Margarete M Trachez

Universidade Federal Fluminense, Vila Real da Praia Grande, Rio de Janeiro, Brazil

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Publications (21)45.47 Total impact

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    ABSTRACT: New chemicals or adjuvants with analgesic effects on chronic pain are needed and clinically relevant due to the limited number of effective compounds which possess these characteristics. LASSBio-873, a pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivative, activates muscarinic cholinergic receptors (mAchRs) and has potent analgesic effects on acute and inflammatory pain. The present study evaluated the therapeutic and prophylactic effects of oral administration of LASSBio-873 in a spinal nerve ligation (SNL) model of chronic peripheral nerve injury. LASSBio-873 (100 mg/kg) inhibited the development of thermal hyperalgesia and mechanical allodynia when administered immediately after SNL surgery and reversed these symptoms when administered therapeutically. LASSBio-873 treatments did not alter rat behavior in open field testing measured during the first 24 hr and after 7 continuous days administration. The analgesic effect of LASSBio-873 was inhibited by intrathecal methoctramine (type 2 muscarinic (M2) receptor antagonist), implicating the M2 signaling pathway in the drug's action. These results reinforce the potential of LASSBio-873 as a possible prototype for development of more effective alternatives for the treatment of neuropathic pain. This article is protected by copyright. All rights reserved.
    Clinical and Experimental Pharmacology and Physiology 04/2013; · 2.41 Impact Factor
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    ABSTRACT: Diabetes is a metabolic disorder characterized by hyperglycemia. When not properly controlled, complications include neuropathy, coronary artery disease, and renal failure. Several drugs are approved for diabetes treatment; however their use is associated with side effects and lack of efficacy in attenuating the development of long-term complications. This work describes the virtual screening and synthesis of a novel series of sulfonylhydrazone derivatives designed as peroxisome proliferator-activated receptor gamma (PPAR) agonists and investigation of the analogs for hypoglycemic activity in a murine model of diabetes. Docking studies identified LASSBio-331 (5) as having theoretical affinity for PPAR similar to the prototype (S)-rosiglitazone. Several structural modifications were proposed for the structure of LASSBio-331, resulting in the synthesis of five novel compounds, which showed experimental affinity for PPAR. Among these new compounds, LASSBio-1471 (15) had the best theoretical binding energy for PPAR and was selected for testing in STZ-induced diabetes. Four weeks after single intravenous injection of STZ (60 mg/kg), Wistar rats were treated with vehicle (DMSO) or LASSBio-1471 (20 mg/kg, i.p.) for 7 days. The blood glucose levels of rats treated with LASSBio-1471 were reduced from 548.4 ± 26.0 mg/dL before treatment to 259.6 ± 73.1 mg/dL (P < 0.05). Paw with-drawal threshold was significantly reduced in diabetic rats and was restored from 21.9 ± 1.7 g to 36.7 ± 1.2 g after 7 days of treatment with LASSBio-1471 (P < 0.05). Thus, the novel sulfonylhydrazone derivative is a PPAR ligand that is ef-fective for treatment of diabetic neuropathy in STZ-injected rats.
    Current Topics in Medicinal Chemistry; 12/2012
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    ABSTRACT: Diabetes is a metabolic disorder characterized by hyperglycemia. When not properly controlled, complications include neuropathy, coronary artery disease, and renal failure. Several drugs are approved for diabetes treatment; however their use is associated with side effects and lack of efficacy in attenuating the development of long-term complications. This work describes the virtual screening and synthesis of a novel series of sulfonylhydrazone derivatives designed as peroxisome proliferator-activated receptor gamma (PPARγ) agonists and investigation of the analogs for hypoglycemic activity in a murine model of diabetes. Docking studies identified LASSBio-331 (5) as having theoretical affinity for PPARγ similar to the prototype (S)-rosiglitazone. Several structural modifications were proposed for the structure of LASSBio-331, resulting in the synthesis of five novel compounds, which showed experimental affinity for PPARγ. Among these new compounds, LASSBio-1471 (15) had the best theoretical binding energy for PPARγ and was selected for testing in STZ-induced diabetes. Four weeks after single intravenous injection of STZ (60 mg/kg), Wistar rats were treated with vehicle (DMSO) or LASSBio-1471 (20 mg/kg, i.p.) for 7 days. The blood glucose levels of rats treated with LASSBio-1471 were reduced from 548.4 ± 26.0 mg/dL before treatment to 259.6 ± 73.1 mg/dL (P < 0.05). Paw withdrawal threshold was significantly reduced in diabetic rats and was restored from 21.9 ± 1.7 g to 36.7 ± 1.2 g after 7 days of treatment with LASSBio-1471 (P < 0.05). Thus, the novel sulfonylhydrazone derivative is a PPARγ ligand that is effective for treatment of diabetic neuropathy in STZ-injected rats.
