- Email: [email protected]
CLONIDINE IS NOT NEUROTOXIC
876 INTERFERONS FROM CULTURE
SCORING OF MORBIDITY INDEX
DIG=disseminated intravascular
coagulation.
fulfilled the selection criteria for septic shock. Unselected patients from this group then received anti-LPS by chance, according to the availability of anti-LPS. That the two groups were successfully randomised (table) was indicated by their morbidity indexes upon entry to the study, scored by Aitchison himself, of I -04 and 1 -00 for the conventionally treated and anti-LPS treated groups, respectively. In as yet unpublished paper dealing with the septic abortion cases only, Aitchison (second author) writes: "The patients were essentially randomised in selection into one group or the other. This is shown by the fact that on entry to the study both groups had almost the same morbidity indexes". He thus holds two contradictory views at the same time. Aitchison et al stated that the treated groups were "often" given booster doses of anti-LPS when in fact only 2 of the 23 patients received them. The ideal dosage of anti-LPS for each patient remains tube defined. The ultimate proof of any treatment is a double blind study which we have long planned. In view of the above, we question the source of "information" upon which Aitchison et al base their letter and fail to understand why they presented it in this fashion, particularly when it is borne in mind that Aitchison has been content to associate himself with related publications as a co-author. Department of Physiology, University of Natal, Congella 4013, South Africa
EYLON LACHMAN S. B. PITSOE STEPHEN L. GAFFIN
1. Braude AI. Endotoxic immunity. Adv Intern Med 1980; 26: 427-45. 2. Ziegler EJ, McCutchan JA, Fierer J, Glauser M, Sadoff J, Douglas
H, Braude A. Treatment of gram negative bacteremia and shock with human antiserum to a mutant E coli. N Engl J Med 1982; 307: 1225-30.
VISITS FROM THE HEALTH ADVISORY SERVICE
SIR,-Thank you for drawing attention to the annual report of the NHS Health Advisory Service (Sept 29, p 763). The question of how comprehensive HAS activities should be has concerned me a lot. It may be that the full-scale HAS visit of the future will be reserved for services revealed to be "in trouble" by developments of performance assessment, perhaps along the lines being pioneered at the Health Services Management Centre in Birmingham. In the meantime, I submit that the HAS does provide a unique sampling of services provided for elderly and mentally ill people, of sufficient size to make its findings a reliable indication of effectiveness of provision. From 1985, the publication of our hitherto highly confidential reports on individual services will strengthen our influence considerably. Our reports, though primarily designed to enable individual authorities to understand and develop their services, are already used widely in government as a guide to conditions and problems in the health services. Finally, The Rising Tide, produced under the former HAS directorship of Dr Donald Dick, continues to stimulate the development of effective services for elderly people with mental illness. More similar "special projects" are on the way.
SiR,—Dr Nicholson (Sept 8, p 562) correctly states that most interferons for clinical trial have, until lately, been obtained at low purity from peripheral blood lymphocytes and that human interferon genes have now been introduced into bacteria and yeast to produce some particular single type of interferon in bulk. He does not mention that very large quantities of highly purified a-interferons can also be obtained from cultured human cells. The human lymphoblastoid cells which Wellcome Biotechnology Ltd handles in 8000 litre tanks produce a mixture of many different subtypes of a-interferon. The antiviral and other properties of this mixture differ from those of any single interferon made by recombinant DNA techniques, and the elegance of these techniques should not blind one to the fact that under natural circumstances in the body many interferons are generated, not just one. Furthermore, human a-interferon proteins will be formed with greater fidelity when they are made by human cells rather than by bacteria containing an artificially introduced human gene; this may prove significant, for example, in connection with the development of antibodies to interferons administered for therapeutic purposes. We have issued our highly purified product for large-scale clinical trials in many countries over the past five years, and envisage no difficulty in supplying the amounts likely to be required for routine clinical use. Wellcome
Biotechnology Ltd,
CLONIDINE IS NOT NEUROTOXIC agree with Dr Coombs (Sept 22, p 689) that drugs be given close to the CNS without knowledge about possible neurotoxic effects. May we give some background to the cases we reported in your issue of July 28 (p 231). We studied the possibility of using clonidine as an analgesic in clinical practice, starting with a controlled double-blind study of intravenous clonidine, pethidine, and placebo for postoperative pain. The results indicated an analgesic effect of clonidine.We also investigated the possible neurotoxicity of clonidine in animals.
