3...... .4 JV. 3.1;: .- ‘23 {6‘ r... 6. s E . . u». L w” 0 g r.“ WWI. O I”... 13.6 10‘. a 1me v.2? I... “v.3 ., v Cr. 7“ a. o O O I . y u l I \1 '1: d: on. IL"! .0 ~ i .3“. a n. i. 4 my. =3 ”a... “,2 . .1. . (AV! 1.. rake. 3...... falc “c5 . .3.- .13 R f X. . a 4., .0 I ‘50. “‘7... p‘§\ fl: DS.‘ “a“ \ F." II. . ”.3 («V . «.W flirt 4.... UK. tom .3: ‘t‘ o :m‘ an. .5.” ., .. if. a a o I t E‘ s. o g . a. n n93 .- a; I-.. : f .2; :2: ”pun ' "m:- SOME EFFECTS OF TRIFLUPROMAZINE HYDROCHLORIDE IN GOATS by Saroj Kant Jha AN ABSTRACT Submitted to the College of Veterinary Medicine Michigan State University of Agriculture and Applied Science in partial fulfillment of , 'the requirements for the degree of MASTER OF SCIENCE Department of Surgery and Medicine / / y // / ./ / /); / //I ’ , i I 1/ :l/ ,‘ '/"./l I, ’ A , _.__.. _ .. - . Approved J/x/4Zf <2{:?Z/AAJ ’ztéefi,- ”“ 1959 2 SAROJ KANT JHA ABSTRACT This study was made to determine the effects of tri- flupromazine hydrochloride (vetame*) on respiratory rate, pulse rate, arterial blood pressure, rectal temperature, electrocardiogram, and spontaneous motor activity of goats. A permanent 100p of the left carotid artery was established for recording arterial blood pressure. A Sanborn multi- channel recorder and electromanometer were used for recording blood pressure, electrocardiogram and pulse rate. A New Haven pedometer was used for recording spontaneous motor activity. Respiratory rates were determined by means of a stethosc0pe. Three dose levels of vetame were used intravenously=-O.5, 1.0 and 2.0 milligrams per pound of body weight. Readings were made at 30 minute intervals. With 0.5 milligram and 1.0 milligram doses, three readings were taken. With 2.0 milligram doses, readings were usually taken at 30 minute intervals up to a minimum of six hours. Some of the readings, due to technical or mechanical difficulty, could not be recorded. After administration of the drug, depression, labored breathing, cyanosis of mucous membranes of varying degree, salivation and incoordination of hind quarters were the symptoms observed. When the drug was administered at the rate of 0.5 milligrams per pound of body weight, *E. R. Squibb and Sons, New Brunswick, New Jersey. 3 SAROJ KANT JHA ABSTRACT respiratory rate was lowered in 7l.h percent of the goats at 30 minutes, and in 57.1 percent at 60 and 90 minutes. When it was injected at the rate of one milligram per pound of body weight, reSpiratory rate was lowered in 62.5 percent at 30 minutes, and in 75 percent at 60 minutes. Statis- tically, the difference between the normal and the 30 and 60 minute readings was insignificant. At the rate of two milligrams per pound of body weight, reSpiratory rate was lowered in all goats. At 0.5 milligrams per pound of body weight, pulse rate was increased in 85.7 percent at 30 minutes, and at one milligram it was increased in 75 percent of animals throughout. In the former case, it was statistically in- significant, but in the latter it was found significant at the five percent level. At two milligrams per pound of body weight fluctuating pulse rate was recorded. At 0.5 milligrams, blood pressure was decreased in 57.1 percent of the animals at 30 minutes. At one milli- gram, lower blood pressure was recorded in 75 percent at 30 minutes, in 62.5 percent at 60 minutes, and in 85.7 percent at 90 minutes, but statistically the changes were insignificant. At two milligrams, blood pressure was lower in all goats up to 60 minutes, in 80 percent up to 120 minutes, and in #0 percent throughout the period of observation. At one milligram, rectal temperature was lowered in 4 SAROJ KANT JHA ABSTRACT two of three goats at 30 and 60 minutes, and normal tempera- ture was recorded in all at 90 minutes. At two milligrams, lower rectal temperature was recorded in all animals from 30 to A20 minutes. The changes were statistically in- significant. A No electrocardiogram change was found which could be attributed to this drug. The drug showed its spontaneous motor activity de- pressant action in 75 percent of eight goats. This change was found to be statistically significant at the five percent level. SOME EFFECTS OF TRIFLUPROMAZINE HYDROCHLORIDE IN GOATS by Saroj Kant Jha A THESIS Submitted to the College of Veterinary Medicine Michigan State University of Agriculture and Applied Science in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Department of Surgery and Medicine 1959 Dedicated to My parents--Ratikant and Aagam and My wife--Veena ACKNOWLEDGMENTS A deep sense of gratitude is expressed to Dr. Wm. V. Lumb, Associate Professor, Department of Surgery and Medicine, without whose untiring assistance, guidance and encouragement this project would never have been a success. Thanks are due to Dr. R. F. Johnston, Associate Pro- fessor, Department of Physiology and Pharmacology, for his precious help and assistance. Appreciation is expressed to Dr. W. O. Brinker, Pro- fessor and Head of the Department of Surgery and Medicine, and to Dr. B. V. Alfredson, Professor and Head, Department of Physiology and Pharmacology for facilities and equip- ment offered in carrying out this research. Sincere thanks are due to Mr. Art Berkey, a SOphO- more student, for his assistance in this project. Appreciation is expressed to those members of the teaching staff, Department of Surgery and Medicine, who have, in one way or another, helped in this project. Thanks are also due to the fellow graduate students for their invaluable assistance. TABLE OF CONTENTS CHAPTER PAGE I. Introduction. . . . . . . . . . 1 II. Review of the Literature. . . . . . 3 A. Tranquilizing Drugs . . . . . 5 B. Triflupromazine Hydrochloride. . . 14 C. Carotid Loop . . . . . . . . 18 III. Materials and Methods. . . . . . . 20 IV. Results. . . . . . . . . . . 27 V. Discussion . . . . . . . . . . 58 VI. Summary and Conclusion . . . . . . 44 VII. Bibliography. . . . . . . . . . 64 LIST OF TABLES TABLE PAGE 1. Effects of Vetame (0.5 Milligram per Pound of Body Weight). . . . . . . . . . #6 2. Effects of Vetame (1.0 Milligram per Pound of Body Weight). . . . . . . . . . A9 3. Effects of Vetame in Goat 9 (2.0 Milligram per Pound of Body Weight) . . . . . . 53 h. Effects of Vetame in Goat 10 (2.0 Milligram per Pound of Body Weight. . . . . . . 5h 5. Effects of Vetame in Goat 13 (2.0 Milligram per Pound of Body Weight. . . . . . . 55 6. Effects of Vetame in Goat 1A (2.0 Milligram per Pound of Body Weight. . . . . . . 56 7. Effects of Vetame in Goat 20A (2.0 Milligram per Pound of Body Weight. . . . . . . 57 8. Effects of Vetame on Electrocardiogram (0.5 Milligram per Pound of Body Weight . . . 58 9. Effects of Vetame on Electrocardiogram (1.0 Milligram per Pound of Body Weight . , . 59 10. Effects of Vetame on Electrocardiogram (2.0 Milligrams per Pound of Body Weight . . , 60 11. Effects of Vetame on Spontaneous Motor ACtiVity. o o o o o o o o o o o 61 12. Effects of Sling. . . . . . . . . . 62 LIST OF PICTURES PICTURES PAGE 1. Method of connecting manometer and ECG leads to goats. . . . . . . . . 25 2. Close-up of carotid loop in goat 9 . . 25 3. Complete apparatus showing from left to right goat stand, electromanometer, and Sanborn multichannel recorder. . . . 26 a. New Haven pedometer for recording Spontaneous motor activity. . . . . 