    Current topics in medicinal chemistry 11/2012; · 4.47 Impact Factor
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    ABSTRACT: Tramadol is a centrally acting analgesic, whose mechanism of action involves opioid-receptor activation. Previously, we have shown that tramadol and its enantiomers had a negative inotropic effect on the papillary muscle in which the (+)-enantiomer is more potent than (-)- and (±)-tramadol. In this study, we investigated the effects of tramadol and its enantiomers on L-type calcium current (ICa-L). The experiments were carried out in isolated Wistar rat ventricular myocytes by using the whole cell patch clamp technique. Tramadol (200 µM) reduced the peak amplitude of ICa-L at potentials from 0 to +50 mV. At 0 mV, I(Ca-L) was reduced by 33.7 ± 7.2%. (+)- and (-)-tramadol (200 µM) produced a similar inhibition of ICa-L, in which the peak amplitude was reduced by 64.4 ± 2.8% and 68.9 ± 5.8%, respectively at 0 mV (p > 0.05). Tramadol, (+)- and (-)-tramadol shifted the steady-state inactivation of ICa-L to more negative membrane potentials. Also, tramadol and (+)-tramadol markedly shifted the time-dependent recovery curve of I(Ca-L) to the right and slowed down the recovery of I(Ca-L) from inactivation. The time constant was increased from 175.6 ± 18.6 to 305.0 ± 32.9 ms (p < 0.01) for tramadol and from 248.1 ± 28.1 ms to 359.0 ± 23.8 ms (p < 0.05) for (+)-tramadol. The agonist of µ-opioid receptor DAMGO had no effect on the I(Ca-L). The inhibition of ICa-L induced by tramadol and its enantiomers was unrelated to the activation of opioid receptors and could explain, at least in part, their negative cardiac inotropic effect.
    Arquivos brasileiros de cardiologia 10/2011; 97(4):324-31. · 1.32 Impact Factor
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    ABSTRACT: The susceptibility of children and newborns to cardiotoxicity from racemic bupivacaine, RS(±)-bupivacaine, is controversial. Some studies indicate that newborns can sustain higher bupivacaine plasma levels than adults, without severe toxicity. In this study, we compared the influence of age on cardiotoxicity from RS(±)-bupivacaine and S(-)-bupivacaine in rats. The effects of these local anesthetics (LAs) on the regulation of intracellular Ca(2+) concentrations in cardiac fibers were also investigated. The lethal dose was determined in ventilated male Wistar rats at 2, 4, 8, and 16 weeks of age by monitoring when cardiac electrical activity stopped after infusion of RS(±)-bupivacaine and S(-)-bupivacaine (4 mg · kg(-1) · min(-1)). The effects on cardiac muscle contraction were investigated by in vitro measurement of papillary muscle twitches in the presence and absence of RS(±)-bupivacaine or S(-)-bupivacaine. Skinned ventricular fibers were used to investigate the intracellular effects on Ca(2+) regulation induced by both LAs. The lethal dose for RS(±)-bupivacaine and S(-)-bupivacaine in 2-week-old animals (46.0 ± 5.2 and 91.3 ± 4.9 mg · kg(-1), respectively) was higher than in 16-week-old animals (22.7 ± 1.3 and 22.0 ± 2.7 mg · kg(-1), respectively). Papillary muscle twitches were reduced in a dose-dependent manner, with significant difference between young and adult hearts. In adults, the muscle twitches were reduced to 8.6% ± 0.8% of control by RS(±)-bupivacaine, and to 18.1% ± 2.7% of control by S(-)-bupivacaine (100 μM). S(-)-bupivacaine had a positive inotropic effect at <10 μM, but only in 2-week-old animals. In chemically skinned ventricular fibers, RS(±)-bupivacaine and S(-)-bupivacaine induced similar increases in Ca(2+) release from the sarcoplasmic reticulum (SR) preactivated with caffeine (1 mM), and this effect was greater in younger rats than adults. In 16-week-old rats, caffeine-induced tension was 53.9% ± 1.7% of the maximal fiber response with RS(±)-bupivacaine, and 54.1% ± 3.2% with S(-)-bupivacaine. The caffeine response in 2-week-old rats was 81.1% ± 3.7% of the maximal response with RS(±)-bupivacaine, and 78.1% ± 4.5% with S(-)-bupivacaine. The Ca(2+) sensitivity of contractile proteins was equally increased at both ages tested, with RS(±)-bupivacaine or S(-)-bupivacaine. Ca(2+) uptake from the SR was not altered by the LA or by age. Differences in the mechanisms for regulating intracellular SR Ca(2+) may contribute to the decreased susceptibility of young animals to cardiodepression induced by RS(±)-bupivacaine and S(-)-bupivacaine.
