Chloral hydrate

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Chloral hydrate
Chloral hydrate.svg
Chloral hydrate ball-and-stick model.png
   Carbon, C
   Chlorine, Cl
   Oxygen, O
   Hydrogen, H
Chloralhydrat by Danny S. - 001.JPG
Names
Preferred IUPAC name
2,2,2-Trichloroethane-1,1-diol
Other names
  • Trichloroacetaldehyde monohydrate
  • Chlorali hydras
  • Tradenames:
  • Aquachloral
  • Chloradorm
  • Chloratol [1]
  • Noctec
  • Novo-Chlorhydrate
  • Somnos
  • Somnote
Identifiers
3D model (JSmol)
1698497
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.005.562 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 206-117-5
101369
KEGG
PubChem CID
RTECS number
  • FM875000
UNII
UN number 2811
  • InChI=1S/C2H3Cl3O2/c3-2(4,5)1(6)7/h1,6-7H Yes check.svgY
    Key: RNFNDJAIBTYOQL-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C2H3Cl3O2/c3-2(4,5)1(6)7/h1,6-7H
    Key: RNFNDJAIBTYOQL-UHFFFAOYAY
  • ClC(Cl)(Cl)C(O)O
Properties [2]
CCl3CH(OH)2
Molar mass 165.39 g·mol−1
AppearanceColorless solid
Odor Aromatic, slightly acrid
Density 1.9081 g/cm3
Melting point 57 °C (135 °F; 330 K)
Boiling point 98 °C (208 °F; 371 K) (decomposes)
660 g/(100 ml)
Solubility Very soluble in benzene, ethyl ether, ethanol
log P 0.99
Acidity (pKa)9.66, 11.0 [3]
Structure
Monoclinic
Pharmacology
N05CC01 ( WHO )
Oral syrup, rectal suppository
Pharmacokinetics:
Well absorbed
Hepatic and renal (converted to trichloroethanol)
8–10 hours
Bile, feces, urine (various metabolites not unchanged)
Legal status
Hazards
GHS labelling:
GHS-pictogram-skull.svg GHS-pictogram-exclam.svg
Danger
H301, H315, H319
P264, P270, P280, P301+P310, P302+P352, P305+P351+P338, P321, P330, P332+P313, P337+P313, P362, P405, P501
Lethal dose or concentration (LD, LC):
1100 mg/kg (oral)
Safety data sheet (SDS) External MSDS [ dead link ‍]
Related compounds
Related compounds
 Chloral, chlorobutanol, Triclofos
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Chloral hydrate is a geminal diol with the formula Cl 3 C−CH(OH)2. It was first used as a sedative and hypnotic in Germany in the 1870s. Over time it was replaced by safer and more effective alternatives but it remained in usage in the United States until at least the 1970s. [4] It sometimes finds usage as a laboratory chemical reagent and precursor. It is derived from chloral (trichloroacetaldehyde) by the addition of one equivalent of water.

Uses

Hypnotic

Chloral hydrate has not been approved by the FDA in the United States nor the EMA in the European Union for any medical indication and is on the FDA list of unapproved drugs that are still prescribed by clinicians. [5] Usage of the drug as a sedative or hypnotic may carry some risk given the lack of clinical trials. However, chloral hydrate products, licensed for short-term management of severe insomnia, are available in the United Kingdom. [6] Chloral hydrate was voluntarily removed from the market by all manufacturers in the United States in 2012.[ citation needed ] Prior to that, chloral hydrate may have been sold as a "legacy" or "grandfathered" drug; that is, a drug that existed prior to the time certain FDA regulations took effect and therefore, some pharmaceutical companies have argued, has never required FDA approval. New drugs did not have to be approved for safety until Congress passed the Federal Food, Drug, and Cosmetic Act (the "FD&C Act") in 1938. Further, a new drug did not have to be proven effective until 1962, when Congress amended the Act. Manufacturers contend that such "legacy drugs", by virtue of the fact that they have been prescribed for decades, have gained a history of safety and efficacy.

