http://exhibits.library.stonybrook.edu/mfp/files/original/4829a346731c642d4b009d69ede20ef4.pdf f52f80e5b4fabf3b53f885310a3d6354 PDF Text Text Clinical and electroencephalographic effects of Megimide in patients Without cerebral disease Martin A. Green, M.D., and Max Fink, M.D. the introduction of Megimide (beta, beta methylethylglutarimide) as an antagonist for barbiturate intoxication in 1955, considerable interest has been stimulated in its clinical applicability. Initial reports noted its efficacy in barbiturate poisoning,1—4 but subsequent studies failed to substantiate this applicationf)"8 In this laboratory, barbiturates are frequently administered under the standardized conditions of the “amobarbital test.”9 It was thus possible to assess the efficacy of Megimide in altering the behavioral response of human subjects to physiologic equivalent amounts of barbiturate. In addition to its suggested antagonism to barbiturate, Megimide induces both paroxys— mal discharges in the electroencephalogram and clinical grand mal seizures.10—14 The present report concerns our experience with both the behavioral and electroencephalographic effects of Megimide. FOLLOWIXG AIATERIAL AND METHODS Thirty-four hospitalized voluntary psychiatric patients with psychoneurosis, depression, or schizophrenia, ranging in age from 27 to 64 years, were studied. Megimide in a concentration of 5 mg. per cc. was administered intravenously at the rate of 0.5 mg. per kg. per minute, until definite changes were observed in the electroencephalogram and often beyond this point. The amount of Megimide varied from 45 mg. to 250 mg. In 15 subjects Megimide was administered without prior amobarbital. In 19 patients it was given following the administration of in— travenous amobarbital which was injected at 0.5 mg. per kg. every 40 seconds, in amounts necessary to induce nystagmus, slurred speech, and marked drowsiness or sleep. All experiments were undertaken in the elec- troencephalographic laboratory. An electroencephalogram was made prior to the injections and was run continuously during the administration of both drugs. The electrode placement consisted of frontal, motor—parietal, occipital, anterior temporal, posterior temporal, vertex, and earlobe'. Both scalp—to-earlobe and scalp-to-scalp combinations were used. RESULTS The electroencephalogram in all subjects prior to the administration of the drugs was “normal,” that is, symmetric and non-dysrhythmic. Electroencephalographic Response In the amount and rate of injection of Megimide employed, electroencephalographic changes occurred in every patient. The type of response and the amount of drug necessary to induce such a response were highly variable. The electroencephalographic changes included irregular low- and moderate-voltage slow ac— tivity, bursts of slow activity (usually of high voltage), single spike discharges, and spikewave forms (figure 1 A, B, and C). These ef— fects were diffuse and symmetric, with greatest prominence in the temporal leads. The sequence of these responses was inconstant. Irregular, low-voltage slow activity was the most frequent initial change in the record. In other instances, bursts of highvoltage slow activity or spike activity appeared initially. As the injection continued, the amplitude and per cent time delta activity inFrom the department of experimental psychiatry, Hillside Hospital, Glen Oaks, Long Island, New York. Read at the meeting of the Eastern Association of Electroencephalographers, New York, December 1956. Aided by Grant M 927, National Institute of Mental Health, National Institutes of Health, US. Public Health Service. Reprinted from NEUROLOGY, Minneapolis, September 1958, Vol. 8, N0. 9 Copyright 1958, by Lancet Publications, Inc. �EFFECTS OF MEGIMIDE "NV‘VV Mvw LP-RP *V‘JlWMAA/‘fr'rwm“MWHWIMS‘WWVWWMmeLMMA. L0‘ R 0 (memwwmewwWWW» WM WflM‘j(Ml/\rlY/‘Vr'j‘fluj'wwMWWWWWWJWMW VWLWMW WWW/wWWJMWW *WWWWWWW AT R P T I‘ 5A , ”v w. a WW1 '«M “-34x4“ MW‘WMMWW I ‘A ‘M’m‘rv‘v‘rfi‘w Jam.M’w’M—‘fi' draw; R “ij MW ® .I 50 35cc MEGIMIDE (5 cc/ MIN) mv lSEC, LP-RP @ 30 cc MEGIMIDE (Soc/MIN.) ' SEC' creased. Bursts of high—voltage slow activity were seen eventually in almost all patients. Spike discharges, however, were less frequent, even with relatively large doses of Megimide. For example, the tracings in one subject after receiving 220 mg. of Megimide and in another after receiving 250 mg. showed irregular diffuse slow activity without spike activity. Seizures Because of the nature of the population and the goals of our study, we specifically avoided administering Megimide in rates and amounts that would produce clinical grand mal seizures. Despite these precautions, a grand mal seizure was inadvertently induced in one patient. A 33 year old woman was given 200 mg. of Megimide at the rate of 50 mg. per minute. Up to 150 mg. there was only a decrease in the voltage of the alpha activity. After 200 mg. there was a sudden long run of diffuse, rhythmic 4 to 5% cycles per second high voltage