and have found that there are fewer recurrences with it than with ampicillin therapy in groups matched for age, infecting organism and severity of disease. SAMUEL E. MCLINN, MD 2645 North Third St. Harrisburg, PA
Lipid research clinic program To the editor: I am writing to obtain your help in contacting all practising physicians in Toronto, Hamilton and surrounding communities about a vital problem that affects all of us. It concerns the success or failure of the coronary primary prevention trial being conducted at St. Michael's, Toronto General and Hamilton General hospitals, and sponsored by the National Heart & Lung Institute, the Ontario Heart Foundation, the University of Toronto and McMaster University. This prevention program is attempting to answer the important question "Can we prevent first heart attacks and prolong life by lowering the plasma cholesterol concentration in men at high risk for coronary heart disease?" The question is important when one remembers that 30% of all deaths in our population are attributable to heart attacks. This program has been in progress since July 1971. Our budget in Toronto and Hamilton approaches $1 million annually and requires a staff of about 75 persons. Multiply this by the costs and effort of 16 other clinics and control centres of various types in North America and you have a good idea of the total cost. Also you can deduce that the scientific community has a large stake in this program and its outcome. The initial hurdle was to find more than 300 men aged 35 to 59 with plasma cholesterol values consistently greater than 270 mg/dl but without coronary heart disease. We are pleased with the response from our colleagues in allowing us to see their patients and in advising their patients to volunteer for the program. More than 50000 men have been screened so far and some 260 eligible men identified. Although we still need help in finding another 125 suitable men, a different and still higher hurdle confronts us now. This concerns the critical issue of adherence to the treatment program by the participating patients. Nonadherence to the study diet or medication by even a small percentage of the patients who have volunteered could compromise the statistical power of the program and spoil our chances of learning anything about the value of lowering the plasma cholesterol concentration. Again we need the active
collaboration of the medical community to safeguard the coronary prevention program. We want every medical doctor in the province to know that what he says to patients and to the public could seriously affect the outcome of this program. Therefore, we wish to explain our position carefully. We are not claiming that lowering the plasma cholesterol concentration will definitely prevent heart attacks. We merely say that there is a theoretical possibility that this is so. The weight of scientific evidence indicates that a high concentration of plasma cholesterol increases the risk of subsequent development of coronary heart disease. However, we do not know whether lowering the concentration in men with hypercholesterolemia will prevent or delay the onset of ischemic heart disease and this is the reason the coronary prevention program is being conducted. We are asking all doctors to support us in their statements to laymen. The program is designed to be satisfactory both to those doctors who believe that lowering the plasma cholesterol concentration may be beneficial and to those who doubt that it may be beneficial. It should at the end give an honest answer to our basic question. The treatment program is without much risk for the participants. The therapeutic diet, containing up to 400 mg of cholesterol per day and having a ratio of polyunsaturated to saturated fatty acids of 1, is conservative and practical for long-term use. It lowers the plasma cholesterol concentration an average of 5% from baseline in outpatients. Cholestyramine, the study medication prescribed to lower plasma cholesterol concentration, has been used for more than 12 years in our clinics in Toronto and Hamilton without serious toxic side effects. Unlike the other "lipid-lowering" medications it is not absorbed systemically and there have been no large-scale studies of its effectiveness in either primary or secondary prevention of coronary heart disease. The patients in the program are monitored in the lipid research clinics every 2 months; they have minor check-ups every 6 months and complete examinations annually. We are careful not to take the place of the family physician. Indeed, we insist on each participant having a personal physician with whom we can communicate information and discuss problems. We only request the privilege of regulating the cholesterol-lowering diet and medication and of monitoring the results. There is an overall net benefit of this program to the medical community in terms of the information we have provided about the thousands of persons screened for hyperlipoproteinemia and
