Tenocyclidine

/ALTERNATIVE and IN VITRO TESTS/ ... In vitro interactions of Tenocyclidine (TCP)and its adamantane derivative--TAMORF with human erythrocyte acetylcholinesterase (AChE) /were investigated/. Moreover, their genotoxicity and radioprotective activity on human white blood cells were studied using the alkaline comet assay, viability testing and the analysis of the structural chromosome aberrations. The tested compounds were ... weak inhibitors of AChE, for TCP IC(50)=1 x 10-5 M and for TAMORF IC(50)>1 x 10-3 M, without reactivating and protective effects on AChE inhibited by soman. Results suggest that TCP modified by the replacement of the cyclohexyl ring with an adamantane ring and piperidine with morpholine group (TAMORF) have lower toxicity. Both compounds possess low cytotoxicity and radioprotective activity, but TAMORF also shows cell growth inhibitory effects. ... Since TAMORF was found to significantly inhibit cell growth and proliferation in vitro, it is reasonable to consider it as a source molecule promising for further modifications and development of more potent substances with antitumor properties rather than radioprotector or antidote in organophosphorus poisoning.

/LABORATORY ANIMALS: Acute Exposure/ A series of phencyclidine (PCP) related analogs ... were compared pharmacologically in mice for their ability to produce ataxia using the rotarod method and toxicologically for their acute 4-hr lethality. ... Responses for all analogs, metabolites and precursors produced curves parallel to that of PCP. Ataxia potencies of all PCP-related compounds ranged from 0.05 to 2.15 times PCP and durations of action ranged from 18 to 65 min. N-ethyl-1-phenylcyclohexylamine, 1-[1-(2-thienyl)-cyclohexyl]-piperidine and 1-[1-(2-thienyl)-cyclohexyl]-pyrrolidine were most potent and least potent were 1-(1-phenyl-cyclohexyl)-4-methylpiperidine, the phenyl and thienyl morpholines and 4-phenyl-4-piperidinocyclohexanol. Among the PCP analogs, modifying the piperidine or aromatic ring effected changes only in potency. Seizures and respiratory depression characterized the lethal effects of PCP, its analogs, metabolites and precursors. However, the precursors failed to elicit the stereotyped movements and hyperactivity that preceded seizures produced by the other compounds. Overall potencies for lethality relative to PCP covered a narrow range (0.16-1.83) with the carbonitrile precursors being most potent. Therapeutic indices indicated relatively large margins of safety for 1-[1-(2-thienyl)-cyclohexyl]-piperidine, 1-[1-(2-thienyl)-cyclohexyl]-piperidine, N-ethyl-1-phenylcyclohexylamine and ketamine and the smallest were for 1-(1-phenylcyclohexyl)-4-methylpiperidine, the metabolite 4-phenyl-4-piperidinocyclohexanol and the three precursors.

/LABORATORY ANIMALS: Neurotoxicity/ TCP (N-[1-(2-thienyl)cyclohexyl]piperidine), a PCP (phencyclidine) derivative, has been shown to possess antiepileptic and neuroprotective efficacy against chemically induced seizures. However, it is known that other antagonists of the NMDA receptor impair spatial learning. This study was thus undertaken to explore the eventual effects of TCP on memory. The same study was done with MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine ), one of the most studied NMDA receptor antagonists, which can be considered as a reference molecule. Three doses of each drug were chosen: 0.05, 0.1, and 0.2 mg/kg for MK-801 and 0.5, 1, and 2 mg/kg for TCP, the second dosage corresponding to the minimal required for antiseizure activity. The drugs were injected IP 30 min each day before a classical procedure of acquisition in a Morris water maze test. At the highest dose of each drug, the animals did not learn the position of the platform. At 0.1 mg/kg MK-801, the rats used a praxis strategy to find the platform but they did not known where the platform was. Contrary to MK-801, TCP at 1 mg/kg did not induce any memory impairment. At the lowest doses used, no memory impairment was found. It thus appears that, at the minimal therapeutic dose effective against chemically induced seizures (0.1 mg/kg for MK-801 and 1 mg/kg for TCP), TCP, contrary to MK-801, does not induce any memory impairment. Furthermore, at all the doses used, TCP presents the particularity that its locomotor side effects are not long lasting, being no longer observed from 30 min after the injection.

/LABORATORY ANIMALS: Neurotoxicity/ Phencyclidine (1-(1-phenylcyclohexyl)piperidine, PCP) self-administration has been demonstrated in rhesus monkeys, baboons, dogs and rats. Generally, an orderly inverted U-shaped dose-response curve for rates of self-injection has been observed. Total drug intake appears to increase slightly with increases in unit dose; however, this increase is much less than might be expected with other CNS depressants such as barbiturates or morphine. Additionally, several arylcyclohexylamine analogues of PCP and some members of the benzomorphan and dioxolane classes referred to collectively as "phencyclinoids" are self-administered by primates and dogs. New data are presented in this review profiling the self-administration of some of these drugs in rats, as well as a characterization of the self-administration of higher unit doses of PCP than previously reported. Also, preliminary results of the assessment of the reinforcing efficacy of some PCP analogues measured by the progressive ratio procedure are presented. /Phencyclinoids/

/LABORATORY ANIMALS: Neurotoxicity/ /Locomotion, stereotypy, and ataxia /in rats/ were rated via behavioral observations for all compounds, using behavioral rating scales devised specifically for PCP ... Behaviors were rated by observing each animal for 1 or 2 minutes at the midpoint of each 30-minute dosing interval during collection of the EEG.PCP increased behavioral rating scores for stereotypy and ataxia as a function of increasing dose, from 0.2 to 3.2 mg/kg cumulative IV. For PCP-induced locomotion, behavioral rating scores increased up to 1.6 mg/kg, and declined at 3.2 mg/kg. Similar scores were generated for the other compounds over doses ranging from 0.1 to 12.8 mg/kg. When scores for one behavior increased, concomitant increases in the scores for each of the behaviors resulted, making only quantitative differences between these phencyclinoids observable. Consequently, similar relative potencies were obtained from consideration of any one of these three behaviors. The rank order of potency for locomotion, stereotypy, and ataxia was TCP > PCP = PCPY = TCPY > PCE = NsBPCA > NMPCA > ketamine = PCA = SKF-10,047. PCE was unusual in that its potency for ataxia was nearly equal to PCP's, yet it was only about one-third as potent in inducing locomotion and about two-thirds as potent for producing stereotypy. TCP was more potent, TCPY and PCPY were about equipotent, and PCA was less potent than PCP.

For more Non-Human Toxicity Excerpts (Complete) data for TENOCYCLIDINE (6 total), please visit the HSDB record page.

/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 as necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on 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. /Incapacitating Agents/

/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 it necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . Demonstrate a friendly attitude and use firm restraint when necessary. All dangerous objects must be removed from the area and anything likely to be swallowed should be kept away from patients, because bizarre delusions may occur. For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Use rapid cooling techniques to manage hyperthermia ... . 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. Administer activated charcoal ... . /Incapacitating Agents/

/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 ... . 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 (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient is hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Treat seizures or sedate ... patients with diazepam (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Incapacitating Agents/

Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids.