Tranquilizing Agents
A traditional grouping of drugs said
to have a soothing or calming effect on mood, thought, or behavior. Included
here are the ANTI-ANXIETY AGENTS (minor tranquilizers), ANTIMANIC AGENTS, and
the ANTIPSYCHOTIC AGENTS (major tranquilizers). These drugs act by different
mechanisms and are used for different therapeutic purposes
Chloral
hydrate
Chloral hydrate is a sedative
and hypnotic
drug
as well as a chemical reagent and precursor. The name
chloral hydrate indicates that it is formed from chloral
(trichloroacetaldehyde) by the addition of one molecule of water. Its chemical
formula is C2H3Cl3O2.Chemistry
It was discovered through the chlorination of ethanol in 1832 by Justus von Liebig in Gießen.Its sedative properties were first published in 1869 and subsequently, because of its easy synthesis, its use was widespread.[4] It was widely used recreationally and misprescribed in the late 19th century. Chloral hydrate is soluble in both water and alcohol, readily forming concentrated solutions. A solution of chloral hydrate in alcohol called "knockout drops" was used to prepare a Mickey Finn .More reputable uses of chloral hydrate include its use as a clearing agent for chitin and fibers and as a key ingredient in Hoyer's mounting medium, which is used to prepare permanent or semipermanent microscope slides of small organisms, histological sections, and chromosome squashes.
It is, together with chloroform,
a minor side-product of the chlorination
of water when organic residues are present in the water, though concentrations
rarely exceed 5 micrograms per litre (µg/L).
Synthesis
Chloral hydrate is a starting point for the synthesis of more complex
chemicals. 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:
SAR
Chloral hydrate is produced from chlorine and ethanol in acidic solution. In basic conditions the haloform reaction takes place and chloroform is produced.
4 Cl2 + C2H5OH
+ H2O → Cl3CCH(OH)2 + 5 HCl
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 renal, cardiac and hepatic
failure. Physiochemical properties
Chloral hydrate exerts its pharmacological properties via enhancing the GABA receptor complex.[10] It is 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.
Properties
|
|
C2H3Cl3O2
|
|
165.40 g/mol
|
|
Appearance
|
Colorless solid
|
1.91 g/cm3
|
|
| 57 °C, 330 K, 135 °F | |
| 98 °C, 371 K, 208 °F | |
Acidity (pKa)
|
9.66, 11.0
|
References
2.
^ Justus Liebig (1832). "Ueber die Zersetzung des Alkohols
durch Chlor". Annalen der Pharmacie 1 (1): 31–32. doi:10.1002/jlac.18320010109.
3.
^ Justus Liebig (1832). "Ueber die Verbindungen, welche durch
die Einwirkung des Chlors auf Alkohol, Aether, ölbildendes Gas und Essiggeist
entstehen". Annalen der Pharmacie 1 (2): 182–230. doi:10.1002/jlac.18320010203.
4.
^ Liebreich, Oskar (1869). Das Chloralhydrat : ein neues
Hypnoticum und Anaestheticum und dessen Anwendung in der Medicin ; eine
Arzneimittel-Untersuchung. Berlin: Müller.
6.
^ Tariq, Syed H. and Shailaja Pulisetty; “Pharmacotherapy
for Insomnia”, Clinics in Geriatric Medicine (24), 2008 p. 93-105 PMID 18035234
9.
^ R. Baselt, Disposition of Toxic Drugs and Chemicals in
Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp.
259–261.
10. ^ Lu, J; Greco, MA (2006). "Sleep circuitry and the hypnotic
mechanism of GABAA drugs.". Journal of Clinical Sleep Medicine 2
(2): S19–26. PMID 17557503.
Methocarbamol
2-hydroxy-3-(2-methoxyphenoxy)propyl
carbamate
Methocarbamol is a central muscle relaxant used to treat skeletal muscle spasms. It is the carbamate of guaifenesin, but does not produce guaifenesin
as a metabolite, since the carbamate bond is not hydrolyzed metabolically;
metabolism is by Phase I ring hydroxylation and O-demethylation, followed by
Phase II conjugation. All the major metabolites are unhydrolyzed carbamates.
Chemistry
Methocarbamol,
3-(2-methoxyphenoxy)-1,2-propanediol-1 carbamate, is synthesized by successive
reaction with phosgene
and then ammonia into 3-(2-methoxyphenoxy)propane-1,2-diol.
