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Mikko Kuoppamäki - One of the best experts on this subject based on the ideXlab platform.
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five year efficacy and safety of levodopa ddci and entacapone in patients with parkinson s disease
Journal of Neural Transmission, 2008Co-Authors: David J. Brooks, Mikko Kuoppamäki, Mika Leinonen, Helena NissinenAbstract:This was a retrospective pooled analysis of data from four comparably designed, double-blind, placebo-controlled, Phase III studies and their long-term open-label extensions. Patients on levodopa and a dopa Decarboxylase Inhibitor (DDCI) were randomized to entacapone or to placebo in the 6-month, double-blind phase, with all patients subsequently receiving entacapone in the extension phase. UPDRS III motor scores improved by −2.1 points during the first 6 months of levodopa/DDCI and entacapone therapy, and remained below baseline for up to 2 years. Increased daily ‘ON’ time, together with response duration to a single morning dose of levodopa and clinical global evaluation, also supported the long-term efficacy of levodopa/DDCI and entacapone. The mean daily dose of levodopa did not increase over the 5-year follow-up period. Long-term therapy with levodopa/DDCI and entacapone was well-tolerated.
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2 213 improved antiparkinsonian effects during the night with levodopa dopa Decarboxylase Inhibitor and entacapone compared with levodopa dopa Decarboxylase Inhibitor in parkinson s disease patients experiencing symptom re emergence due to wearing of
Parkinsonism & Related Disorders, 2007Co-Authors: H. Nissinen, Mikko Kuoppamäki, M. LeinonenAbstract:examined using multivariate regression to control for pre-index MPR with LC and other patient characteristics. Results: Satisfactory adherence (n = 617) compared with unsatisfactory adherence (MPR< 80%, n = 598) was associated with a 39% reduction in PD-related hospitalization (95% confidence interval [CI]: 20−54%; p< 0.001), a 47% reduction in all-cause inpatient costs (95%CI: 18−65%; p = 0.004) and an 18% reduction in all-cause total costs (95%CI: 11−24%; p< 0.001). On an adjusted basis, patients with satisfactory adherence had costs of $3508 less than those with unsatisfactory adherence. Results were qualitatively similar in those receiving LCE or LC and E. Conclusion: Better adherence to therapy is associated with reduced PDrelated and all-cause medical care utilization and lower treatment costs. Strategies to improve treatment adherence, may result in substantial cost savings.
Lo Persson - One of the best experts on this subject based on the ideXlab platform.
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cgp 48664 a potent and specific s adenosylmethionine Decarboxylase Inhibitor effects on regulation and stability of the enzyme
Biochemical Journal, 1997Co-Authors: Fredrik Svensson, Helmut Mett, Lo PerssonAbstract:Mammalian S-adenosylmethionine Decarboxylase (AdoMetDC) catalyses a regulatory important step in the biosynthesis of polyamines and is a potential target for therapeutic agents against various parasitic diseases and proliferative disorders. In the present study we examined the effects of a newly synthesized AdoMetDC Inhibitor. 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664), on polyamine metabolism in the mouse leukaemia cell line L1210. Treatment of the cells with 2 microM CGP 48664 led to a depletion of cellular spermidine and spermine. The putrescine content, in contrast, was markedly increased. Cells seeded in the presence of the Inhibitor showed a significant decrease in growth rate, which was fully reversed by the addition of 2 microM spermidine or 1 microM spermine. The syntheses of ornithine Decarboxylase and AdoMetDC were greatly increased in cells treated with CGP 48664. These increases were not correlated with similar changes in the mRNA levels, indicating the involvement of a translational mechanism. CGP 48664 was demonstrated to be a very poor competitor of spermidine uptake in the L1210 cells. L1210 cells deficient in polyamine transport were as sensitive to the antiproliferative effect of the Inhibitor as were the parental cells, indicating that CGP 48664 did not enter the cells by the polyamine transport system. In addition to inhibiting AdoMetDC, CGP 48664 stabilized the enzyme against degradation. In the present study we also demonstrated that aminoguanidine (AMG), which is frequently used in cellular systems to inhibit any action of serum polyamine oxidase, apparently inhibits AdoMetDC by an irreversible mechanism that markedly stabilizes the enzyme against proteolytic degradation. CGP 48664 and the parental compound methylglyoxal bis(guanylhydrazone), which is also a potent Inhibitor of AdoMetDC, contain one or two AMG-like moieties; the importance of these residues in the inhibition of AdoMetDC is discussed.
