554
erythrocyte sedimentation rate was raised and she had microcytic anaemia, increased serum alkaline phosphatase, and a positive faecal occult blood test. Osteoporosis of the axial skeleton was present. Ultrasonography demonstrated steatosis of the liver and cholecystolithiasis. Liver biopsy revealed steatosis. Activated megakaryopoiesis was seen on bone marrow biopsy. Other investigations were non-contributory, except that lung function tests suggested fibrosis. She refused jejunal biopsy and bronchoscopy. At the end of 1989 frequent vomiting developed with hypoproteinaemia, hypoalbuminaemia, and a low serum carotene. Electrocardiography revealed non-specific ST-T changes. Endoscopy revealed erythematous lesions in the descending duodenum. Biopsy demonstrated infiltration with foamy periodicacid/Schiff (PAS) positive macrophages and Whipple’s disease was suspected. The patient died suddenly in an attack of arrhythmia. Necropsy revealed infiltration of the gut mucosa, mesenteric lymph nodes, and myocardium with PAS-positive macrophages. On electronmicroscopy there were typical microbial bodies in the endothelium of myocardial capillaries. An unexpected observation was dense infiltration of the myocardial interstitium with lymphocytes mixed with some eosinophils. This finding was compatible with the histological diagnosis of interstitial lymphocytic myocarditis. Department of Medicine, University Clinics, Institute of Pathology I, Charles University, Prague 2, Czechoslovakia
TOMÀŠ PELECH PŘEMYSL FRIC ALENA HUSLAROVÁ ADAM JIRÁSEK
1. McAllister HA Jr, Fenoglio JJ Jr. Cardiac involvement in Whipple’s disease. Circulation 1975; 52: 152-56. 2. Southern JF, Moscicki RA, Margo C, Dickersin GR, Fallot JT, Bloch KJ. Lymphedema, lymphocytic myocardins, and sarcoid-like granulomatosis: manifestation of Whipple’s disease. JAMA 1989; 261: 1467-70.
Aluminosilicate in
synovial fluid
of
a
dialysed patient.
(A) Scanning electron micrograph of aluminosilicate, (6) and (C) X-ray respectively
maps of aluminium and silicon,
Interaction between
pethidine and selegiline
SIR,-Dr Zornberg and colleagues’ (Jan 26, p 246) report a serious drug interaction between pethidine (meperidine) and selegiline, a selective inhibitor of monoamine oxidase (MAO) type B. They state that the "Physician’s Desk Reference reports no known drug interactions" with selegiline. The PDR, which adds that clinical experience with the drug is limited, refers the reader to its warning section. There, it is pointed that fatal reactions have occurred when MAO inhibitors have been given in combination with pethidine. It is then quite clearly stated "because the mechanism of interaction between MAOIs and meperidine (pethidine) is unknown, it seems prudent, in general, to avoid this combination". I believe it is wise to read all pertinent drug information presented in a reference book before prescribing the drug.
(two) origin. They had normal renal function and had not received compounds in the preceding months. Synovial fluid was drawn into polypropylene syringes to avoid contamination with silicon. Synovial concentrations of aluminium and silicon, measured by argon plasma emission spectrometry (’Spectrospan V’, Beckman), were significantly higher in the haemodialysis patients: aluminium
out
Drug Topics Magazme, Oradeli, NJ 07649. USA
CYNTHIA STARR
The synovial fluid of six haemodialysis patients and ten controls filtered (Millipore, 0-45 and 5 )-uft). The filter was made conductive by a carbon film laid under a vacuum. It was then studied in a scanning electron microscope (Cambridge S250) with an energy dispersive X-ray microanalysis system (PGT III was
detector).
