Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The monohydroxy metabolites of phencyclidine (PCP) have been suggested to contribute to the pharmacologic activity of PCP, and perhaps account for its prolonged action. The disposition kinetics of the monohydroxy metabolites of PCP were examined in dogs. Intravenous doses of the piperidine-hydroxylated metabolite (PCHP) and the trans- and cis-forms of the cyclohexyl-hydroxylated metabolite (trans-PPC and cis-PPC) were each administered to three dogs. The elimination half-life of each metabolite was short, with harmonic mean values of 1.29, 0.98 and 0.92 hr for PCHP, trans-PPC and cis-PPC, respectively. The compounds had large volumes of distribution, with average values of 6.7, 4.7 and 4.4 liters/kg for PCHP, trans-PPC and cis-PPC, respectively. Systemic clearances were high for each compound (51.9, 50.9 and 54.2 ml/min/kg for PCHP, trans-PPC and cis-PPC, respectively), but renal clearances were low (average values ranged from 2 to 8% of systemic clearance), suggesting that these metabolites undergo further metabolism. Analysis of acid-hydrolyzed serum and urine samples indicated that all three compounds were conjugated and that these conjugates were the primary metabolites. The conjugated metabolites exhibited elimination half-lives longer than the parent compounds after administration of the monohydroxy forms and after PCP dosing. The disposition of these metabolites suggest that these compounds are not produced in sufficient quantities or do they exhibit pharmacokinetic behavior which would be consistent with the prolonged effects from PCP.
J Pharmacol Exp Ther 1986 Sep
PMID:Disposition kinetics of the monohydroxy metabolites of phencyclidine in the dog. 374 67

Chronic phencyclidine (PCP) administration has been shown to produce tolerance to a number of its pharmacological actions. We have suggested that PCP interacts with the 5-HT2 receptors since it inhibits [3H]spiperone binding to 5-HT2 receptors in vitro. In the present study, we investigated whether methysergide (a 5-HT2 receptor blocker) induces the precipitated withdrawal syndrome in PCP-tolerant rats. The body weight of the rats in the abrupt and precipitated withdrawal groups was significantly lower 5 days and 1-5 days after withdrawal, respectively, than that in the control group. Furthermore, other typical precipitated abstinence syndrome characteristics such as jumping, wet-dog shake and ptosis were also observed in the precipitated withdrawal group. These results suggest that PCP produces its behavioral effects via an agonistic interaction with 5-HT2 receptor sites and that our method may be very useful for the development of a rat model for studying physical dependence on PCP.
Neurosci Lett 1986 Sep 12
PMID:Methysergide-induced precipitated withdrawal syndrome in phencyclidine-dependent rats. 376 58

We examined 221 patients with postmyocardial infarctions 8 weeks after MI using radionuclide ventriculography (RNVA) at rest (EFR) and during supine submaximal exercise (delta EF). Mortality rates were evaluated 2 1/2 and 3 1/2 years later by interviewing patients and/or their homephysicians. Sixteen patients were dead (6.7%) 2 1/2 years after MI, 28 (12.7%) were dead after 3 1/2 years. Thirty percent of patients with a resting EF less than 30% had died 2 1/2 years after MI, and 40% were dead within 3 1/2 years. The mortality rate was significantly higher than in patients who had EF greater than or equal to 30% 8 weeks after MI. Patients with a decrease of delta EF (greater than or equal to 5%) showed a 2 1/2 year mortality of 10.8% and after 3 1/2 years of 18.5%. Mortality was significantly higher in patients with decreasing EF during exercise than in those who increased their EF during exercise. This prognostic value of EFR and delta EF was compared with other parameters (angina pectoris, ECG at rest and during exercise, heart volume, Holter ECG, floating catheter PCP [rest and exercise], coronary angiography). Radionuclide ventriculography at rest and during exercise showed a tendency to be the best determining factor for prognosis, and is therefore recommended to determine prognosis in post-MI patients.
Z Kardiol 1985 Sep
PMID:[Significance of the ejection fraction at rest and by stress using radionuclide ventriculography for the prognosis of myocardial infarct patients--comparison with other study methods]. 387 79

