- Email: [email protected]
Fenoterol and its bromide
1613
We have more recently completed a study on the effects of the oral NSAID, tiaprofenic acid (as ’Surgam SA’), and now report results which we believe have a bearing on the current debate about chondoprotection. 12 adult Merino wethers were subjected to unilateral medial meniscectomy. All animals were housed in similar pens but 12 weeks postmeniscectomy half of the group (randomly selected) were given tiaprofenic acid daily (20 mg/kg orally). Joint synovial fluid was aspirated one week before drug treatment and on weeks 15, 20, and 24 after surgery. Animals were killed on week 26. The amounts of cartilage proteoglycan fragments in synovial fluid were measured with an ELISA for keratan sulphate epitopes9 in both drug and non-drug treated animals. Histological, biochemical, and metabolic studies on the cartilage, bone, and synovium were also undertaken and these will be reported elsewhere. We found that cartilage proteoglycan metabolism was not suppressed in the drug-treated group. Non-drug treated animals showed a progressive increase in the release of proteoglycan epitopes into joint fluid during the experimental period (figure). Tiaprofenic acid given half-way through the study failed to suppress the release of this marker in the first two months of treatment, but by the third month a statistically significant reduction in the quantity of proteoglycan fragments in synovial fluid was observed suggesting a reduction in proteoglycan catabolism. Our findings indicate that tiaprofenic acid may have a chondoprotective effect in vivo. Furthermore, the route and dose schedule in our experiments were shown by analysis of drug blood concentrations (20 fig/mi) to be similar to that achieved in man.
dysfunction.
Raymond Purves Research Laboratories, University of Sydney, Royal North Shore Hospital of Sydney, St Leonards, New South Wales 2065, Australia School of Veterinary Studies, Murdoch University,
Murdoch, Western Australia 6150
PETER GHOSH CHRISTINE HOLBERT RICHARD READ SARAH ARMSTRONG DIANNA WILSON
1. Ghosh P Chondoprotective drugs and osteoarthritis. Ann Rheum Dis 1990; 49: 338-39. 2. Ghosh P, Brooks P. Chondoprotection: exploring the concept. J Rheumatol 1991; 18: 161-66. 3. Buckland-Wright JC, Macfarlane DG, Lynch JA, Clark B. Quantitative microfocal radiographic assessment of progression in osteoarthritis of the hand. Arthritis Rheum 1990; 33: 57-65. 4. Karvonen RL, Negendank WG, Fraser SM, et al. Articular cartilage defects of the knee: correlation between magnetic resonance imaging and gross pathology. Ann Rheum Dis 1990; 49: 672-75. 5. Shinmei M, Inamori Y, Yoshiwara Y, et al. Molecular markers of joint disease: significance of the level of type II c-propeptide chondroitin sulphate and TIMP in joint fluid. Trans Orthop Res Soc 1991; 16: 230. 6. Ghosh P, Burkhardt D, Read R, Bellenger C. Recent advances in animal models for evaluating chondoprotective drugs. J Rheumatol 1991; 18 (suppl 27). 143-46. 7. Hannan N, Ghosh P, Bellenger C, Taylor TKF. The systemic administration of glycosaminoglycan polysulphate (Arteparon) provides partial protection of articular cartilage from damage produced by meniscectomy. J Orthop Res 1987; 5: 47-59. 8. Ghosh P, Sutherland JM, Taylor TKF, et al. The effects of postoperative joint immobilisation on articular cartilage degeneration following meniscectomy. J Surg Res 1983; 35: 461-73. 9. Kongtawelert P, Ghosh P. A new sandwich ELISA method for the determination of keratan sulphate peptides in biological fluids employing a monoclonal antibody and labelled avidin biotin technique. Clin Chim Acta 1990; 195: 17-26.