26 CHAPTER I INTRODUCTION In human medicine, tranquilizing drugs have been used for numerous indications. However, most of the use is for mental disturbances. According to Rose (37), in 1957 fifty million prescriptions were written for these drugs in the United States alone. Thus, in 1957 in the United States, five percent of patients under medication at any time were receiving tranquilizers. These drugs have also been introduced into veterinary medicine for various indications. Their use as chemical restraint in place of physical restraint has been found very satisfactory (24). Encouraged by their successful effects, pharmaceutical concerns are now synthesizing many new ataractic compounds. About nineteen tranquilizing drugs are available at present in human and veterinary medicine. Triflupromazine hydrochloride, a phenothiazine derivative, is a new addition to them. Drugs of this group depress the central nervous system. This depression causes clinical soothing or obvious tranquilization. Besides their sedative action, they also exert some action on other body systems. If these actions are within certain limits, the animal's life is not endangered. But, on the contrary, if the 2 the action is too severe, the animal may be depressed be- yond recovery. With this in mind, the effect of this drug on blood pressure, electrocardiogram, body temperature, respiratory rate, pulse rate, and Spontaneous motor activity has been studied. Effects of different tranquilizers on dogs, horses, and cattle have been studied by many persons. A search of the literature reveals that almost no work has been done on the effect of tranquilizers in goats. CHAPTER II REVIEW OF THE LITERATURE A. Tranquilizing Drugs "Tranquilizers" or "ataraxics" are agents that quiet seriously disturbed psychotics, cause remission of schizo- phrenic and paranoic symptoms, bring peace of mind to overwrought neurotics or antagonize the manifestations of hallucinogenic agents (5). According to Tyndel (#5), "ataractic drugs constitute a new method of control of the disturbed patient, thus creating a feeling of security for both patient and staff". According to pharmacological actions, there are two distinct classes of tranquilizers (5): Class I - Central relaxants. The most important among these are meprobamate, mephenesin, glyketal and styramate. Class II - The auto- nomic suppressants. The reserpine and other rauwolfia compounds and phenothiazine derivatives constitute the members of this class. Mephenesin, which was produced by Berger (3) in 1946, was the first compound of Class I. It was put on the market as a safe muscle relaxant. Berger (h) found that meprobamate produced muscle relaxation and sedation as well. Smith and co-workers (39) reported that mepro- ‘r bamate was not a true tranquilizer because its main action, to relax skeletal muscle, resulted in relief of tension and excitement. Reserpine and related alkaloids are derived from the root of Rauwolfia serpentina (Ophioxylon serpentinum). This plant grows in India and other neighboring countries. For hundreds of years, it has been used in India against snake bite, insanity, corneal opacity, diarrhea, dysentery and also as an ecbolic (30, #8). The plant was named by Plumier after Leonhard Rauwolf, a German physician and botanist who made extensive study and use of it (36). In 1931, Sen and Bose first reported on the hypotensive effect of Rauwolfia serpentina (38). The first report of the use of this drug in hypertension in the United States was made in 1952 by Wilkins, Judson and Stanton (#9, #8). Wilkins reported that unlike other sedatives Rauwolfia did not produce grogginess, stupor and incoordination, and his patients appeared to be relaxed, quiet and tranquil (23). The powerful acting alkaloid reserpine was isolated from Rauwolfia by Mueller, Schlittler and Bein in 1952 (32). Damm and Trautner reported that reserpine reduced blood pressure by exerting an effect on the central nervous system (11). Today practically all commercial drug houses market it under some trade name. The majority of the tranquilizers available at pres sent are phenothiazine derivatives. Phenothiazine was prepared by Bernthsen (#6, #3) in 1885. In 19#0, Taylor and Sanderson (#3) reported anthelmintic prOperties of phenothiazine useful in veterinary medicine. At the Rhone-Poulenc Research Laboratory at Vitry-Sur-Seine (France), various amine derivatives of phenothiazine were reported to possess antihistaminic and vagal ganglio- blocking activity (#6). Winter (50) reported that di- methyl aminOprOpyl phenothiazine prolonged the sleep- producing effects of hexobarbital. Interest was thus stimulated in the usefulness of this and related compounds as adjuncts in anesthesiology. In 1950, a systematic search was begun at the Rhone-Poulenc Research Laboratories to discover other compounds in this same chemical series which might possess clinical usefulness (#6). Thus, chlorpromazine was synthesized by Carpentier of France in December, 1951 (#7). According to Lehman (26) Laborit was the first to take chlorpromazine out of the laboratory into clinics, and Delay and Deniker were the first to introduce chlorpromazine (Largactil) in psychiatry in Europe. According to Johnston (23), in 195# Lehman and Henrahan reported that chlorpromazine relieved nausea and vomiting. In the same year, Kline reported that reserpine relieved nausea and hypertension. These persons further reported that chlorpromazine and reserpine also reduced greatly the anxiety, tension and hostility of patients without severely affecting mental and physical well being. As reported by Lehman, Delay and Deniker pr0posed A ‘\J a generic name "neurOplegic" drugs for these compounds (26). Fabing (17) suggested a second generic name "ataractics" or "ataraxics" for these drugs. The latter names have been derived from the Greek word "ataraktos", meaning without confusion, cool and steady. "Ataraxia", the Greek noun, means freedom from confusion and peace of mind. In English, it is ataraxy, meaning freedom from disturbance of mind or passion. This name and its synonym "tranquilizer" have gained wide-spread general usage by both doctors and laymen. The following tranquilizers are already available on the market: a. Chlorpromazine (largactil, thorazine, megaphen) b. Promazine (sparine) c. Promethazine (phenergan) - mostly used as an antihistaminic drug d. Mepazine (paxital, pacatal) e. ProclOperazine (compazine) f. Perphenazine (trilafon) g. Mephenesin h. Meprobamate (miltown, equanil) i. Glyketal j. Styramate k. Hydroxyzine (atarax) l. Benactyzine (suovitil) m. Azacyclonol (frenquel) no Ethylcrotonyl urea (nostyn) o. Phenaglycodol (acalo ultran) p. Capsodiamin (suvren) q. Diparcol r. Reserpine and other Rauwolfia alkaloids s. Ethyl isobutrazine Triflupromazine hydrochloride (vesprin, vetame) is an addition to the above list. Chlorpromazine, which is a phenothiazine derivae tive, has been extensively studied. Because it is pharmacologically very similar to triflupromazine hydrochloride, its pharmacological actions are re- viewed. In 1953, chlorpromazine hydrochloride was shown to be effective in suppressing nausea and vomiting caused by a wide variety of clinical conditions (19). Moyer (31) in 195# showed it to be an effective anti- emetic agent. Boyd 33 31. (7), in 195A, reported that chlorpromazine hydrochloride effectively inhibited and, in many instances, completely suppressed apomorphine induced vomiting in dogs. In 1955, Benaron and others (2) concluded that chlorpromazine could be expected to produce excellent results in the large majority of pregnant women with vomiting or hyperemesis. They further reported that it did not have any harmful effect on either the mother or the child. Estrada (16) in 1956 reported that chlorpromazine was invaluable in persistant emesis in dogs. Das 33 31. (12) in 195# reported dramatic changes in the behavior of monkeys due to chlorpromazine. Ag- gressive rhesus monkeys (Macaca mullatta) became peaceful and no restraint was required outside the cage. Estrada (16) in 1956 reported that due to chlorpromazine unfriendly dogs acquired a more friendly attitude and "shy" dogs became less "shy". In 1956, Martin and Beck (28) reported that chlorpromazine was administered at the rate of one milligram per kilogram of body weight to a belligerant mare. She then allowed her foal to suckle which prior to this time she had refused to do. In 1956, Duff £2 £1. (15) reported that when chlorpromazine was administered intravenously, increase of blood volume flowing through skin of hands and feet of healthy persons was observed. They further observed that the heart rate was slightly increased. Spur and others (#0) observed that chlorpromazine in doses of two milligrams and five milligrams per kilogram of body weight produced an initial hypotension in anesthetized dogs. This was followed by return of mean arterial blood pressure to near control levels. During the next sixty to sixty-five minutes, there was a secondary decline in the blood pressure to hypo- tensive levels. Dobkin and others (l#) reported that pulse rate showed a moderate rise following chlorpromazine administration. In 1956, Martin and Beck (28) reported that re- peated doses of chlorpromazine hydrochloride, over a three day period at the rate of two milligrams per kilogram of body weight, produced a fall in circulating erythrocytes and in hemoglobin concentration of horses. Hoerlein and Marsh (22), in 1957, reported that chlor— promazine hydrochloride, when injected into calves, lowered blood counts and hematocrit values for twenty- four hours. In l95#, Stevenson and Albert (#1) observed that intramuscular injection of chlorpromazine in human hypertensives decreased