ベナクチジン

DEA NFLIS-Drug Category -> Depressants and Tranquilizers

Pharmaceuticals -> Listed in ZINC15

177-178 (Hydrochloride salt)

51 °C

Crystals from alcohol + ether; mp: 169-170 °C /Methobromide/

Crystals from acetone; mp: 177-178 °C; 14.9 g soluble in 100 ml water at 25 °C; practically insoluble in ether /HCl/

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.

/HUMAN EXPOSURE STUDIES/ Benactyzine is an anticholinergic agent which has been used in past years in psychiatry, but is little used today. It has central and peripheral anticholinergic effects, and when administered intramuscularly, it has a rapid onset of action. This may make it useful as an antidote for organophosphate poisoning, in spite of side-effects such as deficits of short term memory, concentration, and attention. As an anticholinergic drug it could also be expected to produce vision changes by its action on the intraocular musculature controlling the pupil and lens accommodation. ... The drug /was tested/ on six volunteer subjects to establish the visual side-effects of intramuscular administration. ... It reduced static and dynamic visual acuity, increased pupil size, reduced amplitude of accommodation and contrast sensitivity, while having little or no effect on glare recovery, color vision, intraocular pressure, stereoacuity, oculomotor tracking, and distance heterophoria. Benactyzine produced reductions in visual performance for up to 3 hr and had the greatest effects on functions which have significant cognitive components. ...

/HUMAN EXPOSURE STUDIES/ ... The effects of an anticholinergic drug, benactyzine HCl on vision and vision function /were investigated/. ...The time course and severity of benactyzine effects on visual acuity for static and moving targets, amplitude and dynamics of accommodation, pupil response to light and the spatial contrast sensitivity function /were assessed/. A single dose of the drug (4.14 mg/70 kg body weight, which is within the therapeutic range) and placebo were administered intramuscularly to 12 subjects. Large and significant decrements in visual function were demonstrated after the administration of benactyzine, particularly for those functions performed at near focus. The drug effect was rapid in onset, beginning 7-10 min after injection, peaked at approximately 30-40 min, and declined to baseline values over the next 2 hr. The drug increased pulse rate and blood pressure, and induced an intoxicated state involving loss of concentration, attention, and short-term memory. /Benactyzine hydrochloride/

/SIGNS AND SYMPTOMS/ PSYCHOSES & HALLUCINATIONS HAVE BEEN PRECIPITATED IN HUMANS BY DOSES OF 50-200 MG.

/SIGNS AND SYMPTOMS/ ...MAY CAUSE BLURRING OF VISION FROM MYDRIASIS & CYCLOPLEGIA AFTER AN INITIAL DOSE EXCEEDING 2 MG. /HYDROCHLORIDE/

/LABORATORY ANIMALS: Acute Exposure/ Five Macaca mulatta were tested for performance changes following exposure to benactyzine HCl (intramuscular) at four doses ranging from 0.054 mg/kg to 1.7 mg/kg. Subjects simultaneously operated a primate equilibrium platform and responded to a multiple alternative reaction task. Performance on both the continuous and discrete tasks were progressively degraded as benactyzine dose increased. At the higher doses it appeared that they concentrated their efforts on one of the tasks while neglecting the other. Thus, performance on one task might be normal and at the same time performance on another task would be degraded.

/OTHER TOXICITY INFORMATION/ The purpose of the present study was to make a comparative assessment of potential cognitive effects of benactyzine (0.3 mg/kg), biperiden (0.11 mg/kg), caramiphen (10 mg/kg), procyclidine (3 mg/kg), and trihexyphenidyl (0.12 mg/kg) separately and each in combination with physostigmine (0.1 mg/kg). The results showed that benactyzine, caramiphen, and trihexyphenidyl reduced rats' innate preference for novelty, whereas biperiden and procyclidine did not. When benactyzine, caramiphen, and trihexyphenidyl were combined with physostigmine the cognitive impairment disappeared. This counteracting effect, however, caused changes in locomotor and rearing activities not seen by each drug alone. Acetylcholinesterase inhibitors and anticholinergics used as prophylactics can offset each other, but exceptions are observed in a previous study when a very potent anticholinergic (scopolamine) or a high dose of procyclidine still results in cognitive deficits in spite of coadministration with physostigmine. /Benactyzine hydrochloride/

/OTHER TOXICITY INFORMATION/ Working and reference memory processes were simultaneously evaluated during the performance of a paired discrimination (PD) task in which visual and spatial discrimination trials were combined within the same session. Atropine (1 and 5 mg/kg), scopolamine (0.02-0.20 mg/kg), benactyzine (1-4 mg/kg), trihexyphenidyl (1-10 mg/kg), and aprophen (5-20 mg/kg) were all found to increase the number of errors performed by overtrained rats during the spatial but not during the visual trials. Although all the anticholinergic drugs tested induced specific working memory impairment at low doses, they differentially affected other, simultaneously recorded, behavioral parameters. Thus, while atropine affected most of the recorded parameters, aprophen induced only a mild effect. Benactyzine was found to have the most specific effect on working memory, with only minimal side effects, a combination that supports its use as the preferred psychopharmacological model of working memory impairment.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

