Lung disease in farmers C.P.W. WARREN, MB, FRCP[C]

Lung diseases in farmers attributable to their occupation Include (a) farmer's lung, caused by exposure to mouldy hay, (b) the asthma caused by exposure to grain dust and (c) silo-filler's disease. Their prevalence in Canada is unknown. Farmer's lung results from inhalation of mould spores in hay; the mechanism is immunologic. The exact cause and mechanism of grain dust asthma are unknown but may be immunologic. Silo-filler's disease is caused by the toxic effects of inhaled nitrogen dioxide.

cases of asthma after exposure to wheat rust (Puccinia graminis). What is now known as farmer's lung was first described by Campbell' in 1932 in England: five farmers had dyspnea and pulmonary infiltrates after exposure to wet hay from which white mould dust arose. To grain dust asthma and farmer's lung as respiratory hazards of farming, Lowry and Schuman4 in 1956 added silo-filler's disease. The following review examines lung disease in farmers, with an emphasis on Canadian workers.

Chez les fermiers les maladies pulmonaires occasionn6es par leur m6tier peuvent .tre (a) Ia maladie du poumon du fermier, causee par l'exposition au foin moisi, (b) l'asthme occasionne par Ia pousslere de grain et (c) Ia pneumopathologle de l'ensileur. Leur prevalence au Canada est inconnue. La cause de Ia maladie du poumon du fermier est l'inspiration des spores de Ia moisissure dans le foin; le m6canisme est immunologique. La cause exacte et le mecanisme de I'asthme occasionne par Ia poussiere de grain sont inconnus mais ii est possible qu'ils soient immunologiques. La cause de Ia pneumopathologie de l'ensileur est l'effet toxique d'avoir inspire I'azote bioxyde.

Farmer's lung: extrinsic allergic alveolitis

In 1713 Ramazzini' observed that grain handlers and farmers of the Po valley were troubled by lung diseases. The first modern mention of lung disease in farmers is attributed to Cadham1 in Winnipeg in 1924; he reported three From the respiratory section, department of medicine, University of Manitoba and the clinical investigation unit, St. Boniface General Hospital, Winnipeg Reprint requests to: Dr. C.P.W. Warren, Clinical investigation unit, St. Boniface General Hospital, 409 Tache Ave., Winnipeg, Man. R2H 2A6

Etiologic aspects Hargreave' has reviewed extrinsic allergic alveolitis, of which farmer's lung due to mould inhalation is one type, but he concentrated on bird fancier's lung, in which the immunologic reactions have been studied more fully. Farmer's lung has been detected in several Canadian . but its prevalence is unknown. In the United States a prevalence of 3 % among farmers has been reported from Wyoming,9 whereas in Scotland10 and England11 rates of up to 8.6 and 9.6%, respectively, have been given. The disease is more common in wetter climates, where damp hay ferments and heats, and moulds grow. The spores of these moulds may be inhaled in prodigious numbers: 10'/m' was the count in the air of one barn.12 In the 1960s Williams1' showed that the reaction in the lungs occurred some hours after inhalation of the mouldy hay dust, that it occurred in the peripheral parts of the lung and that it was accompanied by a systemic febrile reaction. Pepys'4 observed an association with serum antibodies precipitated

by extracts of mouldy hay. He then showed that thermophilic actinomycetes - in particular Micropolyspora faeni and sometimes Thermoactinomyces vulgaris - were the responsible moulds. Antibodies against these moulds were found in 80% Gf patients with farmer's lung but, since they were also found in 20% of healthy farmers, they indicated only exposure to the mould. Detection of such antibodies should be considered diagnostic only in the appropriate clinical context. Pepys'4 believed that the disease is the result of an antigen (the mould)antibody reaction that activates complement, producing an Arthus reaction. However, the presence of granulomas in lung biopsy specimens and of precipitins in healthy people led others to suspect that cellular lymphocyte-mediated hypersensitivity is involved. Recent studies of pigeon-breeder's lung15 and animal models have confirmed that cellular hypersensitivity is more likely to be the responsible mechanism. As yet, cellular hypersensitivity has not been demonstrated in farmer's lung' and precipitin detection is still the only immunologic means of identifying the problem. The moulds have a nonspecific irritant effect on the skin and so cannot be used for skin testing.