Amorphous aluminosilicates in synovial fluid in
dialysis-associated arthropathy
SIR,-Aluminium accumulates in the synovial tissue and articular cartilage of long-term haemodialysis patients, especially when there are &bgr;2-microglobulin amyloid deposits.’ This metal is toxic to bone and nervous tissue, and promotes inflammation in rats and rabbits.2 However, its role in the physiopathology of dialysisassociated arthropathy (DAA) is poorly understood. Silicon, which sometimes binds to aluminium, accumulates in the serum of haemodialysis patients.3 We have measured aluminium and silicon concentrations in the synovial fluid of long-term haemodialysis patients with joint complications. The six patients (four men, two women) had been on haemodialysis for 1 5-16 years (mean 10 25 years) and had joint effusions of the knee (five patients) or shoulder (one). Five had DAA, in three cases associated with histologically proven &bgr;2-microglobulin amyloidosis. The controls were fifteen patients with knee effusions of either inflammatory (thirteen) or mechanical
Aluminosilicates were observed on the filters with the synovial fluids of three haemodialysis patients, in one case accompanied by calcium phosphate crystals. The aluminosilicates looked like tiny plates up to 70 pm across (figure). The largest plates, which seemed crystalline, were collected with tweezers and studied with X-ray by the oscillating-crystal method. They turned out to be amorphous In some controls we saw sodium urate crystals or calcium
phosphate, in keeping with the joint disorders of these patients (eg, gout or articular chondrocalcinosis). An aluminosilicate compound was seen in one control, suggesting either contamination despite our precautions or aluminium silicates in a small number of nondialysed patients. The first explanation is the more likely-indeed, two aluminosilicate compounds were also found when distilled water was processed under the same conditions. The X-ray maps of the aluminosilicate compounds from the synovial fluids of the haemodialysis patients showed an apparently homogeneous distribution of silicon and aluminium in the preciptated compounds (figure). This may indicate a true aluminosilicate, though even at the pH of synovial fluid one cannot
555
rule out some co-precipitation of aluminium and silicon oxides and hhydroxides; hydrothermal synthesis of aluminosilicates from synovial fluid should provide the answer. The role of these aluminosilicate deposits in DAA is worth investigating. The deposits could indicate a storage disease (resulting from the accumulation of aluminium and silicon and favoured by the affinity of aluminium for silicon), ageing, tissue destruction, or amyloid deposits with no clinical significance. However, the articular toxicity of aluminium is well known in animals, and silicon may be toxic.3,4 In Alzheimer’s disease there is evidence for involvement of aluminium. Raised intracellular concentrations of both aluminium and silicon have been reported in the neurofibrillary-tangle-bearing neurons,5 and aluminium and silicon have been found as amorphous aluminosilicate at the centre of the senile-plaque core.6 Aluminosilicates may initiate or accelerate the formation of senile plaques and other cellular lesions3 in Alzheimer’s disease and may favour the formation locally of amyloid A4 protein.7 Perhaps in DAA also there is synergy between aluminium2,8 and/or aluminosilicates and &bgr;2-microglobulin fragments that cause amyloid depostis to form joint and bone abnormalities. We thank Prof J. Benoit (Hopital Ambroise Pare, Paris), Dr S. Delons (Centre E. Rist, Paris), and Dr J. L. Fabre (Hôpital St Andre, Metz) for their help, and Mr A. Kohler (scanning microscope services unit, Faculty of Sciences, Vandoeuvre-les-Nancy) for his assistance. URA CNRS 1228 and
Department of Chemistry, Faculty of Medicine, 54505 Vandoeuvre-lès-Nancy, France, Department of Mineral Chemistry, Faculty of Sciences, Vandoeuvre-lès-Nancy, and Centre Viggo Petersen, Hôpital Lariboisière, Paris
P. NETTER J. STEINMETZ P. GILLET M. KESSLER T. BARDIN
P. FENER D. BURNEL A. GAUCHER J. POUREL B. BANNWARTH
