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An early study of the plasma disposition of 1 mg Konakion given orally or intra- muscularly at birth showed wide inter-individual differences during the first 24 h anima sound medicine buy generic levaquin 750mg, especially after oral administration (McNinch et al treatment abbreviation order levaquin with a visa. The peak plasma concen- tration after an oral dose occurred after 4 h; the median concentration was 73 ng/mL in treatment generic levaquin 500mg visa, which fell to 23 ng/mL after 24 h. The plasma concentration after administration of 1 mg of Konakion intramuscularly exceeded those after oral administration at all times, and after 24 h the median was 444 ng/mL. Physiologically, these concentrations compare with adult endogenous levels of about 0. By 24 days, the concentrations in both groups were mainly within the adult physiological range (0. In this study, however, the plasma concentrations after 24 days were significantly higher after intramuscular injection, consistent with the hypothesis of the depot effect of intramuscular phyllo- quinone (Loughnan & McDougall, 1996; see also section 4. They calculated from published studies that a realistic estimate of the terminal plasma half-time in neonates was 26–193 h (median, 76 h), as compared with 8–22 h (median, 14 h) in adults after intravenous administration (Øie et al. This longer terminal half- time may reflect the poorly developed organ systems of neonates and a reduced capacity to metabolize and excrete vitamin K (Stoeckel et al. The plasma profile of an oral dose of this preparation in five-day- old infants appeared to be similar to that of phylloquinone; after a 4-mg dose, a peak concentration of about 100 ng/mL was achieved after 3–4 h, before declining to about 30 ng/mL by 12 h (Shinzawa et al. The liver has often been assumed to be a major depot for vitamin K because it is the site of synthesis of the vitamin K-dependent coagulation proteins. Measurements of phyllo- quinone in livers obtained at autopsy from 32 adults in the United Kingdom revealed hepatic concentrations ranging from 1. Similar hepatic concentrations of phylloquinone were found in a smaller number of analyses of post-mortem samples from adults in Japan (10 ng/g) (Uchida & Komeno, 1988) and in The Netherlands (11 ng/g) (Thijssen & Drittij-Reijnders, 1996). The distribution of the various forms of vitamin K in the liver is quite different from that in plasma in that the major transport form, phylloquinone, represents the minority of total hepatic stores (about 10%); the remainder comprises bacterial menaquinones, mainly menaquinones- 6–13 (Shearer et al. The pattern of individual menaquinones in the liver varies considerably between individuals (Shearer et al. This proposal is supported by the finding that two menaquinones, -10 and -11, which are major forms in most liver samples (Uchida & Komeno, 1988; Thijssen & Drittij- Reijnders, 1996), are known to be synthesized by Bacteroides species which are predom- inant members of the human intestinal flora (Conly & Stein, 1992); yet menaquinone- 10 and menaquinone-11 do not make appreciable contributions to normal diets (Shearer et al. The concentration in the heart (~5 ng/g) [~10 pmol/g] is comparable to those in the liver, and even higher concen- trations (~13 ng/g) [~25 pmol/g] are found in the pancreas, but lower concentrations (< 1 ng/g) [< 2 pmol/g] were detected in brain, kidney and lung. These tissues do not appear to contain appreciable concentrations of menaquinones except for the short- chain menaquinone-4. Particularly high concentrations of menaquinone-4 relative to phylloquinone are present in the kidney, brain and pancreas. Although these and other tissues contain the enzymes of the vitamin K epoxide cycle (see Figure 1) and carry out vitamin K-dependent carboxylation of protein precursors, this would not appear to account for the tissue-specific accumulation of menaquinone-4 and may suggest a hitherto unrecognized physiological role for menaquinone-4 in certain tissues (Shearer, 1992; Thijssen & Drittij-Reijnders, 1996). Indeed, menaquinone-4 may arise by tissue synthesis from phylloquinone itself (Davidson et al. Osteocalcin is a major vitamin K-dependent bone protein synthesized by osteo- blasts and therefore requires a source of vitamin K for γ-glutamyl carboxylation. Both trabecular and cortical bone contain ample reserves of vitamin K, with phylloquinone predominating and smaller amounts of shorter-chain menaquinones (Hodges et al. With the absence of the typical hepatic forms menaquinones- 10–13, the vitamin K content of bone resembles that of other extrahepatic tissues. The endogenous stores of vitamin K in the liver of the newborn differ both quantitatively and qualitatively from those of adults because the concentrations and total reserves of phylloquinone are lower than those of adults (Shearer et al. The carboxylation reaction is driven by a vitamin K-dependent carboxylase activity (1) coupled to vitamin K- epoxidase activity (1) which simultaneously converts vitamin K quinol to vitamin K 2,3-epoxide. Vitamin K 2,3-epoxide is reduced back to the quinone by vitamin K epoxide reductase (2A). The cycle is completed by the reduction of recycled vitamin K quinone by vitamin K reductase activity (2B). The activities of both vitamin K epoxide (2A) and vitamin K reductase (2B) are dithiol-dependent (dithiol and disulfide denote reduced and oxidized dithiols) and are inhibited by coumarin anticoagulants such as warfarin. The median hepatic con- centration of 1 ng/g in term infants is equivalent to a total liver pool of about 0.
