1422 It is also difficult to understand Dr McCarthy’s claim that the outlook in lymphoblastic leukaemia is as good after management at district hospitals as at the special centres that he has investigated. The figures which he provides contradict this conclusion: at the district hospitals 19 out of 25 patients had died within three years of diagnosis; after treatment at the special centres, 4 out of 27 had died within a similar time. There are, of course, important considerations in addition to survival, but without survival they become immaterial. Working at a district general hospital, in the proximity of a special centre, I would have a vested interest in Dr McCarthy’s conclusions-but his argument doesn’t add up. St. George’s Hospital, Blackshaw Road, London SW17 0QT.

MICHAEL S. ROSE.

*** This letter has been shown whose reply follows.-ED. L.

to

Dr

McCarthy,

SiR,-The comparison in my study to which I drew was between two special centres and those district hospitals that had used comparable treatment regimens. The latter group included several London undergraduate teaching hospitals. The study was limited in size because attention

interviews were needed to measure other outcomes; strict statistical analysis did not therefore seem appropriate. I wished to emphasise that a regional organisational policy based on consensus between all clinicians looking after children with leukxmia would particularly benefit those at present with short survival. Data routinely collected in this way, linking treatment and outcomes on a population basis, would allow far better resolution of the site-of-care question I raised. Hammersmith Hospital, Du Cane Road, London W12 OHS.

or

Watkin’s letter that there is Ministry of

no

risk.

Agriculture, Fisheries, and Food, Fisheries Laboratory, Burnham-on-Crouch.

Public Health Laboratory, Royal Cornwall Hospital (City), Truro TR1 2HZ.

P. C. WOOD.

G. I. BARROW.

IMPROVING THE BIOAVAILABILITY OF DIGOXIN

SiR,-Therapeutic blood-levels of digoxin after oral administration of the drug are dependent on the content of digoxin in the tablet and an adequate rate of dissolution 1-5 (a dissolution-rate in an acid medium of over 70% per hour being satisfactory 2). A solution of digoxin (’ Lanoxin’ elixir) is absorbed better than digoxin in tablet form,3 but lately we have had the opportunity of studying the absorption of a capsule preparation (’ Lanoxicap’) of digoxin and we report our initial results and impressions below. Six healthy volunteers, aged 26 to 42 years, with normal creatinine clearances underwent study on five separate occasions, each separated by at least 2 weeks. The single-dose treatments ABSORPTION OF DIFFERENT DIGOIXN PREPARATIONS

MARK MCCARTHY.

FISH AND SHELLFISH HYGIENE SIR,-Following your editorial (May 3, p. 1020) on the recent W.H.O. report,1 we read with interest the letter by Dr Simmons and Mr Watkin (May 24, p. 1185). We agree with the sentiments expressed on consumer protection, and we are glad to note that every source of supply is investigated-both bacteriologically and through inquiries to local public-health authorities-by the Fishmongers’ Company. However, about 100 samples a year does not seem many in relation either to the number of producers in the U.K. or to the large market trade. It should be noted that samples of shellfish taken at source by some local authorities are also examined bacteriologically by publichealth or other laboratories, not only at the beginning of each season, but on a continuing basis. We consider these practices essential for effective control. We note that Vibrio parahaemolyticus was not found in imported shrimps and prawns examined by the Fishmongers’ Company, although it has often been isolated from other samples of supplies entering the country. Indeed, imported cooked and peeled prawns have lately been responsible for at least one outbreak of food-poisoning caused by this organism. Vibrio parahamolyticus has also been isolated from British sources,2 including shellfish, sea water, and sediments. Furthermore, it has caused an outbreak of food-poisoning associated with indigenous crabmeat.33 A number of laboratories are therefore collaborating with us in a survey of its distribution in British

coastal waters. We do not wish

parahaemolyticus are great, either from home-profrom imported marine products, but equally we cannot accept the implication in Dr Simmons’ and Mr Vibrio duced

*

Results extrapolated from previous experiments of subjects are shown in parentheses.

suggest that health hazards from

1. Fish and Shellfish Hygiene. W.H.O. techn. Rep. Ser. 1974, no. 550. 2. Barrow, G. I., Miller, D. C. Lancet, 1972, i, 485. 3. Hooper, W. L., Barrow, G. I., McNab, D. J. N. ibid. 1974, i, 1100.

