- Email: [email protected]
Betel-nut chewing and asthma
1134
2. Keane WF, Kasiske BL. Hyperlipidemia in the nephrotic syndrome. N Engl J Med 1990; 323: 603-04. 3. Mallick NP, Short CD. The nephrotic syndrome and ischemic heart disease. Nephron 1981; 25: 54-57. 4. Diamond JR, Karnovsky MJ. Focal and segmental glomerulosclerosis: analogies to atherosclerosis. Kidney Int 1988; 33: 917-24. 5. Moorhead JF, Wheeler DC, Varghese Z. Glomerular structures and lipids in progressive renal disease. Am J Med 1989; 87: 12-20. 6. Schmitz PG, Kasiske B, O’Donnell MP, Keane F. Lipids and progressive renal injury. Semin Nephrol 1989; 9: 354-69. 7. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502. 8. Maroni BJ, Steinman TI, Mitch WE. A method for estimating nitrogen intake in patients with chronic renal failure. Kidney Int 1985; 27: 58-65. 9. Sacks FM, Castelli WP, Donner A, Kass EH. Plasma lipids and lipoproteins in vegetarians and controls. N Engl J Med 1975; 292: 1148-51. 10. Meinertz H, Nilausen K, Faegerman O. Soy protein and casein in cholesterol-enriched diets: effects on plasma lipoproteins in normolipidemic subjects. Am J Clin Nutr 1989; 50: 786-93. 11. Connor WE. Dietary fiber—nostrum or critical nutrient? N Engl J Med 1990; 322: 193-95. 12. Klahr S, Buerkert J, Purkerson ML. Role of dietary factors in the progression of chronic renal disease. Kidney Int 1983; 24: 579-87. 13. Kaysen GA, Jones H Jr, Martin V, Hutchison FN. A low-protein diet restricts albumin synthesis in nephrotic rats. J Clin Invest 1989; 83: 1623-29. 14. D’Amico G, Remuzzi G, Maschio G, et al. Effects of dietary proteins and lipids in patients with membranous nephropathy and nephrotic syndrome. Clin Nephrol 1991; 6: 237-42. 15. Kasiske BL, Velosa JA, Halstenson CE, La Belle P, Langendorfer A, Keane WF. The effects of lovastatin in hyperlipidemic patients with the nephrotic syndrome. Am J Kidney Dis 1990; 15: 8-15. 16. Shaefer EJ, Levy RI, Ernst ND, Van Sant FD, Brewer HB. The effects of low cholesterol, high polyunsaturated fat, and low fat diets on plasma lipid and lipoprotein cholesterol levels in normal and hypercholesterolemic subjects. Am J Clin Nutr 1981; 34: 1758-63.
Betel-nut L. M.
P, Ringrose H, Taylor R, Zimmet P, Sloman G. High density lipoprotein apoprotein variability in a biracial population.
17. Nestel
Arteriosclerosis 1983; 3: 132-37.
JH, Katan MB, Grott PHE, Havekes LM, Hautvast JGAJ. lipoproteins of healthy persons fed a low-fat diet or a polyunsaturated fat diet for three months: a comparison of two cholesterol-lowering diets. Atherosclerosis 1982; 42: 205-19. Kestin M, Clifton P, Belling GB, Nestel PJ. n-3 fatty acids of marine origin lower systolic blood pressure and triglycerides but raise LDL cholesterol compared with n-3 and n-6 fatty acids from plants. AmJ
18. Brussaard Serum
19.
Clin Nutr 1990; 51: 1028-34. 20. Kontessis P, Jones S, Dodds R, et al. Renal, metabolic and hormonal responses to ingestion of animal and vegetable proteins. Kidney Int
1990; 38: 136-44. Levey AS, Berg RL, Gassman JJ, Hall FM, Wlaker WG. Creatinine filtration, secretion and excretion during progressive renal disease. Kidney Int 1989; 36 (suppl 27): 73S-80S. 22. Feehally J, Baker F, Walls J. Dietary protein manipulation in experimental nephrotic syndrome. Nephron 1988; 50: 247-52. 23. Kaysen GA, Gambertoglio J, Jimenez I, Jones H, Hutchison FN. Effect of dietary protein intake on albumin homeostasis in nephrotic patients. Kidney Int 1986; 29: 572-77. 24. Rosenberg ME, Swanson JE, Thomas BL, Hostetter TH. Glomerular 21.
and hormonal responses to dietary protein intake in human renal disease. Am J Physiol 1987; 253: F1083-90. 25. Remuzzi A, Perticucci E, Battaglia C, D’Amico G, Gentile MG, Remuzzi G. Low-protein diet and glomerular size-selective function in membranous glomerulopathy. Am J Kidney Dis 1991; 17: 317-22. 26. Kaysen GA, Al Bander H, Martin V, Jones H Jr, Hutchinson FN. Branched-chain amino acids augment neither albumin synthesis nor albuminuria in nephrotic rats. Am J Physiol 1991; 260: F177-84. 27. Keane WF, Mulkahy WS, Kasiske BL, Kim Y, O’Donnell P. Hyperlipidemia and progressive renal disease. Kidney Int 1991; 39 (suppl 31): 41S-48S. 28. Schreiner GF. Dietary treatment of immunologically mediated renal disease. Kidney Int 1991; 39 (suppl 31): 49S-56S. 29. Barcelli UO. Effect of dietary prostaglandin precursors on the progression of renal disease in animals. Kidney Int 1991; 39 (suppl 31): 57S-64S.
