Hexobarbital

Last updated

Hexobarbital
Hexobarbital.svg
Hexobarbital ball-and-stick.png
Clinical data
Trade names Hexobarbital, Hexobarbitone, Methylhexabital, Methexenyl, Evipal
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 25%
Identifiers
  • 5-(cyclohex-1-en-1-yl)-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.241 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C12H16N2O3
Molar mass 236.271 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
Density 1.1623 g/cm3
Melting point 146.5 °C (295.7 °F)
Boiling point 378.73 °C (713.71 °F)
Solubility in water 0.435 mg/mL (20 °C)
  • O=C1N(C(=O)NC(=O)C1(/C2=C/CCCC2)C)C
  • InChI=1S/C12H16N2O3/c1-12(8-6-4-3-5-7-8)9(15)13-11(17)14(2)10(12)16/h6H,3-5,7H2,1-2H3,(H,13,15,17) Yes check.svgY
  • Key:UYXAWHWODHRRMR-UHFFFAOYSA-N Yes check.svgY
   (verify)

Hexobarbital or hexobarbitone, sold both in acid and sodium salt forms as Citopan, Evipan, and Tobinal, is a barbiturate derivative having hypnotic and sedative effects. It was used in the 1940s and 1950s as an agent for inducing anesthesia for surgery, as well as a rapid-acting, short-lasting hypnotic for general use, and has a relatively fast onset of effects and short duration of action. [1] Modern barbiturates (such as Thiopental) have largely supplanted the use of hexobarbital as an anesthetic, as they allow for better control of the depth of anesthesia. [2] Hexobarbital is still used in some scientific research. [3]

Contents

History

The chemical class of barbiturates are one of the oldest sedative-hypnotic agents known, dating back from the introduction of barbital in the early 20th century. [4] In Eastern Europe, hexobarbital (and other barbiturates) have been regularly used as drugs by pregnant women attempting suicide. [4] Hexobarbital was long thought to have potentially teratogenic and fetotoxic effects. The FDA has classified them as Pregnancy Category D or C. [5] Some research however, indicate that ingestion of Hexobarbital might cause congenital abnormalities. [4]

During World War II, Herta Oberheuser was a Nazi physician and convicted war criminal, investigating the effects of hexobarbital. The experiments were mostly performed on woman prisoners in the Ravensbrück concentration camp.

Application in research

Hexobarbital is used as the narcotic in the Hexobarbital Sleep Test (HST). HST identifies rodents with high or low intensity of microsomal oxidation, so fast (FM) or slow metabolizers (SM). The sleep test is for example used to predict the susceptibility and resistance to post-traumatic stress disorder (PTSD) [6] or to determine the effect of toxic compounds on sleep time. [7] [8]

Synthesis

Hexobarbital can be synthesized by reacting cyclohex-1-enyl 2-cyanopropanoate with guanidine and sodium methylate. A hexobarbital sodium intermediate is then formed which can be  methylated with dimethyl sulfate. [9]

Another pathway for hexobarbital synthesis is reacting ethyl 2-cyano-2-(cyclohex-1-enyl)propanoate with N-methylurea. [10] This reaction is done in two stages, in the first stage the reactants are added with tert-butylate in tert-butyl alcohol at 20-50 °C. In the second stage hydrogen chloride is added with ethanol and water as solvent.

Synthesis of hexobarbital by reacting cyclohex-1-enyl 2-cyanopropanoate with guanidine and sodium ethylate, afterwards another methyl group is added through dimethyl sulfate Hexobarbital synthesis.jpg
Synthesis of hexobarbital by reacting cyclohex-1-enyl 2-cyanopropanoate with guanidine and sodium ethylate, afterwards another methyl group is added through dimethyl sulfate
Alternative pathway for synthesis of hexobarbital by reacting ethyl 2-cyano-2-(cyclohex-1-enyl)propanoate with N-methylurea. Hexobarbital synthesis through ester and urea.png
Alternative pathway for synthesis of hexobarbital by reacting ethyl 2-cyano-2-(cyclohex-1-enyl)propanoate with N-methylurea.

