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ANTACIDS AND DRUG TRIALS FOR DUODENAL ULCER
896
fibrinolysis can lead to thrombosis.’ In most healthy people desmopressin stimulates both fibrinolysis and coagulation, increasing plasma levels of tissue plasminogen activator (t-PA) and plasmin activity. However, in the presence of high levels of t-PA inhibition desmopressin infusion increases neither t-PA activity nor plasmin activity.2 Plasma levels of t-PA inhibition are increased in patients with coronary artery disease,3and are predictive of recurrent myocardial infarction.4 It seems reasonable to avoid desmopressin in patients with coronary artery disease. One possible mechanism for the increased risk of thrombosis in such patients could be high levels of t-PA inhibition, which prevent the normal fibrinolytic response to desmopressin. However, the normal t-PA activity response in the Dutch physician with coronary thrombosis suggests that other mechanisms also contribute. Haemophilia and Thrombosis Unit, University Department of Medicine, Royal Infirmary, Glasgow G4 0SF
G. D. O. LOWE
1. Astrup T. Fibrinolysis m the organism. Blood 1956; 11: 781-806. 2. Lowe GDO, Douglas JT, Small M, Forbes CD, Kluft C. Evidence for plasminmediated fibrinolysis after release of tissue-type plasminogen activator by desmopressin infusion. In: Lowe GDO, Douglas JT, Forbes CD, Henschen A, eds. Fibrinogen 2: biochemistry, physiology and clinical relevance. Amsterdam: Excerpta Medica, 1987: 285-88. 3. Paramo JA, Colucci M, Collen D, van de Werf F. Plasminogen activator inhibitor in the blood of patients with coronary artery disease. Br Med J 1985; 291: 573. 4. Hamsten A, Wiman B, DeFaire U, et al. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-63.
ANTACIDS AND DRUG TRIALS FOR DUODENAL ULCER
SIR,-Professor Lam (Feb 18, p 384) comments that the 59% duodenal ulcer healing rate after 8 weeks on treatment with cimetidine 400 mg twice daily cited in Dr Marshall and his colleagues’ paper (Dec 24/31, p 1438) is incorrect and should be about 90%. Clinical trials of Hz-blockers for duodenal ulcer healing have allowed the use of antacid tablets as required. Marshall’s patients "were cautioned not to take antacids". The interaction between small doses of antacids and Hz-blockers on neutralisation of gastric acid, protection of duodenal mucosa, and impact on duodenal ulcer healing is not known. In in-vitro experiments Lam et all found that two antacid tablets (800 mg) neutralised 25 mmol hydrochloric acid (0’11 mmol/1) in 150 min, a neutralising capacity close to that of a similar antacid liquid preparation. Peterson and co-workersz reported that cimetidine 300 mg four times a day plus antacid seven times a day was significantly better than cimetidine alone in raising gastric pH. Reduction of gastric acidity was similarly obtained with cimetidine 600 mg twice daily plus antacids four times a day, and this combination was very effective in reducing nocturnal gastric acidity.3 In a double-blind, randomised, multicentre trial 4 weeks of treatment with low doses of antacids (one tablet four times daily) resulted in a duodenal ulcer healing rate of 71-1%, similar to the 78 -4 % obtained with 800 mg cimetidine.4 When evaluating ulcer healing rates in trials with Hz-blockers in a heterogeneous group such as duodenal ulcer patients, the confounding variable of antacid tablets should be allowed for. Only then will we know whether healing rates lie close to 59% or to 90%. Division of Gastrointestinal and Coagulation Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20857, USA
NAFAMOSTAT TO STABILISE PLASMA SAMPLES TAKEN FOR COMPLEMENT MEASUREMENTS
