Phenacemide

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Antiepileptics

Log Kow = 0.87

0.8

0.66

CRYSTALS FROM ALCOHOL

WHITE TO PRACTICALLY WHITE, FINE, CRYSTALLINE POWDER

WHITE TO CREAMY WHITE CRYSTALLINE SOLID

VERY SLIGHTLY SOL IN WATER; SLIGHTLY SOL IN ALC, BENZENE, CHLOROFORM, ETHER

SLIGHTLY SOL IN ACETONE

1.06e+00 g/L

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

212-216 °C

215 °C

148.19 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

128.3 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 39 reports by companies from 1 notifications to the ECHA C&L Inventory.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

Troupin AS; Drug Saf 14: 299-328 (1996). Dose related adverse effects of anticonvulsants.

Badalian LO, et al; Zh Nevropatol Psikhiatr Im S S Korsakova 93 (1): 90-3 (1993). Epilepsy and pregnancy a review.

Dostert P, Benedetti MS; Encephale 10 (5): 199-209 (1984). The first part of this article presents the mechanisms for the hepatotoxicity of xenobiotics known to date, in particular the interference with the metabolism of bilirubin, hepatotoxicity arising from the metabolism of drugs as well as hepatotoxicity due to immunological factors. In the second part, the classification of the diverse hepatic diseases due to drugs is presented: acute injury (cytotoxic, cholestatic, mixed) and chronic damage. The extrahepatic manifestations of drug induced hepatic injury are also mentioned. Finally, in the third part, ... the principal cases of hepatotoxicity caused by psychotropic drugs /is presented/: antidepressants (MAOIs and tricyclics), neuroleptics, phenothiazines, thioxanthenes, butyrophenones and benzamides) and anxiolytics, and ... the anticonvulsants (phenytoin, phenacemide, oxazolidinediones, carbamazepine and valproic acid). ...

Concurrent use of alcohol or CNS depression-producing medications with phenacemide may enhance CNS depression.

There is a risk of additive toxicity when other anticonvulsants (especially ethotoin) are used concurrently with phenacemide. Concurrent use of ethotoin with phenacemide has been reported to cause paranoid symptoms. Extreme caution is recommended during concurrent use of phenacemide with other anticonvulsants.

Overdosage of phenacemide produces excitement or mania followed by drowsiness, ataxia, and coma which has persisted for nearly 24 hours.

Clinical effects of overdose /of phenacemide/ include excitement or mania (unusual nervousness or irritability), ataxia (clumsiness or unsteadiness), and severe drowsiness.

OBJECTIVE: To report two cases of incr true serum creatinine (Scr) without renal failure caused by an anticonvulsant drug, phenacemide, and to discuss the possible mechanisms. CASE SUMMARY: Two patients treated with phenacemide were investigated for markedly incr Scr and decr creatinine clearance (Clcr) values. Glomerular filtration rates, as determined by (125)I-iothlalamate clearance, were normal in both patients and analytical interferences with the Jaffe reaction were excluded. After discontinuation of the drug, phenacemide concn became undetectable within 2 days but it took 7-14 days for Scr and Clcr to return to normal values. DISCUSSION: The Scr increase with phenacemide (120-170 percent) was higher than that reported with cimetidine or trimethoprim (10-40%) and could not be explained solely by inhibition of the tubular secretion of creatinine. The hypothesis of an overproduction of creatinine caused by phenacemide was ruled out by experimental studies in rats. Creatinine incr in tissues was lower than that in the serum of rats given phenacemide. In vitro creatinine influx into red blood cells was inhibited in a dose dependent way by phenacemide. CONCLUSIONS: Incr Scr concn in these patients could be related to an inhibition of transport and a decr in creatinine volume of distribution. Creatinine concn should not be considered when dosage adjustments of renally eliminated drugs are being calculated for patients with such metabolic interferences.