14 CMA JOURNAL/JANUARY 10, 1976/VOL. 114
COMPOSITION: Each uncoated, scored, light tan tablet contains spironolactone, 25 mg. Aldactone offers an entirely new approach to the treatment of essential hypertension, edema and ascites, including resistant states. Aldactone specifically blocks the effects on the kidneys of mineralocorticoids and antagonizes the sodium retaining and water retaining effects of aldosterone which is important in the production of edema. INDICATIONS: Aldactone is indicated in the treatment of edema and ascites of congestive heart failure, hepatic cirrhosis, the nephrotic syndrome, and idiopathic edema as well as that due to malignant effusions especially if not responding well to conventional diuretics. Aldactone is also indicated for lowering blood pressure in essential hypertension, correcting hypokalemic alkalosis in severe hypertension and in the treatment of myasthenia gravis. DOSAGE: Edema-the initial recommended adult dose is one 25 mg tablet four times daily. Rarely a patient may require up to 300 mg per day and others as little as 75 mg per day. If adequate diuresis with Aldactone is not obtained within five days, Aldactizide should be substituted in its usual dosage to obtain the synergistic effect of the spironolactone and the thiazide components. In an occasional patient with severe, resistant edema, it may be necessary to add a glucocorticoid to this combined therapy. In children a dosage providing 1.5 mg of Aldactone per pound of body weight should be employed. Essential hypertension-One tablet four times a day, treatment should be continued at least two weeks. PRECAUTIONS: Other than acute renal insufficiency there are no known contraindications to Aldactone. It should be used judiciously in patients with hyponatremia or hyperkalemia. SIDE EFFECTS: Side effects are mild and infrequent; drowsiness, mental confusion and maculopapular or erythematous eruptions have occurred rarely, subsiding within forty-eight hours on discontinuation of the drug. Gynecomastia and mild androgenic manifestations have also been reported in a few patients. TOXICITY: No reports of fatal overdosage in man. No adverse effects from high dosage in chronic animal studies. Symptoms of Overdosage-True toxicity has not been reported; drowsiness, mental confusion or a maculopapular or erythematous rash has occurred rarely. These manifestations disappear promptly on discontinuance of medication. Hyperkalemia may be exacerbated. Treatment-No specific antidote. No true toxicity has occurred or is expected. Appearance of effects described above require only discontinuance of the drug. For hyperkalemia, reduce potassium intake, administer potassiu m-excreting diuretics, intravenous glucose with regular insulin or oral ion exchange resins. SUPPLY: Bottles of 100, 1,000 and 2,500 tablets. Complete prescribing information available on request.
Aldactone® (SP.RONOLACTONE)
the only specific, competitive aldosterone antagonist for gradual, sustained diuresis with minimal possibility of potassium loss.. .especially indicated for the digitalized patient. Searle Pharmaceuticals Oakv,IIe, Ontario
ease or other severe systemic condi- higher rate of occurrence of the infections; acute mesenteric lymphadenitis, tion, and is a result of the pioneer usually as an acute syndrome of the work of Dr. Lucette Lafleur of Montright iliac fossa; and erythema nodo- real8'9 and the recent work of the nasum, usually associated with other tional reference centre in Toronto.'0 symptoms of Yersinia infection. An additional 125 Y. enterocolitica culThe most frequent clinical form of tures were received from the United Yersinia infection produced only by Y. States for identification and bioseroenterocolitica is acute gastroenteritis. typing; in most instances (115) the orMore than two thirds of the cases are ganisms had been isolated from water in infants and young children. Until specimens during a survey. 1972, human cases of gastroenteritis due to Y. enterocolitica had been either Yersinia pseudotuberculosis sporadic or confined to small family Eight cultures of Yersinia pseudooutbreaks. However, during the past 3 tuberculosis were received for identifiALICK LITTLE, MD Project director years outbreaks have been described in cation and serotyping. In six instances Toronto-McMaster Lipid Research Clinic Project 1 Spadina Cres. Japan,4'5 Finland6 and the United the organisms had been isolated from Toronto, ON States.7 Other clinical conditions pro- the cecal content of swine slaughtered duced by Y. enterocolitica are Reiter's for human consumption (serotype III); Incidence of Yersinia enterocolitica and