Antinociceptive Effect of the Combination of a Novel α4β2* Agonist with Donepezil in a Chronic Pain Model.

Chronic pain presents a major challenge in contemporary medicine, given the limited effectiveness and numerous adverse effects linked to available treatments. Recognizing the potential of the cholinergic pathway as a therapeutic target, the present work evaluates the antinociceptive activity of a combination of Cris-104, a novel α4β2* receptor agonist, and donepezil, a central anticholinesterase agent. Isobolographic analysis revealed that equimolar combination was approximately 10 times more potent than theoretically calculated equipotent additive dose.

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.

New Benzofuran -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 -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.

Reduction of cardiac and renal dysfunction by new inhibitor of DPP4 in diabetic rats.

Background: Increased mortality due to type 2 diabetes mellitus (T2DM) has been associated with renal and/or cardiovascular dysfunction. Dipeptidyl dipeptidase-4 inhibitors (iDPP-4s) may exert cardioprotective effects through their pleiotropic actions via glucagon-like peptide 1-dependent mechanisms. In this study, the pharmacological profile of a new iDPP-4 (LASSBio-2124) was investigated in rats with cardiac and renal dysfunction induced by T2DM.

Human Mesenchymal Stem Cell Therapy Reverses Su5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Mice.

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. 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 injections; PAH mice).

Novel agonist of αβ* neuronal nicotinic receptor with antinociceptive efficacy in rodent models of acute and chronic pain.

Objective: To demonstrate the antinociceptive and antihypersensitivity mechanisms of Cris-104 (1-{2-[5-(4-fluorophenyl)-1H-pyrazol-4-yl]ethyl}piperidine), a novel selective αβ* nicotinic acetylcholine receptor (nAChR) agonist, in rodent acute/inflammatory and chronic pain models.

Materials And Methods: Hot-plate and formalin tests in mice were used to examine Cris-104-induced antinociceptive effects on thermal/inflammatory pain. Cris-104 effects on hypersensitivity, norepinephrine (NE) release in the spinal dorsal horn, and neuronal activity in the locus coeruleus (LC) were examined in rats with lumbar spinal nerve ligation using behavioral, microdialysis, and extracellular recording methods.

Cardioprotection Induced by Activation of GPER in Ovariectomized Rats With Pulmonary Hypertension.

Pulmonary hypertension (PH) is a disease of women (female-to-male ratio 4:1), and is associated with cardiac and skeletal muscle dysfunction. Herein, the activation of a new estrogen receptor (GPER) by the agonist G1 was evaluated in oophorectomized rats with monocrotaline (MCT)-induced PH. Depletion of estrogen was induced by bilateral oophorectomy (OVX) in Wistar rats.

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).

Antihyperalgesic effects of a novel muscarinic agonist (LASSBio-873) in spinal nerve ligation in rats.

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.

Docking, synthesis and anti-diabetic activity of novel sulfonylhydrazone derivatives designed as PPAR-gamma agonists.

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.

Inhibition of L-type calcium current by tramadol and enantiomers in cardiac myocytes from rats.

Background: 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.

Objective: In this study, we investigated the effects of tramadol and its enantiomers on L-type calcium current (ICa-L).

The influence of age on bupivacaine cardiotoxicity.

Background: 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.

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).

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.

The synergistic interaction between morphine and maprotiline after intrathecal injection in rats.

Background: 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.

Comparative effects of tramadol on vascular reactivity in normotensive and spontaneously hypertensive rats.

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.

Vasodilatory activity of novel carbamate derivatives of isatin.

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.

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.

Sedative-hypnotic profile of novel isatin ketals.

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.

Regulation of intracellular calcium by bupivacaine isomers in cardiac myocytes from Wistar rats.

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.

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.