newer drugs. Sound bacterial studies require a large volume of patients and smaller centres may require years to acquire meaningful data. However, in spite of his warning, Dr. McCraken tabulated a long list of drugs for the uninitiated.
P K 0.0005). Our results in a group of hemophiliacs are at apparent variance. Of 21 unrelated individuals with hemophilia (Factor VIII or IX deficiency) 1 was a carrier of HB8Ag and 14 possessed anti-HR8. Five of the 21(24%) patients possessed HL-A8, all of whom also HAROLD L. DAVIES, MD 190 Tache Ave. possessed anti-HB,. However, the paWinnipeg, MB tients with HL-A8 had relatively lower titres of anti-HB, compared with paImmune response to HB8Ag tients lacking HL-A8 (Table I). The To the editor: We have recently re- difference in the titres could not be ported data on hepatitis B surface anti- explained on the basis of treatment gen (HB.Ag) infection in our hemodial- alone - that is, on the amount of ysis unit, showing that HL-A8 may be blood, plasma or cryoprecipitate renegatively associated with the forma- ceived. These patients have not been tion of hepatitis B surface antibody studied serially and the determination (anti-HB,).1 We studied 51 subjects (28 of anti-HR5 was done only once, at the hemodialysis patients and 23 healthy time of tissue typing. Thus, the posindividuals at high risk - staff of the sibility that patients with HL-A8 had hemodialysis unit and the immunohe- lower titres of anti-HR5 by chance matology laboratory), of whom 22 (18 alone, and in the past may have had hemodialysis patients and 4 healthy in- high titres, is not ruled out. Also undividuals) were found to possess HB.Ag known is when these patients became and 29 (10 hemodialysis patients and positive for anti-HR8 for the first time. 19 healthy individuals), anti-HB,. Serial studies are now being underSince January 1975, six additional in- taken. dividuals have been found to possess Although the results from the two HB8Ag and seven, anti-HB8. Of the six studies are at apparent variance they HB.Ag-positive individuals three were can probably be reconciled. It has been hemodialysis patients and three were observed that uremic patients more healthy individuals at high risk; one often become carriers upon exposure to individual in each group possessed HL- HR.Ag, while healthy subjects more A8. Of the three healthy subjects with often produce anti-HR8 (see page 945 HB5Ag one had had severe clinical of this issue of the Journal). Hemohepatitis and two had mild hepatitis and philiacs probably have intact immune increased concentrations of serum en- mechanisms and, therefore, like healthy zymes. Of the seven individuals (two subjects, may respond to HR8Ag more hemodialysis patients and five healthy often by producing anti-HR8. Furtherindividuals) with anti-HR. none pos- more, the dose of antigen and the route sessed HL-A8. of infection may differ in these two Thus, among 64 infected indivi- groups of subjects. The hemophiliacs duals) HB5Ag was detected in 28 had received repeated treatment with and anti-HR. in 36. The frequency of blood, plasma and cryoprecipitate, each HL-A8 in the general population is of which has been reported to transmit 18%. HL-A8 was present in 10 of the the infecting agent. Rlood transfusions 28 (36.0%) individuals with HB8Ag are restricted to the absolute minimum and in none of the 36 with anti-HR. - in hemodialysis patients, and none of a significant difference (x' = 12.649; the healthy individuals at high risk had Table 1-Titres of hepatitis B surface antibody and types of histocompatibility antigens in hemophiliacs
Patient Age no. (yr) 1 19 2 14 3 21 4 16 5 21 6 20 7 37 8 16 9 24 10 30 11 17 12 19 13 23 14 22 *Fresh frozen plasma.