Reactivity

One of the cytochrome P450 isozymes is coded by the gene CYP2B1, where hexobarbital is the substrate. Hexobarbital and the isozyme can form an enzyme-substrate-complex through a hydroxylation reaction, which is involved in the metabolism of xenobiotics. the concentration of hexobarbital also plays a role in oxygenase and oxidase activity of hepatic microsomal cytochrome P450. [11]

Triacetyl oleandomycin, an inhibitor for isozyme CYP3A4, also inhibits hexobarbital metabolism and biological activity, indicating a close relationship between hexobarbital and cytochrome P450. [12]

Toxicity

Mechanism of actions

Molecular structure of S(+) and R(-) enantiomers of hexobarbital Enantiomers of Hexobarbital.jpg
Molecular structure of S(+) and R(-) enantiomers of hexobarbital

The biological effects of hexobarbital depend primarily on its ability to penetrate the central nervous system. [13] Hexobarbital can potentiate GABAA receptors, like all barbiturates. It has been found over the years that the S(+) enantiomer of hexobarbital potentiates GABAA receptors more effectively than its R(-) enantiomer. [14] When GABA binds to the GABAA receptor, the chloride ion channels open such that chloride ions can flow into the neuron. This causes a hyperpolarization in the membrane potential of the neuron, which makes it less likely for the neuron to start an action potential. Therefore, this type of receptor is the major inhibitory neurotransmitter receptor in the mammalian central nervous system. [15] As a GABAA receptor potentiator, hexobarbital binds to the barbiturate binding site localized in the chloride ion channel, thereby increasing the binding of GABA and benzodiazepines to their respective binding site, allosterically. [16] Moreover, hexobarbital causes the chloride ion channel opening to their longest open state of 9 milli seconds, thereby causing the postsynaptic inhibitory effect to be extended. [14] In contrast to GABA, glutamate is the major excitatory neurotransmitter in the mammalian brain. In addition to the inhibitory effect, hexobarbital blocks, like all barbiturates, AMPA receptors, kainate receptors, neural acetylcholine receptors. And above all, barbiturates inhibit glutamate release by causing an open channel block on P/Q‐type high‐voltage activated calcium channels. [17] All in all, hexobarbital causes an CNS-depressant effect on the brain by inhibiting the glutamate release and potentiating the GABA-effect.

Metabolism

The hepatic metabolism of hexobarbital (HB) can be divided into different pathways all forming different metabolites. [18] The S(+) enantiomer of HB preferentially metabolizes into β-3'-hydroxyhexobarbital and the R(-) enantiomer preferentially metabolizes into α-3'-hydroxyhexobarbital, the reaction thus is stereoselective. Both enantiomers, however, form both α- and β-isomers. In total four enantiomers for 3'-hydroxyhexobarbital (3HHB) can be metabolized. This reaction is catalyzed by a cytochrome P450, CYP2B1. [19] All 3HHB isomers formed can undergo further metabolism via glucuronidation or dehydrogenation.

If 3HHB undergoes a glucuronidation reaction, via UDP-glucuronosyl transferases (UGTs), it is readily excreted. 3HHB can also undergo dehydrogenation, forming a reactive ketone, 3'-oxohexobarbital (3OHB). The biotransformation of 3HHB into 3OHB is via the enzyme 3HHB dehydrogenase (3HBD), a NAD(P)+ linked oxidation. [20] This enzyme is part of the aldo-keto reductase (AKR) superfamily. In humans, 3HBD has a high preference for NAD+. [19] These reactions are also stereospecific, the R(-) conformation preferentially forms 3OHB as 3HBD has the highest activity for this enantiomer in both alpha and beta form. [21]

New evidence proved the further metabolism of 3OHB into 1,5-dimethylbarbituric acid and a cyclohexenone glutathione adduct. [19] This biotransformation step takes place via an epoxide-diol mechanism. [22] [23] The formation of a reactive epoxide, leads to the formation of the compounds mentioned.