syndrome, meningitis, abscesses, uri- the other sources were products of a Y. pseudotuberculosis infections in nary tract infections and localized mu- bovine abortion (IB) and autopsy speciCanada; 1975 semiannual report cosal infections. Until recently Y. en- mens from a wild bird (hA). To the editor: The Ontario Ministry of terocolitica was isolated from humans Health instituted at the end of 1974 a or different animal species only; lately Serologic investigation of human national reference service for Yersinia it has been increasingly isolated from yersiniosis enterocolitica and Y. pseudotuberculo- water specimens, vegetables, fruit, milk A total of 230 human serum specisis infections, in collaboration with the and other sources. mens were received for serologic exBelow is a summary of the activity amination for Y. enterocolitica and Laboratory Centre for Disease Control, health protection branch, Health and of the Yersinia national reference pseudotuberculosis. We used a tube agWelfare Canada. The need for this centre for the first half of 1975. glutination technique with a twofold centre became evident with the increas- Yersinia enterocolitica serial dilution of serum and the coming number of Y. enterocolitica infecmonest Yersinia antigens in Canada: tions in humans reported during the Of the 127 Y. enterocolitica cultures Y. enterocolitica 0:3; 5,27; 6,30; and last decade.1 In 1966 there were only received for identification and biosero- 8; and Y. pseudotuberculosis I, II and 23 recorded cases of such infections, typing (Table I) 105 were of human III. Most of the specimens were from but Mollaret reported 642 cases in 1970 origin and 22 of nonhuman origin. In Ontario (205); others were from Queand more than 1000 in 1972.2 The most instances (92) of human infection bec (10), British Columbia (4), Alberta total number of cases reported has organisms had been isolated from fecal (4), New Brunswick (2) and the United now exceeded 5000 and the incidence specimens from patients with acute States (5). Thirteen yielded distinctly of this infection is increasing world- gastroenteritis. Most of the patients positive titres (1:200 or higher); 11 wide. It was first diagnosed in north- were 16 years of age or less and the were positive for Y. enterocolitica 0:3 western Europe and is now common in predominant serotype was Y. enteroco- and two for Y. pseudotuberculosis seroeastern and central Europe, Africa utica indole-negative, 0:3. The other type II. (South Africa and Zaire), Japan and sources were blood (one), abscesses The technique of Yersinia seroaggluNorth America. In Canada in 1974, (two), joint fluid (one), gallbladder tination testing is cumbersome for the data pertaining to the identification and fluid (one) and sputum (one); in seven following reasons: typing of 278 cultures of Y. enteroco- instances the source was not stated. 1. Many Yersinia antigens are reutica were published; 256 of the iso- The 22 nonhuman isolates were from quired for serologic examination. Preplates were from humans and 22 were swine (19), milk (2) and water (1). aration of these antigens is laborious of nonhuman origin.3 The majority of cultures were received because Yersinia cultures tend to beY. enterocolitica and Y. pseudotuber- from Ontario and Quebec. The ap- come "rough" and the "live" merthiolculosis sometimes produce similar clin- parent higher incidence of Y. enterc'- ate-treated antigens we are using have ical pictures, such as the following: colitica infection in these two provinces a relatively short shelf-life. septicemia, occurring mostly in people reflects a greater awareness by physi2. Most of the indole-positive Y. debilitated by diabetes, malignant dis- cians of this organism rather than a enterocolitica strains do not induce deTable 1-Versinia enterocolitica cultures received by national reference centre, January to June 1975 Age of patient Source of (yr) organism Serotypes Origin of No. of culture cultures 16 NS* Feces Othert 0:3 5,27 6,30 8 Others Human Quebec 70 50 3 17 62 8 62 2 2 4 Ontario 27 18 9 24 3 22 2 1 1 1 BritishColumbia 4 3 1 2 2 1 1 2 NovaScotia 2 1 1 2 2 NewBrunswick 1 1 1 1 Newfoundland 1 1 1 1 Total 105 71 14 20 92 13 86 5 5 2 7 Nonhuman Ontario 22 7 2 1 1 11 *NS = Not stated. IBlood, abscesses, joint fluid, gallbladder fluid, sputum or not stated. .O:5; 7,13; 14; 16; 20; or nontypable. the hundreds we have referred to physicians because of hypertriglyceridemia and other diseases excluding them from the program. We welcome any questions from physicians about the coronary prevention program. We want physicians to be fully informed about it. And we do need their understanding and collaboration so that some day all of us can say honestly to our patients "Yes, there is" or "No, there is not any evidence that lowering your cholesterol value will prevent heart attacks."
