BRITISH MEDICAL JOURNAL
12 FEBRUARY 1977
seemed somewhat unnecessary when one was primarily attempting to determine the incidence of diarrhoea in a large number of patients. Both trials showed the incidence of diarrhoea to be halved in the patients receiving talampicillin and these results were shown to be statistically significant (P < 0-02 in both studies). Dr Grant is perfectly entitled to express his personal opinion of these antibiotics, but other clinicians appear to have come to a different conclusion and amoxycillin is now very widely used in both hospital and general practice in this country and overseas. Finally, I am sure that Dr Grant would be the first to appreciate that he is getting better value for money when he provides drugs that are well absorbed rather than those that, for the most part, go down the drain. E T KNUDSEN Medical Director, Beecham Pharmaceuticals Division
443
between low levels of human placental lactogen and poor outcome of pregnancy but also that, in their practice, use of the assay in high-risk pregnancies can lead to a significant reduction in the antepartum death rate. We have been unable to trace comparable evidence relating to other methods of fetal risk prediction. Urinary oestrogen assay and serial ultrasound cephalometry have been widely used in Britain during recent years and the table printed below documents their increased use in one geographically defined population. Recent research2-4 has raised questions concerning the value of these techniques, but these studies have failed to provide any clear answers. Chards has drawn attention to the fact that "much effort is spent on the identification of new parameters of feto-placental function when the main requirement is for detailed evaluation and refinement of tests which are already available." However, some centres have already replaced urinary oestrogen assays with plasma oestriol measurements and introduced other biochemical and physical methods of antepartum fetal monitoring. Spellacy's example with human placental lactogen should be followed by using randomised controlled trials to assess the value of the increasing variety of methods in use. Who knows, fetal movement counts by the mother6 may prove as effective as other competitors and an even more convenient and economically attractive proposition than your recommended "best buy" of urinary oestrogen assay at 25p a time.
Brentford, Middx Nakazawa, S, Amoxycillin (BRL 2333) International Symposium, London, September 1973, II, 24. 2 Robinson, G N, Nouvelle Presse Medicale, 1975, 4, 2461. 3 Comber, K R, Osborne, Christine D, and Sutherland, R, Antimicrobial Agents and Chemotherapy, 1975, 7, 179. May, J R, and Ingold, A, British Journal of Diseases of the Chest, 1972, 66, 185. Molla, A L, Practitioner, 1974, 212, 123. 6 Pines, A, et al, Chemotherapy, 1977, 23, 58. 7 Ingold, A, British Journal of Diseases of the Chest, 1975, 69, 211. Burgi, H, Chemotherapy, 1973, 18, suppl, p 19. 9 Burns, M W, and Devitt, L, Journal of Infectious Diseases, 1974, 129, S 194. 10 Khan, A A, Journal of International Medical Research, 1975, 3, 230. Scragg, J N, and Rubidge, C J, American Journal of Tropical Medicine and Hygiene, 1975, 24, 860. 12 Scragg, J N, British Medical Journal, 1976, 2, 1031. We are grateful to Professor K T Evans and 3 Afifi, A M, Adnan, M, and Garf, A A, British Medical Dr Huw Gravelle, Department of Radiology, Journal, 1976, 2, 1033. 14 Leigh, D A, et al, British Medical Journal. 1976, 1, Welsh National School of Medicine, for access to 1378. ultrasonogram records. 15 Middleton, R S W, Clinical Trials Journal, 1976, 13, ANNE C DAVIES 23. Final-year medical student 6Jaffe, G, Murphy, J E, and Robinson, 0 P W, Practitioner, 1976, 216, 455. 17Knudson, E T, and Harding, J W, British Journal of IAIN CHALMERS Clinical Practice, 1975, 29, 255. Welsh National School of Medicine,
abnormality. Professor C F George and Dr C M Castleden (1 January, p 47) consider the various other factors which might explain the results of Dr Schneider and his colleagues. As mentioned above, we do not dispute that propranolol is virtually completely absorbed from the gastrointestinal tract and, as indicated in our previous letter, we still consider that altered rates of absorption from the gut are a likely explanation of the results. However, we are sceptical whether accelerated gastric emptying really does occur in coeliac disease as has been previously reported.5 While we accept that a reduction in the first pass metabolism of the drug as a result of liver dysfunction is a possible mechanism in Crohn's disease, in which minor histological abnormality of the liver is a relatively frequent DIANA RIAD FAHMY occurrence,6 this seems unlikely in coeliac
Cardiff
