Benactyzine

327.42

327.42

206-123-8

595EG71R3F

DTXSID0022644

Crystals

2922509090

49.8

2.89 (est)

1.115 g/cm3

51 °C

409.3ºC at 760 mmHg

201.4ºC

1.557

In water, 1.01X10+3 mg/L at 25 deg C (est)

2-8°C

2.15X10-8 mm Hg at 25 deg C (est)

Henry's Law constant = 2.07X10-10 atm-cu m/mol at 25 °C (est)

pKa = 8.31 (amine) (est)

Hydroxyl radical reaction rate constant = 1.05X10-10 cu cm/molec-sec at 25 °C (est)

23/24/25

36/37/39-45

T

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.

CONSERVATIVE TREATMENT IS ADVISED BECAUSE BENACTYZINE POTENTIATES THE SEDATIVE ACTIONS OF BARBITURATES.

Antidepressive Agents; Muscarinic Antagonists; Parasympatholytics|/EXPL THER/ Potent cholinesterase inhibitors (e.g., soman, sarin), induce a wide range of deleterious effects including convulsions, behavioral impairments and ultimately, death. Due to the likelihood of various scenarios of military or terrorist attacks by these and other chemical weapons, research has to be aimed at finding optimal therapies. Early accumulation of acetylcholine in synaptic clefts was suggested to trigger an array of toxic events including an excessive release of glutamate, culminating in the activation of its receptors. Stimulation of the N-Methyl-D-Aspartate (NMDA) subtype of these receptors was associated with the neuronal injury that initiates organophosphate-induced brain damage. The notion of a stepwise mechanism yielded treatments based on a combination of an immediate administration of enzyme reactivators and anticholinergic drugs. This strategy dramatically increased survival rates but did not abolish convulsions and failed to prevent the ensuing cognitive dysfunction. Efforts to improve this paradigm by adding anticonvulsants or antiglutamatergic drugs with anti-epileptic characteristics produced dubious results. Under these conditions, benactyzine and caramiphen, agents with anticholinergic and antiglutamatergic properties, provided improved protection when introduced as adjunct agents to oximes, reversible cholinesterase inhibitors and/or specific antimuscarinic drugs such as atropine. In contrast, the specific antimuscarinic drug scopolamine failed to block soman-induced changes in glutamatergic and behavioral parameters even when given prophylactically. These findings along with a large number of additional reports led towards the conclusion that the therapeutic advantage of drugs such as benactyzine and caramiphen could derive from their ability to modulate central cholinergic and glutamate neurotransmission.|/EXPL THER/ To study the influence of antidotes on tabun-induced neurotoxicity, the rats were injected intramuscularly with organophosphate tabun (LD50). The efficacy of choice antidotal treatment consisting of acetylcholinesterase reactivator obidoxime and one of four anticholinergic drugs (atropine, benactyzine, biperiden, scopolamine) was compared. Testing of tabun-induced neurotoxicity progress was carried out using the method Functional observational battery. The experimental animals as well as controls were observed at 24 hours and 7 days following tabun or saline administration. The results were compared to the condition of animals without anticholinergic drug (oxime alone) and control rats that received physiological solution instead of tabun and treatment. Antidotal treatment involving centrally acting anticholinergic drugs (benactyzine, biperiden, scopolamine) showed significantly higher neuroprotective efficacy compared to antidotal treatment containing atropine.|/EXPL THER/ 1 The effect of pharmacological pretreatment (pyridostigmine, benactyzine and trihexyphenidyle), designated Panpal, and antidotal treatment (the oxime HI-6 plus benactyzine) in soman poisoning was investigated in a rat model with on-line monitoring of respiratory and circulatory parameters. 2 Soman poisoning caused a high decrease in respiratory rate as well as minute respiratory volume and an increase in mean arterial pressure from 30-120 min following soman challenge. Soman at sublethal dose also significantly inhibited acetylcholinesterase activity in diaphragm and various brain parts. 3 Panpal pretreatment as well as antidotal treatment were effective in improving the respiratory and circulatory function disturbed by soman without the ability to increase significantly soman-inhibited acetylcholinesterase activity in all brain parts studied. 4 The efficacy of combined Panpal pretreatment and antidotal treatment against sublethal soman poisoning was not different from the efficacy of Panpal pretreatment or antidotal treatment alone. 5 The results of this investigation suggest that Panpal pretreatment as well as antidotal treatment are able to restore respiratory and circulatory function in soman-poisoned rats without significant reactivation of brain acetylcholinesterase.|/EXPL THER/ Sarin, a potent cholinesterase inhibitor, induces an array of toxic effects including convulsions and behavioral impairments. We report here on the protection provided by post-exposure antidotal treatments against a lethal dose of sarin (1.2xLD50) by scopolamine, benactyzine, trihexyphenidyl or caramiphen, administered 5, 10 or 20 min after the initiation of convulsions. A mixture of the oxime TMB4 and atropine (TA) was injected 1 min following poisoning a paradigm that may represent a scenario reminiscent of a terror incident. Surviving TA-treated rats exhibited marked tonic-clonic convulsions, weight loss, poor clinical status and abnormal cognitive performance as assessed by the Morris water maze. Additionally, a dramatic increase in the density of peripheral benzodiazepine receptors (PBRs), a faithful marker for neuronal damage, was noted. Animals treated 5 min after the development of toxic signs with benactyzine, trihexyphenidyl or caramiphen demonstrated control levels of PBR values, whereas scopolamine produced binding densities significantly above basal levels. Examined at the 10-min time point, scopolamine and trihexyphenidyl afforded no protection against brain damage and did not differ from TA-injected rats. All four drugs failed to significantly prevent the alterations when applied 20 min after onset of convulsions. Assessment of learning processes yielded similar results, where caramiphen exibited some protection at the 20-min time point. Our results show that caramiphen and benactyzine, agents with combined anticholinergic and antiglutamatergic pharmacological profiles, offer considerable shielding against sarin, even when their administration is delayed. 8

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. ...|... 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/

TOLERANCE TO THE SEDATIVE EFFECT USUALLY OCCURS DURING CHRONIC USE. /NONPRESCRIPTION SEDATIVE-HYPNOTIC DRUGS/

Agents that inhibit the actions of the parasympathetic nervous system. The major group of drugs used therapeutically for this purpose is the MUSCARINIC ANTAGONISTS. (See all compounds classified as Parasympatholytics.)|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. (See all compounds classified as Muscarinic Antagonists.)|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. (See all compounds classified as Antidepressive Agents.)

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.

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.

HALF LIFE ... IN BLOOD WAS AN ESTIMATED 80 MIN.

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.

/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/

/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/

Amizil

ION-PAIR HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC SEPARATION OF MULTICOMPONENT ANTICHOLINERGIC DRUG FORMULATION.|ULTRAMICRO HPLC METHOD FOR ASSAYING ION-PAIR SPECIES OF BENACTYZINE & SEPARATION FROM BENZILIC ACID.|METHOD FOR MICRODETERMINATION OF BENACTYZINE WITH BROMOCRESOL GREEN BY ION-PAIR EXTRACTION WITH CHCL3 & SEPARATION OF LIBERATED DYE WITH 0.1 N NAOH. AMT OF 5-150 MUG IN COMMERCIAL DRAGEES.|Analyte: benzactyzine; matrix: solutions; procedure: high-performance liquid chromatography with electrochemical oxidation detection|Analyte: benzactyzine; matrix: solutions; procedure: high-performance liquid chromatography with ultraviolet detection at 220 nm

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