There is a widely held view within the drugs field that the current legal framework has failed to deliver its intended goals of reducing illicit drug use symptoms 7 days past ovulation buy cheap levaquin 250mg on-line. There are strong views on both sides of this debate symptoms after flu shot cheap levaquin 500mg mastercard, but it should be informed by the best evidence medicine 48 12 purchase levaquin online from canada. While it must be accepted that international consensus dictates that supply and possession of illicit drugs must remain a criminal offence, this framework deserves to be re-examined in a way that takes account of all the evidence available. Doctors are ideally placed to play a key role in refocusing debate and influencing global drug policy, so that it is based on public health principles, and founded on rigorous scientific evidence. Dr James Bell Professor Bailey was dual trained in child Consultant in Addictions Medicine, and adolescent psychiatry and forensic South London and Maudsley psychiatry. Dr Bell has been complex mental health needs who present active in the development of training as high risk of harm to others and programmes for health professionals, and themselves. She has worked in specialist was a leading figure in establishing the inpatient and community services, and has Chapter of Addiction Medicine within the interests in human rights in practice, and Royal Australasian College of Physicians. His mental health and social care policy in major research interest is the treatment of national and international contexts. Through opioid dependence but he has also recently various roles in the Royal College of developed a ‘party drugs’ clinic in South Psychiatrists, Professor Bailey has worked London, and has been involved in to support stronger partnerships between developing a new clinical pathway for users, carers and families. She has sought to management of acute alcohol withdrawal increase recognition of the importance of presenting to emergency departments. He has been Declaration of interests: funded to attend conferences and seminars Professor Bailey declares no support from by Reckittbenckiser, Schering-Plough any organisation for the submitted work and Corporation and Titan Pharmaceuticals. The Foundation has organised Addiction Psychiatry at the Chelsea and nine influential international drug policy Westminster Hospital and Honorary Senior seminars, hosted mainly at the House of Lecturer at Imperial College. He oversees Lords, and has commissioned over 35 books, three teams providing treatment for alcohol, drug policy reports and proceedings drugs and mental health problems. Dr Bowden-Jones is the drugs conventions that would give individual Chair of the Faculty of Addictions, Royal signatory countries more freedom to College of Psychiatrists. In this role he sits on experiment with alternative drug policies; a number of working groups. The position and (2) A cost/benefit analysis of a regulated also requires regular meetings with and taxed cannabis market in England and Government and other professional groups. Declaration of interests: Amanda Feilding declares that she has no conflicts of interests. Emily is Clinical Director for the Addictions Clinical Professor Sir Ian Gilmore Academic Group, with responsibility for Immediate Past President, addiction services across Lambeth, Royal College of Physicians Southwark, Bexley, Greenwich and Croydon, Professor Sir Ian Gilmore is a Professor of and inpatient services based at the Maudsley Medicine at the University of Liverpool and Hospital. From 2004 to 2007, Emily was the was a consultant physician at the Royal Clinical Team Leader at the National Liverpool University Hospitals until April Treatment Agency, where she took a lead in 2011. He has particular interest secretariat for the 2007 joint publication of in harms related to alcohol misuse and the the Department of Health (England), the role of regulation in reducing this. A blueprint guidelines on clinical management, and a for a coherent alcohol strategy. Emily is also a member of the also been appointed as Chair of the Addictions Executive of the Royal College of European Alcohol and Health Forum Science Psychiatrists. He received a Knighthood in National Institute for Health and Clinical the Queen’s Birthday Honours in 2010. He Alcohol and Public Health to the Royal appears before all levels of the domestic College of Physicians. In 2010 Ms Arsha Gosine he was the Chairman of the Bar Council of Policy Adviser, Crown Prosecution England and Wales. In his capacity as Service Chairman of the Bar he was involved in Arsha is a Policy Adviser with the Crown leading negotiations with Government on Prosecution Service and is their policy lead behalf of the profession on all issues from for drugs. Arsha holds a Masters in reform of criminal and civil justice systems to International Law and has presented on legal aid reform. Prior to provides legal guidance and updates for becoming Chairman he had been a member prosecutors nationally. He of the Association of Chief Police Officers has subsequently been appointed as the Drugs Committee. Chairman of the Advocacy Training Council, a body that facilitates and coordinates the Declaration of interests: training of and professional support for the Arsha Gosine has no competing interests Bar. He has held a long-term interest in the that might be perceived as posing a conflict impact of drugs policy upon the or bias.
