E EDITORIAL
Another Steroid Hypnotic: More of the Same or Something Different? Markus W. Hollmann, MD, PhD, DEAA,* and John W. Sear, MA, BSc, MBBS, PhD, FFARCS, FANZCA†
D
uring the past years, there has been considerable interest in neurosteroid physiology and the development of neurosteroid analogs for the treatment of a variety of disorders of central nervous system function. This has been accompanied by research into neurosteroids as potentially useful IV general anesthetics. Peripheral glands (e.g., adrenal cortex and ovaries) produce gamma-aminobutyric acid receptor class A (GABAA)active steroids that cross the blood barrier and influence mood and behavior in circumstances such as pregnancy or stress.1 Supraphysiologic levels of neurosteroids may also contribute to certain psychiatric disorders, including major depression, postpartum depression, premenstrual tension, panic attacks, and schizophrenia. Other psychoactive drugs, such as ethanol or fluoxetine, can influence neurosteroid physiology and modulate GABAA receptor activity, contributing to behavioral changes associated with synthetic neurosteroids.2 Neurosteroids are among the most potent and efficacious (endogenous) allosteric regulators of GABAA receptor function. Steroids acting at the GABAA receptor site modulate neuronal inhibition. The brain and the spinal cord have the necessary enzymatic tools to produce these GABAA receptor–active steroids, enabling local production of steroids within the central nervous system. In addition to functioning as endocrine messengers that influence brain function, neurosteroids may act in a paracrine or autocrine (self-regulation) manner to locally modulate synaptic and extrasynaptic GABAA receptor function. Locally produced neurosteroids may fine-tune the neuronal excitability of the GABAA receptor. For a neurosteroid to show anesthetic activity, there needs to be an oxygen function (either hydroxyl or ketone group) at each end of the molecule (i.e., at C3 and C20 positions of pregnanes or C17 position for androstanes). Substitutions into the steroid ring structure, such as hydroxyl groups, reduce anesthetic activity and may From the *Department of Anesthesiology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands; and †Nuffield Department of Anaesthetics, Green Templeton College University of Oxford, Oxford, United Kingdom. Accepted for publication January 13, 2015. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Markus W. Hollmann, MD, PhD, DEAA, Department of Anesthesiology, Academic Medical Center Amsterdam, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands. Address e-mail to [email protected]. Copyright © 2015 International Anesthesia Research Society DOI: 10.1213/ANE.0000000000000661
980 www.anesthesia-analgesia.org
introduce convulsant properties (see with 11β-hydroxyl groupings). Anesthetic activity is seen among compounds of both the 5β-series and 5α-series. The C3 hydroxyl group can be either in the α-position or β-position, but in general, 3α-hydroxy-5α-molecules and 3α-hydroxy-5β-molecules have the greatest anesthetic activity. C3-keto substituents have little or no anesthetic activity. Esters of these hydroxyl compounds are in general less active and more slowly acting than the parent alcohols.3
ALFAXALONE
Following the initial demonstration of the anesthetic properties of a colloidal suspension of cholesterol in a cat in 1927 by Cashin and Moravek, Hans Selye in 1941 demonstrated that certain steroids could rapidly induce anesthesia. Since that time, multiple steroidal IV anesthetic agents have been developed. The most successful of these was a mixture of alfaxalone (3α-hydroxy-5α-pregnane-11,20-dione) and alfadolone acetate dissolved in a 20% solution of polyoxyethylated castor oil surfactant. This combination came to be known under its trade name, Althesin® (Glaxo, London, UK). Both steroids in Althesin showed anesthetic effects in animals, with the potency of alfaxalone being twice that of alfadolone acetate. The alfadolone was only added to the mixture to increase the solubility of alfaxalone. Because of their hydrophobicity, the mixture was formulated in Cremophor® (BASF, Ludwigshafen, Germany) EL (polyoxyethylated