Chloral hydrate was used for the short-term treatment of insomnia and as a sedative before minor medical or dental treatment. It was largely displaced in the mid-20th century by barbiturates [7] and subsequently by benzodiazepines. It was also formerly used in veterinary medicine as a general anesthetic but is not considered acceptable for anesthesia or euthanasia of small animals due to adverse effects. [8] It is also still used as a sedative prior to EEG procedures, as it is one of the few available sedatives that does not suppress epileptiform discharges. [9]

In therapeutic doses for insomnia, chloral hydrate is effective within 20 to 60 minutes. [10] In humans it is metabolized within 7 hours into trichloroethanol and trichloroethanol glucuronide by erythrocytes and plasma esterases and into trichloroacetic acid in 4 to 5 days. [11] It has a very narrow therapeutic window making this drug difficult to use. Higher doses can depress respiration and blood pressure. Tolerance to the drug develops after a few days of use. [4]

In organic synthesis

Chloral hydrate is a starting point for the synthesis of other organic compounds. It is the starting material for the production of chloral, which is produced by the distillation of a mixture of chloral hydrate and sulfuric acid, which serves as the desiccant.

Notably, it is used to synthesize isatin. In this synthesis, chloral hydrate reacts with aniline and hydroxylamine to give a condensation product which cyclicizes in sulfuric acid to give the target compound: [12]

Synthesis of isatin.svg

Moreover, chloral hydrate is used as a reagent for the deprotection of acetals, dithioacetals and tetrahydropyranyl ethers in organic solvents. [13]

The compound can be crystallized in a variety of polymorphs. [14]

Botany and mycology

Hoyer's mounting medium

Chloral hydrate is also an ingredient used for Hoyer's solution, a mounting medium for microscopic observation of diverse plant types such as bryophytes, ferns, seeds, and small arthropods (especially mites). Other ingredients may include gum arabic and glycerol. An advantage of this medium includes a high refractive index and clearing (macerating) properties of small specimens (especially advantageous if specimens require observation with differential interference contrast microscopy).[ citation needed ]

Because of its status as a regulated substance, chloral hydrate can be difficult to obtain. This has led to chloral hydrate being replaced by alternative reagents [15] [16] in microscopy procedures.

Melzer's reagent

Chloral hydrate is an ingredient used to make Melzer's reagent, an aqueous solution that is used to identify certain species of fungi. The other ingredients are potassium iodide, and iodine. Whether tissue or spores react to this reagent is vital for the correct identification of some mushrooms.

Safety

Chloral hydrate was routinely administered in gram quantities. Prolonged exposure to its vapors is unhealthy, with an LD50 for 4-hour exposure of 440 mg/m3. Long-term use of chloral hydrate is associated with a rapid development of tolerance to its effects and possible addiction as well as adverse effects including rashes, gastric discomfort and severe kidney, heart, and liver failure. [17]

Acute overdosage is often characterized by nausea, vomiting, confusion, convulsions, slow and irregular breathing, cardiac arrhythmia, and coma. The plasma, serum or blood concentrations of chloral hydrate and/or trichloroethanol, its major active metabolite, may be measured to confirm a diagnosis of poisoning in hospitalized patients or to aid in the forensic investigation of fatalities. Accidental overdosage of young children undergoing simple dental or surgical procedures has occurred. Hemodialysis has been used successfully to accelerate clearance of the drug in poisoning victims. [18] It is listed as having a "conditional risk" of causing torsades de pointes. [19]

Production

Chloral hydrate is produced from chlorine and ethanol in acidic solution.