Experiments in man indicated the major metabolites to be 3HHB, 3OHB and 1,5-dimethylbarbituric acid. [22]

Metabolic pathway of hexobarbital Metabolic pathway of hexobarbital.png
Metabolic pathway of hexobarbital

Health effects in man

Excretion

The plasma half-life of HB in man is estimated at 222±54 min. [22] The clearance of HB differs between the two enantiomers and the age of the human subject. The clearance of the R(-) enantiomer is almost 10-fold greater than the clearance of the S(+) enantiomer. Clearance on average in elderly people, compared to young subjects, is slower. [24] Excretion is mainly via urine, for the three major metabolites. [19] [22] The cyclohexenone glutathione adduct is excreted in the bile. [19]

Symptoms

An intoxication in man with hexobarbital can result in sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgment, drowsiness or coma, shallow breathing and staggering. In some severe cases coma and death can be the result of an overdose. [18]

Effects on animals

The following table presents the studies about the effects of hexobarbital on animals, which are done in the 1900s. Most of these studies showed that hexobarbital has short-term toxicity effects and that it can induce hypnotic effects in mice, rabbits and frogs.

Table 1: Effects of hexobarbital on animals [25]
OrganismTesttypeRouteDoseEffectReference
ratLD50intraperitoneal330 mg/kg (330 mg/kg) [26]
ratLDLosubcutaneous400 mg/kg (400 mg/kg) [27]
mouseLD50oral468 mg/kg (468 mg/kg)Prolongation of sleeping time [28]
mouseLD50intraperitoneal270 mg/kg (270 mg/kg)Prolongation of sleeping time and immobility time, which are potentiated by L-asparagine [29]
mouseLDLosubcutaneous250 mg/kg (250 mg/kg) [30]
mouseLD50intravenous133 mg/kg (133 mg/kg)Behavioural: somnolence (general depressed activity)Archives Internationales de Pharmacodynamie et de Therapie., 163(11), 1966
mouseLDLointrapleural340 mg/kg (340 mg/kg)Hypnotic effect, which is potentiated by 4,5-dihydro-6-methyl-2[2-(4-pyridyl)-ethyl]-3-pyridazinone (U-320) [31]
mouseLD50parenteral160 mg/kg (160 mg/kg)Pharmacology and Toxicology.  English translation of FATOAO., 20(569), 1957
rabbitLDLooral1200 mg/kg (1200 mg/kg)Ultra-short actors; hypnotic effect

Minimal lethal dose: 1200 mg/kg

Minimal hypnotic dose: 15 mg/kg

 [32]
rabbitLDLointravenous80 mg/kg (80 mg/kg)Ultra-short actors; hypnotic effect

Minimal lethal dose: 80 mg/kg

Minimal hypnotic dose: 15 mg/kg

 [32]
rabbitLDLorectal175 mg/kg (175 mg/kg)Ultra-short actors; hypnotic effect

Minimal lethal dose: 175 mg/kg

Minimal hypnotic dose: 15 mg/kg

 [32]
frogLDLointraperitoneal30 mg/kg (30 mg/kg) [33]
frogLD50parenteral148 mg/kg (148 mg/kg)Pharmacology and Toxicology.  English translation of FATOAO., 20(569), 1957

In Agatha Christie's 1937 mystery Cards on the Table , Hexobarbital is used in conjunction with Veronal to induce overdose. It is referred to by Hercule Poirot as both N-methyl-cyclo-hexenyl-methyl-malonyl urea and Evipan. [34]

Related Research Articles

<span class="mw-page-title-main">GABA</span> Main inhibitory neurotransmitter in the mammalian brain

GABA is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system.

<span class="mw-page-title-main">GABA receptor</span> Receptors that respond to gamma-aminobutyric acid

The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABAA and GABAB. GABAA receptors are ligand-gated ion channels ; whereas GABAB receptors are G protein-coupled receptors, also called metabotropic receptors.

<span class="mw-page-title-main">Muscimol</span> Neurotransmission inhibitor

Muscimol is one of the principal psychoactive constituents of Amanita muscaria and related species of mushroom. Muscimol is a potent and selective orthosteric agonist for the GABAA receptor and displays sedative-hypnotic, depressant and hallucinogenic psychoactivity. This colorless or white solid is classified as an isoxazole.