    Anesthesia and analgesia 02/2011; 112(3):574-80. · 3.08 Impact Factor
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    ABSTRACT: Malignant hyperthermia (MH) is a pharmacogenetic disease triggered by volatile anesthetics and succinylcholine. Deaths due to MH have been reported in Brazil. The first Malignant Hyperthermia Diagnostic and Research Center in Latin America was inaugurated in 1993 at the Federal University of Rio de Janeiro, Brazil. The center followed the diagnostic protocols of the North America MH Group, in which the contractures of biopsies from the vastus lateralis muscle are analyzed after exposure to caffeine and halothane (CHCT). CHCT was performed in individuals who survived, their relatives and those with signs/symptoms somewhat related to MH susceptibility (MHS). Here, we report data from 194 patients collected over 16 years. The Southeast (N = 110) and South (N = 71) represented the majority of patients. Median age was 25 (4-70) years, with similar numbers of males (104) and females (90). MHS was found in 90 patients and 104 patients were normal. Abnormal responses to both caffeine and halothane were observed in 59 patients and to caffeine or halothane in 20 and 11 patients, respectively. The contracture of biopsies from MHS exposed to caffeine and halothane was 1.027 +/- 0.075 g (N = 285) and 4.021 +/- 0.255 g (N = 226), respectively. MHS was found in patients with either low or high blood creatine kinase and also, with a low score on the clinical grading scale. Thus, these parameters cannot be used with certainty to predict MHS. We conclude that the CHCT protocol described by the North America MH Group contributed to identification of MHS in suspected individuals at an MH center in Brazil with 100% sensitivity and 65.7% specificity.
    Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 06/2010; 43(6):549-56. · 1.08 Impact Factor
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    ABSTRACT: The efficacy of intravenous (IV) administration of azumolene (Az), an analogue 30-fold more soluble than dantrolene, on pigs susceptible to malignant hyperthermia (MH) is incompletely understood. To evaluate efficacy of Az on MH crisis in pigs. Eight normal (MHN) and 7 susceptible to MH (MHS) pigs (Landrace × Large White × Pietran). Prospective, laboratory trial. Hypermetabolic crisis was observed in MHS pigs, but not in MHN pigs, after a combined administration of inhaled halothane (1.5%) and IV injection of succinylcholine (SCh; 2.5 mg/kg). Susceptibility was confirmed using a caffeine and halothane contracture test. Az was administered 15 minutes after administration of SCh. Results: Respiratory acidosis (pH 7.16 ± 0.02; Pco(2) , 46.2 ± 9.1 mmHg, HCO(3) , 22.5 ± 2.3 mmol/L), fever (38.2 ± 1.1°C), cardiac arrhythmias, and muscle contracture were observed in MHS pigs. MHS pigs (n = 5) treated with Az (2 mg/kg IV) survived the crisis with attenuation of signs (pH 7.30 ± 0.10; Pco(2) , 36.3 ± 4.5 mmHg; HCO(3) , 22.9 ± 2.3 mmol/L) and recovery of normal muscle tone and cardiac rhythm. Az represents a possible substitute for dantrolene to reverse MH crisis in susceptible pigs.
