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In Metabolic, the diabetes treatments Avandia Avandamet continue to perform very strongly, with overall sales of 1.3 billion up 18% ; . In the USA, sales grew 14% to 977 million. Avandia Avandamet is also establishing a strong position in Europe, with sales rising 52% to 157 million helped by the launch of Avandamet throughout the region. Sales in International markets rose 13% to 195 million. Boniva Bonviva, a new once-monthly oral bisphosphonate for the treatment of osteoporosis, which was developed with Roche, had a strong launch in the USA and now has a 10% share of new prescriptions for oral bisphosphonates. Boniva injection, the first-ever quarterly treatment for osteoporosis, was approved in the USA in January 2006 and received a positive opinion from the CHMP in Europe on 27th January 2006. The vaccines business performed well with total sales rising 15% to 1.4 billion, led by Infanrix. Vaccine sales were particularly strong in the USA, where turnover rose 26% to 338 million, helped by the launch of two new products Fluarix and Boostrix.
ABSTRACT It is generally thought that the cardiovascular and renal effects of clonidine, an alpha-2 adrenergic agonist, are mediated by central mechanisms. Our previous work has shown that diuresis and natriuresis caused by central administration of clonidine are mediated by an enhanced release of atrial natriuretic factor ANF ; . Because clonidine has been shown to have peripheral actions the objective of the present study was to determine whether ANF is also involved in these actions. Studies were performed with use of a structural clonidine analog, ST-91, which does not cross the blood-brain barrier. Intravenous injection of various doses 0 250 g rat ; of ST-91 into conscious, normally hydrated female Sprague-Dawley rats 200 250 g ; produced dose-related increases in urinary output, which were accompanied by significant increases in urinary sodium, potassium and cGMP excretion. Compared with saline, the highest dose of ST-91 250 g rat ; during the first hour of treatment significantly P .001, n 18 ; enhanced urinary output 0.2.
Embers of managed care programs typically coordinate all health care through their primary care physicians. In fact, many members can receive all the care they need through these doctors. However, some members with chronic or serious illnesses may find that having direct access to their specialists may help them find more efficient care. For this reason, the BCBSVT and TVHP managed care plans allow exceptions to some of their guidelines in certain circumstances.
Eicosapentaenoic acid on the incidence of coronary artery restenosis after angioplasty. JAm Coll Cardiol 1989; 13: 665-672 Reis GJ, Boucher TM, Sipperly ME, Silverman DI, McCabe CH, Baim DS, Sacks FM, Grossman W, Pasternak RC: Randomised trial of fish oil for prevention of restenosis after coronary angioplasty. Lancet 1989; 2: 177-181 Roy L, Meyer F, Gingras S, Auger L: A double-blind randomized placebo controlled study comparing the efficacy of fish oil and low dose ASA to prevent coronary saphenous vein graft obstruction after CABG. abstract ; Circulation 1991; 84 suppl II ; : II-285 Spector AA, Yorek MA: Membrane lipid composition and cellular function. J Lipid Res 1985; 26: 1015-1035 Cistola DP, Small DM: Fatty acid distributions in systems modeling the normal and diabetic human circulation. A 13C nuclear magnetic resonance study. J Clin Invest 1992; 87: 1431-1441 Lefkowith JB, Rogers M, Lennartz M, Brown E: Essential fatty acid deficiency impairs macrophage spreading and adherence: Role of arachidonate in cell adhesion. J Biol Chem 1992; 226: 1071-1076 Terano T, Hirai A, Hamazaki T, Kobayashi S, Fujita T, Tamura Y, Kumagai A: Effect of oral administration of highly purified eicosapentaenoic acid on platelet