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Chemistry

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Also known as: Peganone, 86-35-1, 3-ethyl-5-phenylimidazolidine-2,4-dione, Accenon, 3-ethyl-5-phenylhydantoin, Ethotoine
Molecular Formula
C11H12N2O2
Molecular Weight
204.22  g/mol
InChI Key
SZQIFWWUIBRPBZ-UHFFFAOYSA-N
FDA UNII
46QG38NC4U

Ethotoin
Ethotoin is a hydantoin anticonvulsant with anti-epileptic activity. The mechanism of action is not completely known, but is thought to be fairly similar to phenytoin. Ethotoin influences synaptic transmission by altering sodium and calcium ion influx across neuronal membranes in the repolarization, depolarization, and membrane stability phase and interferes with the calcium uptake in presynaptic terminals. This inhibits neuronal firing and results in the stabilization of neuronal membranes, thereby preventing the spread of seizure activity at the motor cortex.
Ethotoin is an Anti-epileptic Agent. The physiologic effect of ethotoin is by means of Decreased Central Nervous System Disorganized Electrical Activity.
1 2D Structure

Ethotoin

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
3-ethyl-5-phenylimidazolidine-2,4-dione
2.1.2 InChI
InChI=1S/C11H12N2O2/c1-2-13-10(14)9(12-11(13)15)8-6-4-3-5-7-8/h3-7,9H,2H2,1H3,(H,12,15)
2.1.3 InChI Key
SZQIFWWUIBRPBZ-UHFFFAOYSA-N
2.1.4 Canonical SMILES
CCN1C(=O)C(NC1=O)C2=CC=CC=C2
2.2 Other Identifiers
2.2.1 UNII
46QG38NC4U
2.3 Synonyms
2.3.1 MeSH Synonyms

1. Peganone

2.3.2 Depositor-Supplied Synonyms

1. Peganone

2. 86-35-1

3. 3-ethyl-5-phenylimidazolidine-2,4-dione

4. Accenon

5. 3-ethyl-5-phenylhydantoin

6. Ethotoine

7. Ethotoinum

8. Etotoina

9. Ethotoine [inn-french]

10. Ethotoinum [inn-latin]

11. Etotoina [inn-spanish]

12. 3-ethyl-5-phenylimidazolidin-2,4-dione

13. 1-ethyl-2,5-dioxo-4-phenylimidazolidine

14. 3-ethyl-5-phenyl-2,4-imidazolidinedione

15. 2,4-imidazolidinedione, 3-ethyl-5-phenyl-

16. Hydantoin, 3-ethyl-5-phenyl-

17. (+-)-3-ethyl-5-phenylhydantoin

18. Ac-695; Accenon

19. Nsc-760074

20. 3-ethyl-5-phenyl-imidazolidine-2,4-dione

21. Ethotoin (200 Mg)

22. 46qg38nc4u

23. Chebi:4888

24. (+/-)-3-ethyl-5-phenylhydantoin

25. Mfcd00072127

26. Pegoanone

27. Peganone (tn)

28. Accenon (tn)

29. Hsdb 3580

30. Einecs 201-665-1

31. Ethotoin (jan/usp/inn)

32. Brn 0188272

33. Unii-46qg38nc4u

34. Ethotoin [usp:inn:ban:jan]

35. Cas-86-35-1

36. Ncgc00016340-01

37. Ethotoin [hsdb]

38. Ethotoin [inn]

39. Ethotoin [jan]

40. Ethotoin [mi]

41. Ethotoin [vandf]

42. (.+/-.)-ethotoin

43. Prestwick0_000696

44. Prestwick1_000696

45. Prestwick2_000696

46. Prestwick3_000696

47. Dsstox_cid_3020

48. Ethotoin [mart.]

49. Ethotoin [usp-rs]

50. Ethotoin [who-dd]

51. Chembl1095

52. Dsstox_rid_76833

53. Dsstox_gsid_23020

54. Oprea1_374844

55. Schembl34301

56. Bspbio_000851

57. 5-24-08-00005 (beilstein Handbook Reference)

