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Margit Kapas - One of the best experts on this subject based on the ideXlab platform.
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cariprazine rgh 188 a potent d3 d2 dopamine receptor partial agonist binds to dopamine d3 receptors in vivo and shows antipsychotic like and procognitive effects in rodents
Neurochemistry International, 2011Co-Authors: Istvan Gyertyan, Bela Kiss, Katalin Saghy, Judit Laszy, Gyorgyi Szabo, Tamas Szabados, Larisza I Gemesi, Gabriella Pasztor, Maria Zajerbalazs, Margit KapasAbstract:Abstract We investigated the in vivo effects of orally administered cariprazine (RGH-188; trans-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-N′,N′-dimethyl-urea), a D3/D2 dopamine receptor partial agonist with ∼10-fold preference for the D3 receptor. Oral bioavailability of cariprazine at a dose of 1 mg/kg in rats was 52% with peak plasma concentrations of 91 ng/mL. Cariprazine 10 mg/kg had good blood–brain barrier penetration, with a brain/plasma AUC ratio of 7.6:1. In rats, cariprazine showed dose-dependent in vivo displacement of [3H](+)-PHNO, a dopamine D3 receptor-preferring radiotracer, in the D3 receptor-rich region of cerebellar lobules 9 and 10. Its potent inhibition of apomorphine-induced climbing in mice (ED50 = 0.27 mg/kg) was sustained for 8 h. Cariprazine blocked amphetamine-induced hyperactivity (ED50 = 0.12 mg/kg) and conditioned avoidance response (CAR) (ED50 = 0.84 mg/kg) in rats, and inhibited the locomotor-stimulating effects of the noncompetitive NMDA antagonists MK-801 (ED50 = 0.049 mg/kg) and phencyclidine (ED50 = 0.09 mg/kg) in mice and rats, respectively. It reduced novelty-induced motor activity of mice (ED50 = 0.11 mg/kg) and rats (ED50 = 0.18 mg/kg) with a maximal effect of 70% in both species. Cariprazine produced no catalepsy in rats at up to 100-fold dose of its CAR inhibitory ED50 value. Cariprazine 0.02–0.08 mg/kg significantly improved the learning performance of scopolamine-treated rats in a water-labyrinth learning paradigm. Though risperidone, olanzapine, and aripiprazole showed antipsychotic-like activity in many of these assays, they were less active against phencyclidine and more cataleptogenic than cariprazine, and had no significant effect in the learning task. The distinct in vivo profile of cariprazine may be due to its higher affinity and in vivo binding to D3 receptors versus currently marketed typical and atypical antipsychotics.
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cariprazine rgh 188 a potent d3 d2 dopamine receptor partial agonist binds to dopamine d3 receptors in vivo and shows antipsychotic like and procognitive effects in rodents
Neurochemistry International, 2011Co-Authors: Istvan Gyertyan, Bela Kiss, Katalin Saghy, Judit Laszy, Gyorgyi Szabo, Tamas Szabados, Larisza I Gemesi, Gabriella Pasztor, Maria Zajerbalazs, Margit KapasAbstract:Abstract We investigated the in vivo effects of orally administered cariprazine (RGH-188; trans-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-N′,N′-dimethyl-urea), a D3/D2 dopamine receptor partial agonist with ∼10-fold preference for the D3 receptor. Oral bioavailability of cariprazine at a dose of 1 mg/kg in rats was 52% with peak plasma concentrations of 91 ng/mL. Cariprazine 10 mg/kg had good blood–brain barrier penetration, with a brain/plasma AUC ratio of 7.6:1. In rats, cariprazine showed dose-dependent in vivo displacement of [3H](+)-PHNO, a dopamine D3 receptor-preferring radiotracer, in the D3 receptor-rich region of cerebellar lobules 9 and 10. Its potent inhibition of apomorphine-induced climbing in mice (ED50 = 0.27 mg/kg) was sustained for 8 h. Cariprazine blocked amphetamine-induced hyperactivity (ED50 = 0.12 mg/kg) and conditioned avoidance response (CAR) (ED50 = 0.84 mg/kg) in rats, and inhibited the locomotor-stimulating effects of the noncompetitive NMDA antagonists MK-801 (ED50 = 0.049 mg/kg) and phencyclidine (ED50 = 0.09 mg/kg) in mice and rats, respectively. It reduced novelty-induced motor activity of mice (ED50 = 0.11 mg/kg) and rats (ED50 = 0.18 mg/kg) with a maximal effect of 70% in both species. Cariprazine produced no catalepsy in rats at up to 100-fold dose of its CAR inhibitory ED50 value. Cariprazine 0.02–0.08 mg/kg significantly improved the learning performance of scopolamine-treated rats in a water-labyrinth learning paradigm. Though risperidone, olanzapine, and aripiprazole showed antipsychotic-like activity in many of these assays, they were less active against phencyclidine and more cataleptogenic than cariprazine, and had no significant effect in the learning task. The distinct in vivo profile of cariprazine may be due to its higher affinity and in vivo binding to D3 receptors versus currently marketed typical and atypical antipsychotics.
