Alfaxalone

Last updated
Alfaxalone
Alphaxolone.svg
Alfaxan bottle.jpg
Clinical data
Trade names Alfaxan
Other namesAlphaxalone; Alphaxolone; Alfaxolone; 3α-Hydroxy-5α-pregnane-11,20-dione; PHAX-001; Phaxan, Alphaxalone (BAN UK)
AHFS/Drugs.com International Drug Names
License data
Drug class
ATCvet code
Legal status
Legal status
Pharmacokinetic data
Protein binding 30–50%
Metabolism Hepatic
Metabolites
  • Alfaxalone glucuronide (major in dogs)
  • 20-Hydroxyalfaxalone sulfate (major in cats)
Elimination half-life
  • 25 min (dogs)
  • 45 min (cats)
Excretion Mostly renal
Identifiers
  • (3R,5S,8S,9S,10S,13S,14S,17S)-17-acetyl-3-hydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-11-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.164.405 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H32O3
Molar mass 332.484 g·mol−1
3D model (JSmol)
  • O=C2[C@H]3[C@H]([C@@H]1CC[C@H](C(=O)C)[C@@]1(C)C2)CC[C@H]4C[C@H](O)CC[C@]34C
  • InChI=1S/C21H32O3/c1-12(22)16-6-7-17-15-5-4-13-10-14(23)8-9-20(13,2)19(15)18(24)11-21(16,17)3/h13-17,19,23H,4-11H2,1-3H3/t13-,14+,15-,16+,17-,19+,20-,21+/m0/s1 Yes check.svgY
  • Key:DUHUCHOQIDJXAT-OLVMNOGESA-N Yes check.svgY
   (verify)

Alfaxalone, also known as alphaxalone or alphaxolone and sold under the brand name Alfaxan, is a neuroactive steroid and general anesthetic which is used currently in veterinary practice as an induction agent for anesthesia and as an injectable anesthetic. [1] [2] [3] Though it is more expensive than other induction agents, [4] it often preferred due to the lack of depressive effects on the cardiovascular system. The most common side effect seen in current veterinary practice is respiratory depression when Alfaxan is administered concurrently with other sedative and anesthetic drugs; when premedications aren't given, veterinary patients also become agitated and hypersensitive when waking up.

Contents

Alfaxalone works as a positive allosteric modulator on GABAA receptors and, at high concentrations, as a direct agonist of the GABAA receptor. It is cleared quickly by the liver, giving it a relatively short terminal half-life and preventing it from accumulating in the body, lowering the chance of overdose.

Veterinary use

Alfaxalone is used as an induction agent, an injectable anesthetic, and a sedative in animals. [5] While it is commonly used in cats and dogs, it has also been successfully used in rabbits, [6] horses, sheep, pigs, and exotics such as red-eared turtles, axolotl, green iguanas, marmosets, [7] and koi fish. [8] As an induction agent, alfaxalone causes the animal to relax enough to be intubated, which then allows the administration of inhalational anesthesia. Premedication (administering sedative drugs prior to induction) increases the potency of alfaxalone as an induction agent. [7] Alfaxalone can be used instead of gas anesthetics in surgeries that are under 30 minutes, where it is given at a constant rate via IV (constant rate infusion); this is especially useful in procedures such as bronchoscopies or repairing tracheal tears, as there is no endotracheal tube in the way. [4] [9] Once the administration of alfaxalone stops, the animal quickly recovers from anesthesia. [10]

Alfaxalone can be used as a sedative when given intramuscularly (IM), though this requires a larger volume (and not all countries allow alfaxalone to be administered IM). [11] [12]

Despite its use as an anesthetic, alfaxalone itself has no analgesic properties. [7]

Available forms

Though alfaxalone is not licensed for IM or subcutaneous use in the United States (as both cause longer recoveries with greater agitation and hypersensitivity to stimuli), it is routinely used IM in cats, and is licensed as such in other countries. [4] [13]

Alfaxalone is dissolved in 2-hydroxypropyl-β cyclodextrin. [14] The cyclodextrin is a large, starch-derived molecule with a hydrophobic core where alfaxalone stays, allowing the mixture to be dissolved in water and sold as an aqueous solution. They act as one unit, and only dissociate once in vivo. [11] [15]

