Edward F. Domino

Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581.

HERE IS A definite need for safe and T potent intravenously administered anesthetics of short duration which combine analgesic and sleep-producing effects without significant cardiovascular and respiratory depression. Recently, a number of compounds related to phenylcyclohexylamine have aroused clinical interest because they appear to approach such requirements. Phencyclidine hydrochloride was the prototype of this group of agents. After preliminary laboratory studies1 its clinical usefulness as an anesthetic was investigated by Greifenstein and associates.2

Neurobiology of Phencyclidine (Sernyl), A Drug With An Unusual Spectrum of Pharmacological Activity

Publisher Summary This chapter reviews some of the available literature describing the unusual actions of phencyclidine. The chapter emphasizes on the pharmacology of phencyclidine. Phencyclidine is 1- (l-phencyclohexyl) piperidine hydrochloride. It is also known as Sernyl or CI-395. The effects of phencyclidine, like any other drug, are dose dependent. The pharmacological actions of phencyclidine appear to be complex. The effects depend upon the species and dose. Evidence is available that in subanesthetic doses the drug alters the reactivity of the central nervous system to various sensory inputs. The drug acts at spinal cord, brainstem, diencephalic, and cerebral cortical levels. Schizophrenic subjects appear to be quite sensitive to phencyclidine and become much worse, in contrast to their behavior after LSD-25 and mescaline. The metabolic effects of phencyclidine may be the result of uncoupling of oxidation from phosphorylation, similar to dinitrophenol, or result from a potentiation of the metabolic actions of catecholamines Phencyclidine possesses a pharmacological spectrum of activity uniquely different from other psychotomimetic or anesthetic drugs.

Taming the Ketamine Tiger

Pharmacologic Effects of CI-581, a New Dissociative Anesthetic, in Man. By E. F. Domino, P. Chodoff, G. Corssen. Clin Pharmacol Ther 1965; 6:279–91. Reprinted by permission from Macmillan Publishers Ltd., copyright 1965. Abstract:Pharmacologic actions of CI-581, a chemical derivative of phencyclidine, were determined in 20 volunteers from a prison population. The results indicate that this drug is an effective analgesic and anesthetic agent in doses of 1.0 to 2.0 mg per kilogram. With intravenous administration the onset of action is within 1 min and the effects last for about 5 to 10 min, depending on dosage level and individual variation. No tachyphylaxis was evident on repeat doses. Respiratory depression was slight and transient. Hypertension, tachycardia, and psychic changes are undesirable characteristics of the drug. Whether these can be modified by preanesthetic medication was not determined in this study. Recovery from analgesia and coma usually took place within 10 min, although from electroencephalographic evidence it may be assumed that subjects were not completely normal until after 1 to 2 h. No evidence of liver or kidney toxicity was obtained. CI-581 produces pharmacologic effects similar to those reported for phencyclidine, but of shorter duration. The drug deserves further pharmacologic and clinical trials. It is proposed that the words “dissociative anesthetic” be used to describe the mental state produced by this drug.

Changing concepts in pain control during surgery: dissociative anesthesia with CI-581. A progress report.

RADITIONAL agents and methods for genT e r a 1 anesthesia have provided effective pain control through total depression of the central nl‘rvous system, including cortical and subcortical regions and various pathways involved in the conduction and perception of affwent impulses in general. Recently, a trend has become apparent toward the selective blocking of pain conduction and perception, leaving those parts of the central nervous system free from the depressant effects of drugs which do not participate in pain transmission and perception.

