卡介菌多糖核酸和抗组胺药物联合治疗慢性特发性荨麻疹的临床疗效观察

目的:探讨免疫调节剂卡介菌多糖核酸联合抗组胺药物对慢性特发性荨麻疹的治疗效果,分析治疗机理,为慢性荨麻疹的临床治疗提供参考。方法:将220例慢性特发性荨麻疹患者随机分为观察组(卡介菌多糖核酸联合抗组胺药物治疗)和对照组(抗组胺药物治疗),比较两组的治疗效果。结果:观察组治疗总有效率高于对照组(92.7%vs 78.2%),两组比较,P<0.05,差异有统计学意义。治疗后随访3个月,观察组荨麻疹患者皮肤点刺试验阳性率均低于对照组,两组比较,P<0.05。结论:卡介菌多糖核酸联合抗组胺药物治疗慢性特发性荨麻疹可对患者机体致敏原的耐受性进行较好的调节,降低患者机体对致敏原的敏感性,缓解患者的主客观症状。     

Efficacy of terfenadine in the treatment of common cold. A double-blind comparison with placebo

Summary We have assessed the effects of terfenadine on rhinitis symptoms associated with the common cold in 91 patients in a double-blind placebo-controlled study. The patients received three doses of either terfenadine 60 mg (n=44) or placebo (n=47) at about 12-h intervals, starting in most patients within 48 h from the onset of symptoms. Because of deviations from the protocol, 28 cases were classified as not eligible for efficacy evaluation, but were nevertheless analysed.Excellent/good or moderate efficacy was reported by 63% of eligible and 59% of all patients who received terfenadine (placebo 40% and 51% respectively,p=0.049 and 0.113 respectively). 68% of eligible and 52% of all patients indicated that they would take terfenadine again (placebo 23%, for bothp=0.002). Two h after tablet intake mean nasal airflow was increased by 11 l·min^–1, SD 8 (placebo –1 l·min^–1, SD 6,p=0.005). Symptoms were improved and rhinoscopy showed reduced swelling and redness of the mucosa and reduced nasal secretion and obstruction (basically unchanged in the placebo group).Therefore, terfenadine seems to act favourably on the acute rhinitis symptoms associated with the common cold. Since terfenadine is devoid of anticholinergic activity, nose symptoms during the initial stage of the common cold may be mediated to an important degree by histamine.     

Correlation between histamine-induced neuronal excitability and activation of adenylate cyclase in the guinea pig hippocampus

In a homogenate of guinea pig hippocampus histamine activated adenylate cyclase and in a hippocampal slice preparation it increased the firing rate of pyramidal cells in the CA3 region. Both activities were apparently mediated by H2 receptors. The concentration of histamine and of the H2 receptor agonist, impromidine, required to stimulate activity was similar in each test preparation with impromidine being about 100-fold more potent than histamine. Moreover, the H2 receptor antagonists, cimetidine and ICIA 5165, each reversed the activation by histamine of the two test preparations, with ICIA 5165 being about 100-fold more potent than cimetidine. Thus, there is a correlation between activation of cyclase and neuronal excitability induced by histamine. These observations support a large body of evidence suggesting that histamine is a neurotransmitter or modulator in the CNS.     

Comparison of pharmacokinetics and metabolism of desloratadine, fexofenadine, levocetirizine and mizolastine in humans

Abstract Absorption, distribution, metabolism and excretion of desloratadine, fexofenadine, levocetirizine, and mizolastine in humans have been compared. The time required to reach peak plasma levels (tmax) is shortest for levocetirizine (0.9 h) and longest for desloratadine (> or =3 h). Steady-state plasma levels are attained after about 6 days for desloratadine, 3 days for fexofenadine, 2-3 days for mizolastine and by the second day for levocetirizine. The apparent volume of distribution is limited for levocetirizine (0.4 L/kg) and mizolastine (1-1.2 L/kg), larger for fexofenadine (5.4-5.8 L/kg) and particularly large for desloratadine (approximately 49 l/kg). Fexofenadine and levocetirizine appear to be very poorly metabolized (approximately 5 and 14% of the total oral dose, respectively). Desloratadine and mizolastine are extensively metabolized. After administration of 14C-levocetirizine to healthy volunteers, 85 and 13% of the radioactivity are recovered in urine and faeces, respectively. In contrast, faeces are the preferential route of excretion for 14C-fexofenadine (80% vs. 11% of the radioactive dose in urine). The corresponding values are 41% (urine) and 47% (faeces) for 14C-desloratadine, 84-95% (faeces) and 8-15% (urine) for 14C-mizolastine. The absolute bioavailability is 50-65% for mizolastine; it is high for levocetirizine as the percentage of the drug eliminated unchanged in the 48 h urine is 77% of the oral dose; the estimation for fexofenadine is at least 33%; no estimation was found for desloratadine. Fexofenadine is a P-glycoprotein (P-gp) substrate and P-gp is certainly involved both in the poor brain penetration by the compound and, at least partially, in a number of observed drug interactions. An interaction of desloratadine with P-gp has been suggested in mice, whereas the information on mizolastine is very poor. The fact that levocetirizine is a substrate of P-gp, although weak in an in vitro model, could contribute to prevent drug penetration into the brain, whereas it is unlikely to be of any clinical relevance for P-gp-mediated drug interactions.     