Specific populations

Alfaxalone has been used to perform C-sections in pregnant cats; though it crosses the placental barrier and had some effects on the kittens, there is no respiratory depression and no lasting effect. Alfaxalone has also been found to be safe in young puppies and kittens. [16] [17]

Alfaxalone has been noted to be a good anesthetic agent for dogs with ventricular arrhythmias and for sighthounds. [13] [18]

There seems to be marked difference in sex response: anaesthesia in the male rat requires about four times more than in the female. [19]

Side effects

Alfaxalone has relatively few side effects compared to other anesthetics; most notable is its lack of cardiovascular depression at clinical doses, which makes it unique among anesthetics. [10] [13] The most common side effect is respiratory depression: in addition to apnea, the most prevalent, alfaxalone can also decrease the respiratory rate, minute volume, and oxygen saturation in the blood. [17] Alfaxalone should be administered slowly over a period of at least 60 seconds or until anesthesia is induced, as quick administration increases the risk of apnea. [5] [13] Alfaxalone has some depressive effects on the central nervous system, including a reduction in cerebral blood flow, intracranial pressure, and body temperature. [17]

Greyhounds, who are particularly susceptible to anesthetic side effects, can have decreased blood flow and oxygen supply to the liver. [17]

When no premedications are used, alfaxalone causes animals (especially cats) to be agitated when recovering. [4] [13] Dogs and cats will paddle in the air, vocalize excessively, may remain rigid or twitch, and have exaggerated reactions to external stimuli such as light and noise. For this reason, it is recommended that animals recovering from anesthesia by alfaxalone stay in a quiet, dark area. [17]

Overdose

The quick metabolism and elimination of alfaxalone from the body decreases the chance of overdose. [10] It would take over 28 times the normal dose to cause toxicity in cats. [11] Such doses, however, can cause low blood pressure, apnea, hypoxia, and arrhythmia (caused by the apnea and hypoxia). [11]

Pharmacology

Pharmacodynamics

GABAA receptor and the location of various ligand-binding sites. GABAa receptor.gif
GABAA receptor and the location of various ligand-binding sites.

Alfaxalone is a neuroactive steroid derived from progesterone, though it has no glucocorticoid or mineralocorticoid action. [4] [10] Instead, it works by acting on GABAA receptors. [20] It binds to the M3/M4 domains of the α subunit and allosterically modifies the receptor to facilitate the movement of chloride ions into the cell, resulting in hyperpolarization of the post-synaptic nerve (which inhibits actions potentials). At concentrations over 1 micromolar, [21] alfaxalone binds to a site at the interface between the α and β subunits (near the actual GABA binding site) and acts as a GABA agonist, similar to benzodiazepines. [17] [22] Alfaxalone, however, does not share the benzodiazepine binding site, [23] and actually prefers different GABAA receptors than benzodiazepenes do. It works best on the α1-β2-γ2-L isoform. [11] Research suggests that neuroactive steroids increase the expression of GABAA receptors, making it more difficult to build tolerance. [22]

Pharmacokinetics

Alfaxalone is metabolized quickly and does not accumulate in the body; its use as an induction agent thus doesn't increase the time needed to recover from anesthesia. [4] [10] If it administered more slowly by diluting it in sterile water, less actual alfaxalone is needed. [9] Alfaxalone binds to 30–50% of plasma proteins, [24] and has a terminal half-life of 25 minutes in dogs and 45 minutes in cats when given at clinical doses (2 mg/kg and 5 mg/kg respectively). The pharmacokinetics are nonlinear in cats and dogs. [14] [25]

Most alfaxalone metabolism takes place in the liver, though some takes place in the lungs and kidneys as well. [25] In the liver, it undergoes both phase I (cytochrome P450-dependent) and phase II (conjugation-dependent) metabolism. The phase I products are the same in cats and dogs: allopregnatrione, 3β-alfaxalone, 20-hydroxy-3β-alfaxalone, 2-hydroxyalfaxalone, and 2α-hydroxyalfaxalone. [11] [17] In dogs, the phase II metabolites are alfaxalone glucuronide (the major metabolite), 20-hydroxyalfaxalone sulfate, and 2α-hydroxyalfaxalone glucuronide. In cats, there is a greater production of 20-hydroxyalfaxalone sulfate than alfaxalone glucuronide; cats also have 3β-alfaxalone-sulfate, which is not present in dogs. [11] [17]

Alfaxalone is mostly excreted in the urine, though some is excreted in the bile as well.

