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Gastric antisecretory actions of (15S)-15-methyl prostaglandin E2 methyl ester and natural prostaglandin E2 in rhesus monkeys
PROSTAGLANDINS
GASTRIC ANTISECRETORY ACTIONS OF (1X)-15-METHYL PROSTAGLANDIN Ep METRYL ESTER AND NATURAL PROSTAGLANDIN Ep IN RHRSUS MONREYS
Esam 2. Dajani and David A. Callison
Department of Biological Research, Searle Laboratories, P.O. Box 5110, Chicago, Illinois 60680 U.S.A.
ABSTRACT
The gastric antisecretory actions of (15S)-15-methyl prostaglandin E2 methyl ester (Me-PGE2) and Prostaglandin E2 (PGE2) were evaluated in the unanesthetixed gastric fistula rhesus monkey. Secretion was submaximally stimulated by multiple subcutaneous injections of histamine acid phosphate given every hour for four consecutive hours. When a steady-state plateau of gastric secretion was reached, the PG's were administered as a single bolus dose either intravenously (i.v.) or intragastrically (i.g.). Both PG's inhibited histamine-stimulated gastric secretion. The PG's showed greater sensitivity in inhibiting acid concentration while not affecting volume output. Active i.v. and 1.g. antisecretory doses of Me-PGE2 ranged from 3 to 10 pg/kg, while PGE2 showed significant antisecretory activity at i.v. bolus doses of 30-100 ug/kg and i.g. bolus dose of 1.0 mg/kg. Thus, Me-PGE2 is estimated to be at least 10 and 300 times more potent than PGE2 by the i.v. and i.g. administration routes, respectively. These findings indicate that the rhesus monkey shows some similarities to man in responsiveness to gastric secretory inhibition by E-prostaglandins.
ACRNOWLEDGBMRNTS The authors wish to thank Mrs. Carole A. Ryan and Mrs. Gerianne Vargason for their assistance in the preparation of the manuscript and to Mr. Robert G. Bianchi for expert technical assistance.
MAY 1976 VOL. 11 NO. 5
799
PROSTAGLANDINS
INTRODUCTION Using primates, particularly the rhesus monkey, as experimental subjects in gastric secretory studies appears to be rapidly increasing (1,2,3) because like man, but unlike the dog, rhesus monkeys secrete gastric juice during fasting (4). Also, in gastric secretion stimulated by histamine or pentagastrin, the rhesus monkey appears to respond very similarly to man in sensitivity to the stimulus, onset of acid response, and response to supramaximal stimulation (3). Although gastric antisecretory actions of E prostaglandins have been well documented in the rat, cat and dog (5,6), none of these animal models can accurately predict all aspects of the pharmacological responses to be expected in man. Thus, we became interested in evaluating the gastric antisecretory actions of E-prostaglandins in the rhesus monkey. Our aim was to investigate and compare the gastric antisecretory actions of (15S)15-methyl PGE2 methyl ester (Me-PGE2) and natural PGE, on histaminestimulated gastric secretion in conscious monkeys after intragastric (i.g.) and intravenous (i.v.) administration.
METHODS Drugs. Prostaglandin E2 and Me-PGE2 were synthesized by Mr. Clifford R. Dorn, Department of Chemical Research, Searle Laboratories. The PG's were prepared as 1.0 mg/ml stock solutions in 95% ethanol and stored at -1O'C when not in use. The stock solutions were diluted with an iso-osmotic phosphate buffer solution (7) so that the alcohol concentration did not exceed 20%. Histamine acid phosphate (Pierce Chemical Company, Rockford, Illinois) was prepared in a 0.15M sodium chloride solution immediately prior to the experiment. Antisecretory Studies. Adult female rhesus monkeys (Macaca mulatta) weighing 4.4-5.2 kg were equipped with a modified Thomas gastric cannula implanted in the most dependent portion of the stomach. The monkeys had been trained to sit quietly in primate chairs and were conscious during all the studies. When not in use, the monkeys were maintained in individual cages with complete freedom of movement. The surgery was done about 6 weeks before these studies were started. The animals were not used more than twice per week. Experiments were initiated by fasting the monkeys for 18 hours. On the morning of an experiment the monkeys were individually placed in primate chairs and the stomach was gently rinsed with tepid water. Gastric
800
MAY 1976 VOL. 11 NO. 5
PROSTAGLANDINS
juice was collected by gravity drainage through a polyethylene catheter at 30-minute intervals and measured for volume to the nearest 0.1 ml. After 30 minutes of basal secretion, the monkeys received subcutaneous injections of histamine acid phosphate at the submaximal dose of 0.1 mg/kg every hour for four consecutive hours (4). Approximately one hour after the first injection of histamine, a steady-state plateau of gastric secretion was obtained. At this time, the PG's were administered as a single bolus either intravenously or intragastrically. For intragastric efficacy studies the PG's were administered through a specially constructed dosage plug and the fistula was closed for 30 minutes to allow sufficient contact with the gastric mucosa (8). At the end of 30 minutes, gastric secretion interval collections were resumed. That is, the first collection was made one hour after intragastric administration of the prostaglandins. Gastric samples were measured for total acidity by titration with O.lN sodium hydroxide solution to pH 7.0 (Radiometer, Copenhagen). A cross-over experimental design was used to quantitatively assess gastric secretory inhibition. The differences in the means of volume, acid concentration and acid output for each 30-minute interval for each tested dose were determined by comparing the values obtained in treated animals at various times with those obtained in controls using the paired Student's t test at P < 0.05 (9,lO). Throughout the studies, the monkeys were closely obse?ved for frank side effects, if any.
RESULTS 1.
Gastric Antisecretory Actions of Intravenously Administered Prostaglandins.
Intravenous bolus administration of Me-PGE2 and natural PGE, at doses of 10 and 100 pg/kg, respectively, significantly inhibited steady-state gastric secretion (Figure 1) while doses at 3.0 and 30 ug/kg, respectively, only slightly inhibited gastric secretion. As evident in Figure 1, volume output (ml/30 minutes) of gastric secretion was not significantly changed from previously established steady-state values. However, gastric acid concentrations (mEq/L) showed marked inhibition with the maximum equivalent to 57% for PGE2 and near 100% for Me-PGE2 and for 1% hours for PGE2 and more than 3% hours for Me-PGE2. Total acid output paralleled inhibition of the acid concentration since it resulted primarily from an inhibition of the concentration rather than the volume. 2.
Gastric Antisecretory Actions of Intragastrically Administered Prostaglandins.
Intragastric bolus administration of Me-PGE2 at doses of 3.0 and 10 ug/kg produced dose-dependent inhibition of gastric secretion (Figure 2). As evident in Figure 2, intragastric administration of Me-PGE2 produced similar patterns of gastric secretory inhibition to those noted with intravenous administration. Minimally effective i.g.
MAY 1976 VOL. 11 NO. 5
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dosages were not established, but a dose of 1.0 ug/kg did not inhibit histamine-stimulated gastric secretion in monkeys. Intragastric bolus administration of 1.0 mg/kg of PGE2 inhibited histamine-stimulated gastric secretion (Figure 3). Minimally effective dosages of PGE2 were not established, but a dose of 300 ug/kg, i.g. did not inhibit histamine-stimulated gastric secretion. 3.
Side Effects.
The side effects noted with either an i.v. dose of PGE2 or the low dose (3.0 pg/kg) of Me-PGE2 were primarily sedation, slight trembling or shivering and facial erythema. Defecation, diarrhea and urination were observed in 215 monkeys only with the high (10 ug/kg) i.v. bolus dose of Me-PGE2. The side effects noted following intragastric administration of Me-PGE2 were transient and characterized by sedation, shivering and facial erythema. Intragastric administration of 1.0 mg/kg of PGE2 produced emesis and retching in 415 animals, brief sedation and trembling. Thus, it appeared that an effective intragastric antisecretory dose of 1.0 mgfkg of PGE2 is not well tolerated.