chewing and asthma
R. F. H. TAYLOR N. AL-JARAD E. JOHN D. M. CONROY N. C. BARNES
Two Asian patients admitted to hospital with acute severe asthma had been chewing betel nut immediately before the attacks. Arecoline, a cholinergic alkaloid, is a major constituent of Areca catechu (betel) nut and causes the euphoric effects. We sought an association between betel-nut chewing and bronchoconstriction in asthmatic
In the UK, the rate of hospital admission for acute asthma is higher among Asians than among other groups in the population; betel-nut chewing may be one of several factors that affect asthma control and
severity of attacks. Lancet 1992; 339: 1134-36.
patients. In vitro, arecoline caused dose-related contraction of human bronchial smooth-muscle strips, with one-tenth the potency of methacholine. In a doubleblind challenge study, inhalation of arecoline caused bronchoconstriction in six of seven asthmatic patients and one of six healthy subjects; methacholine caused bronchoconstriction in all the asthmatic patients and in five controls. The geometric mean concentrations of arecoline and methacholine that caused 20% falls in the forced expiratory volume in 1 s (PC20 FEV1) in the asthmatic subjects were 5·2 mg/ml and 1·6 mg/ml, respectively. We then studied four Bengali asthmatic patients, regular users of betel nut, during a betel-nut challenge. Three showed no adverse effects, but one showed a 30% fall in FEV1 by 150 min after chewing; the effect was
reproducible.
Introduction The betel-nut quid consists of areca nut wrapped in a betel vine leaf (Piper betle) smeared with a paste of burnt lime. Betel is chewed by an estimated 200 million people world wide1 for the euphoric effects, which are derived from arecoline, a cholinergic agent and volatile alkaloid. Arecoline increases the amount of acetylcholine in the brain;2 the betel leaf contains a phenolic volatile oil with a central-stimulant action and small traces of an alkaloid, reputed to have cocaine-like properties. It is likely that arecoline is absorbed from the buccal mucosa, since the quid (pahn) is chewed for up to an hour, between two and twelve times a day. ADDRESSES London Chest Hospital, London (R. F H. Taylor, MRCP, N Al-Jarad, MRCP, L M E John, N C Barnes, MRCP) and Royal College of Surgeons of England, London, UK (D M. Conroy, PhD). Correspondence to Dr R. F. H. Taylor, Department of Cystic Fibrosis, Royal Brompton Hospital, Sydney Street, London SW3
6NP, UK
1135
Our attention was drawn to this habit when we noted that two patients, both frequent attenders at our hospital with acute asthma, had been chewing betel immediately before and during attacks. We set out to establish whether there is betel-nut chewing and any association between bronchoconstriction in asthma.
PC20 FEV, FOR METHACHOLINE AND ARECOLINE IN ASTHMATIC AND HEALTHY SUBJECTS
Subjects and methods Case-reports Patient 1-A 44-year-old Bangladeshi woman who had lived in the UK for 10 years, was admitted to hospital with acute severe asthma eight times during 15 months. Between admissions, she was maintained on 5-20 mg prednisone daily and nebulised salbutamol, 5 mg four times daily. When she was stable, spirometry confirmed a severe obstructive defect, with a forced expiratory volume in 1 s (FEVJ 38% of predicted;4 the FEV1 increased by 16% after inhalation of 200 (ig salbutamol, confirming parrial reversibility. Serial peak expiratory flow recordings (PEFR) were unreliable owing to her poor coordination. Four different doctors admitting the patient on separate occasions noted that she had been chewing betel immediately before the attack. Once she had a respiratory arrest on arrival at the hospital and remnants of a betel quid, which were not obstructing her airway, were taken from her mouth before successful resuscitation. Patient 2-This 47-year-old man from Bangladesh, who had lived in the UK for 20 years, had been chewing betel nut immediately before he was admitted with acute asthma. He was receiving no treatment at the time. PEFR rose from 3601/min to 440 l/min with bronchodilators. Later, at an outpatient visit, he admitted that he chewed betel regularly and noticed that his asthma deteriorated afterwards. Patients 1 and 2 have been lost to follow-up and were not included in our challenge tests.
ln-vitro studies The activity and potency of arecoline and methacholine were measured in strips of guineapig trachea and lung parenchyma and human bronchus super-perfused at 5 ml/min in a cascade system with Tyrode solution at 37°C.5 Agonists were administered as bolus injections into the super-perfusing fluid.