Plasma levels of ketamine and two of its metabolites in surgical patients using a gas chromatographic mass fragmentographic assay

Ketamine and two of its metabolites were determined up to 24 hours by a sensitive and specific gas chromatographic mass fragmentographic (GCMF) assay in the plasma of seven premedicated surgical patients. Each patient received ketamine in a dose between 2.0 and 2.2 mg/kg given intravenously over a 30-second period. Plasma levels of ketamine varied from 9,000 to 25,800 ng/ml 1 minute after injection to approximately 1,000 ng/ml when the patients began to recover consciousness. Within the next 24 hours, the patients had a complex logarithmic decline in plasma levels of ketamine. Some patients showed approximately 5 to 15 ng/ml levels of ketamine 24 hours after injection. The data suggest rather complex pharmacokinetics with multiple compartments. Ketamine metabolites I and II were also found in the plasma over comparable periods of time. Ketamine metabolite I levels ranged from a high of 245 to 668 ng/ml within 30 minutes after ketamine administration to as low as 15 ng/ml 24 hours later. Ketamine metabolite II levels were lower with a peak of 515 ng/ml in approximately 60 minutes to 13 to 27 ng/ml 24 hours later. Recovery from anesthesia was related to the first two phases of rapid redistribution of ketamine. The plasma levels of the two ketamine metabolites were first detectable approximately 5 minutes after ketamine injection. Their relatively low levels throughout ketamine anesthesia and postanesthesia do not correlate with recovery from anesthesia. CSTRIP and NONLIN analysis indicated that a three-exponential equation best approximated the data obtained. It is concluded that a three-compartment open model best approximates ketamine pharmacokinetics in these patients.

Some effects of muscarinic cholinergic blocking drugs on behavior and the electrocorticogram

SummaryResults are presented for the effects of drugs with muscarinic cholinergic blocking actions, both central and peripheral (scopolamine and 1-hyoscyamine) and primarily peripheral (methyl atropine and methyl scopolamine), on conditioned avoidance behavior, spontaneous motor activity, and the ECG in the rat.Low doses of the agents with central actions retarded acquisition of conditioned avoidance, while high doses virtually abolished it. Both low and high doses were essentially ineffective in altering retention of conditioned avoidance. Agents with primarily peripheral actions had no effect on acquisition or retention.Most of the agents produced an increase in spontaneous activity although there was a definite suggestion that higher doses depress activity.All of the agents used provoked a high amplitude, slow frequency ECG. This phenomenon was dose-related; scopolamine appeared to be most effective.It is suggested that the disruption of the acquisition, but not retention, of conditioned avoidance is due to a deficit of recent memory. A possible site of action of cholinergic blocking drugs is proposed.

Electroencephalographic and eye movement patterns during sleep in chronic schizophrenic patients

Abstract Continuous all night sleep EEG recordings were obtained from a group of 25 chronic, hospitalized schizophrenic patients and ten normal control subjects for 5 consecutive nights. Analyses are presented for the second night of sleep. Results for mean percentage of stages I, II, III, IV and I-REM for control subjects were found to be similar to values reported for comparable control populations using similar scoring techniques. In contrast, 40% (N = 10) of the schizophrenic patients failed to manifest any scorable stage IV and were significantly reduced in amount of stage III. For all patients, a reduction in amplitude of the delta wave component of stages III and IV was apparent relative to control subject records. Schizophrenic patients were found to have a more disturbed sleep compared to controls, although no distinction was apparent between patients with or without stage IV present. Differences in time of onset, duration, and number of sleep stage changes were noted between schizophrenic and control subjects. Possible implications arising from the observed disturbance of “slow wave” patterns in the sleep EEGs of schizophrenic patients are discussed in light of research on the loci of this activity in the brain, as well as recent reports linking amino acid levels and EEG sleep patterns.

Preischemic But Not Postischemic Zinc Protoporphyrin Treatment Reduces Infarct Size and Edema Accumulation After Temporary Focal Cerebral Ischemia in Rats

