Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, including phencyclidine (PCP) and ketamine, protect against brain damage in neurological disorders such as stroke. However, these agents have psychotomimetic properties in humans and morphologically damage neurons in the cerebral cortex of rats. It is now shown that the morphological damage can be prevented by certain anticholinergic drugs or by diazepam and barbiturates, which act at the gamma-aminobutyric acid (GABA) receptor-channel complex and are known to suppress the psychotomimetic symptoms caused by ketamine. Thus, it may be possible to prevent the unwanted side effects of NMDA antagonists, thereby enhancing their utility as neuroprotective drugs.
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PMID:NMDA antagonist neurotoxicity: mechanism and prevention. 183 99

Thirty-nine male patients (average age 50.8 years +/- 8.4 years) with a large anterior myocardial infarction (average 45.6 days +/- 10.5 days ago) and with moderate to severe left-ventricular dysfunction (RNVA EF less than 50%) participated in the study. The patients were randomly assigned to either a training group or to a control group. They were also subdivided into training/control groups (EF less than 30% and EF = 30-50%). The training program consisted of three to four sessions per day, 5 days a week, at an intensity of up to 1 W/kg body wt. (approximately 4-5 METS). The following evaluations were recorded prior to and following the 4-week training program: relative heart volume (x-ray), echocardiographic data (enddiastolic diameter, ES-distance, and shortening fraction), and exercise stress test (work capacity, heart rate). Filling pressures, cardiac outpout, and stroke volume index were calculated from right-heart catheterization (Swan-Ganz) at rest and during exercise. Results indicate that there were no significant changes in relative heart volume, end-diastolic volume, ES-distance, resting heart rate, PCP at rest, and ejection fraction during exercise as a result of the training program. Shortening fraction showed a tendency to improve (not significant). Work capacity increased by 15 W (p less than 0.05) in the training group and by 28 W (1.5 METS, p less than 0.05) in the EF less than 30% training-group as compared with the control group. Cardiac output at rest decreased by 10% (p less than 0.05). Stroke-volume index increased in the EF greater than 30% training-group, while heart rate was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Four-week training of patients with large anterior wall infarct: comparison with a randomized untrained control group]. 208 63

We studied nine patients (56 +/- 7 years) with complete AV-block and permanent dual-chamber pacemaker (DDD) under different pacing modes: ventricle pacing (VVI) 70 bpm, DDD 106 +/- 4 bpm, rate adaptive pacing (VVI-FA) 108 +/- 3 bpm. Exercise was performed supine on the bicycle ergometer at 50 watts for 5 min at each setting. DDD-paced patients showed significantly higher mixed venous oxygen saturation, being 45 +/- 2% after the fourth minute, (VVI 38 +/- 2%, p less than 0.01 and VVI-FA paced patients 40 +/- 1%, p less than 0.01). Pressures were normal under DDD pacing during exercise (RAP 7 +/- 2 mm Hg; PCP 14 +/- 3 mm Hg) and showed further increase to abnormal levels during VVI (RAP 13 +/- 2 mm Hg, p less than 0.01; PCP 21 +/- 3 mm Hg, p less than 0.02) and VVI-FA pacing (RAP 10 +/- 2 mm Hg, p less than 0.05; PCP 20 +/- 3 mm Hg, p less than 0.01). Stroke volume increased from 71 +/- 5 ml to 105 +/- 7 ml during VVI and from 64 +/- 7 ml to 81 +/- 7 ml during DDD pacing. Stroke volume remained unchanged (69 +/- 5 ml) during VVI-FA pacing. The peak levels of ANP during and after exercise were significantly higher under VVI (951 +/- 248 pg/ml) than under DDD pacing (650 +/- 140 pg/ml, p less than 0.01) and were not different between DDD and VVI-FA pacing (677 +/- 97 pg/ml). These results show that VVI pacing effects a more pronounced increase of ANP level than other pacing modes. Under moderate exercise, rate-responsive pacing compared to VVI pacing showed no differences in mixed venous oxygen saturation and in atrial pressures. Only DDD pacing showed higher oxygen saturation and a normalization of atrial pressures when compared to other types of single chamber pacing.
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PMID:[Effect of AV synchronization and rate increase on hemodynamics and on atrial natriuretic peptide in patients with total AV block]. 214 4