Istvan Gyertyan - One of the best experts on this subject based on the ideXlab platform.
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cariprazine rgh 188 a potent d3 d2 dopamine receptor partial agonist binds to dopamine d3 receptors in vivo and shows antipsychotic like and procognitive effects in rodents
Neurochemistry International, 2011Co-Authors: Istvan Gyertyan, Bela Kiss, Katalin Saghy, Judit Laszy, Gyorgyi Szabo, Tamas Szabados, Larisza I Gemesi, Gabriella Pasztor, Maria Zajerbalazs, Margit KapasAbstract:Abstract We investigated the in vivo effects of orally administered cariprazine (RGH-188; trans-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-N′,N′-dimethyl-urea), a D3/D2 dopamine receptor partial agonist with ∼10-fold preference for the D3 receptor. Oral bioavailability of cariprazine at a dose of 1 mg/kg in rats was 52% with peak plasma concentrations of 91 ng/mL. Cariprazine 10 mg/kg had good blood–brain barrier penetration, with a brain/plasma AUC ratio of 7.6:1. In rats, cariprazine showed dose-dependent in vivo displacement of [3H](+)-PHNO, a dopamine D3 receptor-preferring radiotracer, in the D3 receptor-rich region of cerebellar lobules 9 and 10. Its potent inhibition of apomorphine-induced climbing in mice (ED50 = 0.27 mg/kg) was sustained for 8 h. Cariprazine blocked amphetamine-induced hyperactivity (ED50 = 0.12 mg/kg) and conditioned avoidance response (CAR) (ED50 = 0.84 mg/kg) in rats, and inhibited the locomotor-stimulating effects of the noncompetitive NMDA antagonists MK-801 (ED50 = 0.049 mg/kg) and phencyclidine (ED50 = 0.09 mg/kg) in mice and rats, respectively. It reduced novelty-induced motor activity of mice (ED50 = 0.11 mg/kg) and rats (ED50 = 0.18 mg/kg) with a maximal effect of 70% in both species. Cariprazine produced no catalepsy in rats at up to 100-fold dose of its CAR inhibitory ED50 value. Cariprazine 0.02–0.08 mg/kg significantly improved the learning performance of scopolamine-treated rats in a water-labyrinth learning paradigm. Though risperidone, olanzapine, and aripiprazole showed antipsychotic-like activity in many of these assays, they were less active against phencyclidine and more cataleptogenic than cariprazine, and had no significant effect in the learning task. The distinct in vivo profile of cariprazine may be due to its higher affinity and in vivo binding to D3 receptors versus currently marketed typical and atypical antipsychotics.