Response to inhaled arecoline and methacholine Four women and three men, aged 20-40 years, with mild asthma (baseline FEV! > 70% predicted), and four men and two women, aged 22-40 years, without asthma, were challenged on 2 separate days with arecoline and methacholine in a double-blind way. No patient chewed betel, smoked tobacco, or had had a respiratory infection within the previous 6 weeks. Solutions of serial equimolar doubling concentrations (1-32 mg/ml for methacholine and 1-2-384 mg/ml for arecoline) stored at 4°C were warmed to room temperature before use. Aerosols were generated by a Wright nebuliser containing 3 ml test solution and driven by compressed air at a flow rate of 8 I/min. The subject inhaled solutions of increasing concentration through a face mask for 2 min, breathing tidally through the open mouth. A dry bellows spirometer (Vitalograph, UK) was used to measure FEVin triplicate at baseline and 1 .5 min, 45 min, 75 min, and 105 min after inhalation of the saline diluent and all test solutions. Each subject did the two tests at the same time of day and baseline FEV, values did not vary by more than 5% on each study day. The challenge was discontinued when the FEV! had fallen by 20% of the prechallenge, postsaline value. The drug
dose that induced a 20% reduction in FEV! (PC2o FEV1) was determined by interpolation from the logarithmic dose-response curve. Synthetic arecoline hydrobromide (Sigma, Poole, Dorset, UK) and methacholine chloride were used; purity and identification were verified by the Northwest Thames Regional Quality Control Centre (Edgware General Hospital, London, UK).
Betel-nut challenges Four Bengali patients with stable asthma aged 50-61years, three and one woman, who regularly chew betel, were observed
men
NR= no response to
maximum
dose of test solution.
during and after they each chewed a single quid. The patients were taking only inhaled bronchodilators and inhaled steroids. Each betel-nut challenge consisted of a quarter of a crushed nut (about 20 mg arecoline), wrapped in a P betle leaf, smeared with lime paste; after 30 min, the quid remnants were either removed from the mouth or swallowed. Spirometry was done at baseline and 15 min, 30 min, 60 min, 120 min, 150 min, and 180 min after the end of quid chewing; all values were recorded by one observer (L.M.E.J.). Patients were asked not to chew betel during the 48 h before the challenge or to use bronchodilators during the 6 h beforehand; inhaled steroids were continued. The duration and quantity of the betel chew were the smallest used by any of the four patients. All patients admitted to chewing betel for euphoric effects and reported that prolonged betel chewing induced coughing or wheezing. One patient inhales salbutamol prophylactically before he chews betel. All subjects gave informed consent; the clinical studies were approved by the ethics committee of the National Heart and Chest Hospitals.
Results In vitro, arecoline and methacholine induced dose-related contractions of all three tissues studied. Arecoline had the same potency as methacholine in the guineapig trachea but was only one-tenth as potent in the guineapig lung parenchymal and human bronchial preparations. Both arecoline and methacholine caused dose-related bronchoconstriction in six of the asthmatic patients challenged. The geometric means of the PC20 FEV values were 5-2 mg/ml and 1-6 mg/ml for arecoline and Patient 7 showed methacholine, respectively. bronchoconstriction with methacholine but did not respond to the maximum concentration of arecoline (38-4 mg/ml; see table). Five of the healthy controls responded to methacholine (geometric mean PC20 FEV1 5-4 mg/ml). However, only one control subject showed bronchoconstriction with arecoline (PC2o FEV1 34-2 mg/ml). One of the four patients who took part in the betel-nut challenge, a 60-year-old man (baseline FEV1 83% predicted), complained of chest tightness 90 min after he had finished chewing the betel nut. At 150 min FEV had fallen to 70% of baseline; this fall was reversed with 200 µg inhaled salbutamol. When the challenge was repeated 5 days later, the same pattern of bronchoconstriction was observed. At the same time of day, a week later, this patient’s
1136
self-recorded PEFR values fluctuated between 450 and 5001/min during 5 h in which no bronchodilators were used; thus the 30% fall in FEV1 after betel-nut chewing was not within the limits of variation when he was untreated. The other patients showed no significant change in FEV during the study.