castor oil). With the exception of the United States, Althesin was widely used for both the induction and maintenance of anesthesia from 1972 to 1984. The attraction was a rapid onset, short duration of action, and large therapeutic index of 30.4 with only minor cardiovascular and respiratory effects.4 The typical hemodynamic features of Althesin were a decrease in arterial blood pressure, stroke volume, systemic vascular resistance, and central venous pressure. Cardiac output either remained unchanged or was slightly increased due to compensatory tachycardia. Over a wide range of infusion rates, usage of oxygen by the myocardium remained more or less unchanged. Because of reductions in cerebral blood flow, both intracranial pressure and cerebrospinal fluid pressure were decreased in the ventilated patient. Recovery from Althesin anesthesia was faster than for thiopental and similar to that of propofol. In the spontaneously breathing patient, infusion rates up to 4 times the maintenance rate led to only minor increases in Paco2.5 Althesin also had little influence on renal or hepatic function6,7 and appeared to be a useful anesthetic for the management of patients May 2015 • Volume 120 • Number 5
Neurosteroids and Anesthesia
susceptible to malignant hyperthermia. However, it was considered unsafe in patients with acute porphyria. Undesirable side effects were hiccups, coughing, laryngospasm, and involuntary muscle movements. However, the most prominent unwanted side effect of the mixture was a hypersensitivity reaction that occurred with an incidence of about 1 in 1000.8 Because of the hypersensitivity, Althesin was withdrawn from human clinical practice although its use has continued for some veterinary species. It was eventually determined that the hypersensitivity was caused by the vehicle Cremophor EL and not the neurosteroid constituents. Neurosteroids in general can be viewed as interesting molecules. Endogenous and exogenous progesterone, androstane, and deoxycorticosterone bind to GABAA receptors and allosterically modulate their function.1 Low (nM) concentrations of neurosteroids increase the probability of the GABAAgated ion channel being in the open state, modulate chloride ion transport, and inhibit neurotransmission. Direct activation of the GABAA receptor can occur at concentrations higher than that required for GABAA modulation. Endogenous neurosteroids may act in a paracrine or autocrine manner to locally modulate synaptic and extrasynaptic GABAA receptor function, thus locally regulating and fine-tuning neuronal excitability. Endogenous neurosteroids are thought to cause the analgesia and reduced minimal alveolar concentration associated with pregnancy. Exogenous neurosteroids with sedative-hypnotic properties have been developed into general anesthetics.2 Consistent with an action on GABAA receptors, neurosteroid anesthetics possess anxiolytic, anticonvulsant, analgesic, sedative, and anesthetic activity. Alfaxalone (Fig. 1) has now been reformulated as new aqueous solutions dissolved in either 2-hydroxypropylβ-cyclodextrin9 or 7-sulfobutyl-ether-β-cyclodextrin (Phaxan-CD, Drawbridge Pharmaceuticals, Melbourne, Australia). Unlike the predecessors formulated in Cremophor, the new alfaxalone formulations do not seem to be associated with histamine release and anaphylaxis. In addition, these newer formulations produce a safe and effective anesthetic induction, with significant isoflurane-sparing effects in rose flamingos,10 terrapins and tortoises,11 and alpacas.12 Even when alfaxalone was administered as an induction and maintenance anesthesia agent via water immersion, it provided rapid and reliable anesthesia of koi with no mortality.13 We have no idea why the investigators in these studies chose such an odd assortment of animals in which to test alfaxalone. The paper by Goodchild et al.14 in this issue of Anesthesia & Analgesia describes the ongoing evaluation of the new formulation of alfaxalone using a β-cyclodextrin as the solubilizing agent. Although these solvents replaced Cremophor EL in the veterinary preparation, Alfaxan® (Jurox Pty Ltd., Rutherford, NSW, Australia), the 2-hydroxypropyl-β-cyclodextrin has
Figure 1. Alfaxalone.