DISCUSSION Multiple hourly subcutaneous bolus injections of histamine effectively stimulated continuous gastric secretion in rhesus monkeys. A steady-state plateau was easily obtained, which was maintained for the duration of the secretory test. The results obtained with this form of stimulation do not generally differ from the intravenous infusion approach commonly used in similar studies in dogs and humans (8, 9 and 11). Intravenous infusion studies could, however, be performed using chronically implanted intravenous cannulas in monkeys that are continuously maintained in primate chairs. Multiple subcutaneous Injections were used however for simplicity and for ease in maintaining and housing the monkeys (4). These studies demonstrate that Me-PGE2 and PGE2 significantly inhibit histamine-stimulated gastric secretion in conscious rhesus monkeys. The methylated analog is estimated to be 10 and 300 times more potent than natural PGE2 when administered intravenously and intragastrically, respectively. The compound Me-PGE2 has also been reported to be ten times more potent than PGE2 when administered i.v. for its oxytocic action in the rhesus monkey (12). Thus, it appears that the i.v. potency of the natural and the synthetic methylated analog of PGE2 in two biological test systems are comparable. The greater potency (i.v. and i.g. administration) and prolonged antisecretory activity of Me-PGE2 are likely to be due to a decreased rate
MAY 1976 VOL. 11 NO. 5
PROSTAGLANDINS
in metabolic conversion of C-15 hydroxyl to the corresponding ketone. The 15-methyl analog is not a substrate for the enzyme 15-hydroxyprostaglandin dehydrogenase (13,14). Another possible explanation for this greater potency may be from differences between free acid and methyl ester. It has been shown recently that methyl esterification of PGEl significantly increased the potency of PGEl as a gastric antisecretory and antiulcer agent in both the rat and dog (9). The nature of the inhibitory actions of E2 prostaglandins in the rhesus monkey is apparently unique to this species. In the histamine-stimulated Heidenhain pouch dog, the i.v. administration of either PGE2 or Me-PGE2 profoundly inhibited volume output and acid concentration (15). In our studies with rhesus monkeys, PGE2 and Me-PGE2 did not appreciably affect volume output but did significantly inhibit acid concentration. In man, the nature of the inhibitory aspects of E-prostaglandins on gastric secretion is somewhat controversial since the inhibition is obviously related to the type and level of stimulation used in these studies. Two separate clinical studies (16, 17) showed that Me-PGE2, 16,16-dimethyl PGE2 and 16,16-dimethyl PGE2 methyl ester inhibited volume and acid concentration in pentagastrin-stimulated gastric secretion in adult volunteers. On the other hand, Karim et al. (18 and 19) showed that the 15-methyl and 16,16-dimethyl PGE2 analogs reduced acid output mainly by reducing acid concentration rather than by lowering the volume of secretion in the basal and pentagastrinstimulated gastric secretion in man. More recently Wilson -et al. (11) have shown that the compound 16,16-dimethyl PGE2 showed greater sensitivity towards the inhibition of acid concentration than of volume output in histamine-stimulated adult volunteers. From all available clinical experience with E-prostaglandins, it appears that the rhesus monkey and man are closely similar. Parenteral administration of PGE2 and Me-PGE2 commonly produces pronounced side effects (diarrhea, retching and emesis) at or near active antisecretory doses in both dogs (15) and rata (20). In our ,current studies, intragastric administration of 1.0 mg/kg of PGE2 produced retching and emesis in four of five monkeys. On the other hand, intravenous administration of Me-PGE2 and PGE2 and intragastric administration of Me-PGE2 were tolerated, at least in the active antisecretory dose range. Thus, it would seem that the rhesus monkey is similar to man.
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REFERENCES 1.
Rosato, E. F., J. L. Mullen, G. Lanciault, F. E. Rosato and F. P. Brooks. Fasting Acid Output and Plasma Gastrin in Conscious Monkeys. Proc. Sot. Exp. Biol. Med. 139:833, 1972.
2.
Rosato, E. F., J. L. Mullen, G. Lanciault, F. E. Rosato and F. P. Brooks. The Dissociation of Gastric Acid Output and Plasma Gastrin Concentration After Calcium Infusions in Conscious Monkeys. Surgery 73(2):207, 1973.
3.
Rosato, E. F., L. J. Mayer, S. Arenschield, F. E. Rosato and F. P. Brooks. Acid Secretory Responses to Histamine and Pentagastrin in Conscious Monkeys. Dig. Dis. 19(12):1111, 1974.
4.
Brodie, D. A. and R. W. Marshall. A Survey. Science 141:174, 1963.
5.
Wilson, D. E. Prostaglandins, Their Actions on the Gastrointestinal Tract. Arch. Inter. Med. 133:112, 1974.
6.
Katz, R. L. and G. J. Katz. Prostaglandins-Basic and Clinical Considerations. Anesthesiology 40~471, 1974.
7.
Lee, Y. II.,W. D. Cheng, R. G. Bianchi, K. Mollison and J. Hansen. Effects of Oral Administration of PGE2 on Gastric Secretion and Experimental Peptic Ulcerations. Prostaglandins 3:29, 1973.
8.
Dajani, E. Z., D. R. Driskill, R. G. Bianchi, P. W. Collins and R. Pappo. Influence of the Position of the Side Chain Hydroxy Group on the Gastric Antisecretory and Antiulcer Actions of El Prostaglandin Analogs. Prostaglandins 10(5):733, 1975.