both systolic and diastolic pressure during standing, but had no significant change in recumbent blood pressure. Pea gt a1. (3#), in l95#, observed that acute hypotension developed in human patients after chlorpromazine administration. In l95#, Moyer gt_§1. (31) also reported about its hypotensive action. Azima and Durost (l), in 1957, reported that chlorpromazine had moderate hypotensive effect. Blood pressure fell in all cases; systolic on an average dropped by 25 mm. of mercury, whereas diastolic fell 15 mm. of mercury in twenty-four hours. Renzetti and Padget (35) observed that the arterial blood pressure decreased to a variable degree after administration of chlorpromazine in man. Feldman gt 31. (18) reported that rapid intra- venous injection of chlorpromazine caused a dr0p in blood pressure ani intramuscular injection of the drug caused a moderate drop in blood pressure in a mongrel cat. Martin and Beck (28) reported that two to four milligrams per kilogram of chlorpromazine intra— muscularly produced a slight tachycardia and hypotension in horses. Moyer and others (31) reported that none of the human control subjects showed changes in electrocardio- gram (ECG) after chlorpromazine administration. However, they further observed that changes in ECG might occur in seriously ill patients. Boyd gt El. (7) reported that large doses of chlorpromazine hydrochloride produced a respiratory phasic sinus arrythmia. Dobkin and others (l#) observed that after chlorpromazine administration the ECG showed frequent sinus arrythmia. Stowe (#2) mentioned that chlorpromazine had a depressant action on the central nervous system of man and domesticated animals. Dobkin and others (l#) reported that chlorproma- zine depressed gastric secretion in man. Haverlock at 31. (20) reported that chlorpromazine reduced the volume of gastric secretion, but did not significantly change the free acidity. Duff 22 31. (15) reported that after administration of chlorpromazine to humans oral temperature regularly fell a little. Martin and Beck (28) reported that two to four milligrams per kilogram of chlorpromazine in k...) in: horses produced a slight fall in rectal temperature. Hoerlein and Marsh (22) reported that there was a slight (0.6 to 1.00 F.) fall of temperature from one-andmoneu half to twentyefour hours after chlorpromazine administration in calves. Owen and Neal (33) reported that chlorpromazine caused slight hypothermia in horses (0.5 to 1.00 F.). Martin and Beck (28) reported that of ten trials in which spontaneous motor activity was measured, in six there was a decrease in activity during the twenty- four hour period following chlorpromazine administration, and in four trials, the activity increased. Davis (13) reported that chlorpromazine in rhesus monkeys produced a marked reduction in all activities when administered in quantities significantly smaller than those required to produce "taming". Brodey and Christensen (9) concluded that chlor- promazine appeared to have a potentiating effect on pentobarbital anesthesia in dogs. Estrada (16) in 1956, reported good effects using chlorpromazine as a preanesthetic sedative in conjunction with pentobarbital anesthesia in dogs. Azima and Durost (1) observed that chlorpromazine potentiated the effect of barbiturates in man. In 1957, Owen and Neal (33) reported that chlorpromazine potentiated chloral hydrate anesthesia in horses. Dobkin and others (l#) stated that after administration of chlorpromazine to humans respiratory rate varied; usually it was slightly increased, while, in some cases, reSpiration became irregular. Martin and Beck (28) reported that chlorpromazine at the rate of two to four milligrams per kilogram of body weight in horses produced a slower, more regular and deeper breathing pattern. Hoerlein and Marsh (22) reported that respiratory rate increased from 36 per minute to 50 per minute half an hour after injection of chlor- promazine hydrochloride. It decreased to 3# per minute one-andmonemhalf hours after injection, 32 per minute after five hours, and 32 per minute after twenty-four hours. Feldman and Kidron (18) reported that high doses of chlorpromazine in humans caused short apnea followed by transient hyperpnea. Renzetti and Padget (35) observed that chlorpromazine had a respiratory depressant action. Friend gt gt. (19) reported that dryness of mouth, occasional mild sedation, and rarely a mild transient attack of faintness, palpitation and flushing of the face were the only side effects observed in man. Azima and Durost (1) observed drowsiness while Hodges and Lazerte (21) reported a persistant jaundice and fatal agranulocytosis. Bernstein and Klotz (6) described nasal stuffiness, dermatitis, photon sensitivity, pruritis, influenzaalike syndrome, agranulocytosis, jaundice and laryngeal edema as side 13. effects. Martin and Beck (28) in 1954, reported that intramuscular injections caused local reaction in horses. They also reported a decrease in circulating erythrocytes and hemoglobin concentration after three to five days of treatment. Kurtz (25) stated that chlorpromazine was used in humans for the following indications : Manic psychosis Senile agitation Schizophrenia Anxiety reactions Chronic anxiety or chronic neurotic tension Sedation of acute alcoholism Potentiation of barbiturates and narcotics Nausea and vomiting of pregnancy Vomiting and anorexia caused by radiation therapy Lehman (26) reported that chlorpromazine was used in human beings for manic states, acute psychotic breakdown, anxiety and panic states, delirium, porphyria, chronic schizophrenia and epilepsy. Troughton §£.él- (44) reported the use of chlorpromazine in dogs for; hysteria, prior to local anesthesia, to control chronic vomiting in pyometra, for heat stroke, and in shock due to trauma. Estrada (16) used this with mineral oil and parenteral pur- gative in removing hair balls from a cat. In 1957, Clifford (10) reported preanesthetic use of la chlorpromazine with pentobarbital anesthesia in cats. Troughton gt 1 . {#A) recommended the use of g I... -. L chlcrnromazine in horses for shoeing, clipping, colic, preaneSLhetizing, tetanus. painful conditions and prior to travel. Martin gt gt. (28) reported the use of chlorpromaz1ne for quieting horses. Lundvall and Campbell (27) reported sufficient relaxation of penis in stallions follow1ng chlorpromazine administration. Troughton gt g1. i##) used chlorpromazine for preanesthetic medication in cattle. Lundvall and Campbell (27) reported relaxation of the penis in bulls following chlorpromazine administration. Ward (8) used tranquilizer for handling nervous dairy animals at milking time. There was no noticeable effect on either milk production or butter fat content. When a large dose of tranquilizer was used, the cow became "dopey" and would not eat much. This resulted in low milk production until the effects of the tranquilizer wore offo B. Triflupromazine Hydrochloride Triflupromazine hydrochloride (#6) (vesprin, vetame) is 10r(32dimethylaminopropyl):2e(trifluoro= methyl) phenothiazine hydrochloride. Its empirical formula is 018H19F3N28.HCL. Its structural formula is 15 CH2 C H2 CH: N(CH‘3)2. HCI . N CF3 S It is a white powder with a melting point of 172 to l7#o C., and is soluble in water to about 1 gram in 10 cc. It is soluble in ethanol and acetone, but is insoluble in ether. The pH of a two percent aqueous solution is #.1. At pH 6.