    Journal of Veterinary Internal Medicine 01/2010; 24(5):1224-8. · 2.06 Impact Factor
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    ABSTRACT: Justificativa e objetivos: Uso clínico de formulação lipídica de propofol causa dor durante injeção, reação alérgica e crescimento microbia-no. Propofol tem sido reformulado em diferentes apresentações não lipídicas para reduzir os efeitos adversos, mas essas mudanças podem modificar sua farmacocinética e farmacodinâmica. Neste trabalho, investigamos a farmacologia e a toxicologia do propofol lipídico (CLP) e da nanoemulsão não lipídica (NLP). Método: CLP and NLP foram infundidos na veia jugular de ratos sob medida da pressão arterial (PA), frequência cardíaca (FC) e frequência res-piratória (FR). Ambas as formulações (1%) foram infundidas (40 µL.min -1) durante 1 hora. Doses hipnóticas e anestésicas, assim como recupera-ções, foram determinadas. A dor induzida pelo veículo do CLP e NLP foi comparada por meio da contagem do número de contorções abdominais ("writhing test") após injeção intraperitonial (i.p.) em camundongos. Ácido acético (0,6%) foi usado como controle positivo. Resultados: As doses hipnóticas e anestésicas com 1% CLP (6,0 ± 1,3 e 17,8 ± 2,6 mg.kg -1 , respectivamente) e 1% NLP (5,4 ± 1,0 e 16,0 ± 1,4 mg.kg -1 , respectivamente) não foram significativamente diferentes. A recuperação da hipnose e da anestesia foi mais rápida com NLP do que com CLP. As alterações de FC, PA e FR causadas pelo NLP não foram significativamente diferentes das do CLP. Ácido acético e veículo do CLP provocaram 46,0 ± 2,0 e 12,5 ± 0,6 contorções em 20 min após injeção i.p., respectivamente. Observou-se ausência de contorções abdominais com veículo de NLP. Nenhuma resposta inflamatória abdominal foi notada com a injeção i.p. de ambos os veículos de propofol.
    01/2010;
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    ABSTRACT: The clinical use of a lipid propofol formulation causes pain during injection, allergic reactions, and bacterial growth. Propofol has been reformulated in different non-lipid presentations to reduce the incidence of adverse effects, but those changes can modify its pharmacokinetics and pharmacodynamics. In the present study, we investigate the pharmacology and toxicology of lipid propofol (CLP) and the non-lipid nanoemulsion (NLP). Conventional lipid formulation of propofol and NLP were infused in the jugular veins of rats and blood pressure (BP), heart rate (HR), and respiratory rate (RR) were measured. Both formulations (1%) were infused (40 μL.min⁻¹) over 1 hour. Hypnotic and anesthetic doses as well as recoveries were determined. The pain induced by the CLP and NLP vehicles was compared by counting the number of abdominal contortions ("writhing test") after the intraperitoneal (i.p.) injection in mice. Acetic acid (0.6%) was used as positive control. Hypnotic and anesthetic doses of 1% CLP (6.0 ± 1.3 and 17.8 ± 2.6 mg.kg⁻¹, respectively) and 1% NLP (5.4 ± 1.0 and 16.0 ± 1.4 mg.kg⁻¹, respectively) were not significantly different. Recovery from hypnosis and anesthesia was faster with NLP than with CLP. Changes in HR, BP, and RR caused by NLP were not significantly different from those caused by CLP. Acetic acid and the vehicle of CLP caused 46.0 ± 2.0 and 12.5 ± 0.6 abdominal contortions 20 min after i.p. injection, respectively. The absence of abdominal contractions was observed with the vehicle of NLP. Abdominal inflammatory response was not observed after the i.p. injection of both propofol vehicles. Non-lipid formulation of propofol can be a better alternative to CPL for intravenous anesthesia with fewer adverse effects.
    Revista brasileira de anestesiologia 01/2010; 60(5):475-83.