58. Mls002153961

59. Spbio_002772

60. Ethotoin [orange Book]

61. 2,4-imidazolidinedione, 3-ethyl-5-phenyl-, (+-)-

62. Bpbio1_000937

63. Gtpl7183

64. Dtxsid6023020

65. Ethotoin [usp Monograph]

66. Hms1570k13

67. Hms2097k13

68. Hms2232m06

69. Hms3371o03

70. Hms3714k13

71. Hms3887i05

72. Pharmakon1600-01505428

73. Hy-b1642

74. Tox21_110383

75. Nsc760074

76. Akos008947805

77. Ccg-213433

78. Db00754

79. Nsc 760074

80. Ncgc00179401-01

81. Ncgc00179401-03

82. Ns-02146

83. Smr001233300

84. 3-ethyl-5-phenyl-2,4-imidazolidinedione #

85. Ab00513897

86. Cs-0013593

87. C07839

88. D00708

89. Ab00513897_07

90. Sr-01000841832

91. Q4533122

92. Sr-01000841832-2

93. Z53845223

94. 1-ethyl-2-hydroxy-4-phenyl-4,5-dihydro-1h-imidazol-5-one

95. 2,4-imidazolidinedione, 3-ethyl-5-phenyl-, (+/-)-

2.4 Create Date
2005-03-25
3 Chemical and Physical Properties
Molecular Weight 204.22 g/mol
Molecular Formula C11H12N2O2
XLogP31
Hydrogen Bond Donor Count1
Hydrogen Bond Acceptor Count2
Rotatable Bond Count2
Exact Mass204.089877630 g/mol
Monoisotopic Mass204.089877630 g/mol
Topological Polar Surface Area49.4 Ų
Heavy Atom Count15
Formal Charge0
Complexity272
Isotope Atom Count0
Defined Atom Stereocenter Count0
Undefined Atom Stereocenter Count1
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Information
1 of 2  
Drug NamePeganone
PubMed HealthEthotoin (By mouth)
Drug ClassesAnticonvulsant
Drug LabelPEGANONE (ethotoin tablets, USP) is an oral antiepileptic of the hydantoin series and is chemically identified as 3-ethyl-5-phenyl-2,4-imidazolidinedione. It is represented by the following structural formula:PEGANONE tablets are available in a dosag...
Active IngredientEthotoin
Dosage FormTablet
RouteOral
Strength250mg
Market StatusPrescription
CompanyRecordati Rare

2 of 2  
Drug NamePeganone
PubMed HealthEthotoin (By mouth)
Drug ClassesAnticonvulsant
Drug LabelPEGANONE (ethotoin tablets, USP) is an oral antiepileptic of the hydantoin series and is chemically identified as 3-ethyl-5-phenyl-2,4-imidazolidinedione. It is represented by the following structural formula:PEGANONE tablets are available in a dosag...
Active IngredientEthotoin
Dosage FormTablet
RouteOral
Strength250mg
Market StatusPrescription
CompanyRecordati Rare

4.2 Therapeutic Uses

Anticonvulsants

National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)


Hydantoin anticonvulsants are indicated in the suppression and control of tonic-clonic (grand mal) and simple or complex partial (psychomotor or temporal lobe) seizures. Ethotoin may be administered as a second-line agent when seizures have not been adequately controlled by the primary anticonvulsants and before proceeding to more toxic anticonvulsants. /Hydantoin anticonvulsants; Included in US product labeling./

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 259


Hydantoin anticonvulsants are not indicated in the treatment of absence (petit mal) seizures, or as first-line treatment of febrile, hypoglycemic, or other metabolic seizures. When tonic-clonic (grand mal) seizures coexist with absence seizures, combined therapy may be necessary. /Hydantoin anticonvulsants; NOT included in US product label/

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 259


Ethotoin may be substituted for phenytoin without loss of seizure control for improvement of gum hyperplasia, or other side effects, during anticonvulsant therapy. Ethotoin doses are usually 4 to 6 times greater than those of phenytoin. /NOT included in US product label/

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 267


4.3 Drug Warning

Ethotoin is contraindicated in patients with hepatic abnormalities or hematologic disorders.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2212


Although the etiologic role of ethotoin has not been definitely established, blood dyscrasias have been reported in patients receiving the drug, and clinicians should be alert to the possibility of their occurrence. Patients should be advised to report immediately any sign or symptom indicative of hematologic toxicity (e.g., sore throat, fever, malaise, petechiae, easy bruising, epistaxis). Complete blood cell counts should be performed before and at monthly intervals for several months after initiation of ethotoin therapy. The drug should be discontinued if marked depression of blood cell count occurs.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2212


Liver function tests should be performed in patients receiving ethotoin if there is clinical evidence of possible hepatic dysfunction. If signs of hepatotoxicity occur during ethotoin therapy, the drug should be discontinued.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2212


Ataxia and gingival hyperplasia have been reported only rarely during ethotoin therapy and usually only in patients receiving an additional hydantoin derivative. When ethotoin has replaced other hydantoin-derivative anticonvulsants, both of these reactions have subsided in some patients.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2212


For more Drug Warnings (Complete) data for ETHOTOIN (16 total), please visit the HSDB record page.


4.4 Drug Indication

For the control of tonic-clonic (grand mal) and complex partial (psychomotor) seizures.


5 Pharmacology and Biochemistry
5.1 Pharmacology

Ethotoin is a hydantoin derivative and anticonvulsant. Ethotoin exerts an antiepileptic effect without causing general central nervous system depression. The mechanism of action is probably very similar to that of phenytoin. The latter drug appears to stabilize rather than to raise the normal seizure threshold, and to prevent the spread of seizure activity rather than to abolish the primary focus of seizure discharges.


5.2 MeSH Pharmacological Classification

Voltage-Gated Sodium Channel Blockers

A class of drugs that inhibit the activation of VOLTAGE-GATED SODIUM CHANNELS. (See all compounds classified as Voltage-Gated Sodium Channel Blockers.)