16 CMA JOURNAL/JANUARY 10, 1976/VOL. 114
Lipid research clinic program To the editor: I am writing to obtain your help in contacting all practising physicians in Toronto, Hamilton and surrounding communities about a vital problem that affects all of us. It concerns the success or failure of the coronary primary prevention trial being conducted at St. Michael's, Toronto General and Hamilton General hospitals, and sponsored by the National Heart & Lung Institute, the Ontario Heart Foundation, the University of Toronto and McMaster University. This prevention program is attempting to answer the important question "Can we prevent first heart attacks and prolong life by lowering the plasma cholesterol concentration in men at high risk for coronary heart disease?" The question is important when one remembers that 30% of all deaths in our population are attributable to heart attacks. This program has been in progress since July 1971. Our budget in Toronto and Hamilton approaches $1 million annually and requires a staff of about 75 persons. Multiply this by the costs and effort of 16 other clinics and control centres of various types in North America and you have a good idea of the total cost. Also you can deduce that the scientific community has a large stake in this program and its outcome. The initial hurdle was to find more than 300 men aged 35 to 59 with plasma cholesterol values consistently greater than 270 mg/dl but without coronary heart disease. We are pleased with the response from our colleagues in allowing us to see their patients and in advising their patients to volunteer for the program. More than 50000 men have been screened so far and some 260 eligible men identified. Although we still need help in finding another 125 suitable men, a different and still higher hurdle confronts us now. This concerns the critical issue of adherence to the treatment program by the participating patients. Nonadherence to the study diet or medication by even a small percentage of the patients who have volunteered could compromise the statistical power of the program and spoil our chances of learning anything about the value of lowering the plasma cholesterol concentration. Again we need the active
collaboration of the medical community to safeguard the coronary prevention program. We want every medical doctor in the province to know that what he says to patients and to the public could seriously affect the outcome of this program. Therefore, we wish to explain our position carefully. We are not claiming that lowering the plasma cholesterol concentration will definitely prevent heart attacks. We merely say that there is a theoretical possibility that this is so. The weight of scientific evidence indicates that a high concentration of plasma cholesterol increases the risk of subsequent development of coronary heart disease. However, we do not know whether lowering the concentration in men with hypercholesterolemia will prevent or delay the onset of ischemic heart disease and this is the reason the coronary prevention program is being conducted. We are asking all doctors to support us in their statements to laymen. The program is designed to be satisfactory both to those doctors who believe that lowering the plasma cholesterol concentration may be beneficial and to those who doubt that it may be beneficial. It should at the end give an honest answer to our basic question. The treatment program is without much risk for the participants. The therapeutic diet, containing up to 400 mg of cholesterol per day and having a ratio of polyunsaturated to saturated fatty acids of 1, is conservative and practical for long-term use. It lowers the plasma cholesterol concentration an average of 5% from baseline in outpatients. Cholestyramine, the study medication prescribed to lower plasma cholesterol concentration, has been used for more than 12 years in our clinics in Toronto and Hamilton without serious toxic side effects. Unlike the other "lipid-lowering" medications it is not absorbed systemically and there have been no large-scale studies of its effectiveness in either primary or secondary prevention of coronary heart disease. The patients in the program are monitored in the lipid research clinics every 2 months; they have minor check-ups every 6 months and complete examinations annually. We are careful not to take the place of the family physician. Indeed, we insist on each participant having a personal physician with whom we can communicate information and discuss problems. We only request the privilege of regulating the cholesterol-lowering diet and medication and of monitoring the results. There is an overall net benefit of this program to the medical community in terms of the information we have provided about the thousands of persons screened for hyperlipoproteinemia and