1988, i 886-87 2. Netter P, Kessler M, Gaucher A, Bannwarth B. Does aluminium have a pathogenic role m dialysis associated arthropathy? Ann Rheum Dis 1990; 49: 573-75. 3. Hosokawa S, Morinaga M, Nishitani H, Maeda T, Yoshida O. Silicon in chronic hemodialysis patients Trans Am Soc Artif Intern Organs 1987; 33: 260-64. 4. Hershey CO, Ricanati ES, Hershey LA, Vares AW, Lavin PJM, Strain WH. Silicon as a potential uremic neurotoxin. trace elements analysis in patients with renal failure. Neurology 1983; 33: 786-89. 5. Perl DP, Brody AR Alzbeimer’s disease: X-ray spectrometric evidence of aluminium accumulation m neurofibrillary tangle-bearing neurons. Science 1980; 208: 297-99. 6. Candy JM, Oakley AE, Klinowski J, et al Aluminosilicates and senile plaque formation in Alzheimer’s disease. Lancet 1986; i: 354-57. 7. Edwardson JA, Candy JM Aluminium and the pathogenesis of senile plaques in Alzheimer’s disease, Down’s syndrome and chronic renal dialysis. Ann Med 1989; 21: 95-97. 8 Kleinman KS, Cobum JW. Amyloid syndromes associated with haemodialysis. Kidney Int 1989; 35: 567-75
&bgr;2-agonists SIR,-Dr Sears and his colleagues (Dec 8, p 1391) report that evenly spaced doses of fenoterol led to worse "overall control" (a compound function of eight variables) of asthma than fewer doses given irregularly on an as required basis. This might seem to contradict common sense. Clinicians know that patients with deteriorating asthma who are not responding to increased doses of inhaled &bgr;2-agonists do respond to yet higher doses of these agents given by nebuliser or parenterally. However, these observations are necessarily contradictory. patients using an inhaled &bgr;2-agonist regularly show tachyphylaxis then, provided there are spare receptors in bronchial
not
If
smooth
increase in dose will still lead to a maximum response, although the concentration needed to produce a given response will be higher. However, if there are no spare receptors tachyphylaxis will be manifest as a decreased maximum response, which would not be overcome by increased concentrations of &bgr;2-agonist. Are there spare receptors in bronchial smooth muscle? The answer is yes. In-vitro exposure of bronchial smooth muscle strips to 0,-agonists decreases sensitivity 30-fold without decreasing the maximum relaxation to carbachol induced contraction.1 This indicates a considerable receptor reserve-ie, occupancy by agonists of only a fraction of bronchial smooth muscle &bgr;2-adrenoceptors leads to a maximum response.
muscle,
an
If the
worsening control noted by Sears
et
al
was
due
to
tachyphylaxis, increases in dosage would have overcome this. But would this in itself not induce further tachyphylaxis? The control of 0-adrenoceptor regulation is complex, involving receptor phosphorylationsequestration from the cell surface, and alterations in the G-proteins which couple receptors to adenylate cyclase.3 These processes are under feedback control, can be attenuated by corticosteroids,3and are, presumably, saturable. A minority of asthma patients exhibit more than 50% variation in daily peak flow measurement despite intensive treatment with inhaled bronchodilators and corticosteroids, oral steroids, and theophylline.4 Continuous subcutaneous infusion of terbutaline leads to plasma levels averaging 50 nmol/1, which is 10-fold greater than levels found after inhalations and produces impressive improvements that last for years with no evidence of tachyphylaxis.4 That regular low doses of an inhaled &bgr;z-agonist worsened control in patients with mild-to-moderate asthma is not inconsistent with the durable efficacy of continuous subcutaneous terbutaline in more severe asthma, given the R-adrenoceptor reserve of bronchial smooth muscle, the saturability of the physiochemical processes of tachyphylaxis, and the very high levels of (32 agonist achieved with continuous subcutaneous terbutaline. The results reported by Sears et al will, if confirmed, affect management in most cases of asthma. It will be interesting to see if tachyphylaxis to salmeterol emerges, and if increasing the dose overcomes it. Department of Respiratory Medicine, East Birmingham Hospital, Birmingham B9 5ST, UK
JON G. AYRES A. P. SYKES DAVID R. FERRY
