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A GASTRIC SECRETION ANTAGONIST'S EFFECT
720 nuclei was found between the cases of breast cancer from the two groups, which were therefore combined to give 139 cases of breast cancer and 191 controls. The results are summarised in tables i and II. The mean values for the frequency of chromatin-positive nuclei of 31-6% in women with breast cancer and 34-6% in controls are not significantly different. Table n shows that no distinct subgroup, as described by Stanley et al. among women with breast cancer, can be defined on the basis of a lowered frequency of chromatin-positive nuclei in buccal smears.
positive
M.R.C. Clinical Effects of Radiation Research Unit, Western General Hospital, Crewe Road, Edinburgh 4.
A. O. LANGLANDS ROSEMARY CATHELS
lant. If the stimulant is 0-5 g. gastrin 11 per kg. per hou effective dose of SC 15396 (producing 80% inhibition) gastric-fistula dogs is 4 mg. per kg. given by intrave injection, while 8 mg. per kg. given orally to a Heideri pouch dog produces 90% inhibition. A similar dose-I is effective to the same extent in rats. We have, in addition, found that SC 15396 is eff( against other gastric secretory stimuli when tested in preparations. Secretion produced by 0-15 unit of insuli kg. subcutaneously was reduced 90% when 3 mg. per kg given intravenously to a gastric-fistula dog, and was rec 70% when 20 mg. per kg. was given intragastrically. antrectomised dog with a gastric fistula also respondedI inhibition) to SC 15396 when given intravenously along
insulin. A GASTRIC SECRETION ANTAGONIST’S EFFECT SIR,-Mr. Bedi and his colleagues,l using vagally innervated and Heidenhain-pouch dogs, have demonstrated the inhibition of gastrin-stimulated acid secretion by 2-phenyl-2-(2-pyridyl) thioacetamide ("antigastrin", ’SC 15396’ [G. D. Searle & Co Ltd.]). They claim that it is a specific gastrin antagonist, since they failed to demonstrate any effect on histaminestimulated or methacholine-stimulated secretion. We have confirmed that SC 15396 effectively depresses the acid secretory response to gastrin 11 and peptavlon (’ICI 150123 ’, pentagastrin) in conscious dogs prepared with gastric fistulas, Pavlov pouches, or Heidenhain pouches. It is effective given intravenously (dissolved in dimethyl sulphoxide in 0-9% sodium-chloride solution [1/1, v/v]), intragastrically or orally. We have also found that it depresses gastrin-induced acid secretion in the anaesthetised rat when given intravenously. In both species, intravenous administration of the drug inhibits secretion already established by prior treatment with gastrin, and also delays and depresses the promotion of secretion when administered before the stimu1.
Bedi, B. S., Gillespie, G., Gillespie, I. E. Lancet, 1967, i, 1240.
The drug also inhibits histamine-stimulated seer Oral administration of 10 mg. per kg. during contii histamine infusion (0-1mg. per kg. per hour) pro( inhibition of secretion in both Pavlov and HeidenhainI dogs, the effect being more striking on the secretion fro] denervated pouch (see accompanying figure), whereas tion from gastric-fistula dogs was unaffected. The same order (10 mg. per kg.) given intravenously to a fistul: produced 75% inhibition of secretion for at least two 1 whereas 1 mg. per kg. resulted in inhibition of the or( 30% lasting only 45 minutes, secretion in this animal provoked by an infusion of 0-05 mg. histamine per k; hour. These studies suggest that SC 15396 is not a specific g antagonist. The failure of Mr. Bedi and his colleagues to d( strate the action of the drug on histamine-stimulated sec may well be attributable to the smaller doses of the drug in their experiments (10 mg. per animal, and 140 mg. 0’ minutes per animal), whereas in our studies the dose B the order of 200 mg. per animal, given as one injection one oral treatment. Their use of vagally innervated dogs may also explain in part the reported lack of inhi of histamine-stimulated secretion. It may be that a c ratio of drug to stimulant may have to be achieved f. drug to be effective; this is suggested by the results rel here, and by other studies using the rat preparation. TtlfRf qtilciieq will 11P rpnnrtprl in
Department of Surgery, Queen’s University, Belfast. Department of Medicine, Western General Hospital, University of Edinburgh.
Department of Clinical Surgery, University of Edinburgh.
Department of Clinical Chemistry,
University of Edinburgh.
Influence of pouch innervation on effect of oral SC15396 on histanifne-stimulated gastric secretion. There is greater inhibition in the denervated pouch (P<0’01).
greater
detail elsewhere.
A. M. CONNELL. W. SIRCUS. R. A. HILL I. B. MACLEOD.
C. G. THOMSON.
EFFECT OF PENTAGASTRIN AFTER VAGOTOMY SIR,-The apparent discrepancy between the responses of the inervated and denervated human stomach to pentagastrin reported in the multicentre study (Sept. 9, p. 534) is probably related to the infusion method employed. Continuous infusion of gastrin or its derivatives in man, as in animals, is accompanied by a reduction of response with time. This reduction is most prominent with near-maximal doses. In the multicentre study, the infusion of 12 g. per kg. per hour of pentagastrin followed a 60-90 minute period of infusion with a near-maximal dose of 6 {.tg. per kg. per hour and thus coincided with the period of reduction of response. The response to 12 {.tg. is located near the asymptote of the dose-response curve: any increase in response to this larger dose is likely to be small and will be masked by the more prominent reduction of response during this particular period of infusion. The response of the denervated stomach, on the other hand, is around 50% of maximum and is located on the rising slope of a dose-response curve where doubling the dose from 6 to
positive
M.R.C. Clinical Effects of Radiation Research Unit, Western General Hospital, Crewe Road, Edinburgh 4.