function, blood viscosity and red cell deformability in healthy human subjects. Atherosclerosis 1983; 46: 321-331 Clubb FJ Jr, Schmitz JM, Butler MM, Buja LM, Willerson JT, Campbell WB: Effect of dietary omega-3 fatty acid on serum lipids, platelet function, and atherosclerosis in Watanabe heritable hyperlipidemic rabbits. Arteriosclerosis 1989; 4: 529-537 Nilsen DWT, Dalaker K, Nordoy A, Osterud B, Ingebretsen OC, Lyngmo V, Almdahl S, Vaage J, Rasmussen K: Influence of a concentrated ethylester compound of n-3 fatty acids on lipids, platelets and coagulation in patients undergoing coronary bypass surgery. Thromb Haemost 1991; 66: 195-201 Lelouche F, Fradin A, FitzGerald GA, Maclouf J: Enzyme immunoassay measurement of urinary metabolites of thromboxane A2 and prostacyclin. Prostaglandins 1990; 40: 297-310 Knapp HR, Reilly IA, Alessandrini P, FitzGerald GA: In vivo indexes of platelet and vascular function during fish-oil administration in patients with atherosclerosis. N Engi J Med 1986; 314: 937-942 Harker LA, Kelly AB, Hanson SR: Experimental arterial thrombosis in nonhuman primates. Circulation 1991; 83 suppl IV ; : IV-41-IV-44 Schneider PA, Hanson SR, Price TM, Harker LA: Confluent durable endothelialization of endarterectomized baboon aorta by early attachment of cultured endothelial cells. J Vasc Surg 1990; 11: 365-372 Kelly AB, Marzec UM, Krupski W, Bass A, Cadroy Y, Hanson SR, Harker LA: Hirudin interruption of heparin-resistant arterial thrombus formation in baboons. Blood 1991; 77: 1006-1012 Krupski WC, Bass A, Kelly AB, Hanson SR, Harker LA: Reduction in thrombus formation by placement of endovascular stents at endarterectomy sites in baboon carotid arteries. Circulation 1991; 84: 1749-1757 Lumsden AB, Kelly AB, Schneider PA, Krupski WC, Dodson T, Hanson SR, Harker LA: Lasting safe interruption of endarterectomy thrombosis by transiently infused antithrombin peptide D-Phe-Pro-ARGCH2Cl in baboons. Blood 1992, in press ; Hanson SR, Powell JS, Dodson T, Lumsden A, Kelly AB, Anderson JS, Clowes AW, Harker LA: Effects of angiotensin converting enzyme inhibition with cilazapril on intimal hyperplasia in injured arteries and vascular grafts in the baboon. Hypertension 1991; 18 suppl II ; : II-70-II-76 Fish Oil Test Materials Program, Department of Health and Human Services, Bethesda, Md Availability of Fish Oil Test Materials, NIH Guide for Grants and Contracts, vol. 21, January 17, 1992 Lipid Research Clinic Program: Manual of Laboratory Operations, Lipid and Lipoprotein Analysis, ed 2. Bethesda, Md, DHHS Publications NIH ; , 1982 Allain CC, Poon LS, Chan CS, Richmond W, Fu PC: Enzymatic determination of total serum cholesterol. Clin Chem 1974; 20 and avastin.
1. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: Prevalence and predictors. JAMA 1999; 281: 537-44.
Products for which SMC advice is expected in the next quarter are listed below. Details of expected advice dates are available on the upgraded SMC website scottishmedicines ; under "Work Programme". Cardiovascular system Nicotinic acid modified release tablets Niaspan ; Valsartan hydrochlorthiazide Co-Diovan ; Clopidogrel Plavix ; Cilostazole Pletal ; Respiratory system Budesonide eformoterol Symbicort Turbohaler ; Central Nervous System Quetiapine Seroquel ; Olanzapine Zyprexa velotab ; Methylphenidate Equasym XL ; Lamotrigine Lamictal ; Botulinum type A neurotoxin Botox ; resubmission Buprenorphine patch Transtec ; Ariprazole Abilify ; Alteplase rt-PA ; Actilyse ; Infections Ertapenem Invanz ; Endocrine system Somatropin Norditropin SimpleXx ; Rosiglitazone Avandia ; Rosiglitazone maleate metformin Avandamet ; Malignant disease & immunosuppression Temoporfin Foscan ; Macrogol Idrolax ; Darbepoetin alfa Aranesp ; Musculoskeletal & joint diseases Infliximab Remicade ; Skin Clindamycin benzoyl peroxide Duac and avc!