Helmut Mett - One of the best experts on this subject based on the ideXlab platform.
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cgp 48664 a potent and specific s adenosylmethionine Decarboxylase Inhibitor effects on regulation and stability of the enzyme
Biochemical Journal, 1997Co-Authors: Fredrik Svensson, Helmut Mett, Lo PerssonAbstract:Mammalian S-adenosylmethionine Decarboxylase (AdoMetDC) catalyses a regulatory important step in the biosynthesis of polyamines and is a potential target for therapeutic agents against various parasitic diseases and proliferative disorders. In the present study we examined the effects of a newly synthesized AdoMetDC Inhibitor. 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664), on polyamine metabolism in the mouse leukaemia cell line L1210. Treatment of the cells with 2 microM CGP 48664 led to a depletion of cellular spermidine and spermine. The putrescine content, in contrast, was markedly increased. Cells seeded in the presence of the Inhibitor showed a significant decrease in growth rate, which was fully reversed by the addition of 2 microM spermidine or 1 microM spermine. The syntheses of ornithine Decarboxylase and AdoMetDC were greatly increased in cells treated with CGP 48664. These increases were not correlated with similar changes in the mRNA levels, indicating the involvement of a translational mechanism. CGP 48664 was demonstrated to be a very poor competitor of spermidine uptake in the L1210 cells. L1210 cells deficient in polyamine transport were as sensitive to the antiproliferative effect of the Inhibitor as were the parental cells, indicating that CGP 48664 did not enter the cells by the polyamine transport system. In addition to inhibiting AdoMetDC, CGP 48664 stabilized the enzyme against degradation. In the present study we also demonstrated that aminoguanidine (AMG), which is frequently used in cellular systems to inhibit any action of serum polyamine oxidase, apparently inhibits AdoMetDC by an irreversible mechanism that markedly stabilizes the enzyme against proteolytic degradation. CGP 48664 and the parental compound methylglyoxal bis(guanylhydrazone), which is also a potent Inhibitor of AdoMetDC, contain one or two AMG-like moieties; the importance of these residues in the inhibition of AdoMetDC is discussed.
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cgp 48664 a new s adenosylmethionine Decarboxylase Inhibitor with broad spectrum antiproliferative and antitumor activity
Cancer Research, 1994Co-Authors: Urs Regenass, Helmut Mett, Jaroslav Stanek, Marcel Mueller, Debora L Kramer, Carl W PorterAbstract:Inhibitors of the polyamine biosynthetic enzyme S-adenosylmethionine Decarboxylase (SAMDC), derived from methylglyoxal-bis(guanylhydrazone) (MGBG), have been shown to have significant antitumor activity in several human solid tumor systems (U. Regenass et al., Cancer Res., 52:4712-4718, 1992). From an ongoing effort to synthesize derivatives with increased enzyme specificity and potency and improved antitumor efficacy, we have now identified CGP 48664, a 4-amidinoindan-1-one 2'-amidinohydrazone (J. Stanek et al., J. Med. Chem., 36:2168-2171, 1993). The compound displays potent inhibition of SAMDC (50% Inhibitory concentration, 5 nM), modest inhibition of diamine oxidase (50% Inhibitory concentration, 4 microM), and no detectable inhibition of ornithine Decarboxylase. CGP 48664 inhibits the growth of a panel of human and mouse tumor cell lines, including one which expresses the multidrug resistance phenotype, with 50% Inhibitory concentrations ranging between 0.3 and 3 microM. CGP 48664 does not seem to utilize the polyamine transport carrier system since it competes poorly with spermidine for uptake into L1210 cells (Ki 