Haemodynamic monitoring, using a Swan-Ganz balloon catheter, was done in 14 patients with pump failure associated with acute myocardial infarction, before and for 8 h after single 6 mg oral dose of molsidomine. The following changes effects were found: HR fell by 1.6 to 4.7% (significant at 4th hour; p less than 0.05); SBP was 8.4% lower after 1 h (p less than 0.05); PCP was decreased by approximately 30%, a significant effect that lasted for 8 hours (p less than 0.002). CI did not change significantly, although individual analysis showed it to have increased in 6 out of 12 cases. Stroke volume index was increased by about 6% (significant after 1 h, p less than 0.025). The left ventricular stroke work index also increased from 9.8 to 24.5% (significant after 1 and 4 h, p less than 0.01 and 0.025). These findings show the beneficial haemodynamic effects of molsidomine in pump failure complicating acute myocardial infarction.
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PMID:Haemodynamic effects of oral molsidomine in pump failure complicating myocardial infarction. 654 66

In 20 infarct patients, whose age varies from 43 to 78 years (m 59.6), continuous hemodynamic measurements were made to determine the cardiovascular effects of propranolol without and during a simultaneous infusion treatment with nitroglycerin. In cases of compensated ventricular function and pulmonary wedged pressures of 15 mm Hg or less (N = 10), a mean intravenous propranolol dose of 6.1 +/- 1.3 mg led to a significant reduction of the LVSWI and a simultaneous increase of the PCP by 31% of the control value (P less than or equal to 0.005). A simultaneously performed infusion treatment with nitroglycerin at a mean dose of 3.0 +/- 1.6 mg/h resulted in totally cutting off the propranolol-induced PCP increase, whereas a decrease of the heart rate and the LVSWI due to a beta-receptor-blockade remained completely unchanged. In the case of pre-existing congestion insufficiency of the left ventricle (N = 10) and of a pulmonary wedged pressure of above 15 mm Hg, the administration of a mean dose of propranolol of 5.8 +/- 1.1 mg for protection of the myocardium resulted in a partly disquieting decrease of the volume of cardiac output (P less than or equal to 0.005) which was 28% of the control value for the CI an 12% for the SVI. Correspondingly the left ventricular stroke work decreased to 18%. Nitroglycerin has a reducing influence on these changes, but not down to the initial level. In cases of sufficient ventricular function, propranolol has a favorable influence on the myocardial O2-metabolism via its depressor effect on heart rate and contractility. By means of nitroglycerin, an increase of the pulmonary wedged pressure occurring under this condition can be inhibited. However, in the case of a pre-existing congestion insufficiency, propranolol can lead to a partly disquieting depression of the circulation, which, apart from the hemodynamic risks, makes a rather unfavorable influence on the myocardial O2-metabolism seem likely.
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PMID:[The treatment of acute myocardial infarctions with beta-receptor-blockers. II. Hemodynamic effects of propranolol with and without combination therapy with nitroglycerin (author's transl)]. 679 41

