Vascular symptomatic relief during administration of ethylchlorophenoxyisobutyrate (clofibrate)

Vascular Symptomatic Relief During Administration of Ethylchlorophenoxyisobutyrate By MONROE ALBERT AND MARION J. (clofiEthylchlorophenoxyisobutyrate brate) is known to promote changes in numerous biochemical parameters, but relatively little evidence is available to indicate its role in the symptomatic relief of vascular disease. Ninety-five patients of both sexes ranging in age from 30 to 96 years were given clofibrate orally for periods up to 17 months. All individuals were examined at monthly intervals. In addition to the anticipated lowering of serum cholesterol levels, recession of skin xanthomata was noted in all 3 patients having the condition, subjective satisfactory relief of vertigo was reported by 22 of 23 patients with cerebrovascular ischemia, and the exercise tolerance in the group with peripheral atherosclerosis was doubled. Electrocardiographic patterns of coronary insufficiency showed im-

(Clofibrate) STANSELL

provement in all 15 patients with the condition. All individuals in this group decreased their use of sublingual nitrates by 50 per cent and increased their exercise tolerance by more than 100 per cent. One 96-year-old male with marked visual impairment due to severe atherosclerotic retinopathy and macular degeneration exhibited striking improvement of vision during therapy. Two other patients exhibited marked changes in the intima and subintima of the carotid arteries as evidenced by carotid endarterectomy. Further, more rigidly controlled investigation is required to determine a firm causal relationship between clofibrate therapy and the observed changes. (Metabolism 18: No. 8, August 635-645, 1969)

(clofibrate) has long been known to promote reduction of elevated serum lipid levels.iJ In addition, there is evidence that clofibrate administration leads to decreased platelet stickiness,3-6 to increased plasminogen and plasmin levels,7 to decreased plasma fibrinogen concentration, s to increased lipoprotein lipase activity9 and to decreases in serum uric acid levek2 Relatively little evidence is available, however, to indicate its role in the symptomatic relief of vascular disease. During the past two decades, there has been controversy regarding the role of serum lipids in the pathogenesis of atherosclerosis. This report describes evidence germane to this controversy and also suggests other significant effects of clofibrate therapy. These effects include relief of pain due to myocardial ischemia, decrease of vertigo in cerebrovascular ischemia, relief of claudication in peripheral atherosclerosis, regression of cutaneous xanthomata tuberosum, changes in atheromatous plaques, and improvement of electrocardiographic patterns of myocardial ischemia. THYLCHLOROPHENOXYISOBUTYRATE

E

From the Monroe Albert Clinic, San Antonio, Texas. Received for publication March 24, 1969. MONROE ALBERT, M.D., F.A.C.A.: Monroe Albert Clinic, San Antonio, J. STANSELL, MAJOR, USAF, B.S.C., PH.D.: Chief, Clinical Pathology School of Aerospace Medicine, Brooks Air Force Base, Texas. METABOLISM,VOL. 18, No. 8 (AUGUST) 1969