May 2015 • Volume 120 • Number 5
been demonstrated to be toxic to humans.15,16 This necessitated finding another of these ring structures. Goodchild et al. chose sulfobutyl-ether-β-cyclodextrin for their present formulation, Phaxan-CD. The authors examined the pharmacology of the drug in a rat model in a comparative study with alfaxalone (together with alfadolone acetate) in 20% Cremophor EL and propofol (Diprivan® [Astra Zeneca, UK] in 10% soya bean oil emulsion). Both formulations of alfaxalone resulted in a rapid onset of anesthesia followed by complete recovery, assessed by return of the righting reflex and recovery of balance using the rotarod test. There were no significant differences in the recovery indices or in the 50% effective doses for both loss of righting reflex and loss of response to tail pinch. Limited hemodynamic studies revealed similar changes in heart rate and blood pressure. When compared with propofol, Phaxan resulted in a similar recovery profile with less cardiovascular depression. All initial studies of new agents offer but a taste of the overall properties of the drug. Here, there are a number of questions and issues that further studies will need to consider. Early studies with Althesin in animals showed minimal cardiorespiratory depression when compared with other drugs available at that time. This feature has also been seen with the 2-hydroxypropyl-β-cyclodextrin formulation. The present sulfobutyl-ether-β-cyclodextrin formulation does not appear to have any different effects in the rat. This should not infer that the same will be true when the drug is given to human subjects. One feature seen with most of the steroid anesthetic agents has been the occurrence of involuntary or excitatory movements during induction and recovery from anesthesia. These have been reported in a dose-related manner for the Alfaxan formulation given to the rat17 but has not been reported for any of the 3 agents used in the experiments of Goodchild et al. Why? It is possible that the rate of drug administration, the site of administration, or unique species-to-species differences account for the lack of involuntary movement. The other interesting outcome from the present studies is the greater therapeutic index for Phaxan-CD when compared with alfaxalone alone made up in 20% Cremophor. It is possible this is due to the different solvents of these 2 formulations. Furthermore, comparison of therapeutic indices for the 2 alfaxalone formulations can only be made with certainty if the slopes of the dose-response curves are similar. The available evidence suggests this may not be the case, as the paper of Goodchild et al. did not fully define the 50% lethal dose for the Phaxan-CD formulation. There are few data relating to the use of sulfobutylether-β-cyclodextrin as a solvent. Studies by Egan et al.18 examined the kinetics and dynamics of propofol solvent in Intralipid (Fresenius Kabi, Uppsala, Sweden) or Captisol (Ligand Technology, La Jolla, CA) in a porcine model. Here, the solvent had no effect on propofol’s pharmacokinetics, but there was a difference in the pharmacodynamics of propofol when assessed by comparison of the slope of the concentration-effect relation and maximal drug effect (as measured by electroencephalography). However, this was not seen when etomidate was formulated in Captisol and compared with the commercially available Amidate formulation with no differences in the drug’s pharmacokineticpharmacodynamic relation.19
www.anesthesia-analgesia.org
981
E Editorial As the end point of the toxicity studies was cardiorespiratory death, the authors raise the question whether the sulfobutyl-ether-β-cyclodextrin solvent might offer protection to the rat. Another possibility is that the solvent affects the free drug concentration, with an increased avidity of drug binding to the cyclodextrin rings, lowering the blood concentration at the same drug dose. Many anesthesiologists in Europe and Australasia lamented the passing of Althesin. In the interim, propofol supplanted the other IV hypnotics and has been uniformly adopted as the IV hypnotic of choice worldwide. We await further animal and human studies before seeing if a reformulated alfaxalone has a potential role in the future of anesthesia. E RECUSE NOTE
