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91.
H Rollema A Shrikhande KM Ward FD Tingley III JW Coe BT O'Neill E Tseng EQ Wang RJ Mather RS Hurst KE Williams M de Vries T Cremers S Bertrand D Bertrand 《British journal of pharmacology》2010,160(2):334-345
Background and purpose:
Smoking cessation trials with three high-affinity partial agonists of α4β2 neuronal nicotinic acetylcholine receptors (nAChRs) have demonstrated differences in their clinical efficacy. This work examines the origin of the differences by taking into account brain exposure and pharmacological effects at human α4β2 nAChRs.Experimental approach:
Rat plasma and brain pharmacokinetics were characterized and used to predict human steady-state plasma and brain concentrations following recommended doses of each of the three compounds. The pharmacological characterization included in vitro affinities at different nAChR subtypes, functional efficacies and potencies at the human α4β2 nAChR, as well as in vivo effects on rat mesolimbic dopamine turn-over.Key results:
A comparison of predicted human brain concentrations following therapeutic doses demonstrated that varenicline and nicotine, but not dianicline and cytisine, can extensively desensitize and, to a lesser extent, activate α4β2 nAChRs. The limited clinical efficacy of dianicline may be accounted for by a combination of weak functional potency at α4β2 nAChRs and moderate brain penetration, while recommended doses of cytisine, despite its high in vitro potency, are predicted to result in brain concentrations that are insufficient to affect α4β2 nAChRs.Conclusions and implications:
The data provide a plausible explanation for the higher abstinence rate in smoking cessation trials following treatment with varenicline than with the two other α4β2 nAChR partial agonists. In addition, this retrospective analysis demonstrates the usefulness of combining in vitro and in vivo parameters with estimated therapeutic human brain concentrations for translation to clinical efficacy. 相似文献92.
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Characteristics of a large cohort of patients with diabetes having at‐risk feet and outcomes in patients with foot ulceration referred to a tertiary care diabetes unit 下载免费PDF全文
Musarrat Riaz Zahid Miyan Syed I Zaidi Syed FD Alvi Asher Fawwad Muhammad Y Ahmadani Asim B Zafar Rayaz A Malik Abdul Basit 《International wound journal》2016,13(5):594-599
To identify in a large population cohort the clinical and biochemical characteristics of patients with diabetes at risk of foot ulceration and outcomes in those with foot ulcers. All patients with diabetes attending Baqai Institute of Diabetology and Endocrinology from January 2004 to April 2012 included in the study. Clinical, biochemical and socio‐demographic data were collected and patients were categorised into those at no risk of ulceration, at risk of ulceration and those with foot ulcer, according to the University of Texas classification. Patients with foot ulceration followed for their final outcome, that is complete healing, persisted non‐healed ulcer, lower extremity amputation, lost to follow‐up or death. A total of 18 119 patients with diabetes underwent assessment, 3576 (19·7%) patients defined as at high risk for foot ulceration and 3731 (20·6%) presented with foot ulcer. Age, male gender, hypertension, higher glycated haemoglobin (HbA1c), history of smoking and presence of neuropathy were risk factors (P < 0·000) for foot ulceration. Amputation rate in patients with foot ulceration was significantly related to severity of ulceration at presentation. Preventive foot care practices were followed by 19·02% patients. One thousand eight hundred seventy three (50·2%) patients completely healed, 293 (11%) patients underwent amputation and 397 (10·1%) patients continued to be treated in the foot clinic. All patients with diabetes should be screened for neuropathy to identify those at risk of foot ulceration, as it is the major contributory factor for foot ulceration. The final outcome of foot ulceration was determined by the severity and grade of ulcer at presentation. 相似文献
96.
为了评估美国内科委员会(American Board of Internal Medicine,ABIM)开展的实践改善单元(Practice Improvement Module,PIM)教育活动的效果,以及参与心脏疾病预防PIM教育活动的专科医师临床实践改善的表现,美国内科委员会进行了一项以自我指导为基础的观察研究. 相似文献
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Perumal Venkatachalam Solomon FD Paul Balasubramonian Karthikeya Prabhu Mary N Mohankumar Rani K Jeevanram 《Journal of Medical Imaging and Radiation Oncology》2001,45(4):464-471
The frequency of different biological end‐points such as translocation, dicentrics (DC) and micronuclei (MN) was studied in 14 radiation workers and 21 non‐radiation workers. The average frequencies for different types of aberrations were significantly higher in radiation workers compared to those of respective aberrations in non‐radiation workers. Out of 14 radiation workers, eight subjects showed a dose above the detection limit as per translocation and seven subjects as per DC frequency and no patient showed a dose above the detection limit as per MN frequency. Regression analysis carried out between the recorded doses according to Thermo Luminescence Dosimeter (TLD) and the dose estimated as per translocation frequency gave a correlation coefficient of 0.32, whereas that obtained with TLD dose and the dose estimated as per DC was 0.81. When the correlation was made between the TLD dose, which was above 0.15 Gy (the detection limit for translocation), and the dose estimated as per translocation frequency in these subjects, a correlation coefficient of 0.98 was found. A similar analysis between the TLD dose above 0.5 Gy (the detection limit for DC) and the dose estimated as per DC frequency in these subjects, a correlation coefficient of 0.26 resulted. This paper discusses the reasons for the poor correlation obtained between TLD dose and dose estimated as per DC and MN frequency. 相似文献
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