Anticonvulsants

Drugs used to prevent SEIZURES or reduce their severity. (See all compounds classified as Anticonvulsants.)


5.3 FDA Pharmacological Classification
5.3.1 Active Moiety
ETHOTOIN
5.3.2 FDA UNII
46QG38NC4U
5.3.3 Pharmacological Classes
Decreased Central Nervous System Disorganized Electrical Activity [PE]; Anti-epileptic Agent [EPC]
5.4 ATC Code

N - Nervous system

N03 - Antiepileptics

N03A - Antiepileptics

N03AB - Hydantoin derivatives

N03AB01 - Ethotoin


5.5 Absorption, Distribution and Excretion

Absorption

Fairly rapidly absorbed, however, the extent of oral absorption is not known.


Ethotoin is fairly rapidly absorbed from the GI tract following oral administration; the extent of absorption is not known.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2212


Therapeutic serum concentrations range from 15 to 50 ug/mL (74 to 245 umol/L) for ethotoin.

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 260


Ethotoin and phenytoin are distributed into breast milk...

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 261


Limited data suggest that ethotoin and, to a lesser degree, 5-phenylhydantoin (the N-deethylated metabolite) may exhibit nonlinear pharmacokinetics following oral administration of single 500-, 1000-, and 1500-mg doses of ethotoin. The degree of nonlinearity may increase following oral administration of multiple doses (with a dosing interval of 4-6 hours) of ethotoin when compared with single doses, probably secondary to accumulation of the drug in plasma.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2213


For more Absorption, Distribution and Excretion (Complete) data for ETHOTOIN (9 total), please visit the HSDB record page.


5.6 Metabolism/Metabolites

Hepatic. The drug exhibits saturable metabolism with respect to the formation of N-deethyl and p-hydroxyl-ethotoin, the major metabolites.


Ethotoin is metabolized by the liver to p-hydroxylated and m-hydoxylated derivatives following N-deethylation; these metabolites are conjugated with glucuronic acid. The N-deethylated metabolite may also be metabolized to 2-phenylhydantoic acid. Ethotoin appears to exhibit saturable metabolism with respect to the formation of the p-hydroxylated and N-deethylated metabolites.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2212


The rate of hepatic biotransformation is increased in younger children, in pregnant women, in women during menses, and in patients with acute trauma; rate decreases with advancing age. /Hydantoin anticonvulsants/

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 260


The urinary excretion pattern of ethotoin and five metabolites were examined in three patients receiving continuous treatment with ethotoin at two dose levels, in order to investigate the mechanism behind the dose-dependent kinetics of this anticonvulsant drug. The results suggest a partial saturation in the dealkylation process at high dose levels in three patients. A rough approximation of the Michaelis-Menten constants for different enzymatic processes was attempted. On the basis of the results obtained, the p-hydroxylation may be a saturable process. The dose-dependent kinetics of ethotoin in man seem to be explicable by the existence of partly saturable enzymatic pathways.

PMID:10117 Naestoft J et al; Clin Exp Pharmacol Physiol 3 (5): 453-9 (1976)


5.7 Biological Half-Life

3 to 9 hours


At plasma concentrations less than about 8 ug/mL, ethotoin reportedly has an elimination half-life of 3-9 hours.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2213


Ethotoin administration was 25 mg per kilogram in 5 patients. Ethotoin Tmax was 2 hours, with a T 1/2 of 5 hours. Saliva accurately represented the unbound fraction for ... /ethotoin/. Mean salivary levels (as percentage of total levels) were ... 54% for ethotoin.

PMID:42344 Troupin A et al; Ann Neurol 6 (5): 410-4 (1979)


5.8 Mechanism of Action

The mechanism of action is probably very similar to that of phenytoin. The latter drug appears to stabilize rather than to raise the normal seizure threshold, and to prevent the spread of seizure activity rather than to abolish the primary focus of seizure discharges. Ethotoin inhibits nerve impulses in the motor cortex by lowering sodium ion influx, limiting tetanic stimulation.


The mechanism of action is not completely known, but it is thought to involve stabilization of neuronal membranes at the cell body, axon, and synapse and limitation of the spread of neuronal or seizure activity. ... Hydantoin anticonvulsants have an excitatory effect on the cerebellum, activating inhibitory pathways that extend to the cerebral cortex. This effect may also produce a reduction in seizure activity that is associated with an increased cerebellar Purkinje cell discharge. /Hydantoin anticonvulsants/

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 259


FDA Orange Book

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ETHOTOIN

Brand Name : PEGANONE

Dosage Form : TABLET;ORAL

Dosage Strength : 250MG

Approval Date : 1982-01-01

Application Number : 10841

RX/OTC/DISCN : DISCN

RLD : Yes

TE Code :

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02

DDL Conference
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DDL Conference
Not Confirmed

ETHOTOIN

Brand Name : PEGANONE

Dosage Form : TABLET;ORAL

Dosage Strength : 500MG

Approval Date : 1982-01-01

Application Number : 10841

RX/OTC/DISCN : DISCN

RLD : No

TE Code :

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