Chemistry

Progesterone (left) and its derivative, alfaxolan (right); the differences are highlighted in pink. Progesterone vs alfaxalone.svg
Progesterone (left) and its derivative, alfaxolan (right); the differences are highlighted in pink.

Alfaxalone, also known as 11-oxo-3α,5α-tetrahydroprogesterone, 5α-pregnan-3α-ol-11,20-dione, or 3α-hydroxy-5α-pregnane-11,20-dione, is a synthetic pregnane steroid and a derivative of progesterone. [1] It is specifically a modification of progesterone in which the C3 ketone has been reduced to a hydroxyl group, the double bond between the C4 and C5 positions has been reduced and is now a single bond, and a ketone has been substituted at the C11 position. [1] Alfaxalone is also a derivative of allopregnanolone, differing from it only by the addition of the C11 ketone. [1] Other closely related steroids include ganaxolone, hydroxydione, minaxolone, pregnanolone, and renanolone. [1]

History

In 1941, progesterone and 5β-pregnanedione were discovered to have CNS depressant effects in rodents. This began a search to make a synthetic steroid that could be used as an anesthetic. Most of these efforts were aimed at making alfaxalone more water-soluble. [22]

In 1971, a combination of alfaxalone and alfadolone acetate was released as the anesthetics Althesin (for human use) and Saffan (for veterinary use). [7] [25] The two were dissolved in Cremophor EL: a polyoxyelthylated castor oil surfactant. [14]

Althesin was removed from the market in 1984 for causing anaphylaxis; it was later found that this was due to Cremphor EL, which caused the body to release histamine, rather than alfaxolone or alfadolone. [7] [13] [22] Saffan was removed from use for dogs only, but stayed on for other animals, none of which histamine release to the same extant that dogs did. [26] It was still especially valued in cats for its lack of depressant effects on the cardiovascular system, which made it three times less fatal than any other anesthetic on the market at the time. [7] [9] The release of histamine caused most cats (70%) to have edema and hyperemia in their ears and paws; [27] only some also got laryngeal or pulmonary edema. [26]

In 1999, a lyophilized form of alfaxalone was released for cats. [11] The new drug, Alfaxan, used a cyclodextrin as a carrier agent to make alfaxalone more water-soluble rather than Camphor EL. [13] Alfadolone was not included in the mixture, as its hypnotic effects were quite weak. [26] An aqueous form of Alfaxan was released in Australia in 2000–2001, and Saffan was finally removed from the market in 2002. Alfaxan was released in the UK in 2007, central Europe in 2008, Canada in 2011, and the United States in 2012. [11] [12]

Currently, a human form of alfaxalone is in development under the name "Phaxan": alfaxalone will be dissolved in 7-sulfo-butyl-ether-β-cyclodextrin, which, unlike the cyclodextrin used in Alfaxan, is not toxic to people. [14]

Society and culture

Generic names

Alfaxalone is the INN Tooltip International Nonproprietary Name, BAN Tooltip British Approved Name, DCF Tooltip Dénomination Commune Française, and JAN Tooltip Japanese Accepted Name of alfaxolone. Alphaxalone was the former BAN of the drug, [1] [2] but this was eventually changed. Alphaxolone and alfaxolone are additional alternative spellings. [1] [2] [3] [28]

Brand names

Alfaxalone was marketed in 1971 in combination with alfadolone acetate under the brand name Althesin for human use and Saffan for veterinary use. [17] [29] Althesin was withdrawn from the market in 1984, whereas Saffan remained marketed. [30] A new formulation containing alfaxalone only was introduced for veterinary use in 1999 under the brand name Alfaxan. [17] [29] Following the introduction of Alfaxan, Saffan was gradually discontinued and is now no longer marketed. [30] [31] Another new formulation containing alfaxalone alone is currently under development for use in humans with the tentative brand name Phaxan. [14] [32]

