764 response to CO2 resulting, at least in part, from an increase in the work of breathing. The rise in PC02 after relief of hypoxia in acute exacerbations is greater because there is even less central drive to ventilation than in remission. We are not aware of any studies of the ventilatory response to CO2 in acute exacerbations and would ourselves consider such studies that of Rudolf et al., unethical. Our hypothesis, therefore, will be difficult to substantiate.
ventilatory
like
Mill Hospital, Sutton-in-Ashfield, Nottinghamshire
King’s
L.
J. CLANCY
of Respiratory Diseases,
Department City Hospital, Edinburgh, EH10
A. G. LEITCH
5SB
AGRANULOCYTOSIS, LEVAMISOLE, AND HLA-B27 SIR,-Dr Schmidt and Dr Mueller-Eckhardt (July 9, p. 85) suggest that possession of HLA-B27 might carry an increased risk of agranulocytosis in a patient with rheumatoid arthritis who is given levamisole. However, not all such patients having this side-effect are carriers of antigen B27. In Ghent 94 rheumatoid-arthritis patients and in Basle 85 patients were treated with 150 mg/day of levamisole continuously or intermittently (3 or 4 days a week) for 6 months or more. 5 patients in Ghent and 1 in Basle had typical reversible agranulocytosis. 3 of these 6 patients had HLA B27. The typing results were A2,10/B13,22; Al,2/B8-; A1,10/B7,27; A3,28/BW15,27; A1,-/B8,W16; and A2,9/B5,27. In Belgium and in Switzerland the prevalence of this antigen in the general population ranges from 6 to 8% and the prevalence among patients with rheumatoid arthritis is also within these limits. This antigen does seem to be unusually common in rheumatoid-arthritis patients in whom agranulocytosis develops as a complication of levamisole treatment.
On the other hand, Goebel et al.’ had only 1 case of agranulocytosis in 37 seronegative B27-positive patients with ankylosing spondylitis, psoriatic arthritis, or Reiter syndrome. Our patients had rheumatoid arthritis and were all seropositive.
These data indicate that other
predisposing
factors
as
well
may remain to be determined. Department of Rheumatology, University of Ghent, B-9000 Ghent, Belgium
E. M. VEYS H. MIELANTS
Department of Rheumatology, University of Basle, CH-4055 Basle, Switzerland
M. ROSENTHAL
ANTI-PROTEINASE THERAPY FOR ACUTE PANCREATITIS
SiR,—The results of the Medical Research Council multitrial of glucagon and aprotinin (Sept. 24, p. 632) have
centre
that in the doses used neither drug diminished the risk of death from acute pancreatitis. It would be wrong to conclude from this study that the release of proteinase enzymes is an epiphenomenon of no pathogenetic importance in this condition, and it would be equally unwise if attempts to assess other forms of anti-proteinase therapy were to be abandoned. K. J. Worthington and I have reported our findings on plasma proteolytic activity and its in-vitro inhibition by proteinase inhibitors during acute pancreatitis.2 At a dose of 2000 kallikrein-inactivating units (K.l.U.) per 0.3 ml of plasma, inhibition was in the range 82 + 24%. Total inhibition was achieved in only 46% of the samples whilst less than 50% inhibition was achieved in 13% of the samples. This low inhibition did not necessarily correspond with high proteolytic acti-
clearly indicated
vity. This amount of aprotinin is far in excess of the amount required totally to inhibit an equivalent amount of trypsin giving the same esterolytic activity and is equivalent to a clinical dose of 20 x 106 K.t.u. of aprotinin. In the M.R.C. study, aprotinin was administered at a dose of 1.2 x 106 K.t.u. daily. Furthermore, the half-life of aprotinin after intravenous injection is 30-60 min. It is, therefore, not unexpected that the regimen for aprotinin used in the M.R.C. study was ineffective in reducing mortality from acute pancreatitis. What seems obvious is that aprotinin is a relatively ineffective inhibitor in that the doses required (3 litres/day) to achieve significant inhibition of proteinase activity in vivo would almost certainly incur a significant complication-rate. Surely the time has come for newer methods of anti-proteinase therapy to be investigated. Department of Surgery, University of Dundee, Ninewells Hospital, Dundee DD1 9SY
PROLACTIN CONTROL IN HUNTINGTON’S CHOREA
SIR,-Our data’differ in several respects from those of Dr Hayden and his colleagues (Aug. 27, p. 243).
