pancuronium and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch- and chronic itch-challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch.

Topics: Animals; Behavior, Animal; Cell-Free System; Dermatitis, Contact; Disease Models, Animal; Ganglia, Spinal; Humans; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pruritus; Receptors, Atrial Natriuretic Factor; Reproducibility of Results; Signal Transduction; Small Molecule Libraries

Translational correlates to pain with activities after deep tissue injury have been rarely studied. We hypothesized that deep tissue incision causes greater activation of nociception-transmitting neurons evoked by muscle contraction. In vivo neuronal activity was recorded in 203 dorsal horn neurons (DHNs) from 97 rats after sham, skin-only, or skin + deep muscle incision. We evaluated DHN responses to static, isometric muscle contractions induced by direct electrical stimulation of the muscle. The effect of pancuronium on DHN response to contractions was also examined. Approximately 50% of DHNs with receptive fields in the hindpaw were excited during muscle contraction. One-second .5- and 1.0-g muscle contractions produced greater DHN activity after skin + deep muscle incision (median [interquartile range], 32 [5-39] impulses, P = .021; and 36 [26-46] impulses, P = .006, respectively) than after sham (6 [0-21] and 15 [8-32] impulses, respectively). Neuromuscular blockade with pancuronium inhibited the muscle contractions and DHN activation during electrical stimulation, demonstrating contraction-induced activation. The greater response of spinal DHNs to static muscle contraction after skin + deep muscle incision may model and inform mechanisms of dynamic pain after surgery. PERSPECTIVE: Completion of various activities is an important milestone for recovery and hospital discharge after surgery. Skin + deep muscle incision caused greater activation of nociception-transmitting DHNs evoked by muscle contraction compared with skin-only incision. This result suggests an important contribution of deep muscle injury to activity-evoked hyperalgesia after surgery.

Topics: Animals; Disease Models, Animal; Electric Stimulation; Isometric Contraction; Male; Neuromuscular Nondepolarizing Agents; Nociceptors; Pain, Postoperative; Pancuronium; Posterior Horn Cells; Rats; Rats, Sprague-Dawley

The benefits of spontaneous breathing over muscle paralysis have been proven mainly in mild lung injury; no one has yet evaluated the effects of spontaneous breathing in severe lung injury. We investigated the effects of spontaneous breathing in two different severities of lung injury compared with muscle paralysis.. Prospective, randomized, animal study.. University animal research laboratory.. Twenty-eight New Zealand white rabbits.. Rabbits were randomly divided into the mild lung injury (surfactant depletion) group or severe lung injury (surfactant depletion followed by injurious mechanical ventilation) group and ventilated with 4-hr low tidal volume ventilation with spontaneous breathing or without spontaneous breathing (prevented by a neuromuscular blocking agent). Inspiratory pressure was adjusted to control tidal volume to 5-7 mL/kg, maintaining a plateau pressure less than 30 cm H2O. Dynamic CT was used to evaluate changes in lung aeration and the regional distribution of tidal volume.. In mild lung injury, spontaneous breathing improved oxygenation and lung aeration by redistribution of tidal volume to dependent lung regions. However, in severe lung injury, spontaneous breathing caused a significant increase in atelectasis with cyclic collapse. Because of the severity of lung injury, this group had higher plateau pressure and more excessive spontaneous breathing effort, resulting in the highest transpulmonary pressure and the highest driving pressure. Although no improvements in lung aeration were observed, muscle paralysis with severe lung injury resulted in better oxygenation, more even tidal ventilation, and less histological lung injury.. In animals with mild lung injury, spontaneous breathing was beneficial to lung recruitment; however, in animals with severe lung injury, spontaneous breathing could worsen lung injury, and muscle paralysis might be more protective for injured lungs by preventing injuriously high transpulmonary pressure and high driving pressure.

Topics: Acute Lung Injury; Acute-Phase Proteins; Animals; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Doxapram; Neuromuscular Nondepolarizing Agents; Neutrophils; Pancuronium; Positive-Pressure Respiration; Prospective Studies; Pulmonary Atelectasis; Pulmonary Gas Exchange; Pulmonary Surfactants; Rabbits; Random Allocation; Respiration, Artificial; Respiratory Mechanics; Respiratory Paralysis; Respiratory Physiological Phenomena; Respiratory System Agents; Severity of Illness Index; Tidal Volume; Tomography, X-Ray Computed; Ventilator-Induced Lung Injury

The mechanisms underlying acute quadriplegic myopathy (AQM) are poorly understood, partly as a result of the fact that patients are generally diagnosed at a late stage of the disease. Accordingly, there is a need for relevant experimental animal models aimed at identifying underlying mechanisms.. Pigs were mechanically ventilated and exposed to various combinations of agents, i.e. pharmacological neuromuscular blockade, corticosteroids and/or sepsis, for a period of 5 days. Electromyography and myofibrillar protein and mRNA expression were analysed using sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), confocal microscopy, histochemistry and real-time polymerase chain reaction (PCR).. A decreased compound muscle action potential, normal motor nerve conduction velocities, and intact sensory nerve function were observed. Messenger RNA expression, determined by real-time PCR, of the myofibrillar proteins myosin and actin decreased in spinal and cranial nerve innervated muscles, suggesting that the loss of myosin observed in AQM patients is not solely the result of myofibrillar protein degradation.. The present porcine AQM model demonstrated findings largely in accordance with results previously reported in patients and offers a feasible approach to future mechanistic studies aimed at identifying underlying mechanisms and developing improved diagnostic tests and intervention strategies.