Action of H1 and H2 inhibitors on the response of histamine sensitive adenyly cyclase from guinea-pig mucosa.

In the guinea-pig, it has been shown that homogenates of mucosa from the fundus contain an adenylyl cyclase system that is activated by histamine as well as by prostaglandins PGE1 and PGA1. The effects of burimamide, an H2-inhibitor, and mepyramine and chlorpheniramide, both H1-inhibitors, were tested. Both H1 and H2 inhibitors behaved kinetically as competitive inhibitors of histamine, but the Km derived for burimamide (2.5 - 4.1 . 10(-5)) was significantly lower than that for either chlorpheniramine (0.9 - 1.9 . 10(-4)) or mepyramine (1.3 - 1.4 . 10(-4)). On the other hand none of the three inhibitors influenced the cyclase activation by PGE1 and PGA1. These results suggest that there are at least two types of receptors in the preparation studied, one responsive to histamine and the other to the prostaglandins, and that the specificity of H1- and H2-receptors is not absolute in the broken cell preparation.     

Caring for patients with allergic rhinitis

PURPOSE: Allergic rhinitis (AR) affects up to 40 million Americans, with an estimated cost of $2.7 billion per annum. This review discusses several therapeutic options that reduce the symptoms of AR, including allergen avoidance, antihistamines, intranasal corticosteroids (INS), leukotriene receptor antagonists, and immunotherapy. DATA SOURCES: The articles included in this review were retrieved by a search of Medline literature on the subjects of AR, antihistamines, INS, leukotriene antagonists, and immunotherapy, as well as current published guidelines for the treatment of AR. CONCLUSIONS: Allergen avoidance is recommended for all patients prior to pharmacologic therapy. Oral and nasal H(1)-antihistamines are recommended to alleviate the mild and intermittent symptoms of AR, and INS are recommended as the first-line treatment choice for mild persistent and more moderate-to-severe persistent AR. IMPLICATIONS FOR PRACTICE: There are a number of different types of therapy for the management of AR; with so many options available, successful tailoring of treatment to suit individual requirements is realistically achievable.     

Highly selective N-glucuronidation of four piperazine-containing drugs by UDP-glucuronosyltransferase 2B10

Background: N-glucuronidation is known to be an important metabolic pathway for detoxification and elimination of drugs containing aromatic amines. However, the metabolic pathways for piperazine-containing drugs are not fully established.

Methods: N-glucuronidation potential of four piperazine-containing drugs, namely two antihistamines (i.e. cyclizine and chlorcyclizine) and two tetracyclic antidepressants (i.e. mirtazapine and mianserin), was determined by using expressed UDP-glucuronosyltransferase (UGT) enzymes and liver microsomes from both human and animals.

Results: Among 13 expressed UGT enzymes, only UGT1A4 and UGT2B10 showed conjugating activities toward these four drugs. Reaction phenotyping, chemical inhibition, and activity correlation analysis revealed that UGT2B10 was a high-affinity enzyme and mainly responsible for hepatic N-glucuronidation of all drugs except mianserin. Both UGT1A4 and UGT2B10 were important contributors to mianserin N-glucuronidation. Moreover, significant species differences were observed in N-glucuronidation of all test drugs. In particular, liver microsomes from four experimental animals (i.e. mouse, rat, dog, and monkey) showed none or negligible activity in catalyzing N-glucuronidation of four drugs.

Conclusions: UGT2B10 plays a critical role in N-glucuronidation of piperazine-containing drugs. Also, conventional experimental animals might be inappropriate models for studying human N-glucuronidation.

Abbreviations: CL_int: intrinsic clearance; CL_max: maximal clearance; HLM: human liver microsomes; K_m: Michaelis–Menten constant; K_i: substrate inhibition constant; MS: mass spectroscopy; NNAL: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; QTOF: Quadrupole time-of-flight; S₅₀: the substrate concentration resulting in 50% of V_max; UDP-GlcA: uridine diphosphoglucuronic acid; UGT: UDP-glucuronosyltransferase; UPLC: ultra performance liquid chromatography; V_max: maximal velocity.