Today medicine 20 discount levaquin 250 mg fast delivery, rare disease research and development is a key plank in the planning of most large pharmaceutical companies symptoms zenkers diverticulum buy 500 mg levaquin visa. The success of a small number of pio- neering biotechnology companies such as Genzyme and Amgen demon- strated that it was possible to create feasible alternative business models that would deliver health gain and a return on investment medicine 1800s buy 500 mg levaquin overnight delivery. A fourth element in this mix was the granting of competence in the eld of public health to the European Commission by the Maastricht Treaty in 1992. These documents contained calls to action in respect of coding and classication, research, centres of expertise, the clinical added value of orphan drugs and patient empower- ment. These are the key elements of any effective strategy, and the adoption of the Recommendations opened a window that allowed for the creation of concerted campaigns to respond to the unmet medical needs of rare disease patients across the whole of Europe. View Online Foreword ix The insights from the Human Genome Project and other international collaborations which aimed to address the fundamental biology of health and disease had an impact on the research community too. Traditional priority areas were adjusted to make space for rare diseases, both because they were seen as important in themselves, but also because of the insight they could provide into common complex diseases in the context of a growing awareness of the importance of personalised (or stratied) medicine and the development of targeted therapies for genotypically distinct but phenotypi- cally similar common diseases. Advances in biology, increased opportunities for treating rare diseases, a growing sense of empowerment and engagement by patients at patient advocacy groups and realisation amongst politicians and policy makers that ‘rare’ did not equate with uncommon, simply because of the large number of different rare diseases that have been identied, has resulted in rare diseases being recognised as a signicant public health issue. Paradoxically this has coincided with a downward trend in the economies of much of the developed world, putting healthcare decision makers between a rock and a hard place. The opportunity to do more, coupled with increasing awareness of nite resources necessitated the creation of new systems for licensing novel ther- apies and determining policy with regard to clinical utility and reimburse- ment. The transi- tional gold standard of the large, multicentre randomised double-blind trial does not work for drugs developed for tiny populations and while patients have no interest in drugs that do not work, new methods for proving quality, safety and efficacy need to be developed if orphan drugs are to make it onto the market. Again traditional methods do not work, simply because its data is lacking in most instances to form a robust assessment of clinical effectiveness and a rational policy for deter- mining patient access, pricing and reimbursement. The challenge facing many healthcare providers and payment agencies today is to develop systems which will provide a framework that carries the trust of patients and families, or which will enable fair decision making in healthcare and resource allo- cation now and sustainably into the future. Patients and other key stake- holders are actively engaging to try and bring this about, but the shape of a sustainable healthcare future for rare disease patients is not yet clear anywhere across the globe. So, we have a potent mix of elements, all of which have come together to raise the prole of rare diseases and the patients of families affected by them. View Online x Foreword Rising to the challenge is a critical priority for all involved if patients are to see their expectations for effective therapies realised, scientists to generate the insights that will create clinical service improvements for doctors and the possibility of a return on investment for industry. Regulators, policy makers and politicians are intimately involved as well if we are to see the promise realised and a sustainable, affordable healthcare system that incorporates current scientic understanding and good clinical practice intertwined in systems that provide timely, appropriate, user-friendly care for rare disease patients wherever they live across the globe. This book is a timely contri- bution to the literature in this fast-changing eld. It will serve as a useful primer to those new to the subject, and for those already engaged it provides a reminder of the breadth of the eld today, reinforcing the importance of rare diseases as a subject for pioneering research, as a commercial oppor- tunity for innovative pharma and biotech companies, but most of all as a call to action on behalf of the patients and families with rare diseases for whom there is as yet no effective therapy. This book demonstrates clearly that there is no disease that is too rare, too difficult or too expensive not to warrant the attention of the scientic and clinical community, industry, policy makers and politicians alike in the search for a response to the needs of patients, and the importance of sustainable progress towards the continued production of novel therapies for currently unmet needs. Council Recommendations on action in the eld of rare diseases, European Commission, Luxembourg, 2009. Preface As a term, ‘rare diseases’ covers an enormous and hugely diverse range of diseases, disorders and conditions. In a similar way, the term ‘orphan drug’ is also subject to some confusion and misconception within the drug discovery community. When we decided to undertake the editing of this book, we had a number of aims in mind. First and foremost, we wished to produce a broadly accessible book that would set out clearly what is meant by the terms rare diseases and orphan drugs. In so doing, we wanted to highlight the critical role that disease advocacy has played and continues to play in building drug discovery efforts in this area of biomedical science, and discuss some of the unique challenges that this eld presents. Secondly, we wished to present the range of innovative science taking place to create therapies directed at rare diseases through a combination of review and case studies, highlighting the breadth of drug modalities that research in the eld has produced. Research and clinical development in this area has oen been both path-nding and innovative, and in many cases this has been pioneered by small biotech- nology companies, or in some cases small parts of much larger companies. As such, undertaking to write a book chapter from within a small group is a signicant commitment, and we are most grateful to the chapter authors for contributing their time to the writing of this book.