Availability

Alfaxalone is marketed for veterinary use under the brand name Alfaxan in a number of countries, including Australia, Belgium, Canada, France, Germany, Ireland, Japan, the Netherlands, New Zealand, South Africa, South Korea, Spain, Taiwan, the United Kingdom, and the United States. [3] [33] [34]

Related Research Articles

General anaesthetics are often defined as compounds that induce a loss of consciousness in humans or loss of righting reflex in animals. Clinical definitions are also extended to include an induced coma that causes lack of awareness to painful stimuli, sufficient to facilitate surgical applications in clinical and veterinary practice. General anaesthetics do not act as analgesics and should also not be confused with sedatives. General anaesthetics are a structurally diverse group of compounds whose mechanisms encompass multiple biological targets involved in the control of neuronal pathways. The precise workings are the subject of some debate and ongoing research.

<span class="mw-page-title-main">Isoflurane</span> General anaesthetic given via inhalation

Isoflurane, sold under the brand name Forane among others, is a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia, due to airway irritation with isoflurane. Isoflurane is given via inhalation.

<span class="mw-page-title-main">Sevoflurane</span> Inhalational anaesthetic

Sevoflurane, sold under the brand name Sevorane, among others, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflurane, it is the volatile anesthetic with the fastest onset. While its offset may be faster than agents other than desflurane in a few circumstances, its offset is more often similar to that of the much older agent isoflurane. While sevoflurane is only half as soluble as isoflurane in blood, the tissue blood partition coefficients of isoflurane and sevoflurane are quite similar. For example, in the muscle group: isoflurane 2.62 vs. sevoflurane 2.57. In the fat group: isoflurane 52 vs. sevoflurane 50. As a result, the longer the case, the more similar will be the emergence times for sevoflurane and isoflurane.

<span class="mw-page-title-main">Theories of general anaesthetic action</span> How drugs induce reversible suppression of consciousness

A general anaesthetic is a drug that brings about a reversible loss of consciousness. These drugs are generally administered by an anaesthetist/anesthesiologist to induce or maintain general anaesthesia to facilitate surgery.

<span class="mw-page-title-main">Acepromazine</span> Antipsychotic medication

Acepromazine, acetopromazine, or acetylpromazine is a phenothiazine derivative antipsychotic drug. It was used in humans during the 1950s as an antipsychotic, but is now almost exclusively used on animals as a sedative and antiemetic. A closely related analogue, chlorpromazine, is still used in humans.

Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term neurosteroid was coined by the French physiologist Étienne-Émile Baulieu and refers to steroids synthesized in the brain. The term, neuroactive steroid refers to steroids that can be synthesized in the brain, or are synthesized by an endocrine gland, that then reach the brain through the bloodstream and have effects on brain function. The term neuroactive steroids was first coined in 1992 by Steven Paul and Robert Purdy. In addition to their actions on neuronal membrane receptors, some of these steroids may also exert effects on gene expression via nuclear steroid hormone receptors. Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy and traumatic brain injury. Ganaxolone, a synthetic analog of the endogenous neurosteroid allopregnanolone, is under investigation for the treatment of epilepsy.

<span class="mw-page-title-main">Mental nerve</span> Sensory nerve of the face

The mental nerve is a sensory nerve of the face. It is a branch of the posterior trunk of the inferior alveolar nerve, itself a branch of the mandibular nerve (CN V3), itself a branch of the trigeminal nerve (CN V). It provides sensation to the front of the chin and the lower lip, as well as the gums of the anterior mandibular (lower) teeth. It can be blocked with local anaesthesia for procedures on the chin, lower lip, and mucous membrane of the inner cheek. Problems with the nerve cause chin numbness.

Alfaxolone/alfadolone is a short acting intravenous anesthetic agent. It was withdrawn from the market due to severe drug reactions. It is composed of a 3:1 mixture of alfaxalone and alfadolone, two neurosteroids.

