An Efficient, Green Chemical Synthesis of the Malaria\ud Drug, Piperaquine

To provide a robust, efficient synthesis of the malaria drug piperaquine for potential use in resource-poor settings. We used in-process analytical technologies (IPAT; HPLC) and a program of experiments to develop a synthesis of piperaquine that avoids the presence of a toxic impurity in the API and is optimized for overall yield and operational simplicity. A green-chemical synthesis of piperaquine is described that proceeds in 92 – 93 % overall yield. The chemistry is robust and provides very pure piperaquine tetraphosphate salt (> 99.5 %). The overall process utilizes modest amounts (about 8 kg/kg) of 2-propanol and ethyl acetate as the only organic materials not incorporated into the API; roughly 60 % of this waste can be recycled into the production process. This process also completely avoids the formation of a toxic impurity commonly seen in piperaquine that is otherwise difficult to remove. An efficient synthesis of piperaquine is described that may be useful for application in resource-poor settings as a means of expanding access to and reducing the cost of ACTs

Joint Medicines Regulatory Procedure in the East African Community: Registration Timelines and Way Forward

A review of the East African Community (EAC) joint regulatory review process was conducted, registration timelines analyzed and key milestones, challenges and opportunities documented for the period of July 2015 to January 2020. A total of 113 applications were submitted for joint scientific review. Among these, 109 applications were assessed, 57 were recommended for marketing authorisation, 52 applications had queries to applicants and four applications were under review. A total median approval time for all products ranged from 53 to 102 days. The maximum time taken by a regulator to review the dossier was 391 days and the minimum time was 44 days. For applicants, the maximum time to respond to queries was 927 days and the minimum time was nine days. The total median time for granting marketing authorisation by the National Medicines Regulatory Authorities (NMRA) decreased from 174 to 39 working days in 2015 and 2019 respectively. However, not all EAC NMRA has granted marketing authorisation to all 57 products due to non-payment of applicable fees by applicants. Long regulatory approval timelines were contributed by limited capacity for timely scientific review of dossier by some NMRA, lack of online portal to share dossiersand assessment reports, delay in responding to queries by applicants and deficiencies in dossier. The metric tool and register of medical products submitted for joint scientific review had incomplete data. Challenges were identified and actions recommended to ensure regional regulatory system optimization, efficiency, transparency, sustainability and accountability

Electronic structure and molecular orientation of a Zn-tetra-phenyl porphyrin multilayer on Si(111)

The electronic properties and the molecular orientation of Zn-tetraphenyl-porphyrin films deposited on Si(111) have been investigated using synchrotron radiation. For the first time we have revealed and assigned the fine structures in the electronic spectra related to the HOMOs and LUMOs states. This is particularly important in order to understand the orbital interactions, the bond formation and the evolution of the electronic properties with oxidation or reduction of the porphyrins in supramolecular donor-acceptor complexes used in photovoltaic devices.Comment: text 11 pages, 4 figures submitted for publicatio

Perceptual impairment and psychomotor control in virtual laparoscopic surgery

Background: It is recognised that one of the major difficulties in performing laparoscopic surgery is the translation of two-dimensional video image information to a three-dimensional working area. However, research has tended to ignore the gaze and eye-hand coordination strategies employed by laparoscopic surgeons as they attempt to overcome these perceptual constraints. This study sought to examine if measures related to tool movements, gaze strategy, and eye-hand coordination (the quiet eye) differentiate between experienced and novice operators performing a two-handed manoeuvres task on a virtual reality laparoscopic surgical simulator (LAP Mentor™). Methods: Twenty-five right-handed surgeons were categorised as being either experienced (having led more than 60 laparoscopic procedures) or novice (having performed fewer than 10 procedures) operators. The 10 experienced and 15 novice surgeons completed the "two-hand manoeuvres" task from the LAP Mentor basic skills learning environment while wearing a gaze registration system. Performance, movement, gaze, and eye-hand coordination parameters were recorded and compared between groups. Results: The experienced surgeons completed the task significantly more quickly than the novices, used significantly fewer movements, and displayed shorter tool paths. Gaze analyses revealed that experienced surgeons spent significantly more time fixating the target locations than novices, who split their time between focusing on the targets and tracking the tools. A more detailed analysis of a difficult subcomponent of the task revealed that experienced operators used a significantly longer aiming fixation (the quiet eye period) to guide precision grasping movements and hence needed fewer grasp attempts. Conclusion: The findings of the study provide further support for the utility of examining strategic gaze behaviour and eye-hand coordination measures to help further our understanding of how experienced surgeons attempt to overcome the perceptual difficulties inherent in the laparoscopic environment. © 2011 The Author(s).published_or_final_versionSpringer Open Choice, 21 Feb 201

Advice or exercise for chronic whiplash disorders? Design of a randomized controlled trial

BACKGROUND: Whiplash-associated disorder (or "whiplash") is a common condition incurring considerable expense in social and economic terms. A lack of research on effective therapy for patients with chronic whiplash associated disorders prompted the design of the current study. The primary aim of this randomised controlled trial is to determine the effects of a physical activity program for people with chronic (symptoms of > 3 months duration) whiplash. A secondary aim is to determine if pain severity, level of disability and fear of movement/(re)injury predict response to a physical activity program. METHODS / DESIGN: This paper presents the rationale and design of a randomised controlled trial examining the effects of advice and individualized sub-maximal exercise programs in the treatment of whiplash associated disorders. DISCUSSION: This paper highlights the design, methods and operational aspects of a significant clinical trial in the area of whiplash and chronic pain

Evaluation of molecular descriptors for antitumor drugs with respect to noncovalent binding to DNA and antiproliferative activity

34 pages, 6 additional files, 5 tables, 4 figures.[Background ] Small molecules that bind reversibly to DNA are among the antitumor drugs currently used in chemotherapy. In the pursuit of a more rational approach to cancer chemotherapy based upon these molecules, it is necessary to exploit the interdependency between DNA-binding affinity, sequence selectivity and cytotoxicity. For drugs binding noncovalently to DNA, it is worth exploring whether molecular descriptors, such as their molecular weight or the number of potential hydrogen acceptors/donors, can account for their DNA-binding affinity and cytotoxicity.[Results] Fifteen antitumor agents, which are in clinical use or being evaluated as part of the National Cancer Institute’s drug screening effort, were analyzed in silico to assess the contribution of various molecular descriptors to their DNA-binding affinity, and the capacity of the descriptors and DNA-binding constants for predicting cell cytotoxicity. Equations to predict drug-DNA binding constants and growth-inhibitory concentrations were obtained by multiple regression following rigorous statistical procedures.[Conclusions] For drugs binding reversibly to DNA, both their strength of binding and their cytoxicity are fairly predicted from molecular descriptors by using multiple regression methods. The equations derived may be useful for rational drug design. The results obtained agree with that compounds more active across the National Cancer Institute’s 60-cell line data set tend to have common structural features.Supported by a grant from the former Spanish Ministry of Education and Science (BFU2007-60998) and the FEDER program of the European Community.Peer reviewe