Fenoterol and its bromide SIR,-There have been three papers in the past 18 months from New Zealand suggesting that fenoterol prescriptions are associated with increased risk of death, especially in patients with severe asthma.1-3 Another paper suggests that regular use of fenoterol is associated with worsening asthma.4 These reports indicate that, at least in New Zealand, regular use of fenoterol may make asthma worse. We do need to know if this is a class effect, applicable to all
beta-agonists, or whether it is specific to fenoterol. Fenoterol is the only beta-agonist drug that is formulated as a bromide. Eosinophils frequently use bromide rather than chloride to generate a halogenating oxidant with characteristics similar to those of hypobromous acid.s Hypobromous acid is an oxidant
capable of destroying a wide range of cells.5,6 It disrupts oc2-macroglobulin function7 which is important because
ocz-macroglobulin
function may be
one
of the main mechanisms
whereby cationic proteins released from eosinophils are inactivated. The normal bromide concentration in the blood can be as low as 10 I1g/l. This amount is thought to be sufficient to produce oxidants that damage the heart.6 Bands of fibrous tissue were found in the hearts of some young asthmatics who died from asthma who had not had infusions of catecholamines.8 The concentration of bromide delivered by a ’Berotec’ (fenoterol) metered dose aerosol is 20 000 times that in the blood, and this high concentration of bromide in the airways may increase the potential for tissue damage by
hypobromous oxidants from eosinophils. Experiments are in progress to find out if fenoterol increases the oxidant properties of eosinophils from asthmatic patients. If it does, that may be one explanation for the apparent harmful effects of fenoterol which would not apply to the other &bgr;2-specific agonists. Furthermore, it may be a mechanism whereby damage from oxidants occurs both in the lungs and in the heart. Department of Medicine, University of Sydney, Sydney, NSW 2006, Australia, and Institute of Respiratory Medicine, Royal Price Alfred Hospital, Sydney
W. F. GREEN
1. Crane J, Pearce N, Flatt A, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-83: case-control study. Lancet 1989; i: 917-22. 2. Pearce N, Grainger J, Atkinson M, et al. Case-control study of prescribed fenoterol and death from asthma in New Zealand, 1977-81. Thorax 1990; 45: 170-75. 3. Grainger J, Woodman K, Pearce N, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-7: a further case-control study. Thorax 1991; 46: 105-11. 4. Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990; 336: 1391-96. 5. Weiss SJ, Test ST, Eckmann CM, et al. Brominating oxidants generated by human eosinophils. Science 1986; 234: 200-02. 6. Slungaard A, Mahoney JR Jnr. Bromide-dependent toxicity of eosinophil peroxidase for endothelium and isolated working rat hearts: a model for eosinophilic 7.
endocarditis. J Exp Med 1991; 173: 117-26. Reddy VY, Pizzo SV, Weiss SJ. Functional inactivation and structural disruption of human alpha 2 macroglobulin by neutrophils and eosinophils. J Biol Chem 1989;
264: 13801-09. 8. Schoen FJ. Cardiac pathology in asthma. J
Allergy Clin Immunol 1987; 80:
419-23.
Photodynamic therapy in patient with xeroderma pigmentosum SIR,-Xeroderma pigmentosum (XP), a heritable disease with increased sensitivity to cellular injury by ultraviolet radiation (UVR) and certain DNA-damaging chemicals associated with abnormal DNA repair, is characterised by the development of multiple skin tumours.’ It could be an advantage to use photodynamic therapy (PDT)2,3 if many tumours are present because a large number of them can be managed in short treatment sessions.4 We report our experience of topical PDT with endogenous porphyrin, a novel therapy described by Kennedy et al.5 A 47-year-old woman with XP of complementation group C was admitted for a skin tumour on the back of her left hand, a sharply demarcated, slightly elevated, scaly, hyperkeratotic plaque 1 -55 cm in diameter. Punch biopsy indicated superficial squamous cell carcinoma. An oil-in-water emulsion containing 40% 5aminolaevulinic acid (ALA) was applied under occlusive dressing to the tumour and adjacent skin for 4 h before exposure to 90 J /em2 of visible light from a Leica slide projector equipped with a 250 W lamp with a Schott RG 570 long-wave-pass colour glass filter. We observed an abnormally delayed peak erythema and oedema of the exposed area 72 h after therapy (normal 8-24 h); the induced erythema persisted for more than 2 weeks (normal 2-4 days), and the reaction on adjacent skin was unusually strong, with blistering. However, healing of the carcinoma could be observed within 4 weeks; the erythema on the adjacent skin resolved gradually, leaving residual pigmentation. 6 months later there was no clinical sign of tumour recurrence.
