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Liver Blood Flow
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
Intravenous agents such as thiopental, etomidate, althesin and propofol have been shown to cause a dose-dependent reduction in hepatic blood flow, presumably as a result of reduced cardiac output and obtundation of the hepatic arterial buffer mechanism.
Modulation of NTS Function By Multiple Descending Inputs: An Overview
Published in I. Robin A. Barraco, Nucleus of the Solitary Tract, 2019
There is evidence in the literature indicating that the arterial chemoreceptor reflex is able to induce the autonomic and respiratory features of the defense reaction in the althesin-anesthetized cat and rat.6,7 Further stimulation in the HDA appears to be able to facilitate the chemoreceptor reflex.25 This mutual facilitatory interaction contrasts with the mutually inhibitory interaction between baroreceptor afferent activation and the effects of stimulating in the HDA (see above). The synaptic basis of this descending facilitatory influence had not been investigated until recently, although details of the pattern of innervation of the NTS by the arterial chemoreceptors have emerged in a series of investigations.26-29
Taking pharmacy practice into the 21st century
Published in Phil Wiffen, Evidence-based Pharmacy, 2017
Good implies effective, but it must also be safe and acceptable. Harm is self-evident but is often overlooked in the intensity of treatment. The search for a cure can lead to long-term damage, which may not be reversible. There are many examples of new pharmacological developments where the benefits are actively promoted but the adverse-effect profile only emerges over a considerable period of time. These effects may be caused by the active agent or by additional ingredients or the vehicle used. One example was the use of a polyethoxylated castor oil vehicle for the intravenous anaesthetic agent alphaxalone (Althesin™). This vehicle was later associated with severe anaphylactic reactions, hyperlipidaemias and alterations in blood viscosity.
GABA(A) receptor-targeted drug development -New perspectives in perioperative anesthesia
Published in Expert Opinion on Drug Discovery, 2019
Bernd Antkowiak, Gerhard Rammes
The pregnane steroid alphaxalone, an analogue of progesterone and its metabolite 3α,5α-THPROG, is also a synthetic neurosteroid which potentiates GABAergic function with high selectivity [195]. The compound has anxiolytic, sedating, anaesthetic, anticonvulsant, and neuroprotective properties [196–200] and was formulated as a mixture, together with alphadolone, to Althesin® (or Alfathesin®) which was commercially marketed after approval in Europe in the 1970s [201]. The product was a versatile short-acting IV anaesthetic used in clinical practice in many countries. This mixture showed a wide safety margin with minor cardiovascular and respiratory depression and was characterized by rapid onset and offset of hypnotic effect [190,202]. No progestational, estrogenic, mineralocorticoid or thymolytic activity was described [203]. Due to a rare but serious, mainly histaminoid reaction in humans to the vehicle Cremophor®, a non-ionic surfactant additive and used to formulate Althesin®, it has been withdrawn from clinical studies [204]. However, alfaxolone (Alfaxan® or Saffan®) is still used in veterinary medicine [202]. Currently, alphaxalone has been re-formulated as Phaxan™ in 7-sulfobutylether β-cyclodextrin (SBECD), an excipient devoid of producing hypersensitivity which has been used for dissolution of hydrophobic drugs for IV injections [205,206]. In a study with rats, the properties of propofol, Althesin® and Phaxan™ were compared by applying equipotent doses that cause anaesthesia (loss of righting reflex and response to tail pinch). Fast-onset and offset anaesthesia was similar for Phaxan™ and Althesin® whereas the therapeutic index of alphaxalone was increased when dissolved in SBECD. Phaxan™ was also slightly superior to propofol regarding safety margin [206]. In a phase 1c human, randomized and double blind-study the efficacy and safety of Phaxan™ was compared with the standard lipid preparation of propofol in common clinical use [207]. The new aqueous formulation showed a similar potency to Althesin and a similar onset and offset time course for sedation as propofol whereas the cognitive function recovered more rapidly. At equipotent doses, the side effect profile of Phaxan™ was much more beneficial than that of propofol, regarding especially some of the disadvantages of propofol such as pain on injection, cardiorespiratory depression, and risk of solvent toxicity [207]. Even though further trials are required, Phaxan may have the potential to match propofol in performance as a fast-onset, fast-offset IV anaesthetic with a more beneficial side effect profile [33].