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.

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New chemicals or adjuvants with analgesic effects on chronic pain are needed and clinically relevant due to the limited number of effective compounds that possess these characteristics. LASSBio-873, a pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivative, activates muscarinic cholinergic receptors 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 once daily for 7 consecutive days after SNL surgery and reversed these symptoms. LASSBio-873 treatment did not alter rat behaviour in open field testing measured during the first 24 h after administration and again after 7 continuous days administration. The analgesic effect of LASSBio-873 was inhibited by intrathecal methoctramine, an M2 receptor antagonist, implicating the muscarininc M2 receptor signalling pathway in the drug's action. These results reinforce the potential of LASSBio-873 as a possible prototype for the development of more effective alternatives for the treatment of neuropathic pain.

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.

Aims: Pulmonary arterial hypertension (PAH) is a disease characterized by an increase in pulmonary vascular resistance and right ventricular (RV) failure. We aimed to determine the effects of human mesenchymal stem cell (hMSC) therapy in a SU5416/hypoxia (SuH) mice model of PAH.Methods and Results: C57BL/6 mice (20–25 g) were exposure to 4 weeks of hypoxia combined vascular endothelial growth factor receptor antagonism (20 mg/kg SU5416; weekly s.c. injections; PAH mice). Control mice were housed in room air. Following 2 weeks of SuH exposure, we injected 5 × 105 hMSCs cells suspended in 50 μL of vehicle (0.6 U/mL DNaseI in PBS) through intravenous injection in the caudal vein. PAH mice were treated only with vehicle. Ratio between pulmonary artery acceleration time and RV ejection time (PAAT/RVET), measure by echocardiography, was significantly reduced in the PAH mice, compared with controls, and therapy with hMSCs normalized this. Significant muscularization of the PA was observed in the PAH mice and hMSC reduced the number of fully muscularized vessels. RV free wall thickness was higher in PAH animals than in the controls, and a single injection of hMSCs reversed RV hypertrophy. Levels of markers of exacerbated apoptosis, tissue inflammation and damage, cell proliferation and oxidative stress were significantly greater in both lungs and RV tissues from PAH group, compared to controls. hMSC injection in PAH animals normalized the expression of these molecules which are involved with PAH and RV dysfunction development and the state of chronicity.Conclusion: These results indicate that hMSCs therapy represents a novel strategy for the treatment of PAH in the future.

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.

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.

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.Malignant hyperthermia is a pharmacogenetic disorder characterized by abnormal increase of Ca 2+ release from sarcoplasmic reticulum triggered by volatile halogenated anaesthetics and/or succinylcholine [1]. The cause for malignant hyperthermia and consequently the dysregulation of myoplasmic Ca 2+ is related to a mutation of the Ca 2+ release channel (RyR1) of sarcoplasmic reticulum [2,3]. RyR1 causal mutations have been found in over 50% of malignant hyperthermiasusceptible families [4]. Dantrolene, 1-<{[5-(4-nitrophenyl)-2-furfuryl]methylene}amino>-2,4-imidazoleidinedione, is the only drug effective for treatment and prevention of malignant hyperthermia and as a consequence of its clinical introduction, mortality decreased from 70% to 5 -10% [5]. Dantrolene is a skeletal muscle relaxant that modulates the activity of RyR1 promoting inhibition of Ca 2+ efflux from sarcoplasmic reticulum [6,7]. The treatment of a malignant hyperthermia episode consists of an initial intravenous injection of 2.5 mg/kg of dantrolene sodium [8]. Due to low water solubility (about 0.3 mg/ml) this amount of dantrolene sodium must be dissolved in about 500 ml of water in a 70-kg patient that represents risks from consuming time and for aggravating the cardiac failure usually present in an malignant hyperthermia crisis. A 30-fold mo...