(1) They found significantly lower baseline prolactin levels eight adults with Huntington’s chorea than in healthy controls. We found significantly higher levels in fourteen of seventeen patients aged 22-63 than in controls although wide fluctuations in this level was found when the same subject was
in
tested on different occasions. (2) We found that a dopamine-receptor blocker, sulpiride, taken orally for 10 days starting at 200 mg and rising to 600 mg daily) induced a rise in plasma-prolactin (up to 70-80 ng/ml) in three of four patients. This contrasts with the poor prolactin response in Hayden’s patients after a single injection of chlorpromazine, another dopamine blocker. (3) We found that the rise in plasma-prolactin induced by 400 g intravenous thyrotropin-releasing hormone (T.R.H.) was identical in Huntington’s chorea and controls whereas Hayden et al. found abnormally low responses. There may be two major reasons for these differences. First, Hayden et al. and his colleagues measured absolute rises in plasma-prolactin instead of relative prolactin increases after chlorpromazine and T.R.H. This point is crucial since their patients had lower baseline prolactin levels than did the controls. Second, the doses of T.R.H. (100 p.g) and chlorpromazine (25 mg) are probably too small since they evoked poor prolactin responses even in controls. In our studies, 1,2 the serum-prolactin in Huntington’s chorea was less susceptible to lowering by dopaminergic drugs (bromocriptine, apomorphine, levodopa) which act at both central nervous system and pituitary sites but was inhibited normally by dopamine (20 mg intravenously over 60 min), a stimulus which acts mainly at the pituitary level. This was confirmed by Caine et al.4 who also found high baseline prolactin levels in Huntington’s chorea. We suggest therefore that in Huntington’s chorea there is a primary alteration in brain dopaminergic neurotransmission while dopamine receptors at the pituitary level function normally and not abnormally as Hayden et al. claim. We cannot explain the very low baseline prolactin values in their patients and emphasise that the high levels found by us and others4 do not support their hypothesis 1.
Caraceni, T., Panerai, A. E., Parati, E. A., Cocchi, D., Müller, E. E. J. clin.
Endocrin. Metab. 1977, 44, 870. 2. Müller, E. E., Parati, E. A., Panerai, A. E., Cocchi, D., Caraceni, T. Proc 11th Wld Congr. Neurol., p. 91. (Excerpta med. int. Congr. Ser. 1977. no.
3.
Goebel, K. M., Schubotz, R., Goebel, F. D., Hahn, E., Neurath, F. Lancet, 1977, i, 214. 2. Worthington, K. J., Cuschien, A. Br. J. exp. Path. 1976, 57,165.
1
A. CUSCHIERI
427).
Tagliamonte, A., De Montis, G., Olianas, M., vargiu, L., Corsini, G. U. Gessa, G. L. J. Neurochem. 1975, 24, 707. 4. Caine, E. D., Kartzinel, R., Ebert, M., Carter, A. C. Neurology, 1977, 27, 392 (abstr.).
ventilatory
like
Mill Hospital, Sutton-in-Ashfield, Nottinghamshire
King’s
L.
J. CLANCY
of Respiratory Diseases,
Department City Hospital, Edinburgh, EH10
A. G. LEITCH
5SB
AGRANULOCYTOSIS, LEVAMISOLE, AND HLA-B27 SIR,-Dr Schmidt and Dr Mueller-Eckhardt (July 9, p. 85) suggest that possession of HLA-B27 might carry an increased risk of agranulocytosis in a patient with rheumatoid arthritis who is given levamisole. However, not all such patients having this side-effect are carriers of antigen B27. In Ghent 94 rheumatoid-arthritis patients and in Basle 85 patients were treated with 150 mg/day of levamisole continuously or intermittently (3 or 4 days a week) for 6 months or more. 5 patients in Ghent and 1 in Basle had typical reversible agranulocytosis. 3 of these 6 patients had HLA B27. The typing results were A2,10/B13,22; Al,2/B8-; A1,10/B7,27; A3,28/BW15,27; A1,-/B8,W16; and A2,9/B5,27. In Belgium and in Switzerland the prevalence of this antigen in the general population ranges from 6 to 8% and the prevalence among patients with rheumatoid arthritis is also within these limits. This antigen does seem to be unusually common in rheumatoid-arthritis patients in whom agranulocytosis develops as a complication of levamisole treatment.
On the other hand, Goebel et al.’ had only 1 case of agranulocytosis in 37 seronegative B27-positive patients with ankylosing spondylitis, psoriatic arthritis, or Reiter syndrome. Our patients had rheumatoid arthritis and were all seropositive.
