528 SINGLE ORAL DOSE OF CIMETIDINE AND PROLACTIN
SIR,-Plasma-prolactin
rises 15-30 min after intravenous
cimetidine (300 mg).’2 We studied plasma-prolactin for 3 h after an oral dose of 400 mg cimetidine in four adult males with peptic ulcer (aged 23, 3 3, 3 5, 5 3). Plastrla-prolactin did not increase in any of the patients, probably because cimetidine was given orally. Oral cimetidine bioavailability is 62-72% 3 4 at the usual therapeutic doses (200-400 mg each dose), so plasma levels of the drug after 300 mg intravenously and 400 mg orally would be similar. The crucial difference is that after 300 mg intravenously the early plasma-cimetidine levels are much higher than after a 400 mg oral dose, and the plasma-prolactin peak occurs earlier. Prolactin release thus seems to depend upon a critical concentration of cimetidine in the blood not achieved with a single oral dose of 400 mg. R. VALCAVI G. BEDOGNI 2nd Department of Internal Medicine, A. DALL’ASTA Endocrine Metabolic Unit, C. DOTTI S. Maria Nuova Hospital, I. PORTIOLI 42100 Reggio Emilia, Italy IMMUNE COMPLEXES IN DIABETES
SIR,-Dr Pussell and colleagues (Aug. 13,
,
p.
359) referred
immune complexes in the sera of diabetics.5 stated that there is little evidence that these However, they of are importance in this disease. Findpathogenic complexes ings to be reported elsewhere6suggest that in diabetes the possible relevance of immune complexes should be considered in two different situations-close to the time when diabetes is first diagnosed and some years afterwards. At diagnosis, immune complexes, as detected by the solid phase Clq and by the Raji assay,8 correlate remarkably well with the presence of islet-cell antibodies in the serum. Although this has so far only been shown for cytoplasmic isletcell antibodies, it may be anticipated that they will also correlate with cell surface islet-cell antibodies9 as a fair correlation between these two types of islet cell antibodies has been demonstrated."* In this situation it is conceivable that such complexes may contribute to islet cell damage by "arming" K-cells to render them specifically cytotoxic for islet cells or possibly by initiating the production of biologically active components of the complement system within the islets. On the other hand, Pussell et al. may be correct in that these complexes may be secondary and of little significance consequent to damage to the islets by a virus or chemical. Some years after diagnosis of diabetes immune complexes can be commonly detected in the sera by the same methods, but are probably not related in a major way to either islet-cell antigens or to insulin.7 They occur in diabetics treated with insulin as well as in diabetics treated solely with diet and oral hypoglycaemic agents. They may result from the impaired clearance of immune complexes consequent upon abnormal to our
work
on
function which is known to occur in poorly controlled diabetics." There is evidence that their prevalence is increased in long-standing diabetics with proliferative retinopathy compared with diabetics of comparable duration without retinopathy. Their prevalence is also increased in diabetics of only a few years’ duration with retinopathy compared with diabetics of comparable duration without retinopathy.7 It is conceivable, therefore, that immune complexes in diabetes may have some pathogenic significance, not only in relation to the onset of islet-cell failure, but also in relationship to the development of diabetic microangiopathy.
phagocytic
Unit/ Immunology Laboratories (Medicine), Royal Infirmary, Edinburgh Endocrine
W.
JAMES IRVINE
IN-VITRO ACTIVITY OF NEW CEPHALOSPORIN (HR 756) AND CEFAZOLIN
SIR,-Dr Vanhoof and colleagues (July 22,
p.
In table I the organisms in the first three groups were chosen because of various resistance patterns which made them interesting for the purposes of comparison. Table II shows the mean peak levels of cefotaxime obtained in volunteers (supplied by Roussel). If these values are reproducible in patients (and there is no reason to doubt this) then Vanhoofs comment is invalid. By analogy, he would, for the same reason, never have used carbenicillin: average M.l.c.s were too high for a dose of, say, 500 mg or even 1 g, whereas, once the 20-30 g/day dose was advocated and practisedl3 most isolates of that time had M.l.c.s within the attainable concentration of the drug, with successful clinical results (peak serum levels after 1 g intramuscularly 18.6fLg/mI,14 but after 5 g intravenous bolus
>500
TABLE I-MEDIAN
g/mt). (AND -RANGE) M.I.C. AERUGINOSA
OF
40
STRAINS OF PS.