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    ABSTRACT: We investigated the toxicity of azumolene (Az), a more water-soluble compound than dantrolene, after 14 days of intraperitoneal (i.p.) administration in rats at doses of 1, 2.5 or 10 mg/kg/day. No animals died or presented signs of toxicity. No significant differences in water and food consumption or weight gain were noted among the groups. Blood analysis revealed no significant alteration by Az treatment in the number of blood cells. However, Az treatment induced a perivascular inflammatory reaction in the liver and non-diffuse necrosis of skeletal muscle, both of which occurred only at the highest dose of Az and were completely reversed 14 days after cessation of treatment. Congestion and inflammation in the kidneys were only partially reversed. Caffeine-induced contracture of skeletal muscle was not altered during 7 days of i.p. injection of Az (2.5 mg/kg/day). In conclusion, Az is a safe compound for long-term administration, but does cause a mild, reversible reaction in skeletal muscle and kidney.
    Fundamental and Clinical Pharmacology 11/2009; 24(4):491-500. · 1.99 Impact Factor
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    ABSTRACT: Antidepressant drugs act as potent inhibitors of norepinephrine and/or serotonin reuptake and are widely used with opioids for the treatment of chronic pain. The mechanism of this increased analgesic action is unclear. We compared the antinociceptive effects of the intrathecal administration of morphine with that of a nonselective (amitriptyline) or selective (maprotiline or citalopram) antidepressant drug using the thermal withdrawal test in rats. We also investigated the possible mechanisms involved in the interactions of these drugs. Male Wistar rats were anesthetized with sevoflurane and administered morphine and antidepressant drugs, or saline, through intrathecal injection. The antinociceptive effect was evaluated using the thermal withdrawal test before and after drug administration. The time for the withdrawal reaction was expressed as percentage of maximum possible effect (MPE). Animals were also pretreated with yohimbine (a nonselective alpha2-adrenergic antagonist) and naloxone (a nonselective opioid antagonist) for mechanism of action studies. Pharmacologic interaction was evaluated using isobolographic analysis of simultaneous administration of fixed proportions of maprotiline and morphine. Single intrathecal administration of morphine (2 microg), amitriptiline (125 microg), citalopram (144 microg), and maprotiline (1.25 microg) produced 51.6% +/- 8.9%, 10.3% +/- 3.2%, 33.8% +/- 5.2%, and 48.5% +/- 9.2% MPE, respectively. The antinociceptive effect of morphine was increased when combined with amitriptyline (91.3% +/- 4.6% MPE) and maprotiline (86.9% +/- 9.2% MPE) but not with citalopram (40.6% +/- 4.6% MPE). Coadministration of maprotiline increased the antinociceptive duration of morphine by 4-fold (from 120 to 480 min), which was reversed by pretreatment with the alpha-2 adrenoceptor inhibitor, yohimbine, and the mu-type opioid receptor antagonist, naloxone. Isobolographic analysis demonstrated a synergistic interaction between morphine and maprotiline. Selective norepinephrine reuptake inhibitors can significantly increase the intensity and duration of morphine antinociceptive activity via both alpha(2)-adrenergic and opioid receptors. This interaction was not observed with the selective serotonin inhibitor, citalopram.
    Anesthesia and analgesia 10/2009; 109(4):1312-7. · 3.08 Impact Factor
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    ABSTRACT: The aim of the present study was to determine the effects of tramadol on vascular reactivity in aortic rings from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Aortic rings, with or without endothelium, were obtained from male WKY rats and SHR (15-20 weeks old) and prepared for isometric tension recording. Aortic rings were precontracted with phenylephrine (10 micromol/L) or 40 mmol/L KCl and then exposed to cumulative concentrations of tramadol (0.1-1 mmol/L). Tramadol produced a concentration-dependent relaxation of precontracted aortic rings from WKY rats and SHR, which was not dependent on functional endothelium. Vascular relaxation was significantly greater in rings from SHR than WKY rats. The concentration of tramadol necessary to produce a 50% reduction of the maximal contraction to phenylephrine (IC(50)) in rings with and without endothelium from SHR was 0.47 +/- 0.08 and 0.44 +/- 0.03 mmol/L, respectively (P = 0.76). Tramadol attenuated the contracture elicited by Ca2+ in depolarized tissue, suggesting that it may inhibit L-type Ca2+ channels. However, pretreatment with nicardipine (1 micromol/L) prevented the relaxation induced by tramadol in aortic rings from WKY rats and partially reduced its inhibitory effect in aortic rings from SHR. 6. Pretreatment of endothelium-denuded aorta with glybenclamide (3 micromol/L), 4-aminopyridine (3 mmol/L), tetraethylammonium (3 mmol/L) and naloxone (100 micromol/L) did not affect tramadol-induced vasodilation of aortic rings from either WKY rats or SHR. Intravenous administration of tramadol (10 mg/kg) to conscious SHR significantly reduced both systolic and diastolic blood pressure from 171.4 +/- 5.3 to 129.3 +/- 5.3 (P = 0.002) and from 125.0 +/- 6.5 to 57.8 +/- 8.9 mmHg (P = 0.003), respectively.
