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18. Lscher W, Honack D, Fassbender CP, Nolting B: The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. III. Pentylenetetrazole seizure models. Epilepsy Res, 1991, 8, 171189. Lscher W, Schmidt D: Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations. Epilepsy Res, 1988, 2, 145181. uszczki JJ, Borowicz KK, OEwider M, Czuczwar SJ: Interactions between oxcarbazepine and conventional antiepileptic drugs in the maximal electroshock test in mice: an isobolographic analysis. Epilepsia, 2003, 44, 489499. uszczki JJ, Czuczwar SJ: How significant is the difference between drug doses influencing the threshold for electroconvulsions? Pharmacol Rep, 2005, 57, 782786. uszczki JJ, Czuczwar SJ: Isobolographic characterisation of interactions among selected newer antiepileptic drugs in the mouse pentylenetetrazole-induced seizure model. Naunyn Schmiedebergs Arch Pharmacol, 2005, 372, 4154. uszczki JJ, Ratnaraj N, Patsalos PN, Czuczwar SJ: Isobolographic analysis of interactions between loreclezole and conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model. Naunyn Schmiedebergs Arch Pharmacol, 2006, 373, 169181. uszczki JJ, Wjcik-wika J, Andres MM, Czuczwar SJ: Pharmacological and behavioral characteristics of interactions between vigabatrin and conventional antiepileptic drugs in pentylenetetrazole-induced seizures in mice: an isobolographic analysis. Neuropsychopharmacology, 2005, 30, 958973. Marangos PJ, Martino AM, Paul SM, Skolnick P: The benzodiazepines and inosine antagonize caffeine-induced seizures. Psychopharmacology Berl ; , 1981, 72, 269273. Morgan PF, Deckert J, Jacobson KA, Marangos PJ, Daly JW: Potent convulsant actions of the adenosine receptor antagonist, xanthine amine congener XAC ; . Life Sci, 1989, 45, 719728. Motulsky HJ, Christopoulos A: Fitting models to biological data using linear and nonlinear regression. A practical guide to curve fitting. GraphPad Software Inc., San Diego CA, USA, 2003. 28. Nehlig A, Daval JL, Debry G: Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Rev, 1992, 17, 139170. nap readingroom books labrats.
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Integrated Neurohormonal Therapy for Obesty INTO ; Amylin's unique, new approach to the treatment of obesity is based on combination therapies using peptide and protein hormones that may be substantially more effective than monotherapies in improving the outcomes for people struggling to lose weight. virtually all of the peptides identified in Amylin laboratories are neurohormones that communicate with the brain even though they are produced from peripheral tissues. The hormone amylin, for example, secreted from the beta cell, communicates to the part of the brain that regulates a number of gastrointestinal functions, including appetite and satiety. Neurohormones work in concert, however, and it is their combination that leverages the power of integrated physiology. for Amylin scientists today, three molecular franchises are the primary focus in our obesity research: amylin, through its synthetic version pramlintide and other amylinomimetics; PYY 3-36, a molecule that is secreted in the gut and provides satiety or hunger control in the post-meal period; and leptin, a protein hormone produced from the fat cell that plays a fundamental role in metabolism and also communicates to the brain. Each molecular franchise includes analogs, which are chemicals with similar structures to each other, but with slightly different compositions; and PhYBrIDS, an acronym for peptide hormone hybrids. Each of these can be studied independently or in various combinations and with different drug delivery strategies. Amyln: The Cornerstone Based on preclinical and clinical data, an amylinomimetic such as pramlintide has the potential to play an important role in the INTO strategy. In a 52-week study evaluating the safety and efficacy of pramlintide in obese patients, there was a very significant reduction in body weight -- and maintenance of that reduction -- among patients using pramlintide in conjunction with lifestyle intervention diet and exercise ; , as compared to those using lifestyle intervention alone. As the active ingredient in SYMLIN, pramlintide is an approved product currently on the market with more than 50, 000 patients treated for its diabetes indication and a large safety database. This compound has the potential to become the first neurohormonal therapy for obesity.
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FIGURE 4. Cross-reactivity of xenoreactive Abs produced during the acute rejection of hamster a and b ; or mouse hearts c and d ; . Sera harvested during AXR were pooled n 35 ; , and diluted 1 5 in PBS. Diluted sera 150 l ; were incubated for 30 min, and at 4C, with 50 l of packed Lewis rat, hamster, or mouse erythrocytes x-axis ; . This adsorption was repeated three times, and the levels of IgM in the preadsorbed sera that bound to hamster a and d ; or mouse b and c ; erythrocytes were quantified by flow cytometry, as described in Figure 1. Data are presented as mean channel fluorescence of triplicates SE, and are the representative of two to three experiments.