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cariprazine rgh 188 a potent d3 d2 dopamine receptor partial agonist binds to dopamine d3 receptors in vivo and shows antipsychotic like and procognitive effects in rodents
Neurochemistry International, 2011Co-Authors: Istvan Gyertyan, Bela Kiss, Katalin Saghy, Judit Laszy, Gyorgyi Szabo, Tamas Szabados, Larisza I Gemesi, Gabriella Pasztor, Maria Zajerbalazs, Margit KapasAbstract:Abstract We investigated the in vivo effects of orally administered cariprazine (RGH-188; trans-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-N′,N′-dimethyl-urea), a D3/D2 dopamine receptor partial agonist with ∼10-fold preference for the D3 receptor. Oral bioavailability of cariprazine at a dose of 1 mg/kg in rats was 52% with peak plasma concentrations of 91 ng/mL. Cariprazine 10 mg/kg had good blood–brain barrier penetration, with a brain/plasma AUC ratio of 7.6:1. In rats, cariprazine showed dose-dependent in vivo displacement of [3H](+)-PHNO, a dopamine D3 receptor-preferring radiotracer, in the D3 receptor-rich region of cerebellar lobules 9 and 10. Its potent inhibition of apomorphine-induced climbing in mice (ED50 = 0.27 mg/kg) was sustained for 8 h. Cariprazine blocked amphetamine-induced hyperactivity (ED50 = 0.12 mg/kg) and conditioned avoidance response (CAR) (ED50 = 0.84 mg/kg) in rats, and inhibited the locomotor-stimulating effects of the noncompetitive NMDA antagonists MK-801 (ED50 = 0.049 mg/kg) and phencyclidine (ED50 = 0.09 mg/kg) in mice and rats, respectively. It reduced novelty-induced motor activity of mice (ED50 = 0.11 mg/kg) and rats (ED50 = 0.18 mg/kg) with a maximal effect of 70% in both species. Cariprazine produced no catalepsy in rats at up to 100-fold dose of its CAR inhibitory ED50 value. Cariprazine 0.02–0.08 mg/kg significantly improved the learning performance of scopolamine-treated rats in a water-labyrinth learning paradigm. Though risperidone, olanzapine, and aripiprazole showed antipsychotic-like activity in many of these assays, they were less active against phencyclidine and more cataleptogenic than cariprazine, and had no significant effect in the learning task. The distinct in vivo profile of cariprazine may be due to its higher affinity and in vivo binding to D3 receptors versus currently marketed typical and atypical antipsychotics.
Philip S Portoghese - One of the best experts on this subject based on the ideXlab platform.
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ligands that interact with putative mor mglur5 heteromer in mice with inflammatory pain produce potent antinociception
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Eyup Akgun, Muhammad I Javed, Mary M Lunzer, Branden A Smeester, Al J Beitz, Philip S PortogheseAbstract:The low effectiveness of morphine and related mu opioid analgesics for the treatment of chronic inflammatory pain is a result of opioid-induced release of proinflammatory cytokines and glutamate that lower the pain threshold. In this regard, the use of opioids with metabotropic glutamate-5 receptor (mGluR5) antagonist has been reported to increase the efficacy of morphine and prevent the establishment of adverse effects during chronic use. Given the presence of opioid receptors (MORs) and mGluR5 in glia and neurons, together with reports that suggest coexpressed MOR/mGluR5 receptors in cultured cells associate as a heteromer, the possibility that such a heteromer could be a target in vivo was addressed by the design and synthesis of a series of bivalent ligands that contain mu opioid agonist and mGluR5 antagonist pharmacophores linked through spacers of varying length (10–24 atoms). The series was evaluated for antinociception using the tail-flick and von Frey assays in mice pretreated with lipopolysaccharide (LPS) or in mice with bone cancer. In LPS-pretreated mice, MMG22 (4c, 22-atom spacer) was the most potent member of the series (intrathecal ED50 ∼9 fmol per mouse), whereas in untreated mice its ED50 was more than three orders of magnitude higher. As members of the series with shorter or longer spacers have ≥500-fold higher ED50s in LPS-treated mice, the exceptional potency of MMG22 may be a result of the optimal bridging of protomers in a putative MOR-mGluR5 heteromer. The finding that MMG22 possesses a >106 therapeutic ratio suggests that it may be an excellent candidate for treatment of chronic, intractable pain via spinal administration.