Three adolescent patients with severe seizure disorders were treated with phenacemide. All three patients showed elevated serum creatinine and normal blood urea nitrogen values while on phenacemide. Simultaneous urea and creatinine clearance studies performed on each patient demonstrated normal urea clearances and decr creatinine clearances. Inulin clearance performed in one patient was normal. The medication was discontinued in two of the patients because of co-existing neutropenia. Serum creatinine values returned to normal after phenacemide treatment was terminated. The elevation in serum creatinine values with phenacemide appears to be dose related, reversible, and unrelated to impairment of glomerular filtration.

The Hungarian Case-Control Surveillance of Congenital Anomalies from 1980-1987, involved 10,698 malformed cases and 21,546 non-malformed controls. Ninety-five pregnant women were treated by 144 anticonvulsants excluding diazepam and barbiturates. The rate of anticonvulsant use was 2.9 times higher in pregnant women having malformed offspring than in control mothers and this difference was greater in polytherapy than in monotherapy.

HIGH DOSES OF PHENACEMIDE IN ANIMALS CAUSE CNS DEPRESSION.

... In this paper the ... parameters for the description of teratogenic potency and hazard in quantitative terms /is detailed/.. Derivation and calculation of the parameters are illustrated by the analysis of adult lethality and teratogenicity data of eight structurally related anhydrides and imides, following testing in the CD-1 mouse. Teratogenicity was evaluated following treatment on Days 8-10 of gestation, using an average of four dose groups per compound and at least 10 dams per group. Adult lethality was estimated following a similar 3 day dosage schedule with an average of 6 dose groups per compound and at least 8 animals per group. Dose response relationships of teratogenicity were fitted to a probit model from which tD50 (median effective dose), and other effective doses were computed. It is proposed that tD05, as a minimum teratogenic dose, best represents teratogenic potency. In this study, potency ranged from 0.17 mmol/kg/day for phenytoin to 5.2 mmol/kg/day for ethosuximide. In order to measure teratogenic hazard a ratio between adult toxic (lethality was chosen as the most appropriate measure) and teratogenic responses was made. Since the dose response slopes of lethality and teratogenicity were different, a simple ratio between median effective doses could not be used. It is shown that a ratio of LDOl to tD05 provides a Relative Teratogenic Index (RTI) which reflects the teratogenic hazard of a test agent. The following RTI values (LDOl/tD05) were computed in this study: phthalic anhydride, 0.9; phensuximide, 1.0; succinic anhydride, 1.0; ethosuximide, 1.2; phenytoin, 1.6; phenacemide, 3.3; trimethadione, 4.0; and sodium valproate, 4.1. For these data, tD05 and RTI clearly represent the differing teratogenic potencies and hazards of the tested compounds. it is suggested that these parameters may be useful in comparative teratogenicity studies and may be valuable components of developmental toxicity risk assessment.

Human lymphocytes incubated with a mouse hepatic microsomal drug metabolizing system were used to study the cytotoxicity of four anticonvulsants. In vitro toxicity assessed by trypan blue dye exclusion was significantly greater for compounds with relatively high clinical toxicity (mephenytoin and phenacemide) than those with only rare cytotoxic complications (phenytoin and phenobarbital). No toxicity occurred in the absence of microsomes and toxicity was enhanced by inhibitors of epoxide hydrolase suggesting that the cytotoxicity of the drugs may result from arene oxide metabolites. In vivo, the covalent binding of such metabolites to cell macromolecules could lead to cell death and, by acting as haptens, to secondary hypersensitivity reactions. The method may be useful in assessing the potential of a drug for toxicity, the mechanism of cell damage and individual differences in cell defenses within the human population.

Initial treatment should include gastric lavage and/or induction of emesis and general supportive measures. The patient's renal, hepatic, and hematologic status, and mental state should be carefully evaluated following recovery from acute overdosage.

There is no specific antidote for phenacemide overdose. Recommended treatment consists of the following. To decrease absorption - evacuation of stomach by induction of emesis or lavage. Supportive care - patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation. Following recovery, evaluation of hepatic and renal function, mental state, and blood-forming organs should be performed.