BACKGROUND AND PURPOSE Zinc protoporphyrin (ZnPP) has multiple actions. It is an interleukin-1 antagonist as well as a hemeoxygenase inhibitor. Interleukin-1 is produced in ischemic brain and probably contributes to ischemic injury, although the role of heme oxygenase during ischemia is unknown. Whether ZnPP treatment is more effective before or after ischemia, as well as whether it is more protective in permanent or temporary cerebral ischemia, is also unknown. Therefore, we investigated the effect of ZnPP on infarction size and edema in a rodent model of temporary and permanent focal cerebral ischemia. METHODS Two groups of adult male Sprague-Dawley rats were pretreated with either 50 mg/kg ZnPP IP or saline and subjected to permanent middle cerebral artery occlusion 30 minutes later. Four additional groups of animals were subjected to 2 hours of temporary middle cerebral artery occlusion followed by 22 hours of reperfusion. Two of these groups were pretreated 30 minutes before middle cerebral artery occlusion with either 50 mg/kg ZnPP IP or saline. The other groups received ZnPP at either 2 or 4 hours after middle cerebral artery occlusion. Regional cerebral blood flow in the ischemic cortex was monitored with laser Doppler flowmetry. Cerebral infarct size and brain water were measured 24 hours after the onset of either form of ischemia. RESULTS Regional cerebral blood flow after occlusion was approximately 13% to 20% of baseline after either permanent or temporary ischemia. ZnPP had no effect on regional cerebral blood flow, infarct size, or edema formation in permanent ischemia. In contrast, pretreatment significantly reduced infarct size (17.2 +/- 6.6% in controls versus 6.2 +/- 2.9% in pretreated rats) and edema formation (center zone, 4.00 +/- 0.71% water in controls versus 1.18 +/- 0.26% water in pretreated rats) in the model of temporary ischemia, but treatment after occlusion had no effect. CONCLUSIONS ZnPP treatment protected the brain when administered early in the temporary ischemia model.

Some cardiovascular effects of marihuana smoking in normal volunteers

Marihuana smoking caused a significant increase in heart rate in 25 normal male volunteers. The degree of techycardia was significantly related to the dose of Δ‐9‐ tetrahydrocannabinol (Δ‐9‐THC). The marihuana smoked contained 0.5 and 2.9 per cent Δ‐9‐THC and was compared to extracted marihuana as a control in a single‐blind experimental design. Dose of Δ‐9‐THC was expressed as the total amount available in the number of cigarettes smoked under standard conditions. The tachycardia reached a maximum within 30 minutes and persisted longer than 90 minutes. Systolic and diastolic blood pressures were significantly elevated after total doses of marihuana containing more than 10 mg. of THC, but blood pressure was better correlated to heart rate than to dose. Changes in the electrocardiogram were minimal, but there were premature ventricular contractions in some subjects.

Nicotine effects on regional cerebral blood flow in awake, resting tobacco smokers

The hypothesis for this research was that regional cerebral blood flow (rCBF) would increase following nasal nicotine administration to overnight abstinent tobacco smokers in relationship to the known brain distribution of nicotinic cholinergic receptors (nAChRs). Nine male and nine female healthy adult smokers were studied. They abstained overnight from tobacco products for 10 or more hours prior to study the next morning. Nicotine nasal spray was given in doses of 1–2.5 mg total with half in each nostril while the subject was awake and resting in a supine position. Oleoresin of pepper solution in a similar volume was used as an active placebo to control for the irritating effects of nicotine. Both substances were given single blind to the subjects. Positron emission tomography (PET) with H215O was used to measure rCBF. The data from each subject volunteer were normalized to global activity to better assess regional brain changes. Both nasal nicotine and pepper spray produced similar increases in CBF in somesthetic area II, consistent with the irritant effects of both substances. The mean rCBF effects of nasal pepper were subtracted from those of nasal nicotine to determine the actions of nicotine alone. The latter produced increases in rCBF in the thalamus, pons, Brodman area 17 of the visual cortex, and cerebellum. Some brain areas that contain a large number of nAChRs, such as the thalamus, showed an increase in CBF. Other areas that have few nAChRs, such as the cerebellum, also showed an increase in relative CBF. The hippocampal/parahippocampal areas showed greater regional decreases (left) and lesser increases (right) in CBF that correlated with the increase in plasma arterial nicotine concentrations. The results obtained indicate complex primary and secondary effects of nicotine in which only some regional brain CBF changes correlate with the known distribution of nAChR. No gender differences were noted. Synapse 38:313–321, 2000.