For registration purposes, test samples of products containing fairly stable active ingredients are taken from two different production batches; in contrast, samples should be taken from three batches of products containing easily degradable active ingredients or substances on which limited stability data are available. The batches to be sampled should be representative of the manufacturing process, whether pilot plant or full production scale. Where possible, the batches to be tested should be manufactured from different batches of active ingredients. In on-going studies, current production batches should be sampled in accordance with a predetermined schedule. The following sampling schedule is suggested: ! one batch every other year for formulations considered to be stable, otherwise one batch per year; ! one batch every 3-5 years for formulations for which the stability profile has been established, unless a major change has been made, e.g. in the formulation or the method of manufacture. Detailed information on the batches should be included in the test records, namely the packaging of the drug product, the batch number, the date of manufacture, the batch size, etc. 3.2 3.2.1 Test conditions Accelerated studies.
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A variety of epidemiological and clinical data suggest that genetic factors are intimately involved in the pathogenesis of IBD including familial aggregation pattern of disease with a much higher disease frequency in first degree relatives of affected individuals compared with the general population. Twin studies provide the argument for a genetic basis for IBD, with a much higher rate of disease concordance observed in monozygotic than in dizygotic twins and wide variations in the incidence and prevalence of IBD among different populations. IBD is now considered a non-Mendelian polygenic disorder with important environmental interactions e.g. microbial factors, smoking ; . There are two main approaches to identifying genes in complex multifactorial diseases: the positional cloning approach based on linkage studies, and the candidate gene approach based on association studies. Linkage analysis studies the cosegregation of the disease with a marker within the families. Linkage analysis allows scanning of the whole genome. Eleven of these total genome scans have been undertaken in IBD, resulting in a number of susceptibility regions on chromosomes 1, 3, 4, and X. According to their initial date of reporting and independent confirmations, the regions on chromosomes 16q, 12, 6, and 10 have been renamed IBD 1 to IBD 9, respectively. However, new genes have been reported recently. All susceptibility genes discovered can be categorized into different levels of susceptibility: 1 ; Innate immunity; 2 ; Human leucocyte antigen HLA ; molecules; 3 ; Epithelial integrity 4 Drug transporter; and 5 ; Cell adhesion.
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1. Medical equipment may be rented or leased on a temporary basis until it is determined that the individual will have a continuing long term need. 2. The program will request warranties at time of approval. 3. Previously provided items may be replaced if an individual's medical needs change. 4. When a MS&E item is rented, the rental agreement must include maintenance and repair costs, as the NIHB Program does not pay for maintenance or repairs of rental equipment. 5. MS&E items that have an annual quantity limitation must be provided and billed for no more than a 3-month period at a time. This applies to items claimed with or without prior approval.
