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The Discovery and Pharmacology of Tirilazad Mesylate
Published in John J. Lemasters, Constance Oliver, Cell Biology of Trauma, 2020
The 21-aminosteroids (lazaroids) are exemplified by tirilazad mesylate (U74006F, 21 -(4-(2,6-di-1 -pyrrolidinyl-4-pyrimidinyl)-1 -piperazinyl)-16 alphamethylpregna-1,4,9 (11)-triene-3,20-dione monomethanesulfonate). Tirilazad mesylate is effective in many animal models of acute neurologic disorders. In addition, it is active in other ischemic, oxidative, and allergic models. It is being clinically evaluated in head and spinal cord injury and in ischemic and hemorrhagic stroke. Tirilazad mesylate lacks hormonal activity. The pharmacology of tirilazad mesylate and its close structural analog, U74389G, is described below (see Figure 1 for structures).
Central nervous system
Published in Brian J Pollard, Gareth Kitchen, Handbook of Clinical Anaesthesia, 2017
Use these drugs with caution as they may mask seizure activity. Succinylcholine increases EEG activity but not seizure activity. It is not advised in cases of prolonged status due to potentially fatal rises in potassium levels. Antiepileptic agents are enzyme inducers which may cause resistance to the aminosteroids – neuromuscular monitoring is advisable. Atracurium’s metabolite laudanosine has epileptogenic potential in animals but not in humans.
Neuromuscular Blocking Drugs
Published in Kate McCombe, Lara Wijayasiri, Paul Hatton, David Bogod, The Primary FRCA Structured Oral Examination Study Guide 2, 2017
Kate McCombe, Lara Wijayasiri, Paul Hatton, David Bogod
The greater the dose, the longer recovery takes. Drug metabolism:Aminosteroids are minimally metabolised in the liver and excreted in the bile and urine (both as unchanged and changed products). Liver and renal impairment can lead to accumulation of the drugs and therefore prolong their effects.Atracurium (benzylisoquinolinium ester) is broken down by Hoffman degradation, a process of spontaneous drug breakdown at body pH and temperature. Acidosis and hypothermia will slow this breakdown and prolong its effects.Drug interactions:Drugs that induce liver enzymes will reduce the effects of the aminosteroids, e.g. co-administration of phenytoin results in an 80% increase in the necessary dose of aminosteroid.Co-administration of magnesium sulphate, which competes with calcium, will prolong the action of neuromuscular blockers by inhibiting the release of ACh from its vesicular stores at the neuromuscular junction. Only 30–50% of the normal dose of relaxant should be used.Administration of ‘reversal agents’:Anticholinesterases: Until relatively recently the only drugs available to reverse the effects of non-depolarising neuromuscular blockers were anticholinesterases, e.g. neostigmine, which worked by increasing the concentration of ACh at the neuromuscular junction.Sugammadex: Licensed for use with rocuronium and vecuronium. This modified γ-cyclodextrin works by completely enveloping the aminosteroid and terminating its effects as it can no longer interact with the nAChR. The drug–drug compound is then excreted in the urine. Given 3 minutes after an intubating dose of rocuronium, it will terminate its effects in 1.5 minutes.
The Effect of Sugammadex on Time of Sciatic Block by Perineural Bupivacaine in Rats
Published in Journal of Investigative Surgery, 2022
Fatih Dogu Geyik, Dilek Eker, Yucel Yuce, Kutlu Hakan Erkal, Dilek Yavuzer, Hanife Gulnihal Ozdemir, Banu Cevik, Kemal Tolga Saracoglu
In recent years, sugammadex has been used to reverse postoperative residual blocks due to neuromuscular blocking agents (NMB) used for comfortable intubation and surgery by causing muscle laxity during general anesthesia.12,13 Sugammadex is a modified γ-cyclodextrin specifically designed to encapsulate chemically similar aminosteroid muscle relaxants such as rocuronium and vecuronium14 Although sugammadex has no affinity for many drugs used during anesthesia (such as hypnotics, analgesics, antibiotics, cardiovascular drugs), cyclodextrins have been used to formulate different substances used in anesthesia, including propofol, etomidate, bupivacaine, sufentanil, or intranasal midazolam. It is known to contain a family of cyclic oligosaccharides.15
Beneficial Effect of U-74389 G and Sildenafil in An Experimental Model of Flap Ischemia/Reperfusion Injury in Swine. Histological and Biochemical Evaluation of the Model
Published in Journal of Investigative Surgery, 2020
Stavros-Loukas Karamatsoukis, Eleni-Andriana Trigka, Marianna Stasinopoulou, Antigoni Stavridou, Argyro Zacharioudaki, Kalliopi Tsarea, Maria Karamperi, Theodoros Pittaras, Othon Papadopoulos, Efstratios Patsouris, Nikolaos Nikiteas, Georgios C. Zografos, Apostolos E. Papalois
Therapeutic approaches for IRI, focusing on antioxidant treatment, therapy against the complement system and leukocytes, as well as pre-conditioning for ischemia, have been studied in different experimental models [31,32]. Free radicals produced during reperfusion have been implicated as the main mechanism for causing damage in tissues that have undergone IRI [33,34]. Literature already acknowledges that lazaroids (21-aminosteroids) can improve the impact of IRI in many organs by suppressing the secretion of cytokines, the expression of adhesion molecules and neutrophils’ infiltration [35,36]. Sildenafil has also been shown to lower lipid peroxidation and reactive oxygen species (ROS) production in an experimental model of lung IRI. MDA levels measured in the treatment group exhibited statistically significant differences with the control and IRI groups [32].
Safety of sugammadex for reversal of neuromuscular block
Published in Expert Opinion on Drug Safety, 2019
GHM Honing, CH Martini, A Bom, M van Velzen, M Niesters, LPHJ Aarts, A Dahan, M Boon
Cyclodextrins are cone-shaped oligosaccharides that consist of six, seven or eight glucose monomers (α-, β- and γ-cyclodextrins). In pharmacology, they are widely used to increase the solubility of lipophilic medical compounds in water [20]. Sugammadex, originally known as ORG 25,969, is a modified variant of the natural γ-cyclodextrin and was developed as a solvent for rocuronium. By linkage of a side-chain to every 6th carbon-hydroxyl group, the length of the molecular cavity was increased to fit the rocuronium molecule. In addition, eight polar hydroxyl groups were placed at the end of each side-chain to create negatively charged outer-ends that are able to interact with positively charged nitrogen atoms of rocuronium (see Figure 1 and Box 1) [10,11,21]. One molecule of sugammadex is able to bind one molecule of the aminosteroid rocuronium. In addition, sugammadex binds other aminosteroidal NMBDs as well; binding affinity is highest for pipecuronium (Ka 161 × 106 M−1) followed by rocuronium (Ka 25 × 106 M−1), vecuronium (Ka 10 × 106 M−1) and pancuronium (Ka 2.6 × 106 M−1) [10,22,23].