<span class="mw-page-title-main">CYP3A4</span> Enzyme that metabolizes substances by oxidation

Cytochrome P450 3A4 is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by CYP3A4 gene. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body. It is highly homologous to CYP3A5, another important CYP3A enzyme.

<span class="mw-page-title-main">Zopiclone</span> Hypnotic medication

Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine, specifically a cyclopyrrolone, used to treat difficulty sleeping. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases the normal transmission of the neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system, via modulating GABAA receptors similarly to the way benzodiazepine drugs do inducing sedation but not with the anti-anxiety properties of the benzodiazepines.

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

Picrotoxin, also known as cocculin, is a poisonous crystalline plant compound. It was first isolated by the French pharmacist and chemist Pierre François Guillaume Boullay (1777–1869) in 1812. The name "picrotoxin" is a combination of the Greek words "picros" (bitter) and "toxicon" (poison). A mixture of two different compounds, picrotoxin occurs naturally in the fruit of the Anamirta cocculus plant, although it can also be synthesized chemically.

GABA<sub>A</sub> receptor Ionotropic receptor and ligand-gated ion channel

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS). Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions and, to a lesser extent, bicarbonate ions.

The GABAA-rho receptor is a subclass of GABAA receptors composed entirely of rho (ρ) subunits. GABAA receptors including those of the ρ-subclass are ligand-gated ion channels responsible for mediating the effects of gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the brain. The GABAA-ρ receptor, like other GABAA receptors, is expressed in many areas of the brain, but in contrast to other GABAA receptors, the GABAA-ρ receptor has especially high expression in the retina.

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

Butabarbital is a prescription barbiturate sleep aid and anxiety medication. Butabarbital has a particularly fast onset of effects and short duration of action compared to other barbiturates, which makes it useful for certain applications such as treating severe insomnia, relieving general anxiety and relieving anxiety before surgical procedures; however it is also relatively dangerous particularly when combined with alcohol, and so is now rarely used, although it is still prescribed in some Eastern European and South American countries. Its intermediate duration of action gives butabarbital an abuse potential slightly lower than secobarbital. Butabarbital can be hydrolyzed to valnoctamide.

<span class="mw-page-title-main">Adinazolam</span> Triazolobenzodiazepine drug

Adinazolam is a tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring. It possesses anxiolytic, anticonvulsant, sedative, and antidepressant properties. Adinazolam was developed by Jackson B. Hester, who was seeking to enhance the antidepressant properties of alprazolam, which he also developed. Adinazolam was never FDA approved and never made available to the public market; however, it has been sold as a designer drug.

<span class="mw-page-title-main">CYP1A2</span> Enzyme in the human body

Cytochrome P450 1A2, a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the CYP1A2 gene.

<span class="mw-page-title-main">CYP2C9</span> Enzyme protein

Cytochrome P450 family 2 subfamily C member 9 is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the protein is encoded by the CYP2C9 gene. The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme.

<span class="mw-page-title-main">GABA receptor agonist</span> Category of drug

A GABA receptor agonist is a drug that is an agonist for one or more of the GABA receptors, producing typically sedative effects, and may also cause other effects such as anxiolytic, anticonvulsant, and muscle relaxant effects. There are three receptors of the gamma-aminobutyric acid. The two receptors GABA-α and GABA-ρ are ion channels that are permeable to chloride ions which reduces neuronal excitability. The GABA-β receptor belongs to the class of G-Protein coupled receptors that inhibit adenylyl cyclase, therefore leading to decreased cyclic adenosine monophosphate (cAMP). GABA-α and GABA-ρ receptors produce sedative and hypnotic effects and have anti-convulsion properties. GABA-β receptors also produce sedative effects. Furthermore, they lead to changes in gene transcription.