Haemodynamic and echocardiographic studies of isosorbide dinitrate were conducted in 12 patients (8 men and 4 women) with left ventricular failure consecutive to recent myocardial infarction. The groups: group I received 5 mg/h and group II 10 mg/h Risordan intravenously. After one hour treatment, group I patients showed a significant fall in both PAP (from 32.3 +/- 5.3 to 26.7 +/- 6.9 mmHg; p less than 0.01) and PCP (from 21.8 +/- 4.7 to 17.3 +/- 7.7 mmHg; p less than 0.05). These haemodynamic changes were amplified after a second hour of treatment: PAP fell to 24 +/- 7.9 mmHg (p less than 0.01) and PCP to 14.2 +/- 4.4 mmHg (p less than 0.001). RAP decreased from 7.2 +/- 5.1 to 3.5 +/- 5 (p less than 0.05). There were no changes in heart rate, systemic arterial pressure, peripheral resistance, cardiac index, forward stroke work nor, on echocardiography, in ventricular diameters, shortening fraction and VCF. After one hour treatment, group II patients showed a fall in PAP (from 30.5 +/- 4.7 to 21.7 +/- 3.5 mmHg; p less than 0.01), PCP (from 21.7 +/- 4.8 to 14.8 +/- 4.9 mmHg: p less than 0.001) and RAP (from 10.3 +/- 2.9 to 7.2 +/- 2; p less than 0.01). The systolic diameter of the left ventricle was reduced from 66.3 +/- 10.6 to 64.3 +/- 11.3 (p less than 0.01). After 4 hours, improvement in PAP and PCP was maintained; the other values remained stable. The effectiveness of Risordan i.v. in left ventricular failure consecutive to acute myocardial infarction is due to reduction of filling pressures in the left ventricule. With the 10 mg/h dose, as opposed to the 5 mg/h dose, the systemic arterial pressure and the double and triple products tend to be reduced, which suggests greater effectiveness.
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PMID:[Use of isosorbide dinitrate (Risordan) injection in left ventricular failure following acute myocardial infarction (author's transl)]. 711 Sep 69

Keeping pre-transplant patients alive while waiting for a suitable donor is still a major challenge. New pharmacological agents which can provide improved hemodynamics are urgently needed in patients with severe heart failure who are on the waiting list for cardiac transplantation. Intravenous enoximone therapy (an initial 0.5 mg/kg bolus, then 1.25-5.0 mcg/kg/min infusion) was administered to 35 transplant candidates with progressive heart failure despite optimal drug regimen including digoxin, diuretics, and ACE-inhibitors. In 18 out of 35 patients complete hemodynamic, echocardiographic, neurohumoral, and Holter-ECG studies were performed before and 24 hours after intravenous enoximone infusion. Patients were then continued on chronic oral therapy of 100 mg twice a day. Enoximone infusion increased the cardiac index (CI) (1.78 +/- 0.45 l/min/m2 vs 3.04 +/- 0.83 l/min/m2; p < 0.001) and stroke volume index (SVI)(22.33 +/- 9.45 ml/m2 vs 32.28 +/- 7.29 ml/m2; p < 0.05) and decreased wedge pressure (PCP)(24.1 +/- 11.98 mmHg vs 17.78 +/- 8.76 mmHg; p < 0.05) while mean arterial pressure (MAP) was unchanged. Left ventricular ejection time (LVET)(225.1 +/- 26.9 ms vs 242.2 +/- 25.8 ms; p < 0.05) was increased whereas other echocardiographic parameters were unchanged (Left ventricular end-diastolic dimension LVEDD, left ventricular end-systolic dimension LVESD, fractional shortening FS, early diastolic relaxation parameter Te). Plasma neurohumoral parameters did not change (Aldosterone, epinephrine, renin, atrial natriuretic factor) except for a significant drop in norepinephrine (936.7 +/- 443.2 pg/ml vs 522.4 +/- 287.6 pg/ml; p < 0.05). Holter-ECG parameters (ventricular premature beats VPB, couplets, ventricular tachycardia VT) were not influenced by enoximone infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enoximone therapy as pharmacological bridging to cardiac transplantation. 837 84

The noncompetitive (PCP) site of the N-methyl-D-aspartate (NMDA) receptor complex has been implicated in a number of pathologies, including the etiology of ischemic stroke. Recent testing has shown that cis-1,2,3,4,9,9a-hexahydro-N-methyl-4aH-fluoren-4a-amine (1), a rigid analog of PCP, is a potent antagonist at this site (IC50 = 30 nM for displacement of [3H]TCP). On the basis of this finding, a number of derivatives encompassing variations in stereochemistry, amine substitution and position, aromatic and aliphatic ring substitution, and heteroatom ring substitution have been prepared to explore the structure-activity relationships around this ring system. All compounds were evaluated for their PCP receptor affinity; potent compounds were also tested in vitro (cultured neurons) and in vivo (prevention of NMDA-induced lethality in mice). The present hexahydrofluorenamines demonstrated a wide range of potencies, with optimal affinity concentrated in analogs containing a heteroatom (sulfur) in the B ring (IC50 of 11 nM versus [3H]TCP for 16b), methyl substitution on the amine, and R stereochemistry at the 4a position. No significant improvement in affinity was seen with aromatic ring substitution. Aliphatic ring substitution, large amine substituents, and alterations in the position of amine substitution on the ring system resulted in a loss of potency. To explore the effect of simultaneous hydrogen bonding with a putative receptor atom from two directions, the 2-hydroxymethyl derivatives were prepared. This substitution resulted in a loss in receptor binding affinity. Molecular modeling, X-ray, and NMR studies have been used to determine an optimal conformation of the hexahydrofluoreneamines at the receptor site.
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PMID:Synthesis and pharmacological evaluation of hexahydrofluorenamines as noncompetitive antagonists at the N-methyl-D-aspartate receptor. 845 95