Discussion
sought to answer the question of whether betel-nut chewing exacerbates asthma by means of in-vitro and in-vivo studies to assess the bronchoconstrictive properties of arecoline, a major constituent of the nut. In vitro, We
arecoline caused dose-related contraction of human bronchial preparations, and inhalation of nebulised arecoline led to substantial bronchoconstriction in asthmatic patients. Arecoline was a less potent bronchoconstrictor than methacholine: the lack of response in all but one healthy subject to inhaled arecoline. points to a low risk of bronchoconstriction in healthy subjects who chew betel. One of the four asthmatic patients who underwent betel-nut challenge showed severe bronchoconstriction. The lack of response in the other three could be due to variability in the individual response to arecoline, the short duration and low arecoline dose used for the challenge, and protection afforded by continuation of inhaled steroids. Bronchoconstriction did not occur until 90 min after the betel-nut challenge, by contrast with the immediate effects after the nebulised arecoline challenges. This finding suggests that arecoline from chewed betel nut is absorbed through the buccal mucosa and exerts its bronchoconstrictive properties from the circulation. The chemical structure of arecoline and methacholine are similar,6 although arecoline lacks a quaternary ammonium ion, so is more lipophilic and penetrates cell membranes more easily.6 Arecoline has identical actions to pilocarpine, another muscarinic agent, and when taken by mouth arecoline has mild systemic cholinergic effects ;6,7 however, to our knowledge, bronchoconstriction has not been
reported previously. Betel nut also contains trace amounts of guvacoline, a related alkaloid; hydrolysis of arecoline and guvacoline to the acids, arecaidine and guvacine, is catalysed by lime.8 Tannins and glycerides of lauric acid and oleic acid are also found in the nut, and the leaf contains eugonol, an aromatic unsaturated volatile substance;8,9 one or more of these agents may also have bronchoconstrictive properties. Betel-nut chewing is associated with malignant disorders of the buccal mucosa. 9,10 By contrast with the bronchoconstriction associated with allergic reactions to foods, such as soybean flour,il green coffee beans, and castor beans,12 that in response to betel-nut chewing seems to be chemically mediated by cholinergic stimulation. Similarly, capsaicin, a component of chilli peppers, which are used widely in Asian cooking, is an airway irritant that causes bronchoconstriction partly by a cholinergic vagal reflex.13 The distribution and prevalence of betel-nut chewing among the Asian population in the UK is unknown, although the practice is common among Bengali patients attending the London Chest Hospital. In the UK, the rate of hospital admission for asthma is higher among the Asian population than among other groups,14 which suggests that asthma in Asians may be less well controlled. There are likely to be many factors causing the difference in asthma control or severity; our study suggests that betel-nut chewing may be one of these factors.
We thank Miss M. Toufexis, Miss R. Gillman, Mr E. Pauley, and Dr B. 0.
Hughes (pharmacy departments of London Chest and Royal Brompton Hospitals) for their help, and Dr D. M. Geddes for helpful comments and suggestions. REFERENCES times encyclopedia of recreational drugs. New York: Stonehill, 1978: 80-82. 2. Holmstedt B, Lindgren G. Arecoline, nicotine and related compounds: tremorgenic activity and effect upon brain acetylcholine. Ann N Y Acad Sci 1967; 142: 126. 3. Nadkarni AK. Indian materia medica, 3rd ed, vol 1. Dhootapapesahwar Prakashan: Panvel, 1954. 4. Cotes JE. Lung function: assessment and application in medicine. Oxford: Blackwell, 1979. 5. Samhoun MN, Conroy DM, Piper PJ. Pharmacological profile of leukotriene E4, N-AceE4 and four of their novel and oxidative metabolites in airways of guinea-pigs and man in vitro. Br J Pharmacol 1989; 98: 1406-12. 6. Juptner H. Clinical and experimental observations on the effects of intense betel chewing among the natives of the Tribriand Islands, New Guinea. Trop Dis Bull 1968; 65: 1176. 7. Voller RL. Cholinomimetic drugs. In: Diploma JR, ed. Drill’s pharmacology in medicine, 4th ed. New York: Blakiston, 1971: 591-92. 8. Reynolds JEF, ed. Martindale: the extra pharmacopoeia, 29th ed. London: Pharmaceutical Press, 1989: 49. 9. Muir CS, Kirk R. Betel, tobacco and cancer of the mouth. Br J Cancer 1960; 14: 587-608. 10. Muir CS. Oral cavity. In: Raven RW, Roe FJC, eds. The prevention of cancer. London: Butterworth, 1967: 75-81. 11. Bush R, Schroeckenstein D, Meier-Davis S, Balmes J, Rempel D. Soybean flour asthma: detection of allergens by immunoblotting. J Allergy Clin Immunol 1988; 82: 251-55. 12. Thomas KE, Trigg CJ, Baxter PJ, et al. Factors relating to the development of respiratory symptoms in coffee process workers. Br J Indust Med 1991; 48: 314-22. 13. Fuller RW, Dixon CMS, Barnes PJ. Bronchoconstrictor response to inhaled capsaicin in humans. J Appl Physiol 1985; 58: 1080-84. 14. Ayres JG. Acute asthma in Asian patients; hospital admissions and durations of stay in a district with a high immigrant populations. Br J Dis Chest 1986; 80: 242-48. 1.
High
REPORTS
SHORT
Does pralidoxime affect outcome of management in acute
organophosphorus poisoning? H.
J. DE SILVA
R. WIJEWICKREMA
N. SENANAYAKE
organophosphorus (OP) poisoning is usually treated with atropine plus cholinesterase Acute
reactivators such as oximes, but controlled trials to assess the efficacy of oximes in OP poisoning have not been done. A period when the acetyl cholinesterase reactivator pralidoxime chloride was not available in Sri Lanka gave us the opportunity to compare atropine alone for treatment of moderate to severe OP poisoning (21 patients) with atropine plus pralixodime (24 patients). Outcome, as assessed clinically, was similar in the two groups. These results cast doubt on the necessity of cholinesterase reactivators for treatment of acute OP poisoning. Lancet 1992; 339: 1136-38.