9.
Dajani, E. Z., D. R. Driskill, R. G. Bianchi and P. W. Collins. Comparative Gastric Antisecretory and Antiulcer Effects of Prostaglandin EI and its Methyl Ester in Animals. Prostaglandins 10(2):205, 1975.
Gastric Content of Fasted Primates:
10.
Snedecor, G. W. and W. G. Cochran. Statistical Methods. State University Press, Ames, Iowa, 1967, p. 91.
11.
Wilson, D. E., G. Winnan, J. Quertarmus and P. Tao. Effects of an Orally Administered Prostaglandin Analogue (16,16_dimethylProstaglandin E2) on Human Gastric Secretion. Gastroenterology 69: 607, 1975.
12.
Kirton, K. T. and A. D. Forbes. Activity of (15S)-15-Methyl Prostaglandin E2 and Fza as Stimulants of Uterine Contractility, Prostaglandins 1:319, 1972.
804
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13.
Weeks, J. R., D. W. Ducharm, W. E. Magee and W. L. Miller. The Biological Activity of the (15S)-15-Methyl Analogs of Prostaglandins E2 and F2u. J. Pharmacol. Exp. Therap. 186:67, 1973.
14.
Bundy, G. L., E. W. Yankee, J. R. Weeks and W. L. Miller. The Synthesis and Biological Activity of a Series of 15-Methyl Prostaglandins. Advances in Biosciences 9:125, 1973.
15.
Robert, A. and B. J. Magerlein. 15-Methyl PGE;!and 16,16-Dimethyl PGE2: Potent Inhibitors of Gastric Secretion, in International Symposium of Prostaglandins. Advances in Biosciences 9:247, 1973.
16.
Nylander, B. and S. Andersson. Gastric Secretory Inhibition by Three Methyl Analogs of Prostaglandin E2 Administered Intragastrically to Man. Stand. J. Gastroenterol. 9:751, 1974.
17.
Robert, A., B. Nylander and S.Andersson. Marked Inhibition of Gastric Secretion by Two Prostaglandin Analogs Given Orally to Man. Life Sciences 14:533, 1974.
18.
Karim, S. M. M., D. C. Carter, D. Bhana and P. A. Ganesan. Effect of Orally Administered Prostaglandin E2 and its 15-Methyl Analogues on Gastric Secretion. Brit. Med. J. 1:143, 1973.
19.
Karim, S. M. M., D. C. Carter, D. Bhana and P. A. Ganesan. The Effect of Orally and Intravenously Administered Prostaglandin 16:16dimethyl Eg Methyl Ester on Human Gastric Secretion. Prostaglandins 4(1):71, 1973.
20.
Main, I. H. M. and B. J. R. Whittle. Methyl Analogues of Prostaglandin Ep and Gastrointestinal Function in the Rat. Brit. J. Pharmacol. Chemotherap. 52:113P, 1974.
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Figure 1. Comparative Gastric Antisecre'tory Effects of (lSS)-15-Methyl PGE2 Methyl Ester and PGEp When Administered at Doses of 10 and 100 ug/kg I.V. Bolus, Respectively. Secretion was submaximally stimulated by multiple subcutaneous injections of histamine. Values represent mean t SE of two studies conducted in three animals at the control and each of the PGE2 and Me-PGEZ doses. Asterisks denote periods in which the differences between the control and treated series are significant (P _< 0.05).
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MAY 1976 VOL. 11 NO. 5
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1.2-
1.0.
8.
Ir_. <
B d- 0.4. 2
0.2.
Figure 2. Gastric Antisecretory Effects of (15S)-15-Methyl PGE:!Methyl Ester Administered Intragastrically on Histamine-Stimulated Gastric Secretion in Rhesus Monkeys. The prostaglandin or vehicle were administered immediately after collecting Period #3 secretion, and the cannula was closed for 30 minutes. At the end of 30 minutes, the cannula was opened to empty gastric contents and interval collection was then resumed (Periods 15 through #lo). Values represent mean ? SE of two studies conducted in three animals at the control and each of the Me-PGE2 doses. Asterisks denote periods in which the differences between the control and treated series are significant (P 2 0.05).
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h
Figure 3. Gastric Antisecretory Effects of PGE2 Administered Intragastrically on Histamine-Stimulated Gastric Secretion in Rhesus Monkeys. Values represent mean + SE of two studies conducted in three animals at the control and PGE2 dose. Asterisks denote periods in which the differences between the control and treated series are significant (P < 0.05).