Texas. MAFUON Brunch, USAF

635

ALBERT

636 MATERIALS

AND STANSELL

AND METHODS

Clofibrate was administered to 95 patients, 57 male and 38 female, in dosage of 500 mg. four times per day, for periods ranging from 1 to 17 months. Prior to being given clofibrate, 47 patients had taken other serum cholesterol lowering agents for a period of 6 months to 49 months, with a mean of 21 months. These agents consisted of nicotinic acid (100 mg. 4 times daiIy), estrogens (2.5 mg. per day), thyroid extract and synthetic thyroid. The dosage of all thyroid agents had been individually adjusted for each patient so that clinical symptoms of hyperthyroidism were avoided. Abnormally low protein bound iodine and triiodothyronine uptake levels had been found in seven individuals, and these were normalized during the preclofibrate period of observation before administering clofibrate. Upon beginning administration of clofibrate, all other blood lipid lowering agents were discontinued with the exception of thyroid agents in the hypothyroid group. Each patient was placed on a low cholesterol diet consisting of 35 Gm. lipid, 155 Gm. protein and 355 Gm. carbohydrate daily for a total caloric content of approximately 2350 kilocalories. Twenty-seven patients had histories of one or more myocardial infarctions 2 months to 10 years prior to treatment with clofibrate. All 27 exhibited symptoms of myocardial ischemia. A total of 34 patients showed clinical evidence of myocardial ischemia and 15 of these had electrocardiographic patterns of coronary insufficiency. The criteria used to evaluate relief in this group were ( 1) increased tolerance to exercise, (2) degree of reduction in daily requirements of sublingual nitrates and meperidine hydrochloride orally, and (3) improved electrocardiographic patterns of coronary insufficiency. Ten patients had asymptomatic hypercholesterolemia. Two individuals had symptomatic lower limb atherosclerosis with poor dorsalis pedis and popliteal artery pulsations, abnormal oscilIometric readings, and claudication elicited on walking 100 meters. Four individuals in the total group were diabetic and ten had hyperuricemia. The 47 patients who had received other serum cholesterol lowering agents before being given clofibrate received serum cholestrol determinations bimonthly during the preclofibrate period. All patients received a baseline serum cholesterol determination prior to beginning clofihrate administration and were given subsequent serum cholesterol estimations at monthly intervals during the course of therapy. A modified Liebermann-Burchard procedurelo was used for serum cholesterol determinations. Al1 patients were examined clinically each month. The examination consisted of pertinent history, blood pressure determination, weight measurement, and chest examination. Oscillometric readings and palpation of peripheral arteries were performed in those patients with peripheral atherosclerosis. Blood glucose levels were assayed every 60 days in those individuals with diabetes, and serum uric acid was measured monthly in the group with hyperuricemia. Serial electrocardiograms were prepared semiannually on the group manifesting ECG evidence of coronary insufficiency.

RESULTS Data for 95 patients were coded for statistical analysis. The variables were age, sex, pretreatment weight, pretreatment systolic and diastolic blood pressure, pretreatment serum uric acid, pretreatment serum cholesterol; treatment weight, treatment systolic and diastolic blood pressure, treatment serum cholesterol, treatment serum uric acid, months on treatment, diagnosis and symptoms, side effects, pretreatment therapy, treatment therapy, percent serum cholesterol and uric acid lowering. Serial electrocardiograms were made on 15 patients with patterns of myocardial ischemia. Carotid endarterectomy was performed on 2 patients while on clofibrate therapy. Electrocardiographic patterns of coronary insufficiency suggested improvement in 13 patients, but 2 showed unequivocal patterns of improvement. Using the values from Table 2, a t-statistic was computed to test

VASCULAR

SYMPTOMATIC

637

RELIEF

25-

ZO-

Y

5

= c 6

F

IS-

I

% $

lo-

5-

OO

21

28

I

35

t-l 4

49

PercentCholaterol Lowwing Fig. L-Distribution

of patients in per cent cholesterol lowering categories. Table I.-Averages

Pretreatment Cholesterol Weight Systolic blood pressure Diastolic blood pressure Treatment Cholesterol Weight Systolic blood pressure Diastolic blood pressure

for AI1 Patients Average

Standard Deviation

283 160 129 79

mg./lOO ml. Ibs. mm. Hg mm. Hg

31 Ibs. 20 mm. Hg 9 mm. Hg

228 158 125 76

mg./lOO ml. lbs. mm. Hg mm. Hg

42 30 11 5

59 mg./lOO

ml.

mg./lOO ml. Ibs. mm. Hg mm. Hg

the hypothesis of no difference in per cent cholesterol lowering between males and females. The computed t was 2.39 and the hypothesis of no difference was rejected. A t-statistic was also computed for those patients taking pentaerythrito1 tetranitrate and those not taking pentaerythritol tetranitrate. The computed t was 1.75 and led to the rejection of the hypothesis of no difference in percent serum cholesterol lowerings. There was also a difference in percent serum cholesterol lowering between those patients taking previous serum cholesterol lowering agents and those not taking such agents. Pretreatment serum uric acid levels and treatment serum uric acid levels