In Sri Lanka, poisoning with cholinesterase-inhibiting compounds such as organophosphorus (OP) insecticides accounts for over 10 000 hospital admissions, with about 1000 deaths, annually.1 Although occupational exposure
2. Keane WF, Kasiske BL. Hyperlipidemia in the nephrotic syndrome. N Engl J Med 1990; 323: 603-04. 3. Mallick NP, Short CD. The nephrotic syndrome and ischemic heart disease. Nephron 1981; 25: 54-57. 4. Diamond JR, Karnovsky MJ. Focal and segmental glomerulosclerosis: analogies to atherosclerosis. Kidney Int 1988; 33: 917-24. 5. Moorhead JF, Wheeler DC, Varghese Z. Glomerular structures and lipids in progressive renal disease. Am J Med 1989; 87: 12-20. 6. Schmitz PG, Kasiske B, O’Donnell MP, Keane F. Lipids and progressive renal injury. Semin Nephrol 1989; 9: 354-69. 7. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502. 8. Maroni BJ, Steinman TI, Mitch WE. A method for estimating nitrogen intake in patients with chronic renal failure. Kidney Int 1985; 27: 58-65. 9. Sacks FM, Castelli WP, Donner A, Kass EH. Plasma lipids and lipoproteins in vegetarians and controls. N Engl J Med 1975; 292: 1148-51. 10. Meinertz H, Nilausen K, Faegerman O. Soy protein and casein in cholesterol-enriched diets: effects on plasma lipoproteins in normolipidemic subjects. Am J Clin Nutr 1989; 50: 786-93. 11. Connor WE. Dietary fiber—nostrum or critical nutrient? N Engl J Med 1990; 322: 193-95. 12. Klahr S, Buerkert J, Purkerson ML. Role of dietary factors in the progression of chronic renal disease. Kidney Int 1983; 24: 579-87. 13. Kaysen GA, Jones H Jr, Martin V, Hutchison FN. A low-protein diet restricts albumin synthesis in nephrotic rats. J Clin Invest 1989; 83: 1623-29. 14. D’Amico G, Remuzzi G, Maschio G, et al. Effects of dietary proteins and lipids in patients with membranous nephropathy and nephrotic syndrome. Clin Nephrol 1991; 6: 237-42. 15. Kasiske BL, Velosa JA, Halstenson CE, La Belle P, Langendorfer A, Keane WF. The effects of lovastatin in hyperlipidemic patients with the nephrotic syndrome. Am J Kidney Dis 1990; 15: 8-15. 16. Shaefer EJ, Levy RI, Ernst ND, Van Sant FD, Brewer HB. The effects of low cholesterol, high polyunsaturated fat, and low fat diets on plasma lipid and lipoprotein cholesterol levels in normal and hypercholesterolemic subjects. Am J Clin Nutr 1981; 34: 1758-63.
Betel-nut L. M.
P, Ringrose H, Taylor R, Zimmet P, Sloman G. High density lipoprotein apoprotein variability in a biracial population.
17. Nestel
Arteriosclerosis 1983; 3: 132-37.
JH, Katan MB, Grott PHE, Havekes LM, Hautvast JGAJ. lipoproteins of healthy persons fed a low-fat diet or a polyunsaturated fat diet for three months: a comparison of two cholesterol-lowering diets. Atherosclerosis 1982; 42: 205-19. Kestin M, Clifton P, Belling GB, Nestel PJ. n-3 fatty acids of marine origin lower systolic blood pressure and triglycerides but raise LDL cholesterol compared with n-3 and n-6 fatty acids from plants. AmJ
18. Brussaard Serum
19.
Clin Nutr 1990; 51: 1028-34. 20. Kontessis P, Jones S, Dodds R, et al. Renal, metabolic and hormonal responses to ingestion of animal and vegetable proteins. Kidney Int
1990; 38: 136-44. Levey AS, Berg RL, Gassman JJ, Hall FM, Wlaker WG. Creatinine filtration, secretion and excretion during progressive renal disease. Kidney Int 1989; 36 (suppl 27): 73S-80S. 22. Feehally J, Baker F, Walls J. Dietary protein manipulation in experimental nephrotic syndrome. Nephron 1988; 50: 247-52. 23. Kaysen GA, Gambertoglio J, Jimenez I, Jones H, Hutchison FN. Effect of dietary protein intake on albumin homeostasis in nephrotic patients. Kidney Int 1986; 29: 572-77. 24. Rosenberg ME, Swanson JE, Thomas BL, Hostetter TH. Glomerular 21.
and hormonal responses to dietary protein intake in human renal disease. Am J Physiol 1987; 253: F1083-90. 25. Remuzzi A, Perticucci E, Battaglia C, D’Amico G, Gentile MG, Remuzzi G. Low-protein diet and glomerular size-selective function in membranous glomerulopathy. Am J Kidney Dis 1991; 17: 317-22. 26. Kaysen GA, Al Bander H, Martin V, Jones H Jr, Hutchinson FN. Branched-chain amino acids augment neither albumin synthesis nor albuminuria in nephrotic rats. Am J Physiol 1991; 260: F177-84. 27. Keane WF, Mulkahy WS, Kasiske BL, Kim Y, O’Donnell P. Hyperlipidemia and progressive renal disease. Kidney Int 1991; 39 (suppl 31): 41S-48S. 28. Schreiner GF. Dietary treatment of immunologically mediated renal disease. Kidney Int 1991; 39 (suppl 31): 49S-56S. 29. Barcelli UO. Effect of dietary prostaglandin precursors on the progression of renal disease in animals. Kidney Int 1991; 39 (suppl 31): 57S-64S.