#, the compound pre- cipitates from aqueous solutions. Median lethal intravenous dose for dogs was l6.7:#.2 milligrams per kilogram. -Ataxia was the first sign of disability. Struggling during in- jection, followed occasionally by convulsions was observed in dogs receiving #5 milligrams per kilo- gram intravenously. They also showed extreme depression of motor activity. Death was immediately preceded by violent convulsions and seemed to result from asphyxiation. Triflupromazine was administered to dogs in the dose of 10 to 80 milligrams per kilogram of body weight each day, five days a week for 15 to 16 weeks. There was no change in erythrocyte and leucocyte counts and in hemoglobin values. No significant changes were observed in the electrocardiogram or the blood pressure reading. In dogs, no tremors or extensor rigidity were seen the first day after intramuscular administration of 30, #5, and 60 milligrams per kilogram of body weight as a 20 percent aqueous solution. Two dogs which were given 100 milligrams per kilogram of body weight in 20 percent aqueous solution exhibited some signs of local irritation. The immediate effect of the drug on blood pressure was depressant. As a persistent effect, pulse rate fell with triflupromazine in unanesthetized dogs. There was in» significant change of pulse rate in anesthetized dogs. In humans, vesprin has been of great value in the alleviation of restlessness, anxiety, insomnia, anorexia and other emotional side effects commonly accompanying the withdrawal of alcohol. Because of its "tranquilizing effect", vesprin often either eliminated or lessened the need for the administration of barbiturates or other sleep inducing drugs during alcohol withdrawal. Vesprin has been found to produce a unique type of "sedation" characterized by sleep, c00peration, easy arousability and mental clarity without depressing vital functions. It has been used with great success pre and postoperatively. It has been noted to be particularly beneficial in apprehensive children in whom a tranquilizing effect was desirable. It has been indicated in the prevention and control of nausea and vomiting associated with a l7 variety of clinical disorders. It has been found useful in the prevention and treatment of nausea and vomiting associated with certain drugs, radiation therapy, nitrogen mustard therapy and intravenous chclangiography. It has been useful in early nausea and vomiting of pregnancy up to and including the 12th week. It was also found useful for the management of pernicious vomiting of pregnancy. Excellent results have been reported with vesprin as an adjunct to narcotics and general anesthetics during the first and second stages of labor. No apparent effects on the newborn have been encountered following its use in obstetrics. Vesprin has been used as an effective agent in the treatment of several mental disorders. The drug was found useful in the management of psychomOtor agitation associated with various acute and chronic psychoses including schiz0phrenia, mania, depression, delirium, senile psychoses and psychoses due to organic brain disease and mental deficiency. It might be used in mental disorders associated with epilepsy. It has shown a unique ability to control psychomotor agitation without producing marked sedation or drowsiness. Drowsiness or somnolence, if it occurred, was seldom sufficiently intense to require discontinuation of this drug therapy and generally subsided after the first few weeks of treatment. Allergic phenomena and .hotosensitivit have been encountered com arativel P -\ U ( . infreouently. Symptoms of w akness and dizziness, anXietv and restlessness have been reported to occur occaSionally. These symptoms could be relieved readily by moderation of dosage. Orthostatic hypotension and simple tachycardia both transitory in nature occasionally were encountered following parenteral use of the drug. In both animal experiments and in clinical studies, veeprin has exhibited pharmacological activities similar to those of chlorpromazine. It has been observed that triflupromazine caused less persistent depression of the blood pressure in unanesthetized animals than did chlorpromazine. It was observed that triflupromazine as an antiemetic agent was at least five times as potent as chlorpromazine, In terms of dosage required, it was fourd two to five times more potent than chlorpromazine in controlling psychotic manifestations. C. Carotid Loop In 1950, McClymont (29) described the establish- ment of carotid 100ps in cattle. He made an incision about 18 cm. long along a line immediately dorsal to the upper limit of the jugular vein, which was raised by digital pressure. By blunt dissection, the carotid artery was reached and was separated from the structures of the carotid sheath. Any smaller vessels were ligated and cut close to the main vessel. A 19 second incision was made parallel to the first and 7 cm. dorsal to it. The consequent strip of skin was freed from the subcutaneous tissues. Traction was applied to the middle of the length of the freed artery. The skin was then wrapped around the artery to form a sheath, open along the medial side. The two free edges of the sheath were then sutured to- gether. There was considerable elastic pressure of the artery on the sutures. Bandaging of the loop relieved this pressure to some extent. The two free edges of the skin, left after formation of the sheath from the strip of skin, were then sutured together. Care was taken to obtain good approximation at the junction of the loop with the adjoining skin surface. A considerable edematous swelling usually formed cranial to the incision, but disappeared after a few days. CHAPTER III MATERIALS AND METHODS All the goats used in this experiment were mature females of mixed breed and age. Their body weights varied from forty to one hundred and ten pounds. Some of them were pregnant. They were housed in a separate boxstall and all were maintained on the same feed and management routine. Food supplied consisted of alfalfa hay and ground dairy feed*. No additional dietary supplements were added to the feed. Water was available at all times. All animals were examined for internal parasites and many of them were found to be suffering from coccidia and strongyle infestation. They were * at the rate treated for strongyles with phenothite* of one to two ounces, depending on body weight. For coccidia, they were given teniatol*** at the rate of one ounce per animal. Each goat was fasted for about twentyafour hours before the operation to establish the carotid loop for this experiment. About four hours before the Operation, ~4-.---.-.‘--4.“—.—— >:‘Okemos Elevator Co., Okemos, Michigan. **Fort Dodge Lab., Fort Dodge, Iowa. ***Pitman-Moore Co., Division of Allied Laboratories, Inc., Indianapolis, Indiana. 21 one ounce of turcapsol* was administered through a stomach tube to retard fermentation. Ten minutes before the operation, the goat was given vetame** at the rate of one milligram per pound of body weight intravenously either in the cephalic or the saphenous vein. The left side of the neck was then clipped liberally and the goat secured to the Operating table in right lateral recumbency. AtrOpine sulphate (1/75 grain) was mixed with 10 cc. of surita1***. This mixture was injected intravenously for effective anesthesia and prevention of excessive salivation. After the goat was anesthetized, the site of Operation was thoroughly scrubbed with liquid germicidal detergent***. The operatoris hands were thoroughly scrubbed with liquid detergent. Sterile gloves and a sterile surgical pack were used during the Operation. The area of Operation was covered with a sterile shroud. An incision approximately four inches long was made. The loop was established according to the method of McClymont (29) with the following exceptions: a. the subcutaneous tissue was not removed from the strip of skin. *Pitman-Moore Co. Division of Allied Laboratories, Inc., Indianapolis, Indiana. **E. R. Squibb and Sons, New Brunswick, New Jersey. ***Parke, Davis and Co., Detroit, Michigan. 22 b. the first skin incision was made at the junction of the middle and lower third of the jugular furrow. c. the second incision was made ventral to the first incision. d. normal saline solution was used on the exposed artery to prevent drying. A wooden stand with sling was developed for this experiment. The goat was weighed and placed on the sling with its legs through the holes of the sling. The two forelimbs were tied together, and the two hind limbs were tied together using separate ropes. The head was secured to the stand (Figure 3). For recording arterial blood pressure and electrocardiogram, a Sanborn multichannel recorder* * were used. These were and a Sanborn electromanometer calibrated before each use. The needle electrodes of the ECG were inserted through the skin and secured with adhesive tape. Using four channels, three ECG leads and the carotid blood pressure were recorded simultaneously. Readings were taken with three dose levels of vetame, oneehalf, one and two milligrams per pound of body weight. With the animal in the stand, a 20 gauge needle was inserted into the lumen of the carotid loop *Sanborn Company, Waltham, Massachusetts. 