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ligands that interact with putative mor mglur5 heteromer in mice with inflammatory pain produce potent antinociception
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Eyup Akgun, Muhammad I Javed, Mary M Lunzer, Branden A Smeester, Al J Beitz, Philip S PortogheseAbstract:The low effectiveness of morphine and related mu opioid analgesics for the treatment of chronic inflammatory pain is a result of opioid-induced release of proinflammatory cytokines and glutamate that lower the pain threshold. In this regard, the use of opioids with metabotropic glutamate-5 receptor (mGluR5) antagonist has been reported to increase the efficacy of morphine and prevent the establishment of adverse effects during chronic use. Given the presence of opioid receptors (MORs) and mGluR5 in glia and neurons, together with reports that suggest coexpressed MOR/mGluR5 receptors in cultured cells associate as a heteromer, the possibility that such a heteromer could be a target in vivo was addressed by the design and synthesis of a series of bivalent ligands that contain mu opioid agonist and mGluR5 antagonist pharmacophores linked through spacers of varying length (10–24 atoms). The series was evaluated for antinociception using the tail-flick and von Frey assays in mice pretreated with lipopolysaccharide (LPS) or in mice with bone cancer. In LPS-pretreated mice, MMG22 (4c, 22-atom spacer) was the most potent member of the series (intrathecal ED50 ∼9 fmol per mouse), whereas in untreated mice its ED50 was more than three orders of magnitude higher. As members of the series with shorter or longer spacers have ≥500-fold higher ED50s in LPS-treated mice, the exceptional potency of MMG22 may be a result of the optimal bridging of protomers in a putative MOR-mGluR5 heteromer. The finding that MMG22 possesses a >106 therapeutic ratio suggests that it may be an excellent candidate for treatment of chronic, intractable pain via spinal administration.
Saganuwan Alhaji Saganuwan - One of the best experts on this subject based on the ideXlab platform.
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determination of median effective dose ED50 of scorpion antivenom against scorpion envenomation using a newly developed formula
Animal Models and Experimental Medicine, 2018Co-Authors: Saganuwan Alhaji SaganuwanAbstract:Background About 50 species of scorpions cause fatal scorpionism worldwide. Most of these are members of the Buthidae family, and include, among others, Mesobuthus eupeus, Androctonus crassicauda, Leiurus abdullahbayrami, Leiurus quinquestriatus, Tityus pachyurus and Androctonus australis. Because high doses of scorpion venom and antivenom can cause death and hypersensitive reactions, there is a need to develop a formula that can be used to calculate both lethal and effective doses for scorpion venom and antivenom, respectively, thereby obviating the need for laboratory experiments. Methods In view of this, a literature search was carried out with the aim of modifying the formula ( LD50=ED503×Wa×10-4 ) for calculation of the median lethal dose (LD50) of scorpion venom and the ED50 of antivenom. The human equivalent dose (HED) formula was assessed for extrapolation of LD50 and ED50 from animals to human for comparison and relevance with the new formula. Results The findings showed that the newly developed formula (LD50 = ED501/3 × Wa × 10-4) yielded results that are very close to the reported values. Therefore, the newly developed and HED formulas can be used for calculation of LD50 and ED50 values for scorpion venom and antivenom, respectively. Conclusion The new formula yielded better results than the HED formula, confirming its predictive validity, precision, and reliability, thereby obviating the need for rigorous experiments and justifying the principles of reduction, refinement, and replacement (3Rs).