Synthesis
Physiochemical properties
Potential side-effects include:
drowsiness, dizziness, upset stomach, flushing, blurred vision, and fever.
Serious side-effects include the development of a severe skin rash or itching,
slow heart rate, fainting, jaundice, persistent nausea/vomiting, stomach/abdominal
pain, mental/mood changes, clumsiness, trouble urinating, signs of infection.
In addition, methocarbamol may cause urine to turn black, blue, or green.
However, this effect is harmless.
Molecular
Formula:
C11-H15-N-O5
C11-H15-N-O5
Molecular
Weight:
241.24
Color/Form:
Crystals from benzene
Melting Point:
92-94 deg C
Octanol/Water Partition Coefficient:
log Kow = 0.61
Solubilities:
Sol in alcohol, propylene glycol
In water, 7.20X10+3 mg/L at 25 deg C
Spectral Properties:
UV max (water): 222, 274 nm (E 1% 1 cm 298, 94)
Vapor Pressure:
3.41X10-7 mm Hg at 25 deg C (est)
Other Chemical/Physical Properties:
Henry's Law constant = 6.53X10-16 atm-cu m/mole at 25 deg C (est)
Hydroxyl radical reaction rate constant = 4.51X10-11 cu cm/molec-sec at 25 deg C (est)
241.24
Color/Form:
Crystals from benzene
Melting Point:
92-94 deg C
Octanol/Water Partition Coefficient:
log Kow = 0.61
Solubilities:
Sol in alcohol, propylene glycol
In water, 7.20X10+3 mg/L at 25 deg C
Spectral Properties:
UV max (water): 222, 274 nm (E 1% 1 cm 298, 94)
Vapor Pressure:
3.41X10-7 mm Hg at 25 deg C (est)
Other Chemical/Physical Properties:
Henry's Law constant = 6.53X10-16 atm-cu m/mole at 25 deg C (est)
Hydroxyl radical reaction rate constant = 4.51X10-11 cu cm/molec-sec at 25 deg C (est)
References
1.
^ Sica DA,
Comstock TJ, Davis J, Manning L, Powell R, Melikian A, Wright G. (1990).
"Pharmacokinetics and protein binding of methocarbamol in renal
insufficiency and normals". European Journal of
Clinical Pharmacology 39 (2): 193–4. doi:10.1007/BF00280060. PMID 2253675.
2.
^
Methocarbamol. In: DRUGDEX System [intranet database]. Greenwood
Village, Colorado: Thomson Healthcare; c1974–2009 [cited 2009 Feb 10].
3.
^ Bruce RB,
Turnbull LB, Newman JH. (1971 Jan). "Metabolism of methocarbamol in the
rat, dog, and human". J Pharm Sci 60 (1): 104–106. doi:10.1002/jps.2600600120. PMID 5548215.
4.
^ "New
Drugs and Indications Reviewed at the May 2003 DEC Meeting" (PDF). ESI Canada. Retrieved 2008-11-14.
6.
^ "Subjective and
behavioral effects of diphenhydramine, lorazepam and methocarbamol: evaluation
of abuse liability". Journal
of Pharmacology and Experimental Therapeutics. Retrieved 2011-05-06.
7.
^ METHOCARBAMOL
– ORAL (Robaxin) side effects, medical uses, and drug interactions. Medicinenet.com. Retrieved on 2011-11-09.
Meprobamate
Meprobamate
(marketed under the brand names Miltown
by Wallace Laboratories, Equanil
by Wyeth, and Meprospan) is a carbamate
derivative which is used as an anxiolytic
drug.
Chemistry
Meprobamate, 2-methyl-2-propyl-1,3-propandiol
dicarbamate is synthesized by the reaction of 2-methylvaleraldehyde with two
molecules of formaldehyde and the subsequent transformation of
the resulting 2-methyl-2-propylpropan-1,3-diol into the dicarbamate
via successive reactions with phosgene
and ammonia.
Synthesis
A number of mono- and dicarbamate esters of 2,2-disubstituted
1,3-propanediols have been prepared for evaluation as anticonvulsants. The
dicarbamate esters were synthesized by phosgenation of the substituted
propanediols followed by amidization of the bis-(chlorocarbonate) derivatives.