BP, Jenne JW Desensitization of isolated bronchial smooth muscle to beta-receptor agonists. J Allergy Clin Immunol 1981; 68: 51-57. 2 Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz RJ. &bgr;-arrestin: a protein that regulates &bgr;-adrenergic fucntion. Science 1990; 248: 1547-50. 3. Davies AO, Lefkowitz RJ. Regulation of beta adrenoceptors by steroid hormones Ann Rev Physiol 1984; 46: 119-30. 4. O’Driscoll BRC, Ruffles SP, Ayres JG, Cochrane GM. Long term treatment of severe asthma with subcutaneous terbutaline. Br J Dis Chest 1988; 82: 360-67 5 Sykes AP, Higgins AS, Ayres JG. Continuous subcutaneous terbutaline is effective in the treatment of brittle asthma by achieving high serum levels. Thorax 1987; 42: 1. Avner
231
SIR,-Dr Sears and his colleagues’ study questions the value of regular inhaled bronchodilator therapy. The results seem convincing, but questions remain. Did the two groups of patients have the same severity of asthma; what about the proportions of intrinsic and allergic asthma; was the percentage of patients on inhaled steroids the same in the two groups? Only 4 of the 64 patients were on inhaled cromoglycate-a very small proportion in our experience. Fenoterol has more adverse effects than other &bgr;2-agonists such as salbutamol, as Dr Wong and colleagues show (Dec 8, p 1396), and no study has compared regular and on-demand inhaled bronchodilator therapy with other &bgr;2-agonists. The study was done in New Zealand, where very high death rates from asthma have been reported. We do not know whether the results can be transferred to other countries, where asthma deaths are less common. Before a switch to on-demand bronchodilator therapy in asthma we suggest the following: use salbutamol instead of fenoterol in regular inhaled bronchodilator therapy; and prescribe the lowest
possible dose, never using a p-agonist as regular monotherapy;l recommend regular 0-agonist therapy only in combination with anti-inflammatory agents, and this means, in our view, combining cromoglycate and inhaled steroids; study the new long-acting &bgr;2-agonists in the same way as the New Zealand study. University Children’s Hospital, D-1000 Berlin 19, Germany 1.
B. NIGGEMANN U. WAHN
van Essen-Zandvliet, Neijens HJ. Effect of long-term treatment with inhaled corticosteroids and beta-agonists on the bronchial responsiveness in children with asthma. J Allergy Clin Immunol 1987; 79: 653-59.
Kerrebijn KF,
***These two letters were inadvertently omitted from the group published in our issue of Feb 2, to which Dr Taylor and Professor Sears replied in the Feb 16 Lancet (p 426).
erythrocyte sedimentation rate was raised and she had microcytic anaemia, increased serum alkaline phosphatase, and a positive faecal occult blood test. Osteoporosis of the axial skeleton was present. Ultrasonography demonstrated steatosis of the liver and cholecystolithiasis. Liver biopsy revealed steatosis. Activated megakaryopoiesis was seen on bone marrow biopsy. Other investigations were non-contributory, except that lung function tests suggested fibrosis. She refused jejunal biopsy and bronchoscopy. At the end of 1989 frequent vomiting developed with hypoproteinaemia, hypoalbuminaemia, and a low serum carotene. Electrocardiography revealed non-specific ST-T changes. Endoscopy revealed erythematous lesions in the descending duodenum. Biopsy demonstrated infiltration with foamy periodicacid/Schiff (PAS) positive macrophages and Whipple’s disease was suspected. The patient died suddenly in an attack of arrhythmia. Necropsy revealed infiltration of the gut mucosa, mesenteric lymph nodes, and myocardium with PAS-positive macrophages. On electronmicroscopy there were typical microbial bodies in the endothelium of myocardial capillaries. An unexpected observation was dense infiltration of the myocardial interstitium with lymphocytes mixed with some eosinophils. This finding was compatible with the histological diagnosis of interstitial lymphocytic myocarditis. Department of Medicine, University Clinics, Institute of Pathology I, Charles University, Prague 2, Czechoslovakia
TOMÀŠ PELECH PŘEMYSL FRIC ALENA HUSLAROVÁ ADAM JIRÁSEK
1. McAllister HA Jr, Fenoglio JJ Jr. Cardiac involvement in Whipple’s disease. Circulation 1975; 52: 152-56. 2. Southern JF, Moscicki RA, Margo C, Dickersin GR, Fallot JT, Bloch KJ. Lymphedema, lymphocytic myocardins, and sarcoid-like granulomatosis: manifestation of Whipple’s disease. JAMA 1989; 261: 1467-70.
Aluminosilicate in
synovial fluid
of
a
dialysed patient.