These data indicate that other
predisposing
factors
as
well
may remain to be determined. Department of Rheumatology, University of Ghent, B-9000 Ghent, Belgium
E. M. VEYS H. MIELANTS
Department of Rheumatology, University of Basle, CH-4055 Basle, Switzerland
M. ROSENTHAL
ANTI-PROTEINASE THERAPY FOR ACUTE PANCREATITIS
SiR,—The results of the Medical Research Council multitrial of glucagon and aprotinin (Sept. 24, p. 632) have
centre
that in the doses used neither drug diminished the risk of death from acute pancreatitis. It would be wrong to conclude from this study that the release of proteinase enzymes is an epiphenomenon of no pathogenetic importance in this condition, and it would be equally unwise if attempts to assess other forms of anti-proteinase therapy were to be abandoned. K. J. Worthington and I have reported our findings on plasma proteolytic activity and its in-vitro inhibition by proteinase inhibitors during acute pancreatitis.2 At a dose of 2000 kallikrein-inactivating units (K.l.U.) per 0.3 ml of plasma, inhibition was in the range 82 + 24%. Total inhibition was achieved in only 46% of the samples whilst less than 50% inhibition was achieved in 13% of the samples. This low inhibition did not necessarily correspond with high proteolytic acti-
clearly indicated
vity. This amount of aprotinin is far in excess of the amount required totally to inhibit an equivalent amount of trypsin giving the same esterolytic activity and is equivalent to a clinical dose of 20 x 106 K.t.u. of aprotinin. In the M.R.C. study, aprotinin was administered at a dose of 1.2 x 106 K.t.u. daily. Furthermore, the half-life of aprotinin after intravenous injection is 30-60 min. It is, therefore, not unexpected that the regimen for aprotinin used in the M.R.C. study was ineffective in reducing mortality from acute pancreatitis. What seems obvious is that aprotinin is a relatively ineffective inhibitor in that the doses required (3 litres/day) to achieve significant inhibition of proteinase activity in vivo would almost certainly incur a significant complication-rate. Surely the time has come for newer methods of anti-proteinase therapy to be investigated. Department of Surgery, University of Dundee, Ninewells Hospital, Dundee DD1 9SY
PROLACTIN CONTROL IN HUNTINGTON’S CHOREA
SIR,-Our data’differ in several respects from those of Dr Hayden and his colleagues (Aug. 27, p. 243).
(1) They found significantly lower baseline prolactin levels eight adults with Huntington’s chorea than in healthy controls. We found significantly higher levels in fourteen of seventeen patients aged 22-63 than in controls although wide fluctuations in this level was found when the same subject was
in
tested on different occasions. (2) We found that a dopamine-receptor blocker, sulpiride, taken orally for 10 days starting at 200 mg and rising to 600 mg daily) induced a rise in plasma-prolactin (up to 70-80 ng/ml) in three of four patients. This contrasts with the poor prolactin response in Hayden’s patients after a single injection of chlorpromazine, another dopamine blocker. (3) We found that the rise in plasma-prolactin induced by 400 g intravenous thyrotropin-releasing hormone (T.R.H.) was identical in Huntington’s chorea and controls whereas Hayden et al. found abnormally low responses. There may be two major reasons for these differences. First, Hayden et al. and his colleagues measured absolute rises in plasma-prolactin instead of relative prolactin increases after chlorpromazine and T.R.H. This point is crucial since their patients had lower baseline prolactin levels than did the controls. Second, the doses of T.R.H. (100 p.g) and chlorpromazine (25 mg) are probably too small since they evoked poor prolactin responses even in controls. In our studies, 1,2 the serum-prolactin in Huntington’s chorea was less susceptible to lowering by dopaminergic drugs (bromocriptine, apomorphine, levodopa) which act at both central nervous system and pituitary sites but was inhibited normally by dopamine (20 mg intravenously over 60 min), a stimulus which acts mainly at the pituitary level. This was confirmed by Caine et al.4 who also found high baseline prolactin levels in Huntington’s chorea. We suggest therefore that in Huntington’s chorea there is a primary alteration in brain dopaminergic neurotransmission while dopamine receptors at the pituitary level function normally and not abnormally as Hayden et al. claim. We cannot explain the very low baseline prolactin values in their patients and emphasise that the high levels found by us and others4 do not support their hypothesis 1.
Caraceni, T., Panerai, A. E., Parati, E. A., Cocchi, D., Müller, E. E. J. clin.
Endocrin. Metab. 1977, 44, 870. 2. Müller, E. E., Parati, E. A., Panerai, A. E., Cocchi, D., Caraceni, T. Proc 11th Wld Congr. Neurol., p. 91. (Excerpta med. int. Congr. Ser. 1977. no.
3.
Goebel, K. M., Schubotz, R., Goebel, F. D., Hahn, E., Neurath, F. Lancet, 1977, i, 214. 2. Worthington, K. J., Cuschien, A. Br. J. exp. Path. 1976, 57,165.
1
A. CUSCHIERI
427).
Tagliamonte, A., De Montis, G., Olianas, M., vargiu, L., Corsini, G. U. Gessa, G. L. J. Neurochem. 1975, 24, 707. 4. Caine, E. D., Kartzinel, R., Ebert, M., Carter, A. C. Neurology, 1977, 27, 392 (abstr.).