    Clinical and Experimental Pharmacology and Physiology 10/2008; 35(10):1197-203. · 2.41 Impact Factor
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    ABSTRACT: Isatin (1H-indole-2,3 dione) is an endogenous compound that may act as a physiological regulator of muscle contraction by reducing cGMP production by inhibition of guanylyl cyclase (GC) activity. Intracellular cGMP levels can regulate the contractile response of smooth muscle. Therefore, in the present study we investigated the effects of seven novel carbamate derivatives of isatin, namely C1-C7, on the contractility of aortic rings from Wistar rats. Carbamates C1 and C6 most effectively promoted endothelium-dependent relaxation of aortic rings pretreated with 10 micromol/L phenylephrine (PE) to induce contraction. The concentration of the C1 and C6 carbamates necessary to reduce PE-induced aortic contraction by 50% (IC(50)) was 5.6 +/- 1.0 and 48.4 +/- 3.4 micromol/L, respectively. Carbamate derivative-induced vasodilation required an intact endothelium, which is responsible for nitric oxide (NO) release. Pretreatment of rings with 100 micromol/L naloxone or 10 micromol/L atropine prevented the C1- and C6-mediated vascular relaxation, indicating that the vasodilatory activity was dependent on the activation of opioid or muscarinic receptors, respectively. The results of our studies provide insights into the role of novel carbamates in the regulation of vascular tone. Carbamates could stimulate NO synthesis, which induces vasodilation primarily by stimulation of GC and cGMP production. Taken together, our findings suggest that carbamate derivative-induced vasodilation may be considered an alternative treatment for primary and/or secondary hypertension.
    Clinical and Experimental Pharmacology and Physiology 09/2008; 35(9):1091-6. · 2.41 Impact Factor
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    ABSTRACT: 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 microM, respectively. The IC(50) of dantrolene sodium in these muscles was 1.6 +/- 0.4 and 3.5 +/- 1.2 microM, respectively, with no difference in comparison to azumolene. Previous in vitro exposure of mouse soleus muscle to azumolene and dantrolene sodium (10 microM) 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 microM, 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.
    Basic & Clinical Pharmacology & Toxicology 04/2008; 102(3):308-16. · 2.18 Impact Factor
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    ABSTRACT: Isatin (1H-indol-2,3-dione) is an endogenous compound found in many tissues and fluids. Isatin and its derivatives exert pharmacological effects on the central nervous system, including anxiogenic, sedative and anticonvulsant activities. Two new groups of isatin derivatives were synthesized (nine dioxolane ketals and nine dioxane ketals) and studied for their sedative, hypnotic and anesthetic effects using pentobarbital-induced sleeping time, locomotor activity evaluation and intravenous infusion. The dioxolane ketals were more potent than dioxane ketals for inducing sedative-hypnotic states, causing up to a three-fold increase in pentobarbital hypnosis. The dioxolane ketals produced sedation, demonstrated by decreased spontaneous locomotor activity in an open field. Hypnosis and anesthesia were observed during intravenous infusion of 5'-chlorospiro-[1,3-dioxolane-2,3'-indolin]-2'-one (T3) in conscious Wistar rats. Complete recovery from hypnosis and anesthesia required 39.1+/-7.3 and 6.8+/-2.4 min, respectively. Changes in hemodynamic parameters after infusion of 5.0 mg/kg/min were minimal. These findings suggest that these new isatin derivatives represent potential candidates for the development of new drugs that act on the central nervous system and may lead to a new centrally acting anesthetic with no toxic effects on the cardiovascular or respiratory systems.