Chemogenomics Approaches for Receptor Deorphanization and Extensions of the Chemogenomics Concept to Phenotypic Space symptoms xanax treats order levaquin once a day. Combining Aggregation with Pareto Optimization: A Case Study in Evolutionary Molecular Design treatment nerve damage discount 500 mg levaquin mastercard. In Evolutionary Multi-Criterion Optimization; Lecture Notes in Computer Science; Springer Berlin / Heidelberg symptoms 2dpo purchase levaquin amex, 2009; Vol. Enhancing search space diversity in multi-objective evolutionary drug molecule design using niching. Evolutionary algorithms for automated drug design towards target molecule properties. A Prospective Cross-Screening Study on G Protein- Coupled Receptors: Lessons Learned in Virtual Compound Library Design [Manuscript in preparation, joint first author] 236 Curriculum Vitae (Nederlands) Eelke van der Horst werd geboren op 12 januari 1976 te Voorburg, en groeide op in Den Haag. Na het voltooien van het voorgezet onderwijs aan de Vrije School Den Haag (in 1996), begon hij zijn studie Bio-Farmaceutische Wetenschappen aan de Universiteit van Leiden, waar hij in 2003 zijn doctoraalexamen behaalde. Hij liep zijn eerste stage bij de vakgroep medische farmacologie onder begeleiding van Dr. Zijn tweede stage vond plaats bij de vakgroep farmacochemie onder begeleiding van Dr. Hier ontwikkelde hij een programma voor het berekenen en visualiseren van oppervlakteeigenschappen van (virtuele) moleculen. Dit programma helpt farmacochemici bij het voorspellen van passief membraantransport zoals dat plaatsvindt in de darmwand en bloed-hersen barrière. Na zijn afstuderen heeft hij bij twee innovatieve softwarebedrijven gewerkt, eerst bij SemLab B. After completing secondary education at the Vrije School Den Haag in 1996, he started his study Bio-Pharmaceutical Sciences at the University of Leiden, where he received his M. He served his first internship at 237 Curriculum Vitae the division of medical pharmacology under the supervision of Dr. His second internship was conducted at the division of medicinal chemistry under the supervision of Dr. This application helps medicinal chemists predict passive transport over membranes such as the intestinal wall and blood-brain barrier. After his graduation, he worked at two innovative software companies, first at SemLab B. Als kind had ik een klein laboratoriumpje op m’n kamer waar ik druk experimenteerde met fel gekleurde zouten, de sterkste zuren, en krachtigste explosies. Hierdoor zaten er geregeld gaten in mijn kleding, wat later voorkomen werd door het dragen van een labjas waar een tante de tekst “de verstrooide professor” op genaaid had. Ook mijn ooms droegen op een positieve manier bij aan mijn hobby door me te leren met welke chemicaliën je met gemak een heel plein onder de rook kon zetten. Het vereiste natuurlijk wel wat creativiteit om die chemicaliën ook te bemachtigen, maar ik had al snel door wat het beste excuus was om geen argwaan te wekken bij de winkelier. Zo zat ik uren in de bibliotheek, het Internet van die tijd, om de chemie te doorgronden. Vooral de structuurformules, met name die van farmacologisch actieve verbindingen, lieten me niet los; reden voor mijn toenmalige scheikundeleraar om farmacie als studierichting aan te raden. De magie van de structuur heeft me nooit meer verlaten en ik mag me gelukkig prijzen dat ik daar uiteindelijk een promotieonderzoek aan heb mogen wijden. Bij het tot stand komen van dit proefschrift zijn een aantal mensen betrokken die ik hierbij expliciet wil bedanken. Allereerst de chemici, Hans, Jaco, Maris, en Patricia die verantwoordelijk waren voor de selectie en synthese van de nieuwe liganden beschreven in hoofdstuk 6. Above all, I would like to thank Patricia for her massive effort in synthesizing the compounds. Patricia, I am really grateful for your substantial contribution to the last research chapter. Omdat cheminformatics alleen maar kan bestaan bij de gratie van het experiment en de data die dit oplevert, zou ik ook graag de mens achter de affiniteitswaarde willen bedanken: Thea, Henk, en Rianne, bedankt voor jullie noeste arbeid. Ook wil ik hierbij mijn begeleiders, Ad en Andreas, bedanken: Ad, bedankt voor de academische sturing, wijsheid en vooral geduld, en Andreas, thanks for your 239 Nawoord guidance and for boosting my (chem)informatics skills.