delayed peak in, but persistent, erythema with striking acute damage in XP is well known after exposure to UVR.1,6 However, in this patient UVR treatment was not used and exposure to natural UVR can also be excluded because the patient was in A skin
We have more recently completed a study on the effects of the oral NSAID, tiaprofenic acid (as ’Surgam SA’), and now report results which we believe have a bearing on the current debate about chondoprotection. 12 adult Merino wethers were subjected to unilateral medial meniscectomy. All animals were housed in similar pens but 12 weeks postmeniscectomy half of the group (randomly selected) were given tiaprofenic acid daily (20 mg/kg orally). Joint synovial fluid was aspirated one week before drug treatment and on weeks 15, 20, and 24 after surgery. Animals were killed on week 26. The amounts of cartilage proteoglycan fragments in synovial fluid were measured with an ELISA for keratan sulphate epitopes9 in both drug and non-drug treated animals. Histological, biochemical, and metabolic studies on the cartilage, bone, and synovium were also undertaken and these will be reported elsewhere. We found that cartilage proteoglycan metabolism was not suppressed in the drug-treated group. Non-drug treated animals showed a progressive increase in the release of proteoglycan epitopes into joint fluid during the experimental period (figure). Tiaprofenic acid given half-way through the study failed to suppress the release of this marker in the first two months of treatment, but by the third month a statistically significant reduction in the quantity of proteoglycan fragments in synovial fluid was observed suggesting a reduction in proteoglycan catabolism. Our findings indicate that tiaprofenic acid may have a chondoprotective effect in vivo. Furthermore, the route and dose schedule in our experiments were shown by analysis of drug blood concentrations (20 fig/mi) to be similar to that achieved in man.
dysfunction.
Raymond Purves Research Laboratories, University of Sydney, Royal North Shore Hospital of Sydney, St Leonards, New South Wales 2065, Australia School of Veterinary Studies, Murdoch University,
Murdoch, Western Australia 6150
PETER GHOSH CHRISTINE HOLBERT RICHARD READ SARAH ARMSTRONG DIANNA WILSON
1. Ghosh P Chondoprotective drugs and osteoarthritis. Ann Rheum Dis 1990; 49: 338-39. 2. Ghosh P, Brooks P. Chondoprotection: exploring the concept. J Rheumatol 1991; 18: 161-66. 3. Buckland-Wright JC, Macfarlane DG, Lynch JA, Clark B. Quantitative microfocal radiographic assessment of progression in osteoarthritis of the hand. Arthritis Rheum 1990; 33: 57-65. 4. Karvonen RL, Negendank WG, Fraser SM, et al. Articular cartilage defects of the knee: correlation between magnetic resonance imaging and gross pathology. Ann Rheum Dis 1990; 49: 672-75. 5. Shinmei M, Inamori Y, Yoshiwara Y, et al. Molecular markers of joint disease: significance of the level of type II c-propeptide chondroitin sulphate and TIMP in joint fluid. Trans Orthop Res Soc 1991; 16: 230. 6. Ghosh P, Burkhardt D, Read R, Bellenger C. Recent advances in animal models for evaluating chondoprotective drugs. J Rheumatol 1991; 18 (suppl 27). 143-46. 7. Hannan N, Ghosh P, Bellenger C, Taylor TKF. The systemic administration of glycosaminoglycan polysulphate (Arteparon) provides partial protection of articular cartilage from damage produced by meniscectomy. J Orthop Res 1987; 5: 47-59. 8. Ghosh P, Sutherland JM, Taylor TKF, et al. The effects of postoperative joint immobilisation on articular cartilage degeneration following meniscectomy. J Surg Res 1983; 35: 461-73. 9. Kongtawelert P, Ghosh P. A new sandwich ELISA method for the determination of keratan sulphate peptides in biological fluids employing a monoclonal antibody and labelled avidin biotin technique. Clin Chim Acta 1990; 195: 17-26.
