pD2-, pA2- and pD2'-values of a series of compounds in a histaminic and a cholinergic system.

(1) Affinity and intrinsic activity values of 75 compounds for a histaminergic and a cholinergic system are presented. The quantitative correlations between the affinity values of 35 compounds and some physicochemical constants (Van der Waals volume, lipophilicity, number of hydrogen atoms on the protonated amine) are discussed. (2) Absence of systematic differences between pD2 and pA2 of partial agonists supports the assumption that these values are equivalent expressions of the same affinity. (3) The "mimetic moiety" in a number of the antihistaminic test compounds hardly contributes to their affinity. The affinity mainly depends on an interaction tendency with additional receptor areas. (4) The correlation between pA2 and pD2' of the whole series of compounds in the histaminergic system is artificial. The method only allows determination of both values if their ratio lies between certain limits. (5) The correlation between pA2 and pD2' for 16 closely related compounds in the guinea pig ileum and for nearly all compounds in the rat intestine has to be explained by an influence of the structural differences on drug transference and/or the less specific binding forces. (6) The metactoid receptors in the two systems are different structures. (7) Possible molecular modifications to maximize the separation of antihistaminic form cholinergic affinity are suggested.     

Lipophilicity and brain disposition of clonidine and structurally related imidazolidines

Summary The apparent partition coefficients (P) of clonidine and 27 of its structurally related imidazolidines were determined in the octanol/buffer (pH=7.4) system as a measure of lipophilic behaviour. Lipophilicity of the imidazolidines is limited to the free bases and the principle of additivity is valid for this series of structurally similar compounds.Brain concentrations of clonidine and a number of its derivatives, achieved at the moment of maximal decrease in blood pressure, were determined following intravenous administration to anaesthetized rats. These brain concentrations represent the maximally attainable values. The ratio of log brain concentration/ dose administered intravenously, log (C_brain/C_i.v.), was employed as a measure of the penetration ability of the imidazolidines into the brain. The octanol/buffer (pH=7.4) system proved a satisfactory reference model in order to describe the transport process of the present imidazolidines from the blood to the brain. The penetration ability of these compounds into the brain could be expressed mathematically by a highly significant, parabolic relationship in log P. Ideal lipophilic character for optimal brain concentrations is connected with a log P value of 2.16.     

Development of multifocal duodenal erosions after anti-Helicobacter pylori triple therapy.

BACKGROUND AND PURPOSE: Anti-Helicobacter pylori triple therapy is effective for healing duodenal ulcer (DU) diseases and reducing disease recurrence. However, multifocal duodenal erosions or shallow ulcers may develop after triple therapy. The purpose of this study was to investigate the incidence and outcome of duodenal erosions that developed after triple therapy. METHODS: A total of 106 Taiwanese with active DU and with H. pylori infection were enrolled in this study. All patients received anti-H. pylori triple therapy (i.e., 2 weeks of antimicrobial agents combined with treatment for 4 to 6 weeks with acid suppression agents). Follow-up endoscopy was performed immediately after stopping treatment. The incidence of multifocal erosions or shallow ulcers over the bulb and/or second portion of the duodenum was studied. Additional acid suppression agent was given for 4 weeks whenever duodenal erosions or shallow ulcers were found. RESULTS: Out of 106 patients, 11 (10.4%) were found to have multifocal duodenal erosions and/or shallow ulcers on the duodenal bulb and/or second portion of the duodenum at the end of treatment. Ten of the 11 patients with newly developed erosions had healed DU in the S1 or S2 stage, and all 11 had successful H. pylori eradication. The duodenal erosions and/or shallow ulcers of these 11 patients were healed after an additional 4 weeks of histamine-2-receptor antagonist therapy. CONCLUSIONS: Multifocal duodenal erosions and/or shallow ulcers were noted in around 10% of Taiwanese DU patients who received anti-H. pylori triple therapy. An additional 4 weeks therapy with acid suppression agents healed these lesions.     