638

ALBERT

Table 2.Per

AND

STANSELL

Cent Lowering of Cholesterol No.of Patients

Grouping Sex

Male Female Patients with coronary atherosclerosis Patients with documented past myocardial infarction Patients taking pentaeryritol tetranitrate Patients not taking pentaeryritol tetranitrate Patients taking previous cholesterol lowering agents Patients not taking previous cholesterol lowering agents Age 30-45 46-55 56-65 Over 65

Table 3.Tndividual P.N.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

PT CH

PTWT

PTSBP

272 262 257 290 421 270 238 257 318 349 268 266 261 361 282 314 346 295 314 340 350 314 364 184 272 304 260 257 220 215 267 263 282 364

156 182 130 120 137 184 126 158 174 195 172 128 130 198 168 145 146 228 172 176 187 201 151 100 147 172 206 145 115 124 223 152 180 217

110 130 120 140 118 122 160 140 152 170 122 160 142 130 142 110 102 110 110 130 110 110 110 100 142 110 118 138 110 130 132 160 132 130

57 38 74 27 15 80 47 48

15.0 22.0 18.1 21.3 12.0 19.0 15.7 20.0

14.5 12.7 14.5 14.2 15.9 13.9 16.7 11.6

12

19.6 14.2 19.2 18.3

16.4 14.1 12.6 15.7

23 30 30

Patient Summary

PTDBP

TCH

TWT

TSBP

TDBP

72 72 82 80 72 82 80 82 90 100 80 90 80 80 82 70 72 72 74 80 72 72 72 72 82 72 72 82 72 80 72 90 82 82

227 214 204 235 230 238 219 252 230 262 226 179 211 229 255 219 231 271 271 237 249 267 342 127 202 288 233 269 209 204 205 207 228 233

159 189 117 120 125 183 127 153 175 186 170 124 118 179 169 145 145 224 173 174 185 197 149 97 145 172 201 150 115 127 215 148 181 213

119 127 114 114 125 130 135 121 132 139 116 145 119 131 134 121 110 110 110 133 117 132 127 103 120 114 118 128 110 115 124 154 128 120

73 78 74 72 78 81 82 72 81 78 73 76 73 81 78 75 72 72 72 75 77 80 77 71 72 74 72 81 72 73 77 85 70 76

PCT. L

16.4 18.3 20.5 19.0 45.3 11.8 7.9 2.1 27.7 24.9 15.5 32.7 19.2 36.6 9.7 30.3 33.2 8.0 13.7 30.4 28.9 14.8 6.2 30.8 25.7 5.2 10.4 -4.6 5.0 5.0 23.1 21.3 19.1 36.1

VASCULAR

SYMPTOMATIC

639

RELIEF

TabIe 3.Individual P.N.

F’TCH

PT WT

PTSBP

35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87

400 250 292 170 249 240 278 250 334 290 261 232 179 200 265 283 229 265 329 290 304 200 240 305 233 266 260 276 287 626 373 340 250 287 318 200 287 298 214 294 251 251 258 322 304 276 264 261 320 311 201 270 247

206 179 203 117 181 140 188 154 136 152 221 150 134 124 124 151 162 240 196 196 158 132 154 183 164 166 160 115 154 159 157 115 131 164 226 124 154 132 158 136 134 189 157 220 176 139 140 188 162 143 142 199 122

118 170 160 110 140 130 120 130 118 180 150 110 120 130 104 200 132 130 160 110 110 120 130 160 110 110 120 118 110 140 170 110 122 142 130 132 130 130 110 132 110 130 118 130 132 104 140 110 118 110 130 130 130

Patient Summary (Cont’d)