14 CMA JOURNAL/JANUARY 10, 1976/VOL. 114
COMPOSITION: Each uncoated, scored, light tan tablet contains spironolactone, 25 mg. Aldactone offers an entirely new approach to the treatment of essential hypertension, edema and ascites, including resistant states. Aldactone specifically blocks the effects on the kidneys of mineralocorticoids and antagonizes the sodium retaining and water retaining effects of aldosterone which is important in the production of edema. INDICATIONS: Aldactone is indicated in the treatment of edema and ascites of congestive heart failure, hepatic cirrhosis, the nephrotic syndrome, and idiopathic edema as well as that due to malignant effusions especially if not responding well to conventional diuretics. Aldactone is also indicated for lowering blood pressure in essential hypertension, correcting hypokalemic alkalosis in severe hypertension and in the treatment of myasthenia gravis. DOSAGE: Edema-the initial recommended adult dose is one 25 mg tablet four times daily. Rarely a patient may require up to 300 mg per day and others as little as 75 mg per day. If adequate diuresis with Aldactone is not obtained within five days, Aldactizide should be substituted in its usual dosage to obtain the synergistic effect of the spironolactone and the thiazide components. In an occasional patient with severe, resistant edema, it may be necessary to add a glucocorticoid to this combined therapy. In children a dosage providing 1.5 mg of Aldactone per pound of body weight should be employed. Essential hypertension-One tablet four times a day, treatment should be continued at least two weeks. PRECAUTIONS: Other than acute renal insufficiency there are no known contraindications to Aldactone. It should be used judiciously in patients with hyponatremia or hyperkalemia. SIDE EFFECTS: Side effects are mild and infrequent; drowsiness, mental confusion and maculopapular or erythematous eruptions have occurred rarely, subsiding within forty-eight hours on discontinuation of the drug. Gynecomastia and mild androgenic manifestations have also been reported in a few patients. TOXICITY: No reports of fatal overdosage in man. No adverse effects from high dosage in chronic animal studies. Symptoms of Overdosage-True toxicity has not been reported; drowsiness, mental confusion or a maculopapular or erythematous rash has occurred rarely. These manifestations disappear promptly on discontinuance of medication. Hyperkalemia may be exacerbated. Treatment-No specific antidote. No true toxicity has occurred or is expected. Appearance of effects described above require only discontinuance of the drug. For hyperkalemia, reduce potassium intake, administer potassiu m-excreting diuretics, intravenous glucose with regular insulin or oral ion exchange resins. SUPPLY: Bottles of 100, 1,000 and 2,500 tablets. Complete prescribing information available on request.
Aldactone® (SP.RONOLACTONE)
the only specific, competitive aldosterone antagonist for gradual, sustained diuresis with minimal possibility of potassium loss.. .especially indicated for the digitalized patient. Searle Pharmaceuticals Oakv,IIe, Ontario
ease or other severe systemic condi- higher rate of occurrence of the infections; acute mesenteric lymphadenitis, tion, and is a result of the pioneer usually as an acute syndrome of the work of Dr. Lucette Lafleur of Montright iliac fossa; and erythema nodo- real8'9 and the recent work of the nasum, usually associated with other tional reference centre in Toronto.'0 symptoms of Yersinia infection. An additional 125 Y. enterocolitica culThe most frequent clinical form of tures were received from the United Yersinia infection produced only by Y. States for identification and bioseroenterocolitica is acute gastroenteritis. typing; in most instances (115) the orMore than two thirds of the cases are ganisms had been isolated from water in infants and young children. Until specimens during a survey. 1972, human cases of gastroenteritis due to Y. enterocolitica had been either Yersinia pseudotuberculosis sporadic or confined to small family Eight cultures of Yersinia pseudooutbreaks. However, during the past 3 tuberculosis were received for identifiALICK LITTLE, MD Project director years outbreaks have been described in cation and serotyping. In six instances Toronto-McMaster Lipid Research Clinic Project 1 Spadina Cres. Japan,4'5 Finland6 and the United the organisms had been isolated from Toronto, ON States.7 Other clinical conditions pro- the cecal content of swine slaughtered duced by Y. enterocolitica are Reiter's for human consumption (serotype III); Incidence of Yersinia enterocolitica and syndrome, meningitis, abscesses, uri- the other sources were products of a Y. pseudotuberculosis infections