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MAY 1976 VOL.
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5
GASTRIC ANTISECRETORY ACTIONS OF (1X)-15-METHYL PROSTAGLANDIN Ep METRYL ESTER AND NATURAL PROSTAGLANDIN Ep IN RHRSUS MONREYS
Esam 2. Dajani and David A. Callison
Department of Biological Research, Searle Laboratories, P.O. Box 5110, Chicago, Illinois 60680 U.S.A.
ABSTRACT
The gastric antisecretory actions of (15S)-15-methyl prostaglandin E2 methyl ester (Me-PGE2) and Prostaglandin E2 (PGE2) were evaluated in the unanesthetixed gastric fistula rhesus monkey. Secretion was submaximally stimulated by multiple subcutaneous injections of histamine acid phosphate given every hour for four consecutive hours. When a steady-state plateau of gastric secretion was reached, the PG's were administered as a single bolus dose either intravenously (i.v.) or intragastrically (i.g.). Both PG's inhibited histamine-stimulated gastric secretion. The PG's showed greater sensitivity in inhibiting acid concentration while not affecting volume output. Active i.v. and 1.g. antisecretory doses of Me-PGE2 ranged from 3 to 10 pg/kg, while PGE2 showed significant antisecretory activity at i.v. bolus doses of 30-100 ug/kg and i.g. bolus dose of 1.0 mg/kg. Thus, Me-PGE2 is estimated to be at least 10 and 300 times more potent than PGE2 by the i.v. and i.g. administration routes, respectively. These findings indicate that the rhesus monkey shows some similarities to man in responsiveness to gastric secretory inhibition by E-prostaglandins.
ACRNOWLEDGBMRNTS The authors wish to thank Mrs. Carole A. Ryan and Mrs. Gerianne Vargason for their assistance in the preparation of the manuscript and to Mr. Robert G. Bianchi for expert technical assistance.
MAY 1976 VOL. 11 NO. 5
799
PROSTAGLANDINS
INTRODUCTION Using primates, particularly the rhesus monkey, as experimental subjects in gastric secretory studies appears to be rapidly increasing (1,2,3) because like man, but unlike the dog, rhesus monkeys secrete gastric juice during fasting (4). Also, in gastric secretion stimulated by histamine or pentagastrin, the rhesus monkey appears to respond very similarly to man in sensitivity to the stimulus, onset of acid response, and response to supramaximal stimulation (3). Although gastric antisecretory actions of E prostaglandins have been well documented in the rat, cat and dog (5,6), none of these animal models can accurately predict all aspects of the pharmacological responses to be expected in man. Thus, we became interested in evaluating the gastric antisecretory actions of E-prostaglandins in the rhesus monkey. Our aim was to investigate and compare the gastric antisecretory actions of (15S)15-methyl PGE2 methyl ester (Me-PGE2) and natural PGE, on histaminestimulated gastric secretion in conscious monkeys after intragastric (i.g.) and intravenous (i.v.) administration.
METHODS Drugs. Prostaglandin E2 and Me-PGE2 were synthesized by Mr. Clifford R. Dorn, Department of Chemical Research, Searle Laboratories. The PG's were prepared as 1.0 mg/ml stock solutions in 95% ethanol and stored at -1O'C when not in use. The stock solutions were diluted with an iso-osmotic phosphate buffer solution (7) so that the alcohol concentration did not exceed 20%. Histamine acid phosphate (Pierce Chemical Company, Rockford, Illinois) was prepared in a 0.15M sodium chloride solution immediately prior to the experiment. Antisecretory Studies. Adult female rhesus monkeys (Macaca mulatta) weighing 4.4-5.2 kg were equipped with a modified Thomas gastric cannula implanted in the most dependent portion of the stomach. The monkeys had been trained to sit quietly in primate chairs and were conscious during all the studies. When not in use, the monkeys were maintained in individual cages with complete freedom of movement. The surgery was done about 6 weeks before these studies were started. The animals were not used more than twice per week. Experiments were initiated by fasting the monkeys for 18 hours. On the morning of an experiment the monkeys were individually placed in primate chairs and the stomach was gently rinsed with tepid water. Gastric
800
MAY 1976 VOL. 11 NO. 5
PROSTAGLANDINS
juice was collected by gravity drainage through a polyethylene catheter at 30-minute intervals and measured for volume to the nearest 0.1 ml. After 30 minutes of basal secretion, the monkeys received subcutaneous injections of histamine acid phosphate at the submaximal dose of 0.1 mg/kg every hour for four consecutive hours (4). Approximately one hour after the first injection of histamine, a steady-state plateau of gastric secretion was obtained. At this time, the PG's were administered as a single bolus either intravenously or intragastrically. For intragastric efficacy studies the PG's were administered through a specially constructed dosage plug and the fistula was closed for 30 minutes to allow sufficient contact with the gastric mucosa (8). At the end of 30 minutes, gastric secretion interval collections were resumed. That is, the first collection was made one hour after intragastric administration of the prostaglandins. Gastric samples were measured for total acidity by titration with O.lN sodium hydroxide solution to pH 7.0 (Radiometer, Copenhagen). A cross-over experimental design was used to quantitatively assess gastric secretory inhibition. The differences in the means of volume, acid concentration and acid output for each 30-minute interval for each tested dose were determined by comparing the values obtained in treated animals at various times with those obtained in controls using the paired Student's t test at P < 0.05 (9,lO). Throughout the studies, the monkeys were closely obse?ved for frank side effects, if any.