Clinical features and lung function (Tables I and II) Acute disease: In the classic case, 3 to 4 hours after exposure to the mould the farmer experiences cough, dyspnea, fever, chills, myalgia and malaise. Crepitations are audible in the lung and leukocytosis is detected. The chest radiograph reveals reticular linear densities or small nodules or both, as Zylak and colleagues'6 have described in their review of the alveolitis of bird fancier's lung. In the acute phase areas of conCMA JOURNAL/FEBRUARY 19, 1977/VOL. 116 391

solidation due to alveolar filling may appear, as in viral or bacterial pneumonia. The clinician may be misled by an apparent response of the disease to treatment with antibiotics; the improvement is actually due to the removal of the sick farmer from his work. Relapse may occur on return to work and should alert the physician to obtain a work history, asking specifically about exposure to mouldy hay or grain. The disease has also been reported in nonfarming Torontonians who rode for exercise and were exposed to hay at the stable.17 In the acute phase lung function tests reveal loss of lung volume, little or no impairment of gas flow, reduced compliance and ventilation-perfusion imbalance resulting in hypoxemia and impaired gas transfer.'. Chronic disease: This problem may be more difficult to pin down: systemic symptoms of fatigue, weight loss and malaise may dominate, and a nonproductive cough be the sole respiratory symptom. Dyspnea can be attributed to malaise. In fact in one such farmer, who had a normal chest radiograph, neurosis had been diagnosed. The pa-

tient improved on the psychiatric ward but relapsed after returning to work; the chest radiograph was then abnormal. Lung function testing would have shown what was happening. The disease may also develop insidiously and become chronic, producing permanent dyspnea. All patients with chronic lung disease, particularly pulmonary alveolar fibrosis, should be questioned closely about their environment. In the chronic phase the changes in lung function are varied, with hyperinflation, reduced gas flow and increased compliance in some patients, and "stiff" lungs and restricted volume in others. These changes have been studied in pigeon-breeder's lung18 and have been observed in patients in Manitoba.'9 In Manitoba the disease is uncommon in smokers.2 A study of farmers in the United Kingdom has shown that precipitins against M. faeni are twice as common in nonsmokers.21 This aspect of the disease needs further investigation if these observations are substantiated elsewhere. Laboratory investigation Once the physician has been alerted

Table I-Summary of clinical features of lung disease in farmers Features Farmer's lung Grain dust asthma Symptoms Cough, dyspnea, Cough, tightness in fever chest (fever) Signs Crepitations Wheeze Time of onset after exposure

3- 4 hours

Silo-filler's disease Cough, dyspnea Crepitations

Immediate and 4 hours Immediate; with recovery, relapse after some weeks

Table Il-Summary of results of investigation of lung disease in farmers Area of investigation Farmer's lung Grain dust asthma Silo-filler's disease Chest radiograph Widespread nodular Normal Diffuse miliary and linear shadows nodular shadowing Lung function Acute Restriction Hyperinflation 1st phase, restriction Normal airflow Airway obstruction 2nd phase, obstruction Chronic Restrictive or emphysematous Responsible agent Inhaled mould spores Crude grain dust Nitrogen dioxide Skin tests Nonspocific Maybe spocific Negative Serum precipitins

Positive

Negative

Pathologic features Cellular infiltration Unknown of alveolar and bronchiolar walls with formation of granulomas and giant cells

392 CMA JOURNAL/FEBRUARY 19, 1977/VOL. 116

Negative Bronchiolitis obliterans

by the patient's history of exposure to a wet harvest, hay lying in the fields or mouldy hay or grain, the patient's serum should be studied by immunodiffusion for precipitating antibodies against M. faeni or the related T. vulgaris or Thermomonospora viridis. These antibodies have been found in some Canadian patients.'8 Their detection in a patient with the appropriate clinical features is sufficient. Inhalation challenge will confirm their significance but is usually unnecessary. The changes in symptoms and lung function subsequent to inhalation of mouldy hay are summarized in Fig. 1 Some hours after inhalation of the hay extract the 1-second forced expiratory volume (FEy,) and vital capacity (VC) decrease equally, indicating restrictive lung disease. Lung biopsy should not be necessary; besides, the histologic changes may not be specific for the disease and do not identify its cause. Antibodies against M. faeni, T. vulgaris and T. viridis are not found in the serum of Manitobans with farmer's lung. However, from the hay of one patient Aspergiltus glaucus was cultured by Drs. S. Parker and K. Tse of the University of Manitoba; antibodies against this organism have been detected in 14 patients with farmer's lung and 12% of farmers entering hospital. Whether it is the agent responsible for farmer's lung in Manitoba is as yet undecided. Certainly the dry climate of the Prairies may not provide appropriate growth conditions for thermophilic actinomycetes, so another mould could be involved. Allergic alveolitis due to Aspergillus has been22 reported in two ofin thea farmer in Wisconsin, other Canadian studies6'8 and in malt workers in Scotland.23 This suggests that more than the standard farmer's LUNG FIR4CTION 5, YC