Predicting fetal death SIR,-The antepartum monitoring techniques considered in your recent leading article (15 January, p 123) may well be more or less precise predictors of fetal death, but they were introduced with a view to preventing death, not predicting it. This may seem a statement of the obvious, but the research surrounding these physical and biochemical techniques suggests that there may be some confusion of these two roles. The fact that retrospective studies have demonstrated reasonable correlation between the outcome of pregnancy and measurements made with these techniques does not establish that their use will prevent fetal death. You refer to the only study of which we are aware which was specifically designed to assess the extent to which use of a fetal risk predictor may alter the natural history of a pregnancy.' Spellacy and his colleagues have certainly provided encouraging evidence not only of a reasonable correlation
Supraregional Assay Service, Tenovus Institute of Cancer Research, Cardiff. lSpellacy, W N, Buhi, W C, and Birk, S A, American Journal of Obstetrics and Gynecology, 1975, 121, 835. 2Chalmers, I, et al, British Medical Journal, 1976, 1, 735. 3Chalmers, I, Lawson, J G, and Turnbull, A C, British Journal of Obstetrics and Gynaecology, 1976, 83, 921. 4 Chalmers, I, Lawson, J G, and Turnbull, A C, British Journal of Obstetrics and Gynaecology, 1976, 83, 930. 5 Chard, T, Journal of Clinical Pathology, 1976, 29, suppl 10, p 18. 6 Pearson, J F, and Weaver, J B, British Medical Journal, 1976, 1, 1305.
Plasma propranolol levels in Crohn's disease and coeliac disease SIR,-In reply to Dr R E Schneider and others (27 November, p 1324) it is not disputed that propranolol might eventually be fully absorbed in the patients or in the controls in their
Frequency and intensity of antepartum monitoring among parturients resident in Cardiff, 1967-74
Referred for oestrogen assay () Mean number of assays per case referred Referred for diagnostic ultrasound* during pregnancy () Mean number of ultrasound examinations per case referred *All indications.
1967
1968
1969
1970
1971
1972
1973
1974
-
30
3-2
90
19-4
19-7
17-6
16-4
2-6
2-8
2-5
2-9
2-8
3-2
3-6
-
investigation (2 October, p 794). The problem is why the plasma levels of propranolol were higher over 1-6 h after ingestion in patients with Crohn's disease and at 1 h after ingestion in treated coeliac patients than in healthy volunteers. However, an explanation for their results has not been provided, nor has our proposal (6 November, p 1135) of the possible role of the jejunal acid microclimate in regulation of propranolol absorption from the proximal jejunum been disproved. Higher propranolol levels in rheumatoid arthritis and pneumonia' do not conflict with the jejunal acid microclimate hypothesis. The occurrence of folic acid deficiency in rheumatoid arthritis2-4 provides some indirect evidence which suggests that the proximal jejunal acid microclimate could be deficient in these nongastrointestinal disorders. Our own unpublished observations on seven patients with folic acid deficiency and normal jejunal histology have shown that the proximal jejunal luminal surface pH in these patients was significantly less acid than in normal controls. Therefore it is possible that the acid microclimate could be deficient in rheumatoid arthritis in spite of no obvious intestinal
07 10
101
14-3
200
210
2-1
2-3
2-5
2-2
disease, in which liver dysfunction is rare. In our own series of 300 adult patients with coeliac disease only three cases of chronic liver disease have been seen. We were disappointed that Dr R L Parsons and his colleagues (8 January, p 103) have found that two drugs with a low pKa, aspirin and indomethacin, are absorbed normally or even faster than normal in coeliac disease. Unfortunately it is not clear from their letter whether their coeliac patients were on normal or gluten-free diets. In a previous paper,7 referred to in their letter, they found that plasma propranolol levels after ingestion were higher in coeliacs, all of whom were on a gluten-free diet, when compared with normals, and no details of jejunal morphology at the time of study were provided. Obviously in deciding the role of the jejunum and its acid microclimate in the absorption of drugs it is important to have details of the jejunal morphology at the time of study. Nevertheless, it is strange that, whereas two drugs with a low pKa appear to be normally absorbed in coeliac disease, folic acid, which is probably 50°O unionised at pH 3.58 (it has two carboxyl groups and therefore cannot have one pKa value), is malabsorbed in untreated coeliac disease.9-'1 The jejunal acid microclimate must affect absorption of drugs which are weak acids, such as folic acid, aspirin, and indomethacin, or weak bases, such as propranolol, and so its deficiency in untreated coeliac
