Tolamolol in the Treatment of Hypertension: An Open Evaluation Study

Transcription

1 J Int Med Res (9V) 5, 00 Tolamolol in the Treatment of Hypertension: An Open Evaluation Study κ Harno, MD, The Municipal Health Centre of Kerava, Finland The effect of tolamolol mg three times daily in the treatment of 30 patients with mild-severe hypertension was studied. The duration of therapy in the nmjority of cases was 3-6 months. There was a highly significant reduction of mean blood pressure (p < 0-00) for the group as a whole. Overall, 6% of patients became normotensive or showed a reduction in severity of hypertension. In the majority of cases, this improvement occurred within the first four weeks of therapy. There was no postural hypertension. Apart from one patient with Prurigo Besnier who developed asthma, another patient who developed severe headache and a third patient who stopped treatment without giving a reason, treatment was well tolerated and there were no other serious side or toxic effects. Introduction The objectives of this study were:. To determine the efficacy of tolamolol in the treatment of hypertension. 2. To determine the length of treatment required to produce a hypotensive effect. 3. To determine the dosage range. 4. To determine the toleration and safety of tolamolol in the treatment of hypertension. Patient selection Only adult out-patients with essential hypertension were included in the trial. Patients admitted to the trial were new hypertensive cases, those who had previously failed to respond adequately to other forms of hypotensive therapy, and those patients suffering from essential or renal hypertension (not suitable for surgery) - inclusion was at the discretion of the investigator. Patients were excluded from the study if they were over the age of 65 years; females of child-bearing age; cardiac failure cases; had a heart rate of less than 55 beats per minute or had malignant hypertension. Also excluded were patients with hepatic or renal disease or with a history of depressive illness. Dosage Tolamolol was administered at a starting dose of 50 mg three times daily. The dosage was increased at not less than weekly intervals by increments of 50 or 00 mg three times daily according to the individual patient's response. The maximum daily dosage was 900 mg daily. The decision to increase the dosage was based on a combination of the presence or absence of side-effects, the absence of a satisfactory hypotensive effect and the maintenance of heart rate above 55 beats per minute. It was intended that patients would remain

2 κ Harm in the study for a further 6 months if treatment proved to be satisfactory in the dose titration phase. Method This was an open evaluation study. Before entering the study, patients were examined clinically and samples of blood and urine were obtained for laboratory testing. Baseline blood pressure and heart rate measurements were made three times over a two week period in the lying and standing position following a 5-5 minute period of rest. Following commencement of tolamolol therapy patients were seen at weekly intervals for the first four weeks and at two-week intervals for the next month and at four-week intervals thereafter. At each visit blood pressure and heart rate were recorded in a similar way and under similar conditions as for the baseline period. Side-effects were recorded and the following laboratory tests were carried out pre-treatment and following weeks 4, 8, 2 and 24 of treatment: Haemoglobin, haematocrit, red cell count, whitecell count anddifferential, ESR, bilirubin, total serum protein and albumin; SGOT, SGPT, alkaline phosphatase and creatinine, uric acid, potassium, cholesterol and fasting blood glucose; 0 Urine analysis for albumin, glucose and microscopy of spun deposit. Results (a) Patienl Details A total of 30 patients were included in the study. There were 24 males and 6 females with a mean age of 50-5 years (range years). The average duration of hypertension was 3 years (range 0-3 years) in 28 of these patients. (b) Dosage Fifteen patients received 50 mg/day, 8 patients 300 mg/day, 2 patients 450 mg/day and 5 patients mg/day. The average dosage for all patients in the trial was 295 mg/day. The duration of treatment was over six months in patients, 3-6 months in 8 and less than three months in patient. (c) Efficacy Paired comparison analysis (weeks 0^, 6, 4) of the mean blood pressure shows a highly significant reduction (p < 0 00) in systolic and diastolic blood pressures in both the supine and standing position (Table ). From the Table, it can be seen that the antihypertensive effect was consistently maintained throughout the first twelve Table I Overall mean reduction* in blood pressure (mm Hg) and heart rate (min~^) from baseline lveelc4 fveekó yveeic 4 Weelc final Systolic pressure, supine (p < 0 05) -8-5 (p < 00) Diastolic pressure, supine Heart rate, supine Systolic pressure, standing Diastolic pressure, standing Heart rate, standing *p < 0 00 for each measurement and at each time interval

3 02 The Journal of International Medical Research weeks of treatment. Apart from two patients who experienced excessive bradycardia no untoward reduction of heart rate was seen. Table 2(a) shows the percentage of patients experiencing a reduction in severity of standing blood pressure categorized into normal, mild, moderate, severe and gross grades of hypertension following treatment with tolamolol. At three months (4 weeks) 59% (6 of 27 patients) with mild, moderate or severe hypertension had a reduction in severity; 48% (4 of 29 patients) experienced a reduction at six weeks and 55% (20 of 30 patients) showed a reduction following the first four weeks of treatment. Similarly, Table 2(b) shows the reduction in severity of blood pressures measured in the supine position. At three months (4 weeks) 77% (20 of 26 patients) with moderate or severe hypertension experienced a reduction in severity. In both supine and standing positions patients initially graded as having severe hypertension appeared to show a greater response than patients graded as mild/ moderate. Table 3(a) shows the number of patients becoming normotensive and/or achieving a clinical improvement. At week fourteen, 0 of the 27 patients were clinically improved or had returned to normotensive levels, based on blood pressure readings made in the standing position. Table 3(b) shows results for the Table 2(a) Distribution of patients before, during and at tlie end of tolamolol treatment, by grade of hypertension (blood pressure measured in the standing position) Before treatment Time (_weel<s) Number Grade following treatment of patients Gross Severe Moderate Mild Normal Patients with reduced grade 4 0% Mild 6 0% 4 0% Final I 0% % Moderate % % Final % % Severe % % Final % Grade of Hypertension (diastolic blood pressure): mild mm Hg; moderate ^ 00-4 mm Hg; severe = 5-29 mm Hg; gross ^ 30 mm Hg or more