(fLg/ml)
5. Irvine. W.
10.
1978. Irvine, W.
J., Feek, C. M., Freedman, Z. R., Lernmark, A., Huen, A., Steinder, D. F., Rubenstein, A. H. ibid.
com-
organisms.
1. Carlson, H.E, Ippoliti, A.F.J. clin Endocr. Metab. 1977, 45, 367. 2. Daubresse, J. C., Meunier, J. C., Ligny, G. Lancet, 1978, i, 99. 3. Walkenstein, S. S., Dubb, J. W., Randolph, W. C., Westlake, W. J., Stote, R. M., Intoccia, A. P. Gastroenterology, 1978, 74, 360. 4. Griffiths, R., Lee, R. M., Taylor, D. C. in Cimetidine: Proceedings of 2nd International Symposium on Histamine H2-receptor Antagonists; p. 38.
Amsterdam, 1977. J., Al-Khateeb, S. F., Di Mario, U., Feek, C. M., Gray, R. S., Edmond, B., Duncan, L. J. P. Clin. expr. Immun. 1977, 30, 16. 6. Irvine, W. J., Di Mario, U., Guy, K., Gray, R. S., Duncan, L. J. P. J. clin. Lab. Immun. (in the press). 7. Irvine, W. J., Di Mario, U., Guy, K., lavicoli, M., Pozzilli, P., Lumbroso, B., Andreani, D. ibid. (in the press). 8. Lambert, P. H., and others ibid. 1978, 1, 1. 9. Lernmark, A., Freedman, Z. F., Kanatsuna, T., Patzelt, C., Rubenstein, A. H., Steiner, D. F. in The Immunology of Diabetes: Proceedings of the Edinburgh International Symposium (edited by W. J. Irvine). Edinburgh,
209)
the activity of a new cephalosporin, HR 756 (Hoechst) with that of cefazolin against a variety of clinical isolates. They note the new congener’s inherent and much increased activity against Enterobacteriaceae but then, surprisingly, state that "almost all the pseudomonads, although they were more susceptible to HR 756 than to cefazolin, may be defined as resistant (M.I.C.S > 16 · 1 mg/1)". This cephalosporin was first adverted to in the medical literature in a Lancet editorial. It is also known as RU 24756 (Roussel) and is tentatively named cefotaxime. At St. Vincents’ Hospital, Melbourne,12 Dixson and I have been using HR 756 in laboratory studies for nearly a year and have compared it with all cephalosporins available in Australia, but also against a range of anti-pseudomonad drugs. With regard to pseudomonad resistance I would question the conclusion drawn by Vanhoof et al., while agreeing in general with their findings with other gram-positive and gram-negative
pared
11. Bagdade, J. D. Acta endocr. 1976, 83, suppl. 205, p. 27. 12. Lancet, 1978, i, 863. 13. Stratford, B. C. Med. J. Aust. 1968, ii, 890. 14. Brumfitt, W., Percival, A., Leigh, D. A. Lancet, 1967, i, 1289.
529
Certain strains of Pseudomonas ceruginosa certainly appear resistant to cefotaxime-although why most of our 10 isolates from 1967 fall into this category is unknown-but most isolates can be considered sensitive (45% of all P. ceruginosa are sensitive at 6.25 fLg/ml). Quite apart from its excellent grampositive and gram-negative range, which is better than that of other cephalosporins, HR 756 is therefore unique within its group in that it does have clinically useful properties against Pseudomonas. Perhaps it will not be long before clinicians managing a serious Pseudomonas sepsis will be faced with the hitherto improbable prospect of prescribing in combination a penicillin and a cephalosporin. I wonder why Vanhoof et al. chose cefazolin for comparison; this drug has no activity against Pseudomonas so far as I am aware.