    Pharmacology Biochemistry and Behavior 05/2007; 86(4):678-85. · 2.82 Impact Factor
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    ABSTRACT: In this study we investigated the effects of a racemic mixture of bupivacaine (RS(+/-)bupivacaine) and its isomers (S(-)bupivacaine and R(+)bupivacaine) on the Ca2+ handling by ventricular myocytes from Wistar rats. Single ventricular myocytes were enzymatically isolated and loaded with the fluorescent Ca2+ indicator fura 2-am to estimate intracellular Ca2+ concentration during contraction and relaxation cycles. S(-)bupivacaine (10 muM) significantly increased peak amplitude and the rate of increase of Ca2+ transients in 155% +/- 54% (P < 0.05) and 194% +/- 94% (P < 0.01) of control. However, exposure to R(+)bupivacaine had no effect on either peak amplitude or rate of increase at any concentration tested. Saponin-skinned ventricular fibers were used to investigate the effect of bupivacaine on the intracellular Ca2+ regulation by sarcoplasmic reticulum (SR) and on the Ca2+ sensitivity of contractile system. S(-), R(+), and RS(+/-)bupivacaine induced Ca2+ release from SR (P < 0.01). In SR-disrupted skinned ventricular cells, bupivacaine and its isomers (5 mM) increased the sensitivity of contractile system to Ca(2+). S(-), RS(+/-), and R(+)bupivacaine significantly increased pCa50 from 5.8 +/- 0.1, 5.8 +/- 0.1, and 5.8 +/- 0.1, to 6.1 +/- 0.1 (P < 0.05), 6.0 +/- 0.1 (P < 0.05), and 6.1 +/- 0.1 (P < 0.05). Ca2+ release from SR through RyR2 activation could explain the increase of Ca2+ transients in cardiac cells. Increased intracellular Ca2+ in cardiac myocytes display a stereoselectivity to S(-)bupivacaine.
    Anesthesia and analgesia 04/2006; 102(3):792-8. · 3.08 Impact Factor
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    ABSTRACT: Tramadol ((+/-)-tramadol) is an analgesic agent formulated as a racemic mixture (1:1) of (-)- and (+)-tramadol, which differ in their potency to bind to mu-opioid receptors and to inhibit monoamine-reuptake. We investigated the stereoselectivity of in vitro tramadol-induced vasodilatation of aortic rings and its effect on the arterial blood pressure measured in conscious Wistar rats. (+)-Tramadol, but not (-)-tramadol, produced a concentration-dependent relaxation of aorta precontracted with phenylephrine. The concentration-response curve was significantly altered by the removal of endothelium. Vascular relaxation was also inhibited by pre-incubation of endothelium-intact aorta with naloxone, suggesting the involvement of opioid receptors. The vasodilatation produced by tramadol was stereoselective, and the (+)-tramadol-induced vasodilatation was mediated by mu-opioid receptors and partially dependent on endothelium integrity. The hypotensive response induced by (+)-tramadol was also observed after bolus injection of 5.0 and 10.0 mg/kg. The results indicate that only high doses of tramadol cause cardiac depression and hypotension, indicating that it can be used safely.
    European Journal of Pharmacology 02/2006; 530(1-2):117-23. · 2.59 Impact Factor
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    ABSTRACT: Racemic [RS(+/-)] bupivacaine can be associated with severe cardiotoxicity. The S(-) isomer is known to be less neuro- and cardiotoxic, but demonstrates a lower potency to block motor activity than RS(+/-) bupivacaine. Thus, the potency and toxicity of a non-racemic bupivacaine mixture were studied. Gastrocnemic muscle twitches induced by electrical stimulation of sciatic nerves in rats were used to compare the impact by bupivacaine solutions on motor activity. Field stimulation at 1 Hz eliciting ventricular muscle twitches was used to investigate the effects on cardiac contractility. The lethal dose of each local anesthetic agent was determined following drug infusions during general anesthesia in mechanically ventilated rats. Non-racemic (75S:25R) bupivacaine was more potent (P<0.05) than S(-) or R(+) enantiomers to block motor nerve activity. The concentrations of RS(+/-), 75S:25R, R(+) and S(-) bupivacaine to inhibit nerve conduction by 50% were 0.84 (0.37- 2.20), 0.84 (0.47-2.48), 2.68 (0.98-3.42) and 2.11 mM (1.5-4.03), respectively. Pronounced reductions in ventricular muscle twitches were observed with RS(+/-) and R(+) bupivacaine at low concentrations (0.5-4 microM). Lethal doses for 75S:25R (39.9 mg kg(-1)), and S(-) (34.7 mg kg(-1)) were higher (P<0.05) than for R(+) (16.2 mg kg(-1)) and RS(+/-) bupivacaine (18.4 mg kg(-1)), respectively. The potency of S(-) bupivacaine to block the motor activity in the sciatic nerve was enhanced when 25% of the S(-) isomer was replaced by the antipode R(+) bupivacaine. This effect was not associated with increased toxicity.