4 κ Hamo 03 Table 2(b) Distribution of patients before, during and at the end of tolamolol treatment, by grade of hypertension (blood pressure measured in the supine position) Before treatment Time {weeks) Number Grade following treatment of patients Severe Moderate Mild Normal Patients with reduced grade 4 00% Mild 6 0% 4 0% Final 00% % Moderate % % Final % % Severe % % Final % Grade of Hypertension (diastolic blood pressure): mild mm Hg; moderate 00-4 mm Hg; severe mm Hg. same patients when blood pressures were measured in the supine position. The time to first response in both standing and sitting positions occurred within the first month of treatment in the majority of patients (63 %) and a small additional number (0%) responded during the second month of treatment (Tables 4(a) and 4(b)). (d) (i) Safety SIDE-EFFECTS The total number of patients reporting tolamolol related side-effects was twelve. Table 5 displays those side-effects. All were of mild severity and were tolerated or disappeared with continuing treatment in the majority. Three patients discontinued treatment due to side-effects. One other patient developed a drug-induced lichen rubra planus at week 26. This was found to be reversible on cessation of treatment with tolamolol and the diagnosis was confirmed by the University Department of Dermatology. (ii) LABORATORY TESTS Haematology Minor changes in haemoglobin, haematocril and cell counts were recorded. In many cases, these were single isolated findings which are not considered to be of clinical significance.

5 04 The Journal of International Medical Research Table 3(a) Distribution of patients becoming normotensive or showing clinical improvement* by initial grade of hypertension (blood pressure measured in standing position) Number of patients Before treatment Time (weeks) Becoming normotensive Sttowing Responding clinical improvemeiu* No. % 4 0/ 0 Mild 6 0/ 0 4 0/ 0 Final 0/ /7 59 Moderate 6 5 5/ /6 56 Final 2 9 / /2 25 Severe 6 2 2/ 8 4 /0 0 Final 3 3/ /30 43 Total 6 7 7/ /27 37 Final 2 2 4/30 47 * Definition of Clinical Improvement A reduction of > 20 mm in severe hypertension A reduction of > 0 mm in mild or moderate hypertension

6 κ Hamo 05 Table 3(b) Distribution of patients becoming normotensive or sliowing clinical improvement* by initial grade of hypertension (blood pressure measured in supine position) Number of patients Treatment Time {weeks) Normotensive Responding clinical improvement* No. % 4 / 00 Mild 6 0/ 0 4 0/ 0 Final / /22 8 Moderate / /2 57 Final 5 6 / /7 42 Severe 6 2 2/ /5 0 Final 2/ /30 73 Total / /4 44 Final 7 7 4/30 47 * Definition of Clinical Improvement A reduction of > 20 mm in severe hypertension A reduction of > 0 mm in moderate hypertension

7 06 The Journal of International Medical Research Table 4(a) Time of patients' first response* (supine position) by weelt number and initial grade of hypertension Weelis of treatment Grade of hypertension** No response to date Mild Moderate 3 6 Severe Total Definition of first response: reduction of > 0 mm Hg diastolic pressure in moderate or severe hypertension; reduction of > 5 mm Hg diastolic pressure in mild hypertension **Grade of hypertension (diastolic blood pressure): mild = mmhg; moderate 00-4 mmhg; severe ^ 5-29 mm Hg Table 4(b) Time of patients' first response* (standing position) by week number and initial grade of hypertension WeeliS of treatment Grade of hypertension** No response to date Mild Moderate Severe 6 2 I 2 Total »Definition of first response: reduction of > 0 mm Hg diastolic pressure in moderate or severe hypertension; reduction of > 5 mm Hg diastolic pressure in mild hypertension **Grade of hypertension (diastolic blood pressure): mild ^ mm Hg ; moderate = mm Hg; severe -"5-29 mm Hg

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9 08 The Journal of International Medical Research ESR Five patients with normal pre-treatment levels had minor elevations of ESR. In 4 of them they were single isolated findings which are not considered clinically significant. One patient had minor elevations of ESR which was returning to normal limits with continuation of treatment. Trend analysis and paired comparison analysis of haematology and ESR results at various intervals did not reveal any consistent significant changes. Biochemistry Minor elevations of SGOT, SGPT and alkaline phosphatase were recorded which were isolated and not considered to be clinically significant. One patient had elevated bilirubin values on two occasions which were considered by the investigator to be of no clinical significance. Five patients had elevation of glucose on several occasions, 4 of them were known to be diabetic. The remaining patient was not a known diabetic and the possibility of a drug-related change in glucose tolerance cannot be excluded. No consistent significant changes were recorded in the trend analysis and paired comparison analyses carried out on the results of biochemical laboratory testing. LE cells and ANF Twenty of the 30 patients were tested before and after treatment for the presence of LE cells and/or anti-nuclear factor. No treatment-related changes were seen. Urine No treatment-related changes were seen.