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STIMULATION OF PANCREATIC SECRETION IN MAN BY SECRETIN SNUFF
509
STIMULATION OF PANCREATIC SECRETION IN MAN BY SECRETIN SNUFF B. HADORN M. KLEEB
P. B’HEND B. HALDEMANN H. LÜTHI Gastrointestinal Research Unit,
Department of Pœdiatrics, University of Berne, Freiburgstrasse 23, Berne, Switzerland Sum ary
The
pancreatic
response to secretin
administered via the nasal
mucosa
measured in eight healthy adult (secretin snuff) of secretin is as effective in Inhalation subjects. stimulating pancreatic secretion as intravenous administration. Secretin snuff could be used therapeutically to treat pancreatic disorders associated with insufficient bicarbonate secretion and duodenal ulcer. was
minutes, 100 units of secretin (Gastrointestinal Hormone Research Institute, Karolinska Institutet, Stockholm) were applied as the dry powder to the external orifice of one nostril. The other nostril was closed with the fingertip and the powder was gently inhaled into the nasal cavity. The duodenal contents were then collected from 41 to 80 minutes and from 81 to 120 minutes. 75 units of secretin were then applied in the same way and the secretions collected for another 40-minute period. Results
Each secretin administration was followed by a pronounced increase of bicarbonate output into the duodenum (fig. 1). In subject 2 bicarbonate concentrations rose to 110 meq. per litre and in subject 6 values of 80 meq. per litre were reached after each dose of the hormone (fig. 2). The chloride concentrations behaved reciprocally. Chloride concentrations
Introduction
POLYPEPTIDE hormones such as vasopressin,1 oxytocin,2and pentagastrin3 can affect their target organs when inhaled and absorbed through the nasal mucosa. Secretin, which stimulates pancreatic bicarbonate secretion and inhibits gastric-acid production, is another polypeptide which may have therapeutic applications. Since secretin can only be administered parenterally, its use as a therapeutic agent has been restricted. Frequent dosage would seem to be necessary because of secretin’s short-lived activity. We have investigated the effectiveness of secretin administered in the form of snuff. Materials and Methods
Eight healthy adults aged from 22 to 24 years (five male medical students and three female laboratory technicians) were investigated. Informed consent for the investigation The duodenum was was obtained from each individual. intubated with a Dreiling tube fitted with a gastric and a duodenal channel but without occlusive balloons. Gastric contents were aspirated continuously with a pump (Fricar). Duodenal contents were aspirated by hand with a 20 ml. plastic syringe. This procedure gave a more reliable sample of duodenal juice than pump aspiration. Samples of duodenal juice were collected on ice every 5 minutes. The volume, bicarbonate concentration (Natelson ’Microgasometer’), and pH (Radiometer pH meter model 26) were measured in each sample immediately after collection. Chloride-ion concentrations were determined on the fresh samples or on samples which were kept frozen for not longer than 48 hours.5 After a basal collection lasting 40 LIEUT.-COL. EDELMAN AND OTHERS :
Fig. 1-Duodenal bicarbonate
content
after
pernasal application
of secretin.
Healthy
man
aged
23.
REFERENCES—continued
12. Harland, P. S. E. G. Lancet, 1965, ii, 719. 13. Lloyd, A. V. C. Br. med. J. 1968, iii, 529. 14. McLaren, D. S., Pellet, P. L., Read, W. W. C. Lancet, 1967, i, 533 15. Gomez, F., Galvan, R. R., Cravioto, J., Frenk, S. Adv. Pediat 1955, 7, 131. 16. Catalona, W. J., Taylor, P. T., Rabson, A. S. New Engl. J. Med 1972, 286, 399. 17. Catalona, W. J., Taylor, P. T., Jr., Chretien, P. B. ibid. p. 1162. 18. Vithayasai, V., Suskind, R., Edelman, R. Unpublished. 19. Smythe, P. M., Campbell, J. A. H. S. Afr. med. J. 1959, 33, 777. 20. Phillips, I., Wharton, B. Br. med. J. 1968, i, 407. 21. Lopez, V., Davis, S. D., Smith, N. J. Pediat. Res. 1972, 6, 779. 22. Harland, P. S. E. G., Brown, R. E. E. Afr. med. J. 1965, 42, 233.
Fig. 2-Bicarbonate and chloride concentrations in duodenal contents of two healthy adult subjects after pernasal application of secretin.
510 40-MINUTE
Schweizerischer Nationalfonds schaftlichen Forschung.