Dr. Markus W. Hollmann is the Section Editor for Preclinical Pharmacology for Anesthesia & Analgesia. This manuscript was handled by Dr. Steven L. Shafer, Editor-in-Chief, and Dr. Hollmann was not involved in any way with the editorial process or decision. DISCLOSURES
Name: Markus W. Hollmann, MD, PhD, DEAA. Contribution: This author helped write the manuscript. Attestation: Markus W. Hollmann approved the final manuscript. Name: John W. Sear, MA, BSc, MBBS, PhD, FFARCS, FANZCA. Contribution: This author helped write the manuscript. Attestation: John W. Sear approved the final manuscript. REFERENCES 1. Purdy RH, Morrow AL, Moore PH Jr, Paul SM. Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain. Proc Natl Acad Sci U S A 1991;88:4553–7 2. Kumar S, Fleming RL, Morrow AL. Ethanol regulation of gamma-aminobutyric acid A receptors: genomic and nongenomic mechanisms. Pharmacol Ther 2004;101:211–26 3. Phillips GH. Structure-activity relationships in steroidal anaesthetics. J Steroid Biochem 1975;6:607–13 4. Child KJ, Currie JP, Dis B, Dodds MG, Pearce DR, Twissell DJ. The pharmacological properties in animals of CT1341—a new steroid anaesthetic agent. Br J Anaesth 1971;43:2–13
982 www.anesthesia-analgesia.org
5. Sear JW, Prys-Roberts C. Dose-related haemodynamic effects of continuous infusions of Althesin in man. Br J Anaesth 1979;51:867–73 6. Sear JW, Prys-Roberts C, Dye A. Hepatic function after anaesthesia for major vascular reconstructive surgery. Br J Anaesth 1983;55:603–9 7. Towler CM, Garrett RT, Sear JW. Althesin infusions for maintenance of anaesthesia. Anaesthesia 1982;37:428–39 8. Clarke RS. Adverse effects of intravenously administered drugs used in anaesthetic practice. Drugs 1981;22:26–41 9. Brewster ME, Estes KS, Bodor N. Development of a non-surfactant formulation for alfaxalone through the use of chemicallymodified cyclodextrins. J Parenter Sci Technol 1989;43:262–5 10. Villaverde-Morcillo S, Benito J, García-Sánchez R, Martín Jurado O, Gómez de Segura IA. Comparison of isoflurane and alfaxalone (Alfaxan) for the induction of anesthesia in flamingos (Phoenicopterus roseus) undergoing orthopedic surgery. J Zoo Wildl Med 2014;45:361–6 11. Knotek Z. Alfaxalone as an induction agent for anaesthesia in terrapins and tortoises. Vet Rec 2014;175:327 12. Del Álamo AM, Mandsager RE, Riebold TW, Payton ME. Evaluation of intravenous administration of alfaxalone, propofol, and ketamine-diazepam for anesthesia in alpacas. Vet Anaesth Analg 2015;42:72–82 13. Minter LJ, Bailey KM, Harms CA, Lewbart GA, Posner LP. The efficacy of alfaxalone for immersion anesthesia in koi carp (Cyprinus carpio). Vet Anaesth Analg 2014;41:398–405 14. Goodchild CS, Serrao JM, Kolosov A, Boyd BJ. Alphaxalone reformulated: a water-soluble intravenous anesthetic preparation in sulfobutyl-ether-beta-cyclodextrin. Anesth Analg 2015;120:1025–31 15. Brewster ME, Estes KS, Bodor N. An intravenous toxicity study of 2-hydroxypropyl-β-cyclodextrin, a useful drug solubilizer, in rats and monkeys. Int J Pharmaceut 1990;59:231–43 16. MacKenzie CR, Fawcett JP, Boulton DW, Tucker IG. Formulation and evaluation of a propanidid hydroxypropyl-β-cyclodextrin solution for intravenous anaesthesia. Int J Pharmaceut 1997;159:191–6 17. Lau C, Ranasinghe MG, Shiels I, Keates H, Pasloske K, Bellingham MC. Plasma pharmacokinetics of alfaxalone after a single intraperitoneal or intravenous injection of Alfaxan® in rats. J Vet Pharmacol Ther 2013;36:516–20 18. Egan TD, Kern SE, Johnson KB, Pace NL. The pharmacokinetics and pharmacodynamics of propofol in a modified cyclodextrin formulation (Captisol) versus propofol in a lipid formulation (Diprivan): an electroencephalographic and hemodynamic study in a porcine model. Anesth Analg 2003;97:72–9 19. McIntosh MP, Schwarting N, Rajewski RA. In vitro and in vivo evaluation of a sulfobutyl ether beta-cyclodextrin enabled etomidate formulation. J Pharm Sci 2004;93:2585–94
anesthesia & analgesia
Another Steroid Hypnotic: More of the Same or Something Different? Markus W. Hollmann, MD, PhD, DEAA,* and John W. Sear, MA, BSc, MBBS, PhD, FFARCS, FANZCA†