COUGH,DY5PNEA, IEADACHE. C.8LLS, MYALGIA

A. FEY1

I CHALLENGE A.IA.DY HAY

4.J TEMP. 3 3 37 WBC iGi .jYOYAL

0

1

2 3 HOURS

4

5

24

FIG. 1-Effects of inhalation of mouldy hay extract on lung function (vital capacity [VCJ and 1-second forced expfratory volume [FEy,] in litres), temperature (C) and leukocyte count (WBC, total and neutrophils [NSJ, x 10./l).

farmer's lung in Canada. Prognosis It is difficult when one first sees a patient with farmer's lung to forecast the natural history of the disease for that individual. Although death has occurred in the acute phase,. most patients recover spontaneously. It has been suggested that 20% have further attacks or chronic disease.25 Treatment Avoidance of the moulds is paramount, but to stop farming is a radical step and should not be advised hastily. The harvest conditions that provided a medium for the mould to grow may not recur for many seasons in a normally dry climate. Moreover, hay can be dried or help employed to handle the hay. If this fails and there is no deterioration in lung function one might prescribe steroids to prevent attacks;13 it is said that many Welsh farmers use these drugs during haymaking. Steroids probably help recovery in the acute phase and also may help the chronic disease.25 Whether beclomethasone will be useful in the treatment or prevention of this disease is unknown. Cromolyn sodium26 may also help, for there is some evidence it also prevents attacks after inhalation challenge in the laboratory. There is no preparation available for desensitization.

layed (48-hour) skin reactions were observed. Warren, Cherniack and Tse31 examined 17 subjects with respiratory symptoms and occupational exposure to grain dust. Lung function studies showed hyperinflation and airway obstruction. Chest radiographs were normal. The disease seemed to be unlike extrinsic allergic alveolitis and was probably better considered to be asthma. Immediate wheal and flare reactions on skin testing with grain dust extract were observed in half the subjects. Inhalation challenge produced in some subjects an immediate asthmatic reaction (Fig. 2) and in others an immediate reaction followed by a late (4-hour) reaction sometimes accompanied by fever (Fig. 3). This dual reaction, in which FEy1 decreases more than VC, indicating obstruction, has LUNG FUNCTION 4COUGH1 WHEEZE'

3

FEY

2

CHALLENGE GRAIN DUST

Prognosis and treatment

40' TEMP 39 38 37 151 WBC

-

.TOTAL

Grain dust asthma Clinical and etiologic features (Tables I and 11) In 1964 Williams, Skoulas and Merriman27 reported how common respiratory symptoms were in grain elevator agents in Saskatchewan. Several years later Kleinfeld and colleagues28 found the same in grain handlers in the New York docks but blamed cigarettes. In 1973 Tse and associates29 reported that of 68 grain elevator agents in southern Manitoba 50% had a cough with sputum, 28% had dyspnea on exertion and 43% had dyspnea on exposure to grain dust. Moreover, these symptoms were observed in some of the 12 nonsmoking agents. One quarter of the agents experienced flu-like symptoms - "grain fever" - after exposure to grain dust and this was not necessarily related to dyspnea. Skoulas, Williams and Merriman50 concluded from results of skin tests in symptomatic grain elevator agents that hypersensitivity to grain dust and in particular to moulds was common. Testing with Aspergillus extracts produced most of the reactions, and de-

been described in other occupational asthmas by Chan-Yeung and Grzybowski.32 Skin testing with crude extract of grain dust gave positive immediate wheal and flare reactions in those whose lungs reacted to inhalation challenge, suggesting there is an allergic basis to the disease. Grain fever (fever, headache and myalgia) occurred in some of the subjects. In a control group no pulmonary reactions occurred after inhalation of grain dust but the symptoms of grain fever developed in some, which suggests that those symptoms are nonspecific effects of grain dust inhalation. What it is in the grain dust that causes the trouble is not known. In this study skin reactions to moulds were uncommon, although 48-hour reactions were not sought. In general, farmers say barley dust is the worst offender. Many of the features of grain dust asthma are similar to those of byssinosis, in which the mechanism of the reaction to vegetable textile dusts is unclear. Asthma has also been reported in millers and bakers33 and in laboratory workers?. The latter reacted to the wheat weevil (Sitophilus granarius) and may have had allergic alveolitis.

