1-[α-(p-クロロフェニル)ベンジル]-4-メチルピペラジン

LogP = 3.45

4.15

1 G SOL IN ABOUT 2 ML H2O, 11 ML ALC; 1 G SOL IN ABOUT 4 ML CHLOROFORM; PRACTICALLY INSOL IN ETHER, BENZENE /CHLORCYCLIZINE HYDROCHLORIDE/

FREELY SOL IN WATER; SOL IN ALC /CHLORCYCLIZINE DIHYDROCHLORIDE/

ODORLESS OR ALMOST ODORLESS; ITS SOLN ARE ACID TO LITMUS; PH (1 IN 100 SOLN) BETWEEN 4.8 & 5.5 /CHLORCYCLIZINE HYDROCHLORIDE/

AQ SOLN IS ACID TO LITMUS /CHLORCYCLIZINE DIHYDROCHLORIDE/

WHITE, CRYSTALLINE POWDER /CHLORCYCLIZINE HYDROCHLORIDE/

PRISMS FROM ALCOHOL PLUS ETHER /CHLORCYCLIZINE DIHYDROCHLORIDE/

Solutions acid to litmus, pH (1 to 100 solution) 4.8-5.5 /Chlorcyclizine hydrochloride/

Warning

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

P264, P270, P273, P301+P317, P330, P391, and P501 (click each P-code to see the statement)

The GHS information provided by 1 company from 1 notification 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).

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

SEVERAL REVIEWS BRIEFLY MENTIONED THAT ANTIHISTAMINES INTERFERE WITH ANTICOAGULANT THERAPY; HOWEVER, NO DOCUMENTATION WAS PRESENTED, NO CASE REPORTS OF ANTICOAGULATION PROBLEMS CAUSED BY ANTIHISTAMINES HAVE APPEARED. /ANTIHISTAMINES/

TERATOGENICITY OF CHLORCYCLIZINE IN MICE...IS DIMINISHED BY PRE-TREATMENT EITHER WITH SKF 525A /PROADIFEN/ OR WITH PHENOBARBITONE, & MORE THAN ONE BIOTRANSFORMATION MUST BE INVOLVED.

Plocamadine A (1 ug/ml) produced a slow onset, sustained contraction of the guinea-pig isolated ileum. This was insensitive to atropine (1 umol/l) and tetrodotoxin (1 umol/L), but was significantly reduced by H1-histamine receptor antagonists including mepyramine (10 nmol/l), chlorcyclizine (10 nmol/l) and diphenhydramine (0.1 umol/l).

A method to determine whether chlorcyclizine hydrochloride (I) antihistamine activity could be demonstrated when I was applied topically in combo with 0.5% hydrocortisone acetate (Mantadil; II) cream was described. Hydrocortisone 5%, II, and placebo cream were studied in 30 subjects. The data indicated that a wheal and flare reaction induced in the subjects was decr by the I component of the combo. /Chlorcyclizine hydrochloride/

...NO EVIDENCE OF HARM TO HUMAN FETUS HAS BEEN REPORTED DESPITE WIDE USE OVER...PAST 15 YEARS.

ADULTS HAVE SURVIVED SINGLE DOSES OF 2.5-5.0 G. CHILDREN MAY BE DISPROPORTIONATELY MORE SUSCEPTIBLE; 30-60 MG/KG HAS PRODUCED SERIOUS POISONINGS & DEATH IN TODDLERS, & IN 1 FATAL CASE DOSE WAS ABOUT 10 MG/KG. /ANTIHISTAMINICS/

.../AFTER/ EXTENSIVE EPIDEMIOLOGICAL INVESTIGATIONS IN SWEDEN, CANADA & US... THERE WAS DISAGREEMENT AS TO WHETHER CHLORCYCLIZINE WAS A TERATOGEN IN HUMANS; EPIDEMIOLOGIC INVESTIGATION OF CHLORCYCLIZINE COULD NOT PROVE EXISTENCE OF HARMFUL EFFECT IN HUMANS.