23 and connected to the manometer tube. The normal reading was then recorded. After the reading, the needle was stoppered. This stopper was removed, the needle was flushed and cleaned of clot with heparinized water prior to each subsequent reading. Readings were taken on four goats, 9, 13, 18 and 20, to determine the effect of the sling without vetame. Two of them, 9 and 18, were placed in the sling before each reading and then were taken out. Three readings, at half an hour intervals, were taken. Goats 13 and 20 were kept on the sling continuously, and three readings were recorded at intervals of 30 minutes (Table XII). A pedometer* was used to note the effect of vetame on spontaneous motor activity of the goat. A thin layer of cotton was applied to the front leg and the pedometer, covered with a second layer of cotton, was secured by adhesive tape. The normal reading was taken after twenty-four hours and the pedometer was reset to the zero line. It was again fixed to the leg as mentioned above and vetame was injected intravenously at the rate of one milligram per pound of body weight. Twelve hours later, vetame was again injected intravenously at the rate of one milligram per pound of body weight. At the end of the twenty-four hour *New Haven Clock and Watch Co., New Haven, Connecticut. 21+ period, the pedometer was removed from the goat and this reading was used for comparison with the normal. In each of two goats, 2 and 20A, only one milligram of vetame was injected. T-tests were run on the results obtained from measuring respiratory rate, pulse rate, blood pressure, rectal temperature and Spontaneous motor activity. l. Kethod of connecting manometer and ECG leads to goats. 2. Close-up of carotid lOOp in goat 9. ill.lrll‘lillr. l. .1. , I. I'liloli-nilr 1.1. 1.1.! I. It. in 3. Complete apparatus showing from left to right goat stand, electromanometer, and Sanborn multichannel recorder. #. Jew Haven pedometer for recording Spontaneous motor activity. CHAPTER IV RESULTS General symptoms observed after vetame administration: A. At 0.5 milligram per pound of body weight. About five minutes after intravenous adminis- tration of vetame, the goats became depressed. There was labored breathing, the mucous membranes became slightly cyanotic and there was slight dribbling of saliva. B. At one milligram per pound of body weight. About five minutes after intravenous adminis- tration of the drug, the animals became depressed, kept eyes half closed, and there was labored stertorous breathing and slight cyanosis of the mucous membranes. Some frothy salivary secretion was observed on the animal's lips. C. At two milligrams per pound of body weight. There was an excessive frothy, thick salivary secretion. The mucous membranes were more cyanotic. In the case of goat l#, there was violent movement of the whole body and extreme difficulty in breathing following which it died. Frequent urination and passage of flatus were seen. In almost all goats, incoordination of hind quarters was also Observed. 28 In many of these animals, there was trembling of the whole body. Goat 9 passed coffeeacolored urine about four hours after drug administration. Effects of the drug on respiratory rate: A. At 0.5 milligrams per pound of body weight (Table I). Seven goats, varying in body weight from forty to one hundred and ten pounds were used. The average weight was 91.9 pounds. Definite reSpiratory depression was observed in five goats and stimula- tion in one. In goats 9, 13, 20 and 2#, reSpiratory depression was observed up to 90 minutes after drug administration. In goat 20A, slight respiratory depression was Observed 30 minutes after drug administration, and respiratory rate was normal after 60 minutes. In goat 10, the respiratory rate was stimulated up to 90 minutes after drug adminis~ tration. In goat 18, reSpiratory rate was observed to be slightly higher than normal 60 minutes after drug administration and slightly lower after 90 minutes. The mean respiratory rate for the group was lower than the mean normal respiratory rate through- out. Statistically the difference was insignificant at the five percent level. B. At one milligram per pound of body weight (Table II). There were eight goats in this series, varying 29 from forty to one hundred and ten pounds in body weight, with mean body weight of 9#.l pounds. In five goats, 9, 10, 13, l# and 18, the reSpiratory rate remained below normal throughout. In two goats, 20 and 20A, the respiratory rate remained higher than the normal. In one goat, number 2#, it was slightly higher than normal 30 minutes after drug administration, but be- came slightly lower 60 minutes later. It was again normal 90 minutes after drug administration. The mean normal respiratory rate. Statistically the difference was insignificant at the five percent level. C. At two milligrams per pound of body weight (Tables III, IV, V, VI and VII). There were five animals in this group, varying from forty to one hundred and ten pounds in body weight with mean weight of 92 pounds. In all these animals, respiratory rate was lower than normal, even #20 minutes after drug administration. In goat number l#, the respiratory rate dropped to 7 just prior to death. Effect Of the drug on pulse rate: A. At 0.5 milligram per pound of body weight (Table 1). Elevation of pulse rate was observed in six of seven goats 30 minutes after drug administration. In goat 9, a lowered pulse rate was observed at 30 30 minutes. In three goats, 20, 20A and 2#, there was a rise in pulse rate at 60 minutes, in two, 13 and 18, pulse rate was lower than normal at 60 minutes. In the remaining two, 9 and 10, pulse rate was normal at 60 minutes. In three, 18, 20 and 20A, there was a higher pulse rate at 90 minutes, in two, 10 and 13, the pulse rate was lower than normal. The mean pulse rate was higher than the mean normal pulse rate 30 and 60 minutes after drug administration, and was lower at 90 minutes. Statistically the change was insignificant at the five percent level. B. At one milligram per pound of body weight (Table II). 0f eight goats, there was increased pulse rate in six, 9, 10, 13, l#, 20 and 2#, 30 minutes after drug administration. In one goat, 18, there was no change 30 minutes after drug administration, whereas in goat 20A, there was depression in pulse rate at 30 minutes. In six of the goats there was increased pulse rate 60 minutes after drug administration; there was no change in number 10, and in number 18 the pulse rate was lower. In six goats, 9, l#, 18, 20, 20A and 22, there was increased pulse rate after 90 minutes, whereas in one goat, 13, there was lower pulse rate after 90 minutes. The mean pulse rate was observed to be higher than the normal through- out. Statistically the changes were significant at 31 the five percent level. C. At two milligrams per pound of body weight (Tables III, IV, V, VI, VII). Five animals were used and pulse rate was rem ccrrcleri Ziri a.l]- ()f Llluhl. ilitz ITC5.N. pxilsae [“1t63 rif1;e1‘ drug admiristrztion was very slightly lower in one, but was higher in the remaining four. The pulse rate fluctuated widely in all animals during the postadministration period. Effects on rectal temperature: A. At one milligram per pound of body weight (Table II). Readings were taken in three goats. There was slight lowering of temperature in two goats 9 and 20, 30 minutes after drug administration, whereas in the other, there was no change. There was slight lowering of temperature at 60 minutes in goats 9 and 13. Normal temperature was recorded 90 minutes after drug administration in all three. The mean temperature readings were lower than the mean normal temperature throughout. Statistically changes were insignificant at the five percent level. B. At two milligrams per pound of body weight (Tables III, IV, and V). Rectal temperature was recorded in three goats. In two, 10 and 20A, temperatures lower than normal were recorded even #20 minutes after drug administration. 32 In the third goat, 13, lower body temperature was recorded up to 360 minutes after drug administration, at which time recordings ceased. The mean temperature in all three remained lower than the mean normal temperature throughout. Effect on arterial blood_pressure: A. At 0.5 milligram per pound of body weight (Table I). There were seven animals in this series. In four, there was decreased blood pressure, whereas in three there was an increase in blood pressure 30 minutes after drug administration. After 60 minutes, there was a decrease in three, and an increase in four. At 90 minutes, there was low blood pressure in two of them, and high in four. Due to technical difficulties a 90 minute reading was not made in goat 9. The mean arterial blood pressure was always lower than the normal mean blood pressure. Statisti- cally the changes were insignificant at the five percent level. B. At one milligram per pound of body weight (Table II). There were eight animals in this group. Six showed lower blood pressure after 30 minutes, and in two, there was slight rise in blood pressure after 30 minutes. Five animals showed lower blood pressure after 60 minutes, and three showed a rise 33 in blood pressure. Six of them showed lower blood pressure after 90 minutes, and one showed a rise in blood pressure at 90 minutes. Technical difficulties prevented making a 90 minute reading in goat 10. The mean blood pressures at 30, 60 and 90 minutes were lower than the mean normal blood pressure. Statisti- cally changes were insignificant at the five percent level. C. At two milligrams per pound of body weight (Tables III, IV, V, VI, and VIII). 