Antinociceptive Effect of Lodenafil Carbonate in Rodent Models of Inflammatory Pain and Spinal Nerve Ligation-Induced Neuropathic Pain.

INTRODUCTION: New therapeutic alternatives for pain relief include the use of phosphodiesterase-5 (PDE5) inhibitors, which could prevent the transmission of painful stimuli by neuron hyperpolarization via nitric oxide (NO)/cyclic 3',5'-guanosine monophosphate (cGMP) pathway. The present work investigated the antinociceptive activity of a new PDE5 inhibitor, lodenafil carbonate, in inflammatory and neuropathic pain models. METHODS AND RESULTS: Although no effect was detected on neurogenic phase of formalin test in mice, oral administration of lodenafil carbonate dose-dependently reduced reactivity in the inflammatory phase (200.6 ± 39.1 to 81.9 ± 18.8 s at 10 µmol/kg, p= 0.0172) and this effect was totally blocked by NO synthase inhibitor, L-Nω-nitroarginine methyl ester (L-NAME). Lodenafil carbonate (10 µmol/kg p.o.) significantly reduced nociceptive response as demonstrated by increased paw withdrawal latency to thermal stimulus (from 6.8 ± 0.7 to 10.6 ± 1.3 s, p= 0.0006) and paw withdrawal threshold to compressive force (from 188.0 ± 14.0 to 252.5 ± 5.3 g, p<0.0001) in carrageenan-induced paw inflammation model. In a spinal nerve ligation-induced neuropathic pain, oral lodenafil carbonate (10 µmol/kg) also reversed thermal hyperalgesia and mechanical allodynia by increasing paw withdrawal latency from 17.9 ± 1.5 to 22.8 ± 1.9 s (p= 0.0062) and paw withdrawal threshold from 26.0 ± 2.8 to 41.4 ± 2.9 g (p= 0.0196). These effects were reinforced by the reduced GFAP (3.4 ± 0.5 to 1.4 ± 0.3%, p= 0.0253) and TNF-alpha (1.1 ± 0.1 to 0.4 ± 0.1%, p= 0.0111) stained area densities as detected by immunofluorescence in ipsilateral dorsal horns. CONCLUSION: Lodenafil carbonate demonstrates important analgesic activity by promoting presynaptic hyperpolarization and preventing neuroplastic changes, which may perpetuate chronic pain, thus representing a potential treatment for neuropathic pain.

New Benzofuran N-Acylhydrazone Reduces Cardiovascular Dysfunction in Obese Rats by Blocking TNF-Alpha Synthesis.

INTRODUCTION: Diabetic obese patients are susceptible to the development of cardiovascular disease, including hypertension and cardiac dysfunction culminating in diabetic cardiomyopathy (DC), which represents a life-threatening health problem with increased rates of morbidity and mortality. The aim of the study is to characterize the effects of a new benzofuran N-acylhydrazone compound, LASSBio-2090, on metabolic and cardiovascular alterations in Zucker diabetic fatty (ZDF) rats presenting DC. METHODS: Male non-diabetic lean Zucker rats (ZL) and ZDF rats treated with vehicle (dimethylsulfoxide) or LASSBio-2090 were used in this study. Metabolic parameters, cardiovascular function, left ventricle histology and inflammatory protein expression were analyzed in the experimental groups. RESULTS: LASSBio-2090 administration in ZDF rats reduced glucose levels to 85.0 ± 1.7 mg/dL (p < 0.05). LASSBio-2090 also lowered the cholesterol and triglyceride levels from 177.8 ± 31.2 to 104.8 ± 5.3 mg/dL and from 123.0 ± 11.4 to 90.9 ± 4.8 mg/dL, respectively, in obese diabetic rats (p < 0.05). LASSBio-2090 normalized plasma insulin, insulin sensitivity and endothelial function in aortas from diabetic animals (p < 0.05). It also enhanced systolic and diastolic left-ventricular function and reverted myocardial remodeling by blocking the threefold elevation of TNF-α levels in hearts from ZDF rats. CONCLUSION: LASSBio-2090 alleviates metabolic disturbance and cardiomyopathy in an obese and diabetic rat model, thus representing a novel strategy for the treatment of cardiovascular complications in obesity-associated type 2 diabetes mellitus.