Treatment received Deficient Plasma and blood Current monthly HL-A Anti-HB8 coagulation before 1965 cryoprecipitate type titre factor (units) requirement (units) 1,8 1:2 VIII 81 48 1,8,13 1:64 VIII 44 48 9,29,5,8 1:512 VIII 10 16 1,8,50 1:512 VIII 17 48 2,9,8,15 1:1024 VIII 10 8 2,27 1:2048 VIII 72 32 2,3,60 1:4096 VIII 151 4 1,3,15 1:4096 IX 0 3* 2,10 1:8192 IX 10 2/yr* 1,3,7 1:8192 VIII 496 32 1,2,17 1:8192 IX 43 Nottreated since 1972 2,50,15 >1:131072 VIII 32 8 29, 5,14 > 1:131072 VIII 106 12 2,3,5 >1:131072 VIII 17 12
received blood transfusions. Thus, repeated stimulation or immunization may induce production of anti-HB, in HL-A8-positive subjects who might otherwise be "poor responders" to HB8Ag. Our studies were based on small numbers of patients and the interpretation of the results is tentative until confirmed by other centres. However, our results seem to suggest that HL-A8 may be negatively associated with the production of anti-HB, in hemodialysis patients and healthy personnel of hemodialysis units and immunohematology laboratories. It appears that subjects with HL-A8 may also produce anti-HB,, perhaps as a result of repeated stimulus, as in the case of hemophiliacs. However, the titres of anti-HB, may remain low. Whether subjects with HL-A8 are "poor responders" to HB.Ag needs to be further investigated. DHARMENDRA P.S. SENGAR, PH 0 WILLIAM A. MCLEISH, MD, PRCP(CJ MONIQUE SUTHERLAND, RT ARDUR RASHID, MD, FRCP[C] JULES E. HARRIS, MD, FRCP[C] R. KENNEDY SMILEY, MD, l'RCP[C] Departments of laboratory medicine and medicine Ottawa General Hospital University of Ottawa Ottawa, ON
Reference 1. SENGAR DPS, McLEIsH WA, SUTHERLAND M, et al: Hepatitis B antigen (HBAg) infection
in a hemodialysis unit. I. HL-A8 and immune response to HBAg. Can Med Assoc I 112: 968, 1975
Clinical importance of grossly increased erythrocyte sedimentation rate To the editor: Measurement of the erythrocyte sedimentation rate (ESR) is a simple and commonly requested test, and although there may be doubts about its clinical usefulness, it is of established value in screening for disease diagnosed by other methods and for occult disease, and in assessing the prognosis of many diseases states. An extremely high ESR is frequently regarded as a bad prognostic sign. To many, such a finding at once suggests malignant disease, and the patient is then subjected to extensive and often expensive investigations. A study was therefore undertaken to determine the most likely causes of a grossly increased ESR and thus the clinical importance of such a finding. During a 15-month period 4967 ESRs were determined by the Westergren method by laboratory technicians of a cottage hospital serving a rural community in Newfoundland. Measurement was made within 2 hours of blood collection and no correction was made for anemia. The final diagnosis for each patient with a grossly increased ESR was recorded as the most likely cause for the increase. Of the 4967 ESRs 100 (2%) were
CMA JOURNAL/NOVEMBER 22, 1975/VOL. 113 929
extremely high. Of these 100 patients 35% were hospital inpatients, 63% were outpatients and 2% were under the care of their family physician. Infection accounted for 62% of the high readings, collagen disorders for 27% and malignant disease for 11%. Of the 62 patients with infections 30 had urinary tract infections and 19 had respiratory tract infections (16 had bacterial pneumonia; 2, pulmonary tuberculosis; and 1, viral pneumonia). Of the 11 patients with malignant disease 10 had unequivocal evidence of metastases; 6 of the 11 had a carcinoma. A grossly increased ESR is not uncommon: in this study it was found in 1 in 50 determinations; others have reported detection rates of 1 in 601 and 1 in 66.2 More than 50% of the patients studied had infections, mostly bacterial, and about 25% had collagen disorders. Therefore, inflammatory diseases, particularly three common conditions - urinary and respiratory tract infection and connective tissue disorders - are by far the commonest causes of extremely high ESRs. Malignant disease was found to be a less common cause. Payne,1 and Hart, Soots and Sullivan1 arrived at the same conclusion, whereas Zacharski and Kyle3 of the Mayo Clinic, in their review of 263 patients with ESRs greater than 100 mm/h, found a 58% prevalence of malignant disease, lymphoma being the most common type. This discrepancy is probably due to the different types of patients attending a rural hospital and referred to the Mayo Clinic. This study has shown that the finding of a grossly increased ESR can be of much diagnostic help, especially in centres where sophisticated investigations are not undertaken. In a patient with this finding, simple microbiologic investigations of urine, blood and sputum, blood count, radiography of the chest and gastrointestinal tract, and intravenous pyelography are important. Another practical implication of the results of this study is that a grossly increased ESR is not necessarily indicative of a grave and hopeless prognosis, for its association with carcinoma was not as frequent as previously documented. CHIMELE U. ABENGOWE, MA, MB, MRCP, KICH
Department of medicine, Ahmadu Bello University Hospital Kaduna, Nigeria (formerly of the department of medicine Memorial University of Newfoundland St. John's, NP)
References 1. PAYNE RW: Causes of the grossly elevated erythrocyte sedimentation rate. Practitioner 200: 415, 1968 2. HART GD, Socrrs M, SULLIVAN J: Significance of extreme elevation of erythrocyte sedimentation rate. Appi Ther 12: 12, 1970 3. ZACHARIKI LR, KYLE RA: Significance of extreme elevation of erythrocyte sedimentation rate. JAMA 202: 264, 1967
ALDOMET (methyldopa, MSD Std.)