0f five goats, there was lower blood pressure in four. In one animal, 13, blood pressure was lower up to 120 minutes after drug administration, at which time it rose above normal and remained until recordings ceasedat 360 minutes. Effect on spontaneous motor activity: (Table XI) Eight goats used in this experiment varied from forty to one hundred and twenty pounds with an average weight of 91.8 pounds. Six of them showed decrease in activity after drug administration, whereas two showed increase in activity. Normal mean distance traveled was 1.57 miles and mean decrease after drug administration was 0.6# miles or #0.? percent. Statistically changes were significant at the five percent level. Effect on electrocardiogram: 3A A. At 0.5 milligram per pound of body weight (Table VIII). 0f the seven animals in this series, none demonstrated similar electrocardiograms. In goat 9, inverted T waves were found in lead I at 30 minutes. In animal 10, there was increase in QRS potential in lead I at 60 minutes. In goat 13, all waves decreased in potential in leads I and II. There was complete absence of the P wave in the normal and all subsequent readings in animal 18. Goat 20 showed slight decrease in QRS potential at 60 minutes in lead I. There was increase in QRS and T potentials in lead I at 30 minutes, but decrease in these at 60 minutes in goat 20A. Decrease in QRS potentials in leads II and III at 30 minutes and decrease in potential of the T wave in lead III at 90 minutes was recorded in animal 2#. B. At one milligram per pound of body weight (Table IX). Six of eight goats in this group showed some electrocardiogram change, whereas the remaining two did not. In goat 9, both QRS and T potentials were decreased at 30 minutes in lead I. They were de- creased and the T wave was inverted in lead I at 60 minutes. The QRS potential decreased in leads I and II at 90 minutes. In animal 10, slight increase in the T wave was noted in lead II at 30 35 minutes. QRS potentials in lead I and II were in- creased in goat 13 at 30 and 60 minutes. In leads II and III in goat l#, atrial fibrillation type of electrocardiogram was exhibited both in pre and post drug administration periods. It also showed decreased QRS potential at 30 minutes in all the three leads. P and T waves were inverted and QRS potential was found increased in lead I at 60 minutes in goat 18. Animal 20 showed increased QRS potential and inverted T waves in lead I at 30 minutes. C. At two milligrams per pound of body weight (Table XI). In goat 9, QRS potentials were partially in- verted in lead I at 60 minutes. In goat 10, QRS potentials were increased at 30 minutes in lead I. There was increase in T wave potentials in lead II at 60 minutes. In goat 13, QRS potential was in- creased in lead I and III and T waves were inverted in lead III at 30 minutes. QRS potentials were decreased in lead 1, whereas they were increased in lead III at 60 minutes. QRS potential increased in lead I and lead III at 90 minutes. QRS potentials were also increased in lead I from 150 to 300 minutes. T wave potentials increased at 210 and 2#0 minutes in lead I.) The T wave was increased in lead II at 150 minutes and decreased at 180 in lead III. QRS 36 potential was increased from 30 to 90 minutes and again from 210 to 300 minutes in lead III. Inverted T waves were observed at 30, 210 and 2#0 minutes in lead III. At 180 minutes, T wave potential was decreased. In goat l#, increased potential and inverted T waves were recorded at 30 and 60 minutes in lead I. Increased T wave potentials were found in lead II at 30 and 60 minutes. F wave was absent from lead II at 30 minutes. QRS potentials were increased in lead 11 at 60 minutes, and some QRS waves were also inverted. In goat 20A, QRS potentials were found increased at 60, 150 and 180 minutes in lead I and lead II. T wave potentials in- creased at 180 minutes in lead I. An inverted P wave was observed at 180 minutes in lead III. QRS potentials increased at 300 minutes in lead III. Effect of sling: A. On goats continuously on sling. There was no change in rectal temperature in either of them. In goat l3, respiratory rate was slightly lowered at 30 minutes, but was normal at 60 minutes. In goat 20, respiratory rate was lower at 30 minutes, but increased at 60 minutes. In both of these goats, pulse rate increased at 60 minutes. Rise in both systolic and diastolic pressure was recorded in both goats at 60 minutes. B. On goats not continuously on sling. There was little change in pulse rate, 37 reSpiratory rate, and rectal temperature. In goat 9, there was a slight rise in systolic blood pressure, but a fall in diastolic at 30 and 60 minutes. In animal 18, there was a slight fall in systolic blood pressure at 30 and 60 minutes. There was a drop in diastolic at 30 minutes, but very slight rise at 60 minutes. CHAPTER V DISCUSSION This investigation was undertaken to determine the effects of triflupromazine hydrochloride on the arterial blood pressure, pulse rate, reSpiratory rate, electrocardiogram, rectal temperature, and spontaneous motor activity in goats. In the beginning, efforts were made to measure direct blood pressure in the brachial or the femoral artery. Difficulties were experienced in cannulating the vessel owing to the development of perivascular hematomata. It was decided, therefore, to form per- manent carotid loops. Originally, subcutaneous tissue was removed from the strip of skin forming the loop. However, two of three loops thus established became necrotic. In subsequent goats, therefore, the freed carotid artery was placed subcutaneously. Due to develOpment of hematomata during cannulation of the artery recourse was taken again to loop forma- tion. This time, no subcutaneous tissue was removed from the strip of skin, and results were quite satisfactory. Three goats died after loop formation, all three bleeding from the lOOp before death. At necropsy, hemorrhage was given as the cause of death. 39 In one case, a piece of wire with blood stained tip was found near the loop. This wire might have caused perforation of the artery. A horned goat was found to butt the other goats and this might have caused damage to the loops resulting in hemorrhage in the other two goats. Extreme difficulties were experienced in the beginning of the experiment for want of a suitable stand. Jumping and struggling of goats during the experiment led to unsuccessful readings. In the end, a stand and a sling were prepared which served the purpose very well. The first effect noticed after drug adminis- tration was depression. This was followed by labored breathing. Cyanosis of the mucous memb- ranes developed in varying degrees depending upon the amount of drug administered. The amount of salivation also was directly dependent upon the amount of vetame injected. Incoordination of hind quarters was a constant symptom in all animals. When this drug was injected intravenously at the rate of 0.5 milligram per pound of body weight, respiratory rate was lowered in 71.