RESULTS 1.
Gastric Antisecretory Actions of Intravenously Administered Prostaglandins.
Intravenous bolus administration of Me-PGE2 and natural PGE, at doses of 10 and 100 pg/kg, respectively, significantly inhibited steady-state gastric secretion (Figure 1) while doses at 3.0 and 30 ug/kg, respectively, only slightly inhibited gastric secretion. As evident in Figure 1, volume output (ml/30 minutes) of gastric secretion was not significantly changed from previously established steady-state values. However, gastric acid concentrations (mEq/L) showed marked inhibition with the maximum equivalent to 57% for PGE2 and near 100% for Me-PGE2 and for 1% hours for PGE2 and more than 3% hours for Me-PGE2. Total acid output paralleled inhibition of the acid concentration since it resulted primarily from an inhibition of the concentration rather than the volume. 2.
Gastric Antisecretory Actions of Intragastrically Administered Prostaglandins.
Intragastric bolus administration of Me-PGE2 at doses of 3.0 and 10 ug/kg produced dose-dependent inhibition of gastric secretion (Figure 2). As evident in Figure 2, intragastric administration of Me-PGE2 produced similar patterns of gastric secretory inhibition to those noted with intravenous administration. Minimally effective i.g.
MAY 1976 VOL. 11 NO. 5
PRCASTAGLANDINS
dosages were not established, but a dose of 1.0 ug/kg did not inhibit histamine-stimulated gastric secretion in monkeys. Intragastric bolus administration of 1.0 mg/kg of PGE2 inhibited histamine-stimulated gastric secretion (Figure 3). Minimally effective dosages of PGE2 were not established, but a dose of 300 ug/kg, i.g. did not inhibit histamine-stimulated gastric secretion. 3.
Side Effects.
The side effects noted with either an i.v. dose of PGE2 or the low dose (3.0 pg/kg) of Me-PGE2 were primarily sedation, slight trembling or shivering and facial erythema. Defecation, diarrhea and urination were observed in 215 monkeys only with the high (10 ug/kg) i.v. bolus dose of Me-PGE2. The side effects noted following intragastric administration of Me-PGE2 were transient and characterized by sedation, shivering and facial erythema. Intragastric administration of 1.0 mg/kg of PGE2 produced emesis and retching in 415 animals, brief sedation and trembling. Thus, it appeared that an effective intragastric antisecretory dose of 1.0 mgfkg of PGE2 is not well tolerated.