Indications: Sustained moderate through severe hypertension. Dosage Summary: Start usually with 250 mg two or three times daily during the first 48 hours; thereafter adjust at intervals of not less than two days according to the patient's response. Maximal daily dosage is 3.0 g of methyldopa. In the presence of impaired renal function smaller doses may be needed. Syncope in older patients has been related to an increased sensitivity in those patients with advanced arteriosclerotic vascular disease and may be avoided by reducing the dose. Tolerance may occur occasionally between the second and third month after initiating therapy. Effectiveness can frequently be restored by increasing the dose or adding a thiazide. Contralndlcatlons: Active hepatic disease such as acute hepatitis and active cirrhosis; known sensitivity to methyldopa; unsuitable in mild or labile hypertension responsive to mild sedation or thiazides alone; pheochromocytoma; pregnancy. Use cautiously if there is a history of liver disease or dysfunction. Precautions: Acquired hemolytic anemia has occurred rarely. Hemoglobin and/or hematocrit determinations should be performed when anemia is suspected. If anemia is present, determine if hemolysis is present. Discontinue methyldopa on evidence of hemolytic anemia. Prompt remission usually results on discontinuation alone or the initiation of adrenocortical steroids. Rarely, however, fatalities have occurred. A positive direct Coombs test has been reported in some patients on continued therapy with methyldopa, the exact mechanism and significance of which is not established. Incidence has varied from 10 to 20%. If a positive test is to develop it usually does within 12 months following start of therapy. Reversal of positive test occurs within weeks to months after discontinuation of the drug. Prior knowledge of this reaction will aid in crosa matching blood for transfusion. This may result in incompatible minor cross match. If the indirect Coombs test is negative, transfusion with otherwise compatible blood may be carried out. If positive, advisability of transfusion should be determined by a hematologist or expert in transfusion problems. Reversible leukopenia with primary eftect on granulocytes has been seen rarely. Rare cases of clinical agranulocytosis have been reported. Granulocyte and leukocyte counts returned promptly to normal on discontinuance of drug. Occasionally fever has occurred within the first three weeks of therapy, sometimes associated with eosinophilia or abnormalities in one or more liver function tests. Jaundice, with or without fever, may occur also, with onset usually within first 2 or 3 months of therapy. Rare cases of fatal hepatic necrosis have been reported. Liver biopsies in several patients with liver dysfunction showed a microscopic focal necrosis compatible with drug hypersensitivity. Determine liver function, leukocyte and difterential blood counts at intervals during the first six to twelve weeks of therapy or whenever unexplained fever may occur. Discontinue if fever, abnormalitiesinliverfunctiontests, or jaundiceoccur. Methyldopa may potentiate action of other antihypertensive drugs. Follow patients carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on ALDOMET*. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. Hypertension occasionally noted after dialysis in patients treated with ALDOMET* may occur because the drug is removed by this procedure.