in nary tract infections and localized mu- bovine abortion (IB) and autopsy speciCanada; 1975 semiannual report cosal infections. Until recently Y. en- mens from a wild bird (hA). To the editor: The Ontario Ministry of terocolitica was isolated from humans Health instituted at the end of 1974 a or different animal species only; lately Serologic investigation of human national reference service for Yersinia it has been increasingly isolated from yersiniosis enterocolitica and Y. pseudotuberculo- water specimens, vegetables, fruit, milk A total of 230 human serum specisis infections, in collaboration with the and other sources. mens were received for serologic exBelow is a summary of the activity amination for Y. enterocolitica and Laboratory Centre for Disease Control, health protection branch, Health and of the Yersinia national reference pseudotuberculosis. We used a tube agWelfare Canada. The need for this centre for the first half of 1975. glutination technique with a twofold centre became evident with the increas- Yersinia enterocolitica serial dilution of serum and the coming number of Y. enterocolitica infecmonest Yersinia antigens in Canada: tions in humans reported during the Of the 127 Y. enterocolitica cultures Y. enterocolitica 0:3; 5,27; 6,30; and last decade.1 In 1966 there were only received for identification and biosero- 8; and Y. pseudotuberculosis I, II and 23 recorded cases of such infections, typing (Table I) 105 were of human III. Most of the specimens were from but Mollaret reported 642 cases in 1970 origin and 22 of nonhuman origin. In Ontario (205); others were from Queand more than 1000 in 1972.2 The most instances (92) of human infection bec (10), British Columbia (4), Alberta total number of cases reported has organisms had been isolated from fecal (4), New Brunswick (2) and the United now exceeded 5000 and the incidence specimens from patients with acute States (5). Thirteen yielded distinctly of this infection is increasing world- gastroenteritis. Most of the patients positive titres (1:200 or higher); 11 wide. It was first diagnosed in north- were 16 years of age or less and the were positive for Y. enterocolitica 0:3 western Europe and is now common in predominant serotype was Y. enteroco- and two for Y. pseudotuberculosis seroeastern and central Europe, Africa utica indole-negative, 0:3. The other type II. (South Africa and Zaire), Japan and sources were blood (one), abscesses The technique of Yersinia seroaggluNorth America. In Canada in 1974, (two), joint fluid (one), gallbladder tination testing is cumbersome for the data pertaining to the identification and fluid (one) and sputum (one); in seven following reasons: typing of 278 cultures of Y. enteroco- instances the source was not stated. 1. Many Yersinia antigens are reutica were published; 256 of the iso- The 22 nonhuman isolates were from quired for serologic examination. Preplates were from humans and 22 were swine (19), milk (2) and water (1). aration of these antigens is laborious of nonhuman origin.3 The majority of cultures were received because Yersinia cultures tend to beY. enterocolitica and Y. pseudotuber- from Ontario and Quebec. The ap- come "rough" and the "live" merthiolculosis sometimes produce similar clin- parent higher incidence of Y. enterc'- ate-treated antigens we are using have ical pictures, such as the following: colitica infection in these two provinces a relatively short shelf-life. septicemia, occurring mostly in people reflects a greater awareness by physi2. Most of the indole-positive Y. debilitated by diabetes, malignant dis- cians of this organism rather than a enterocolitica strains do not induce deTable 1-Versinia enterocolitica cultures received by national reference centre, January to June 1975 Age of patient Source of (yr) organism Serotypes Origin of No. of culture cultures 16 NS* Feces Othert 0:3 5,27 6,30 8 Others Human Quebec 70 50 3 17 62 8 62 2 2 4 Ontario 27 18 9 24 3 22 2 1 1 1 BritishColumbia 4 3 1 2 2 1 1 2 NovaScotia 2 1 1 2 2 NewBrunswick 1 1 1 1 Newfoundland 1 1 1 1 Total 105 71 14 20 92 13 86 5 5 2 7 Nonhuman Ontario 22 7 2 1 1 11 *NS = Not stated. IBlood, abscesses, joint fluid, gallbladder fluid, sputum or not stated. .O:5; 7,13; 14; 16; 20; or nontypable. the hundreds we have referred to physicians because of hypertriglyceridemia and other diseases excluding them from the program. We welcome any questions from physicians about the coronary prevention program. We want physicians to be fully informed about it. And we do need their understanding and collaboration so that some day all of us can say honestly to our patients "Yes, there is" or "No, there is not any evidence that lowering your cholesterol value will prevent heart attacks."
16 CMA JOURNAL/JANUARY 10, 1976/VOL. 114