Veterinary anesthesia is anesthesia performed on non-human animals by a veterinarian or a Registered Veterinary Technician. Anesthesia is used for a wider range of circumstances in animals than in people, due to animals' inability to cooperate with certain diagnostic or therapeutic procedures. Veterinary anesthesia includes anesthesia of the major species: dogs, cats, horses, cattle, sheep, goats, and pigs, as well as all other animals requiring veterinary care such as birds, pocket pets, and wildlife.

<span class="mw-page-title-main">Minaxolone</span> Chemical compound

Minaxolone (CCI-12923) is a neuroactive steroid which was developed as a general anesthetic but was withdrawn before registration due to toxicity seen with long-term administration in rats, and hence was never marketed. It is a positive allosteric modulator of the GABAA receptor, as well as, less potently, a positive allosteric modulator of the glycine receptor.

<span class="mw-page-title-main">Medetomidine</span> Chemical compound

Medetomidine is a synthetic drug used as both a surgical anesthetic and analgesic. It is often used as the hydrochloride salt, medetomidine hydrochloride, a crystalline white solid. It is an α2 adrenergic agonist that can be administered as an intravenous drug solution with sterile water.

<span class="mw-page-title-main">Maropitant</span> Veterinary medication

Maropitant (INN; brand name: Cerenia, used as maropitant citrate (USAN), is a neurokinin-1 (NK1) receptor antagonist developed by Zoetis specifically for the treatment of motion sickness and vomiting in dogs. It was approved by the FDA in 2007, for use in dogs and in 2012, for cats.

<span class="mw-page-title-main">Atipamezole</span> Veterinary drug

Atipamezole, is a synthetic α2 adrenergic receptor antagonist indicated for the reversal of the sedative and analgesic effects of dexmedetomidine and medetomidine in dogs. Its reversal effect works by competing with the sedative for α2-adrenergic receptors and displacing them. It is mainly used in veterinary medicine, and while it is only licensed for dogs and for intramuscular use, it has been used intravenously, as well as in cats and other animals(intravenous use in cats and dogs is not recommended due to the potential for cardiovascular collapse. This occurs due to profound hypotension caused by reversal of the alpha 1 effects while the reflex bradycardia is still in effect.). There is a low rate of side effects, largely due to atipamezole's high specificity for the α2-adrenergic receptor. Atipamezole has a very quick onset, usually waking an animal up within 5 to 10 minutes.

<span class="mw-page-title-main">Pregnanolone</span> Chemical compound

Pregnanolone, also known as eltanolone, is an endogenous inhibitory neurosteroid which is produced in the body from progesterone. It is closely related to allopregnanolone, which has similar properties.

<span class="mw-page-title-main">Flurothyl</span> Chemical compound

Flurothyl (Indoklon) is a volatile liquid drug from the halogenated ether family, related to inhaled anaesthetic agents such as diethyl ether, but having the opposite effects, acting as a stimulant and convulsant. A clear and stable liquid, it has a mild ethereal odor whose vapors are non-flammable. It is excreted from the body by the lungs in an unchanged state.

<span class="mw-page-title-main">ORG-20599</span> Chemical compound

ORG-20599 is a synthetic neuroactive steroid, with sedative effects resulting from its action as a GABAA receptor positive allosteric modulator and, at higher concentrations, agonist. It was developed for use as an anaesthetic agent but was never marketed for this purpose, although it is still used in scientific research.

<span class="mw-page-title-main">ORG-21465</span> Chemical compound

ORG-21465 is a synthetic neuroactive steroid, with sedative effects resulting from its action as a GABAA receptor positive allosteric modulator. It is similar to related drugs such as ORG-20599, and was similarly developed as an improved alternative to other sedative steroids such as althesin and allopregnanolone, which despite its superior properties in some respects has not proved to offer enough advantages to be accepted into clinical use.

GABA<sub>A</sub> receptor positive allosteric modulator

In pharmacology, GABAA receptor positive allosteric modulators, also known as GABAkines or GABAA receptor potentiators, are positive allosteric modulator (PAM) molecules that increase the activity of the GABAA receptor protein in the vertebrate central nervous system.