161 microM) and inhibits the growth of polyamine transport-deficient Chinese hamster ovary cells. Relative to MGBG or previously described MGBG analogues, CGP 48664 accumulates to much lower intracellular concentrations. Treatment of the L1210 cell for 48 h with 3 microM CGP 48664 decreases SAMDC activity to < 10% of control and initiates a compensatory 3-fold rise in ornithine Decarboxylase. Consistent with SAMDC inhibition, putrescine pools increase 10-fold, whereas spermidine and spermine pools fall to < 10% of control. In contrast to MGBG, CGP 48664 displays attenuated antimitochondrial activity as indicated by a lack of effect on pyruvate oxidation and mitochondrial DNA levels under treatment conditions which inhibit cell proliferation. Specificity of drug action was indicated further by prevention of L1210 cell growth inhibition by exogenous spermidine or spermine. More convincingly, Chinese hamster ovary cells made approximately 1000-fold resistant by chronic exposure to the analogue were found to selectively overexpress SAMDC mRNA due to gene amplification. The new SAMDC Inhibitor showed potent antitumor activity against syngeneic tumors (B16 melanoma and Lewis lung carcinoma) and nude mouse human tumor xenografts (T-24 bladder carcinoma, SK MEL-24 melanoma, and MALME-3M melanoma). On the basis of its novel structure, its apparent specificity of action, and its potent antitumor activity, CGP 48664 is the candidate drug for further preclinical development.
Chandrabhan T. Chopde - One of the best experts on this subject based on the ideXlab platform.
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Agmatine, an endogenous imidazoline receptor ligand modulates ethanol anxiolysis and withdrawal anxiety in rats.
European Journal of Pharmacology, 2010Co-Authors: Brijesh G. Taksande, Mital R Patel, Rajesh R. Ugale, Gajanan P Shelkar, Nandkishor R. Kotagale, Chandrabhan T. ChopdeAbstract:Abstract Present study investigated the role of agmatine in ethanol-induced anxiolysis and withdrawal anxiety using elevated plus maze (EPM) test in rats. The anxiolytic-like effect of ethanol was potentiated by pretreatment with imidazoline I1/I2 receptor agonist agmatine (10–20 mg/kg, i.p.), imidazoline I1 receptor agonists, moxonidine (0.25 mg/kg, i.p.) and clonidine (0.015 mg/kg, i.p.), imidazoline I2 receptor agonist, 2-BFI (5 mg/kg, i.p.) as well as by the drugs known to increase endogenous agmatine levels in brain viz., l -arginine, an agmatine biosynthetic precursor (100 µg/rat, i.c.v.), ornithine Decarboxylase Inhibitor, DFMO (125 µg/rat, i.c.v.), diamine oxidase Inhibitor, aminoguanidine (65 µg/rat, i.c.v.) and agmatinase Inhibitor, arcaine (50 µg/rat, i.c.v.). Conversely, prior administration of I1 receptor antagonist, efaroxan (1 mg/kg, i.p.), I2 receptor antagonist, idazoxan (0.25 mg/kg, i.p.) and arginine Decarboxylase Inhibitor, d -arginine (100 µg/rat, i.c.v.) blocked the anxiolytic-like effect of ethanol. Moreover, ethanol withdrawal anxiety was markedly attenuated by agmatine (10–20 mg/kg, i.p.), moxonidine (0.25 mg/kg, i.p.), clonidine (0.015 mg/kg, i.p.), 2-BFI (5 mg/kg, i.p.), l -arginine (100 µg/rat, i.c.v.), DFMO (125 µg/rat, i.c.v.), aminoguanidine (65 µg/rat, i.c.v.) and arcaine (50 µg/rat, i.c.v.). The anti-anxiety effect of agmatine in ethanol-withdrawn rats was completely blocked by efaroxan (1 mg/kg, i.p.) and idazoxan (0.25 mg/kg, i.p.). These results suggest that agmatine and imidazoline receptor system may be implicated in ethanol-induced anxiolysis and withdrawal anxiety and strongly support further investigation of agmatine in ethanol dependence mechanism. The data also project agmatine as a potential therapeutic target in overcoming alcohol withdrawal symptoms such as anxiety.