The monocarbamate esters were obtained by ammonolysis of the cyclic carbonates
prepared from the substituted propanediols.The anticonvulsant properties of 2,2-disubstituted 1,3-propanediols, a class of compounds bearing little sructural relationships with the accepted anticonvulsants, have recently described. Pharmacological studies on 2,2-diethyl-1,3-propanediol, one of the more active members of this series, indicated that this compound had a powerful but short anticonvulsant action. It was also found that the actions of certain esters was of longer duration than resulting from the diol itself. In an extension to this study, a number of mono- and dicarbamate esters of 2,2-disubstituted 1,3-propanediols have been prepared for pharmacological evaluation as potential anticonvulsant agents. This paper describes the synthesis and physical properties of these compounds. The results of the pharmacological studies carried out on these compounds will be described elsewhere.
Of the variety of procedures which have appeared in the litterature for the preparation of carbamates, we found the method described by Oesper, Broker and Cook most suitable for the conversion of dihydric alcohols to the corresponding dicarbamate derivatives. This method consists of low temperature phosgenation of the substituted 1,3-propanediol in an intert medium in the presence of a tertiary amine, followed by conversion of the bis-(chlorocarbonate) derivative to the desired diamide. In our experience antipyrine gave consistently higher over-all yields of pure carbamates than the other tertiary amines used in the acylation reaction. Although the substituted 1,3-propanediol bis-(chlorocarbonate) derivatives could be readily isolated an purified by distillation, it was advantageous to convert them directly to the diamide by direct ammoniation of the phosgene reaction mixture.
Monocarbamate derivatives of 1,3-propanediols could be prepared in a similar manner, using an equimolar ratio of phosgene and diol, but this reaction yielded, in addition to the desired monocarbamate derivative, a considerable amount of unreacted diol and appreciable quantities of the dicarbamate and cyclic carbamate derivatives. The difficulty of separating these products could be avoided by forming the monocarbamates through ammonolysis of the cyclic carbonate esters.
The latter compounds were prepared by the reaction of equimolar quantities of phosgene and propanediol in the presence of antipyrin at a temperature somewhat higher than that found most suitable for chlorocarbonate formation.
The carbamate and carbonate esters prepared in this study were white crystalline solids or high boiling liquids. Except for the lower members of the monocarbamate series, which possess considerable water solubility, these compounds are relatively insoluble in water.
Preparation of 2,2-disubstituted 1,3-propanediols
2,2-dimethyl-, diethyl-, methyl-n-propyl-, and ethyl-n-butyl-1,3-propanediol were prepared by the conensation of formaldehyde with isobutyraldehyde. 2-ethylbutyraldehyde, 2-methylvaleraldehyde and 2-ethylhexylaldehyde, respectively, following the procedure of [JACS 70, 946 (1948)]. The remaining 1,3-propanediols were obtained by reduction of the corresponding substituted malonic esters with lithium aluminum hydride.Preparation of 2,2-disubstituted 1,3-propanediol dicarbamates
The following procedure illustrates the method that was adopted for the preparation of the dicarbamates listed in Table 1. To a solution of 20g (0.2 mole) of phosgene in 200 ml of toluene at -10°C there was added with stirring a cooled solution of 13.2 grams (0.1 mole) of 2,2-diethyl-1,3- propanediol, and 38 g (0.2 mole) of antipyrine in 100 ml of chloroform, at such a rate that the temperature of the reaction mixture was maintained at -5°C to 0°C. The mixture was allowed to warm slowly to room temperature and to remain at this temperature overnight. The antipyrine hydrochloride was removed by filtration, and the chlorocarbonate was converted directly to the amide by treating the filtrate with gaseous ammonia with moderate cooling. The amide was separated by filtration, freed from ammonium chloride by extracting with 250 ml of cold water and recryztallized from hot water; 17.5 g. (80%) of 2,2-diethyl-1,3-propanediol dicarbamate, mp 149-150°C was obtained.
The dicarbamate esters of 1,3-propanediols
substituted with higher alkyl groups sometimes remained in solution following
treatment with ammonia. In these cases, the amide was obtained by evaporation
of the toluene-chloroform solvent under reduced pressure. All of the
dicarbamates prepared was crystallized from water, and over-all yields of
60-90% purified compounds were obtained
SAR
Physiochemical
properties
218.250 g/mol
|
|
1.229 g/cm³
|
|
105-106 °C (-54 °F)
|
|
200-210 °C (-146 °F)
|
|
References
1.
^ Tone, Andrea (2009). "The Fashionable Pill". The
Age of Anxiety: A History of America's Turbulent Affair with Tranquilizers.
New York: Basic Books. ISBN 978-0-465-08658-0.
3.