DISCUSSION Multiple hourly subcutaneous bolus injections of histamine effectively stimulated continuous gastric secretion in rhesus monkeys. A steady-state plateau was easily obtained, which was maintained for the duration of the secretory test. The results obtained with this form of stimulation do not generally differ from the intravenous infusion approach commonly used in similar studies in dogs and humans (8, 9 and 11). Intravenous infusion studies could, however, be performed using chronically implanted intravenous cannulas in monkeys that are continuously maintained in primate chairs. Multiple subcutaneous Injections were used however for simplicity and for ease in maintaining and housing the monkeys (4). These studies demonstrate that Me-PGE2 and PGE2 significantly inhibit histamine-stimulated gastric secretion in conscious rhesus monkeys. The methylated analog is estimated to be 10 and 300 times more potent than natural PGE2 when administered intravenously and intragastrically, respectively. The compound Me-PGE2 has also been reported to be ten times more potent than PGE2 when administered i.v. for its oxytocic action in the rhesus monkey (12). Thus, it appears that the i.v. potency of the natural and the synthetic methylated analog of PGE2 in two biological test systems are comparable. The greater potency (i.v. and i.g. administration) and prolonged antisecretory activity of Me-PGE2 are likely to be due to a decreased rate
MAY 1976 VOL. 11 NO. 5
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in metabolic conversion of C-15 hydroxyl to the corresponding ketone. The 15-methyl analog is not a substrate for the enzyme 15-hydroxyprostaglandin dehydrogenase (13,14). Another possible explanation for this greater potency may be from differences between free acid and methyl ester. It has been shown recently that methyl esterification of PGEl significantly increased the potency of PGEl as a gastric antisecretory and antiulcer agent in both the rat and dog (9). The nature of the inhibitory actions of E2 prostaglandins in the rhesus monkey is apparently unique to this species. In the histamine-stimulated Heidenhain pouch dog, the i.v. administration of either PGE2 or Me-PGE2 profoundly inhibited volume output and acid concentration (15). In our studies with rhesus monkeys, PGE2 and Me-PGE2 did not appreciably affect volume output but did significantly inhibit acid concentration. In man, the nature of the inhibitory aspects of E-prostaglandins on gastric secretion is somewhat controversial since the inhibition is obviously related to the type and level of stimulation used in these studies. Two separate clinical studies (16, 17) showed that Me-PGE2, 16,16-dimethyl PGE2 and 16,16-dimethyl PGE2 methyl ester inhibited volume and acid concentration in pentagastrin-stimulated gastric secretion in adult volunteers. On the other hand, Karim et al. (18 and 19) showed that the 15-methyl and 16,16-dimethyl PGE2 analogs reduced acid output mainly by reducing acid concentration rather than by lowering the volume of secretion in the basal and pentagastrinstimulated gastric secretion in man. More recently Wilson -et al. (11) have shown that the compound 16,16-dimethyl PGE2 showed greater sensitivity towards the inhibition of acid concentration than of volume output in histamine-stimulated adult volunteers. From all available clinical experience with E-prostaglandins, it appears that the rhesus monkey and man are closely similar. Parenteral administration of PGE2 and Me-PGE2 commonly produces pronounced side effects (diarrhea, retching and emesis) at or near active antisecretory doses in both dogs (15) and rata (20). In our ,current studies, intragastric administration of 1.0 mg/kg of PGE2 produced retching and emesis in four of five monkeys. On the other hand, intravenous administration of Me-PGE2 and PGE2 and intragastric administration of Me-PGE2 were tolerated, at least in the active antisecretory dose range. Thus, it would seem that the rhesus monkey is similar to man.
MAY
1976
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REFERENCES 1.
Rosato, E. F., J. L. Mullen, G. Lanciault, F. E. Rosato and F. P. Brooks. Fasting Acid Output and Plasma Gastrin in Conscious Monkeys. Proc. Sot. Exp. Biol. Med. 139:833, 1972.
2.
Rosato, E. F., J. L. Mullen, G. Lanciault, F. E. Rosato and F. P. Brooks. The Dissociation of Gastric Acid Output and Plasma Gastrin Concentration After Calcium Infusions in Conscious Monkeys. Surgery 73(2):207, 1973.
3.
Rosato, E. F., L. J. Mayer, S. Arenschield, F. E. Rosato and F. P. Brooks. Acid Secretory Responses to Histamine and Pentagastrin in Conscious Monkeys. Dig. Dis. 19(12):1111, 1974.
4.
Brodie, D. A. and R. W. Marshall. A Survey. Science 141:174, 1963.
5.
Wilson, D. E. Prostaglandins, Their Actions on the Gastrointestinal Tract. Arch. Inter. Med. 133:112, 1974.
6.
Katz, R. L. and G. J. Katz. Prostaglandins-Basic and Clinical Considerations. Anesthesiology 40~471, 1974.
7.
Lee, Y. II.,W. D. Cheng, R. G. Bianchi, K. Mollison and J. Hansen. Effects of Oral Administration of PGE2 on Gastric Secretion and Experimental Peptic Ulcerations. Prostaglandins 3:29, 1973.
8.
Dajani, E. Z., D. R. Driskill, R. G. Bianchi, P. W. Collins and R. Pappo. Influence of the Position of the Side Chain Hydroxy Group on the Gastric Antisecretory and Antiulcer Actions of El Prostaglandin Analogs. Prostaglandins 10(5):733, 1975.