activity, with intermixed spike activity which was immediately followed by the seizure. The electroencephalogram during injection and prior to the seizure showed minimal changes, and the seizure was not anticipated 35M: MEGIMIDE (Sac/MIN.) SE“ F IG. 1. Different types of electroencephalographic response to Megimide. A, delta activity, irregularly and in bursts, B, single spike activity, C, spike-wave activity Subjective Response The subjective reaction to Megimide was minimal, even when the induced changes in the electroencephalogram were severe. A few subjects complained of nausea, “dizziness,” “shakiness,” or a peculiar sensation in the abdomen. It was possible, however, to continue the injection without further increase in the symptoms. Two subjects became apprehensive, and in one of these the injection had to be discontinued. Myoclonic jerks occurred frequently. They were usually mild and confined to one extremity. Less frequently they were bilateral and more severe. The relationship between these movements and spike activity was inconstant. The myoclonic jerks usually preceded the appearance of spike activity, althOugh the reverse occurred occasionally. The simultaneous appearance of spike activity with myoclonic jerks was infrequent. The effect of Megimide was short-lived. There were no instances of seizures or other abnormal responses later in the day following its administration. However, since intravenous amobarbital followed in all patients, this may have prevented such occurrences. The clinical and electroencephalographic responses to intravenous amobarbital following Megimide appeared similar to those seen in subjects in whom amobarbital is administered without prior medication. The slow-wave or spike activity induced by Megimide disappeared and the usual patterns associated with barbiturates developed (figure 2). However, �NE UROLOGY 684 the well-modulated high per cent time beta activity usually noted after barbiturate administered was less prominent. M egz’mide Following Amobarbital One group of subjects received intravenous amobarbital prior to Megimide until drowsiness, slurred speech, and nystagmus were induced. The electroencephalogram showed the patterns commonly associated with barbiturates, that is, an increase in voltage and per cent time fast activity and a decrease in amount and voltage of alpha activity. The most prominent clinical change was the awakening of the subject. Within the few minutes necessary for the injection, the patient became more responsive, slurred speech disappeared, and drowsiness, both on subjective and objective evaluation, was minimal or absent. Nystagmus became inconstant, unsustained, or disappeared completely. Gait, including heel-totoe walking, was steady. However, the awakening effect was not uniform for all aspects of behavior altered by barbiturate. For ex— ample, if the subject became euphoric and more talkative with barbiturate, such behavior may have persisted in a milder form, even after the drowsiness of amobarbital was abolished by Megimide. These clinical changes were accompanied by alterations in the electroencephalogram (figure 3). Patterns of drowsy activity disappeared. Alpha activity increased both in amount and voltage. Fast activity induced by amobarbital usually persisted unchanged or was reduced only sightly. In some instances it increased in amount and voltage. The prior administration of amobarbital did not prevent the appearance of paroxysmal discharges. WW W LP-RP W WJMWW LO'RO LF-RF -om A mmwwwwwwvwvv WWW/”WWW AT-PT @RESTING RECORD W wa~VMMMWh~WMphfiwnw~ L AT-F R MMKWWWMMVWVJ @ UL ‘vr—WW‘W wabwuvmh1-vun~pa~h4qu WWW» 50!”?— 1 azsrmc RECORD 252 (28 mg. AIOBARBIYAL rug/40 SEC.) 40 c: IEGEIIDE (5 cc / III.) FIG. 2. Effect of amobarbital following administration of Megimide fiWWA/VWW 38cm MEGIMIDEHScc/MIN.) r. W WWW WWWWHW WWW WWW WVNMWMWWM o LO . R0 F: MNVWVWVWVW—M’NW’ Megimide is similar to pentalenetetrazol (Metrazol) in that it induces delta activity, spike and spike-wave activity in the electro— encephalogram, and clinical grand mal seizures. Such changes occur in nonepileptic subjects without brain disease, and considerable individual variability in the threshold for these changes exists. These discharges are nonspecific and cannot be used as evidence of the presence of a seizure disorder. The possibility of using Megimide in activating the electroencephalogram has received study.10—1‘-’ Several investigators have noted a more gradual onset of the electroencephalographic and clinical changes with Megimide than with Metrazol. For this reason, the opinion is expressed that Megimide may be more facile in reproducing both clinical and electro— encephalographic seizures in patients with seizure disorders. It should be emphasized, however, that in the one patient in the present study in whom a grand mal seizure occurred, the seizure began suddenly and was not anticipated either from the electroencephalogram or previous clinical responses. Megimide is effective in counteracting the clinical effects of small doses of intravenous amobarbital. This property has been previously demonstrated in animals3 and is being utilized LF-RF k WN-WINW‘MWMNWVM DISCUSSION 0%va6Wwaw'wwrwwqp'v LM-RM {-0 Bursts of high-voltage slow activity, spike activity, or spike-wave activity often appeared, usually during or after awakening. Such activity was not a necessary accompaniment of the awakening response, however, since other subjects in whom clinical drowsiness disappeared did not show such discharges. 