4 Cl2 + CH3CH2OH + H2O → Cl3C−CH(OH)2 + 5 HCl

In basic conditions the haloform reaction takes place and chloral hydrate is decomposed by hydrolysis to form chloroform. [20]

Pharmacology

Pharmacodynamics

Chloral hydrate is metabolized in vivo to trichloroethanol, which is responsible for secondary physiological and psychological effects. [21] The metabolite of chloral hydrate exerts its pharmacological properties via enhancing the GABA receptor complex [22] and therefore is similar in action to benzodiazepines, nonbenzodiazepines and barbiturates. It can be moderately addictive, as chronic use is known to cause dependency and withdrawal symptoms. The chemical can potentiate various anticoagulants and is weakly mutagenic in vitro and in vivo.[ citation needed ]

Chloral hydrate inhibits liver alcohol dehydrogenase in vitro. This could be an explanation of the synergeric effect seen with alcohol. [23]

Chloral hydrate is structurally and somewhat pharmacodynamically similar to ethchlorvynol, a pharmaceutical developed during the 1950s that was marketed as both a sedative and a hypnotic under the trade name Placidyl. In 1999, Abbott, the sole manufacturer of the drug in the United States at the time, decided to discontinue the product. After Abbott ceased production, the drug remained available for about a year. Despite the fact that it could have been manufactured generically, no other company in the United States chose to do so.

Pharmacokinetics

Chloral hydrate is metabolized to both 2,2,2-Trichloroethanol (TCE) and 2,2,2-Trichloroacetic acid (TCA) by alcohol dehydrogenase. TCE is further converted to its glucoronide. 2,2-Dichloroacetatic acid (DCA) has been detected as a metabolite in children, but how it gets made is unknown. [24] TCE glucoronide, TCA, and a very small amount of free TCE are excreted in urine in male human adults. This study did not detect significant amounts of DCA; the authors noted that DCA can form during inappropriate sample preparation. Both TCA and DCA cause liver tumors in mice. [25]

TCA is cleared by the kidneys at a rate slower than the expected filtration rate, suggesting that efficient reabsorption of filtered-out TCA happens. [25]

In the United States, chloral hydrate is a schedule IV controlled substance and requires a physician's prescription. Its properties have sometimes led to its use as a date rape drug. [26] [27] The phrase, "slipping a mickey," originally referred specifically to adding chloral hydrate to a person's (alcoholic) drink without the person's knowledge.[ citation needed ]

History

Chloral hydrate was first synthesized by the chemist Justus von Liebig in 1832 at the University of Giessen. Liebig discovered the molecule when a chlorination (halogenation) reaction was performed on ethanol. [28] [29] [30] Its sedative properties were observed by Rudolf Buchheim in 1861, but described in detail and published only in 1869 by Oscar Liebreich; [31] subsequently, because of its easy synthesis, its use became widespread. [32] Through experimentation, physiologist Claude Bernard clarified that the chloral hydrate was hypnotic as opposed to an analgesic. [33] It was the first of a long line of sedatives, most notably the barbiturates, manufactured and marketed by the German pharmaceutical industry. [30] Historically, chloral hydrate was utilized primarily as a psychiatric medication. In 1869, German physician and pharmacologist Oscar Liebreich began to promote its use to calm anxiety, especially when it caused insomnia. [34] [33] Chloral hydrate had certain advantages over morphine for this application, as it worked quickly without injection and had a consistent strength.[ citation needed ]

The compound achieved wide use in both asylums and the homes of those socially refined enough to avoid asylums. Upper- and middle-class women, well-represented in the latter category, were particularly susceptible to chloral hydrate addiction. After the 1904 invention of barbital, the first of the barbiturate family, chloral hydrate began to disappear from use among those with means. [30] It remained common in asylums and hospitals until the Second World War as it was quite cheap. Chloral hydrate had some other important advantages that kept it in use for five decades despite the existence of more advanced barbiturates. It was the safest available sedative until the middle of the twentieth century, and thus was particularly favored for children. [33] It also left patients much more refreshed after a deep sleep than more recently invented sedatives. Its frequency of use made it an early and regular feature in The Merck Manual . [35]