BRYAN C. STRATFORD
PREVENTION OF ALCOHOLIC LIVER DISEASE
SIR,-On the prevention of alcoholic liver disease (Aug. 12, 353) you sounded somewhat evangelical in places. It is
that after decades of study the intake of ethanol discernible toxic effects in humans should remain so controversial. We can relate daily ingestion of ethanol and various statistical probabilities in an ascending table of horrid events:
amazing required
to cause
Yet you make a single reported association3 between ingestion of as little as 20 g ethanol/day in women and signs of liver damage one of the main planks of an indictment of social drinking today. If drinking slightly more than one pint of beer 1. 2. 3. 4.
probably safe to ingest 50-70 g ethanol per day without undue risk and that most people would need to drink twice that amount for many years before cirrhosis or serious damage to the heart or pancreas would arise? Let us not forget that a moderate intake of ethanol has been a small but significant part of man’s diet in many races and cultures for thousands of years. It is wrong to make people worry about the discrete use of one of nature’s great comforters. Would Jesus have turned the water into wine for the wedding guests9 if his Father had regretted His invention of alcoholic fermentation? Department of Chemical Pathology, Guy’s Hospital Medical School,
Department of Microbiology, St. Thomas’s Hospital Medical School, London SE1 7EH
p.
per day really was significant in causing alcoholic liver disease in women we would be on the brink of a global pandemic of alcohol-related cirrhosis. Commonsense makes one reject such reports as scientific twaddle and scaremongering. But having demonstrated to your own satisfaction that ethanol is a fairly deadly poison you hammer home self-righteously the lesson that the gin-drinking well-fed middle class is not exempt from its due punishment. Is not the histopathologist who does necropsies for the coroner best placed to tell us how many people who die suddenly--e.g., in traffic accidents-have a fatty liver and cirrhosis? Is it not a reasonable interpretation of the evidence that it is
P.
London SE1 9RT
BIOCHEMICAL AND HÆMATOLOGICAL MARKERS OF ALCOHOL INTAKE al.’
reported an increase in serum-gamma-glutamyl-transpeptidase (f-c-T.) associated with a relatively moderate alcohol consumption (4 or more drinks a day) SIR,-Whitehead
at
in a group of 146 active men under close surveillance. In a survey of pregnant women carried out at Haguenau in the Alsace region of France, we obtained precise information on alcohol consumption and serum y-G.T. measurements. Results for the first 1706 term births showed that serum y-G.T. is sensitive to very low levels of alcohol intake. Women taking between 1 and 15 g pure alcohol per day (the equivalent of less than 20 ml wine) had a higher mean serum-y-G.T. than nondrinkers (P
SIR,-Plasma-prolactin
rises 15-30 min after intravenous
cimetidine (300 mg).’2 We studied plasma-prolactin for 3 h after an oral dose of 400 mg cimetidine in four adult males with peptic ulcer (aged 23, 3 3, 3 5, 5 3). Plastrla-prolactin did not increase in any of the patients, probably because cimetidine was given orally. Oral cimetidine bioavailability is 62-72% 3 4 at the usual therapeutic doses (200-400 mg each dose), so plasma levels of the drug after 300 mg intravenously and 400 mg orally would be similar. The crucial difference is that after 300 mg intravenously the early plasma-cimetidine levels are much higher than after a 400 mg oral dose, and the plasma-prolactin peak occurs earlier. Prolactin release thus seems to depend upon a critical concentration of cimetidine in the blood not achieved with a single oral dose of 400 mg. R. VALCAVI G. BEDOGNI 2nd Department of Internal Medicine, A. DALL’ASTA Endocrine Metabolic Unit, C. DOTTI S. Maria Nuova Hospital, I. PORTIOLI 42100 Reggio Emilia, Italy IMMUNE COMPLEXES IN DIABETES
SIR,-Dr Pussell and colleagues (Aug. 13,
,
p.