Follow-up of women after a first episode of postmenopausal bleeding and endometrial thickness greater than 4 millimeters

OBJECTIVE: To estimate the incidence of recurrent postmenopausal bleeding among women who were diagnosed with an endometrial thickness greater than 4 mm. METHODS: We designed a prospective cohort study and included consecutive women not using hormone replacement therapy, presenting with a first episode of postmenopausal bleeding. We evaluated patients who had an endometrial thickness greater than 4 mm at transvaginal ultrasonography and benign endometrial sampling; presence of carcinoma was ruled out by office endometrial sampling, hysteroscopy, and/or dilation and curettage. Time until recurrent bleeding was measured, and diagnosis at recurrent bleeding was recorded. RESULTS: Among 318 patients who had an endometrial thickness greater than 4 mm, 222 patients had benign histology results and were available for follow-up. During follow-up, 47 (21%, 95% confidence interval 16-27%) patients had recurrent bleeding, with a median time to recurrent bleeding of 49 weeks (interquartile range 18 to 86 weeks). There was no difference with respect to recurrence rate between patients with polyp removal, patients with a normal hysteroscopy, and patients with office endometrial sampling alone at the initial workup. Two patients were diagnosed with atypical endometrial hyperplasia upon recurrent bleeding. CONCLUSION: The recurrence rate of postmenopausal bleeding in women with endometrial thickness greater than 4 mm is 20%. This recurrence rate is not related to incorporation of hysteroscopy or polyp removal at the initial workup. LEVEL OF EVIDENCE: II.     

Intellectual property rights and traditional medicine: policy dilemmas at the interface

Traditional medicines play an important role in the provision of health care in many developing countries. Their use is also significant in developed countries, increasing their commercial value. Several 'high-profile' cases of patenting of traditional medicines, without consent from or compensation to their holders, have further focussed attention on their importance. Traditional medicine usually involves biological resources and the knowledge of local and indigenous peoples and/or healers regarding their medicinal use; thus, it is interlinked with biodiversity conservation and indigenous peoples' rights over their knowledge and resources. At this multi-faceted interface, complex ethical questions arise. This article provides an overview and discussion of key issues, dilemmas and challenges. It points to possible modifications and at ways to devise new forms of intellectual property ownership that may better suit the needs of those who seek to protect traditional medicine. Yet it also questions whether such protection, which may restrict access, is the preferred option.While intellectual property protection for traditional medicines has multiple and diverse objectives, the priorities are often not clear and the strategies which could be deployed may interfere with each other, as well as with the prioritization of objectives. This is further aggravated by differences in stakeholders' concepts on ownership of knowledge and by uncertain or paradoxical effects of some potentially useful strategies. Thus, policymakers should address the multiple, multi-layered issues and questions, and try to develop a range of solutions in order to address and balance the various objectives and interests.     

Visfatin Polymorphisms,Lifestyle Risk Factors and Risk of Oral Squamous Cell Carcinoma in a Cohort of Taiwanese Males

Oral cancer is the eighth greatest generally diagnosed cancer amongst males worldwide and the fourth most generally malignancy amongst Taiwanese males. The pro-inflammatory adipocytokine visfatin promotes tumor growth. Elevated plasma visfatin levels have been identified in patients with oral squamous cell carcinoma (OSCC), although the biological mechanisms underlying the involvement of visfatin in the pathogenesis of OSCC are not well understood. Moreover, no information is available regarding associations between visfatin polymorphisms and carcinogenic lifestyle factors with OSCC. This study, therefore, investigated the effects of four visfatin gene polymorphisms (rs11977021, rs61330082, rs2110385, and rs4730153) and carcinogenic lifestyle factors (betel nut chewing, alcohol consumption and cigarette smoking) on the risk of developing OSCC in 1,275 Taiwanese males with OSCC, and 1,195 healthy males (controls). We also examined the associations between these visfatin genotypes and OSCC histopathological prognostic factors (pathological stage, tumor status, lymph node status, and metastasis). We found that compared with subjects with the CC genotype of SNP rs11977021, those with the CT+TT genotype were less likely to progress OSCC. In addition, an association was found between the rs4730153 variant and lymph node metastasis in the OSCC cohort.