OUTPUTS OF BICARBONATE BEFORE AND AFTER PERNASAL APPLICATION OF SECRETIN IN 8 HEALTHY ADULTS
Requests
for
zur
Forderung
reprints should be addressed to
der Wissen-
B. H.
REFERENCES 1. 2. 3. 4. 5. 6. 7.
Spiegelman, A. R. J. Am. med. Ass. 1963, 184, 657. Hendricks, C. H., Gabel, R. A. Am. J. Obstet. Gynec. 1960, 79, 780. Wormsley, K. G. Lancet, 1968, i, 57. Johnson, L. R., Grossman, M. I. Gastroenterology, 1971, 60, 120. Schales, O., Schales, S. S. J. biol. Chem. 1941, 140, 879. Hadorn, B., Johansen, P. G., Anderson, C. M. Can. med. Ass. J. 1968, 98, 377. Johansen, P. G., Anderson, C. M., Hadorn, B. Lancet, 1968, i, 455.
ACCESS TO THE CIRCULATION FOR REGULAR HÆMODIALYSIS fell to 40-50 meq. per litre after each secretin application. The pH of duodenal juice remained above The 7-5 throughout the test in both individuals. accompanying table shows the four 40-minute periods in all persons investigated. The responses after the first application of snuff were very varied, but on average the bicarbonate output from 41 to 80 minutes was 15-8 times greater than the basal level. From 81 to 120 minutes the increase was less-5°8 times greater than the average basal output. Although the second dose of hormone was smaller, it resulted in a bicarbonate output which was 16-7 times greater than the basal value. Discussion
Our results show that secretin when given in the form of snuff stimulates pancreatic bicarbonate secretion in man. Secretin has two properties which make it a possible therapeutic agent: it inhibits
gastrin-stimulated gastric-acid production by a noncompetitive mechanism and stimulates pancreatic bicarbonate production. Two diseases which might be influenced by the administration of secretin are cystic fibrosis of the pancreas and duodenal-ulcer disease. In cystic fibrosis, bicarbonate and volume output after stimulation by secretin is insufficient but can be increased if high doses of the hormone are used. The severe damage which occurs to the pancreas in 4
6
this disease is believed to be the result of insufficient volume and bicarbonate secretion.’ In fact, very high concentrations of pancreatic enzymes have been noted in newly diagnosed patients with only slight pathological changes in the pancreas.6 Secretin, by stimulating the normal electrolyte and water component of pancreatic juice, may help to avoid severe damage to the gland caused by the highly concentrated enzyme component. Johnson and Grossman 4 suggested that secretin could be used in the therapy of duodenalSince frequent applications of the ulcer disease. hormone would be necessary, because of its shortlived effect, a rapidly absorbed and simply administered form of secretin such as snuff may be useful. Unfortunately the costs of such therapy will still be very high, but synthetic secretin preparations may provide a cheaper method of production. We thank Dr R. D. G. Milner for advice. This work was grants number 3.483.70 and 3.483.71 Z from the
supported by
J. S. P.
LUMLEY
W. R. CATTELL L. R. I. BAKER
Departments of Surgery and Nephrology, St. Bartholomew’s
Summary
Hospital,
London EC1
Arteriovenous (A.V.) shunts and fistulæ
were studied in fifty patients receiving maintenance hæmodialysis for periods of more than 9 months. The greater survival-time of arm fistulæ and their relative freedom from complications make them the method of choice. In the event of an immediate A.V. shunt being required, it should be inserted in the leg in order to retain non-operated arms for subsequent fistula creation.
Introduction
MAINTENANCE haemodialysis became a practical proposition with the introduction of an external arteriovenous (A.v.) shunt, permitting repeated access to the circulation.1 Experience showed, however, that external shunts were commonly the Achilles heel of regular dialysis, being susceptible to infection and clotting episodes. An alternative means of access using repeated venepuncture of a surgically created
subcutaneous A.v. fistula was later described. There were doubts about the acceptability of this new technique to patients, the life expectancy of fistulx, and their suitability for self-supervised home dialysis. We report our experience with these two methods of
circulatory
access.