Chloral hydrate was also a significant object of study in various early pharmacological experiments. In 1875, Claude Bernard tried to determine if chloral hydrate exerted its action through a metabolic conversion to chloroform. This was not only the first attempt to determine whether different drugs were converted to the same metabolite in the body but also the first to measure the concentration of a particular pharmaceutical in the blood. The results were inconclusive. [36] In 1899 and 1901 Hans Horst Meyer and Ernest Overton respectively made the major discovery that the general anaesthetic action of a drug was strongly correlated to its lipid solubility. However, chloral hydrate was quite polar but nonetheless a potent hypnotic. Overton was unable to explain this mystery. Thus, chloral hydrate remained one of the major and persistent exceptions to this breakthrough discovery in pharmacology. This anomaly was eventually resolved in 1948, when Claude Bernard's experiment was repeated. While chloral hydrate was converted to a different metabolite than chloroform, it was found that it was converted into the more lipophilic molecule 2,2,2-trichloroethanol. This metabolite fit much better with the Meyer–Overton correlation than chloral had. Prior to this, it had not been demonstrated that general anesthetics could undergo chemical changes to exert their action in the body. [37]

Chloral hydrate was the first hypnotic to be used intravenously as a general anesthetic. In 1871, Pierre-Cyprien Oré began experiments on animals, followed by humans. While a state of general anesthesia could be achieved, the technique never caught on because its administration was more complex and less safe than the oral administration of chloral hydrate, and less safe for intravenous use than later general anesthetics were found to be. [38]

Society and culture

Chloral hydrate was used as one of the earliest synthetic drugs to treat insomnia. In 1912, Bayer introduced the drug phenobarbital under the brand name Luminal. In the 1930s, pentobarbital and secobarbital (better known by their original brand names Nembutal and Seconal, respectively) were synthesized. Chloral hydrate was still prescribed, although its predominance as a sedative and a hypnotic was largely eclipsed by barbiturates.

Chloral hydrate is soluble in both water and ethanol, readily forming concentrated solutions. A solution of chloral hydrate in ethanol called "knockout drops" was used to prepare a Mickey Finn. [39]

In 1897, Bram Stoker's epistolary novel Dracula , one of its characters, Doctor John Seward, recorded his use and his molecular formula in his phonographic diary:

I cannot but think of Lucy, and how different things might have been. If I don't sleep at once, chloral, the modern Morpheus — C2HCl3O·H2O! I should be careful not to let it grow into a habit. No I shall take none to-night! I have thought of Lucy, and I shall not dishonor her by mixing the two. [40]

In the conclusion of Edith Wharton's 1905 novel The House of Mirth , Lily Bart, the novel's heroine, becomes addicted to chloral hydrate and overdoses on the substance:

She put out her hand and measured the soothing drops into a glass; but as she did so, she knew they would be powerless against the supernatural lucidity of her brain. She had long since raised the dose to its highest limit, but to-night she felt she must increase it. She knew she took a slight risk in doing so; she remembered the chemist's warning. If sleep came at all, it might be a sleep without waking. [41]

In the James Bond films From Russia With Love and The Living Daylights , chloral hydrate is used as a knockout drug. [42]

Notable users

Environmental

It is, together with chloroform, a minor side-product of the chlorination of water when organic residues such as humic acids are present. It has been detected in drinking water at concentrations of up to 100 micrograms per litre (μg/L) but concentrations are normally found to be below 10 μg/L. Levels are generally found to be higher in surface water than in ground water. [58]

See also

Related Research Articles

<span class="mw-page-title-main">Hypnotic</span> Drug whose use induces sleep

Hypnotic, or soporific drugs, commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to induce sleep and to treat insomnia (sleeplessness).

Chloroform, or trichloromethane, is an organochloride with the formula CHCl3 and a common solvent. It is a volatile, colorless, sweet-smelling, dense liquid produced on a large scale as a precursor to refrigerants and PTFE. Chloroform was once used as an inhalational anesthetic between the 19th century and the first half of the 20th century. It is miscible with many solvents but it is only very slightly soluble in water.