Topics: Adrenal Cortex Hormones; Animals; Betamethasone; Disease Models, Animal; DNA, Complementary; Electric Stimulation; Electrophoresis, Polyacrylamide Gel; Electrophysiology; Endotoxins; Feasibility Studies; Female; Histocytochemistry; Masseter Muscle; Muscle, Skeletal; Muscular Diseases; Neuromuscular Nondepolarizing Agents; Pancuronium; Peroneal Nerve; Quadriplegia; Respiration, Artificial; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Sepsis; Spinal Nerves; Swine

Controversy and speculation exist regarding intracranial pressure (ICP) changes produced by various combinations of rapid sequence intubation (RSI) agents. In this pilot study, we sought to develop a swine model to investigate these changes in classic RSI.. Eight adult swine were instrumented with arterial and intracranial pressure monitors. Four different versions of rapid sequence intubation were then performed sequentially in each animal in a crossover trial design: regimen 1, thiopental; regimen 2, thiopental and succinylcholine; regimen 3, lidocaine, thiopental, and succinylcholine; and regimen 4, pancuronium, lidocaine, thiopental, and succinylcholine. ICP and hemodynamic parameters were recorded and compared. Trials were excluded from analysis if baseline ICP measurements were unstable or if intubation was difficult.. Peak changes in ICP were noted at 2 to 3 minutes after administration of induction agents. Mean values for peak changes in ICP were as follows: regimen 1 (n = 5), 3.6 mm Hg (95% confidence interval [CI], 1.0-6.2 mm Hg); regimen 2 (n = 9), 13.6 mm Hg (95% CI, 9.6-17.6 mm Hg); regimen 3 (n = 2), 16.0 mm Hg (95% CI, -34.8-66.8 mm Hg); and regimen 4 (n = 3), 12.0 mm Hg (95% CI, -8.3-32.3 mm Hg).. The model is effective. It enables investigators to examine the aggregate ICP effects of combinations of RSI medications. RSI regimens with paralysis produced threefold increases in peak ICP change compared with the sedation-only regimen. Pretreatment agents did not affect ICP changes. Future investigations can examine other agents and add experimental manipulation of ICP to simulate head injury physiology. Additional parameters including cerebral metabolism and/or oxygenation may also be explored.

Topics: Animals; Brain Injuries; Cross-Over Studies; Disease Models, Animal; Emergency Treatment; Intracranial Pressure; Intubation, Intratracheal; Lidocaine; Pancuronium; Pilot Projects; Succinylcholine; Swine; Thiopental

The aim of this study was to elucidate the influence of four neuromuscular blocking substances on coronary vascular tone using the model of isolated porcine coronary artery segments. We studied the effects of four muscle relaxants, atracurium, pancuronium, rocuronium, and vecuronium (0.1, 1, and 10 microg mL-1 each), on the contractile response to three vasoconstrictors: acetylcholine, histamine, and serotonin. None of the neuromuscular blocking agents under investigation exerted a significant influence on the vasoconstricting effects of these mediators except for pancuronium, which dose-dependently attenuated acetylcholine-mediated contractions (-10.8% attenuation for 10 microg mL-1 pancuronium, P < 0.05). There was no difference between vessels with intact endothelium and denuded preparations. It is concluded that high-dose pancuronium exerts an antimuscarinic effect in vascular smooth muscle. The other neuromuscular agents studied do not alter vascular reactivity of isolated porcine coronary arteries.

Topics: Acetylcholine; Androstanols; Animals; Atracurium; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Histamine; Muscarinic Antagonists; Muscle, Smooth, Vascular; Neuromuscular Nondepolarizing Agents; Pancuronium; Rocuronium; Serotonin; Statistics as Topic; Swine; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents; Vecuronium Bromide

Intramuscular injection of levomepromazine (0.5 mg/kg) 30 min before intravenous injection of 10 mg/kg pentobarbital sodium induces a good surgical anaesthesia in dogs artificially ventilated with 50% N2O and 50% O2 and given 0.01 mg/kg atropine and 0.1 mg/kg pancuronium intravenously before left thoracotomy. This protocol is suitable for the study of the arrhythmogenic effects of acute one-stage coronary artery ligation in anaesthetized dogs. In fact, minor interference with the autonomic nervous system appears to be involved since heart rate is maintained slow and mean aortic pressure is kept within normal limits, as pH, PaO2, anc PaCO2 during subsequent periods. Acute circumflex coronary arterio-venous pedicle ligation close to the left main trunk division resulted in this model in a high incidence of ventricular fibrillation (10 out of 15 dogs) early (7 +/- 4 min) after occlusion. Specific interventions aimed at reducing the incidence of early post-ischemic life-threatening ventricular arrhythmias might be tested in this model.

Topics: Anesthesia, General; Animals; Arrhythmias, Cardiac; Atropine; Coronary Disease; Coronary Vessels; Disease Models, Animal; Dogs; Electrocardiography; Female; Ligation; Male; Methotrimeprazine; Pancuronium; Pentobarbital; Preanesthetic Medication