SIR,-We
should
technique.
flow
The investigation by Coombs and co-workers5of possible neurotoxicity of clonidine in the sheep also suggests that clonidine is not neurotoxic. In the two cases reported by us where clonidine was
given to patients with pain syndromes, conventional treatment had failed. We considered it justified to try the effect of epidural clonidine, knowing the results of the investigations mentioned above. We have also obtained permission from the Swedish Medical Board to investigate epidural clonidine in humans in limited controlled studies. Department of Anaesthesiology, University Hospital, S-751 85 Uppsala, Sweden
PETER HORROCKS, Director
ANDERS TAMSEN TORSTEN GORDH
TE, Tamsen A. A study on the analgesic effect of clonidine in man. Acta Anaesthesiol Scand 1983; (suppl 78): 72(abstr). 2. Gordh TE, Ekman S, Lagerstedt AS. Evaluation of the possible spinal neurotoxicity of clonidine. Uppsala J Med Sci (in press). 3. Nyström B, Norlén K. Regional spinal cord and brain blood flow in the rat. Neurol Res 1. Gordh
1983; 5:
Advisory Service,
Sutherland House, 29-37 Brighton Road, Sutton, Surrey SM2 5AN
not
Four dogs were given spinal clonidine in doses of 12 - 5 or 25 fg/kg daily for 14 consecutive days. Two dogs served as controls. None of the dogs showed signs of abnormal behaviour during the study except for sedation. After tissue fixation by perfusion with 2% buffered paraformaldehyde and intrathecal injection of 2% buffered glutaraldehyde, the spinal cords were examined by attributable to clonidine could be light microscopy. No signs of neurotoxicity 2 seen in any of the spinal cords.2 To see if epidural clonidine could affect blood flow in the spinal cord, we have studied eleven anaesthetised pigs, each receiving clonidine 3, 10 and 30 g/kg in the epidural space. 60 mm elapsed between the doses. Spinal cord After 3 pg/kg no blood flow was measured with the microsphere change in spinal cord blood flow was observed. After the two higher doses spinal cord blood flow was reduced by 20% and 30%, respectively, indicating in cerebrum, cerebellum, and kidneys was local vasoconstriction. Blood 4 not altered by any of these doses.
5
no
1.
TE, Feuk U, Norlén K. Effekt av epiduralt clonidin på ryggmärgscirkulationen hos gris (Effect of epidural clonidine on spinal cord blood flow in the pig). Opuscula Med (in press) (abstr). Coombs WD, Allen C, Meier F, Fratkin J. Chronic intraspinal clonidine in the sheep Reg Anesth 1984; 9: 47(abstr)
4. Gordh
NHS Health
N. B. FINTER
Beckenham, Kent BR3 3BS
SCORING OF MORBIDITY INDEX
DIG=disseminated intravascular
coagulation.
fulfilled the selection criteria for septic shock. Unselected patients from this group then received anti-LPS by chance, according to the availability of anti-LPS. That the two groups were successfully randomised (table) was indicated by their morbidity indexes upon entry to the study, scored by Aitchison himself, of I -04 and 1 -00 for the conventionally treated and anti-LPS treated groups, respectively. In as yet unpublished paper dealing with the septic abortion cases only, Aitchison (second author) writes: "The patients were essentially randomised in selection into one group or the other. This is shown by the fact that on entry to the study both groups had almost the same morbidity indexes". He thus holds two contradictory views at the same time. Aitchison et al stated that the treated groups were "often" given booster doses of anti-LPS when in fact only 2 of the 23 patients received them. The ideal dosage of anti-LPS for each patient remains tube defined. The ultimate proof of any treatment is a double blind study which we have long planned. In view of the above, we question the source of "information" upon which Aitchison et al base their letter and fail to understand why they presented it in this fashion, particularly when it is borne in mind that Aitchison has been content to associate himself with related publications as a co-author. Department of Physiology, University of Natal, Congella 4013, South Africa
EYLON LACHMAN S. B. PITSOE STEPHEN L. GAFFIN
1. Braude AI. Endotoxic immunity. Adv Intern Med 1980; 26: 427-45. 2. Ziegler EJ, McCutchan JA, Fierer J, Glauser M, Sadoff J, Douglas
H, Braude A. Treatment of gram negative bacteremia and shock with human antiserum to a mutant E coli. N Engl J Med 1982; 307: 1225-30.
VISITS FROM THE HEALTH ADVISORY SERVICE
SIR,-Thank you for drawing attention to the annual report of the NHS Health Advisory Service (Sept 29, p 763). The question of how comprehensive HAS activities should be has concerned me a lot. It may be that the full-scale HAS visit of the future will be reserved for services revealed to be "in trouble" by developments of performance assessment, perhaps along the lines being pioneered at the Health Services Management Centre in Birmingham. In the meantime, I submit that the HAS does provide a unique sampling of services provided for elderly and mentally ill people, of sufficient size to make its findings a reliable indication of effectiveness of provision. From 1985, the publication of our hitherto highly confidential reports on individual services will strengthen our influence considerably. Our reports, though primarily designed to enable individual authorities to understand and develop their services, are already used widely in government as a guide to conditions and problems in the health services. Finally, The Rising Tide, produced under the former HAS directorship of Dr Donald Dick, continues to stimulate the development of effective services for elderly people with mental illness. More similar "special projects" are on the way.