SIR,-Since its discovery by Bordet in 1899, as a system of cooperative serum factors necessary for the lysis of cells by antibody, our knowledge of complement and complement activation has grown at an enormous pace. Excessive activation of the various complement pathways is almost inevitably harmful (eg, in rheumatoid diseases, renal disease, cirrhosis, and septicaemia). One current focus is the measurement of the biologically active anaphylatoxins C3a, C4a, and C5a; several excellent radioimmunoassay kits are available. Unfortunately their value is considerably decreased by in-vitro activation of plasma samples even when these are collected into edetic acid (EDTA) and separated and stored under ideal conditions. The immediate assay of fresh samples poses logistical problems and is prohibitively expensive. We have been evaluating the addition of a synthetic protease inhibitor, nafamostat mesylate (’Futhan’; Amersham International) which, when added to EDTA in the blood sampling tube, greatly increases the stability of complement components. Blood samples (20 ml) were obtained from volunteers and from patients, who gave informed consent. The samples were immediately split into tubes containing EDTA with or without nafamostat and plasma was separated and stored at -20°C. The assays were done in parallel within 2 weeks of collection, using Amersham kits. In controls (50 volunteers from Amersham and from the Royal Hallamshire Hospital) there was no measurable C5a and narrow ranges for both C3a and C4a levels.1 95th percentile ranges in the nafamostat-treated samples were C3a 102-212 ng/ml and C4a 0-571 ng/ml, roughly half those recorded in plasma with EDTA alone (C3a 77-491 ng/1, C4a 0-1683 ng/1). Activities in plasma with EDTA alone depended on the number of freeze-thaw cycles, doubling for each cycle, nafamostat samples were highly stable to such abuse. Clinical studies were done on groups of 20-30 patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), renal disease, liver disease, and a variety of vasculitic conditions including scleroderma. The patients with SLE and RA were thought to be clinically controlled and we present here the data
R. PRIZONT S. B. FREDD
SK, Lam KC, Lai CL, et al. Treatment of duodenal ulcer with antacids and sulfipiride. Gastroenterology 1979; 76: 315-22. 2. Peterson WL, Barnett C, Feldman M Reduction of twenty-four hour gastric acidity with combination drug therapy in patients with duodenal ulcer. Gastroenterology 1979, 77: 1015-20. 3. Mahachai V, Jamali F, Thomson ABR. Effect of combination of antacid and cimetidine on 24-hour intragastric acidity in patients with asymptomatic duodenal ulcer. Clin Ther 1984; 6: 808-23 4. Weberg R, Aubert E, Dahlberg O, et al. Low dose antacids or cimetidine for duodenal ulcer? Gastroenterology 1988; 95: 1465-69. 1. Lam
Plasma C3a anaphylatoxin levels in health and disease.
0 EDTA alone; . nafamostat/EDTA. (Several EDTA samples gave readings in excess of 1000 ng/ml: the computer records all such data as 1000 and a single point at this level may represent several patients.) =
=
fibrinolysis can lead to thrombosis.’ In most healthy people desmopressin stimulates both fibrinolysis and coagulation, increasing plasma levels of tissue plasminogen activator (t-PA) and plasmin activity. However, in the presence of high levels of t-PA inhibition desmopressin infusion increases neither t-PA activity nor plasmin activity.2 Plasma levels of t-PA inhibition are increased in patients with coronary artery disease,3and are predictive of recurrent myocardial infarction.4 It seems reasonable to avoid desmopressin in patients with coronary artery disease. One possible mechanism for the increased risk of thrombosis in such patients could be high levels of t-PA inhibition, which prevent the normal fibrinolytic response to desmopressin. However, the normal t-PA activity response in the Dutch physician with coronary thrombosis suggests that other mechanisms also contribute. Haemophilia and Thrombosis Unit, University Department of Medicine, Royal Infirmary, Glasgow G4 0SF
G. D. O. LOWE
1. Astrup T. Fibrinolysis m the organism. Blood 1956; 11: 781-806. 2. Lowe GDO, Douglas JT, Small M, Forbes CD, Kluft C. Evidence for plasminmediated fibrinolysis after release of tissue-type plasminogen activator by desmopressin infusion. In: Lowe GDO, Douglas JT, Forbes CD, Henschen A, eds. Fibrinogen 2: biochemistry, physiology and clinical relevance. Amsterdam: Excerpta Medica, 1987: 285-88. 3. Paramo JA, Colucci M, Collen D, van de Werf F. Plasminogen activator inhibitor in the blood of patients with coronary artery disease. Br Med J 1985; 291: 573. 4. Hamsten A, Wiman B, DeFaire U, et al. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-63.