Synthesis, solubility, plasma stability, and pharmacological evaluation of novel sulfonylhydrazones designed as anti-diabetic agents.

Neuropathy is a serious complication of diabetes that has a significant socioeconomic impact, since it frequently demands high levels of health care consumption and compromises labor productivity. Recently, LASSBio-1471 (3) was demonstrated to improve oral glucose tolerance, reduce blood glucose levels, and display an anti-neuropathy effect in a murine streptozotocin-induced diabetes model. In the present work, we describe the design, synthesis, solubility, plasma stability, and pharmacological evaluation of novel sulfonylhydrazone derivatives (referred to herein as compounds 4-9), which were designed by molecular modification based on the structure of the prototype LASSBio-1471 (3). Among the compounds tested, better plasma stability was observed with 4, 5, and 9 in comparison to compounds 6, 7, and 8. LASSBio-1773 (7), promoted not only hypoglycemic activity but also the reduction of thermal hyperalgesia and mechanical allodynia in a murine model of streptozotocin-induced diabetic neuropathic pain.

Caracterização anestésica da nanoemulsão não lipídica de propofol / Anesthetic profile of a non-lipid propofol nanoemulsion / Caracterización anestésica de la nanoemulsión no lipídica de propofol

JUSTIFICATIVA E OBJETIVOS: Uso clínico de formulação lipídica de propofol causa dor durante injeção, reação alérgica e crescimento microbiano. 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 respiratória (FR). Ambas as formulações (1 por cento) foram infundidas (40 µL.min-1) durante 1 hora. Doses hipnóticas e anestésicas, assim como recuperações, 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 por cento) foi usado como controle positivo. RESULTADOS: As doses hipnóticas e anestésicas com 1 por cento CLP (6,0 ± 1,3 e 17,8 ± 2,6 mg.kg-1, respectivamente) e 1 por cento 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. CONCLUSÕES: O NLP pode representar melhor alternativa do que o CLP para anestesia venosa com menores efeitos adversos.

BACKGROUND AND OBJECTIVES: 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). METHODS: 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 percent) 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 percent) was used as positive control. RESULTS: Hypnotic and anesthetic doses of 1 percent CLP (6.0 ± 1.3 and 17.8 ± 2.6 mg.kg-1, respectively) and 1 percent 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. CONCLUSIONS: Non-lipid formulation of propofol can be a better alternative to CPL for intravenous anesthesia with fewer adverse effects.

JUSTIFICATIVA Y OBJETIVOS: El uso clínico de la formulación lipídica del propofol, causa dolor durante la inyección, reacción alérgica y crecimiento microbiano. El propofol ha sido reformulado en diferentes presentaciones no lipídicas para reducir los efectos adversos, pero esos cambios pueden modificar su farmacocinética y farmacodinámica. En este trabajo, investigamos la farmacología y la toxicología del propofol lipídico (CLP) y de la nanoemulsión no lipídica (NLP). MÉTODO: El CLP y el NLP fueron infundidos en la vena yugular de ratones midiendo la presión arterial (PA), frecuencia cardíaca (FC) y frecuencia respiratoria (FR). Las dos formulaciones (1 por ciento) fueron infundidas (40 µL.min-1) durante 1 hora. Dosis hipnóticas y anestésicas y recuperaciones, fueron determinadas. El dolor inducido por el vehículo del CLP y NLP se comparó por medio del conteo del número de contorciones abdominales ("writhing test") después de la inyección intraperitoneal en ratones. El ácido acético (0,6 por ciento) fue usado como control positivo. RESULTADOS: Las dosis hipnóticas y anestésicas con 1 por ciento CLP (6,0 ± 1,3 y 17,8 ± 2,6 mg.kg-1, respectivamente) y 1 por ciento NLP (5,4 ± 1,0 y 16,0 ± 1,4 mg.kg-1, respectivamente), no fueron significativamente diferentes. La recuperación de la hipnosis y de la anestesia fue más rápida con NLP que con CLP. Las alteraciones de FC, PA y FR causadas por el NLP no fueron significativamente diferentes de las del CLP. El ácido acético y el vehículo del CLP provocaron 46,0 ± 2,0 y 12,5 ± 0,6 contorciones en 20 minutos después de la inyección i.p., respectivamente. No se observaron contorciones abdominales con vehículo de NLP. Ninguna respuesta inflamatoria abdominal fue notada con la inyección i.p. de los dos vehículos de propofol. CONCLUSIONES: El NLP puede representar una mejor alternativa que el CLP para la anestesia venosa, con menores efectos adversos.