The development of neuroprotective agents for the prevention of neuronal loss in acute conditions such as stroke and epilepsy or chronic neurodegenerative disorders including Parkinson's disease, Alzheimer's disease, Huntington's chorea, and motor neuron disease is currently focusing on drugs that inhibit excitatory amino acid neurotransmission or exhibit antioxidant properties. Unfortunately, potent antagonists at the N-methyl-D-aspartate (NMDA) type glutamate receptor, which is thought to mediate excitotoxic neuronal injury, e.g., MK-801 or phencyclidine (PCP), share a high probability of inducing psychotomimetic side effects. Further, these drugs have been associated with acute neurotoxicity in vitro and in vivo, precluding their clinical use. In contrast, low affinity NMDA receptor antagonists like amantadine and its dimethyl derivative, memantine, have been administered clinically for the management of Parkinson's disease, dementia, neuroleptic drug-induced side effects, and spasticity. These agents have only rarely induced significant psychotomimetic side effects. Recent pharmacologic advances have helped to elucidate how high drug affinity for the PCP binding site of the NMDA receptor may enhance psychotogenicity. Low affinity and associated fast voltage-dependent channel unblocking kinetics are likely to be responsible for the better tolerance of amantadine and memantine compared with MK-801 and PCP. Further factors apparently modulating psychotogenicity of glutamate receptor antagonists include differential actions on neuronal populations in various brain regions and interactions with neurotransmitter receptors other than the NMDA type glutamate receptor.
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PMID:Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy. 901 83

Altered neurotransmission mediated by L-glutamate at the level of the N-methyl-D-aspartic acid (NMDA) receptor complex has been implicated in the pathophysiologic mechanisms of several major neuropsychiatric disorders. Moreover, strategies for the pharmacologic manipulation of NMDA-mediated neural transmission have been discussed for the treatment of disorders as diverse as schizophrenia, seizures, stroke, and traumatic brain injury, MK-801, an uncompetitive allosteric antagonist of the NMDA receptor complex, was shown to antagonize electrically precipitated seizures in a dose-dependent manner and elicit popping behavior in mice. Changes in the ability of MK-801 to antagonize electrically precipitated seizures or elicit popping behavior caused by stress or pharmacologic manipulations may reflect alterations in the populations of NMDA-associated channels responsible for these behavioral actions (e.g., the number of them in the open configuration or their size, shape, and charge characteristics). We used these paradigms to study the pharmacologic actions of an allosteric glycinergic intervention (i.e., milacemide), inhibitors of the "nitric oxide cascade" (i.e., 7-nitroindazole and methylene blue), and conventional (i.e., haloperidol) and atypical (i.e., clozapine) antipsychotic medications on NMDA-mediated neurotransmission in the intact mouse. Also, marked differences in the ability of MK-801 to elicit popping behavior in inbred mouse strains suggest that they differ in their populations of NMDA receptor complexes responsible for mediating this behavior. This latter observation could lend itself to the identification of specific genetic loci contributing to this behavior. In view of the ability of phencyclidine (PCP) to precipitate a schizophreniform psychosis and the action it shares with MK-801 on NMDA-mediated neurotransmission, the characterization of these genetic loci in mice may inform the search for human loci responsible for the susceptibility to "PCP-psychosis" and schizophrenia.
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PMID:Behavioral approaches to the functional assessment of NMDA-mediated neural transmission in intact mice. 933 13


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