Structure-based drug design and the discovery of aliskiren (Tekturna): perseverance and creativity to overcome a R&D pipeline challenge

At Ciba-Geigy (now Novartis), the clinical development of the CGP38560 renin inhibitor was halted due to insufficient pharmacokinetics. This indicated that the peptidomimetic approach to the development of antihypertensive agents was improper. Real non-peptide drug candidates were then expected to provide the necessary framework for obtaining the desired properties. For this purpose a homology model of the enzyme was used to characterize the binding mode of CGP38560 in complex with the renin model and served as a basis for the four chemistry laboratories that were assigned to this project. The renin team worked in a full structure-based perspective with this model, and four chemically-unrelated non-peptide series were discovered acting as renin inhibitors at the 1-3 nanomolar level. One of these leads was selected for further development and led to Aliskiren, which has been just approved by the FDA. Here is presented the successful structure-based strategy that enabled the discovery of several non-peptide inhibitors and the recent launch of a new drug that will be commercialized in the United States under the name Tekturna (for the treatment of high blood pressure as monotherapy or in combination with other high blood pressure medications).     

Problem-based learning in Guyana: a nursing education experiment

O'CONNOR J. & CARR A. (2011) Problem-based learning in Guyana: a nursing education experiment. International Nursing Review59, 376-379 Aim: This paper invites the reader into sharing a journey of change through a new curriculum grounded in a problem-based learning (PBL) approach to education in the first year of a diploma nursing programme in Guyana. Background: In Guyana, students are trained using traditional teaching methods: lectures and a single, often outdated, text. The authors had been dissatisfied previously with their students' knowledge retention, critical thinking skills and application abilities. The authors became advocates for change through the introduction of a PBL approach in nursing education within their school. Methods: PBL is quite different from 'problem solving', and the goal of learning is not to solve the problem, which has been presented. Rather, the problem is used to help students identify their own learning needs as they attempt to understand the problem, to pull together, synthesize and apply information to the problem, and to begin to work effectively to learn from group members as well as tutors. Students met in small groups to identify the problem; explore their pre-existing knowledge; generate hypotheses and possible mechanisms; and identify learning issues. Conclusion: Students in their first exposure to self-directed, small group learning can immediately thrive as active learners with minimal guidance and support. The programme was evaluated with the admission and scoring of homework/exams based on the school syllabus for the individual courses; and continual small group oral as well as a final written qualitative evaluation. Specific positive and negative learning factors are addressed.     

Cancer incidence among male Danish nurses, 1980–2003

KJAER T.K., & HANSEN J. (2010) Cancer incidence among male Danish nurses, 1980–2003. International Nursing Review 57 , 211–216 Background: The cancer risk of female nurses has been examined in several studies, but none has addressed the risk of male nurses, although they may be exposed to the same carcinogens as female nurses. In this register‐based cohort study, we explored cancer incidence among male Danish nurses. Methods: We identified 3369 male nurses from the files of the Danish Nurses Association and followed them up from 1980 to 2003 in the Danish Cancer Registry. Standardized incidence ratios (SIRs) and 95% confidence intervals were calculated on the basis of standardized national rates. We compared the nurses with 3369 other male employees matched to the nurses by year of birth on social variables (vital and marital status). Findings: We observed 90 cancers in the cohort, with significantly increased SIRs for sarcomas and decreased SIRs for cancers of the respiratory system. When the cohort was stratified by educational generation and birth cohort, we observed significantly elevated relative risks for cancers of the brain and nervous system among the youngest nurses and for sarcomas among nurses in all educational generations and those born between 1945 and 1954. Conclusion: The overall risk for cancer among male Danish registered nurses is similar to that of the general male Danish population. The high SIRs observed for cancers of the brain and nervous system merit further attention. The high relative risks for sarcomas and connective tissue tumours reflect a large proportion of cases of Kaposi sarcoma, which is probably not occupationally related.     

梅毒防治中值得重视的几个问题

本文以循证医学的观点,阐述了梅毒等性病防治应以生物一心理一社会医学模式为基点。提示了临床流行病学在梅毒预防控制中的重要作用。     

健康国人年龄性别对主要脑底动脉血流速度的影响及其检测方法的探讨

应用多普勒技术探测颅外脑血管血流速度,1965年由Miyazaki等首先报告,然而,由于骨骼严重衰减超声波,故使用5～10MHz探测频率难以记录颅内血管的血流速度。1982年Aaslid报告了应用脉冲多普勒技术,通过调整取样深度,观察了颅内脑动脉的血流速度,此后,颅内主要脑底动脉的血液动力学变化,以及无创手段对频内脑血管血流速度的监测得到了广泛的研究和深入的开展。我们心功能科自1988年12月引进美国Meda Sonics经颅超声多普勒(TCD)诊断仪以来     

Cause-specific stillbirth and neonatal death in Sweden: a catchment area-based analysis

A register-based study of the impact of obstetric and neonatal care on stillbirth and neonatal death rate was performed on all births in Sweden in 1983-1995. Each birth was assigned to a primary delivery hospital where the mother with a term singleton pregnancy was most likely to have been delivered (not possible for 25% of the deliveries), and the catchment areas of each hospital were classified according to the level of care of that hospital. Only small differences in total mortality existed between the different levels of care of the primary hospital: areas served by primary hospitals with obstetric service and resources for neonatal intensive care including continuous positive airway pressure but without facilities for ventilator treatment for prolonged periods showed a 7% excess risk of stillbirth or neonatal death.     

循证医学与高血压

循证医学是临床流行病学与临床医学结合的产物，它强调在个人临床经验的基础上，任何医疗决策的确定都应以客观的科学研究为依据。循证医学在高血压定义的确立、目标血压的制定和治疗药物选择中具有重要的指导意义，但在具体应用时须进行辨证分析。     

Structural Basis for Complementary and Alternative Medicine: Phytochemical Interaction with Non-Structural Protein 2 Protease—A Reverse Engineering Strategy

Objective: To understand the druggability of the bioactive compounds from traditional herbal formulations "Nilavembu Kudineer" and "Swasthya Raksha Amruta Peya" to heal chikungunya virus (CHIKV) infection. Methods: The efficiency of twenty novel chemical entities from "Nilavembu Kudineer" and "Swasthya Raksha Amruta Peya" to inhibit CHIKV infection in silico were evaluated. Ligands were prepared using Ligprep module of Schr?dinger. Active site was identified using SiteMap program. Grid box was generated using receptor grid generation wizard. Molecular docking was carried out using Grid Based Ligand Docking with Energetics (GLIDE) program. Results: Molecular docking studies showed that among twenty compounds, andrographoside, deoxyandrographoside, neoandrographolide, 14-deoxy-11-oxoandrographolide, butoxone and oleanolic acid showed GLIDE extra precision (XP) score of –9.10, –8.72, –8.25, –7.38, –7.28 and –7.01, respectively which were greater than or comparable with chloroquine (reference compound) XP score (–7.08) and were found to interact with the key residues GLU 1043, LYS 1045, GLY 1176, LEU 1203, HIS 1222 and LYS 1239 which were characteristic functional unit crucial for replication of CHIKV. Conclusion: The binding affinity and the binding mode of chemical entities taken from herbal formulations with non-structural protein 2 protease were understood and our study provided a novel strategy in the development and design of drugs for CHIKV infection.