Patients and Methods The shunt and fistula experience of all patients who started dialysis after Jan. 1, 1967, and who were alive on Aug. 1, 1972, was studied. Initially all patients were dialysed using an A.V. shunt, and the majority were subsequently converted to anA.V. fistula. Shunt Insertion The majority of the surgical procedures were carried out one of us (J. L.). Local anxsthesia was used. A Quinton by ’ Silastic-Teflon ’ cannula system with teflon connectors (Capon Heaton) was used. Cannulae were electively inserted into the radial or posterior tibial arteries 5 cm. proximal to the wrist or ankle joint, respectively. In general, broad-spectrum prophylactic antibiotics were given at the time of any operation. Although the antibiotic of choice varied over the period of the study, usually
STIMULATION OF PANCREATIC SECRETION IN MAN BY SECRETIN SNUFF B. HADORN M. KLEEB
P. B’HEND B. HALDEMANN H. LÜTHI Gastrointestinal Research Unit,
Department of Pœdiatrics, University of Berne, Freiburgstrasse 23, Berne, Switzerland Sum ary
The
pancreatic
response to secretin
administered via the nasal
mucosa
measured in eight healthy adult (secretin snuff) of secretin is as effective in Inhalation subjects. stimulating pancreatic secretion as intravenous administration. Secretin snuff could be used therapeutically to treat pancreatic disorders associated with insufficient bicarbonate secretion and duodenal ulcer. was
minutes, 100 units of secretin (Gastrointestinal Hormone Research Institute, Karolinska Institutet, Stockholm) were applied as the dry powder to the external orifice of one nostril. The other nostril was closed with the fingertip and the powder was gently inhaled into the nasal cavity. The duodenal contents were then collected from 41 to 80 minutes and from 81 to 120 minutes. 75 units of secretin were then applied in the same way and the secretions collected for another 40-minute period. Results
Each secretin administration was followed by a pronounced increase of bicarbonate output into the duodenum (fig. 1). In subject 2 bicarbonate concentrations rose to 110 meq. per litre and in subject 6 values of 80 meq. per litre were reached after each dose of the hormone (fig. 2). The chloride concentrations behaved reciprocally. Chloride concentrations
Introduction
POLYPEPTIDE hormones such as vasopressin,1 oxytocin,2and pentagastrin3 can affect their target organs when inhaled and absorbed through the nasal mucosa. Secretin, which stimulates pancreatic bicarbonate secretion and inhibits gastric-acid production, is another polypeptide which may have therapeutic applications. Since secretin can only be administered parenterally, its use as a therapeutic agent has been restricted. Frequent dosage would seem to be necessary because of secretin’s short-lived activity. We have investigated the effectiveness of secretin administered in the form of snuff. Materials and Methods
Eight healthy adults aged from 22 to 24 years (five male medical students and three female laboratory technicians) were investigated. Informed consent for the investigation The duodenum was was obtained from each individual. intubated with a Dreiling tube fitted with a gastric and a duodenal channel but without occlusive balloons. Gastric contents were aspirated continuously with a pump (Fricar). Duodenal contents were aspirated by hand with a 20 ml. plastic syringe. This procedure gave a more reliable sample of duodenal juice than pump aspiration. Samples of duodenal juice were collected on ice every 5 minutes. The volume, bicarbonate concentration (Natelson ’Microgasometer’), and pH (Radiometer pH meter model 26) were measured in each sample immediately after collection. Chloride-ion concentrations were determined on the fresh samples or on samples which were kept frozen for not longer than 48 hours.5 After a basal collection lasting 40 LIEUT.-COL. EDELMAN AND OTHERS :
Fig. 1-Duodenal bicarbonate
content
after
pernasal application
of secretin.
Healthy
man
aged
23.
REFERENCES—continued
12. Harland, P. S. E. G. Lancet, 1965, ii, 719. 13. Lloyd, A. V. C. Br. med. J. 1968, iii, 529. 14. McLaren, D. S., Pellet, P. L., Read, W. W. C. Lancet, 1967, i, 533 15. Gomez, F., Galvan, R. R., Cravioto, J., Frenk, S. Adv. Pediat 1955, 7, 131. 16. Catalona, W. J., Taylor, P. T., Rabson, A. S. New Engl. J. Med 1972, 286, 399. 17. Catalona, W. J., Taylor, P. T., Jr., Chretien, P. B. ibid. p. 1162. 18. Vithayasai, V., Suskind, R., Edelman, R. Unpublished. 19. Smythe, P. M., Campbell, J. A. H. S. Afr. med. J. 1959, 33, 777. 20. Phillips, I., Wharton, B. Br. med. J. 1968, i, 407. 21. Lopez, V., Davis, S. D., Smith, N. J. Pediat. Res. 1972, 6, 779. 22. Harland, P. S. E. G., Brown, R. E. E. Afr. med. J. 1965, 42, 233.
Fig. 2-Bicarbonate and chloride concentrations in duodenal contents of two healthy adult subjects after pernasal application of secretin.
510 40-MINUTE
Schweizerischer Nationalfonds schaftlichen Forschung.
OUTPUTS OF BICARBONATE BEFORE AND AFTER PERNASAL APPLICATION OF SECRETIN IN 8 HEALTHY ADULTS
Requests
for
zur
Forderung
reprints should be addressed to
der Wissen-
B. H.
REFERENCES 1. 2. 3. 4. 5. 6. 7.