<span class="mw-page-title-main">Sedative</span> Drug that reduces excitement without inducing sleep

A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but the majority of them affect the neurotransmitter gamma-aminobutyric acid (GABA). In spite of the fact that each sedative acts in its own way, most produce relaxing effects by increasing GABA activity.

<span class="mw-page-title-main">Trichloroethylene</span> C2HCl3, widely used industrial solvent

Trichloroethylene (TCE) is a halocarbon with the formula C2HCl3, commonly used as an industrial metal degreasing solvent. It is a clear, colourless, non-flammable, volatile liquid with a chloroform-like pleasant mild smell and sweet taste. Its IUPAC name is trichloroethene. Trichloroethylene has been sold under a variety of trade names. Industrial abbreviations include TCE, trichlor, Trike, Tricky and tri. Under the trade names Trimar and Trilene, it was used as a volatile anesthetic and as an inhaled obstetrical analgesic. It should not be confused with the similar 1,1,1-trichloroethane, which was commonly known as chlorothene.

Depressants, colloquially known as "downers" or central nervous system (CNS) depressants, are drugs that lower neurotransmission levels, decrease the electrical activity of brain cells, or reduce arousal or stimulation in various areas of the brain. Some specific depressants do influence mood, either positively or negatively, but depressants often have no clear impact on mood. In contrast, stimulants, or "uppers", increase mental alertness, making stimulants the opposite drug class from depressants. Antidepressants are defined by their effect on mood, not on general brain activity, so they form an orthogonal category of drugs.

<span class="mw-page-title-main">Triazolam</span> Triazolobenzodiazepine class medication

Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives. It possesses pharmacological properties similar to those of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia. In addition to the hypnotic properties, triazolam's amnesic, anxiolytic, sedative, anticonvulsant, and muscle relaxant properties are pronounced as well.

<span class="mw-page-title-main">Hydroxyzine</span> Antihistamine drug

Hydroxyzine, sold under the brand names Atarax and Vistaril among others, is an antihistamine medication. It is used in the treatment of itchiness, anxiety, insomnia, and nausea. It is used either by mouth or injection into a muscle.

<span class="mw-page-title-main">Diethyl ether</span> Organic chemical compound

Diethyl ether, or simply ether, is an organic compound with the chemical formula (CH3CH2)2O, sometimes abbreviated as Et2O. It is a colourless, highly volatile, sweet-smelling, extremely flammable liquid. It belongs to the ether class of organic compounds. It is a common solvent. It was formerly used as a general anesthetic.

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

Flurazepam is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It produces a metabolite with a long half-life, which may stay in the bloodstream for days. Flurazepam was patented in 1968 and came into medical use the same year. Flurazepam, developed by Roche Pharmaceuticals, was one of the first benzodiazepine hypnotic medications to be marketed.

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

Chloralose is an avicide, and a rodenticide used to kill mice in temperatures below 15 °C. It is also widely used in neuroscience and veterinary medicine as an anesthetic and sedative. Either alone or in combination, such as with urethane, it is used for long-lasting, but light anesthesia.

<span class="mw-page-title-main">Zaleplon</span> Medication used to treat insomnia

Zaleplon, sold under the brand name Sonata among others, is a sedative and hypnotic which is used to treat insomnia. It is a nonbenzodiazepine or Z-drug of the pyrazolopyrimidine class. It was developed by King Pharmaceuticals and approved for medical use in the United States in 1999.