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Stable expression of KCNQ4 channels in HEK-293 cells. KCNQ4 was the kind gift of Dr. Thomas Jentsch in the Xenopus oocyte expression vector pTLN. KCNQ4 was excised from pTLN using HindIII and XhoI and subcloned into the mammalian expression vector pNS1n NeuroSearch ; , a custom-designed derivative of pcDNA3neo InVitrogen ; . HEK293 cells American Type Culture Collection ; were grown in DMEM Life Technologies ; supplemented with 10% FCS Life Technologies ; at 37C in 5% CO2. One day before transfection, 106 cells were plated in a cell culture T25 flask Nunc ; . Cells were transfected with 2.5 g of the plasmid pNS1n KCNQ4 by using Lipofectamine Life Technologies ; according to the manufacturer's instructions. Cells transfected with pNS1n KCNQ4 were selected in media supplemented with 0.5 mg ml geneticin G418; Life Technologies ; . Single clones were picked and propagated in selection media for five passages, after which they were considered stable. Subsequently, the cells were cultured in regular medium without selection agent. Expression of functional KCNQ4 channels was verified by patch-clamp measurements. Electrophysiology. Transfected cells were cultured on glass coverslips diameter 3 mm ; , which were transferred to a small recording chamber. The chamber was perfused with extracellular solutions at a rate of 1 ml min, giving rise to full exchange of the chamber volume 15 l ; each second. Whole cell currents were recorded with the use of a HEKA EPC-9 amplifier and borosilicate glass micropipettes with tip resistances of 1.53 M . The fast and slow capacitances were automatically compensated by using the standard procedures of the HEKA amplifier trains of 5-mV square wave pulses, averaging of the resulting current, and fitting of an exponential to deduce the compensation values required to cancel the capacitative currents ; . The slow capacitance and the series resistance were determined before each sweep. If the cancellation failed or the series resistance rose above 10 M , the experiment was discarded. The series resistance was compensated by 70%. The currents were not leak-subtracted. The sampling interval was 400 s, and the signals were low-pass filtered with a cut-off frequency of 1, 000 Hz. The KCNQ4 current exhibited some rundown during the first minutes following acquisition of whole cell configuration, but a steady current level was always obtained before electrophysiological analysis or drug application. All experiments were performed at room temperature 2125C ; . Igor software WaveMetrics, Lake Oswego, OR ; was used for the analysis. Calculations. Steady-state activation curves were fitted to Boltzmann functions as follows Itail Vm Itail 1 exp Vm V1 2.
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Make of themselves centers of transformation. They must from day to day polarize themselves more completely to attract the higher currents. , If the dense vapors of selfishness sweep over them, they must, if they cannot soar above them, learn to lie low as in a desert sand-storm, till the tempest has passed. If they feel envy, anger, or any selfish ambition or passion, they must learn to seize it promptly before it has made a nest within them, and send it forth transmuted. They must become alchemists in very truth. Every project before receiving their seal of approval must pass the test of tending toward the harmony of the human race. That is to say, they must do these things if they want a clean, wholesome earth to live in; if they want to see justice, sincerity, purity, beauty, everywhere. Who should do it, if not they? Theosophy is quite positive in its statement that only through these mean; can the world attain happiness. Prisons to take care of the criminals; hospitals for the sick; asylums for the insane; officials without limit to guard society; 'probes' into every conceivable department of the social fabric are all very well, yet it would be better if they were not needed. I t almost seems a t times as if, should the lower psychology continue unchecked, all the honest members of society would be needed to protect it against the dishonest. The present methods of stemming the tide of evil are not ?ffective. They are much like trying to drain a swamp with a xiagara somewhere further up in the country feeding it. A new direction for energy is called for. The way demanded by Theosophy may seem intangible to those living quite in the world of m a but logically it is the only method not hopeless. Let those who doubt it try it within themselves and avandamet.
In the present study, the aminopyrimidinimino isatin analogues are designed in accord with this hypothesis. The iminocarbamoyl moiety -N C-CON- ; constitutes the `body' and the aryl ring of isatin and the pyrimidine derivative constitute the `wings' as depicted in Fig.1. The crucial structural components included in the proposed model contain a hydrophilic centre A ; , which is surrounded by 2 hydrophobic outskirts denoted by B and C. The distance between the 3-pharmacophoric points were calculated for minimum four different conformations and are represented as mean standard deviation. The lead compound was found to comply within the specification of the pharmacophoric distance map Fig. 2 and Table 1 ; . During the development of this 3D-pharmacophoric model, molecular superposition techniques have also been used to investigate similarities and differences between the selected points in the test molecule aminopyrimidinimino and baraclude.
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