930 CMA JOURNAL/NOVEMBER 22, 1975/VOL. 113
Rarely involuntary choreoathetotic movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease. Should these movements occur, discontinue therapy. Fluorescence in urine samples at same wave lengths as catecholamines may be reported as urinary catecholamines. This will interfere with the diagnosis of pheochromocytoma. Methyldopa will not serve as a diagnostic test for pheochromocytoma. Usage in Pregnancy: Because clinical experience and follow-up studies in pregnancy have been limited, the use of methyldopa when pregnancy is present or suspected requires that the benefits of the drug be weighed against the possible hazards to the fetus. Adverse ReacUons: Cardiovascular: Angina pectons may be aggravated; reduce dosage if symptoms of orthostatic hypotension occur; bradycardia occurs occasionally. Neurological: Symptoms associated with effective lowering of blood pressure occasionally seen include dizziness, lightheadedness, and symptoms of cerebrovascular insufficiency. Sedation, usually transient, seen during initial therapy or when dose is increased. Similarly, headache, asthenia, or weakness may be noted as early, but transient symptoms. Rarely reported: paresthesias, parkinsonism, psychic disturbances including nightmares, reversible mild psychoses or depression, and a single case of bilateral Bell's palsy. Gastrointestinal: Occasional reactions generally relieved by decrease in dosage: mild dryness of the mouth and gastrointestinal symptoms including distention, constipation, flatus, and diarrhea; rarely, nausea and vomiting. Hematological: Positive direct Coombs test, acquired hemolytic anemia, leukopenia and rare cases of thrombocytopenia. Toxic and Allergic: Occasional drug related fever and abnormal liver function studies with jaundice and hepatocellular damage, (see PRECAUTIONS) and a rise in BUN. Rarely, skin rash, sore tongue or "black tongue", pancreatitis and inflammation of the salivary glands. Endocrine and Metabolic: Rarely, breast enlargement, lactation, impotence, decreased libido; weight gain and edema which may be relieved by administering a thiazide diuretic. If edema progresses or signs of pulmonary congestion appear, discontinue drug. Miscellaneous: occasionally nasal stuffiness, mild arthralgia and myalgia; rarely, darkening of urine after voiding. Detailed Information available on request. How Supplied: Tablets ALDOMET* are yellow, filmcoated, biconvex shaped tablets, supplied as follows: Ca 8737 - each tablet containing 125 mg of methyldopa, marked MSD 135 on one side, supplied in bottles of 100 and 1000. Ca 3290 - each tablet containing 250 mg of methyldopa, marked MSD 401 on one side, supplied in bottles of 100 and 1000. Ca 8733 - each tablet containing 500 mg of methyldopa, marked MSD 516 on one side, supplied in bottles of 100 and 250. Also available: Ca 3293 - Injection ALDOMET* Ester hydrochloride, a clear colourless solution containing 250 mg methyldopate hydrochloride per 5 ml, supplied in 5 ml ampoules. (MC-949a)
O MERCK & DOHME CANADA LIMITED/LIMIT.E
A Leader In Cardiovascular Medicine
P K 0.0005). Our results in a group of hemophiliacs are at apparent variance. Of 21 unrelated individuals with hemophilia (Factor VIII or IX deficiency) 1 was a carrier of HB8Ag and 14 possessed anti-HR8. Five of the 21(24%) patients possessed HL-A8, all of whom also HAROLD L. DAVIES, MD 190 Tache Ave. possessed anti-HB,. However, the paWinnipeg, MB tients with HL-A8 had relatively lower titres of anti-HB, compared with paImmune response to HB8Ag tients lacking HL-A8 (Table I). The To the editor: We have recently re- difference in the titres could not be ported data on hepatitis B surface anti- explained on the basis of treatment gen (HB.Ag) infection in our hemodial- alone - that is, on the amount of ysis unit, showing that HL-A8 may be blood, plasma or cryoprecipitate renegatively associated with the forma- ceived. These patients have not been tion of hepatitis B surface antibody studied serially and the determination (anti-HB,).1 We studied 51 subjects (28 of anti-HR5 was done only once, at the hemodialysis patients and 23 healthy time of tissue typing. Thus, the posindividuals at high risk - staff of the sibility that patients with HL-A8 had hemodialysis unit and the immunohe- lower titres of anti-HR5 by chance matology laboratory), of whom 22 (18 alone, and in the past may have had hemodialysis patients and 4 healthy in- high titres, is not ruled out. Also undividuals) were found to possess HB.Ag known is when these patients became and 29 (10 hemodialysis patients and positive for anti-HR8 for the first time. 19 healthy individuals), anti-HB,. Serial studies are now being underSince January 1975, six additional in- taken. dividuals have been found to possess Although the results from the two HB8Ag and seven, anti-HB8. Of the six studies are at apparent variance they HB.Ag-positive individuals three were can probably be reconciled. It has been hemodialysis patients and three were observed that uremic patients more healthy individuals at high risk; one often become carriers upon exposure to individual in each group possessed HL- HR.Ag, while healthy subjects more A8. Of the three healthy subjects with