<span class="mw-page-title-main">TPA-023</span> Chemical compound

TPA-023 (MK-0777) is an anxiolytic drug with a novel chemical structure, which is used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. It is a mixed, subtype-selective ligand of the benzodiazepine site of α1, α2, α3, and α5-containing GABAA receptors, where it acts as a partial agonist at benzodiazepine sites of the α2 and α3-containing subtypes, but as a silent antagonist at α1 and α5-containing subtypes. It has primarily anxiolytic and anticonvulsant effects in animal tests, but with no sedative effects even at 50 times the effective anxiolytic dose.

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

Kavain is the main kavalactone found mostly in the roots of the kava plant.

<span class="mw-page-title-main">Barbiturate</span> Class of depressant drugs derived from barbituric acid

Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as well as overdose potential among other possible adverse effects. They have been used recreationally for their anti-anxiety and sedative effects, and are thus controlled in most countries due to the risks associated with such use.

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

Methysticin is one of the six major kavalactones found in the kava plant. Research suggests that methysticin and the related compound dihydromethysticin have CYP1A1 inducing effects which may be responsible for their toxicity. Additionally, methysticin has been shown to potentiate GABAA receptor activity, contributing to the overall anxiolytic profile of the kava plant.

Barbiturate dependence develops with regular use of barbiturates. This in turn may lead to a need for increasing doses of the drug to get the original desired pharmacological or therapeutic effect. Barbiturate use can lead to both addiction and physical dependence, and as such they have a high potential for excess or non-medical use, however, it does not affect all users. Management of barbiturate dependence involves considering the affected person's age, comorbidity and the pharmacological pathways of barbiturates.

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

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.

Ionotropic GABA receptors (iGABARs) are ligand-gated ion channel of the GABA receptors class which are activated by gamma-aminobutyric acid (GABA), and include:

References

  1. ↑ Lexikon der Neurowissenschaft: Hexobarbital (in German)
  2. ↑ Pubchem. "Hexobarbital | C12H16N2O3 - PubChem". pubchem.ncbi.nlm.nih.gov. Retrieved 2016-05-02.
  3. ↑ Tseilikman VE, Kozochkin DA, Manukhina EB, Downey HF, Tseilikman OB, Misharina ME, Nikitina AA, Komelkova MV, Lapshin MS, Kondashevskaya MV, Lazuko SS, Kusina OV, Sahabutdinov MV (April 2016). "Duration of hexobarbital-induced sleep and monoamine oxidase activities in rat brain: Focus on the behavioral activity and on the free-radical oxidation". General Physiology and Biophysics. 35 (2): 175–83. doi: 10.4149/gpb_2015039 . PMID   26689857.
  4. 1 2 3 Timmermann G, Czeizel AE, Bánhidy F, Acs N (2008-02-01). "A study of the teratogenic and fetotoxic effects of large doses of barbital, hexobarbital and butobarbital used for suicide attempts by pregnant women". Toxicology and Industrial Health. 24 (1–2): 109–19. Bibcode:2008ToxIH..24..109T. doi:10.1177/0748233708089004. PMID   18818187. S2CID   36948994.
  5. ↑ "FDA Pregnancy Categories - CHEMM". chemm.nlm.nih.gov. Archived from the original on 2021-08-27. Retrieved 2021-02-27.
  6. ↑ Komelkova M, Manukhina E, Downey HF, Sarapultsev A, Cherkasova O, Kotomtsev V, Platkovskiy P, Fedorov S, Sarapultsev P, Tseilikman O, Tseilikman D, Tseilikman V (August 2020). "Hexobarbital Sleep Test for Predicting the Susceptibility or Resistance to Experimental Posttraumatic Stress Disorder". International Journal of Molecular Sciences. 21 (16): 5900. doi: 10.3390/ijms21165900 . PMC   7460591 . PMID   32824478.
  7. ↑ Bornheim LM, Borys HK, Karler R (March 1981). "Effect of cannabidiol on cytochrome P-450 and hexobarbital sleep time". Biochemical Pharmacology. 30 (5): 503–7. doi:10.1016/0006-2952(81)90636-5. PMID   7225146.
  8. ↑ Schnell RC, Prosser TD, Miya TS (May 1974). "Cadmium-induced potentiation of hexobarbital sleep time in rats". Experientia. 30 (5): 528–9. doi:10.1007/BF01926332. PMID   4833683. S2CID   6402325.
  9. ↑ VCH Publishers (2002). Ullman's encyclopedia of industrial chemistry. Wiley-VCH. OCLC   50618230.
  10. ↑ US 2015376136,Chumakova L, Patron A, Priest C, Karanewsky D, Kimmich R, Clayton B, Jeffrey B, Hammaker R, Chumakov V, Zhao W, Noncovich A, Ung J,"Compounds useful as modulators of trpm8",published 31 December 2015,issued 12 December 2017, assigned to Senomyx Inc
  11. ↑ Heinemeyer G, Nigam S, Hildebrandt AG (November 1980). "Hexobarbital-binding, hydroxylation and hexobarbital-dependent hydrogen peroxide production in hepatic microsomes of guinea pig, rat and rabbit". Naunyn-Schmiedeberg's Archives of Pharmacology. 314 (2): 201–10. doi:10.1007/BF00504539. PMID   7453835. S2CID   37489777.
  12. ↑ Timbrell JA (2009). Principles of biochemical toxicology. Informa Healthcare. p. 181. ISBN   978-0-8493-7302-2. OCLC   243818515.
  13. ↑ Andrews PR, Mark LC (October 1982). "Structural specificity of barbiturates and related drugs". Anesthesiology. 57 (4): 314–20. doi: 10.1097/00000542-198210000-00014 . PMID   6751157.
  14. 1 2 Yamakura T, Bertaccini E, Trudell JR, Harris RA (2001-04-01). "Anesthetics and ion channels: molecular models and sites of action". Annual Review of Pharmacology and Toxicology. 41 (1): 23–51. doi:10.1146/annurev.pharmtox.41.1.23. PMID   11264449.
  15. ↑ Sigel E, Steinmann ME (November 2012). "Structure, function, and modulation of GABA(A) receptors". The Journal of Biological Chemistry. 287 (48): 40224–31. doi: 10.1074/jbc.R112.386664 . PMC   3504738 . PMID   23038269.
  16. ↑ Olsen RW, Sapp DM, Bureau MH, Turner DM, Kokka N (1991). "Allosteric actions of central nervous system depressants including anesthetics on subtypes of the inhibitory gamma-aminobutyric acidA receptor-chloride channel complex". Annals of the New York Academy of Sciences. 625: 145–54. doi:10.1111/j.1749-6632.1991.tb33838.x. PMID   1711804. S2CID   12448489.
  17. ↑ Löscher W, Rogawski MA (December 2012). "How theories evolved concerning the mechanism of action of barbiturates". Epilepsia. 53 Suppl 8 (s8): 12–25. doi: 10.1111/epi.12025 . PMID   23205959. S2CID   4675696.
  18. 1 2 "Hexobarbital". go.drugbank.com. Retrieved 2021-03-08.
  19. 1 2 3 4 5 Takenoshita R, Toki S (December 2004). "[New aspects of hexobarbital metabolism: stereoselective metabolism, new metabolic pathway via GSH conjugation, and 3-hydroxyhexobarbital dehydrogenases]". Yakugaku Zasshi. 124 (12): 857–71. doi: 10.1248/yakushi.124.857 . PMID   15577260.
  20. ↑ Endo S, Matsunaga T, Matsumoto A, Arai Y, Ohno S, El-Kabbani O, Tajima K, Bunai Y, Yamano S, Hara A, Kitade Y (November 2013). "Rabbit 3-hydroxyhexobarbital dehydrogenase is a NADPH-preferring reductase with broad substrate specificity for ketosteroids, prostaglandin D₂, and other endogenous and xenobiotic carbonyl compounds". Biochemical Pharmacology. 86 (9): 1366–75. doi:10.1016/j.bcp.2013.08.024. PMID   23994167.
  21. ↑ Furner RL, McCarthy JS, Stitzel RE, Anders MW (October 1969). "Stereoselective metabolism of the enantiomers of hexobarbital". The Journal of Pharmacology and Experimental Therapeutics. 169 (2): 153–8. PMID   5824599.
  22. 1 2 3 4 Vermeulen NP, Rietveld CT, Breimer DD (April 1983). "Disposition of hexobarbitone in healthy man: kinetics of parent drug and metabolites following oral administration". British Journal of Clinical Pharmacology. 15 (4): 459–64. doi:10.1111/j.1365-2125.1983.tb01530.x. PMC   1427803 . PMID   6849782.
  23. ↑ Takenoshita R, Nakamura T, Toki S (August 1993). "Hexobarbital metabolism: a new metabolic pathway to produce 1,5-dimethylbarbituric acid and cyclohexenone-glutathione adduct via 3'-oxohexobarbital". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 23 (8): 925–34. doi:10.3109/00498259309059419. PMID   8284947.
  24. ↑ Smith DA, Chandler MH, Shedlofsky SI, Wedlund PJ, Blouin RA (December 1991). "Age-dependent stereoselective increase in the oral clearance of hexobarbitone isomers caused by rifampicin". British Journal of Clinical Pharmacology. 32 (6): 735–9. doi:10.1111/j.1365-2125.1991.tb03982.x. PMC   1368555 . PMID   1768567.
  25. ↑ PubChem. "Hexobarbital". pubchem.ncbi.nlm.nih.gov. Retrieved 2021-03-07.
  26. ↑ Klinger W (March 1970). "[Toxicity, narcotic effect, blood level after awakening, elimination from the blood and biotransformation of hexobarbital in rats of different ages after induction with barbital and carbon tetrachloride poisoning]". Archives Internationales de Pharmacodynamie et de Therapie. 184 (1): 5–18. PMID   5448769.
  27. ↑ "Naunyn-Schmiedeberg's Archives of Pharmacology | Volumes and issues". SpringerLink. Retrieved 2021-03-09.
  28. ↑ Reinhard JF, Kimura ET, Scudi JV (December 1952). "Pharmacologic characteristics of 1-(ortho-toluoxy)2, 3-bis-(2, 2, 2-trichloro-1-hydroxyethoxy)-propane". The Journal of Pharmacology and Experimental Therapeutics. 106 (4): 444–52. PMID   13023555.
  29. ↑ Forney RB, Hughes FW, Richards AB, Gates PW (November 1963). "Toxicity and depressant action of ethanol and hexobarbital after pretreatment with asparagine". Toxicology and Applied Pharmacology. 5 (6): 790–3. Bibcode:1963ToxAP...5..790F. doi:10.1016/0041-008X(63)90071-1. PMID   14082484.
  30. ↑ Irrgang K (June 1965). "[On the pharmacology of 5-ethyl-5(3-hydroxyisoamyl)-barbituric acid--a breakdown product of 5-ethyl-5-isoamyl-barbituric acid]". Arzneimittel-Forschung. 15 (6): 688–91. PMID   5899249.
  31. ↑ Buller RH, Rockhold WT, Buzard JA, Stern IJ (1961-10-01). "The Potentiating Effect of 4,5-Dihydro-6-Methyl-2[2-(4-Pyridyl)-Ethyl]-3-Pyridazinone (u-320) on Hexobarbital Hypnosis". Journal of Pharmacology and Experimental Therapeutics. 134 (1): 95–99. ISSN   0022-3565.
  32. 1 2 3 Werner HW, Pratt TW, Tatum AL (1937-06-01). "A Comparative Study of Several Ultrashortacting Barbiturates, Nembutal, and Tribromethanol". Journal of Pharmacology and Experimental Therapeutics. 60 (2): 189–197. ISSN   0022-3565.
  33. ↑ Tatum AL (October 1939). "The present status of the barbiturate problem". Physiological Reviews. 19 (4): 472–502. doi:10.1152/physrev.1939.19.4.472.
  34. ↑ Christie A (1937). Cards on the Table. New York: William Morrow. p. 242. ISBN   978-0-06-207373-0.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.