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Antidepressant like effect of selective serotonin reuptake Inhibitors involve modulation of imidazoline receptors by agmatine
Neuropharmacology, 2009Co-Authors: Brijesh G. Taksande, Sunil J. Tripathi, Rajesh R. Ugale, Nandkishor R. Kotagale, Chandrabhan T. ChopdeAbstract:Abstract Recent findings demonstrated the dysregulation of imidazoline receptor binding sites in major depression and their normalization by chronic treatment with antidepressants including selective serotonin reuptake Inhibitors (SSRIs). Present study investigated the role of agmatine and imidazoline receptors in antidepressant like effect of SSRIs and imipramine in mouse forced swimming test (FST) paradigm. The antidepressant like effect of fluoxetine or paroxetine was potentiated by imidazoline I1/I2 receptor agonist agmatine (5–10 mg/kg, ip), imidazoline I1 receptor agonists, moxonidine (0.25–0.5 mg/kg, ip) and clonidine (0.015–0.03 mg/kg, ip), imidazoline I2 receptor agonist, 2-(2-benzofuranyl)-2-imidazoline (5–10 mg/kg, ip) as well as by the drugs known to increase endogenous agmatine levels in brain viz., l -arginine, an agmatine biosynthetic precursor (40 μg/mouse, icv), ornithine Decarboxylase Inhibitor, difluoromethyl ornithine (12.5 μg/mouse, icv), diamine oxidase Inhibitor, aminoguanidine (6.5 μg/mouse, icv) and agmatinase Inhibitor, arcaine (50 μg/mouse, icv). Conversely, prior administration of I1 receptor antagonist, efaroxan (1 mg/kg, ip), I2 receptor antagonist, idazoxan (0.25 mg/kg, ip) and arginine Decarboxylase Inhibitor, d -arginine (100 mg/kg, ip) blocked the antidepressant like effect of paroxetine (10 mg/kg, ip) and fluoxetine (20 mg/kg, ip). On the other hand, antidepressant like effect of imipramine was neither augmented nor attenuated by any of the above drugs. Mice pretreated with SSRIs but not imipramine and exposed to FST showed higher concentration of agmatine in brain as compared to saline control. This effect of SSRIs on agmatine levels was completely blocked by arginine Decarboxylase Inhibitor d -arginine but not by imidazoline receptor antagonists, efaroxan or idazoxan. These results demonstrate that modulation of imidazoline receptors by agmatine are implicated in the antidepressant like effect of SSRIs and may be projected as a potential therapeutic target for the treatment of depressive disorders.
Takehiko Watanabe - One of the best experts on this subject based on the ideXlab platform.
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the disposition of a histidine Decarboxylase Inhibitor s α fluoromethylhistidine in rats
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Eiichi Sakurai, Hiroshi Niwa, Seiji Yamasaki, Kazutaka Maeyama, Takehiko WatanabeAbstract:An amino acid analyser method using ninhydrin was developed for (S)-alpha-fluoromethylhistidine (FMH) with a minimum quantitation limit of 0.2 microgram mL-1. The assay was used to study the kinetics of FMH in rat. After bolus intravenous administration of FMH hydrochloride hemihydrate (50 mg kg-1), plasma concentration decreased biexponentially with half-lives of 4.4 and 32.7 min. The distribution volumes of the central and peripheral compartments were 127.4 and 166.3 mL kg-1, respectively. The tissue concentration of FMH was highest in the kidney and also decreased biphasically. The FMH concentrations in other tissues were lower, but their tissue/plasma ratios of FMH increased continuously after FMH injection, indicating that FMH partitioned into these tissues and was lost from them very slowly.