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The new algorithm for calculation of median lethal dose (LD50) and effective dose fifty (ED50) of Micrarus fulvius venom and anti-venom in mice
International Journal of Veterinary Science and Medicine, 2016Co-Authors: Saganuwan Alhaji SaganuwanAbstract:One million people throughout the world are bitten yearly by poisonous snakes. Of this, one-tenth died and three-tenth suffer some forms of disabilities. In view of this, anti-snake venoms are currently being developed against viper and colubrid snake venoms using mice. Therefore, a new algorithm for calculation of median lethal dose (LD50) and effective dose fifty (ED50) was developed for Micrarus fulvius venom and antivenom respectively. This paper compared the formula of effective dose fifty (ED50) developed by Spearman and Karber with ideal median lethal dose (IMLD50) formula developed by Saganuwan with a view to bringing out their difference and similarity in calculation of ED50 that could be used to develop a new median lethal dose formula for calculation of Micrarus fulvius venom in mice. The findings revealed that ED50 value (477 mg/kg) from Spearman and Karber’s formula (ED50=logED50=logX100-logFDn(Σt-n/2) is comparatively similar with ideal median lethal dose value (428.75 mg/kg) from Saganuwan’s formula (MLD50 + MSD50/2). The new LD50 formula (LD50=ED503×Wm×10-4) yielded value (0.29 mg/kg) of comparative significance with reported value (0.32 mg/kg). When ED50 is equal to 2LD50, the denominator of ED503 becomes 2. In conclusion, the new formula would yield low doses of snake anti-venoms with reduced possibility of hypersensitivity reaction.
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the new algorithm for calculation of median lethal dose ld50 and effective dose fifty ED50 of micrarus fulvius venom and anti venom using mice
The FASEB Journal, 2016Co-Authors: Saganuwan Alhaji SaganuwanAbstract:BackgroundOne million people throughout the world are bitten each year by poisonous snakes. Of this, one-tenth died and three-tenth suffer some forms of disabilities. In view of this, anti-snake ve...
Yota Kapessidou - One of the best experts on this subject based on the ideXlab platform.
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ED50 and ed90 of intrathecal hyperbaric 2 prilocaine in ambulatory knee arthroscopy
Canadian Journal of Anaesthesia-journal Canadien D Anesthesie, 2014Co-Authors: Emmanuel Guntz, Bausard Latrech, Constantin C Tsiberidis, Jonathan Gouwy, Yota KapessidouAbstract:Purpose Hyperbaric 2% prilocaine (HP) is increasingly used for spinal anesthesia in day-case surgery. The aim of this prospective double-blind study was to determine the effective dose (ED)50 and the ED90 of HP for patients undergoing knee arthroscopy.
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ED50 and ed90 of intrathecal hyperbaric 2 prilocaine in ambulatory knee arthroscopy
Canadian Journal of Anaesthesia-journal Canadien D Anesthesie, 2014Co-Authors: Emmanuel Guntz, Bausard Latrech, Constantin C Tsiberidis, Jonathan Gouwy, Yota KapessidouAbstract:Hyperbaric 2% prilocaine (HP) is increasingly used for spinal anesthesia in day-case surgery. The aim of this prospective double-blind study was to determine the effective dose (ED)50 and the ED90 of HP for patients undergoing knee arthroscopy. Doses of HP were determined using an up-and-down sequential allocation technique. Sequences were analyzed by isotonic regression analysis. A subsequent observational study was performed with the calculated ED90 in 50 patients to confirm the initial result and to describe the induced blockade effects and side effects. Times corresponding to onset and duration of sensory and motor block, surgical data, and side effects were recorded. The ED50 was estimated at 28.9 mg (95% confidence interval [CI]: 26.5 to 35.3) and the ED90 was estimated to be 38.5 mg (95% CI: 35.7 to 39.5). A 40 mg dose of HP provided efficient anesthesia in 46 patients (92%, 95% CI: 82 to 98). The average (SD) time to effective anesthesia was 14.5 (3.9) min. Complete sensory block at level T12 was obtained after ten minutes in 44 of 50 patients. The average (SD) duration of the sensory block was 205 (36.1) min. Maximal level of sensory block was obtained at the T8-T11 levels in 41 of 50 patients without hemodynamic instability. A Bromage 3 score was obtained in 40 of the 46 patients who achieved successful anesthesia after 30 min. Patients did not experience urinary retention, nor were any signs of transient neurologic symptoms observed. This study determined the ED50 of HP is 28.9 mg and suggests that a 40-mg dose of HP is adequate to provide successful spinal anesthesia for outpatient knee arthroscopy.
