PLATELET ACTIVATION AND ANÆSTHETICS
1
1367 years, I suggested the same treatment to a consultant surgeon. The suggestion was received with scepticism; the underlying cause was thought more worthy of treatment. Since then I have watched leg ulcers respond minimally to "eusol" and paraffin gauze dressings. The articles in The Lancet of May 31 have given me renewed hope and ammunition in the fight for the use of human amnion in the treatment of chronic ulceration of the legs. The search for the mechanism responsible for its efficacy should prove most interesting. 21 Westminster Road, Leicester LE2 2EH HEATHER SWIFT HONKING SIR,-Your May 10 editorial on "honking" correctly stresses the emotional component which appears to be present in these children with the well recognised syndrome of a repeti- tive brassy or bovine cough which is unresponsive to normal treatment, unassociated with serious disease, and absent at night. However, a recent report’ of the "barking seal syn- drome" (which sounds like the same condition) draws atten- tion to its association with inhalation of glass fibres from cur- tains or roof insulation. In this report bronchial brushings from the airways of affected children were shown to contain glass fibre on microscopy. The last honking child I saw had recently had her bedroom roof insulated with glass fibre. St James’s University Hospital, Leeds LS9 7TF J. M. LITTLEWOOD DRUG SAFETY IN PORPHYRIA SIR,-Barbiturates, pyrazolone analgesics, sulphonamides, and many other drugs of widely different chemical structure2 can precipitate acute attacks in patients with acute intermit- tent porphyria, hereditary coproporphyria, or variegate por- phyria. But what of newly released preparations? To test some of these newer drugs for their porphyrogenicity, we have used a rat model. When rats are given a small (100 mg/kg) dose of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) hsem bio- synthesis is partly blocked at the level of ferrochelatase.4 The rats then exhibit a porphyria which resembles the latent human variegate form, a porphyria characterised by partial blocks in hsern biosynthesis at the levels of protoporphyrinogen oxidase5 and ferrochelatase.6 Rats thus treated become sensi- tive to drugs that can precipitate porphyria; when DDC is administered simultaneously with the drug under test, the bio- chemical picture becomes typical of the acute attack in man.4 This includes increased activity of hepatic 8-aminolaEvulinic acid synthetase (ALA-S), the initial and rate-limiting enzyme of haem biosynthesis, which is increased during the acute attacks in all three of the hereditary "hepatic" porphyrias.7 Using this rat model,3 we have tested the porphyrogenicity of several new drugs by determination of hepatic ALA-S in rats treated simultaneously with the drug in question and DDC. 1. Patterson P, Foster E. The barking seal syndrome. Cystic Fibrosis Club, 1978, abstr. no. 8. 2. Eales L. The acute porphyria attack III: Acute porphyria: the precipitating and aggravating factors. S Afr J Clin Med 1971; 17: 120-25. 3. Blekkenhorst GH, Harrison GG, Cook ES, Eales L. The screening of certain anaesthetic agents for their ability to elicit acute porphyric phases in sus- ceptible patients. Br J Anæsth (in press.) 4. De Matteis F, Abbritti G, Gibbs AH. Decreased liver activity of porphyrin- metal chelatase in hepatic porphyria caused by 3,5 diethoxycarbon-1,4- dihydrocollidine: Studies in rats and mice. Biochem J 1973; 134: 717-27. 5. Brenner DA, Bloomer JR. The enzymatic defect in variegate porphyria. Clin Res 1979; 27: 274A. 6. Viljoen DJ, Cayanis E, Becker DM, Kramer S, Dawson B, Bernstein R. Reduced ferrochelatase activity in fibroblasts from patients with porphyria variegate. Am J Hematol 1979; 6: 185-90. 