Phencyclidine (PCP) disposition kinetics has been examined in dogs as a function of dose and after i.v. and p.o. administration. Intravenous doses ranged from a tracer quantity of [3H]PCP to 5 mg/kg of unlabeled PCP. The elimination half-life of intact PCP was relatively short with harmonic mean values of 2.7, 5.4 and 3.9 hr for the tracer, 1- and 5-mg/kg doses, respectively. In contrast, measurement of total radioactivity gave a much longer half-life (35-52 hr) suggesting slower metabolite elimination. The drug has a large apparent volume of distribution (weighted mean of 20 liters/kg) and a systemic clearance (which is primarily metabolic) that approaches estimates of liver blood flow in the dog. Renal clearance of intact PCP represents a small fraction of total clearance. Percentage of the [3H]PCP dose recovered as total radioactivity was 49% in urine and 12% in feces. Several metabolites of PCP were determined in urine and they account for about 30% of the dose with the aminopentanoic acid derivative being present in the greatest amount. One of the hydroxylated metabolites is present in cis- and trans-forms, with the latter predominating. Three animals received an i.v. dose of [3H] PCP and a p.o. dose of unlabeled PCP at the same time to determine absolute bioavailability. Approximately 25% of the dose is absorbed intact. The p.o. (intrinsic) clearance of PCP is about four times greater than systemic clearance suggesting a blood flow-dependence in clearance and substantial first-pass hepatic metabolism.
J Pharmacol Exp Ther 1985 Sep
PMID:Phencyclidine (PCP) disposition kinetics in dogs as a function of dose and route of administration. 403 85

Elongation factor Ts (EF-Ts) catalyzes the reaction EF-Tu X GDP + nucleotide diphosphate (NDP) reversible EF-Tu X NDP + GDP where NDP is GDP, IDP, GTP, or GMP X PCP. The EF-Ts-catalyzed exchange rates were measured at a series of concentrations of EF-Tu X [3H] GDP and free nucleotide. Plotting the rate data according to the Hanes method produced a series of lines intersecting on the ordinate, a characteristic of substituted enzyme mechanisms. GDP is a competitive inhibitor of IDP exchange, a result predicted for the substituted enzyme mechanism but inconsistent with ternary complex mechanisms that involve an intermediate complex containing EF-Ts and both substrates. The exchange of both GTP and the GTP analog GMP X PCP also follow the substituted enzyme mechanism. The maximal rates of exchange of GDP and GTP are the same, which indicates that the rates of dissociation of EF-Ts from EF-Tu X GDP and EF-Tu X GTP are the same. The steady-state maximal exchange rate is slower by a factor of 20 than the previously reported rate of dissociation of GDP from EF-Ts X EF-Tu. This is interpreted to mean that the rate-determining step in the exchange reaction is the dissociation of EF-Ts from EF-Tu X GDP.
J Biol Chem 1985 Sep 25
PMID:A study of the kinetic mechanism of elongation factor Ts. 404 68