Certain muscarinic antagonists (e.g., atropine, aprophen, and benactyzine) are used as antidotes for the treatment of organophosphate poisoning. ... The interaction of aprophen and benactyzine, both aromatic esters of diethylaminoethanol, with nicotinic acetylcholine receptor (AChR) in BC3H-1 intact muscle cells and with receptor-enriched membranes of Torpedo californica /was examined/. Aprophen and benactyzine diminish the maximal carbamylcholine-elicited sodium influx into muscle cells without shifting Kact (carbamylcholine concentration eliciting 50% of the maximal 22Na+ influx). The concentration dependence for the inhibition of the initial rate of 22Na+ influx by aprophen and benactyzine occurs at lower concentrations (Kant = 3 and 50 microM, respectively) than those needed to inhibit the initial rate of [125I]-alpha-bungarotoxin binding to the agonist/antagonist sites of the AChR (Kp = 83 and 800 uM, respectively). The effective concentration for atropine inhibition of AChR response (Kant = 150 microM in BC3H-1 cells) is significantly higher than those obtained for aprophen and benactyzine. Both aprophen and benactyzine interact with the AChR in its desensitized state in BC3H-1 cells without further enhancing agonist affinity. Furthermore, these ligands do not alter the value of Kdes (equilibrium concentration of agonist which diminishes 50% of the maximal receptor response) in BC3H-1 muscle cells. The affinity of aprophen and benactyzine for the allosterically coupled noncompetitive inhibitor site of the AChR in Torpedo was determined using [3H]phencyclidine as a probe. Both compounds were found to preferentially associate with the high affinity (desensitized) state rather than the resting state of Torpedo AChR. There is a 14- to 23-fold increase in the affinity of aprophen and benactyzine for the AChR (KD = 0.7 and 28.0 uM in the desensitized state compared to 16.4 and 384 uM in the resting state, respectively). These data indicate that aprophen and benactyzine binding are allosterically regulated by the agonist sites of Torpedo AChR. Thus, aprophen and benactyzine are effective noncompetitive inhibitors of the AChR at concentrations of 1-50 uM, in either Torpedo or mammalian AChR. These concentrations correspond very well with the blood level of these drugs found in vivo to produce a therapeutic response against organophosphate poisoning.

Benactyzine and drofenine are widely used anticholinergic drugs. Benactyzine is used to treat organophosphate poisoning and drofenine acts on smooth muscle to stop muscle spasms. Both of these drugs are esters. After they enter the bloodstream, they will interact with butyrylcholinesterase (BChE; acylcholine acyl hydrolase: EC 3.1.1.8), which has an ability to hydrolyze a wide variety of esters. Therefore, the kinetic analysis of their inhibitory effects on human serum BChE was examined using butyrylthiocholine as substrate. Both drugs were competitive inhibitors of BChE and the Ki values of benactyzine and drofenine were calculated to be 0.010 +/- 0.001 and 0.003 +/- 0.000 mM, respectively, using the Systat (version 5.03, 1991) nonlinear regression analysis software package. According to these parameters, drofenine is a more potent competitive inhibitor of BChE than benactyzine.

THE LIVER & KIDNEYS RAPIDLY METABOLIZE THIS COMPD BY HYDROLYSIS.

IN RATS, BIOTRANSFORMATION OF BENACTYZINE, BETA-DIETHYLAMINOETHYL BENZILATE GIVES THREE URINARY EXCRETORY PRODUCTS, UNCHANGED, BENZILIC ACID, & BETA-ETHYLAMINOETHYLBENZILATE.

COMPD STRUCTURALLY SIMILAR TO SKF 525A SUCH AS BENACTYZINE WERE CAPABLE OF FORMING METABOLITE-CYTOCHROME P450 COMPLEXES ABSORBING MAXIMALLY AT 455 NM WHEN METAB BY RAT HEPATIC MICROSOMES.

Mood-stimulating drugs used primarily in the treatment of affective disorders and related conditions. Several MONOAMINE OXIDASE INHIBITORS are useful as antidepressants apparently as a long-term consequence of their modulation of catecholamine levels. The tricyclic compounds useful as antidepressive agents (ANTIDEPRESSIVE AGENTS, TRICYCLIC) also appear to act through brain catecholamine systems. A third group (ANTIDEPRESSIVE AGENTS, SECOND-GENERATION) is a diverse group of drugs including some that act specifically on serotonergic systems.

Agents that inhibit the actions of the parasympathetic nervous system. The major group of drugs used therapeutically for this purpose is the MUSCARINIC ANTAGONISTS.

Drugs that bind to but do not activate MUSCARINIC RECEPTORS, thereby blocking the actions of endogenous ACETYLCHOLINE or exogenous agonists. Muscarinic antagonists have widespread effects including actions on the iris and ciliary muscle of the eye, the heart and blood vessels, secretions of the respiratory tract, GI system, and salivary glands, GI motility, urinary bladder tone, and the central nervous system.

BLOOD LEVELS OF TRITIATED BENACTYZINE IN /RATS/ WERE MAXIMAL WITHIN 1 HR OF AN IP DOSE... THE 24-HR URINE CONTAINED 45%...FECES 15% & GI TRACT 27%, COMMENSURATE WITH BILIARY SECRETION OF TRITIATED BENACTYZINE.

DETOXIFICATION OF BENACTYZINE IN HUMANS IS NEGLIGIBLE; MAJORITY IS BOUND TO PLASMA ALBUMIN. ONLY FREE BENACTYZINE HAS ANTICHOLINERGIC EFFECTS. BOUND BENACTYZINE MAY BE CONSIDERED A POOL FOR STABLE DRUG LEVELS.

THERAP CAT: Antispasmodic

MEDICATION