chewing and asthma
R. F. H. TAYLOR N. AL-JARAD E. JOHN D. M. CONROY N. C. BARNES
Two Asian patients admitted to hospital with acute severe asthma had been chewing betel nut immediately before the attacks. Arecoline, a cholinergic alkaloid, is a major constituent of Areca catechu (betel) nut and causes the euphoric effects. We sought an association between betel-nut chewing and bronchoconstriction in asthmatic
In the UK, the rate of hospital admission for acute asthma is higher among Asians than among other groups in the population; betel-nut chewing may be one of several factors that affect asthma control and
severity of attacks. Lancet 1992; 339: 1134-36.
patients. In vitro, arecoline caused dose-related contraction of human bronchial smooth-muscle strips, with one-tenth the potency of methacholine. In a doubleblind challenge study, inhalation of arecoline caused bronchoconstriction in six of seven asthmatic patients and one of six healthy subjects; methacholine caused bronchoconstriction in all the asthmatic patients and in five controls. The geometric mean concentrations of arecoline and methacholine that caused 20% falls in the forced expiratory volume in 1 s (PC20 FEV1) in the asthmatic subjects were 5·2 mg/ml and 1·6 mg/ml, respectively. We then studied four Bengali asthmatic patients, regular users of betel nut, during a betel-nut challenge. Three showed no adverse effects, but one showed a 30% fall in FEV1 by 150 min after chewing; the effect was
reproducible.
Introduction The betel-nut quid consists of areca nut wrapped in a betel vine leaf (Piper betle) smeared with a paste of burnt lime. Betel is chewed by an estimated 200 million people world wide1 for the euphoric effects, which are derived from arecoline, a cholinergic agent and volatile alkaloid. Arecoline increases the amount of acetylcholine in the brain;2 the betel leaf contains a phenolic volatile oil with a central-stimulant action and small traces of an alkaloid, reputed to have cocaine-like properties. It is likely that arecoline is absorbed from the buccal mucosa, since the quid (pahn) is chewed for up to an hour, between two and twelve times a day. ADDRESSES London Chest Hospital, London (R. F H. Taylor, MRCP, N Al-Jarad, MRCP, L M E John, N C Barnes, MRCP) and Royal College of Surgeons of England, London, UK (D M. Conroy, PhD). Correspondence to Dr R. F. H. Taylor, Department of Cystic Fibrosis, Royal Brompton Hospital, Sydney Street, London SW3
6NP, UK
1135
Our attention was drawn to this habit when we noted that two patients, both frequent attenders at our hospital with acute asthma, had been chewing betel immediately before and during attacks. We set out to establish whether there is betel-nut chewing and any association between bronchoconstriction in asthma.
PC20 FEV, FOR METHACHOLINE AND ARECOLINE IN ASTHMATIC AND HEALTHY SUBJECTS
Subjects and methods Case-reports Patient 1-A 44-year-old Bangladeshi woman who had lived in the UK for 10 years, was admitted to hospital with acute severe asthma eight times during 15 months. Between admissions, she was maintained on 5-20 mg prednisone daily and nebulised salbutamol, 5 mg four times daily. When she was stable, spirometry confirmed a severe obstructive defect, with a forced expiratory volume in 1 s (FEVJ 38% of predicted;4 the FEV1 increased by 16% after inhalation of 200 (ig salbutamol, confirming parrial reversibility. Serial peak expiratory flow recordings (PEFR) were unreliable owing to her poor coordination. Four different doctors admitting the patient on separate occasions noted that she had been chewing betel immediately before the attack. Once she had a respiratory arrest on arrival at the hospital and remnants of a betel quid, which were not obstructing her airway, were taken from her mouth before successful resuscitation. Patient 2-This 47-year-old man from Bangladesh, who had lived in the UK for 20 years, had been chewing betel nut immediately before he was admitted with acute asthma. He was receiving no treatment at the time. PEFR rose from 3601/min to 440 l/min with bronchodilators. Later, at an outpatient visit, he admitted that he chewed betel regularly and noticed that his asthma deteriorated afterwards. Patients 1 and 2 have been lost to follow-up and were not included in our challenge tests.
ln-vitro studies The activity and potency of arecoline and methacholine were measured in strips of guineapig trachea and lung parenchyma and human bronchus super-perfused at 5 ml/min in a cascade system with Tyrode solution at 37°C.5 Agonists were administered as bolus injections into the super-perfusing fluid.
