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Targeting the Nervous System
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Antagonists of the nicotinic cholinergic receptor are also medicinally beneficial. They are present in nerve synapses at neuromuscular junctions and can be used as blocking agents. In the 16th century, when Spanish soldiers, known as conquistadors, invaded South America, the indigenous people used poisonous arrows in retaliation. The Indians used a crude dried extract from a plant called Chondrodendron tomentosum, which caused paralysis and stopped the heart. This extract is known as curare, consisting of a mixture of compounds, but later discovered that the active component was an antagonist of acetylcholine, which blocks nerve transmissions from nerve to muscle. This compound is called tubocurarine, and with controlled dose levels, is found to be medicinally useful for relaxing the abdominal muscles before surgery therefore a lower dose of general anaesthetic can be used, improving safety of operations. However, side effects on the autonomous nervous system meant that better drugs had to be developed.
The Americas
Published in Michael J. O’Dowd, The History of Medications for Women, 2020
The well-known drug, tubocurarine, was isolated by Harold King (1935) from the plant, Strychnos nuxvomica and later from Chondodendron tomentosum. The introduction of tubocurarine, a skeletal muscle relaxant, was one of the most significant advances in clinical anesthesia. It heralded a new and safer era in obstetric anesthesia that would be responsible for a great reduction in maternal and perinatal mortality and morbidity. The origins of the story go back to the year of 1516, when an Italian gossip columnist’ of his time, one Peter Martyr d’Anghera, wrote the first account of the use of arrow poisons by the South American Indians. He gave a detailed account of the preparation of the poison and how it was obtained from the sap of certain trees. In 1684 the word ‘curare’ was first used by Margawius to describe the poison, and much was written about the drug, but it was not until 1935 that the active component, curare, was isolated.
Cholinergic Antagonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Vishal S. Gulecha, Manoj S. Mahajan, Aman Upaganlawar, Abdulla Sherikar, Chandrashekhar Upasani
Ganglionic blocking agents are used for the treatment of chronic hypertension but nowadays they are replaced by other superior agents. These drugs have utility in facilitating but newer alternatives like nitroprusside or other depressive sedatives are superior to produce controlled hypotension and to minimize hemorrhage and blood loss (Fukusaki et al., 1999). Currently, mecamylamine is used therapeutically in the United States. Trimethaphan, a short-acting drug, due to its direct vasodilating properties is used as antihypertensive agents particularly in patients with acute aortic aneurysm. It also produces prolonged neuromuscular blockade and may potentiate the neuromuscular blocking action of tubocurarine (Brunton et al., 2011).
Impaired neuromuscular function by conjoint actions of organophosphorus insecticide metabolites omethoate and cyclohexanol with implications for treatment of respiratory failure
Published in Clinical Toxicology, 2021
Kosala N. Dissanayake, Robert Chang-Chih Chou, Adrian Thompson, Filip Margetiny, Charlotte Davie, Scott McKinnon, Vishwendra Patel, Lester Sultatos, Joseph J. McArdle, Richard E. Clutton, Michael Eddleston, Richard R. Ribchester
Fade and block are characteristic muscle force responses observed after incubating muscles with pharmacological blockers of neuromuscular transmission. But cyclohexanol also produced concentration-dependent inhibition of responses to direct muscle stimulation, after blocking neuromuscular transmission with 5 µM d-tubocurarine (Supplementary Figure 2). The dependence of T1 twitch amplitude on cyclohexanol concentration was similar to that of indirect, nerve-evoked responses. With direct stimulation, however, all four responses to TOF stimulation were attenuated equally: there was no fade. These recordings therefore suggest a complex set of underlying cellular and molecular mechanisms of cyclohexanol toxicity, in addition to block of neuromuscular transmission. We did not examine the temperature sensitivity of the responses to direct stimulation in the present study.