    Acta Anaesthesiologica Scandinavica 02/2005; 49(1):66-71. · 2.36 Impact Factor
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    ABSTRACT: Cardiac toxicity can occur after accidental intravascular injection of bupivacaine. Racemic bupivacaine can inhibit both cardiac Na(+) and Ca(2+) channels, but the contribution of these actions to cardiac depression is not totally understood. We tested whether the effect of R(+) bupivacaine on cardiac electrical activity in isolated hearts and on L-type Ca(2+) channels (I(Ca-L)) in isolated cardiac myocytes could be responsible for its increased cardiotoxicity compared with S(-) bupivacaine. Cardiac electrical activity of spontaneously beating isolated hearts was recorded before and after exposure to increasing concentrations of R(+) and S(-) bupivacaine. An increase of the PR interval (80%) and the QRS duration (370%) by 10microM R(+) bupivacaine (80% and 370%) was significantly higher than for S(-) bupivacaine (25% and 200%, respectively). R(+) but not S(-) bupivacaine produced severe arrhythmias at concentrations larger than 2.5microM. The intensity of I(Ca-L) inhibition did not differ between bupivacaine isomers. At 0 mV, I(Ca-L) was irreversibly reduced by 40.2% +/- 8.8% and 51.4% +/- 3.8% in the presence of 10microM R(+) and S(-) bupivacaine, respectively. The arrhythmogenic effect of R(+) bupivacaine could not be explained by stereoselectivity on the I(Ca-L) inhibition. Thus, other mechanisms could contribute to the cardiac electrical and contractile dysfunction induced by R(+) bupivacaine.
    Anesthesia & Analgesia 03/2001; 92(2):496-501. · 3.30 Impact Factor
  • M M Trachez, R T Sudo, G Suarez-Kurtz
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    ABSTRACT: Isometric tension was recorded in vitro from chemically skinned fibers obtained from normal and 14-day-denervated extensor digitorum longus muscles of the rabbit. Denervation potentiated the tensions elicited by pCa 6.0 but did not modify the pCa value (5.6) required for maximum tension. Ca2+ transport across the membranes of the sarcoplasmic reticulum (SR) was markedly affected by denervation. Thus the rate of ATP-dependent net Ca2+ uptake increased significantly, and the spontaneous release ("leakage") of the Ca2+ stored in the SR was significantly reduced in denervated fibers. These effects lead to increased accumulation of Ca2+ in the lumen of the SR. The dose-response curve for the halothane-induced contractures of Ca2(+)-loaded skinned fibers was displaced to the left after denervation. Thus 0.7 mM halothane, a concentration that elicited no tension in 10 control fibers, induced contractures in the 10 denervated fibers tested. The potentiation of the halothane-induced tensions is attributed mainly to the larger stores of Ca2+ in the SR of denervated fibers. The possibility that denervation may also affect the interaction of halothane with the SR membranes is discussed.
    The American journal of physiology 10/1990; 259(3 Pt 1):C503-6. · 3.28 Impact Factor

Publication Stats

103 Citations
45.47 Total Impact Points

Institutions

  • 2005–2013
    • Universidade Federal Fluminense
      Vila Real da Praia Grande, Rio de Janeiro, Brazil
  • 1990–2013
    • Federal University of Rio de Janeiro
      • • Instituto de Ciências Biomédicas (ICB)
      • • Programa de Desenvolvimento de Fármacos
      • • Instituto de Biofísica Carlos Chagas Filho (IBCCF)
      • • Departamento de Clínica Odontológica
      Rio de Janeiro, Rio de Janeiro, Brazil