<span class="mw-page-title-main">Coinduction (anesthetics)</span>

Coinduction in anesthesia is a pharmacological tool whereby a combination of sedative drugs may be used to greater effect than a single agent, achieving a smoother onset of general anesthesia. The use of coinduction allows lower doses of the same anesthetic agents to be used which provides enhanced safety, faster recovery, fewer side-effects, and more predictable pharmacodynamics. Coinduction is used in human medicine and veterinary medicine as standard practice to provide optimum anesthetic induction. The onset or induction phase of anesthesia is a critical period involving the loss of consciousness and reactivity in the patient, and is arguably the most dangerous period of a general anesthetic. A great variety of coinduction combinations are in use and selection is dependent on the patient's age and health, the specific situation, and the indication for anesthesia. As with all forms of anesthesia the resources available in the environment are a key factor.

<span class="mw-page-title-main">Balanced anesthesia</span> Anesthetic technique

Balanced anesthesia is an anesthetic method for surgical patients during their operation, which was proposed by John Lundy in 1926. The purpose of balanced anesthesia is not only to be less dangerous than using only one drug for general anesthesia but also to minimise the potential adverse side effects which may be caused by the anesthetic agents. The concept of balanced anesthesia is that of applying two or more medications or techniques in order to ease pain, relax the muscles, and have autonomous reflexes suppressed in the patient. In other words, it is an anesthesia method to maintain stable vital signs. There are numerous factors that come into play when the anesthetist decides to use this method of anesthesia. These factors include, but are not limited to: patients' major organ functions, general condition and compensatory capacity. By making use of adequate types and appropriate amounts of agents and accurate anesthesia methods, the anesthetist will promote a successful, safe, and efficient surgery.

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  24. ↑ Maddison JE, Page SW, Church D, eds. (2008). "Alphaxalone (±alphadolone)". Small Animal Clinical Pharmacology. Elsevier Health Sciences. pp. 101–103. ISBN   9780702028588.
  25. 1 2 3 Suarez MA, Dzikiti BT, Stegmann FG, Hartman M (May 2012). "Comparison of alfaxalone and propofol administered as total intravenous anaesthesia for ovariohysterectomy in dogs". Veterinary Anaesthesia and Analgesia. 39 (3): 236–44. doi: 10.1111/j.1467-2995.2011.00700.x . PMID   22405473.
  26. 1 2 3 Welsh L (May 8, 2013). Anaesthesia for Veterinary Nurses. John Wiley & Sons. p. 153. ISBN   9781118693148.
  27. ↑ Liao PT (August 2016). Anesthetic and Cardio-pulmonary Effects of Propofol or Alfaxalone with or without Midazolam Co-Induction in Fentanyl Sedated Dogs (PDF) (DVM). Guelph, Ontario: University of Guelph.
  28. ↑ "Substance Name: Alfaxalone [INN:BAN:DCF:JAN]". ChemIDplus. US National Library of Medicine.
  29. 1 2 Papich MG (October 2015). Saunders Handbook of Veterinary Drugs: Small and Large Animal. Elsevier Health Sciences. pp. 17–18. ISBN   978-0-323-24485-5.
  30. 1 2 Clarke KW, Trim CM (28 June 2013). Veterinary Anaesthesia E-Book. Elsevier Health Sciences. p. 143. ISBN   978-0-7020-5423-5.
  31. ↑ Fish RE (2008). Anesthesia and Analgesia in Laboratory Animals. Academic Press. pp. 315–. ISBN   978-0-12-373898-1.
  32. ↑ "Alfaxalone (PHAX-001; Phaxan)". AdisInsight. Retrieved 27 July 2017.
  33. ↑ Official website of Alfaxan
  34. ↑ Tamura J, Ishizuka T, Fukui S, Oyama N, Kawase K, Miyoshi K, et al. (March 2015). "The pharmacological effects of the anesthetic alfaxalone after intramuscular administration to dogs". The Journal of Veterinary Medical Science. 77 (3): 289–96. doi:10.1292/jvms.14-0368. PMC   4383774 . PMID   25428797. [Alfaxalone] is approved in some countries (e.g., Australia, New Zealand, Europe, Korea, Japan, USA and Canada) as an IV anesthetic agent in dogs and cats.
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