often produce anti-HR8 (see page 945 HB5Ag one had had severe clinical of this issue of the Journal). Hemohepatitis and two had mild hepatitis and philiacs probably have intact immune increased concentrations of serum en- mechanisms and, therefore, like healthy zymes. Of the seven individuals (two subjects, may respond to HR8Ag more hemodialysis patients and five healthy often by producing anti-HR8. Furtherindividuals) with anti-HR. none pos- more, the dose of antigen and the route sessed HL-A8. of infection may differ in these two Thus, among 64 infected indivi- groups of subjects. The hemophiliacs duals) HB5Ag was detected in 28 had received repeated treatment with and anti-HR. in 36. The frequency of blood, plasma and cryoprecipitate, each HL-A8 in the general population is of which has been reported to transmit 18%. HL-A8 was present in 10 of the the infecting agent. Rlood transfusions 28 (36.0%) individuals with HB8Ag are restricted to the absolute minimum and in none of the 36 with anti-HR. - in hemodialysis patients, and none of a significant difference (x' = 12.649; the healthy individuals at high risk had Table 1-Titres of hepatitis B surface antibody and types of histocompatibility antigens in hemophiliacs
Patient Age no. (yr) 1 19 2 14 3 21 4 16 5 21 6 20 7 37 8 16 9 24 10 30 11 17 12 19 13 23 14 22 *Fresh frozen plasma.
Treatment received Deficient Plasma and blood Current monthly HL-A Anti-HB8 coagulation before 1965 cryoprecipitate type titre factor (units) requirement (units) 1,8 1:2 VIII 81 48 1,8,13 1:64 VIII 44 48 9,29,5,8 1:512 VIII 10 16 1,8,50 1:512 VIII 17 48 2,9,8,15 1:1024 VIII 10 8 2,27 1:2048 VIII 72 32 2,3,60 1:4096 VIII 151 4 1,3,15 1:4096 IX 0 3* 2,10 1:8192 IX 10 2/yr* 1,3,7 1:8192 VIII 496 32 1,2,17 1:8192 IX 43 Nottreated since 1972 2,50,15 >1:131072 VIII 32 8 29, 5,14 > 1:131072 VIII 106 12 2,3,5 >1:131072 VIII 17 12
received blood transfusions. Thus, repeated stimulation or immunization may induce production of anti-HB, in HL-A8-positive subjects who might otherwise be "poor responders" to HB8Ag. Our studies were based on small numbers of patients and the interpretation of the results is tentative until confirmed by other centres. However, our results seem to suggest that HL-A8 may be negatively associated with the production of anti-HB, in hemodialysis patients and healthy personnel of hemodialysis units and immunohematology laboratories. It appears that subjects with HL-A8 may also produce anti-HB,, perhaps as a result of repeated stimulus, as in the case of hemophiliacs. However, the titres of anti-HB, may remain low. Whether subjects with HL-A8 are "poor responders" to HB.Ag needs to be further investigated. DHARMENDRA P.S. SENGAR, PH 0 WILLIAM A. MCLEISH, MD, PRCP(CJ MONIQUE SUTHERLAND, RT ARDUR RASHID, MD, FRCP[C] JULES E. HARRIS, MD, FRCP[C] R. KENNEDY SMILEY, MD, l'RCP[C] Departments of laboratory medicine and medicine Ottawa General Hospital University of Ottawa Ottawa, ON
Reference 1. SENGAR DPS, McLEIsH WA, SUTHERLAND M, et al: Hepatitis B antigen (HBAg) infection
in a hemodialysis unit. I. HL-A8 and immune response to HBAg. Can Med Assoc I 112: 968, 1975
Clinical importance of grossly increased erythrocyte sedimentation rate To the editor: Measurement of the erythrocyte sedimentation rate (ESR) is a simple and commonly requested test, and although there may be doubts about its clinical usefulness, it is of established value in screening for disease diagnosed by other methods and for occult disease, and in assessing the prognosis of many diseases states. An extremely high ESR is frequently regarded as a bad prognostic sign. To many, such a finding at once suggests malignant disease, and the patient is then subjected to extensive and often expensive investigations. A study was therefore undertaken to determine the most likely causes of a grossly increased ESR and thus the clinical importance of such a finding. During a 15-month period 4967 ESRs were determined by the Westergren method by laboratory technicians of a cottage hospital serving a rural community in Newfoundland. Measurement was made within 2 hours of blood collection and no correction was made for anemia. The final diagnosis for each patient with a grossly increased ESR was recorded as the most likely cause for the increase. Of the 4967 ESRs 100 (2%) were
CMA JOURNAL/NOVEMBER 22, 1975/VOL. 113 929
extremely high. Of these 100 patients 35% were hospital inpatients, 63% were outpatients and 2% were under the care of their family physician. Infection accounted for 62% of the high readings, collagen disorders for 27% and malignant disease for 11%. Of the 62 patients with infections 30 had urinary tract infections and 19 had respiratory tract infections (16 had bacterial pneumonia; 2, pulmonary tuberculosis; and 1, viral pneumonia). Of the 11 patients with malignant disease 10 had unequivocal evidence of metastases; 6 of the 11 had a carcinoma. A grossly increased ESR is not uncommon: in this study it was found in 1 in 50 determinations; others have reported detection rates of 1 in 601 and 1 in 66.2 More than 50% of the patients studied had infections, mostly bacterial, and about 25% had collagen disorders. Therefore, inflammatory diseases, particularly three common