In vitro models of neuromuscular junctions and their potential for novel drug discovery and development
Published in Expert Opinion on Drug Discovery, 2020
Olaia F Vila, Yihuai Qu, Gordana Vunjak-Novakovic
Tubocurarine chloride pentahydrate, a toxic alkaloid and muscle relaxant that was used with anesthetics in the mids-1900s, is one of the postsynaptic blockers most commonly used in NMJ studies. Treatment with tubocurarine has been shown to dim or stop both spontaneous [38] and glutamate-induced [35] contractions in motoneuron-muscle co-cultures, as well as in mouse microfluidics [54] and human [57] tissue-engineered systems. Smith et al. also showed that tubocurarine was able to block the glutamate-induced contractions in their cantilever system [56]. In addition to these qualitative studies, a dose-response curve performed in a compartmentalized microfluidic system demonstrated an IC50 in agreement with reported results for human AChRs [72,73].
The neural pathway of the hyperthermic response to antagonists of the transient receptor potential vanilloid-1 channel
Published in Temperature, 2023
Andras Garami, Alexandre A. Steiner, Eszter Pakai, Samuel P. Wanner, M. Camila Almeida, Patrik Keringer, Daniela L. Oliveira, Kazuhiro Nakamura, Shaun F. Morrison, Andrej A. Romanovsky
Electrophysiological experiments in anesthetized rats. Rats were anesthetized initially with 2.5% isoflurane in 100% O2 for the following surgical procedures. A femoral artery and vein and the trachea were cannulated. Rats were positioned prone in a stereotaxic frame with a spinal clamp on the tenth thoracic vertebra. To measure deep Tb and brown adipose tissue (BAT) temperature (TBAT), thermocouples were placed 6-cm deep into the colon and into the left interscapular BAT pad, respectively, and then connected to a thermocouple meter (TC-2000, Sable Systems International). Tb was maintained at ~37.0°C with a water jacket wrapped around the trunk and perfused with warm water as required. Postganglionic sympathetic nerve activity (SNA) to BAT was recorded from the central cut end of a small nerve bundle dissected from the ventral surface of the right interscapular BAT pad after dividing the fat pad along the midline and reflecting it laterally. Nerve activity was recorded with bipolar hook electrodes (90% platinum, 10% iridium), filtered (1–300 Hz), and amplified (50,000×; Cyberamp 380, Axon Instruments). After rats were transitioned to inactin (thiobutabarbital sodium salt hydrate, 150 mg/kg, i.v.), had artificial pneumothorax induced, and paralyzed with D-tubocurarine (0.3 mg initial dose, 0.1 mg/h supplements), they were artificially ventilated with O2-enriched room air (60 cycles/min, tidal volume 3.0–4.5 ml). Small adjustments in minute ventilation were made as necessary to maintain basal mixed-expired CO2 levels between 3.0 and 4.5%. AMG0347 (500 µg/kg, i.v.) was administered over 2 minutes, and the physiological variables were monitored for the subsequent hour. BAT SNA and TBAT, were digitized (Micro 1401 MKII; Cambridge Electronic Design) and recorded onto a computer hard drive. Spike 2 software (Cambridge Electronic Design) was used to obtain a continuous measure (4 s bins) of BAT SNA amplitude by calculating the root mean square (rms) amplitude of the BAT SNA (square root of the total power in the 0.1 to 20 Hz band) from the autospectra of sequential 4-s segments of BAT SNA. The control value of BAT SNA was the average of the BAT SNA amplitudes during the 2-min period (i.e., 30 bins of BAT SNA) prior to AMG0347 treatment, and the peak effect was the average of the BAT SNA amplitudes during the 2-min period of the maximal increase in BAT SNA following AMG0347 injection; the treatment-evoked changes in TBAT were calculated as the differences between these two values. Due to the variability in BAT SNA recordings (nerve bundle size, nerve contact with recording hooks, etc.) among rats, the calculated values for the BAT SNA following AMG0347 treatment are expressed as percentages of the baseline, minimum level of BAT SNA when the rat was warmed (deep Tb >37.0°C).