500 mg.AMOBARBlTAL (50 mq./40 SEC.) Effect of Megimide following administration of amobarbital FIG. 3. SEC. �EFFECTS OF MEGIMIDE in anesthesiology to shorten the recovery period from barbiturate anesthesia postoperatively.15 It is questionable whether this action is specific for barbiturates or whether it also applies to states of altered consciousness due to other agents as well.16 CONCLUSIONS Thirty-four psychiatric patients without cerebral disease were given Megimide (beta, beta-methylethylglutarimide) before and after the administration of intravenous amobarbital. 2. Megimide produces irregular delta activ~ ity, bursts of delta activity, and spike and spike-wave activity in the electroencephalo1. 685 gram. Such effects are similar to those produced by pentalenetetrazol (Metrazol). 3. Considerable individual variability exists in the amount of drug necessary to produce these changes. 4. A grand mal seizure was inadvertently induced in one patient. The electroencephalogram during the injection and prior to the seizure showed minimal changes and the seizure was not anticipated. 5. Megimide counteracts the clinical and some of the electroencephalographic effects of small doses of intravenous amobarbital. Megimide supplied through the courtesy of A. las Ltd., Slough, Bucks, England. & I. Nicho- REFERENCES A., SHAW, F. H., CASS, N. M., and \Van, H. M.:M. A new treatment of barbiturate intoxication. Brit. J. 1:1238, 1955. 1. SCHULMAN, to . 3. 4. 5. 6. 1. 8. 9. F. H.: Further experiences with Megimide—a barbiturate antagonist. M. J. Australia 2:889, 1955. SHAW, F. H., SIMON, S. E., CAss, N., and SCHULMAN, .-\.: Barbiturate antagonism. Nature 174:402, 1954. HARRIS, T. A. 13.: A barbiturate antagonist. Lancet 1:268, 1955. L()U\V, A., and SONNE, L. M.: Megimide in the treatment of barbituric acid poisoning. Lancet 2:961, 1956. PEDERSEN, ].: Amusing effect of Megimide and Ami— phenazole in allypropymal poisoning. Lancet 2:965, 1956. PLUM, F., and SWANSON, A. G.: Barbiturate poisoning treated by physiological methods. J.A.M.A. 163:827, 1957. CERSHON, S., and SHAW, F. H.: Effects of Bemegridc on barbiturate overdosage in humans. Brit. M. J. 2: 1509, 1957. \VEINSTEIN, E. A., KAHN, R. L., SUGARMAN, L. A., and LINN, L.: The diagnostic use of amobarbital sodium (“Amytal sodium”) in brain disease. Am. J. Psychiat. 109:889, 1953. SHAW, 10. COURJON, 1., and BONNET, H.: Comparative effects of Metrazol and Megimide in activation of epileptic pa- tients. EEG 11. 12. 13. 14. 15. Clin. Neurophysiol. 8:710, 1956. DROSSOPOULO, G., GASTAUT, H., VERDEAUX, G. and J., and SCHULLER, E.: Comparison of EEG “activation” by pentamethylenetetrazol (Metrazol) and Bemegride (Megimide). EEG & Clin. Neurophysiol. 8:710, 1956. Room, E. A., RUTLEDGE, L. T., and CALHOUN, H. D.: Megimide and Metrazol (A comparison of their convulsant action in man and in the cat). EEG & Clin. Neurophysiol. 10:208, 1958. SOD‘TRBERG, U.: Eflect of Bemegride (Megimide) on cerebral blood flow and electrical activity of brain. Arch. Neurol. & Psychiat. 792239, 1958. PEACOCK, J. M.: An electroencephalographic examina— tion of the effects of Megimide and Daptazole in bar— biturate narcosis. EEG 8: Clin. Neurophysiol. 8:289, 1956. VVYKE, B. D., and FRAYVVORTH, E.: Use of Bemegride in terminating barbiturate anesthesia. Lancet 2:1025, & 1.957. 16. BOTTINGER, L. E., ENGSTEDT, L., and STRANDBERG, 0.: Is Bemegride a specific barbiturate antagonist? Lancet 1:932, 1957. �6mm and m We“: at Was in Patients WW?» 66”me Mum W m A. 11.3. ‘W-AMWI < I . the m Gala, Wt30!.of mm mm. mm swam. Glen 1mm... matting at the Max “manhunt: or m at thoMubor Elsemmm. 1956. Nam Yam-k, " Aiéadhy Grant Wham 3/58 65f I! 92?, Katina}. M‘W‘lfii at mm Kalil), 0.3. fibula Knuth 3031“. mm. 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Magma: as net 6.1119195.qu of men. dawn of tutu-amp“ maba'rhim. etfeete, �� Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Clinical and electroencephalographic effects of megimide in patients without cerebral disease. Neurology. 1958 Sep; 8(9):682-5. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-001-22b-027 Date A point or period of time associated with an event in the lifecycle of the resource 1957 Creator An entity primarily responsible for making the resource Green, Martin A.; <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource [Preprint] and reprint. Reprint from NEUROLOGY, Minneapolis, September 1958, Vol.8, N0.9 Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published