Previous studies have demonstrated that the humoral immune response in mice as measured by the splenic IgM response to sheep erythrocytes (SRBC) is highly sensitive to suppression by technical grade (86%) pentachlorophenol (T-PCP) whereas analytical grade (greater than 99%) PCP is not immunosuppressive. In the present studies, we have examined several contaminant fractions and purified isomers from T-PCP for their humoral immunosuppressive effect. C57BL/6 mice were treated with a single oral dose of the various contaminants 2 days prior to SRBC challenge and the peak splenic IgM antibody response was measured 5 days later. Under these exposure conditions, T-PCP produced a dose-related suppression of the antibody response whereas analytical grade PCP was without effect. The dose of T-PCP producing 50% immunosuppression relative to the vehicle-treated control (ID50) was 83 mg/kg. Results from studies using contaminant fractions extracted from T-PCP indicated that a chlorinated dioxin/furan fraction was significantly immunosuppressive, whereas a chlorinated phenoxyphenol fraction and a chlorinated diphenyl ether fraction were without effect when administered at dose levels expected to occur in the ID50 dose of T-PCP. Several purified phenoxyphenol isomers representing the major pre- and isopredioxins in T-PCP were also not immunosuppressive, nor was octachlorodibenzo-p-dioxin. The 1,2,3,4,6,7,8-hexachlorodioxin (HxCDD), 1,2,3,4,6,7,8-heptachlorodioxin (HpCDD), and 1,2,3,4,6,7,8-heptachlorofuran (HpCDF) isomers were all significantly immunosuppressive. The single, oral ID50s were 7.1, 85 and 208 micrograms/kg for HxCDD, HpCDD and HpCDF, respectively. Coadministration of HxCDD and HpCDD produced an additive immunosuppressive effect suggesting that the toxic dioxin and furan isomers present in T-PCP function in concert to produce the degree of immune suppression observed following T-PCP exposure. When analytical grade PCP was coadministered with HpCDD, the degree of immune suppression was equivalent to that produced by HpCDD alone, indicating no significant influence of PCP on dioxin-induced immunosuppression. The enhanced susceptibility of Ah-responsive C57BL/6 mice to T-PCP induced immune suppression as compared to Ah-nonresponsive DBA/2 mice and the correlation of immune suppression with P1-450 associated monoxygenase induction provided further evidence for the role of the toxic Ah-interactive dioxin and furan contaminants in T-PCP as the mediators of T-PCP immunotoxicity.
Toxicology 1985 Sep
PMID:Humoral immunotoxicity of polychlorinated diphenyl ethers, phenoxyphenols, dioxins and furans present as contaminants of technical grade pentachlorophenol. 404 36

The actions of the tertiary local anesthetic bupivacaine were studied on the nicotinic receptor-ionic channel complex (AChR) using electrophysiological and biochemical methods. Voltage clamp studies of the frog sartorius and cutaneous pectoris neuromuscular junction revealed a concentration-dependent depression of the decay time constant of the end-plate (tau EPC) and spontaneous miniature end-plate (tau MEPC) currents. The relationship of the reciprocal of either tau EPC or tau MEPC and bupivacaine concentration up to 100 microM was linear. Voltage dependence of EPC over the range +60 to -150 mV was reduced, whereas both EPC and MEPC decays were adequately described by a single exponential function at all concentrations tested. Peak MEPC and EPC amplitudes were also depressed in a concentration-dependent manner such that 100 microM bupivacaine reduced peak amplitude by about 50%. The current-voltage relationship remained linear under all conditions tested. Nerve-evoked responses were difficult to study at concentrations greater than 100 microM because of apparent blockade of nerve conduction. Extracellular recording of the MEPC afforded results similar to those obtained with EPCs. The tau MEPC could be reduced to less than 300 mu sec at a bupivacaine concentration of 400 microM. Fluctuation analysis showed that bupivacaine at concentrations of 10 and 25 microM did not change channel conductance but decreased single-channel lifetime to 76% and 39% of control values, respectively. Biochemical studies were performed on Torpedo californica membrane fragments using [3H]phencyclidine ([3H]PCP) and [3H]perhydrohistrionicotoxin ([3H]H12-HTX) as channel probes. Bupivacaine inhibited the binding of [3H]PCP and [3H]H12-HTX with inhibition constants (Ki) of 32 and 25 microM, respectively. The corresponding inhibition constants for bupivacaine methiodide were 1.8 and 3.2 microM. The preincubation of the membranes with carbamylcholine increased the affinity of bupivacaine for the ionic channel sites 5- to 8-fold and the affinity of bupivacaine methiodide 3- to 4-fold. Bupivacaine, however, had no affinity for the agonist recognition site as determined by [3H]ACh and [125I]alpha-bungarotoxin bindings. The electrophysiological and biochemical studies indicate that bupivacaine reacts primarily with the ionic channel of the nicotinic AChR. The results are consistent with a sequential model in which the drug interacts with the sites at the ionic channel of AChR in its open conformation, producing species with little or no conductance. From the present studies there is no evidence for an interaction of bupivacaine with the agonist binding site or closed states of AChR.
Mol Pharmacol 1984 Sep
PMID:Interactions of bupivacaine with ionic channels of the nicotinic receptor. Electrophysiological and biochemical studies. 609 Aug 84