conditions - urinary and respiratory tract infection and connective tissue disorders - are by far the commonest causes of extremely high ESRs. Malignant disease was found to be a less common cause. Payne,1 and Hart, Soots and Sullivan1 arrived at the same conclusion, whereas Zacharski and Kyle3 of the Mayo Clinic, in their review of 263 patients with ESRs greater than 100 mm/h, found a 58% prevalence of malignant disease, lymphoma being the most common type. This discrepancy is probably due to the different types of patients attending a rural hospital and referred to the Mayo Clinic. This study has shown that the finding of a grossly increased ESR can be of much diagnostic help, especially in centres where sophisticated investigations are not undertaken. In a patient with this finding, simple microbiologic investigations of urine, blood and sputum, blood count, radiography of the chest and gastrointestinal tract, and intravenous pyelography are important. Another practical implication of the results of this study is that a grossly increased ESR is not necessarily indicative of a grave and hopeless prognosis, for its association with carcinoma was not as frequent as previously documented. CHIMELE U. ABENGOWE, MA, MB, MRCP, KICH
Department of medicine, Ahmadu Bello University Hospital Kaduna, Nigeria (formerly of the department of medicine Memorial University of Newfoundland St. John's, NP)
References 1. PAYNE RW: Causes of the grossly elevated erythrocyte sedimentation rate. Practitioner 200: 415, 1968 2. HART GD, Socrrs M, SULLIVAN J: Significance of extreme elevation of erythrocyte sedimentation rate. Appi Ther 12: 12, 1970 3. ZACHARIKI LR, KYLE RA: Significance of extreme elevation of erythrocyte sedimentation rate. JAMA 202: 264, 1967
ALDOMET (methyldopa, MSD Std.)
Indications: Sustained moderate through severe hypertension. Dosage Summary: Start usually with 250 mg two or three times daily during the first 48 hours; thereafter adjust at intervals of not less than two days according to the patient's response. Maximal daily dosage is 3.0 g of methyldopa. In the presence of impaired renal function smaller doses may be needed. Syncope in older patients has been related to an increased sensitivity in those patients with advanced arteriosclerotic vascular disease and may be avoided by reducing the dose. Tolerance may occur occasionally between the second and third month after initiating therapy. Effectiveness can frequently be restored by increasing the dose or adding a thiazide. Contralndlcatlons: Active hepatic disease such as acute hepatitis and active cirrhosis; known sensitivity to methyldopa; unsuitable in mild or labile hypertension responsive to mild sedation or thiazides alone; pheochromocytoma; pregnancy. Use cautiously if there is a history of liver disease or dysfunction. Precautions: Acquired hemolytic anemia has occurred rarely. Hemoglobin and/or hematocrit determinations should be performed when anemia is suspected. If anemia is present, determine if hemolysis is present. Discontinue methyldopa on evidence of hemolytic anemia. Prompt remission usually results on discontinuation alone or the initiation of adrenocortical steroids. Rarely, however, fatalities have occurred. A positive direct Coombs test has been reported in some patients on continued therapy with methyldopa, the exact mechanism and significance of which is not established. Incidence has varied from 10 to 20%. If a positive test is to develop it usually does within 12 months following start of therapy. Reversal of positive test occurs within weeks to months after discontinuation of the drug. Prior knowledge of this reaction will aid in crosa matching blood for transfusion. This may result in incompatible minor cross match. If the indirect Coombs test is negative, transfusion with otherwise compatible blood may be carried out. If positive, advisability of transfusion should be determined by a hematologist or expert in transfusion problems. Reversible leukopenia with primary eftect on granulocytes has been seen rarely. Rare cases of clinical agranulocytosis have been reported. Granulocyte and leukocyte counts returned promptly to normal on discontinuance of drug. Occasionally fever has occurred within the first three weeks of therapy, sometimes associated with eosinophilia or abnormalities in one or more liver function tests. Jaundice, with or without fever, may occur also, with onset usually within first 2 or 3 months of therapy. Rare cases of fatal hepatic necrosis have been reported. Liver biopsies in several patients with liver dysfunction showed a microscopic focal necrosis compatible with drug hypersensitivity. Determine liver function, leukocyte and difterential blood counts at intervals during the first six to twelve weeks of therapy or whenever unexplained fever may occur. Discontinue if fever, abnormalitiesinliverfunctiontests, or jaundiceoccur. Methyldopa may potentiate action of other antihypertensive drugs. Follow patients carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on ALDOMET*. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. Hypertension occasionally noted after dialysis in patients treated with ALDOMET* may occur because the drug is removed by this procedure.