D
uring the past years, there has been considerable interest in neurosteroid physiology and the development of neurosteroid analogs for the treatment of a variety of disorders of central nervous system function. This has been accompanied by research into neurosteroids as potentially useful IV general anesthetics. Peripheral glands (e.g., adrenal cortex and ovaries) produce gamma-aminobutyric acid receptor class A (GABAA)active steroids that cross the blood barrier and influence mood and behavior in circumstances such as pregnancy or stress.1 Supraphysiologic levels of neurosteroids may also contribute to certain psychiatric disorders, including major depression, postpartum depression, premenstrual tension, panic attacks, and schizophrenia. Other psychoactive drugs, such as ethanol or fluoxetine, can influence neurosteroid physiology and modulate GABAA receptor activity, contributing to behavioral changes associated with synthetic neurosteroids.2 Neurosteroids are among the most potent and efficacious (endogenous) allosteric regulators of GABAA receptor function. Steroids acting at the GABAA receptor site modulate neuronal inhibition. The brain and the spinal cord have the necessary enzymatic tools to produce these GABAA receptor–active steroids, enabling local production of steroids within the central nervous system. In addition to functioning as endocrine messengers that influence brain function, neurosteroids may act in a paracrine or autocrine (self-regulation) manner to locally modulate synaptic and extrasynaptic GABAA receptor function. Locally produced neurosteroids may fine-tune the neuronal excitability of the GABAA receptor. For a neurosteroid to show anesthetic activity, there needs to be an oxygen function (either hydroxyl or ketone group) at each end of the molecule (i.e., at C3 and C20 positions of pregnanes or C17 position for androstanes). Substitutions into the steroid ring structure, such as hydroxyl groups, reduce anesthetic activity and may From the *Department of Anesthesiology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands; and †Nuffield Department of Anaesthetics, Green Templeton College University of Oxford, Oxford, United Kingdom. Accepted for publication January 13, 2015. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Markus W. Hollmann, MD, PhD, DEAA, Department of Anesthesiology, Academic Medical Center Amsterdam, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands. Address e-mail to [email protected]. Copyright © 2015 International Anesthesia Research Society DOI: 10.1213/ANE.0000000000000661
980 www.anesthesia-analgesia.org
introduce convulsant properties (see with 11β-hydroxyl groupings). Anesthetic activity is seen among compounds of both the 5β-series and 5α-series. The C3 hydroxyl group can be either in the α-position or β-position, but in general, 3α-hydroxy-5α-molecules and 3α-hydroxy-5β-molecules have the greatest anesthetic activity. C3-keto substituents have little or no anesthetic activity. Esters of these hydroxyl compounds are in general less active and more slowly acting than the parent alcohols.3
ALFAXALONE
Following the initial demonstration of the anesthetic properties of a colloidal suspension of cholesterol in a cat in 1927 by Cashin and Moravek, Hans Selye in 1941 demonstrated that certain steroids could rapidly induce anesthesia. Since that time, multiple steroidal IV anesthetic agents have been developed. The most successful of these was a mixture of alfaxalone (3α-hydroxy-5α-pregnane-11,20-dione) and alfadolone acetate dissolved in a 20% solution of polyoxyethylated castor oil surfactant. This combination came to be known under its trade name, Althesin® (Glaxo, London, UK). Both steroids in Althesin showed anesthetic effects in animals, with the potency of alfaxalone being twice that of alfadolone acetate. The alfadolone was only added to the mixture to increase the solubility of alfaxalone. Because of their hydrophobicity, the mixture was formulated in Cremophor® (BASF, Ludwigshafen, Germany) EL (polyoxyethylated castor oil). With the exception of the United