PTDBP

TCH

72 122 90 72 80 72 80 80 72 90 100 80 80 82 72 104 82 72 72 72 72 72 80 100 72 72 80 72 72 90 90 72 72 82 80 82 82 74 72 80 80 80 72 72 82 82 80 72 72 72 82 82 72

335 193 251 197 198 206 202 189 267 199 238 246 249 123 235 225 194 250 214 279 377 169 217 259 215 292 240 204 213 351 245 235 197 236 251 200 229 215 188 217 275 188 218 250 243 168 172 156 222 263 162 175 225

TWT

203 170 204 114 175 126 181 154 136 156 209 157 131 123 128 153 161 237 182 183 156 142 154 174 168 166 160 114 149 149 158 123 126 167 215 122 155 128 165 137 137 187 163 207 176 141 137 191 163 144 141 202 118

TSBP

128 132 133 116 127 130 114 125 121 154 143 155 123 120 118 143 131 124 130 114 110 114 142 122 126 114 120 118 124 132 147 110 126 141 122 130 125 115 122 125 143 133 136 118 123 110 130 114 124 121 137 122 115

TDBP

PCT. L

73 79 74 73 74 72 76 75 73 95 88 73 76 72 74 85 82 72 80 72 72 72 80 77 74 71 80 72 76 79 83 72 73 83 74 72 74 72 73 79 84 80 79 75 80 72 81 72 73 76 79 80 72

16.3 22.6 14.0 -16.1 20.4 14.2 27.5 24.6 20.0 31.4 8.9 -5.9 -39.0 38.8 11.4 20.4 15.3 5.7 34.9 3.9 -24.0 15.4 9.5 15.0 7.8 -9.8 7.7 26.0 25.7 44.0 34.3 30.9 21.3 17.9 21.2 0.0 20.2 27.9 11.9 26.2 -9.4 24.9 15.5 22.4 20.1 39.1 35.0 40.2 30.6 15.3 19.6 35.0 9.0

640

ALBERT

Table 3.Individual P.N. 88

89 90 91 92 93 94 95

PT CH

PT WT

224 347 270 250 270 253 329 326

158 190 153 143 102 131 166 149

PTSBP

The following abbreviations

140 120 120 110 130 180 140 142

Patient

Summary

AND STANSELL

(Cont’d)

PTDBP

TCH

TWT

TSBP

TDBP

PCT. L

80 80 80 72 72 100 80 82

204 272 215 182 189 243 222 229

153 191 153 141 103 131 160 151

128 114 126 111 114 155 120 143

77 73 76 74 72 97 73 82

8.9 21.5 20.2 27.0 29.9 4.0 32.5 29.7

are used:

Patient Number P.N. Pretreatment cholesterol level PT CH Pretreatment weight PTWT Pretreatment systolic blood pressure PTSBP Pretreatment diastolic blood pressure PTDBP Treatment cholesterol level TCH Treatment weight TWT Treatment systolic blood pressure TSBP Treatment diastolic blood pressure TDBP Per cent lowering in cholesterol level. Negative PCT. L. Standard deviation S.D. Note that treatment values are averages.

number

indicates

increase.

were available on 10 patients. The average percent lowering of serum uric acid was 27. Correlation and regression analysis were done using age, weight, sex, months on treatment and concurrent therapy variable “taking pentaerythritol tetranitrate.” Average blood pressure was computed for those patients taking hypotensive agents and clofibrate. Average pretreatment systolic blood pressure was 176, and average pretreatment diastolic blood pressure was 105. The average treatment systolic blood pressure was 143 and average treatment diastolic blood pressure was 83. No change in blood pressure existed in those patients not taking hypotensive agents. Pretreatment cholesterol values for the four age groups in the study (30-45, 46-55, 56-65 and over 65) averaged 298,293 and 265 mg./ 100 ml. respectively. Values ranged from a low of 179 mg./lOO ml. to a high of 626 mg./lOO ml. Average reduction of blood cholesterol level expressed as a percentage of the pretreatment level was 19.6 for the youngest group, 14.2 for the 46-55 year group, 19.2 for the 56-65 year group and 18.3 for the most elderly patients. Generally, the most pronounced deceases occurred in those with the highest pretreatment serum cholesterol levels. In one patient, for example, with a pretreatment level of 421 mg./lOO ml. cholesterol, the concentration dropped by 196 mg./ 100 ml. (47%) during the first month. A second patient with an initial level of 626 mg./lOO ml. cholesterol showed an average decrease of 275 mg./ 100 ml. (44%). The decreases in serum cholesterol levels which were noted after one month of therapy were substantially maintained throughout the course of treatment.