A. O. LANGLANDS ROSEMARY CATHELS
lant. If the stimulant is 0-5 g. gastrin 11 per kg. per hou effective dose of SC 15396 (producing 80% inhibition) gastric-fistula dogs is 4 mg. per kg. given by intrave injection, while 8 mg. per kg. given orally to a Heideri pouch dog produces 90% inhibition. A similar dose-I is effective to the same extent in rats. We have, in addition, found that SC 15396 is eff( against other gastric secretory stimuli when tested in preparations. Secretion produced by 0-15 unit of insuli kg. subcutaneously was reduced 90% when 3 mg. per kg given intravenously to a gastric-fistula dog, and was rec 70% when 20 mg. per kg. was given intragastrically. antrectomised dog with a gastric fistula also respondedI inhibition) to SC 15396 when given intravenously along
insulin. A GASTRIC SECRETION ANTAGONIST’S EFFECT SIR,-Mr. Bedi and his colleagues,l using vagally innervated and Heidenhain-pouch dogs, have demonstrated the inhibition of gastrin-stimulated acid secretion by 2-phenyl-2-(2-pyridyl) thioacetamide ("antigastrin", ’SC 15396’ [G. D. Searle & Co Ltd.]). They claim that it is a specific gastrin antagonist, since they failed to demonstrate any effect on histaminestimulated or methacholine-stimulated secretion. We have confirmed that SC 15396 effectively depresses the acid secretory response to gastrin 11 and peptavlon (’ICI 150123 ’, pentagastrin) in conscious dogs prepared with gastric fistulas, Pavlov pouches, or Heidenhain pouches. It is effective given intravenously (dissolved in dimethyl sulphoxide in 0-9% sodium-chloride solution [1/1, v/v]), intragastrically or orally. We have also found that it depresses gastrin-induced acid secretion in the anaesthetised rat when given intravenously. In both species, intravenous administration of the drug inhibits secretion already established by prior treatment with gastrin, and also delays and depresses the promotion of secretion when administered before the stimu1.
Bedi, B. S., Gillespie, G., Gillespie, I. E. Lancet, 1967, i, 1240.
The drug also inhibits histamine-stimulated seer Oral administration of 10 mg. per kg. during contii histamine infusion (0-1mg. per kg. per hour) pro( inhibition of secretion in both Pavlov and HeidenhainI dogs, the effect being more striking on the secretion fro] denervated pouch (see accompanying figure), whereas tion from gastric-fistula dogs was unaffected. The same order (10 mg. per kg.) given intravenously to a fistul: produced 75% inhibition of secretion for at least two 1 whereas 1 mg. per kg. resulted in inhibition of the or( 30% lasting only 45 minutes, secretion in this animal provoked by an infusion of 0-05 mg. histamine per k; hour. These studies suggest that SC 15396 is not a specific g antagonist. The failure of Mr. Bedi and his colleagues to d( strate the action of the drug on histamine-stimulated sec may well be attributable to the smaller doses of the drug in their experiments (10 mg. per animal, and 140 mg. 0’ minutes per animal), whereas in our studies the dose B the order of 200 mg. per animal, given as one injection one oral treatment. Their use of vagally innervated dogs may also explain in part the reported lack of inhi of histamine-stimulated secretion. It may be that a c ratio of drug to stimulant may have to be achieved f. drug to be effective; this is suggested by the results rel here, and by other studies using the rat preparation. TtlfRf qtilciieq will 11P rpnnrtprl in
Department of Surgery, Queen’s University, Belfast. Department of Medicine, Western General Hospital, University of Edinburgh.
Department of Clinical Surgery, University of Edinburgh.
Department of Clinical Chemistry,
University of Edinburgh.
Influence of pouch innervation on effect of oral SC15396 on histanifne-stimulated gastric secretion. There is greater inhibition in the denervated pouch (P<0’01).
greater
detail elsewhere.
A. M. CONNELL. W. SIRCUS. R. A. HILL I. B. MACLEOD.
C. G. THOMSON.
EFFECT OF PENTAGASTRIN AFTER VAGOTOMY SIR,-The apparent discrepancy between the responses of the inervated and denervated human stomach to pentagastrin reported in the multicentre study (Sept. 9, p. 534) is probably related to the infusion method employed. Continuous infusion of gastrin or its derivatives in man, as in animals, is accompanied by a reduction of response with time. This reduction is most prominent with near-maximal doses. In the multicentre study, the infusion of 12 g. per kg. per hour of pentagastrin followed a 60-90 minute period of infusion with a near-maximal dose of 6 {.tg. per kg. per hour and thus coincided with the period of reduction of response. The response to 12 {.tg. is located near the asymptote of the dose-response curve: any increase in response to this larger dose is likely to be small and will be masked by the more prominent reduction of response during this particular period of infusion. The response of the denervated stomach, on the other hand, is around 50% of maximum and is located on the rising slope of a dose-response curve where doubling the dose from 6 to