Anesthetic profile of a non-lipid propofol nanoemulsion.

BACKGROUND AND OBJECTIVES: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: Non-lipid formulation of propofol can be a better alternative to CPL for intravenous anesthesia with fewer adverse effects.

Toxicological evaluation of azumolene after repeated intraperitoneal administration in rats.

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.

Effects of azumolene on normal and malignant hyperthermia-susceptible skeletal muscle.

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.

In vitro and in vivo vasodilator activity of racemic tramadol and its enantiomers in Wistar rats.

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.

Analgesia pós-operatória de prostatectomia transvesical: estudo comparativo entre morfina peridural e subaracnóidea / Postoperative analgesia of transvesical prostatectomy: comparativbe study between epidural and intrathecal morphine

Estudo comparativo entre a analgesia pós-operatória para prostatectomia transvesical quando utilizada as doses de 2 mg e 0,5mg de morfina nos espaços peridural e subaracnóideo, respectivamente. O grupo morfina subaracnóidea apresentou melhor qualidade e maior duraçäo de analgesia do que o grupo de morfina peridural. Os efeitos colaterais indesejáveis foram semelhantes nos dois grupos

Uso de sangue venoso para determinaçöes gasimétricas durante anestesia geral / The use of peripheral venous blood for gas analysis during general anaesthesia

Foram estudados 20 pacientes submetidos à anestesia geral (técnica näo padronizada). Sangue venoso foi retirado de veia do dorso da mäo, näo-garroteada, simultaneamente com sangue arterial (artéria radial) e analisados quanto ao pCO2, pO2, pH e BE. Os valores das diferenças arteriovenosas expressas como média e desvio-padräo foram: pCO2 = 1,465 + ou - 1,27; pO2 = 112,63 + ou - 151,95; pH = 0,011 + ou - 0,009 e BE = 0,92 + ou - 0,49. As correlaçöes foram significativas estatisticamente. Dos resultados conclui-se que a gasimetria do sangue venoso obtido de veia do dorso da mäo näo-garroteada (em pacientes anestesiados), näo difere importantemente do sangue arterial (com exceçäo da pO2, podendo ser utilizado para avaliaçäo da adequaçäo da ventilaçäo nestes pacientes, evitando-se assim, os riscos à punçäo arterial

Fibrilaçäo ventricular induzida pelo uso de bisturi elétrico em paciente portador de marcapasso / Ventricular fibrillation induced by the use of electric bistoury in patient carrier state of pacemaker

Relata-se o caso de um paciente portador de marca-passo externo que, submetido à cirurgia de vias biliares, sofre fibrilaçäo ventricular durante o uso do bisturi elétrico. Säo discutidas as condutas de reanimaçäo cardiopulmonar e de técnica operatória com relaçäo às possíveis interaçöes com o marca-passo, bem como sobre o uso de aparelhos elétricos e eletrônicos e os possíveis acidentes e métodos de prevençäo dos mesmos