(A) Scanning electron micrograph of aluminosilicate, (6) and (C) X-ray respectively
maps of aluminium and silicon,
Interaction between
pethidine and selegiline
SIR,-Dr Zornberg and colleagues’ (Jan 26, p 246) report a serious drug interaction between pethidine (meperidine) and selegiline, a selective inhibitor of monoamine oxidase (MAO) type B. They state that the "Physician’s Desk Reference reports no known drug interactions" with selegiline. The PDR, which adds that clinical experience with the drug is limited, refers the reader to its warning section. There, it is pointed that fatal reactions have occurred when MAO inhibitors have been given in combination with pethidine. It is then quite clearly stated "because the mechanism of interaction between MAOIs and meperidine (pethidine) is unknown, it seems prudent, in general, to avoid this combination". I believe it is wise to read all pertinent drug information presented in a reference book before prescribing the drug.
(two) origin. They had normal renal function and had not received compounds in the preceding months. Synovial fluid was drawn into polypropylene syringes to avoid contamination with silicon. Synovial concentrations of aluminium and silicon, measured by argon plasma emission spectrometry (’Spectrospan V’, Beckman), were significantly higher in the haemodialysis patients: aluminium
out
Drug Topics Magazme, Oradeli, NJ 07649. USA
CYNTHIA STARR
The synovial fluid of six haemodialysis patients and ten controls filtered (Millipore, 0-45 and 5 )-uft). The filter was made conductive by a carbon film laid under a vacuum. It was then studied in a scanning electron microscope (Cambridge S250) with an energy dispersive X-ray microanalysis system (PGT III was
detector).
Amorphous aluminosilicates in synovial fluid in
dialysis-associated arthropathy
SIR,-Aluminium accumulates in the synovial tissue and articular cartilage of long-term haemodialysis patients, especially when there are &bgr;2-microglobulin amyloid deposits.’ This metal is toxic to bone and nervous tissue, and promotes inflammation in rats and rabbits.2 However, its role in the physiopathology of dialysisassociated arthropathy (DAA) is poorly understood. Silicon, which sometimes binds to aluminium, accumulates in the serum of haemodialysis patients.3 We have measured aluminium and silicon concentrations in the synovial fluid of long-term haemodialysis patients with joint complications. The six patients (four men, two women) had been on haemodialysis for 1 5-16 years (mean 10 25 years) and had joint effusions of the knee (five patients) or shoulder (one). Five had DAA, in three cases associated with histologically proven &bgr;2-microglobulin amyloidosis. The controls were fifteen patients with knee effusions of either inflammatory (thirteen) or mechanical
Aluminosilicates were observed on the filters with the synovial fluids of three haemodialysis patients, in one case accompanied by calcium phosphate crystals. The aluminosilicates looked like tiny plates up to 70 pm across (figure). The largest plates, which seemed crystalline, were collected with tweezers and studied with X-ray by the oscillating-crystal method. They turned out to be amorphous In some controls we saw sodium urate crystals or calcium
phosphate, in keeping with the joint disorders of these patients (eg, gout or articular chondrocalcinosis). An aluminosilicate compound was seen in one control, suggesting either contamination despite our precautions or aluminium silicates in a small number of nondialysed patients. The first explanation is the more likely-indeed, two aluminosilicate compounds were also found when distilled water was processed under the same conditions. The X-ray maps of the aluminosilicate compounds from the synovial fluids of the haemodialysis patients showed an apparently homogeneous distribution of silicon and aluminium in the preciptated compounds (figure). This may indicate a true aluminosilicate, though even at the pH of synovial fluid one cannot
555