States, Althesin was widely used for both the induction and maintenance of anesthesia from 1972 to 1984. The attraction was a rapid onset, short duration of action, and large therapeutic index of 30.4 with only minor cardiovascular and respiratory effects.4 The typical hemodynamic features of Althesin were a decrease in arterial blood pressure, stroke volume, systemic vascular resistance, and central venous pressure. Cardiac output either remained unchanged or was slightly increased due to compensatory tachycardia. Over a wide range of infusion rates, usage of oxygen by the myocardium remained more or less unchanged. Because of reductions in cerebral blood flow, both intracranial pressure and cerebrospinal fluid pressure were decreased in the ventilated patient. Recovery from Althesin anesthesia was faster than for thiopental and similar to that of propofol. In the spontaneously breathing patient, infusion rates up to 4 times the maintenance rate led to only minor increases in Paco2.5 Althesin also had little influence on renal or hepatic function6,7 and appeared to be a useful anesthetic for the management of patients May 2015 • Volume 120 • Number 5
Neurosteroids and Anesthesia
susceptible to malignant hyperthermia. However, it was considered unsafe in patients with acute porphyria. Undesirable side effects were hiccups, coughing, laryngospasm, and involuntary muscle movements. However, the most prominent unwanted side effect of the mixture was a hypersensitivity reaction that occurred with an incidence of about 1 in 1000.8 Because of the hypersensitivity, Althesin was withdrawn from human clinical practice although its use has continued for some veterinary species. It was eventually determined that the hypersensitivity was caused by the vehicle Cremophor EL and not the neurosteroid constituents. Neurosteroids in general can be viewed as interesting molecules. Endogenous and exogenous progesterone, androstane, and deoxycorticosterone bind to GABAA receptors and allosterically modulate their function.1 Low (nM) concentrations of neurosteroids increase the probability of the GABAAgated ion channel being in the open state, modulate chloride ion transport, and inhibit neurotransmission. Direct activation of the GABAA receptor can occur at concentrations higher than that required for GABAA modulation. Endogenous neurosteroids may act in a paracrine or autocrine manner to locally modulate synaptic and extrasynaptic GABAA receptor function, thus locally regulating and fine-tuning neuronal excitability. Endogenous neurosteroids are thought to cause the analgesia and reduced minimal alveolar concentration associated with pregnancy. Exogenous neurosteroids with sedative-hypnotic properties have been developed into general anesthetics.2 Consistent with an action on GABAA receptors, neurosteroid anesthetics possess anxiolytic, anticonvulsant, analgesic, sedative, and anesthetic activity. Alfaxalone (Fig. 1) has now been reformulated as new aqueous solutions dissolved in either 2-hydroxypropylβ-cyclodextrin9 or 7-sulfobutyl-ether-β-cyclodextrin (Phaxan-CD, Drawbridge Pharmaceuticals, Melbourne, Australia). Unlike the predecessors formulated in Cremophor, the new alfaxalone formulations do not seem to be associated with histamine release and anaphylaxis. In addition, these newer formulations produce a safe and effective anesthetic induction, with significant isoflurane-sparing effects in rose flamingos,10 terrapins and tortoises,11 and alpacas.12 Even when alfaxalone was administered as an induction and maintenance anesthesia agent via water immersion, it provided rapid and reliable anesthesia of koi with no mortality.13 We have no idea why the investigators in these studies chose such an odd assortment of animals in which to test alfaxalone. The paper by Goodchild et al.14 in this issue of Anesthesia & Analgesia describes the ongoing evaluation of the new formulation of alfaxalone using a β-cyclodextrin as the solubilizing agent. Although these solvents replaced Cremophor EL in the veterinary preparation, Alfaxan® (Jurox Pty Ltd., Rutherford, NSW, Australia), the 2-hydroxypropyl-β-cyclodextrin has
Figure 1. Alfaxalone.