Without inducing weight gain or increasing the risk of severe hypoglycemia. Pramlintide is approved for use in patients with type 1 diabetes and type 2 diabetes who are receiving insulin. The success of these medications has given us proof of the concept that these are important pathways in glucose regulation. Under consideration by the US Food and Drug Administration FDA ; are oral agents that inhibit dipeptidyl peptidase 4 and result in raised levels of GLP-1 and GIP. These drugs sitagliptin and vildagliptin ; are in the approval stage at the FDA. Inhaled insulin Inhaled insulin has been under development since the mid-1980s. Exubera, an inhaled product, was approved by the FDA and was recently made available. See review in June issue, CCJM ; .13 This product is in the form of lyophilized microspheres in a blister pack that is inserted into an inhaler device about the size of a cucumber. The user turns on a blower motor and inhales the insulin deep into the bronchial tree. Gamma scintigraphic imaging shows that delivery systems such as this distribute the drug well throughout the lungs.14 The epithelial surface of the lungs is about the size of a tennis court, offering a potentially huge area for drug absorption. However, about 10 times more insulin is needed for delivery by inhaler than by subcutaneous injection to get the same response. Interestingly, smokers absorb inhaled insulin more rapidly than nonsmokers, possibly because of vascular changes in their bronchial tree.15 Efficacy of aerosolized insulin, as measured by hemoglobin A1c, is very similar to that of subcutaneously injected insulin.16 Because inhaled insulin is rapid-acting, it is for mealtime use, and subcutaneous insulin still needs to be used for basal coverage. Patient satisfaction is higher with the inhaled delivery system than with the injectable form. Whether it becomes popular will probably depend on its price and insurance coverage. Concern has been raised about possible long-term adverse effects of inhaled insulin on and prevnar.
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With 2005. Operational earnings of the associates increased to EUR 50 million 2005: EUR 43 million ; . In 2006, earnings included incidental gains of EUR 39 million, mainly related to Acordis, while in 2005 net incidental losses of EUR 37 million were recognized, primarily due to the impairment of Methanor. Income taxes included a one-time benefit of around EUR 125 million. This benefit was attributable to an agreement with tax authorities in several countries on transfer pricing issues related to the company's corporate income tax filings covering a period of almost ten years. Excluding this benefit, the tax rate of 2006 amounted to 28%, which was higher than the previous year 2005: 25.
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Patients with type 2 diabetes using insulin lispro were also assessed in a placebo-controlled, cross-over study to determine the most effective time relative to a meal to dose pramlintide at -15, 0, + 15 and + 30min relative to a standard meal ; .43 At each time point, pramlintide significantly lowered postprandial glucose excursions compared with mealtime insulin alone 42% to 81% reduction in incremental area under the concentrations time curve from 04 hours ; , with pramlintide administered immediately prior to the meal having the greatest postprandial glucoselowering effect see Figure 1 ; . These reductions in postprandial glucose concentrations occurred despite a 17% decrease in mealtime insulin dose. Another randomised, cross-over study in patients with type 2 diabetes also demonstrated that adjunctive pramlintide.
Pramlintide itself has antioxidant properties was not explored in this study. In conclusion, results from this study demonstrate that the reduction in postprandial glucose excursions achieved with the addition of pramlintide to regular insulin in type 1 diabetes is accompanied by significant reductions in postprandial oxidative stress. These findings, which merit further investigations, suggest that pramlintide treatment may have a positive impact on long-term diabetes complications through attenuation of hyperglycemia-related oxidant injury and primaquine
Manuscript 06-2003 Version 4 The intent-to-treat ITT ; population included all randomized subjects who received at least one injection of double-blind study medication. The evaluable population included all ITT subjects who remained in the study through Week 16 with no major protocol deviations. Summaries of safety and tolerability were conducted using the ITT population. Changes in body weight and waist circumference were analyzed using both the ITT and evaluable populations. Missing data for the ITT population were imputed utilizing the last observation carried forward LOCF ; method. Laboratory pharmacodynamic parameters and vital signs A1C, fasting plasma glucose, fasting insulin, triglycerides, total cholesterol, HDL-c, LDL-c, systolic and diastolic blood pressure ; were analyzed using the evaluable population. Subgroup analyses [by initial weight loss response 1% and 1% weight loss by Week 4 ; , diabetes status subjects with and without type 2 diabetes ; , gender and the occurrence of treatment-emergent nausea] were conducted to further characterize the weight effect of pramlintide. Correlation analysis was employed to study the interrelationship between change in body weight and change in waist circumference. The Pearson correlation coefficients with P-values ; are presented. Changes from baseline in body weight, waist circumference and other laboratory pharmacodynamic parameters and vital signs were analyzed using a general linear model including factors for treatment, baseline body weight stratum, diabetes status, and study site. P-values were based on the LS mean differences between pramlintide and placebo in the change from baseline to each visit. A sensitivity analysis was conducted to explore the impact of missing data on the change in body weight using data from the ITT population. A mixed effects model was used with factors for treatment, time, treatment-by-time interaction, baseline body weight stratum, and study site. The percentage of subjects achieving 5% weight loss from baseline to.