# percent of goats at 30 minutes, 57.1 percent at 60 and 90 minutes. When it was injected at a dose of one milligram per pound of body weight, the respiratory rate was lowered in 62.5 percent of the animals at 30 minutes, #0 in 75 percent at 60 minutes, and in 50 percent at 90 minutes, but results were statistically insignificant at the five percent level. At the rate of two milli- grams per pound of body weight, reSpiratory rate was lowered in all goats. When action of the drug on the individual animal was considered, it was observed that in goats 9 and 13 the respiratory rate was lowered at all the three dose levels. In goat 10, respiration rate was increased at 0.5 milligram dose, but it was decreased at one and two milligrams doses. In goat l#, res- piratory rate was lowered at both one and two milligrams dose levels. This goat died 60 minutes after administration of 2.0 milligrams per pound, perhaps due to respiration failure. In goat 18, respiratory rate increased at 0.5 milligram, but was depressed at one milligram. In goat 20A, respiratory rate increased at 0.5 and two milligrams per pound of body weight. In goat 2#, the respiratory rate was decreased at 0.5 milligrams per pound of body weight. Taking these facts into consideration, it was observed in this experiment that the drug caused some respiratory depression in a majority of the goats, though not in all goats. With a 0.5 milligram dose, pulse rate was increased in 85.7 percent of the animals at 30 minutes, in #2.8 percent at 60 and 90 minutes. #1 At the five percent level results were statistically insignificant. At the one milligram dose level, pulse rate increased in 75 percent of the animals throughout. These results were statistically significant at the five percent level. When two milligrams per pound of body weight was used a fluctuating pulse rate was recorded. Thus, at 0.5 milligram and one milligram dose levels, this drug increased pulse rate in the majority of goats of this experiment. At 0.5 milligrams, blood pressure was decreased in 57.1 percent of the cases at 30 minutes, in #2.? percent at 60 minutes, and in 28.5 percent at 90 minutes. At one milligram, lower blood pressure was recorded in 75 percent at 30 minutes, in 62.5 percent at 60 minutes, and in 85.7 percent at 90 minutes. At the five percent level results were statistically insignificant. At two milligrams, blood pressure was lower in all goats up to 60 minutes, in 80 percent up to 120 minutes, and in #0 percent throughout. Thus, the drug caused hypotensive effect at all doses in the majority of cases. This hypotensive effect lasted longer with higher doses of the drug. With one milligram, temperature was lowered in two out of three goats at 30 and 60 minutes. Normal temperature was recorded at 90 minutes in all three animals. At two milligrams, lower rectal temperature was recorded in all the three animals from 30 to #20 #2 minutes. Thus, the drug showed some hypothermic effect in goats. These changes were statistically insignificant at the five percent level. Spontaneous motor activity was recorded and in 86.6 percent of the animals the activity was lowered. In two goats, it was administered in a single dOse rate of one milligram per pound of body weight. Lowered spontaneous motor activity was recorded in one of these two goats. In all of eight goats, lowered spontaneous activity was recorded in 75 percent, and the changes were statistically significant at the five percent level. For testing the effect of the drug on Spontaneous motor_activity it was administered to goat 20A at one milligram per pound of body weight. This goat showed symptoms of stimulation and behaved in a peculiar fashion. She was found hanging from the hay rack with her head down, and it is thought she would have suffocated if not set free. Due to this stimulation, a second dose was not administered to her. After this incident, owing to its small body weight, only one milligram of vetame per pound of body weight was used in goat 2. No consistent changes from normal were found in the electrocardiograms after drug administration, however some showed erratic variations. No definite effect of the sling was noted. 1+3 Goats l, 9, 10, 13, 1# and 20 were pregnant. 1, 9, 13 and 20 subsequently produced kids. No bad effect of the drug was evident in the dams or kids. Coat 10 was found to be pregnant on x-ray examination one month after the drug administration. Thus, in this case also there was no effect of the drug on pregnancy. Goat 1# died during the experiment due perhaps to respiratory failure. Three goats died after the experimental work was completed. 0n post mortem, death was attributed to hemorrhage. There had been bleeding, but it did not appear so profuse that it could cause the death of the goat. Due to use of the drug at three dose levels, there may have been a blood dyscrasia. This blood dyscrasia followed by hemorrhage might have hastened death. Therefore, it is suggested that during subsequent work with this drug in goats, blood examinations should be done. Based on this use of the drug in goats, it could be surmised that the safe intravenous tranquilizing dose in this animal is one milligram per pound of body weight. SUMMARY AND CONCLUSIONS Vetame was administered intravenously to goats at three dose levelS--0.5 milligram, 1.0 milligram and 2.0 milligrams per pound of body weight, and the following observations were made: a. General symptoms b. Effect on respiratory rate c. Effect on pulse rate d. Effect on arterial blood pressure e. Effect on electrocardiogram f. Effect on rectal temperature To determine the effect of the drug on spontaneous motor activity during a 2# hour period, 2 doses of vetame were administered to six goats with a 12 hour interval between the first and second doses. A single dose of one milligram per pound of body weight was used in two goats. Depression, labored breathing, cyanosis of mucous membranes of varying degree, salivation and in- coordination of hind quarters were the symptoms observed after intravenous administration of vetame to goats. The drug caused respiratory depression in the majority of goats, though not in all of them. Statistically the depression was insignificant. #5 An increased pulSe rate was observed in the majority of cases at 0.5 and 1.0 milligram dose levels. Statistically the difference was insignificant at 0.5, but significant at 1.0 milligrams. The drug caused hypotension at all dose levels in the majority of goats, but it was statistically insignificant. The hypotensive effect lasted longer with higher doses of vetame. Some hypothermic effect was seen, which was statistically insignificant. Depression of spontaneous motor activity was noted in six of eight animals tested with a pedometer. It was statistically significant at the five percent level. No changes were observed in electrocardiograms that could be definitely attributed to this drug. #6 TABLE I EFFECTS OF VETAME (0.5 milligram per pound of body weight) I Body ReSpiration per Minute Weight ' Goat in Minutes Postin ection Number 1 Pounds Normal 30 60 90 9 100 25 15 14 __* 10 100 25 30 28 28 13 110 32 27 26 26 18 , 100 22 22 2# 20 20 100 50 38 36 36 20A #0 20 15 20 20 24 93 , as a 32 z 22 30 Mean . 91.9 ' 31.3 1 25.5 2#.3 26.6 *Due to technical difficulty no recording was made. 47 TABLL I t-LJ (Continued) EFFECTS OF VETAME (0.5 milligram per pound of body weight) w Pulse per Minute Goat Minutes Postinjection Number Normal 30 60 9O 9 110 90 90 __* I 10 90 110 90 80 13 110 120 100 100 18 110 120 100 120 20 150 160 160 160 I 20A 100 110 120 150 2# 100 120 110 100 Mean 110 118.5 112.8 ‘101.6 *Due to technical difficulty no recording was made. TABLE I (Continued) EFFECTS OF VETAME #8 (0.5 milligram per pound of body weight) Blood Pressure (mm. of Hg) Goat Minutes Postinjection Number Normal 30 60 9O 1 * 11 120 *** 9 136% 77% I68 '— 12 110 1 o 1 o 10 ‘95 ‘88 1%? II? 122 1 o 1 6 1 o 13 '98 TUE I62 1'2 122 106 18, '99 “8% 162 "85 100 10 10 10 20 '78 ‘35 "86 '85 122 112 100 10 20A ‘88 ‘85 "BE 9 12 110 1 8 1 24 166 125 126 9 12 .1 116.8 123.0 119.8 Mean 9 . 97.5 101. ‘ 99-3 *Systolic **Diastolic ***Due to technical difficulty no recording was made. 49 TABLE II EFFECTS OF VETAME (1.0 milligram per pound of body weight) Body Respiration per Minute Weight Goat in Minutes Postin ection Number Pounds Normal 30 6O 1 9O 9 100 28 16 14 __* I I 10 100 38 32 15 __ 13 110 _ 45 26 32 30 11 110 26 11 20 20 9* I 18 1.00 35 15 23 25 :— 20 100 15 35 35 33 ‘ 20A A0 lb 19 21 20 21. 93 15 16 11. 15 I Mean 91.1 22.7 21.6 21.7 - 23.8 — *Due to technical difficulty no recording could be made. 50 TABLE II (Continued) EFFECTS OF VETAME (1.0 milligram per pound of body weight) _‘ Pulse per Minute Goat Minutes Postinjectign Number Normal 30 65’ 9O 9 90 130 160 130 10 90 120 90 _* 13 100 lhO 110 90 1h 80 9O 90 100 18 100 100 80 120 20 100 160 110 120 20A 120 90 150 160 2h 80 110 150 lhO Mean 95 117.5 117.5 1122.3 *Due to technical difficulty no recordings could be made. TABLE II (Continued) EFFECTS OF VETAME 51 (1,0 milligram per pound of body weight) Blood Pressure (mm. of Hg) Goat Minutes Postinjection Number Normal 30 6O 90 1 0* 192 120 10 9 11353“ 93 100 '8; 1 1 1 *** lo 18% :6? 