SiR,—Dr Nicholson (Sept 8, p 562) correctly states that most interferons for clinical trial have, until lately, been obtained at low purity from peripheral blood lymphocytes and that human interferon genes have now been introduced into bacteria and yeast to produce some particular single type of interferon in bulk. He does not mention that very large quantities of highly purified a-interferons can also be obtained from cultured human cells. The human lymphoblastoid cells which Wellcome Biotechnology Ltd handles in 8000 litre tanks produce a mixture of many different subtypes of a-interferon. The antiviral and other properties of this mixture differ from those of any single interferon made by recombinant DNA techniques, and the elegance of these techniques should not blind one to the fact that under natural circumstances in the body many interferons are generated, not just one. Furthermore, human a-interferon proteins will be formed with greater fidelity when they are made by human cells rather than by bacteria containing an artificially introduced human gene; this may prove significant, for example, in connection with the development of antibodies to interferons administered for therapeutic purposes. We have issued our highly purified product for large-scale clinical trials in many countries over the past five years, and envisage no difficulty in supplying the amounts likely to be required for routine clinical use. Wellcome
Biotechnology Ltd,
CLONIDINE IS NOT NEUROTOXIC agree with Dr Coombs (Sept 22, p 689) that drugs be given close to the CNS without knowledge about possible neurotoxic effects. May we give some background to the cases we reported in your issue of July 28 (p 231). We studied the possibility of using clonidine as an analgesic in clinical practice, starting with a controlled double-blind study of intravenous clonidine, pethidine, and placebo for postoperative pain. The results indicated an analgesic effect of clonidine.We also investigated the possible neurotoxicity of clonidine in animals.
SIR,-We
should
technique.
flow
The investigation by Coombs and co-workers5of possible neurotoxicity of clonidine in the sheep also suggests that clonidine is not neurotoxic. In the two cases reported by us where clonidine was
given to patients with pain syndromes, conventional treatment had failed. We considered it justified to try the effect of epidural clonidine, knowing the results of the investigations mentioned above. We have also obtained permission from the Swedish Medical Board to investigate epidural clonidine in humans in limited controlled studies. Department of Anaesthesiology, University Hospital, S-751 85 Uppsala, Sweden
PETER HORROCKS, Director
ANDERS TAMSEN TORSTEN GORDH
TE, Tamsen A. A study on the analgesic effect of clonidine in man. Acta Anaesthesiol Scand 1983; (suppl 78): 72(abstr). 2. Gordh TE, Ekman S, Lagerstedt AS. Evaluation of the possible spinal neurotoxicity of clonidine. Uppsala J Med Sci (in press). 3. Nyström B, Norlén K. Regional spinal cord and brain blood flow in the rat. Neurol Res 1. Gordh
1983; 5:
Advisory Service,
Sutherland House, 29-37 Brighton Road, Sutton, Surrey SM2 5AN
not
Four dogs were given spinal clonidine in doses of 12 - 5 or 25 fg/kg daily for 14 consecutive days. Two dogs served as controls. None of the dogs showed signs of abnormal behaviour during the study except for sedation. After tissue fixation by perfusion with 2% buffered paraformaldehyde and intrathecal injection of 2% buffered glutaraldehyde, the spinal cords were examined by attributable to clonidine could be light microscopy. No signs of neurotoxicity 2 seen in any of the spinal cords.2 To see if epidural clonidine could affect blood flow in the spinal cord, we have studied eleven anaesthetised pigs, each receiving clonidine 3, 10 and 30 g/kg in the epidural space. 60 mm elapsed between the doses. Spinal cord After 3 pg/kg no blood flow was measured with the microsphere change in spinal cord blood flow was observed. After the two higher doses spinal cord blood flow was reduced by 20% and 30%, respectively, indicating in cerebrum, cerebellum, and kidneys was local vasoconstriction. Blood 4 not altered by any of these doses.
5
no
1.
TE, Feuk U, Norlén K. Effekt av epiduralt clonidin på ryggmärgscirkulationen hos gris (Effect of epidural clonidine on spinal cord blood flow in the pig). Opuscula Med (in press) (abstr). Coombs WD, Allen C, Meier F, Fratkin J. Chronic intraspinal clonidine in the sheep Reg Anesth 1984; 9: 47(abstr)
4. Gordh
NHS Health
N. B. FINTER
Beckenham, Kent BR3 3BS