Single unit recording techniques were used to determine the effects of intravenously and microiontophoretically administered phencyclidine (PCP) and the enantiomers of N-allylnormetazocine (SKF-10,047) on the activity of midbrain dopamine (DA) neurons. Intravenous PCP produced a biphasic effect on substantia nigra zona compacta (A9) and ventral tegmental (A10) DA neurons which consisted of excitation followed by inhibition below baseline firing rates as the dose was increased. The high-dose attenuation of firing by PCP, but not the excitatory effects, was antagonized by haloperidol pretreatment. Intravenous (+)- and (-)-SKF-10,047 increased the firing rate of most A9 and A10 DA neurons. In contrast to the intravenous findings, iontophoretic PCP generally exerted only very weak inhibitory actions on neuronal activity, while (+)- and (-)-SKF-10,047 produced no consistent effects. The results suggest that these drugs indirectly influence the activity of DA neurons and that this may be a property shared by drugs classified as sigma receptor agonists.
Eur J Pharmacol 1984 Sep 17
PMID:The effects of phencyclidine and N-allylnormetazocine on midbrain dopamine neuronal activity. 609 17

Possible commonalities in the discriminative stimulus properties of phencyclidine (PCP) and opioids were investigated in rats trained to discriminate between i.p. injections of saline and 2.0 mg/kg of PCP in a two-choice discrete-trial avoidance paradigm. Behavior was considered to be under stimulus control when a rat reliably completed at least 18 trials of a 20-trial session on the appropriate choice lever after receiving PCP or saline. Tests of stimulus generalization were performed over an 8- to 32-fold range of doses with ketamine, a PCP analog, and eight opioids. Dose- and time-dependent stimulus control of behavior comparable to that produced by 2.0 mg/kg of PCP (defined by the number of trials completed on the PCP-appropriate choice lever) were produced by ketamine and the opioids cyclazocine, SKF 10,047 and dextrorphan. These drugs also produced orderly increases in responses during the interval between trials suggestive of a relationship between this effect and PCP-like stimulus control. In contrast, after ethylketocyclazocine, ketocyclazocine, pentazocine and dextromethorphan trials were completed primarily on the saline-appropriate lever and responding between trials produced did not change. Neither the PCP-like stimulus control of behavior nor the increased responding between trials produced by cyclazocine were prevented by pretreatment with naltrexone (1.0 mg/kg). These results provide further evidence that PCP and certain opioids share a common component of action that is probably mediated by neuronal substrates not usually associated with the activity of opioids.
J Pharmacol Exp Ther 1980 Sep
PMID:Phencyclidine-like discriminative effects of opioids in the rat. 610 6

Administration of 5-10 mg/kg of phencyclidine (PCP) caused stereotyped behaviors including sniffing, backpedalling, head weaving and turning in rats. The PCP-induced stereotyped behaviors (backpedalling, head weaving and turning) were attenuated by serotonin (5-HT) depleters [reserpine, p-chlorophenylalanine, p-chloroamphetamine (PCA)] and 5-HT receptor antagonist (cyproheptadine). PCP-induced head weaving and turning were potentiated by 5-HT precursor (tryptophan) and 5-HT releaser (PCA). PCP-induced head weaving were potentiated also by monoamine oxidase inhibitor (pargyline) and 5-HT reuptake inhibitor (imipramine). PCP 5-10 mg/kg significantly increased the content of 5-HT in the thalamus/hypothalamus at 30 and 60 min after the injection, except PCP 5 mg/kg at 60 min. PCP 7.5 and 10 mg/kg increased the rate of increment of 5-HT by pargyline in the thalamus/hypothalamus at 30 and 60 min after the injection, respectively. PCP 10 mg/kg significantly increased the contents of 5-HIAA in the striatum and thalamus/hypothalamus at 30 min, but decreased that of 5-HIAA in all discrete brain areas except the stratium at 60 min after the injection. PCP also significantly prevented the depletion of 5-HT by PCA in all discrete brain areas except the stratium at 60 min after the injection. From these results, PCP-induced stereotyped behaviors are related to an increased serotonergic neuronal activity due to 5-HT releasing action and/or inhibitory action of 5-HT uptake-by this drug.
Pharmacol Biochem Behav 1984 Sep
PMID:Serotonergic involvement in phencyclidine-induced behaviors. 620 63


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