<span class="mw-page-title-main">Ventrolateral preoptic nucleus</span> Nucleus of the anterior hypothalamus

The ventrolateral preoptic nucleus (VLPO), also known as the intermediate nucleus of the preoptic area (IPA), is a small cluster of neurons situated in the anterior hypothalamus, sitting just above and to the side of the optic chiasm in the brain of humans and other animals. The brain's sleep-promoting nuclei, together with the ascending arousal system which includes components in the brainstem, hypothalamus and basal forebrain, are the interconnected neural systems which control states of arousal, sleep, and transitions between these two states. The VLPO is active during sleep, particularly during non-rapid eye movement sleep, and releases inhibitory neurotransmitters, mainly GABA and galanin, which inhibit neurons of the ascending arousal system that are involved in wakefulness and arousal. The VLPO is in turn innervated by neurons from several components of the ascending arousal system. The VLPO is activated by the endogenous sleep-promoting substances adenosine and prostaglandin D2. The VLPO is inhibited during wakefulness by the arousal-inducing neurotransmitters norepinephrine and acetylcholine. The role of the VLPO in sleep and wakefulness, and its association with sleep disorders – particularly insomnia and narcolepsy – is a growing area of neuroscience research.

Chloral, also known as trichloroacetaldehyde or trichloroethanal, is the organic compound with the formula Cl3CCHO. This aldehyde is a colourless liquid that is soluble in a wide range of solvents. It reacts with water to form chloral hydrate, a once widely used sedative and hypnotic substance.

2,2,2-Trichloroethanol is the chemical compound with formula Cl3C−CH2OH. Its molecule can be described as that of ethanol, with the three hydrogen atoms at position 2 replaced by chlorine atoms. It is a clear flammable liquid at room temperature, colorless when pure but often with a light yellow color.

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

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. Modern barbiturates have largely supplanted the use of hexobarbital as an anesthetic, as they allow for better control of the depth of anesthesia. Hexobarbital is still used in some scientific research.

Chlorobutanol (trichloro-2-methyl-2-propanol) is an organic compound with the formula CCl3C(OH)(CH3)2. The compound is an example of a chlorohydrin. The compound is a preservative, sedative, hypnotic and weak local anesthetic similar in nature to chloral hydrate. It has antibacterial and antifungal properties. Chlorobutanol is typically used at a concentration of 0.5% where it lends long term stability to multi-ingredient formulations. However, it retains antimicrobial activity at 0.05% in water. Chlorobutanol has been used in anesthesia and euthanasia of invertebrates and fishes. It is a white, volatile solid with a camphor-like odor.

<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 similar effects. Furthermore, they lead to changes in gene transcription, and are mainly found in autonomic nervous system centers.

<i>tert</i>-Amyl alcohol Chemical compound

tert-Amyl alcohol (TAA) or 2-methylbutan-2-ol (2M2B), is a branched pentanol.

<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">Tribromoethanol</span> Chemical compound

2,2,2-Tribromoethanol, often called just tribromoethanol, is a chemical compound with formula Br3C−CH2OH. Its molecule can be described as that of ethanol, with the three hydrogen atoms in position 2 replaced by bromine. It is a white crystalline solid, soluble in water and other solvents, that absorbs strongly in the UV below 290 nm.

