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.
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.