VASCULAR

SYMPTOMATIC

RELIEF

641

Nearly constant body weight values obtained in 90 of the patients during the treatment period indicate fairly close compliance with the recommended diet by most of the patients. Recession of skin xanthomata was noted in all 3 patients having the condition. One patient experienced complete disappearance of xanthomatous lesions. Subjective satisfactory relief of vertigo was reported by 22 of 23 patients with cerebrovascular ischemia, and all 23 patients insisted on continuation of the regimen. The exercise tolerance in the group with peripheral atherosclerosis was increased about 30 per cent, and oscillimetric readings indicated averages of 20 per cent improvement at the ankle and 40 per cent improvement at a level immediately below the knee on the involved limbs. Electrocardiographic patterns of coronary insufficiency showed remarkable improvement in two patients exhibiting this condition. All individuals in this group decreased their use of sublingual nitrates by 50 per cent and increased their exercise tolerance by more than 50 per cent. No synergistic blood glucose effect was noted in the diabetic group taking insulin or oral hypoglycemic agents. Side Effects of Treatment Nausea was reported by 13 patients, 10 of which received relief from a temporary reduction in clofibrate dosage and/or with antacids. The other three individuals withdrew because of the severity of the nausea. One patient complained of an obnoxious body odor and withdrew. No other untoward effects of clofibrate administration were observed. Three deaths, all of which were not due to clofibrate therapy, occurred in the patient group. One was an SO-year-old male in uremia who had shown a marked reduction in blood urea nitrogen and creatinine levels during 3 weeks of clofibrate treatment, and who had also been placed on a salt free, 20 Gm. per day protein diet. Report

of Cases

Case 1. Sixty-one-year-old male with a past history of myocardial infarction in June 1957. Serial ECG between the years 1958-1966 showed stability. Moderate symptoms of myocardial ischemia were present at rest. The pretreatment serum cholesterol level was 260 mg./lOO ml. Clofibrate therapy was started in February 1967. One month later, the serum cholesterol level was 200 mg./ 100 ml. and angina1 symptoms progressively decreased. In six months, the serum cholesterol level was 168 mg./lOO ml. and was maintained at approximately this level. No sublingual nitrates were required even during periods of moderate exertion. Electrocardiograms prepared during the course of clofibrate therapy showed progressively improved polarity in the T waves of the AVL and V1 through Vq leads (Fig. 2). Case 2. Ninety-six-year-old male with marked visual impairment due to severe atherosclerotic retinopathy and macular degeneration. The pretreatment cholesterol level was 272 mg./lOO ml. During the first year of clofibrate treatment, the serum cholesterol dropped to an average level of 212 mg.1100