1

2

3

4

5

24

HOURS

FIG. 2-Effects of inhalation of grain dust extract on lung function, temperature and leukocyte count. LUNG FUNCTION TIONThESS, DYSPNEA

COUGH,.SPNEA, TIGHTNESS, I*EA.IE, MALAISE vc

4. FEY1

a CHkJLENGE GRMN DUST '.1

F.-'

TEMP. 39 37

4.-,

The natural history of this disease is unknown because only studies of a population at a specific time have been performed. The impression is that chronic obstruction of airways develops, but this could also be attributed to smoking, which was common among those studied. The men in the industry say that frank asthma has developed in many others who have then left the occupations exposing them to grain dust. Thus surveys of these occupational groups probably miss those who have the disease and have left. Treatment is based on that given to other patients with airway obstruction - for example, sympathomimetic drugs and xanthines. Whether steroids help is unknown, but they might be tried when eosinophilia is detected. Cromolyn sodium has not been studied as therapy for this disease. There is no evidence that hyposensitization works and it is most unlikely that it will until a purer antigen is obtained. Atopic children and those with lung disease should be advised not to enter occupations that would expose them to grain dust.

15 1.IjTOTAL

Silo-filler's disease

p

Etiologic and clinical features (Table I) 1

2 3 HOURS

4

5

24

FIG. 3-Effects of inhalation of grain dust extract oa lung function, temperature and leukocyte count: dual reaction.

Nitrogen dioxide is produced from silage by oxidation of the nitrates of plants or nitrogen-rich soil. The gas begins to fill the silo after a few hours,

GMA JOURNAL/FEBRUARY 19, 1977/VOL. 116 393

reaches a maximum concentration after a few days and disperses after weeks. Inhalation of the gas in sufficient concentration irritates the lungs, forcing the worker to leave the silo. With a higher concentration acute pulmonary edema develops. If this is survived the disease may relapse after some weeks and death is then more common. Otherwise complete recovery can be expected.4'35

Radiologic and physiologic findings (Table II) Radiographs show pulmonary edema in the initial phase but the features resemble those of miliary tuberculosis with nodules in the second phase.35 In the acute phase restriction of lung volume and severe hypoxemia are found but in the second phase the changes are more those of obstruction.36

Treatment and prevention Farm workers must be warned of this danger and silos protected from casual intruders such as children. Nitrogen dioxide is brown, so it should be detected. Management of the disease entails administration of oxygen and steroids and probably assistance with ventilation. One must also be aware that silage at the top of the silo may overheat and be a source of farmer's lung antigens. Conclusion There is substantial evidence that the farmer is exposed to respiratory hazards in his work. In any other occupation involving dust exposure the extent of the problem would be better known. Prevalence studies in Canada are needed. It is important that the mould responsible for farmer's lung and the constituent of grain dust producing the asthma be identified. Only then will it be possible to determine the best way to prevent these two diseases. Silofiller's disease is well understood, but the treatment of such acute lung injuries from noxious gases warrants further study. I thank Dr. Donald W. Rae of Portage la Prairie for his helpful comments. This work was supported by grants from the Canadian Thoracic Society and the St. Boniface General Hospital Research Fund. References 1. RAMAZZINI B: De Morbus Artificum Diatriba 1713, Chicago, U of Chicago Pr, 1940, p 60 2. CADHAM FT:

Asthma due to grain rusts.

JAMA 83: 27, 1924

3. CAMPBELL JM: Acute symptoms following work with hay. Br Med J 2: 1143, 1932 4. Lowwhr T, SCHUMAN LM: "Silo-filler's disease - a syndrome caused by nitrogen dioxide. JAMA 162: 153, 1956

5. HARUREAVE FE: Extrinsic allergic alveolitis. Can Med Assoc J 108: 1150, 1973 6. WARREN WP, MANDL MAJ, ROSE B: Farmer s lung. Can Med Assoc J 100: 699, 1969 7. CHARBONNEAU R, SIEGFRIED C, BERNIER J:

.[ucophAq! Metformin Hydrochloride

Trois observations cliniques r6centes de Ia maladie du poumon du fermier. Union Med Can 99: 1828, 1970

8. GHOSE T, LANDRIGAN P, KILLEEN R, et at: Immunopathological studies in patients with

farmer's lung. Clin Allergy 4: 119, 1974

9. MADSEN D, KLOCK LE, WENZEL FJ, et al:

The prevalence of farmer's lung in an agricultural population. Am Rev Respir Dis 113: 171, 1976