^ Ludwig BJ, Piech E. (1951). "Some anticonvulsant agents
derived from 1, 3-propanediol.". J Am Chem Soc. 73 (12):
5779–5781. doi:10.1021/ja01156a086.
5.
^ Author unknown (1956-04-01). "ALCOHOLIC PERIL FOUND IN DRUGS;
Some Tranquilizing Therapy May Be Habit-Forming, Physicians Tell Parley".
New York Times. p. 28. Retrieved
2009-01-23.
7.
^ Carey, Benedict (2008-03-21). "Frank Berger, 94, Miltown
Creator, Dies - New York Times". New York Times.
Retrieved 2009-02-01.
8.
^ "'BEHAVIOR' DRUGS NOW
ENVISIONED; Aldous Huxley Predicts They Will Bring Re-Examining of Ethics and
Religion". New York Times. 1956-10-19.
Retrieved 2009-02-01.
9.
^ Ranzal, Edward (1960-01-28). "TRUST SUIT NAMES 2 DRUG
CONCERNS; Makers of Tranquilizers Are Accused".
New York Times. Retrieved
2009-02-01.
10. ^ "MILTOWN OFF LIST OF
TRANQUILIZERS; But It Will Continue to Be Used as a Sedative".
New York Times. 1965-04-22. Retrieved
2009-02-01.
Deserpidine
Deserpidine is an ester alkaloid drug isolated from
Rauwolfia canescens (family Apocynaceae) with antipsychotic and antihypertensive
properties that has been used for the control of high blood pressure and for
the relief of psychotic behavior.
Chemistry
The epimerization at C3 of reserpine and deserpidine
catalysed by acetic acid has been studied. 3-Deuterio-isoreserpine epimerizes
without loss of label. Reserpine and isoreserpine methosalts do not epimerize
at C3 in acetic acid. 3-Deuterio-isodeserpidine dedeuterates faster than it
epimerizes. It is concluded that epimerization in these alkaloids involves
initial C2 protonation according to Scheme II.
SAR
Interactions
Target : Synaptic vesicular amine transporter
Action : inhibitor
General Function : Carbohydrate transport and metabolism
Specific Function : Involved in the ATP-dependent vesicular transport of biogenic amine neurotransmitters. Pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles. Requisite for vesicular amine storage prior to secretion via exocytosis
Target : Synaptic vesicular amine transporter
Action : inhibitor
General Function : Carbohydrate transport and metabolism
Specific Function : Involved in the ATP-dependent vesicular transport of biogenic amine neurotransmitters. Pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles. Requisite for vesicular amine storage prior to secretion via exocytosis
Synthesis
Methyl deserpidate (0.5 g, 1.30
mmol) was dissolved under nitrogen in dry pyridine (4.0 ml).
3,4,5-Trimethoxybenzoyl chloride (0.5 g, 2.17 mmol) was dissolved in benzene (2
ml), then dropped slowly in the reaction mixture. The reaction was kept under
stirring for 5 days at 5° C. and then quenched with 50 ml of water. This
solution was added with a mixture of concentrated NH3 (2 ml) in 10 ml of H2O.
The solution was then extracted with CH2Cl2 (3×25 ml) and the organic phase was
dried and filtered. The solvent was evaporated under vacuum and the resulting
residue was recrystallized from acetone, to afford 0.168 g (0.440 mmol, 91%)
ofthe desired product.
Physiochemical
Properties
Molecular Weight
|
578.65272 [g/mol]
|
|
Molecular Formula
|
C32H38N2O8
|
|
XLogP3
|
4.1
|
|
H-Bond Donor
|
1
|
|
H-Bond Acceptor
|
9
|
|
Rotatable Bond Count
|
9
|
|
Exact Mass
|
578.262816
|
|
MonoIsotopic Mass
|
578.262816
|
|
Topological Polar Surface Area
|
109
|
|
Heavy Atom Count
|
42
|
|
Formal Charge
|
0
|
|
Complexity
|
953
|
|
Isotope Atom Count
|
0
|
|
Defined Atom Stereocenter Count
|
6
|
|
Undefined Atom Stereocenter Count
|
0
|
|
Defined Bond Stereocenter Count
|
0
|
|
Undefined Bond Stereocenter Count
|
0
|
|
Covalently-Bonded Unit Count
|
1
|
|
Feature 3D Acceptor Count
|
6
|
|
Feature 3D Donor Count
|
1
|
|
Feature 3D Cation Count
|
2
|
|
Feature 3D Ring Count
|
6
|
|
Effective Rotor Count
|
10.6
|
|
Conformer Sampling RMSD
|
1.2
|
|
CID Conformer Count
|
References
1.