In acute poisoning with H1 antagonists, their central excitatory effects constitute the greatest danger. The syndrome includes hallucinations, excitement, ataxia, incoordination, athetosis, and convulsions. Fixed, dilated pupils with a flushed face, together with sinus tachycardia, urinary retention, dry mouth, and fever, lend the syndrome a remarkable similarity to that of atropine poisoning. Terminally, there is deepening coma with cardiorespiratory collapse and death, usually within 2 to 18 hours. /H1 Antagonists/

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

chlorcyclizine

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

WHEN CHLORCYCLIZINE WAS ADMIN TO RATS @ ORAL DOSAGE OF 50 MG/KG DAILY FROM 10TH-15TH DAY OF PREGNANCY, HIGH INCIDENCE OF CLEFT PALATES WAS OBSERVED. ... /WHEN/ GIVEN SAME DAILY DOSAGE...FROM 1ST-15TH DAY OF PREGNANCY, INCIDENCE OF MALFORMATIONS...MARKEDLY REDUCED. ...STUDIES SHOWED THAT.../NORCHLORCYCLIZINE WAS RESPONSIBLE/.

CHLORCYCLIZINE IS A MORE POTENT TERATOGEN THAN CYCLIZINE BUT DID NOT PRODUCE AS MANY FETAL DEATHS, ALTHOUGH SIMILAR SPECTRUM OF MALFORMATIONS WAS SEEN.

TREATMENT /OF PREGNANT SPRAGUE-DAWLEY RATS/ ON VARIOUS DAYS FROM 10-15 WITH CYCLIZINE RESULTED IN 30% RESORPTIONS & APPROX 40% MALFORMED FETUSES. MALFORMATIONS INCL CLEFT PALATE, BRACHYGNATHIA & MICROSTOMIA. ...ALSO FAILURE TO OSSIFY IN...BONES. CATARACTS...DETECTED...& WERE COMMON & CONSISTENT FINDING. /CYCLIZINE/

NORCHLORCYCLIZINE IS ABLE TO INDUCE SAME ARRAY OF MALFORMATIONS AS CHLORCYCLIZINE...& IS PROBABLY THE TERATOGENIC AGENT. HOWEVER, CO-ADMIN OF ACTIVE CMPD WITH CHLORCYCLIZINE REDUCED INCIDENCE OF CLEFT PALATE DUE TO UNCHANGED CHLORCYCLIZINE BUT NOT OTHER MALFORMATIONS DUE TO NORCHLORCYCLIZINE.

For more Non-Human Toxicity Excerpts (Complete) data for CHLORCYCLIZINE (14 total), please visit the HSDB record page.

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).

R - Respiratory system

QR - Respiratory system

ANTIHISTAMINES ACT AS PHARMACOLOGICAL ANTAGONISTS OF HISTAMINE AT MOST OF HISTAMINE RECEPTOR SITES, ALTHOUGH NOT BY PREVENTING RELEASE OF HISTAMINE. HEPATIC MICROSOMAL ENZYME-INDUCING PROPERTIES OF CHLORCYCLIZINE...HAVE SHORTENED DURATION OF ACTION OF SOME BARBITURATES AS A RESULT OF ENZYME INDUCTION.

H1 antagonists inhibit most response of smooth muscle to histamine. Antagonism of the constrictor action of histamine on respiratory smooth muscle is easily shown or in vitro. ... Within the vascular tree, the H1 antagonists inhibit both the vasoconstrictor effects of histamine and, to a degree, the more rapid vasodilator effects that are mediated by H1 receptors on endothelial cells. Residual vasodilatation reflects the involvement of H2 receptors on smooth muscle and can be suppressed only by the concurrent administration of an H2 antagonist. Effects of the histamine antagonists on histamine induced changes in systemic blood pressure parallel these vascular effects. /H1 Antagonists/

H1 antagonists strongly block the action of histamine that results in increased capillary permeability and formation of edema and wheal. /H1 Antagonists/

All H1 antagonists ... can bind to H1 receptors in the CNS ... H1 antagonists can both stimulate and depress the CNS. /H1 Antagonists/

For more Mechanism of Action (Complete) data for CHLORCYCLIZINE (6 total), please visit the HSDB record page.

High concentrations of the N-desmethyl metabolite are found in the liver, lungs, kidney, and spleen.

AFTER CHRONIC ADMIN OF...CHLORCYCLIZINE TO RATS, THE TISSUES CONTAINED DRUG METABOLITES, IN WHICH PIPERAZINE RING FISSION BY MULTIPLE OXIDATIVE N-DEALKYLATION HAD OCCURRED TO GIVE A SUBSTITUTED ETHYLENEDIAMINE. ... ACCUM OF N-(P-CHLOROBENZHYDRYL)ETHYLENEDIAMINE WAS FOUND IN RATS, TREATED WITH CHLOROCYCLIZINE.

OXIDATIVE N-DEALKYLATION IS MAIN METAB PATHWAY OF BENZHYDROLPIPERAZINES... /CHLORCYCLIZINE IS/ TRANSFORMED INTO...NORCHLORCYCLIZINE... CHLORCYCLIZINE N-OXIDE DOES NOT LIE ON METAB PATHWAY CONNECTING CHLORCYCLIZINE WITH NORCHLORCYCLIZINE, BUT RATS & MAN TREATED WITH CHLORCYCLIZINE EXCRETE CHLORCYCLIZINE N-OXIDE IN URINE.

YIELDS DEMETHYLCHLORCYCLIZINE IN RAT. /FROM TABLE/

Readily absorbed after oral administration and widely distributed throughout the body. Metabolised by N-demethylation to form norchlorcyclizine and by N-oxidation.

Slowly excreted in the urine; measurable amounts of norchlorcyclizine have been detected in the urine for up to 3 weeks after the cessation of chronic oral administration. About 0.5% of a single dose is excreted in the urine as the N-oxide.

After a single oral dose of 2 mg/kg to 4 subjects, average peak plasma concentrations of about 0.05 mg/L and 0.03 mg/L were attained in 5 h for unchanged drug and norchlorcyclizine, respectively. After oral administration of 50 mg 3 times a day for 6 days, plasma concentrations of norchlorcyclizine of 0.05 to 0.11 mg/L were reported on the first day after the cessation of treatment and plasma concentrations of 0.02 to 0.04 mg/L were found on the 10th day after cessation of treatment [Kuntzman et al. 1973].

...RATS & MAN TREATED WITH CHLORCYCLIZINE EXCRETE CHLORCYCLIZINE N-OXIDE IN URINE. BENZHYDROLPIPERAZINES & THEIR N-DEALKYLATION PRODUCTS ARE DISTRIBUTED IN ALL TISSUES OF RATS & ARE TRANSFERRED TO FETUS.

...NORCHLORCYCLIZINE IS RETAINED IN HUMANS FOR AT LEAST 20 DAYS AFTER TERMINATION /OF CHLORCYCLIZINE/ THERAPY. .../CHLORCYCLIZINE/ GIVES VERY LOW PLASMA LEVELS SINCE.../IT IS/ MARKEDLY LOCALIZED IN TISSUES, PARTICULARLY LUNG.

STIMULATORY EFFECT OF CHRONIC CHLORCYCLIZINE ADMIN ON ITS OWN METAB IN DOGS: ON DAYS 1-7 DAILY ORAL DOSE OF 10 MG/KG RESULTED IN CHLORCYCLIZINE PLASMA LEVELS OF 4.5 PLUS OR MINUS 1.7 MG/L & ONLY TRACE AMT OF NORCHLORCYCLIZINE. /FROM TABLE/

PREPN.

CHLORCYCLIZINE MAY BE PREPD BY CONDENSING P-CHLOROBENZHYDRYL CHLORIDE WITH N-METHYLPIPERAZINE IN PRESENCE OF SODAMIDE. TREATMENT OF SOLN OF BASE IN SUITABLE ORG SOLVENT WITH HYDROGEN CHLORIDE RESULTS IN PPTN OF THE HYDROCHLORIDE. /CHLORCYCLIZINE HYDROCHLORIDE/

Pharmaceuticals

Pharmaceuticals -> Antihistamines