18% — 10 110 11 13 '8; "8% ‘88 '98 120 11 10 1h 166’ 15% '9; 1 0 110 1 118 18 ‘92; '98 '99 122 88 118 110 20 '9§ '77 '97 ‘92 122 1 2 120 110 201 I00 160 ‘93 12 8 102 10 ___ 24 ‘93 3 ‘32 '90 12 . L 108.g 112.1 108. Mean 3 o E 93 o J 9 0 0 *Systolic **Diastolic ***Due to technical difficulty no recording could be made. TABLE II (Continued) EFFECTS OF VETAME 52 (1.0 milligram per pound of body weight) .W. a... W Rectal Temperature (Fahrenheit) Goat Minutec Posti iectinn Number Normal 30 60 9O 9 103.8 103.1 103.6 103.8 10 * 13 103.1 103.1 103.2 103.1 11. __ __________ 18 20 103.6 103.1 103.6 103.6 201 _____, _____, _____ ._____ 2A Mean 103.6 103.4 103.6 103.5 *Due to technical difficulty no be made. recording could 53 TABLE III EFFECTS OF VETAME IN GOAT 9 (2.0 milligrams per pound of body weight) a-..A.—¢--..—._._-_ _ - .-.....1--1...- -o-—.—--.- . .1..-A.- -'-- Time in Respiration 2 Pulse per Blood Pressure Minutes per Minute Minute (mm. of Hg) Preinjection -“~~ _-M-MHWI~ normal 22 140 135*/115** 30 _1_11_j§i_11. 140 116/102 60 17 _- 130 117/103 90 18 120 120/107 ,- - 120 17 120 126/115 * f —_v 150— 14 140 135/121 ___ 180 14 150 120/105 210 »* 13 150 131/115 240 , 15 - 130 136/118 279” -..-:_ .==*** .___ 300 j_ 13 130 120/100 330 'j( 14” , 150 115/-22._.1.__“ _360 i 15 160 122/ 97 _-._.- 19.9-1_42__--9§9-_ 112/ 9» ____-__,_4§-9_-_-- -___-_-16-_}40-_, 1127 92 .- Mean of l 13 15.6 : 139.2 . 121.7/104.9 *Systolic **Diastolic ***Due to technical difficulty no recording could be made TABLE IV EFFECTS OF VETAME IN GOAT 10 (2.0 milligrams per pound of body weight) -c-tv 5h ,-.._.r_m_1__ 1 1.1 Time in Respiration Pulse per Blood Pressure Temperature Minutes per Minute Minute (mm. of Hg) (Fahrenheit) Pre§ggggilon 38 90 145*/95** 103.0 30 30 132 95/78 102.8 60 23 110 98/88 102.2 90 _*** — __ .— 120 __ ___ I" 150 17 110 88/69 102.0 180 __ ___ I 210 15 130 104/80 102.2 240 22 130 108/84 102.4 270 19 110 112/80 102.4 300 30 120 110/82 102.5 330 18 100 112/75 102.8 360 16 100 108/80 102.7 390 -. 21 MAIIMI2BIMIAIJ 100/85 102.8 420 20 .110". 100/78 102.8 450 25 110 90/72 10310? :IMean of 12 g 21.3 115.1 102/79.2 102.5 *Systolic **Diastolic ***Due to technical difficulty no recording could be made. TABLE V EFFECTS OF VETAME IN GOAT 13 55 (2.0 milligrams per pound of body weight) Time in Respiration Pulse per Blood Pressure Temperature Minutes per Minute Minute (mm. of Hg) (Fahrenheit) Preinjectionw * ** Normal 30 100 125 / 92 103.6 30 24 140 112/ 92 102.2 60 __f** 100 118/ 97 90 27 110 115/ 98 102 120 __ ___ 150 29 100 165/135 102 180 29 90 145/117 102.4 210 23 90 140/115 102.7 240 24 100 130/ 95 102.8 270 20 100 145/112 300 23 100 155/119 102.8 330 __ ___ ___—___ 360 25 110 165/140 103.4 Mean of ' 12 25 104.0 139/112 102.5 *Systolic **Diastolic ***Due to technical difficulty no recordings could be made. 56 TABLE VI EFFECTS OF VETAME IN GOAT 14* (2.0 milligrams per pound of body weight) w Time in Respiration ' Pulse per Blood Pressure Minutes per Minute Minute (mm. of Hg) Prefiggggiion y 18 100 125**/112*** 30 10 120 78/60 60 7 110 100/88 Mean 8.5 115 89/74 *The goat died at 65 minutes after drug administration. **Systolic ***Diastolic TABLE VII EFFECTS OF VETAME IN GOAT 20A 57 (2.0 milligrams per pound of body weight) mgfiém Time in ReSpirationyPulse per Blood Pressure Temperature Minutes per Minute Minute (mm. of Hg) (Fahrenheit) PreAggggiion' 30 120 115*/70** 103.6 30 16 120 70/45 102.6 60 16 120 95/82 101.8 90 _*** _— 120 20 120 100/75 101.6 150 18 130 90/74 101.6 180 20 110 70/48 100.4 210 ‘__ .___ 240 16 140 90/70 100.6 270 22 150 90/65 102.4 300 19 160 102/68 102.6 330 15 140 80/50 101.4 360 13 140 85/70 101.5 390 16 140 90/70 102.8 420 16 110 70/55 102.8 450 __ ___ ._______ 480 16 140 82/56 103.0 Mean of 13 17.1 132.3 85.7/63.7 101.9 *Systolic **Diastolic ***Due to technical difficulty n0 recordings could be made. [I] FFECTS TABLE VIII 58 OF VETAME ON ELECTROCARDIOGRAM (0,5 milligram per pound of body weight) fin.-. ..1 e _- Goat lumber Preinjection At 30 Minutes At 60 Minutes At 90 Minutes 9 Normal ‘Inverted T wave in lead I 10 Normal QRS potential increased in lead I 13 Normal All waves de- creased in potential in leads I & II Complete absence of P wave 18 Complete absence of P wave Complete absence of P wave bomplete absence of P wave 20 Normal Slight de- crease in QRS poten- tial in lead I 20A Normal All waves increased in poten- tial in lead I but decreased in leads II & III Normal 24 Decrease in QRS potential of leads II & LIII Decrease in T wave in lead III *No deviation from normal. “4......” ‘ »-q-—- -o-—~—-~—.-.o.- TABLE IX 59 EFFECTS OF VETAME ON ELECTROCARDIOGRAM (1.0 milligram per pound of body weight) Goat At 30 At 60 At 90 Number Preinjection Minutes Minutes Minutes QRS potential T wave de- QRS po- in lead I de~ creased and tential 9 Normal creasedo T inverted in decreased wave in lead lead I in leads II decreased I & II T wave slight- * 10 Normal ly increased in lead II QRS potential QRS poten- increased in tial in- 13 Normal leads I & II creased in leads I & II Atrial fib- QRS potential Atrial fib- Atrial rilation in decreased in rilation in fibrila- leads II & all leads. leads II & tion in 14 III Atrial fib- III leads II rilation in & III leads II & III QRS potential increased and 18 Normal T wave inverted. in lead I *No deviation from normal. TABLE X 60 EFFECTS OF VETAME ON ELECTROCARDIOGRAM (2.0 milligrams per pound of body weight) =fi=_____W__=__=_——_—_.—====_ Goat Number Lead I Lead II Lead III QRS partially re- 9 versed 60 minutes Normal Normal after drug. QRS potential in— QRS potential in- QRS potential creased 30 90, creased, TP in- increased 30, 150, 180 210, ternal decreased 60, 90, 210, 270 and 300 minu- 30 minutes after 270 and 300 tes after drug. drug and T wave minutes after 10 TP internal de- increased 60 drug. TP in- creased 30 and 60 and 150 minutes ternal de- minutes after drug. after drug. creased 30 T internal decreas- minutes after ed 60 and 210 minu- drug. T in- tes after drug. verted 30 and 210 minutes after drug. T decreased 180 minutes after drug. QRS potential in- Absence of P - QRS potential creased and T in- wave. T wave in- increased 30 verted 30 and 60 creased 30 minu- and 60 minu- minutes after drug. tes after drug. tes after 14 QRS potential in- Some reverse creased and T 60 minutes wave increased after drug. 60 minutes after drug. QRS potential in- QRS potential in- QRS potential creased 60, 150, creased 60 and increased 300 180 minutes after 180 minutes after minutes after drug. TP internal drug. TP internal drug. TP in- very slight 150, decreased 150 min— ternal de- 20A 330 minutes after utes after drug. creased 150, drug. T wave in- creased 180 minu- tes after drug. 300 minutes after drug. Inverted P 180 minutes after drug. TABLE XI 61 EFFECT OF VETAME ON SPONTANEOUS MOTOR ACTIVITY Intravenous Reading* in Reading* in Difference Dose Miles for Miles for Between Weight Milligrams 24 Hours 24 Hours Readings Goat in per Pound Before Drug After Drug (A and B) Number Pounds Body Weight (A) (B) in Miles 1 100 2 3.00 1.00 -2.00 2 60 1 0.12 0.82 +0.70 3 100 2 0.80 1.25 +0.45 5 120 2 1050 0.88 -0962 9 110 2 1070 1025 -00h5 10 100 2 2.25 0.70 -1.55 20A 40 1 2.00 1.31 -0.69 23 105 2 1.20 0.25 -O.95 *As recorded with a Pedometer, New Haven Clock and Watch Company, New Haven, Connecticut. TABLE XII EFFECTS OF SLING 62 A. Goat not continuously on sling. Respiration per Minute Pulse per Minute Goat At 30 At 60 At 30 At 60 Number' Start Minute- Minute . Start Minute Minute 9 17 15 15 80 80 8O 18 26 26 26 105 108 106 Blood Pressure Temperature (mm. of Hg) (Fahrenheit) Goat At 30 At 60 At 30 At 60 Number 1 Start Minute Minute Start Minute Minute 1 0* 1 1 1 9 I37“ I15 I15 104.0 103.8 103.9 1 8 l 0 lg% 18 I06 I00 103.8 103.6 103.8 *Systolic **Diastol ic 63 TABLE XII (Continued) EFFECTS OF SLING B. Goat continuously on sling. W Respiration per Minute Pulse per Minute Goat At 30 At 60 At 30 At 60 Number Start- Minute Minute Start Minute Minute 13 37 33 37 100 100 110 20 24 22 29 70 70 85 Blood Pressure Temperature (mm. of Hg) (Fahrenheit) Goat At 30 At 60 At 30 At 60 Number Start Minute Minute Start Minute Minute 127% 1&1 1 1 13 I03** 4 I09 103.8 103.8 103.8 120 130 122 20 95 97 110 104.0 104.0 104.2 *Systolic **Diastolic 10. BIBLIOGRAPHY Azima H. and Durost, H.: Comparison of the Effects of Promazine and Chlor romazine in Mental Syndromes. Canad. M.A.J. 77,(l957§: 671-675. Benaron, H. B. W., Dorr, E. M., Roddick, W. J. Johnson, R. 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