Response to inhaled arecoline and methacholine Four women and three men, aged 20-40 years, with mild asthma (baseline FEV! > 70% predicted), and four men and two women, aged 22-40 years, without asthma, were challenged on 2 separate days with arecoline and methacholine in a double-blind way. No patient chewed betel, smoked tobacco, or had had a respiratory infection within the previous 6 weeks. Solutions of serial equimolar doubling concentrations (1-32 mg/ml for methacholine and 1-2-384 mg/ml for arecoline) stored at 4°C were warmed to room temperature before use. Aerosols were generated by a Wright nebuliser containing 3 ml test solution and driven by compressed air at a flow rate of 8 I/min. The subject inhaled solutions of increasing concentration through a face mask for 2 min, breathing tidally through the open mouth. A dry bellows spirometer (Vitalograph, UK) was used to measure FEVin triplicate at baseline and 1 .5 min, 45 min, 75 min, and 105 min after inhalation of the saline diluent and all test solutions. Each subject did the two tests at the same time of day and baseline FEV, values did not vary by more than 5% on each study day. The challenge was discontinued when the FEV! had fallen by 20% of the prechallenge, postsaline value. The drug
dose that induced a 20% reduction in FEV! (PC2o FEV1) was determined by interpolation from the logarithmic dose-response curve. Synthetic arecoline hydrobromide (Sigma, Poole, Dorset, UK) and methacholine chloride were used; purity and identification were verified by the Northwest Thames Regional Quality Control Centre (Edgware General Hospital, London, UK).
Betel-nut challenges Four Bengali patients with stable asthma aged 50-61years, three and one woman, who regularly chew betel, were observed
men
NR= no response to
maximum
dose of test solution.
during and after they each chewed a single quid. The patients were taking only inhaled bronchodilators and inhaled steroids. Each betel-nut challenge consisted of a quarter of a crushed nut (about 20 mg arecoline), wrapped in a P betle leaf, smeared with lime paste; after 30 min, the quid remnants were either removed from the mouth or swallowed. Spirometry was done at baseline and 15 min, 30 min, 60 min, 120 min, 150 min, and 180 min after the end of quid chewing; all values were recorded by one observer (L.M.E.J.). Patients were asked not to chew betel during the 48 h before the challenge or to use bronchodilators during the 6 h beforehand; inhaled steroids were continued. The duration and quantity of the betel chew were the smallest used by any of the four patients. All patients admitted to chewing betel for euphoric effects and reported that prolonged betel chewing induced coughing or wheezing. One patient inhales salbutamol prophylactically before he chews betel. All subjects gave informed consent; the clinical studies were approved by the ethics committee of the National Heart and Chest Hospitals.
Results In vitro, arecoline and methacholine induced dose-related contractions of all three tissues studied. Arecoline had the same potency as methacholine in the guineapig trachea but was only one-tenth as potent in the guineapig lung parenchymal and human bronchial preparations. Both arecoline and methacholine caused dose-related bronchoconstriction in six of the asthmatic patients challenged. The geometric means of the PC20 FEV values were 5-2 mg/ml and 1-6 mg/ml for arecoline and Patient 7 showed methacholine, respectively. bronchoconstriction with methacholine but did not respond to the maximum concentration of arecoline (38-4 mg/ml; see table). Five of the healthy controls responded to methacholine (geometric mean PC20 FEV1 5-4 mg/ml). However, only one control subject showed bronchoconstriction with arecoline (PC2o FEV1 34-2 mg/ml). One of the four patients who took part in the betel-nut challenge, a 60-year-old man (baseline FEV1 83% predicted), complained of chest tightness 90 min after he had finished chewing the betel nut. At 150 min FEV had fallen to 70% of baseline; this fall was reversed with 200 µg inhaled salbutamol. When the challenge was repeated 5 days later, the same pattern of bronchoconstriction was observed. At the same time of day, a week later, this patient’s
1136
self-recorded PEFR values fluctuated between 450 and 5001/min during 5 h in which no bronchodilators were used; thus the 30% fall in FEV1 after betel-nut chewing was not within the limits of variation when he was untreated. The other patients showed no significant change in FEV during the study.