10. GRANT IWB, BLYTH W, WAROROP VE, et al:

II. 12. 13. 14.

Prevalence of farmer's lung in Scotland: a pilot survey. Br Med J 1: 530, 1972 MORGAN DC, SMYTh JT, LISTER RW, Ct al: Chest symptoms and farmer's lung: a community survey. Br J md Med 30: 259, 1973 LACEY J, LACEY ME: Spore concentration in the air of farm buildings. Trans Br Mycol Soc 47 (part 4): 547, 1964 WILLIAMs JV: Inhalation and skin tests with extracts of hay and fungi in patients with farmer's lung. Thorax 18: 182, 1963 Pas'Ys J: Monographs in Allergy, vol 4, Hypersensitivity disease of the lungs due to fungi and organic dusts, New York, Karger, 1969

15. MooRE VL, FINK JN, BARBORIAK JJ, et al:

Immunological events in pigeon breeder's disease. J Allergy Clin Immunol 53: 319, 1974

16. ZYLAK CJ, DYCK DR, WARREN CPW, et al: Hypersensitive lung disease due to avian anti-

gens. Radiology 114: 45, 1975

17. SIMMs JG, RossaR WW: Farmer's lung in

urbanites. Can Fain Phys, Nov 1970, p 69

18. SCHLUETER DP, FINK JN, SOSMAN AJ: Pulmonary function in pigeon breeder's disease. A hypersensitivity pneumonitis. Ann Intern Med 70: 457, 1969 19. WARREN CPW, CHERNIAcK RM, TSE KS: Lung mechanics in allergic alveolitis. I Aller-

gy Clin Immunol 55: 69, 1975

20. WARREN CPW, KLASSEN D: Is extrinsic al-

lergic alveolitis a disease of nonsmokers? in Abstracts of Scientific Session, Canadian Thoracic Society, Annual Meeting, Vancouver, June 21-23, 1976 21. MORGAN DC, SMYTH JT, LISTER RW, et al: Chest symptoms in farming communities with special reference to farmer's lung. Br I md Med 32: 228, 1975 22. PATTERSON R, SOMMERS H, FINK iN: Farmer's lung following inhalation of Aspergillus flavus growing in mouldy corn. Clin Allergy

4: 79, 1974

23. RIDDLE HFV, CHANNELL 5, BLYTH W, et al: Allergic alveolitis in a malt worker. Thorax 23. 271, 1968 24. BARROWCLIFF DF, ARBLASTER PG: Farmer's lung. A study of an early acute fatal case.

Thorax 23: 451, 1968

25. BARBEE RA, CALLIES Q, Dicsia HA, et al: The long term prognosis in farmer's lung.

Am Rev Respir Dis 97: 223, 1968

26. PEPYS J, HARGREAvE FE, CHAN M, et at: Inhibitory effects of disodium cromoglycate on allergen-inhalation tests. Lancet 2: 134,

1968 27. WILLIAMS N, SKOULAS A, MERRIMAN JE: Exposure to grain dust. I. A survey of the

effects. I Occup Med 6: 319, 1964 28. KLEINPELD M, MESSITE J, SwstNcIcKI RE, et al: A clinical and physiological study of grain handlers. Arch Environ Health 16: 380, 1968

29. TSE KS, WARREN P, JANUSZ M, et al: Respiratory abnormalities in workers exposed to grain dust. Arch Environ Health 27: 74, 1973 30. SKOULAS A, WILLIAMS N, MERRIMAN JE: Exposure to grain dust. II. A clinical study of the effects. I Occup Med 6: 359, 1964 31. WARREN P, CHERNIACK RM, TSE KS: Hypersensitivity reactions to gratn dust. I Allergy

Clin Immunol 53: 139, 1974

32. CHAN-YEUNG M, GRZYSOWSKI 5: Occupational

asthma. Can Med Assoc 1 114: 433, 1976 33. KLEINFELD M: A comparative clinical and pulmonary function study of grain handlers and bakers. Ann NY Acad Sci 221: 86, 1974 34. FRANKLAND AW, LUNN JA: Asthma caused by the grain weevil. Br I md Med 22: 157, 1965 MOSKOWITZ 35. RL, LYONS HA, Coma HR: Silo filler's disease. Clinical, physiologic and pathologic study of a patient. Am I Med 36: 457, 1964

Classification GLUCOPHAGE (Metformin Hydrochloride) is an oral antidiabetic agent of the biguanide family.