rule out some co-precipitation of aluminium and silicon oxides and hhydroxides; hydrothermal synthesis of aluminosilicates from synovial fluid should provide the answer. The role of these aluminosilicate deposits in DAA is worth investigating. The deposits could indicate a storage disease (resulting from the accumulation of aluminium and silicon and favoured by the affinity of aluminium for silicon), ageing, tissue destruction, or amyloid deposits with no clinical significance. However, the articular toxicity of aluminium is well known in animals, and silicon may be toxic.3,4 In Alzheimer’s disease there is evidence for involvement of aluminium. Raised intracellular concentrations of both aluminium and silicon have been reported in the neurofibrillary-tangle-bearing neurons,5 and aluminium and silicon have been found as amorphous aluminosilicate at the centre of the senile-plaque core.6 Aluminosilicates may initiate or accelerate the formation of senile plaques and other cellular lesions3 in Alzheimer’s disease and may favour the formation locally of amyloid A4 protein.7 Perhaps in DAA also there is synergy between aluminium2,8 and/or aluminosilicates and &bgr;2-microglobulin fragments that cause amyloid depostis to form joint and bone abnormalities. We thank Prof J. Benoit (Hopital Ambroise Pare, Paris), Dr S. Delons (Centre E. Rist, Paris), and Dr J. L. Fabre (Hôpital St Andre, Metz) for their help, and Mr A. Kohler (scanning microscope services unit, Faculty of Sciences, Vandoeuvre-les-Nancy) for his assistance. URA CNRS 1228 and
Department of Chemistry, Faculty of Medicine, 54505 Vandoeuvre-lès-Nancy, France, Department of Mineral Chemistry, Faculty of Sciences, Vandoeuvre-lès-Nancy, and Centre Viggo Petersen, Hôpital Lariboisière, Paris
P. NETTER J. STEINMETZ P. GILLET M. KESSLER T. BARDIN
P. FENER D. BURNEL A. GAUCHER J. POUREL B. BANNWARTH
1988, i 886-87 2. Netter P, Kessler M, Gaucher A, Bannwarth B. Does aluminium have a pathogenic role m dialysis associated arthropathy? Ann Rheum Dis 1990; 49: 573-75. 3. Hosokawa S, Morinaga M, Nishitani H, Maeda T, Yoshida O. Silicon in chronic hemodialysis patients Trans Am Soc Artif Intern Organs 1987; 33: 260-64. 4. Hershey CO, Ricanati ES, Hershey LA, Vares AW, Lavin PJM, Strain WH. Silicon as a potential uremic neurotoxin. trace elements analysis in patients with renal failure. Neurology 1983; 33: 786-89. 5. Perl DP, Brody AR Alzbeimer’s disease: X-ray spectrometric evidence of aluminium accumulation m neurofibrillary tangle-bearing neurons. Science 1980; 208: 297-99. 6. Candy JM, Oakley AE, Klinowski J, et al Aluminosilicates and senile plaque formation in Alzheimer’s disease. Lancet 1986; i: 354-57. 7. Edwardson JA, Candy JM Aluminium and the pathogenesis of senile plaques in Alzheimer’s disease, Down’s syndrome and chronic renal dialysis. Ann Med 1989; 21: 95-97. 8 Kleinman KS, Cobum JW. Amyloid syndromes associated with haemodialysis. Kidney Int 1989; 35: 567-75
&bgr;2-agonists SIR,-Dr Sears and his colleagues (Dec 8, p 1391) report that evenly spaced doses of fenoterol led to worse "overall control" (a compound function of eight variables) of asthma than fewer doses given irregularly on an as required basis. This might seem to contradict common sense. Clinicians know that patients with deteriorating asthma who are not responding to increased doses of inhaled &bgr;2-agonists do respond to yet higher doses of these agents given by nebuliser or parenterally. However, these observations are necessarily contradictory. patients using an inhaled &bgr;2-agonist regularly show tachyphylaxis then, provided there are spare receptors in bronchial
not
If
smooth
increase in dose will still lead to a maximum response, although the concentration needed to produce a given response will be higher. However, if there are no spare receptors tachyphylaxis will be manifest as a decreased maximum response, which would not be overcome by increased concentrations of &bgr;2-agonist. Are there spare receptors in bronchial smooth muscle? The answer is yes. In-vitro exposure of bronchial smooth muscle strips to 0,-agonists decreases sensitivity 30-fold without decreasing the maximum relaxation to carbachol induced contraction.1 This indicates a considerable receptor reserve-ie, occupancy by agonists of only a fraction of bronchial smooth muscle &bgr;2-adrenoceptors leads to a maximum response.