Oral LD50 mice = 5.54 mmol/kg

Oral LD50 rat = >10 mmol/kg

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

N - Nervous system

QN - Nervous system

Phenacemide is a ureal anticonvulsant indicated for control of severe epilepsy, particularly mixed forms of complex partial (psychomotor or temporal lobe) seizures, refractory to other anticonvulsants. Phenacemide elevates the threshold for minimal electroshock convulsions and abolishes the tonic phase of maximal electroshock seizures. It also prevents or modifies seizures induced by pentylenetetrazol or other convulsants.

Phenacemide binds to and blocks neuronal sodium channels or voltage sensitive calcium channels. This blocks or suppresses neuronal depolarization and hypersynchronization. Hypersynchronization is what often causes seizures.

IT ACTS BOTH TO INCR THRESHOLD FOR CONVULSIVE STIMULI REACHING CNS AS WELL AS PREVENTING SPREAD OF SEIZURE DISCHARGE FROM INITIATING FOCI.

...HAS BROAD SPECTRUM OF ANTICONVULSANT ACTIVITY IN EXPTL ANIMALS. IN NONTOXIC DOSES, IT ABOLISHES TONIC EXTENSOR PHASE OF MAX ELECTROSHOCK SEIZURES, ELEVATES THRESHOLD FOR ELECTROSHOCK CONVULSIONS IN NORMAL & HYPONATREMIC ANIMALS, & PREVENTS OR MODIFIES PENTYLENETETRAZOL SEIZURES...

The mechanism of action in humans has not been established. However, in animals, at doses well below those causing neurological signs, phenacemide elevates the threshold for minimal electroshock convulsions and abolishes the tonic phase of maximal electroshock seizures. It also prevents or modified seizures induced by pentylenetetrazol or other convulsants.

22-25 hours.

In one study using 1 control subject and 3 epileptic patients, the half-life of phenacemide was demonstrated to be 22 to 25 hours.

Metabolized in the liver by hepatic microsomal enzymes, where it is inactivated by p-hydroxylation.

BIOTRANSFORMATION OF PHENACETYLUREA IN RABBITS GAVE PHENYLACETIC ACID & PHENACETURIC ACID BY HYDROLYSIS OF UREIDO-GROUP, & 4-HYDROXYPHENACETYLUREA & 3-METHOXY-4-HYDROXYPHENACETYLUREA BY SUCCESSIVE RING-HYDROXYLATION & METHYLATION OF PHENOLIC HYDROXY-GROUP. PHENACETYLUREA N-GLUCURONIDE...DID NOT APPEAR TO BE FORMED...

BIOTRANSFORMATION BY HEPATIC MICROSOMAL ENZYMES INCL INACTIVATION BY PARAHYDROXYLATION OF PHENYL SUBSTITUENT; RING CLOSURE TO FORM HYDANTOIN DOES NOT OCCUR.

Metabolized in the liver by hepatic microsomal enzymes, where it is inactivated by p-hydroxylation. Half Life: 22-25 hours.

Almost completely absorbed.

PHENACEMIDE IS ALMOST COMPLETELY ABSORBED FROM GI TRACT. ... UNCHANGED DRUG IS NOT EXCRETED IN URINE... PLASMA CONCN ASSOCIATED WITH EFFICACY & SAFETY HAVE NOT BEEN ESTABLISHED.

COMPARISON OF EXCRETION OF (14)C-PHENACETYLUREA IN DIFFERENT SPECIES SHOWED DIFFERENCES IN BIOTRANSFORMATION. AFTER ORAL DOSE, RATS EXCRETED 63% OF (14)C IN 48-HR URINE, GUINEA-PIGS 56%, RABBITS 87%, & MICE 62%.

MEDICATION

Therap. cat: Anticonvulsant

Used to control certain seizures in the treatment of epilepsy.