delivery of Tramadol HCl (centrally acting synthetic opioid) following intranasal administration for treatment of depression. Chitosan nanoparticles (NPs) were prepared by ionic gelation method followed by the addition of developed NPs with in the Pluronic and HPMC-based mucoadhesive thermo-reversible gel. Developed formulation optimized based on the various parameters such as particle size, entrapment efficiency, in vitro release study. Depression induction was done by forced swim test and evaluated by various behavioral and biochemical parameters. Furthermore, results showed significantly increased in locomotors activity, body weight as compared to control group. It also showed alteration in biochemical parameters such glutathione level and catalase levels significantly increased other than lipid peroxidation and nitrite level was found to be decreased after intranasal administration of formulation. Thus, intranasal TRM HCl NP-loaded in situ gel was found to be a promising formulation for the treatment of depression.     

盐酸特拉唑嗪片剂溶出度的研究

本文给出了盐酸特拉唑嗪片剂的累积溶出百分率 ,经测定 3批市售片剂的溶出度 ,均符合规定 ,有基于该类药品的质量标准中 ,多将溶出度测定列入正文 ,为此 ,进行研究提供生产及监督部门参考     

Levocetirizine has a longer duration of action on improving total nasal symptoms score than fexofenadine after single administration

AIMS: To compare the onset and duration of action of the new antihistamine levocetirizine with that of the second-generation antihistamine fexofenadine using the Vienna Challenge Chamber (VCC). The latter is an environment where subjects can be exposed to specific aeroallergens in controlled and reproducible conditions allowing for precise comparisons of anti-allergic drugs. METHODS: Ninety-four subjects received a single dose of levocetirizine 5 mg, fexofenadine 120 mg or placebo in a random order using a three-way cross-over design. On day 1, subjects were exposed to grass pollens (1500 grains/m(3)) in the VCC over a period of 4 h. Treatment was given 2 h after the start of challenge. On day 2, 22 h after drug intake, subjects were again exposed to pollens for 6 h. Specified symptoms were assessed by the subjects every 15 min using 5-point scales. The main efficacy parameter was the change from baseline in the Major Symptom Complex Score (MSCS = sum of rhinorrhea, sneezing, itchy nose and eyes). RESULTS: Baseline characteristics, including symptoms scores, were similar in the three study groups. During the first 2 h after drug intake both antihistamines achieved clinically relevant and significant (P < 0.001) improvements in symptom scores. Twenty-two to 24 h after drug intake, mean (SEM) MSCS reductions were: 1.9 (0.3) after placebo (baseline of 9.7), 3.8 (0.3) after fexofenadine (baseline of 9.9), and 5.1 (0.3) after levocetirizine (baseline of 9.8). Levocetirizine was significantly (P < 0.001) more effective than fexofenadine with a score difference of 1.3 (95% CI 0.7, 1.9). This was maintained until the end of the study (up to 28 h). CONCLUSIONS: A rapid onset of action in alleviating seasonal allergic rhinitis (SAR) symptoms of subjects exposed to grass pollens in the VCC was observed after levocetirizine and fexofenadine. Levocetirizine was more effective than fexofenadine at and later than 22 h after drug intake, an indication of the longer-duration of action of levocetirizine.     

Multimodal imaging for a theranostic approach in a murine model of B-cell lymphoma with engineered nanoparticles

Nanoparticles (NPs) are a promising tool for in vivo multimodality imaging and theranostic applications. Hyaluronic acid (HA)-based NPs have numerous active groups that make them ideal as tumor-targeted carriers. The B-lymphoma neoplastic cells express on their surfaces a clone-specific immunoglobulin receptor (Ig-BCR). The peptide A20-36 (pA20-36) selectively binds to the Ig-BCR of A20 lymphoma cells. In this work, we demonstrated the ability of core-shell chitosan-HA-NPs decorated with pA20-36 to specifically target A20 cells and reduce the tumor burden in a murine xenograft model. We monitored tumor growth using high-frequency ultrasonography and demonstrated targeting specificity and kinetics of the NPs via in vivo fluorescent reflectance imaging. This result was also confirmed by ex vivo magnetic resonance imaging and confocal microscopy. In conclusion, we demonstrated the ability of NPs loaded with fluorescent and paramagnetic tracers to act as multimodal imaging contrast agents and hence as a non-toxic, highly specific theranostic system.     

Penta-block copolymer microspheres: Impact of polymer characteristics and process parameters on protein release

Here, we aimed to develop protein loaded microspheres (MSs) using penta-block PLGA-based copolymers to obtain sustained and complete protein release. We varied MS morphology and studied the control of protein release. Lysozyme was used as a model protein and MSs were prepared using the solid-in-oil-in-water emulsion solvent extraction method. We synthesized and studied various penta-block PLGA-based copolymers. Copolymer characteristics (LA/GA ratio and molecular weight of PLGA blocks) influenced MS morphology. MS porosity was influenced by process parameters (such as solvent type, polymer concentration, emulsifying speed), whereas the aqueous volume for extraction and stabilizer did not have a significant effect. MSs of the same size, but different morphologies, exhibited different protein release behavior, with porous structures being essential for the continuous and complete release of encapsulated protein. These findings suggest strategies to engineer the morphology of MSs produced from PLGA-based multi-block copolymers to achieve appropriate release rates for a protein delivery system.     

Enhanced bioavailability of buspirone hydrochloride via cup and core buccal tablets: Formulation and in vitro/in vivo evaluation

This work aims to prepare sustained release buccal mucoadhesive tablets of buspirone hydrochloride (BH) to improve its systemic bioavailability. The tablets were prepared according to 5 × 3 factorial design where polymer type was set at five levels (carbopol, hydroxypropyl methylcellulose, sodium alginate, sodium carboxymethyl cellulose and guar gum), and polymer to drug ratio at three levels (1:1, 2:1 and 3:1). Mucoadhesion force, ex vivo mucoadhesion time, percent BH released after 8 h (Q8h) and time for release of 50% BH (T_50%) were chosen as dependent variables. Additional BH cup and core buccal tablets were prepared to optimize BH release profile and make it uni-directional along with the tablets mucoadhesion. Tablets were evaluated in terms of content uniformity, weight variation, thickness, diameter, hardness, friability, swelling index, surface pH, mucoadhesion strength and time and in vitro release. Cup and core formula (CA10) was able to adhere to the buccal mucosa for 8 h, showed the highest Q8h (97.91%) and exhibited a zero order drug release profile. Pharmacokinetic study of formula CA10 in human volunteers revealed a 5.6 fold increase in BH bioavailability compared to the oral commercial Buspar^® tablets. Conducting level A in vitro/in vivo correlation showed good correlation (r² = 0.9805) between fractions dissolved in vitro and fractions absorbed in vivo.