May 2015 • Volume 120 • Number 5
been demonstrated to be toxic to humans.15,16 This necessitated finding another of these ring structures. Goodchild et al. chose sulfobutyl-ether-β-cyclodextrin for their present formulation, Phaxan-CD. The authors examined the pharmacology of the drug in a rat model in a comparative study with alfaxalone (together with alfadolone acetate) in 20% Cremophor EL and propofol (Diprivan® [Astra Zeneca, UK] in 10% soya bean oil emulsion). Both formulations of alfaxalone resulted in a rapid onset of anesthesia followed by complete recovery, assessed by return of the righting reflex and recovery of balance using the rotarod test. There were no significant differences in the recovery indices or in the 50% effective doses for both loss of righting reflex and loss of response to tail pinch. Limited hemodynamic studies revealed similar changes in heart rate and blood pressure. When compared with propofol, Phaxan resulted in a similar recovery profile with less cardiovascular depression. All initial studies of new agents offer but a taste of the overall properties of the drug. Here, there are a number of questions and issues that further studies will need to consider. Early studies with Althesin in animals showed minimal cardiorespiratory depression when compared with other drugs available at that time. This feature has also been seen with the 2-hydroxypropyl-β-cyclodextrin formulation. The present sulfobutyl-ether-β-cyclodextrin formulation does not appear to have any different effects in the rat. This should not infer that the same will be true when the drug is given to human subjects. One feature seen with most of the steroid anesthetic agents has been the occurrence of involuntary or excitatory movements during induction and recovery from anesthesia. These have been reported in a dose-related manner for the Alfaxan formulation given to the rat17 but has not been reported for any of the 3 agents used in the experiments of Goodchild et al. Why? It is possible that the rate of drug administration, the site of administration, or unique species-to-species differences account for the lack of involuntary movement. The other interesting outcome from the present studies is the greater therapeutic index for Phaxan-CD when compared with alfaxalone alone made up in 20% Cremophor. It is possible this is due to the different solvents of these 2 formulations. Furthermore, comparison of therapeutic indices for the 2 alfaxalone formulations can only be made with certainty if the slopes of the dose-response curves are similar. The available evidence suggests this may not be the case, as the paper of Goodchild et al. did not fully define the 50% lethal dose for the Phaxan-CD formulation. There are few data relating to the use of sulfobutylether-β-cyclodextrin as a solvent. Studies by Egan et al.18 examined the kinetics and dynamics of propofol solvent in Intralipid (Fresenius Kabi, Uppsala, Sweden) or Captisol (Ligand Technology, La Jolla, CA) in a porcine model. Here, the solvent had no effect on propofol’s pharmacokinetics, but there was a difference in the pharmacodynamics of propofol when assessed by comparison of the slope of the concentration-effect relation and maximal drug effect (as measured by electroencephalography). However, this was not seen when etomidate was formulated in Captisol and compared with the commercially available Amidate formulation with no differences in the drug’s pharmacokineticpharmacodynamic relation.19
www.anesthesia-analgesia.org
981
E Editorial As the end point of the toxicity studies was cardiorespiratory death, the authors raise the question whether the sulfobutyl-ether-β-cyclodextrin solvent might offer protection to the rat. Another possibility is that the solvent affects the free drug concentration, with an increased avidity of drug binding to the cyclodextrin rings, lowering the blood concentration at the same drug dose. Many anesthesiologists in Europe and Australasia lamented the passing of Althesin. In the interim, propofol supplanted the other IV hypnotics and has been uniformly adopted as the IV hypnotic of choice worldwide. We await further animal and human studies before seeing if a reformulated alfaxalone has a potential role in the future of anesthesia. E RECUSE NOTE