larger group

administered according to a balanced, incomplete block design and consisted of five out of six schedules: (a) eight capsules containing 0-05 mg. digoxin each; (b) four capsules each containing 0-10 mg.; (c) two capsules containing 0-30 mg.; (d) an intravenous infusion given over 1 hour containing 0-40 mg. injectable digoxin in 250 ml. 5% dextrose in water; (e) two reference digoxin tablets of 0-20 mg. each; and (f) digoxin (lanoxin) solution containing 0-40 mg. Digoxin was administered after an overnight fast; capsules and tablets were swallowed with 250 ml. water and the digoxin solution was added to 200 ml. water containing 3 ml. ethyl alcohol and rinsed with 50 ml. water. Venous blood-samples were taken at 0, to 1, 1, 2, 3, 4, and 6 hours, and the serum analysed in duplicate on two separate occasions, with separate calibration curves prepared from serum from the subject being

were

studied.

All

samples have not yet been analysed, but certain interesting features are obvious. The areas under concentration-time curves (ng./ml. per hour) were measured by planimetry. Three of the subjects were included in a previous study of the absorption of tablet digoxin (0’5 mg.)2 and the results were extrapolated to make them comparable (see accompanying table). Lindenbaum, J., Butler, V. P., Murphy, J. E., Cresswell, R. M. Lancet, 1973, i, 1215. 2. Binnion, P F. Clin. Pharmac. Ther. 1974, 16, 807. 3. Johnson, B. F., Bye, C. Br. Heart J. 1975, 37, 203. 4. Wagner, J. G. Am. Heart J. 1974, 88, 133. 5. Dunning, A. J. Eur. J. Cardiol. 1974, 2, 1. 1.

to

on a

1423 The elixir of digoxin was better absorbed than any of the tablets, as would be expected, since time for dissolution is not required and this effect has been established before .23e Digoxin in solution inside a capsule is absorbed much more readily than in tablet form, even when the tablets have a good dissolution-rate (the low dissolution-rate and very poor absorption of Ketchum has been reported previously 2 and the results are included as an interesting comparison). Digoxin was better absorbed from the capsules than from the elixir in a weak alcoholic solution, and this is probably related to the higher local concentration in the intestine expected from the capsule form, possibly augmented by the solvent used to dissolve the digoxin in the capsule. Hence the most effective preparation of digoxin available for oral ingestion seems to be the capsule form. PETER F. BINNION. Section of Cardiology, Radioisotope Laboratory, Pennsylvania Hospital, Philadelphia, Pennsylvania 19107, RONALD W. KLOPP. U.S.A.

FASTING SERUM-GASTRIN IN CHRONIC GASTRITIS SIR,—In his interesting letter Dr Strickland (Feb. 22, p. 458) emphasised that serum-gastrin measurements and the parietal-cell-antibody test do not identify the majority of patients with severe antral gastritis and less severe, often patchy, atrophic gastritis of the corpus. We have studied serum-gastrin concentrations in 107 fasting with various forms of chronic gastritis diagnosed

patients

LEVELS IN PATIENTS GASTRITIS AND IN CONTROLS

SERUM-GASTRIN

FASTING

*

Fundal

t Fundal

CHRONIC

histologically unaffected. in 83% of the patients less severely affected than

mucosa mucosa

antral

WITH

mucosa.

histologically

in

endoscopic biopsies of the antral

mucosa, and in 27 controls with normal

and corpus

In mucosa. antral mucosa

gastric

both mild and severe superficial gastritis of the and in chronic atrophic gastritis with and without intestinal metaplasia slight elevations of mean serum-gastrin concentrations were found compared with the controls (see table). However, the values did not differ significantly among the patients with the various forms of gastritis.

Thus, in agreement with Dr Strickland’s results, our findings indicate that, in contrast to pernicious anaemia 6.

Klink, P. R., Poust, R. I., Colaizz, J. L., McDonald, R. H. J. pharm. Sci. 1974, 63, 1231.