12 FEBRUARY 1977
seemed somewhat unnecessary when one was primarily attempting to determine the incidence of diarrhoea in a large number of patients. Both trials showed the incidence of diarrhoea to be halved in the patients receiving talampicillin and these results were shown to be statistically significant (P < 0-02 in both studies). Dr Grant is perfectly entitled to express his personal opinion of these antibiotics, but other clinicians appear to have come to a different conclusion and amoxycillin is now very widely used in both hospital and general practice in this country and overseas. Finally, I am sure that Dr Grant would be the first to appreciate that he is getting better value for money when he provides drugs that are well absorbed rather than those that, for the most part, go down the drain. E T KNUDSEN Medical Director, Beecham Pharmaceuticals Division
443
between low levels of human placental lactogen and poor outcome of pregnancy but also that, in their practice, use of the assay in high-risk pregnancies can lead to a significant reduction in the antepartum death rate. We have been unable to trace comparable evidence relating to other methods of fetal risk prediction. Urinary oestrogen assay and serial ultrasound cephalometry have been widely used in Britain during recent years and the table printed below documents their increased use in one geographically defined population. Recent research2-4 has raised questions concerning the value of these techniques, but these studies have failed to provide any clear answers. Chards has drawn attention to the fact that "much effort is spent on the identification of new parameters of feto-placental function when the main requirement is for detailed evaluation and refinement of tests which are already available." However, some centres have already replaced urinary oestrogen assays with plasma oestriol measurements and introduced other biochemical and physical methods of antepartum fetal monitoring. Spellacy's example with human placental lactogen should be followed by using randomised controlled trials to assess the value of the increasing variety of methods in use. Who knows, fetal movement counts by the mother6 may prove as effective as other competitors and an even more convenient and economically attractive proposition than your recommended "best buy" of urinary oestrogen assay at 25p a time.
Brentford, Middx Nakazawa, S, Amoxycillin (BRL 2333) International Symposium, London, September 1973, II, 24. 2 Robinson, G N, Nouvelle Presse Medicale, 1975, 4, 2461. 3 Comber, K R, Osborne, Christine D, and Sutherland, R, Antimicrobial Agents and Chemotherapy, 1975, 7, 179. May, J R, and Ingold, A, British Journal of Diseases of the Chest, 1972, 66, 185. Molla, A L, Practitioner, 1974, 212, 123. 6 Pines, A, et al, Chemotherapy, 1977, 23, 58. 7 Ingold, A, British Journal of Diseases of the Chest, 1975, 69, 211. Burgi, H, Chemotherapy, 1973, 18, suppl, p 19. 9 Burns, M W, and Devitt, L, Journal of Infectious Diseases, 1974, 129, S 194. 10 Khan, A A, Journal of International Medical Research, 1975, 3, 230. Scragg, J N, and Rubidge, C J, American Journal of Tropical Medicine and Hygiene, 1975, 24, 860. 12 Scragg, J N, British Medical Journal, 1976, 2, 1031. We are grateful to Professor K T Evans and 3 Afifi, A M, Adnan, M, and Garf, A A, British Medical Dr Huw Gravelle, Department of Radiology, Journal, 1976, 2, 1033. 14 Leigh, D A, et al, British Medical Journal. 1976, 1, Welsh National School of Medicine, for access to 1378. ultrasonogram records. 15 Middleton, R S W, Clinical Trials Journal, 1976, 13, ANNE C DAVIES 23. Final-year medical student 6Jaffe, G, Murphy, J E, and Robinson, 0 P W, Practitioner, 1976, 216, 455. 17Knudson, E T, and Harding, J W, British Journal of IAIN CHALMERS Clinical Practice, 1975, 29, 255. Welsh National School of Medicine,
abnormality. Professor C F George and Dr C M Castleden (1 January, p 47) consider the various other factors which might explain the results of Dr Schneider and his colleagues. As mentioned above, we do not dispute that propranolol is virtually completely absorbed from the gastrointestinal tract and, as indicated in our previous letter, we still consider that altered rates of absorption from the gut are a likely explanation of the results. However, we are sceptical whether accelerated gastric emptying really does occur in coeliac disease as has been previously reported.5 While we accept that a reduction in the first pass metabolism of the drug as a result of liver dysfunction is a possible mechanism in Crohn's disease, in which minor histological abnormality of the liver is a relatively frequent DIANA RIAD FAHMY occurrence,6 this seems unlikely in coeliac
Cardiff