7. Meyer UA, Schmid R. Hereditary hepatic porphyrias. Fed Proc 1973; 32: 1649-55. EFFECT OF SIMULTANEOUS TREATMENT OF RATS WITH DDC AND VARIOUS DRUGS ON HEPATIC ALA-S Each result represents the mean value for five animals, ±SD 95% of control value, for rats given DDC only, of850±118 (n=30) nmol ALA formed h-l g-11iver. *500 000 units. We were able to divide the drugs tested into two groups (see table). The activities of hepatic ALA-S in the rats treated with DDC and those drugs in group. A were not significantly in- creased when compared to the activities of the enzyme in rats treated with DDC alone. However, drugs in group B caused a significant increase (p<0-05) in hepatic ALA-S activity. We included propanidid and penicillin, which are known to be safe in the hereditary hepatic porphyrias, phenobarbitone and thio- pentone which are hazardous, to serve as a check on the method. Drugs in group A would probably not elicit an acute attack in susceptible porphyric individuals. However, drugs in group B should be regarded as potentially hazardous for pa- tients with a hereditary hepatic porphyria, and alternative known safe preparations should be used. We thank the South African Research Council for financial support. Porphyria Research Unit, University of Cape Town and South African M.R.C., Groote Schuur Hospital, Observatory 7925, Cape, South Africa GERRY H. BLEKKENHORST ELAINE S. COOK LENNOX EALES PLATELET ACTIVATION AND ANÆSTHETICS SIR,-Dr Zahavi and colleagues (May 24, p. 1132) report that platelet activation occurs during even minor operations. Their speculation that this is caused by an effect of anaesthetic agents on platelets is unlikely to be correct, because the anxs- thetic agents immobilise calcium and cause cell membrane expansion, and this is certainly the mechanism whereby they render Kupffer cells sleepy. Indeed in deeper anaesthesia one would expect platelets to be depressed. Hence it would seem that the platelet activation which they describe must be due to sympathetic activation in response to surgical stimulation dur- ing light anaesthesia. This will be an alpha-receptor effect. 33 Hawthorn Gardens, Kenton, Newcastle upon Tyne NE3 3DE E. N. WARDLE 1. Ngai SH. Current concepts in anesthesiology. N Engl J Med 1980; 302: 564-66.
Transcript of PLATELET ACTIVATION AND ANÆSTHETICS
1367
years, I suggested the same treatment to a consultant surgeon.The suggestion was received with scepticism; the underlyingcause was thought more worthy of treatment. Since then Ihave watched leg ulcers respond minimally to "eusol" andparaffin gauze dressings.The articles in The Lancet of May 31 have given me
renewed hope and ammunition in the fight for the use ofhuman amnion in the treatment of chronic ulceration of thelegs. The search for the mechanism responsible for its efficacyshould prove most interesting.21 Westminster Road,Leicester LE2 2EH HEATHER SWIFT
HONKING
SIR,-Your May 10 editorial on "honking" correctlystresses the emotional component which appears to be presentin these children with the well recognised syndrome of a repeti-tive brassy or bovine cough which is unresponsive to normaltreatment, unassociated with serious disease, and absent atnight. However, a recent report’ of the "barking seal syn-drome" (which sounds like the same condition) draws atten-tion to its association with inhalation of glass fibres from cur-tains or roof insulation. In this report bronchial brushingsfrom the airways of affected children were shown to containglass fibre on microscopy. The last honking child I saw hadrecently had her bedroom roof insulated with glass fibre.
St James’s University Hospital,Leeds LS9 7TF J. M. LITTLEWOOD
DRUG SAFETY IN PORPHYRIA
SIR,-Barbiturates, pyrazolone analgesics, sulphonamides,and many other drugs of widely different chemical structure2can precipitate acute attacks in patients with acute intermit-tent porphyria, hereditary coproporphyria, or variegate por-phyria. But what of newly released preparations? To test someof these newer drugs for their porphyrogenicity, we have useda rat model. When rats are given a small (100 mg/kg) doseof 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) hsem bio-synthesis is partly blocked at the level of ferrochelatase.4 Therats then exhibit a porphyria which resembles the latenthuman variegate form, a porphyria characterised by partialblocks in hsern biosynthesis at the levels of protoporphyrinogenoxidase5 and ferrochelatase.6 Rats thus treated become sensi-tive to drugs that can precipitate porphyria; when DDC isadministered simultaneously with the drug under test, the bio-chemical picture becomes typical of the acute attack in man.4This includes increased activity of hepatic 8-aminolaEvulinicacid synthetase (ALA-S), the initial and rate-limiting enzymeof haem biosynthesis, which is increased during the acuteattacks in all three of the hereditary "hepatic" porphyrias.7Using this rat model,3 we have tested the porphyrogenicity ofseveral new drugs by determination of hepatic ALA-S in ratstreated simultaneously with the drug in question and DDC.