^ a
b Benkert, Otto; Hippius, Hanns (2006) (in German). Kompendium
Der Psychiatrischen Pharmakotherapie (6th ed.). Springer. ISBN 978-3-540-34401-8.
2.
^ "Portions of the Pfizer Inc.
2010 Financial Report". Sec.gov (edgar
archives). Retrieved 2011-11-06.
3.
^ Crofford, Leslie J., Rowbotham, Michael C., Mease, Philip J. et
al (April 2005). "Pregabalin for the treatment of
fibromyalgia syndrome: results of a randomized, double-blind,
placebo-controlled trial". Arthritis
& Rheumatism 52 (4):
1264–1273. doi:10.1002/art.20983. PMID 15818684. Retrieved
2011-11-06.
4.
^ Siddall, Philip J.; Cousins, M.J.; Otte, A. et al (2006). "Pregabalin in central neuropathic pain associated
with spinal cord injury: a placebo-controlled trial".
Neurology 67 (10):
1792–1800. doi:10.1212/01.wnl.0000244422.45278.ff.
PMID 17130411. Retrieved
2011-11-06.
5.
^ "FDA Approves First Drug for
Treating Fibromyalgia" (Press
release). U.S. Food and Drug Administration. 2007=06-21.
Retrieved 2011-11-06.
6.
^ Drug Enforcement Administration, Department of Justice (July
2005). "Schedules of controlled
substances: placement of pregabalin into schedule V. Final rule".
Federal register 70
(144): 43633–5. PMID 16050051. Retrieved
2012-01-22.
8.
^ a
b "Lyrica (Pregabalin) Drug Information: Dosage, Side
Effects, Drug Interactions and User Reviews".
Rxlist.com. 2011-06-10. Retrieved
2011-11-06.
9.
^ "Pregabalin Oral Solution - IPCOM000187748D - IP.com".
Priorartdatabase.com. 2009-09-17. Retrieved
2012-01-22.
10^ Fulton, S. C.; Healy, M. D. (1976). "Comparison of the
effectiveness of deserpidine, reserpine, and alpha-methyltyrosine on brain
biogenic amines". Federation proceedings 35 (14): 2558–2562.
Rescinnamine
Chemistry
Rescinnamine is an angiotensin-converting
enzyme inhibitor used as an antihypertensive drug.It
is an alkaloid obtained from Rauwolfia serpentina[1] and other species of Rauwolfia. Rescinnamine
produced the typical pharmacological effects of R. serpentina: bradycardia,
hypotension, sedation and characteristic alterations in cardiovascular
responses. It caused augmentation of the pressor response to epinephrine,
reversal of the pressor response to hypoxia, diminution of the pressor response
to bilateral carotid occlusion, and blockade or reversal of the primary blood
pressure rise elicited by faradization of the afferent vagus. The sedative
effects of rescinnamine were demonstrated by gross observation in dogs, rats
and mice, and by prolongation of pentobarbital induced sleeping time in mice.
Rescinnamine produced marked eyelid ptosis in mice and a copious nasal
discharge in rats. On a wt. basis, it appeared to be several times as potent as
Rauwiloid and similar to reserpine. Rescinnamine is the second highly potent
alkaloid derived from R. serpentina.
SAR
Two redox processes can be4 observed for rescinnamine by cyclic voltammetry. The electroactive group is
identified as the 3,4,5-trimethoxycinnamic. A mechanism including a homogenous
dimerization reacyion following the electron transfer is proposed for the redoz
process which occurs at less negative potentials, and the rate constant for the
homogenous reactions is calculated. Differential pulse voltammetry is proved to
be a suitable method for quantitative determination of the alkaloid.