References

Notes

  1. ↑ Vardanyan, R.S.; Hruby, V.J. (2006). "Soporific Agents (Hypnotics and Sedative Drugs)". Synthesis of Essential Drugs. pp. 57–68. doi:10.1016/B978-044452166-8/50004-2. ISBN   978-0-444-52166-8.
  2. ↑ Lide, D. R., ed. (2005). CRC Handbook of Chemistry and Physics (85th ed.). CRC Press. pp. 3–98. ISBN   978-0-8493-0484-2.
  3. ↑ Gawron, O.; Draus, F. (1958). "Kinetic Evidence for Reaction of Chloralate Ion with p-Nitrophenyl Acetate in Aqueous Solution". Journal of the American Chemical Society. 80 (20): 5392–5394. doi:10.1021/ja01553a018.
  4. 1 2 Kales, Anthony (1 September 1970). "Hypnotic Drugs and Their Effectiveness: All-night EEG Studies of Insomniac Subjects". Archives of General Psychiatry. 23 (3): 226–232. doi:10.1001/archpsyc.1970.01750030034006. PMID   4318151.
  5. ↑ Meadows, Michelle (January–February 2007). "The FDA Takes Action Against Unapproved Drugs". FDA Consumer Magazine. 41 (1): 34–5. PMID   17342837. S2CID   37097870.
  6. ↑ "EMC Search: chloral hydrate". Electronic Medicines Compendium. Archived from the original on 7 March 2018. Retrieved 6 March 2018.
  7. ↑ Tariq, Syed H.; Pulisetty, Shailaja (2008). "Pharmacotherapy for Insomnia". Clinics in Geriatric Medicine. 24 (1): 93–105. doi:10.1016/j.cger.2007.08.009. PMID   18035234.
  8. ↑ Baxter, Mark G.; Murphy, Kathy L.; Taylor, Polly M.; Wolfensohn, Sarah E. (July 2009). "Chloral Hydrate Is Not Acceptable for Anesthesia or Euthanasia of Small Animals". Anesthesiology. 111 (1): 209–210. doi: 10.1097/aln.0b013e3181a8617e . ISSN   0003-3022. PMID   19546703.
  9. ↑ Mohammed M.S. Jan, MBChB, FRCP (C); Marilou F. Aquino, EEG Tech. "The use of chloral hydrate in pediatric electroencephalography" (PDF). Jcc.kau.edu.sa. Archived from the original (PDF) on 18 August 2011. Retrieved 15 November 2018.{{cite web}}: CS1 maint: multiple names: authors list (link)
  10. ↑ Gauillard, J.; Cheref, S.; Vacherontrystram, M. N.; J. C., Martin (May–June 2002). "Chloral hydrate: a hypnotic best forgotten?". Encephale. 28 (3 Pt 1): 200–204. PMID   12091779.
  11. ↑ Beland, Frederick A. "NTP Technical Report on the Toxicity and Metabolism Studies of Chloral Hydrate" (PDF). Toxicity Report Series Number 59. National Toxicology Program. p. 10. Archived (PDF) from the original on 23 October 2011. Retrieved 14 March 2013.
  12. ↑ Marvel, C. S.; Hiers, G. S. (1941). "Isatin". Organic Syntheses ; Collected Volumes, vol. 1, p. 327.
  13. ↑ Chandrasekhar, S.; Shrinidhi, A. (2014). "Chloral Hydrate as a Water Carrier for the Efficient Deprotection of Acetals, Dithioacetals, and Tetrahydropyranyl Ethers in Organic Solvents". Synthetic Communications. 44 (13): 1904–1913. doi:10.1080/00397911.2013.876652. S2CID   94886591. Archived from the original on 20 February 2022. Retrieved 11 December 2021.
  14. ↑ o' Nolan, Daniel; Perry, Miranda L.; Zaworotko, Michael J. (2016). "Chloral Hydrate Polymorphs and Cocrystal Revisited: Solving Two Pharmaceutical Cold Cases". Crystal Growth & Design. 16 (4): 2211–2217. doi:10.1021/acs.cgd.6b00032.
  15. ↑ Villani, Thomas S.; Koroch, Adolfina R.; Simon, James E. (2013). "An Improved Clearing and Mounting Solution to Replace Chloral Hydrate in Microscopic Applications". Applications in Plant Sciences. 1 (5): 1300016. doi:10.3732/apps.1300016. PMC   4105042 . PMID   25202549.
  16. ↑ Li, J.; Pan, L.; Naman, C. B.; Deng, Y.; Chai, H.; Keller, W. J.; Kinghorn, A. D. (2014). "Pyrrole Alkaloids with Potential Cancer Chemopreventive Activity Isolated from a Goji Berry-Contaminated Commercial Sample of African Mango". Journal of Agricultural and Food Chemistry. 62 (22): 5054–5060. doi:10.1021/jf500802x. PMC   4047925 . PMID   24792835.
  17. ↑ Gelder, M.; Mayou, R.; Geddes, J. (2005). Psychiatry (3rd ed.). New York: Oxford. p. 238.
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