930 CMA JOURNAL/NOVEMBER 22, 1975/VOL. 113
Rarely involuntary choreoathetotic movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease. Should these movements occur, discontinue therapy. Fluorescence in urine samples at same wave lengths as catecholamines may be reported as urinary catecholamines. This will interfere with the diagnosis of pheochromocytoma. Methyldopa will not serve as a diagnostic test for pheochromocytoma. Usage in Pregnancy: Because clinical experience and follow-up studies in pregnancy have been limited, the use of methyldopa when pregnancy is present or suspected requires that the benefits of the drug be weighed against the possible hazards to the fetus. Adverse ReacUons: Cardiovascular: Angina pectons may be aggravated; reduce dosage if symptoms of orthostatic hypotension occur; bradycardia occurs occasionally. Neurological: Symptoms associated with effective lowering of blood pressure occasionally seen include dizziness, lightheadedness, and symptoms of cerebrovascular insufficiency. Sedation, usually transient, seen during initial therapy or when dose is increased. Similarly, headache, asthenia, or weakness may be noted as early, but transient symptoms. Rarely reported: paresthesias, parkinsonism, psychic disturbances including nightmares, reversible mild psychoses or depression, and a single case of bilateral Bell's palsy. Gastrointestinal: Occasional reactions generally relieved by decrease in dosage: mild dryness of the mouth and gastrointestinal symptoms including distention, constipation, flatus, and diarrhea; rarely, nausea and vomiting. Hematological: Positive direct Coombs test, acquired hemolytic anemia, leukopenia and rare cases of thrombocytopenia. Toxic and Allergic: Occasional drug related fever and abnormal liver function studies with jaundice and hepatocellular damage, (see PRECAUTIONS) and a rise in BUN. Rarely, skin rash, sore tongue or "black tongue", pancreatitis and inflammation of the salivary glands. Endocrine and Metabolic: Rarely, breast enlargement, lactation, impotence, decreased libido; weight gain and edema which may be relieved by administering a thiazide diuretic. If edema progresses or signs of pulmonary congestion appear, discontinue drug. Miscellaneous: occasionally nasal stuffiness, mild arthralgia and myalgia; rarely, darkening of urine after voiding. Detailed Information available on request. How Supplied: Tablets ALDOMET* are yellow, filmcoated, biconvex shaped tablets, supplied as follows: Ca 8737 - each tablet containing 125 mg of methyldopa, marked MSD 135 on one side, supplied in bottles of 100 and 1000. Ca 3290 - each tablet containing 250 mg of methyldopa, marked MSD 401 on one side, supplied in bottles of 100 and 1000. Ca 8733 - each tablet containing 500 mg of methyldopa, marked MSD 516 on one side, supplied in bottles of 100 and 250. Also available: Ca 3293 - Injection ALDOMET* Ester hydrochloride, a clear colourless solution containing 250 mg methyldopate hydrochloride per 5 ml, supplied in 5 ml ampoules. (MC-949a)
O MERCK & DOHME CANADA LIMITED/LIMIT.E
A Leader In Cardiovascular Medicine