Pharmacology GLUCOPHAGE is rapidly absorbed and excreted. The product is not metabolized and is excreted unchanged in the urine. GLUCOPHAGE lowers glycemia of the diabetic patient but not that of the normal human. Contrary to sulfonylureas hypoglycemia has never been reported at normal dows in diabetic patients treated with GLUCOPHAGE alone. GLUCOPHAGE promotes an increaw in the peripheral utilization of glucow and its activity is mediated through insulin. Therefore, GLUCOPHAGE improves the K coefficient of glucose assimilation and the coefficient of insulin efficiency. In the obew diabetic with hyperinsulinemia, GLUCOPHAGE is reported to normalize insulin output. This normalizing effect is concurrent to that of glycemia. During experiments, GLUCOPHAGE was shown to be devoid of any notable action in the body apart from its specific metabolic activity. Contrary to sulfonylureas, GLUCOPHAGE does not stimulate the pancreatic secretion of insulin.

Indications 11 Uncomplicated maturity onwt diabetes without ketosis which cannot be controlled by dietary measures alone. 21 GLUCOPHAGE is of particular value for the obew diabetic patient; besides its specific action on diabetes it often promotes an important loss of weight in the obese patient. 31 GLUCOPHAGE can also be administered, alone or combined with sulfonylureas, in the case of primary or secondary sulfonyluwa failure. Combined therapy of GLUCOPHAGE with a sulfonylurea can also be of considerable value in older diabetics where failure with either drug alone has occurred. This combined treatment can sometimes offer an alternative to insulin. The two compounds possibly act synergistically, the sulfonylurea promoting insulin release from pancreatic Beta cells and metformin potentiating its action on peripheral tissues. 41 Insulin adjuvant: The addition of GLUCOPHAGE to a regimen of insulin dependent patients may be of value, as the dow of insulin can often be reduced, in particular when insulin dosage is very high or when the patient is poorly controlled with insulin alone.

Clinical Use GLUCOPHAGE has been utilized throughout the world since 1957. Many clinical studies have demonstrated that GLUCOPHAGE is characterized as follows: As a sole medication GLUCOPHAGE does not bring about hypoglycemia in the normal human. Contrary to sulfonylureas, GLUCOPHAGE promotes loss of weight in the obese subject. Weight reduction is not related to dosage or to any anorexiant effect of the drug. GLUCOPHAGE maintains its activity during long treatment.

Adverse reactions Metallic taste in the mouth, epigastric discomfort, nauwa and vomiting. Diarrhea and skin rashes have been reported infrequently.

Precautions If vomiting occurs withdraw drug momentarily then resume dosage progressively. GLUCOPHAGE should be used cautiously in patients with Addison's diseaw and in subjects intolerant to alcohol or sedatives. As with all other oral hypoglycemic agents, it is recommended that complete physical examinations including hepatic tests, blood counts and ophthalmoscopy be performed on a regular basis, in order to prevent or minimize long or short-term complications. Discontinue treatment in prewnce of a significant elevation of lactic acid levels in the blood.

Contraindications GLUCOPHAGE, used alone, is contraindicated in the case of ketotic, juvenile, insulin-deficient diabetes. GLUCOPHAGE is contraindicated in severe acidosis, coma and very unstable diabetes. During stress periods, such as severe infections, trauma or surgical procedures, a temporary change to insulin treatment is recommended. GLUCOPHAGE is contraindicated during pregnancies, jaundice, severe liver and renal disorders. GLUCOPHAGE is contraindicated where there are pre-existing complications peculiar to diabetes, for example: retinopathy, neuropathy, and nephropathy, and in latent and pm-diabetes.

Dosage and administration GLUCOPHAGE is administered orally. The usual dosage is 0.5 g three times a day, but it may be increased up to 3 to4 gdaily. GLUCOPHAGE is best tolerated with meals. According to the results obtained, it may be required to increase the dose within the given limits); the increase should proceed slowly over a period of todays to avoid gastro-intestinal discomfort.

Availability Tablets 10.5 gI white, round, convex, scored. Bottles of 100 and 500 tablets.

36. BECKLAKE MR, GOLDMAN HI, BOSMAN AR,

et al: The long term effects of exposure to nitrous fumes. Am Rev Tuberc 76: 398, 1957

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HARMACEUTIQUES LTEE . PHARMACEUTICALS valQue. Canada.