Açäo de fentanil sobre as alteraçöes cardiocirculatórias provocadas pela laringoscopia e intubaçäo traqueal / The effect of fentanyl on the circulatory changes induced by laringoscopy and tracheal intubation

As alteraçöes cardiocirculatórias observadas durante a laringoscopia e e intubaçäo orotraqueal foram estudadas em 28 pacientes divididos em 4 grupos. Os grupos experimentais receberam 2,5, 5 ou 10 micron-grama.kg-1 de fentanil, enquanto que o grupo controle recebeu soluçäo de cloreto de sódio, 0,9%, imediatamente após a administraçäo de tiopental (4mg.kg-1) e dialiltoxiferina (0,3 mg.kg-1). Os parâmetros estudados foram a pressäo arterial sistólica (PAS), a pressäo arterial diastólica (PAD), a freqüência cardíaca (FC) e o produto PAS x FC, medidos de acordo com a seguinte periodicidade. T1 - Após a induçäo e antes da intubaçäo orotraqueal; T2 - Durante a intubaçäo orotraqueal; T3 - 30 s após a intubaçäo orotraqueal; T4 - 2 min após a intubaçäo orotraqueal; T5 - 4 min após a intubaçäo orotraqueal. Observou-se no grupo controle elevaçäo estatisticamente significativa de todos os parâmetros estudados. O grupos que recebeu 2,5 micron.kg-1 de fentanil näo foi estatisticamente diferente do grupo controle. O grupo que recebeu 5 micron-grama.kg-1 de fentanil näo mostrou elevaçäo da PAS e PAD, sendo que a FC e o Produto PAS x FAC näo foram estatisticamente diferentes do controle. O grupo que recebeu 10 micron-grama.kg-1 de fentanil mostrou proteçäo eficaz em todos os parâmetros estudados, näo havendo elevaçäo superior a 12% em nenhum deles

Curva de tolerância à glicose durante o ato anestésico-cirúrgico / Glucose tolerance curve during anaesthetic-surgery act

A modificaçäo do metabolismo dos carboidratos durante o ato anestésico-cirúrgico foi avaliada através de mensuraçöes seriadas da glicemia, após infeçäo venosa de 12,5g de glicose. Foram estudados 24 pacientes, divididos em grupos de seis, e avaliados de acordo com a intensidade da estimulaçäo cirúrgica. O grupo A (Cirurgia Abdominal) foi subdividido em grupos A1 - Controle (Soro Fisiológico) e A2 - Tratado (Glicose + Soro Fisiológico). O Grupo B (Cirurgia de Superfície) foi subdividido em grupos B1 - Controle (Soro Fisiológico) e B2 - Tratado (Glicose + Soro Fisiológico). Os grupos B1 e B2 näo apresentaram hiperglicemia ou alteraçöes no teste de tolerância à glicose, respectivamente. Os grupos A1 e A2 mostraram hiperglicemia e alteraçäo no teste de tolerância à glicose, respectivamente, indicando que os pacientes destes grupos apresentaram padräo diabético

Infusäo contínua de alfatesin associado ao fentanil / Continous infusion of althesin associated with fentanyl

Vinte e cinco pacientes foram anestesiados usando-se infusäo contínua de Alfatesin associado ao Fentanil. Observou-se o consumo das drogas, os efeitos sobre a pressäo arterial e freqüência cardíaca e as características da recuperaçäo pós-anestésica. O consumo médio de Alfatesin foi de 51,5 + ou - 15 ml correspondendo a uma velocidade de infusäo de 0,0045 ml. kg-1. min-1. O consumo médio de Fentamil foi de 24 + ou - 5,6 ml. Os efeitos cardiovasculares näo foram clinicamente importantes indicando que as drogas produziram alteraçöes hemodinâmicas significativas. Observou-se náuseas e vômitos em 6 pacientes, tremores e calafrios em 11; depressäo respiratória, em 6. Nestes, foi necessário o uso de antagonistas dos narcóticos