ANTACIDS AND DRUG TRIALS FOR DUODENAL ULCER
SIR,-Professor Lam (Feb 18, p 384) comments that the 59% duodenal ulcer healing rate after 8 weeks on treatment with cimetidine 400 mg twice daily cited in Dr Marshall and his colleagues’ paper (Dec 24/31, p 1438) is incorrect and should be about 90%. Clinical trials of Hz-blockers for duodenal ulcer healing have allowed the use of antacid tablets as required. Marshall’s patients "were cautioned not to take antacids". The interaction between small doses of antacids and Hz-blockers on neutralisation of gastric acid, protection of duodenal mucosa, and impact on duodenal ulcer healing is not known. In in-vitro experiments Lam et all found that two antacid tablets (800 mg) neutralised 25 mmol hydrochloric acid (0’11 mmol/1) in 150 min, a neutralising capacity close to that of a similar antacid liquid preparation. Peterson and co-workersz reported that cimetidine 300 mg four times a day plus antacid seven times a day was significantly better than cimetidine alone in raising gastric pH. Reduction of gastric acidity was similarly obtained with cimetidine 600 mg twice daily plus antacids four times a day, and this combination was very effective in reducing nocturnal gastric acidity.3 In a double-blind, randomised, multicentre trial 4 weeks of treatment with low doses of antacids (one tablet four times daily) resulted in a duodenal ulcer healing rate of 71-1%, similar to the 78 -4 % obtained with 800 mg cimetidine.4 When evaluating ulcer healing rates in trials with Hz-blockers in a heterogeneous group such as duodenal ulcer patients, the confounding variable of antacid tablets should be allowed for. Only then will we know whether healing rates lie close to 59% or to 90%. Division of Gastrointestinal and Coagulation Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20857, USA
NAFAMOSTAT TO STABILISE PLASMA SAMPLES TAKEN FOR COMPLEMENT MEASUREMENTS
SIR,-Since its discovery by Bordet in 1899, as a system of cooperative serum factors necessary for the lysis of cells by antibody, our knowledge of complement and complement activation has grown at an enormous pace. Excessive activation of the various complement pathways is almost inevitably harmful (eg, in rheumatoid diseases, renal disease, cirrhosis, and septicaemia). One current focus is the measurement of the biologically active anaphylatoxins C3a, C4a, and C5a; several excellent radioimmunoassay kits are available. Unfortunately their value is considerably decreased by in-vitro activation of plasma samples even when these are collected into edetic acid (EDTA) and separated and stored under ideal conditions. The immediate assay of fresh samples poses logistical problems and is prohibitively expensive. We have been evaluating the addition of a synthetic protease inhibitor, nafamostat mesylate (’Futhan’; Amersham International) which, when added to EDTA in the blood sampling tube, greatly increases the stability of complement components. Blood samples (20 ml) were obtained from volunteers and from patients, who gave informed consent. The samples were immediately split into tubes containing EDTA with or without nafamostat and plasma was separated and stored at -20°C. The assays were done in parallel within 2 weeks of collection, using Amersham kits. In controls (50 volunteers from Amersham and from the Royal Hallamshire Hospital) there was no measurable C5a and narrow ranges for both C3a and C4a levels.1 95th percentile ranges in the nafamostat-treated samples were C3a 102-212 ng/ml and C4a 0-571 ng/ml, roughly half those recorded in plasma with EDTA alone (C3a 77-491 ng/1, C4a 0-1683 ng/1). Activities in plasma with EDTA alone depended on the number of freeze-thaw cycles, doubling for each cycle, nafamostat samples were highly stable to such abuse. Clinical studies were done on groups of 20-30 patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), renal disease, liver disease, and a variety of vasculitic conditions including scleroderma. The patients with SLE and RA were thought to be clinically controlled and we present here the data
R. PRIZONT S. B. FREDD
SK, Lam KC, Lai CL, et al. Treatment of duodenal ulcer with antacids and sulfipiride. Gastroenterology 1979; 76: 315-22. 2. Peterson WL, Barnett C, Feldman M Reduction of twenty-four hour gastric acidity with combination drug therapy in patients with duodenal ulcer. Gastroenterology 1979, 77: 1015-20. 3. Mahachai V, Jamali F, Thomson ABR. Effect of combination of antacid and cimetidine on 24-hour intragastric acidity in patients with asymptomatic duodenal ulcer. Clin Ther 1984; 6: 808-23 4. Weberg R, Aubert E, Dahlberg O, et al. Low dose antacids or cimetidine for duodenal ulcer? Gastroenterology 1988; 95: 1465-69. 1. Lam
Plasma C3a anaphylatoxin levels in health and disease.
0 EDTA alone; . nafamostat/EDTA. (Several EDTA samples gave readings in excess of 1000 ng/ml: the computer records all such data as 1000 and a single point at this level may represent several patients.) =
=