P. Carmo | Universidade Federal do Rio de Janeiro (UFRJ) (original) (raw)
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Papers by P. Carmo
Brazilian Journal of Medical and Biological Research, 2010
Fundamental & Clinical Pharmacology, 2009
Malignant hyperthermia (MH) is a lethal skeletal muscle hypermetabolic syndrome triggered by gene... more Malignant hyperthermia (MH) is a lethal skeletal muscle hypermetabolic syndrome triggered by general anesthetics such as halothane, sevoflurane, and desflurane and the depolarizing muscle relaxant succinylcholine . MH can also be induced by non-drug stimulation, such as stress, in human and pigs . MH is associated mainly with mutations in ryanodine receptors (RyR1), the sarcoplasmic reticulum (SR) Ca 2+ release channel, in skeletal muscle. Dantrolene sodium (1-{[5-(4-nitrophenyl)-2-furfury]methylene}amino-2,4-imidazoleidinedione; DS), which was initially used as a muscle relaxant [3], is a unique, clinically available, agent used to treat MH. DS binds to a specific site on RyR1 [4], decreasing the outflow of Ca 2+ from the SR intraluminal space to the sarcoplasma. Since clinical use of DS became common, the mortality from MH has decreased from 75% to less than 10% .
Basic & Clinical Pharmacology & Toxicology, 2008
Malignant hyperthermia is a pharmacogenetic disease of skeletal muscle in which a life-threatenin... more Malignant hyperthermia is a pharmacogenetic disease of skeletal muscle in which a life-threatening, hypermetabolic syndrome is induced by exposure of susceptible patients to halogenated general anaesthetics and/or succinylcholine. Dantrolene sodium, the only drug effective for treatment of malignant hyperthermia, has low water solubility that makes its clinical use difficult. The aim of this study was to investigate the potency of azumolene, a 30-fold more water-soluble analogue, in comparison to the prototype dantrolene sodium, on mammalian and human skeletal muscles. The twitches of extensor digitorum longus and soleus muscles from mice were inhibited by azumolene with IC 50 of 2.8 ± 0.8 and 2.4 ± 0.6 μ M, respectively. The IC 50 of dantrolene sodium in these muscles was 1.6 ± 0.4 and 3.5 ± 1.2 μ M, respectively, with no difference in comparison to azumolene. Previous in vitro exposure of mouse soleus muscle to azumolene and dantrolene sodium (10 μ M) significantly inhibited 8 mM caffeine-induced contractures. Azumolene was just effective as dantrolene sodium in relaxing caffeine-induced contractures of mouse soleus muscle. Intravenous injection caused dose-dependent decreases in twitches of guinea pig gastrocnemius muscle with IC 50 of 1.2 ± 0.1 and 1.5 ± 0.2 mg/kg for azumolene and dantrolene sodium, respectively. Azumolene, 10 μ M, was effective in blocking and reversing caffeine-induced contracture of human malignant hyperthermia susceptible skeletal muscle in vitro . These studies provide evidence that azumolene is equipotent to dantrolene sodium in blocking pharmacologic-induced muscle contractures and that azumolene should be efficacious for treatment/prevention of malignant hyperthermia.
Brazilian Journal of Medical and Biological Research, 2010
Fundamental & Clinical Pharmacology, 2009
Malignant hyperthermia (MH) is a lethal skeletal muscle hypermetabolic syndrome triggered by gene... more Malignant hyperthermia (MH) is a lethal skeletal muscle hypermetabolic syndrome triggered by general anesthetics such as halothane, sevoflurane, and desflurane and the depolarizing muscle relaxant succinylcholine . MH can also be induced by non-drug stimulation, such as stress, in human and pigs . MH is associated mainly with mutations in ryanodine receptors (RyR1), the sarcoplasmic reticulum (SR) Ca 2+ release channel, in skeletal muscle. Dantrolene sodium (1-{[5-(4-nitrophenyl)-2-furfury]methylene}amino-2,4-imidazoleidinedione; DS), which was initially used as a muscle relaxant [3], is a unique, clinically available, agent used to treat MH. DS binds to a specific site on RyR1 [4], decreasing the outflow of Ca 2+ from the SR intraluminal space to the sarcoplasma. Since clinical use of DS became common, the mortality from MH has decreased from 75% to less than 10% .
Basic & Clinical Pharmacology & Toxicology, 2008
Malignant hyperthermia is a pharmacogenetic disease of skeletal muscle in which a life-threatenin... more Malignant hyperthermia is a pharmacogenetic disease of skeletal muscle in which a life-threatening, hypermetabolic syndrome is induced by exposure of susceptible patients to halogenated general anaesthetics and/or succinylcholine. Dantrolene sodium, the only drug effective for treatment of malignant hyperthermia, has low water solubility that makes its clinical use difficult. The aim of this study was to investigate the potency of azumolene, a 30-fold more water-soluble analogue, in comparison to the prototype dantrolene sodium, on mammalian and human skeletal muscles. The twitches of extensor digitorum longus and soleus muscles from mice were inhibited by azumolene with IC 50 of 2.8 ± 0.8 and 2.4 ± 0.6 μ M, respectively. The IC 50 of dantrolene sodium in these muscles was 1.6 ± 0.4 and 3.5 ± 1.2 μ M, respectively, with no difference in comparison to azumolene. Previous in vitro exposure of mouse soleus muscle to azumolene and dantrolene sodium (10 μ M) significantly inhibited 8 mM caffeine-induced contractures. Azumolene was just effective as dantrolene sodium in relaxing caffeine-induced contractures of mouse soleus muscle. Intravenous injection caused dose-dependent decreases in twitches of guinea pig gastrocnemius muscle with IC 50 of 1.2 ± 0.1 and 1.5 ± 0.2 mg/kg for azumolene and dantrolene sodium, respectively. Azumolene, 10 μ M, was effective in blocking and reversing caffeine-induced contracture of human malignant hyperthermia susceptible skeletal muscle in vitro . These studies provide evidence that azumolene is equipotent to dantrolene sodium in blocking pharmacologic-induced muscle contractures and that azumolene should be efficacious for treatment/prevention of malignant hyperthermia.