Discussion
sought to answer the question of whether betel-nut chewing exacerbates asthma by means of in-vitro and in-vivo studies to assess the bronchoconstrictive properties of arecoline, a major constituent of the nut. In vitro, We
arecoline caused dose-related contraction of human bronchial preparations, and inhalation of nebulised arecoline led to substantial bronchoconstriction in asthmatic patients. Arecoline was a less potent bronchoconstrictor than methacholine: the lack of response in all but one healthy subject to inhaled arecoline. points to a low risk of bronchoconstriction in healthy subjects who chew betel. One of the four asthmatic patients who underwent betel-nut challenge showed severe bronchoconstriction. The lack of response in the other three could be due to variability in the individual response to arecoline, the short duration and low arecoline dose used for the challenge, and protection afforded by continuation of inhaled steroids. Bronchoconstriction did not occur until 90 min after the betel-nut challenge, by contrast with the immediate effects after the nebulised arecoline challenges. This finding suggests that arecoline from chewed betel nut is absorbed through the buccal mucosa and exerts its bronchoconstrictive properties from the circulation. The chemical structure of arecoline and methacholine are similar,6 although arecoline lacks a quaternary ammonium ion, so is more lipophilic and penetrates cell membranes more easily.6 Arecoline has identical actions to pilocarpine, another muscarinic agent, and when taken by mouth arecoline has mild systemic cholinergic effects ;6,7 however, to our knowledge, bronchoconstriction has not been
reported previously. Betel nut also contains trace amounts of guvacoline, a related alkaloid; hydrolysis of arecoline and guvacoline to the acids, arecaidine and guvacine, is catalysed by lime.8 Tannins and glycerides of lauric acid and oleic acid are also found in the nut, and the leaf contains eugonol, an aromatic unsaturated volatile substance;8,9 one or more of these agents may also have bronchoconstrictive properties. Betel-nut chewing is associated with malignant disorders of the buccal mucosa. 9,10 By contrast with the bronchoconstriction associated with allergic reactions to foods, such as soybean flour,il green coffee beans, and castor beans,12 that in response to betel-nut chewing seems to be chemically mediated by cholinergic stimulation. Similarly, capsaicin, a component of chilli peppers, which are used widely in Asian cooking, is an airway irritant that causes bronchoconstriction partly by a cholinergic vagal reflex.13 The distribution and prevalence of betel-nut chewing among the Asian population in the UK is unknown, although the practice is common among Bengali patients attending the London Chest Hospital. In the UK, the rate of hospital admission for asthma is higher among the Asian population than among other groups,14 which suggests that asthma in Asians may be less well controlled. There are likely to be many factors causing the difference in asthma control or severity; our study suggests that betel-nut chewing may be one of these factors.
We thank Miss M. Toufexis, Miss R. Gillman, Mr E. Pauley, and Dr B. 0.
Hughes (pharmacy departments of London Chest and Royal Brompton Hospitals) for their help, and Dr D. M. Geddes for helpful comments and suggestions. REFERENCES times encyclopedia of recreational drugs. New York: Stonehill, 1978: 80-82. 2. Holmstedt B, Lindgren G. Arecoline, nicotine and related compounds: tremorgenic activity and effect upon brain acetylcholine. Ann N Y Acad Sci 1967; 142: 126. 3. Nadkarni AK. Indian materia medica, 3rd ed, vol 1. Dhootapapesahwar Prakashan: Panvel, 1954. 4. Cotes JE. Lung function: assessment and application in medicine. Oxford: Blackwell, 1979. 5. Samhoun MN, Conroy DM, Piper PJ. Pharmacological profile of leukotriene E4, N-AceE4 and four of their novel and oxidative metabolites in airways of guinea-pigs and man in vitro. Br J Pharmacol 1989; 98: 1406-12. 6. Juptner H. Clinical and experimental observations on the effects of intense betel chewing among the natives of the Tribriand Islands, New Guinea. Trop Dis Bull 1968; 65: 1176. 7. Voller RL. Cholinomimetic drugs. In: Diploma JR, ed. Drill’s pharmacology in medicine, 4th ed. New York: Blakiston, 1971: 591-92. 8. Reynolds JEF, ed. Martindale: the extra pharmacopoeia, 29th ed. London: Pharmaceutical Press, 1989: 49. 9. Muir CS, Kirk R. Betel, tobacco and cancer of the mouth. Br J Cancer 1960; 14: 587-608. 10. Muir CS. Oral cavity. In: Raven RW, Roe FJC, eds. The prevention of cancer. London: Butterworth, 1967: 75-81. 11. Bush R, Schroeckenstein D, Meier-Davis S, Balmes J, Rempel D. Soybean flour asthma: detection of allergens by immunoblotting. J Allergy Clin Immunol 1988; 82: 251-55. 12. Thomas KE, Trigg CJ, Baxter PJ, et al. Factors relating to the development of respiratory symptoms in coffee process workers. Br J Indust Med 1991; 48: 314-22. 13. Fuller RW, Dixon CMS, Barnes PJ. Bronchoconstrictor response to inhaled capsaicin in humans. J Appl Physiol 1985; 58: 1080-84. 14. Ayres JG. Acute asthma in Asian patients; hospital admissions and durations of stay in a district with a high immigrant populations. Br J Dis Chest 1986; 80: 242-48. 1.
High
REPORTS
SHORT
Does pralidoxime affect outcome of management in acute
organophosphorus poisoning? H.
J. DE SILVA
R. WIJEWICKREMA
N. SENANAYAKE
organophosphorus (OP) poisoning is usually treated with atropine plus cholinesterase Acute
reactivators such as oximes, but controlled trials to assess the efficacy of oximes in OP poisoning have not been done. A period when the acetyl cholinesterase reactivator pralidoxime chloride was not available in Sri Lanka gave us the opportunity to compare atropine alone for treatment of moderate to severe OP poisoning (21 patients) with atropine plus pralixodime (24 patients). Outcome, as assessed clinically, was similar in the two groups. These results cast doubt on the necessity of cholinesterase reactivators for treatment of acute OP poisoning. Lancet 1992; 339: 1136-38.
In Sri Lanka, poisoning with cholinesterase-inhibiting compounds such as organophosphorus (OP) insecticides accounts for over 10 000 hospital admissions, with about 1000 deaths, annually.1 Although occupational exposure