Spiegelman, A. R. J. Am. med. Ass. 1963, 184, 657. Hendricks, C. H., Gabel, R. A. Am. J. Obstet. Gynec. 1960, 79, 780. Wormsley, K. G. Lancet, 1968, i, 57. Johnson, L. R., Grossman, M. I. Gastroenterology, 1971, 60, 120. Schales, O., Schales, S. S. J. biol. Chem. 1941, 140, 879. Hadorn, B., Johansen, P. G., Anderson, C. M. Can. med. Ass. J. 1968, 98, 377. Johansen, P. G., Anderson, C. M., Hadorn, B. Lancet, 1968, i, 455.
ACCESS TO THE CIRCULATION FOR REGULAR HÆMODIALYSIS fell to 40-50 meq. per litre after each secretin application. The pH of duodenal juice remained above The 7-5 throughout the test in both individuals. accompanying table shows the four 40-minute periods in all persons investigated. The responses after the first application of snuff were very varied, but on average the bicarbonate output from 41 to 80 minutes was 15-8 times greater than the basal level. From 81 to 120 minutes the increase was less-5°8 times greater than the average basal output. Although the second dose of hormone was smaller, it resulted in a bicarbonate output which was 16-7 times greater than the basal value. Discussion
Our results show that secretin when given in the form of snuff stimulates pancreatic bicarbonate secretion in man. Secretin has two properties which make it a possible therapeutic agent: it inhibits
gastrin-stimulated gastric-acid production by a noncompetitive mechanism and stimulates pancreatic bicarbonate production. Two diseases which might be influenced by the administration of secretin are cystic fibrosis of the pancreas and duodenal-ulcer disease. In cystic fibrosis, bicarbonate and volume output after stimulation by secretin is insufficient but can be increased if high doses of the hormone are used. The severe damage which occurs to the pancreas in 4
6
this disease is believed to be the result of insufficient volume and bicarbonate secretion.’ In fact, very high concentrations of pancreatic enzymes have been noted in newly diagnosed patients with only slight pathological changes in the pancreas.6 Secretin, by stimulating the normal electrolyte and water component of pancreatic juice, may help to avoid severe damage to the gland caused by the highly concentrated enzyme component. Johnson and Grossman 4 suggested that secretin could be used in the therapy of duodenalSince frequent applications of the ulcer disease. hormone would be necessary, because of its shortlived effect, a rapidly absorbed and simply administered form of secretin such as snuff may be useful. Unfortunately the costs of such therapy will still be very high, but synthetic secretin preparations may provide a cheaper method of production. We thank Dr R. D. G. Milner for advice. This work was grants number 3.483.70 and 3.483.71 Z from the
supported by
J. S. P.
LUMLEY
W. R. CATTELL L. R. I. BAKER
Departments of Surgery and Nephrology, St. Bartholomew’s
Summary
Hospital,
London EC1
Arteriovenous (A.V.) shunts and fistulæ
were studied in fifty patients receiving maintenance hæmodialysis for periods of more than 9 months. The greater survival-time of arm fistulæ and their relative freedom from complications make them the method of choice. In the event of an immediate A.V. shunt being required, it should be inserted in the leg in order to retain non-operated arms for subsequent fistula creation.
Introduction
MAINTENANCE haemodialysis became a practical proposition with the introduction of an external arteriovenous (A.v.) shunt, permitting repeated access to the circulation.1 Experience showed, however, that external shunts were commonly the Achilles heel of regular dialysis, being susceptible to infection and clotting episodes. An alternative means of access using repeated venepuncture of a surgically created
subcutaneous A.v. fistula was later described. There were doubts about the acceptability of this new technique to patients, the life expectancy of fistulx, and their suitability for self-supervised home dialysis. We report our experience with these two methods of
circulatory
access.
Patients and Methods The shunt and fistula experience of all patients who started dialysis after Jan. 1, 1967, and who were alive on Aug. 1, 1972, was studied. Initially all patients were dialysed using an A.V. shunt, and the majority were subsequently converted to anA.V. fistula. Shunt Insertion The majority of the surgical procedures were carried out one of us (J. L.). Local anxsthesia was used. A Quinton by ’ Silastic-Teflon ’ cannula system with teflon connectors (Capon Heaton) was used. Cannulae were electively inserted into the radial or posterior tibial arteries 5 cm. proximal to the wrist or ankle joint, respectively. In general, broad-spectrum prophylactic antibiotics were given at the time of any operation. Although the antibiotic of choice varied over the period of the study, usually