Fenoterol and its bromide SIR,-There have been three papers in the past 18 months from New Zealand suggesting that fenoterol prescriptions are associated with increased risk of death, especially in patients with severe asthma.1-3 Another paper suggests that regular use of fenoterol is associated with worsening asthma.4 These reports indicate that, at least in New Zealand, regular use of fenoterol may make asthma worse. We do need to know if this is a class effect, applicable to all
beta-agonists, or whether it is specific to fenoterol. Fenoterol is the only beta-agonist drug that is formulated as a bromide. Eosinophils frequently use bromide rather than chloride to generate a halogenating oxidant with characteristics similar to those of hypobromous acid.s Hypobromous acid is an oxidant
capable of destroying a wide range of cells.5,6 It disrupts oc2-macroglobulin function7 which is important because
ocz-macroglobulin
function may be
one
of the main mechanisms
whereby cationic proteins released from eosinophils are inactivated. The normal bromide concentration in the blood can be as low as 10 I1g/l. This amount is thought to be sufficient to produce oxidants that damage the heart.6 Bands of fibrous tissue were found in the hearts of some young asthmatics who died from asthma who had not had infusions of catecholamines.8 The concentration of bromide delivered by a ’Berotec’ (fenoterol) metered dose aerosol is 20 000 times that in the blood, and this high concentration of bromide in the airways may increase the potential for tissue damage by
hypobromous oxidants from eosinophils. Experiments are in progress to find out if fenoterol increases the oxidant properties of eosinophils from asthmatic patients. If it does, that may be one explanation for the apparent harmful effects of fenoterol which would not apply to the other &bgr;2-specific agonists. Furthermore, it may be a mechanism whereby damage from oxidants occurs both in the lungs and in the heart. Department of Medicine, University of Sydney, Sydney, NSW 2006, Australia, and Institute of Respiratory Medicine, Royal Price Alfred Hospital, Sydney
W. F. GREEN
1. Crane J, Pearce N, Flatt A, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-83: case-control study. Lancet 1989; i: 917-22. 2. Pearce N, Grainger J, Atkinson M, et al. Case-control study of prescribed fenoterol and death from asthma in New Zealand, 1977-81. Thorax 1990; 45: 170-75. 3. Grainger J, Woodman K, Pearce N, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-7: a further case-control study. Thorax 1991; 46: 105-11. 4. Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990; 336: 1391-96. 5. Weiss SJ, Test ST, Eckmann CM, et al. Brominating oxidants generated by human eosinophils. Science 1986; 234: 200-02. 6. Slungaard A, Mahoney JR Jnr. Bromide-dependent toxicity of eosinophil peroxidase for endothelium and isolated working rat hearts: a model for eosinophilic 7.
endocarditis. J Exp Med 1991; 173: 117-26. Reddy VY, Pizzo SV, Weiss SJ. Functional inactivation and structural disruption of human alpha 2 macroglobulin by neutrophils and eosinophils. J Biol Chem 1989;
264: 13801-09. 8. Schoen FJ. Cardiac pathology in asthma. J
Allergy Clin Immunol 1987; 80:
419-23.
Photodynamic therapy in patient with xeroderma pigmentosum SIR,-Xeroderma pigmentosum (XP), a heritable disease with increased sensitivity to cellular injury by ultraviolet radiation (UVR) and certain DNA-damaging chemicals associated with abnormal DNA repair, is characterised by the development of multiple skin tumours.’ It could be an advantage to use photodynamic therapy (PDT)2,3 if many tumours are present because a large number of them can be managed in short treatment sessions.4 We report our experience of topical PDT with endogenous porphyrin, a novel therapy described by Kennedy et al.5 A 47-year-old woman with XP of complementation group C was admitted for a skin tumour on the back of her left hand, a sharply demarcated, slightly elevated, scaly, hyperkeratotic plaque 1 -55 cm in diameter. Punch biopsy indicated superficial squamous cell carcinoma. An oil-in-water emulsion containing 40% 5aminolaevulinic acid (ALA) was applied under occlusive dressing to the tumour and adjacent skin for 4 h before exposure to 90 J /em2 of visible light from a Leica slide projector equipped with a 250 W lamp with a Schott RG 570 long-wave-pass colour glass filter. We observed an abnormally delayed peak erythema and oedema of the exposed area 72 h after therapy (normal 8-24 h); the induced erythema persisted for more than 2 weeks (normal 2-4 days), and the reaction on adjacent skin was unusually strong, with blistering. However, healing of the carcinoma could be observed within 4 weeks; the erythema on the adjacent skin resolved gradually, leaving residual pigmentation. 6 months later there was no clinical sign of tumour recurrence.
delayed peak in, but persistent, erythema with striking acute damage in XP is well known after exposure to UVR.1,6 However, in this patient UVR treatment was not used and exposure to natural UVR can also be excluded because the patient was in A skin