Dr. Markus W. Hollmann is the Section Editor for Preclinical Pharmacology for Anesthesia & Analgesia. This manuscript was handled by Dr. Steven L. Shafer, Editor-in-Chief, and Dr. Hollmann was not involved in any way with the editorial process or decision. DISCLOSURES
Name: Markus W. Hollmann, MD, PhD, DEAA. Contribution: This author helped write the manuscript. Attestation: Markus W. Hollmann approved the final manuscript. Name: John W. Sear, MA, BSc, MBBS, PhD, FFARCS, FANZCA. Contribution: This author helped write the manuscript. Attestation: John W. Sear approved the final manuscript. REFERENCES 1. Purdy RH, Morrow AL, Moore PH Jr, Paul SM. Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain. Proc Natl Acad Sci U S A 1991;88:4553–7 2. Kumar S, Fleming RL, Morrow AL. Ethanol regulation of gamma-aminobutyric acid A receptors: genomic and nongenomic mechanisms. Pharmacol Ther 2004;101:211–26 3. Phillips GH. Structure-activity relationships in steroidal anaesthetics. J Steroid Biochem 1975;6:607–13 4. Child KJ, Currie JP, Dis B, Dodds MG, Pearce DR, Twissell DJ. The pharmacological properties in animals of CT1341—a new steroid anaesthetic agent. Br J Anaesth 1971;43:2–13
982 www.anesthesia-analgesia.org
5. Sear JW, Prys-Roberts C. Dose-related haemodynamic effects of continuous infusions of Althesin in man. Br J Anaesth 1979;51:867–73 6. Sear JW, Prys-Roberts C, Dye A. Hepatic function after anaesthesia for major vascular reconstructive surgery. Br J Anaesth 1983;55:603–9 7. Towler CM, Garrett RT, Sear JW. Althesin infusions for maintenance of anaesthesia. Anaesthesia 1982;37:428–39 8. Clarke RS. Adverse effects of intravenously administered drugs used in anaesthetic practice. Drugs 1981;22:26–41 9. Brewster ME, Estes KS, Bodor N. Development of a non-surfactant formulation for alfaxalone through the use of chemicallymodified cyclodextrins. J Parenter Sci Technol 1989;43:262–5 10. Villaverde-Morcillo S, Benito J, García-Sánchez R, Martín Jurado O, Gómez de Segura IA. Comparison of isoflurane and alfaxalone (Alfaxan) for the induction of anesthesia in flamingos (Phoenicopterus roseus) undergoing orthopedic surgery. J Zoo Wildl Med 2014;45:361–6 11. Knotek Z. Alfaxalone as an induction agent for anaesthesia in terrapins and tortoises. Vet Rec 2014;175:327 12. Del Álamo AM, Mandsager RE, Riebold TW, Payton ME. Evaluation of intravenous administration of alfaxalone, propofol, and ketamine-diazepam for anesthesia in alpacas. Vet Anaesth Analg 2015;42:72–82 13. Minter LJ, Bailey KM, Harms CA, Lewbart GA, Posner LP. The efficacy of alfaxalone for immersion anesthesia in koi carp (Cyprinus carpio). Vet Anaesth Analg 2014;41:398–405 14. Goodchild CS, Serrao JM, Kolosov A, Boyd BJ. Alphaxalone reformulated: a water-soluble intravenous anesthetic preparation in sulfobutyl-ether-beta-cyclodextrin. Anesth Analg 2015;120:1025–31 15. Brewster ME, Estes KS, Bodor N. An intravenous toxicity study of 2-hydroxypropyl-β-cyclodextrin, a useful drug solubilizer, in rats and monkeys. Int J Pharmaceut 1990;59:231–43 16. MacKenzie CR, Fawcett JP, Boulton DW, Tucker IG. Formulation and evaluation of a propanidid hydroxypropyl-β-cyclodextrin solution for intravenous anaesthesia. Int J Pharmaceut 1997;159:191–6 17. Lau C, Ranasinghe MG, Shiels I, Keates H, Pasloske K, Bellingham MC. Plasma pharmacokinetics of alfaxalone after a single intraperitoneal or intravenous injection of Alfaxan® in rats. J Vet Pharmacol Ther 2013;36:516–20 18. Egan TD, Kern SE, Johnson KB, Pace NL. The pharmacokinetics and pharmacodynamics of propofol in a modified cyclodextrin formulation (Captisol) versus propofol in a lipid formulation (Diprivan): an electroencephalographic and hemodynamic study in a porcine model. Anesth Analg 2003;97:72–9 19. McIntosh MP, Schwarting N, Rajewski RA. In vitro and in vivo evaluation of a sulfobutyl ether beta-cyclodextrin enabled etomidate formulation. J Pharm Sci 2004;93:2585–94
anesthesia & analgesia