359) referred
immune complexes in the sera of diabetics.5 stated that there is little evidence that these However, they of are importance in this disease. Findpathogenic complexes ings to be reported elsewhere6suggest that in diabetes the possible relevance of immune complexes should be considered in two different situations-close to the time when diabetes is first diagnosed and some years afterwards. At diagnosis, immune complexes, as detected by the solid phase Clq and by the Raji assay,8 correlate remarkably well with the presence of islet-cell antibodies in the serum. Although this has so far only been shown for cytoplasmic isletcell antibodies, it may be anticipated that they will also correlate with cell surface islet-cell antibodies9 as a fair correlation between these two types of islet cell antibodies has been demonstrated."* In this situation it is conceivable that such complexes may contribute to islet cell damage by "arming" K-cells to render them specifically cytotoxic for islet cells or possibly by initiating the production of biologically active components of the complement system within the islets. On the other hand, Pussell et al. may be correct in that these complexes may be secondary and of little significance consequent to damage to the islets by a virus or chemical. Some years after diagnosis of diabetes immune complexes can be commonly detected in the sera by the same methods, but are probably not related in a major way to either islet-cell antigens or to insulin.7 They occur in diabetics treated with insulin as well as in diabetics treated solely with diet and oral hypoglycaemic agents. They may result from the impaired clearance of immune complexes consequent upon abnormal to our
work
on
function which is known to occur in poorly controlled diabetics." There is evidence that their prevalence is increased in long-standing diabetics with proliferative retinopathy compared with diabetics of comparable duration without retinopathy. Their prevalence is also increased in diabetics of only a few years’ duration with retinopathy compared with diabetics of comparable duration without retinopathy.7 It is conceivable, therefore, that immune complexes in diabetes may have some pathogenic significance, not only in relation to the onset of islet-cell failure, but also in relationship to the development of diabetic microangiopathy.
phagocytic
Unit/ Immunology Laboratories (Medicine), Royal Infirmary, Edinburgh Endocrine
W.
JAMES IRVINE
IN-VITRO ACTIVITY OF NEW CEPHALOSPORIN (HR 756) AND CEFAZOLIN
SIR,-Dr Vanhoof and colleagues (July 22,
p.
In table I the organisms in the first three groups were chosen because of various resistance patterns which made them interesting for the purposes of comparison. Table II shows the mean peak levels of cefotaxime obtained in volunteers (supplied by Roussel). If these values are reproducible in patients (and there is no reason to doubt this) then Vanhoofs comment is invalid. By analogy, he would, for the same reason, never have used carbenicillin: average M.l.c.s were too high for a dose of, say, 500 mg or even 1 g, whereas, once the 20-30 g/day dose was advocated and practisedl3 most isolates of that time had M.l.c.s within the attainable concentration of the drug, with successful clinical results (peak serum levels after 1 g intramuscularly 18.6fLg/mI,14 but after 5 g intravenous bolus
>500
TABLE I-MEDIAN
g/mt). (AND -RANGE) M.I.C. AERUGINOSA
OF
40
STRAINS OF PS.
(fLg/ml)
5. Irvine. W.
10.
1978. Irvine, W.
J., Feek, C. M., Freedman, Z. R., Lernmark, A., Huen, A., Steinder, D. F., Rubenstein, A. H. ibid.
com-
organisms.
1. Carlson, H.E, Ippoliti, A.F.J. clin Endocr. Metab. 1977, 45, 367. 2. Daubresse, J. C., Meunier, J. C., Ligny, G. Lancet, 1978, i, 99. 3. Walkenstein, S. S., Dubb, J. W., Randolph, W. C., Westlake, W. J., Stote, R. M., Intoccia, A. P. Gastroenterology, 1978, 74, 360. 4. Griffiths, R., Lee, R. M., Taylor, D. C. in Cimetidine: Proceedings of 2nd International Symposium on Histamine H2-receptor Antagonists; p. 38.
Amsterdam, 1977. J., Al-Khateeb, S. F., Di Mario, U., Feek, C. M., Gray, R. S., Edmond, B., Duncan, L. J. P. Clin. expr. Immun. 1977, 30, 16. 6. Irvine, W. J., Di Mario, U., Guy, K., Gray, R. S., Duncan, L. J. P. J. clin. Lab. Immun. (in the press). 7. Irvine, W. J., Di Mario, U., Guy, K., lavicoli, M., Pozzilli, P., Lumbroso, B., Andreani, D. ibid. (in the press). 8. Lambert, P. H., and others ibid. 1978, 1, 1. 9. Lernmark, A., Freedman, Z. F., Kanatsuna, T., Patzelt, C., Rubenstein, A. H., Steiner, D. F. in The Immunology of Diabetes: Proceedings of the Edinburgh International Symposium (edited by W. J. Irvine). Edinburgh,
209)
the activity of a new cephalosporin, HR 756 (Hoechst) with that of cefazolin against a variety of clinical isolates. They note the new congener’s inherent and much increased activity against Enterobacteriaceae but then, surprisingly, state that "almost all the pseudomonads, although they were more susceptible to HR 756 than to cefazolin, may be defined as resistant (M.I.C.S > 16 · 1 mg/1)". This cephalosporin was first adverted to in the medical literature in a Lancet editorial. It is also known as RU 24756 (Roussel) and is tentatively named cefotaxime. At St. Vincents’ Hospital, Melbourne,12 Dixson and I have been using HR 756 in laboratory studies for nearly a year and have compared it with all cephalosporins available in Australia, but also against a range of anti-pseudomonad drugs. With regard to pseudomonad resistance I would question the conclusion drawn by Vanhoof et al., while agreeing in general with their findings with other gram-positive and gram-negative
pared
11. Bagdade, J. D. Acta endocr. 1976, 83, suppl. 205, p. 27. 12. Lancet, 1978, i, 863. 13. Stratford, B. C. Med. J. Aust. 1968, ii, 890. 14. Brumfitt, W., Percival, A., Leigh, D. A. Lancet, 1967, i, 1289.