642

ALBERT

AND STANSELL

Fig. 2.-Case 1. 61-year-old male. (Top) ECG tracings prepared on Feb. 4, 1967. (Middle) Tracings prepared on Aug. 19,1967. (Bottom) Tracings prepared on Oct. 17, 1967. Polarity of ST segment and T-waves show progressive improvement during course of clofibrate therapy. ml. When first examined by the opthahnologist on June 24, 1966, his uncorrected vision was to count fingers at two feet, right eye, and at six inches, left eye. His vision was rechecked on August 5, September 9, and October 28, 1966, with no objective change in the visual acuity. Reexamination on August 9, 1967, however, revealed that the uncorrected vision had improved to count fingers at eight feet, right eye, and count fingers at four feet, left eye. This improvement in vision while on clofibrate could be attributed to better peripheral visual acuity and reflect improved function of the peripheral retina. Case 3. Seventy-eight-year-old female with clinical and angiographic evidence of occlusive disease of the carotid siphon. Her pretreatment serum cholesterol level was 293 mg./lOO ml. She had taken several antilipemic agents for three years. During clofibrate treatment, the serum cholesterol level was lowered to 220 mg.1100 ml. and the symptoms of cerebrovascular insufficiency were temporarily relieved. After one year of clofibrate therapy, a right carotid endarterectomy was performed, and the intima of the internal carotid grossly resembled the consistency of very soft delicate cartilage with no calcification present. Case 4. Sixty-three-year-old mildly diabetic male with clinical x-ray and angiographic evidence of extensive athero- and arteriosclerotic changes in the major arteries, including the carotid siphon, bilaterally. His pretreatment serum cholesterol level was 258 mg./lOO ml. This patient took clofibrate intermittently and would discontinue therapy during periods of relief of vertigo. The serum cholesterol was significantly (average 218 mg./lOO ml.) lower during periods of treatment. In May 1967, a right carotid endarterectomy was performed. The vascular surgeon found a hard subintimal calcified plaque. Clofibrate therapy was reinstituted, and on July 25, 1967, a left carotid endarterectomy was performed. Strikingly different from the right artery,

VASCULAR SYMPTOMATIC

RELIEF

643

Fig. 3.-Case 6. 36-year-old male. (Top) Master II step EGG tracings prepared on Sept. 30, 1967. ST segments are depressed. (Bottom) Tracings prepared on March 22, 1968. Rate in lead II has decreased and ST segments are normalized. marked degenerative changes were present in the subintimal layer. This was very friable. The microscopic pathology of both plaques was not remarkable. Possibly some tissue changes were present in the intimal and subintimal layers of the vessels, but these were not surgically removed. Case 5. Fifty-five-year-old male with documented history of myocardial infarction in early 1965. He had been taking polysorbate 80 with choline and inosital, isosorbibe dinitrate, meclizine hydrochloride with niacin, and meperidine hydrochloride for a period of I4 months. His pretreatment ECG was consistent with an old inferior wall infarction. The pretreatment serum cholesterol level was 304 mg./lOO ml. After two months of clofibrate therapy, meperidine hydrochloride was discontinued, and after seven months, the meclizine hydrochloride with niacin and isosorbibe dinitrate were discontinued. There was complete disappearance of vertigo, and a few, but mild, angina1 symptoms were experienced. The serum cholesterol was maintained at an average level of 285 mg./lOO ml. Case 6, Thirty-six-year-old male who in January 1967 complained of severe myocardial pain precipitated by slight exertion and frequently experienced at rest. The resting ECG showed nonspecific T-wave inversion in lead AVL. The patient was hospitalized in September I967 because of an increase in intensity and frequency of the symptoms of myocardial ischemia. At this time the resting ECG was unchanged, but a Master II-step provocative test? was interpreted as showing the appearance of an incomplete right bundle branch block and diffuse ST segment depressions immediately after exercise (see Fig. 3, Top). Clofibrate therapy and administration of isosorbibe dinitrate had been continued throughout the period indicated. Following September 1967, a gradual decrease of the angina1 symptoms was reported and in December 1967, the isosorbibe dinitrate was discontinued. In March 1968, the resting ECG showed a diphasic T-wave in lead AVL and the Master II-step provocative test was normal (see Fig. 3, Bottom). The patient had now become completely asymptomatic.