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Action in the civil courts".31 The immunities are thought to be "of considerable assistance in obtaining relevant evidence".32 It is interesting that the Salmon Commission took the view that "the witness's immunity should be extended so that neither his evidence before the tribunal, nor his statement to the Treasury Solicitor, nor any documents he is required to produce to the tribunal, shall be used against him in any subsequent civil or criminal proceedings.".33 The Commission endorses the view that statements provided to an inquiry during its early information-gathering phase should be protected in the same way as evidence given at the public hearings, and therefore is broadly supportive of the policy decision made in section 6 7 ; of the 2002 Act, whereby a person mentioned in subsection 4 ; is entitled to "the same immunities and privileges as if he she were a witness before the [High] Court". However certain points of detail call for consideration. 9.47 In interpreting this provision, it must be borne in mind that there is a distinction to be drawn between an immunity rule on the one hand, and a nonadmissibility rule on the other. An immunity is designed to protect a person against subsequent criminal or civil proceedings arising out of what is said or published at an inquiry, whereas a rule of non-admissibility applies in respect of material that might, without the rule, constitute evidence in a court of law. To be immune from, say, prosecution under the Official Secrets Act 1964 means that within the parameters of that immunity a witness or other individual belonging to a protected class ; can say whatever he pleases without any possibility of being prosecuted under the Official Secrets Act 1964. Non-admissibility is quite different. It simply means that evidence one gives to a tribunal is not admissible in subsequent criminal proceedings; but this of course does not mean that one is immune from such proceedings.34 Evidence may come from other sources. Thus the witness might still be prosecuted for an offence under the Official Secrets Act 1964 for some related episode not the statement before the tribunal, as already explained proven by evidence other than the testimony given before the tribunal. 9.48 There is a very good reason for having separate immunity and nonadmissibility rules. If the mere act of confessing one's crimes to a tribunal were sufficient to render one immune from prosecution in respect of those crimes, then there would be a grave risk that the tribunal might degenerate into a sort of information laundry. By this we mean that individuals would have an incentive to reveal all their sins, however irrelevant to the inquiry, and from the point of view of and primidone.
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A typical experiment are stated in table 1. The total daily allotments of the essential amino acids, except lysine, and of cystine and tyrosine approximated those in 20 gm egg protein Mitchell and Block, '46 ; . They exceeded the min imum requirements reported for women Leverton et al., '56b; Swendseid and Dunn, '56 ; and for men Bose, '49 ; . The L-isomers of the amino acids were incorporated in the supplementary mixtures, except for DL-isoleucine which was supplied in twice the amount indicated in table 1. The optical and praziquantel.
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As a growing medium, therefore, SMS does not provide enough benefits alone to be a great advantage. Use of SMS to suppress soil-borne plant diseases: Research in the UK has investigated the effects of SMS in suppressing diseases in potted seedlings and field vegetable crops. Supression of root rots: Phytophthora nicotianae causes root rot of tomatoes but incorporation of SMS into the growing medium has been shown to reduce the infection. Twenty per cent 20% ; incorporation by volume reduced infection from 60% to 20%. Figure 1 ; Fig 4. Effect of compost additions to soil on Allium white rot Root rot and damping-off of tomato can also be caused by Rhizoctonia solani and, once again, incorporation of SMS into the growing medium has been shown to reduce infection. Ten per cent 10% ; suppressed the disease index from 20% to 6% Figure 2 ; but care is needed since too much SMS in the medium can encourage the disease
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