529
Certain strains of Pseudomonas ceruginosa certainly appear resistant to cefotaxime-although why most of our 10 isolates from 1967 fall into this category is unknown-but most isolates can be considered sensitive (45% of all P. ceruginosa are sensitive at 6.25 fLg/ml). Quite apart from its excellent grampositive and gram-negative range, which is better than that of other cephalosporins, HR 756 is therefore unique within its group in that it does have clinically useful properties against Pseudomonas. Perhaps it will not be long before clinicians managing a serious Pseudomonas sepsis will be faced with the hitherto improbable prospect of prescribing in combination a penicillin and a cephalosporin. I wonder why Vanhoof et al. chose cefazolin for comparison; this drug has no activity against Pseudomonas so far as I am aware.
BRYAN C. STRATFORD
PREVENTION OF ALCOHOLIC LIVER DISEASE
SIR,-On the prevention of alcoholic liver disease (Aug. 12, 353) you sounded somewhat evangelical in places. It is
that after decades of study the intake of ethanol discernible toxic effects in humans should remain so controversial. We can relate daily ingestion of ethanol and various statistical probabilities in an ascending table of horrid events:
amazing required
to cause
Yet you make a single reported association3 between ingestion of as little as 20 g ethanol/day in women and signs of liver damage one of the main planks of an indictment of social drinking today. If drinking slightly more than one pint of beer 1. 2. 3. 4.
probably safe to ingest 50-70 g ethanol per day without undue risk and that most people would need to drink twice that amount for many years before cirrhosis or serious damage to the heart or pancreas would arise? Let us not forget that a moderate intake of ethanol has been a small but significant part of man’s diet in many races and cultures for thousands of years. It is wrong to make people worry about the discrete use of one of nature’s great comforters. Would Jesus have turned the water into wine for the wedding guests9 if his Father had regretted His invention of alcoholic fermentation? Department of Chemical Pathology, Guy’s Hospital Medical School,
Department of Microbiology, St. Thomas’s Hospital Medical School, London SE1 7EH
p.
per day really was significant in causing alcoholic liver disease in women we would be on the brink of a global pandemic of alcohol-related cirrhosis. Commonsense makes one reject such reports as scientific twaddle and scaremongering. But having demonstrated to your own satisfaction that ethanol is a fairly deadly poison you hammer home self-righteously the lesson that the gin-drinking well-fed middle class is not exempt from its due punishment. Is not the histopathologist who does necropsies for the coroner best placed to tell us how many people who die suddenly--e.g., in traffic accidents-have a fatty liver and cirrhosis? Is it not a reasonable interpretation of the evidence that it is
P.
London SE1 9RT
BIOCHEMICAL AND HÆMATOLOGICAL MARKERS OF ALCOHOL INTAKE al.’
reported an increase in serum-gamma-glutamyl-transpeptidase (f-c-T.) associated with a relatively moderate alcohol consumption (4 or more drinks a day) SIR,-Whitehead
at
in a group of 146 active men under close surveillance. In a survey of pregnant women carried out at Haguenau in the Alsace region of France, we obtained precise information on alcohol consumption and serum y-G.T. measurements. Results for the first 1706 term births showed that serum y-G.T. is sensitive to very low levels of alcohol intake. Women taking between 1 and 15 g pure alcohol per day (the equivalent of less than 20 ml wine) had a higher mean serum-y-G.T. than nondrinkers (P