644

ALBERT

AND STANSELL

DISCUSSION

As anticipated, clofibrate lowered serum cholesterol levels in 88 of 95 patients, and serum uric acid in 10 patients with hyperuricemia. The 4655 year group evidenced the poorest response to clofibrate, and interestingly, this group represents the critical period of coronary atherosclerosis in the United States. Associated with serum cholesterol lowering, it can be assumed, based on numerous previous reports, that there is simultaneous alteration in the levels and/or quality of alpha and beta lipoproteins, of the ratios of these two fractions, of chylomicra, of phospholipids, of glycerides and of numerous other blood constituents. The importance of determining which of these effects, individually or all, are associated with the control or regression of cerebral, coronary and peripheral atherosclerosis, and xanthum tuberosum of the skin warrants more critical and exhaustive investigation. ACKNOWLEDGMENTS The clofibrate used in this study was supplied as Atromid-S by J. Noble, M.D., Ayerst Laboratories, New York. Dr. E. Gonzales supplied the vascular surgical reports. Dr. L. Helfer interpreted the cerebroangiograms. Dr. J. Sykes supplied the opthahnological reports. S. J. Stansell performed the laboratory analyses. Southwest Research Institute, San Antonio, Texas, performed the computer data analysis. The views expressed herein are those of the authors and do not necessarily reflect the views of the United States Air Force or the Department of Defense. GENERIC AND TRADE NAhlES OF DRUGS Clofibrate: Atromid-S Meperidine Hydrochloride: Demerol, Mepergan Polysorbate 80 ( Choline-inositol) : Monichol Isosorbibe Dinitrate: Isordil, Isordil Tembids Meclizine Hydrochloride and Niacin: Antivert, Bonadoxin, Bonine Nicotinic Acid: Antivert, Adenocrest, Adrenolin Forte, Barba-Niacin, Estrogens, Conjugated: Premarin, Conjutabs, Femogen, Estratab, Milprem Thyroid: Letter, Cytomel, Android, Armour Thyroid, Curban Thyroxine, Synthroid Sodium, Levoid, Titroid Pentaerythritol Tetranitrate, Peritrate

Benizol Plus, Gerilid Formatrix, Menrium,

REFERENCES 1. Best, M. M., and Duncan, C. H.: Hypoglyceridemic effect of ethyl-ap-chlorophenoxyisobutyrate with and without androsterone. Circulation 28:696, 1963. 2. Berkowitz, D.: The effects of chlorowithout phenoxyisobutyrate with and androsterone on the serum lipids, fat tolerance and uric acid. Metabolism 14:966, 1965. 3. Carson, P., McDonald, L., Pickard, S., Pilkington, I., Davies, B., and Love, F.: Effect of Atromid on platelet stickiness. J. Atheroscler. Res. 3:619, 1963. 4. Gilbert, J. B., and Mustard, J. F.:

Some effects of Atromid on platelet economy and blood coagulation in man. J. Atheroscler. Res. 3:623, 1963. 5. Robinson, R. W.: Platelet adhesiveness and aggregation with chlorophenoxyisobutyric ester. Amer. J. Med. Sci. 253: 106, 1967. 6. Gibelli, A.: Fibrinolytic activity and reduction of platelet adhesiveness following prolonged administration of ethyl-chlorophenoxy-isobutyrate ( Atromid-S ). Hemostase, 6:285, 1966. 7. Strivastava,

S. C., Smith,

M. J., and

VASCULAR

SYMPTOMATIC

RELIEF

Dewar, H. A.: The effect of Atromid on fibrinolytic activity of patients with iscbaemic heart disease and hypercholesterolaemia. J. Atheroscler. Res. 3~640, 1963. 8. Sideri, G. C., Capelli, F., and Centonza, D.: La Fibrinogenemia nell infarto miocardico. Suo valore diagnostic0 e prognostico. Folia Cordiol. 25:202, 1966. 9. Hood, B., Bedding, P., and Carlander,

645 lipoprotein lipase and B.: B-lipoprotein, Atromid. J. Atheroscler. Res. 3:509, 1963. 10. Ferro, P. V., and Ham, A. B.: Rapid determination of total and free cholesterol in serum. Amer. J. Clin. Path. 33:545, 1960. 11. Master, A. M., and Rosenfeld, I.: Criteria for the clinical application of the “two step” exercise test. JAMA, 178:283, 1961.