Zollinger-Ellison syndrome, determinations of fasting serum-gastrin do not contribute much to the diagnosis of simple " chronic gastritis and are not relevant to the differentiation of the superficial and atrophic and the

"

forms of this disease. Department of Medicine, University of Essen, 43 Essen 1, Germany.

H. R. EWERS W. HENGSTEBECK.

RENIN AND FILTRATION FRACTION IN ESSENTIAL HYPERTENSION

SIR,-Professor Reubi and his colleaguesfound no between filtration fraction and plasma-renin activity in essential hypertension. This does not agree

relation

with our earlier observations 2-4 or with our hypothesis on the pathogenesis of essential hypertension.ó Our own analyses 2-4 were confined to untreated benignphase essential hypertension. Although studied, patients with renal disease, reduced glomerular filtration, or increased renal vascular resistance were explicitly excluded from the analysis because it was found that the negative correlation of renin and filtration fraction tended to reverse when renal function was impaired.3,4 Details of patients included in the analysis by the Swiss workers are not given in their letteror in an earlier paper6 two which they refer. Professor Reubi has kindly provided them since. Of 74 patients, 10 had malignantphase hypertension; 9 were receiving hypotensive drug treatment the day before study; 2 had a glomerular filtration-rate less than 15 ml. per min.; 1, apparently not receiving treatment, had a plasma-potassium of 2-8 meq. per 1.; 2 had possible chronic glomerulonephritis, and 8 had high renal vascular resistance. Excluding these, there remain 39 patients with measurements made under basal conditions. Plasma-renin activity and filtration fraction were not related in this smaller group (r=0°29, P>0’05). However, even with the exclusions, the group had unusual features: the patients were remarkably young for a study of essential hypertension (mean age 36), significantly younger than patients in our own study (t=2-24, p > 0-05). Analysis of Professor Reubi’s data shows, in contrast to other reports 2,7-9 no relation between plasma-renin activity and age(r=0-009). Excluding the case with gross hypokalaemia (see above) mean plasma-potassium concentration was lower in the Swiss series than in ours (t=2°576, p > 0-05) and lower than in other studies of essential hypertension (see discussion in ref. 7). 13 of the patients had a plasmarenin activity above the upper limit of the normal range (21 ng. per min. per 1. in ref. 6), again very unusual for benign essential hypertension. Even more unusual is the finding of a lower mean plasma-renin activity in malignant -as compared with benign-phase-essential hypertension.6 Filtration fraction was near-normal in the Swiss patients (0-231), significantly higher in ours (0-286; t=4’961, 1. Reubi, F. C., Hodler, J., Beretta-Piccoli, C. Lancet, 1974, i, 1274. 2. Schalekamp, M. A. D. H., Schalekamp-Kuyken, M. P. A., Birkenhager, W. H. Clin. Sci. 1970, 38, 101. 3. Schalekamp, M. A. D. H., Krauss, X. H., Kolsters, G., Schalekamp, M. P. A., Birkenhager, W. H. Clin. Sci. mol. Med. 1973, 45, 283s. 4. Schalekamp, M. A. D. H., Birkenhager, W. H., Kolsters, G., Lever, A. F. in Hypertension: Current Problems (edited by A. Distler and H. P. Wolff). Stuttgart, 1974. 5. Brown, J. J., Lever, A. F., Robertson, J. I. S., Schalekamp, M. A. Lancet, 1974, ii, 320. 6. Reubi, F. C., Hodler, J. in Actualités nephrologie Hôpital Necker; p. 221. Paris, 1968. 7. Dunn, M. J., Tannen, R. L. Kidney International, 1974, 5, 317. 8. Tuck, M. O., Williams, C. H., Cain, J. P., Sullivan, J. M., Dluhy, R. G. Am. J. Cardiol. 1973, 32, 637. 9. Padfield, P. L., Beevers, D. G., Brown, J. J., Davies, D. L., Lever, A. F., Robertson, J. I. S., Schalekamp, M. A. D., Tree, M. Lancet, 1975, i, 548.

Letter: Improving the bioavailability of digoxin.

1422 It is also difficult to understand Dr McCarthy’s claim that the outlook in lymphoblastic leukaemia is as good after management at district hospit...
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