Predicting fetal death SIR,-The antepartum monitoring techniques considered in your recent leading article (15 January, p 123) may well be more or less precise predictors of fetal death, but they were introduced with a view to preventing death, not predicting it. This may seem a statement of the obvious, but the research surrounding these physical and biochemical techniques suggests that there may be some confusion of these two roles. The fact that retrospective studies have demonstrated reasonable correlation between the outcome of pregnancy and measurements made with these techniques does not establish that their use will prevent fetal death. You refer to the only study of which we are aware which was specifically designed to assess the extent to which use of a fetal risk predictor may alter the natural history of a pregnancy.' Spellacy and his colleagues have certainly provided encouraging evidence not only of a reasonable correlation
Supraregional Assay Service, Tenovus Institute of Cancer Research, Cardiff. lSpellacy, W N, Buhi, W C, and Birk, S A, American Journal of Obstetrics and Gynecology, 1975, 121, 835. 2Chalmers, I, et al, British Medical Journal, 1976, 1, 735. 3Chalmers, I, Lawson, J G, and Turnbull, A C, British Journal of Obstetrics and Gynaecology, 1976, 83, 921. 4 Chalmers, I, Lawson, J G, and Turnbull, A C, British Journal of Obstetrics and Gynaecology, 1976, 83, 930. 5 Chard, T, Journal of Clinical Pathology, 1976, 29, suppl 10, p 18. 6 Pearson, J F, and Weaver, J B, British Medical Journal, 1976, 1, 1305.
Plasma propranolol levels in Crohn's disease and coeliac disease SIR,-In reply to Dr R E Schneider and others (27 November, p 1324) it is not disputed that propranolol might eventually be fully absorbed in the patients or in the controls in their
Frequency and intensity of antepartum monitoring among parturients resident in Cardiff, 1967-74
Referred for oestrogen assay () Mean number of assays per case referred Referred for diagnostic ultrasound* during pregnancy () Mean number of ultrasound examinations per case referred *All indications.
1967
1968
1969
1970
1971
1972
1973
1974
-
30
3-2
90
19-4
19-7
17-6
16-4
2-6
2-8
2-5
2-9
2-8
3-2
3-6
-
investigation (2 October, p 794). The problem is why the plasma levels of propranolol were higher over 1-6 h after ingestion in patients with Crohn's disease and at 1 h after ingestion in treated coeliac patients than in healthy volunteers. However, an explanation for their results has not been provided, nor has our proposal (6 November, p 1135) of the possible role of the jejunal acid microclimate in regulation of propranolol absorption from the proximal jejunum been disproved. Higher propranolol levels in rheumatoid arthritis and pneumonia' do not conflict with the jejunal acid microclimate hypothesis. The occurrence of folic acid deficiency in rheumatoid arthritis2-4 provides some indirect evidence which suggests that the proximal jejunal acid microclimate could be deficient in these nongastrointestinal disorders. Our own unpublished observations on seven patients with folic acid deficiency and normal jejunal histology have shown that the proximal jejunal luminal surface pH in these patients was significantly less acid than in normal controls. Therefore it is possible that the acid microclimate could be deficient in rheumatoid arthritis in spite of no obvious intestinal
07 10
101
14-3
200
210
2-1
2-3
2-5
2-2
disease, in which liver dysfunction is rare. In our own series of 300 adult patients with coeliac disease only three cases of chronic liver disease have been seen. We were disappointed that Dr R L Parsons and his colleagues (8 January, p 103) have found that two drugs with a low pKa, aspirin and indomethacin, are absorbed normally or even faster than normal in coeliac disease. Unfortunately it is not clear from their letter whether their coeliac patients were on normal or gluten-free diets. In a previous paper,7 referred to in their letter, they found that plasma propranolol levels after ingestion were higher in coeliacs, all of whom were on a gluten-free diet, when compared with normals, and no details of jejunal morphology at the time of study were provided. Obviously in deciding the role of the jejunum and its acid microclimate in the absorption of drugs it is important to have details of the jejunal morphology at the time of study. Nevertheless, it is strange that, whereas two drugs with a low pKa appear to be normally absorbed in coeliac disease, folic acid, which is probably 50°O unionised at pH 3.58 (it has two carboxyl groups and therefore cannot have one pKa value), is malabsorbed in untreated coeliac disease.9-'1 The jejunal acid microclimate must affect absorption of drugs which are weak acids, such as folic acid, aspirin, and indomethacin, or weak bases, such as propranolol, and so its deficiency in untreated coeliac