muscle,
an
If the
worsening control noted by Sears
et
al
was
due
to
tachyphylaxis, increases in dosage would have overcome this. But would this in itself not induce further tachyphylaxis? The control of 0-adrenoceptor regulation is complex, involving receptor phosphorylationsequestration from the cell surface, and alterations in the G-proteins which couple receptors to adenylate cyclase.3 These processes are under feedback control, can be attenuated by corticosteroids,3and are, presumably, saturable. A minority of asthma patients exhibit more than 50% variation in daily peak flow measurement despite intensive treatment with inhaled bronchodilators and corticosteroids, oral steroids, and theophylline.4 Continuous subcutaneous infusion of terbutaline leads to plasma levels averaging 50 nmol/1, which is 10-fold greater than levels found after inhalations and produces impressive improvements that last for years with no evidence of tachyphylaxis.4 That regular low doses of an inhaled &bgr;z-agonist worsened control in patients with mild-to-moderate asthma is not inconsistent with the durable efficacy of continuous subcutaneous terbutaline in more severe asthma, given the R-adrenoceptor reserve of bronchial smooth muscle, the saturability of the physiochemical processes of tachyphylaxis, and the very high levels of (32 agonist achieved with continuous subcutaneous terbutaline. The results reported by Sears et al will, if confirmed, affect management in most cases of asthma. It will be interesting to see if tachyphylaxis to salmeterol emerges, and if increasing the dose overcomes it. Department of Respiratory Medicine, East Birmingham Hospital, Birmingham B9 5ST, UK
JON G. AYRES A. P. SYKES DAVID R. FERRY
BP, Jenne JW Desensitization of isolated bronchial smooth muscle to beta-receptor agonists. J Allergy Clin Immunol 1981; 68: 51-57. 2 Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz RJ. &bgr;-arrestin: a protein that regulates &bgr;-adrenergic fucntion. Science 1990; 248: 1547-50. 3. Davies AO, Lefkowitz RJ. Regulation of beta adrenoceptors by steroid hormones Ann Rev Physiol 1984; 46: 119-30. 4. O’Driscoll BRC, Ruffles SP, Ayres JG, Cochrane GM. Long term treatment of severe asthma with subcutaneous terbutaline. Br J Dis Chest 1988; 82: 360-67 5 Sykes AP, Higgins AS, Ayres JG. Continuous subcutaneous terbutaline is effective in the treatment of brittle asthma by achieving high serum levels. Thorax 1987; 42: 1. Avner
231
SIR,-Dr Sears and his colleagues’ study questions the value of regular inhaled bronchodilator therapy. The results seem convincing, but questions remain. Did the two groups of patients have the same severity of asthma; what about the proportions of intrinsic and allergic asthma; was the percentage of patients on inhaled steroids the same in the two groups? Only 4 of the 64 patients were on inhaled cromoglycate-a very small proportion in our experience. Fenoterol has more adverse effects than other &bgr;2-agonists such as salbutamol, as Dr Wong and colleagues show (Dec 8, p 1396), and no study has compared regular and on-demand inhaled bronchodilator therapy with other &bgr;2-agonists. The study was done in New Zealand, where very high death rates from asthma have been reported. We do not know whether the results can be transferred to other countries, where asthma deaths are less common. Before a switch to on-demand bronchodilator therapy in asthma we suggest the following: use salbutamol instead of fenoterol in regular inhaled bronchodilator therapy; and prescribe the lowest
possible dose, never using a p-agonist as regular monotherapy;l recommend regular 0-agonist therapy only in combination with anti-inflammatory agents, and this means, in our view, combining cromoglycate and inhaled steroids; study the new long-acting &bgr;2-agonists in the same way as the New Zealand study. University Children’s Hospital, D-1000 Berlin 19, Germany 1.
B. NIGGEMANN U. WAHN
van Essen-Zandvliet, Neijens HJ. Effect of long-term treatment with inhaled corticosteroids and beta-agonists on the bronchial responsiveness in children with asthma. J Allergy Clin Immunol 1987; 79: 653-59.
Kerrebijn KF,
***These two letters were inadvertently omitted from the group published in our issue of Feb 2, to which Dr Taylor and Professor Sears replied in the Feb 16 Lancet (p 426).