9.
Dajani, E. Z., D. R. Driskill, R. G. Bianchi and P. W. Collins. Comparative Gastric Antisecretory and Antiulcer Effects of Prostaglandin EI and its Methyl Ester in Animals. Prostaglandins 10(2):205, 1975.
Gastric Content of Fasted Primates:
10.
Snedecor, G. W. and W. G. Cochran. Statistical Methods. State University Press, Ames, Iowa, 1967, p. 91.
11.
Wilson, D. E., G. Winnan, J. Quertarmus and P. Tao. Effects of an Orally Administered Prostaglandin Analogue (16,16_dimethylProstaglandin E2) on Human Gastric Secretion. Gastroenterology 69: 607, 1975.
12.
Kirton, K. T. and A. D. Forbes. Activity of (15S)-15-Methyl Prostaglandin E2 and Fza as Stimulants of Uterine Contractility, Prostaglandins 1:319, 1972.
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Weeks, J. R., D. W. Ducharm, W. E. Magee and W. L. Miller. The Biological Activity of the (15S)-15-Methyl Analogs of Prostaglandins E2 and F2u. J. Pharmacol. Exp. Therap. 186:67, 1973.
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Bundy, G. L., E. W. Yankee, J. R. Weeks and W. L. Miller. The Synthesis and Biological Activity of a Series of 15-Methyl Prostaglandins. Advances in Biosciences 9:125, 1973.
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Robert, A. and B. J. Magerlein. 15-Methyl PGE;!and 16,16-Dimethyl PGE2: Potent Inhibitors of Gastric Secretion, in International Symposium of Prostaglandins. Advances in Biosciences 9:247, 1973.
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Nylander, B. and S. Andersson. Gastric Secretory Inhibition by Three Methyl Analogs of Prostaglandin E2 Administered Intragastrically to Man. Stand. J. Gastroenterol. 9:751, 1974.
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Robert, A., B. Nylander and S.Andersson. Marked Inhibition of Gastric Secretion by Two Prostaglandin Analogs Given Orally to Man. Life Sciences 14:533, 1974.
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Karim, S. M. M., D. C. Carter, D. Bhana and P. A. Ganesan. Effect of Orally Administered Prostaglandin E2 and its 15-Methyl Analogues on Gastric Secretion. Brit. Med. J. 1:143, 1973.
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Karim, S. M. M., D. C. Carter, D. Bhana and P. A. Ganesan. The Effect of Orally and Intravenously Administered Prostaglandin 16:16dimethyl Eg Methyl Ester on Human Gastric Secretion. Prostaglandins 4(1):71, 1973.
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Main, I. H. M. and B. J. R. Whittle. Methyl Analogues of Prostaglandin Ep and Gastrointestinal Function in the Rat. Brit. J. Pharmacol. Chemotherap. 52:113P, 1974.
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Figure 1. Comparative Gastric Antisecre'tory Effects of (lSS)-15-Methyl PGE2 Methyl Ester and PGEp When Administered at Doses of 10 and 100 ug/kg I.V. Bolus, Respectively. Secretion was submaximally stimulated by multiple subcutaneous injections of histamine. Values represent mean t SE of two studies conducted in three animals at the control and each of the PGE2 and Me-PGEZ doses. Asterisks denote periods in which the differences between the control and treated series are significant (P _< 0.05).
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1.2-
1.0.
8.
Ir_. <
B d- 0.4. 2
0.2.
Figure 2. Gastric Antisecretory Effects of (15S)-15-Methyl PGE:!Methyl Ester Administered Intragastrically on Histamine-Stimulated Gastric Secretion in Rhesus Monkeys. The prostaglandin or vehicle were administered immediately after collecting Period #3 secretion, and the cannula was closed for 30 minutes. At the end of 30 minutes, the cannula was opened to empty gastric contents and interval collection was then resumed (Periods 15 through #lo). Values represent mean ? SE of two studies conducted in three animals at the control and each of the Me-PGE2 doses. Asterisks denote periods in which the differences between the control and treated series are significant (P 2 0.05).
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Figure 3. Gastric Antisecretory Effects of PGE2 Administered Intragastrically on Histamine-Stimulated Gastric Secretion in Rhesus Monkeys. Values represent mean + SE of two studies conducted in three animals at the control and PGE2 dose. Asterisks denote periods in which the differences between the control and treated series are significant (P < 0.05).
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