1. Patterson P, Foster E. The barking seal syndrome. Cystic Fibrosis Club,1978, abstr. no. 8.
2. Eales L. The acute porphyria attack III: Acute porphyria: the precipitatingand aggravating factors. S Afr J Clin Med 1971; 17: 120-25.
3. Blekkenhorst GH, Harrison GG, Cook ES, Eales L. The screening of certainanaesthetic agents for their ability to elicit acute porphyric phases in sus-ceptible patients. Br J Anæsth (in press.)
4. De Matteis F, Abbritti G, Gibbs AH. Decreased liver activity of porphyrin-metal chelatase in hepatic porphyria caused by 3,5 diethoxycarbon-1,4-dihydrocollidine: Studies in rats and mice. Biochem J 1973; 134: 717-27.
5. Brenner DA, Bloomer JR. The enzymatic defect in variegate porphyria. ClinRes 1979; 27: 274A.
6. Viljoen DJ, Cayanis E, Becker DM, Kramer S, Dawson B, Bernstein R.Reduced ferrochelatase activity in fibroblasts from patients with porphyriavariegate. Am J Hematol 1979; 6: 185-90.
7. Meyer UA, Schmid R. Hereditary hepatic porphyrias. Fed Proc 1973; 32:1649-55.
EFFECT OF SIMULTANEOUS TREATMENT OF RATS WITH DDC ANDVARIOUS DRUGS ON HEPATIC ALA-S
Each result represents the mean value for five animals, ±SD 95% ofcontrol value, for rats given DDC only, of850±118 (n=30) nmol ALAformed h-l g-11iver.*500 000 units.
We were able to divide the drugs tested into two groups (seetable). The activities of hepatic ALA-S in the rats treated withDDC and those drugs in group. A were not significantly in-creased when compared to the activities of the enzyme in ratstreated with DDC alone. However, drugs in group B causeda significant increase (p<0-05) in hepatic ALA-S activity. Weincluded propanidid and penicillin, which are known to be safein the hereditary hepatic porphyrias, phenobarbitone and thio-pentone which are hazardous, to serve as a check on themethod. Drugs in group A would probably not elicit an acuteattack in susceptible porphyric individuals. However, drugs ingroup B should be regarded as potentially hazardous for pa-tients with a hereditary hepatic porphyria, and alternativeknown safe preparations should be used.We thank the South African Research Council for financial support.
Porphyria Research Unit,University of Cape Townand South African M.R.C.,
Groote Schuur Hospital,Observatory 7925, Cape, South Africa
GERRY H. BLEKKENHORSTELAINE S. COOKLENNOX EALES
PLATELET ACTIVATION AND ANÆSTHETICS
SIR,-Dr Zahavi and colleagues (May 24, p. 1132) reportthat platelet activation occurs during even minor operations.Their speculation that this is caused by an effect of anaestheticagents on platelets is unlikely to be correct, because the anxs-thetic agents immobilise calcium and cause cell membrane
expansion, and this is certainly the mechanism whereby theyrender Kupffer cells sleepy. Indeed in deeper anaesthesia onewould expect platelets to be depressed. Hence it would seemthat the platelet activation which they describe must be due tosympathetic activation in response to surgical stimulation dur-ing light anaesthesia. This will be an alpha-receptor effect.
33 Hawthorn Gardens,Kenton, Newcastle upon TyneNE3 3DE E. N. WARDLE
1. Ngai SH. Current concepts in anesthesiology. N Engl J Med 1980; 302:564-66.