Physiochemical
properties
Color/Form
- Fine needles from benzene
- WHITE, OR PALE BUFF TO CREAM-COLORED CRYSTALLINE POWDER
Solubilities
Practically insol in water; moderately sol in methanol, benzene, chloroform, and other organic solvents
Practically insol in water; moderately sol in methanol, benzene, chloroform, and other organic solvents
- Specific optical rotation: -97 deg @ 24 deg C/D (c= 1 in chloroform); UV max absorption (methanol): 228, 302 nm (log e= 4.79, 4.48)
- UV: 2-551 (Organic Electronic Spectral Data, Phillips et al, John Wiley & Sons, New York)
634.71598 [g/mol]
|
||
Molecular Formula
|
C35H42N2O9
|
|
XLogP3-AA
|
4.5
|
|
H-Bond Donor
|
1
|
|
H-Bond Acceptor
|
10
|
|
Rotatable Bond Count
|
11
|
|
Exact Mass
|
634.289031
|
|
MonoIsotopic Mass
|
634.289031
|
|
Topological Polar Surface Area
|
118
|
|
Heavy Atom Count
|
46
|
|
Formal Charge
|
0
|
|
Complexity
|
1080
|
|
Isotope Atom Count
|
0
|
|
Defined Atom Stereocenter Count
|
6
|
|
Undefined Atom Stereocenter Count
|
0
|
|
Defined Bond Stereocenter Count
|
1
|
|
Undefined Bond Stereocenter Count
|
0
|
|
Covalently-Bonded Unit Count
|
1
|
|
Feature 3D Acceptor Count
|
7
|
|
Feature 3D Donor Count
|
1
|
|
Feature 3D Cation Count
|
2
|
|
Feature 3D Ring Count
|
6
|
|
Effective Rotor Count
|
12.6
|
|
Conformer Sampling RMSD
|
1.2
|
|
CID Conformer Count
|
References
a.
^ FIFE R, MACLAURIN JC, WRIGHT JH (December 1960). "Rescinnamine
in treatment of hypertension in hospital clinic and in general practice". British Medical Journal 2 (5216): 1848–50. doi:10.1136/bmj.2.5216.1848. PMC 2098607. PMID 13699407.
b.
^ Owen, Richard T. (September 2007). "Pregabalin: its efficacy,
safety and tolerability profile in generalized anxiety".
Drugs of Today 43 (9): 601–10. doi:10.1358/dot.2007.43.9.1133188.
PMID 17940637. Retrieved
2012-01-22.
c.
^ Simpson, David M.; Schifitto, G.; Clifford, D.B. et al (February
2010). "Pregabalin for painful HIV
neuropathy: a randomized, double-blind, placebo-controlled trial".
Neurology 74 (5): 413–420. doi:10.1212/WNL.0b013e3181ccc6ef.
PMC 2816006.
PMID 20124207.
d.
^ a
b Pfizer Australia Pty Ltd. Lyrica (Australian Approved
Product Information). West Ryde: Pfizer; 2006.
e.
^ Rossi, Simone, ed. (2006). Australian Medicines Handbook,
2006. Australian Medicines Handbook. ISBN 978-0-9757919-2-9.
f.
^ "Medication Guide (Pfizer
Inc.)" (PDF). U.S. Food and Drug Administration.
June 2011. Retrieved 2011-11-06.
g.
^ Murphy, N.G.; Mosher, L. (2008). "Severe myoclonus from
pregabalin (Lyrica) due to chronic renal insufficiency". Clinical
Toxicology 46: 594.
h.
^ Yoo, Lawrence; Matalon, Daniel; Hoffman, Robert S.; Goldfarb,
David S. (2009). "Treatment of pregabalin toxicity by hemodialysis in a
patient with kidney failure". American Journal of Kidney Diseases 54
(6): 1127–30. doi:10.1053/j.ajkd.2009.04.014.
PMID 19493601.
i.
^ Baselt, Randall C. (2008). Disposition of Toxic Drugs and
Chemicals in Man (8th edition ed.). Biomedical Publications.
pp. 1296–1297. ISBN 978-0-9626523-7-0.
j.
^ Micheva KD, Taylor CP, Smith SJ (April 2006). "Pregabalin Reduces the Release
of Synaptic Vesicles from Cultured Hippocampal Neurons".
Molecular Pharmacology 70 (2): 467-476. PMID 16641316.
k.
^ a
b
c
d "Summary of product
characteristics". European Medicines Agency. 19
August 2009. Retrieved 8
September 2009.[dead link]
l.
^ McElroy, Susan L.; Keck, Paul E.; Post, Robert M., eds. (2008). Antiepileptic
Drugs to Treat Psychiatric Disorders. INFRMA-HC. p. 370. ISBN 978-0-8493-8259-8.
n.
^ Chalabianloo, F; Schjøtt J (January 2009). "Pregabalin and its potential
for abuse". Journal of the Norwegian Medical
Association 129 (3): 186–187. doi:10.4045/tidsskr.08.0047. PMID 19180163.[dead link]
