Muscular response to mechanical overload in hypercholesterolemic patients treated with simvastatin: isokinetic evaluation through computerized dynamometry

CURRENT THERAPEUTIC RESEARCH” VOL. 57, NO. 5, MAY 1996

MUSCULAR RESPONSE TO MECHANICAL OVERLOAD IN HYPERCHOLESTEROLEMIC PATIENTS TREATED WITH SIMVASTATIN: ISOKINETIC EVALUATION THROUGH COMPUTERIZED DYNAMOMETRY S. D. GIANNINI,’ J. SCHijLZ,’ A. C. SANTOMAUR0,2 ‘Heart Institute and 2Rehnbilitation

G. T. SHINZATO,’ L. R. BATTISTELA; N. FORTI,’ L. G. SERRO-AZUL,’ AND J. DIAMENT’ Division, University of Sao Paul0 School of Medicine, S6o Pa&o, Brazil

ABSTRACT

This study was designed to evaluate changes in the functioning of striated muscle during treatment with simvastatin. Muscular activity was assessed by computerized dynamometry, which was used to determine maximum torque, total work performed, maximum power, torque acceleration energy, endurance ratio, and recovery ratio. Total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol (LDL-C) were determined using Friedewald’s formula. Fifteen outpatients (10 women and 5 men; mean age, 55.7 f 7.8 years) with primary hypercholesterolemia (LDL-C >4.14 mmol/L) who had not received lipid-lowering therapy in the previous 30 days and who were participating in atheroscleroticdisease primary-prevention programs were selected. All patients received simvastatin 10 mg/d for 30 days, followed by 20 mg/d for 30 more days. Dynamometric measurements were obtained on three occasions: (1) at baseline; (2) after 30 days of treatment with simvastatin 10 mg/d; and (3) after 30 more days of treatment with simvastatin 20 mg/d. On the same days, blood samples were collected for determination of serum lipid levels (total cholesterol, triglycerides, and high-density lipoprotein cholesterol) and serum enzyme activities (creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase), and electroneuromyographic tests were performed to analyze sensitive and motoneuron conduction response. INTRODUCTION

Myotoxicity has rarely been reported in patients being treated with 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors; studiesle7 have indicated an incidence of such adverse events of approximately 0.1% to 0.2%. However, the extent to which such drugs can cause Address correspondence to: Dr. SBrgio D. Giannini, INCOR, Av. Dr. En&s de Carvalho Aguiar, 44-CEP 05403-000, SBO Paulo, SP, Brazil. Received for publication on Jan~lary 19,1996. Printed in the U.S.A. Reproduction in whole or part is not permitted.

376

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striated muscle fiber disorders without evidence of clinical manifestations (ie, myalgia) or changes in creatine phosphokinase (CK) activity is unknown. Research on this subject is important, as patients with coronary artery disease, who frequently receive vastatins to reduce cholesterolemia, are routinely advised to be physically active. However, trials to detect subclinical muscular disorders have not been performed, since equipment sensitive enough to measure such small variations has become available only recently. Currently, muscular function is evaluated using a computerized isokinetic dynamometer (CYBEX 350, LUMEX RONKONKOMA, Bay Shore, New York), which detects minor functional disorders by measuring isokinetic effort (muscular activity against standard resistance).8 Using dynamometry, we evaluated the degree to which simvastatin (at clinically appropriate doses), the most potent HMG-CoA reductase inhibitor, interferes with the muscular functioning of hypercholesterolemic patients after 1 and 2 months of treatment. Simultaneously, the enzymatic response to isokinetic effort and the behavior of sensitive and motoneuron conduction were determined by electromyography. PATIENTS AND METHODS

After exclusion of patients with secondary hypercholesterolemia, 15 patients with serum low-density lipoprotein cholesterol (LDL-C) levels above 4.14 mmol/L after a 30-day diet period (American Heart Association phase I’) were selected from a group of outpatients who were participating in an atherosclerotic disease prevention program. The patients selected had not received lipid-lowering therapy within the previous 30 days or probucol within the previous 120 days. The patients reported no muscular complaints, and muscle enzyme activities were within normal ranges. The study comprised 5 men and 10 women aged 35 to 64 years (mean age, 55.7 + 7.8 years). Three patients had systemic arterial hypertension, as defined by the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure.” The patients were evaluated at baseline (time 01, after 30 days of treatment with simvastatin 10 mg/d (time 11, and after another 30 days of treatment with simvastatin 20 mg/d (time 2). Muscular function was always evaluated in the afternoon (1:OOPM) after a 30-minute rest.

Isokinetic Evaluation An isokinetic dynamometer was used to evaluate muscle function (Figure 1). Measurements were taken following a B-minute exercise period on an ergometric bicycle at 30 rpm without load. Patients were instructed as to the movements they were to perform (flexion and extension against

MUSCULAR

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Figure 1. Patient exercising in the CYBEX 350.

an isokinetic mechanism of resistance using the dominant limb); in addition, they were allowed to familiarize themselves with the bicycle by performing submaximal contractions under different angular velocities. The isokinetic evaluation was then initiated. It consisted of the following steps: (1)three maximal contractions at angular velocities of 60 and 180 Ysec, followed by 20 seconds of rest; (2) 20 maximal contractions at an angular velocity of 240 Vsec, followed by 100 seconds of rest; and (3) another maximal contraction series of exercises, repeating step 2 after 100 seconds of rest.

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After a 5 to lo-minute rest period, we evaluated each patient’s nondominant contralateral limb. Values obtained for the following variables are shown in Figure 2: maximum torque (MT), expressed by N/m at 60 ‘/set; relative maximum torque, expressed by MT/kg of total body weight; total work performed (TW), at 60 ‘/set expressed in joules (J); total work relative to body weight (TW/kg); maximum power (MP) at 240 ‘/set, estimated in watts; mean power relative to body weight (MP/kg); torque acceleration energy at 240 ‘lsec, expressed in J, estimated from the work developed at l/8 set after the beginning of the muscle contraction; total work performed during the first and second sets of 20 repetitions (TW SET 1 and TW SET 2) expressed in J; endurance ratio (ER), estimated from the decreasing work found among the first four (tl) and the last four (t2) contractions performed in the first set of 20 contractions (ER = t2/tl x 100); and recovery ratio, estimated from the decrease in t between the first and second sets of 20 repetitions. The measurements were determined from the knee joint using alternate contractions of the quadriceps and ischiotibial muscles. Electroneuromyographic

Evaluation

The electroneuromyographic values were determined for the ulnar and median nerves in the right upper limb as follows: sensitive neurocon-

Figure 2. Examples

of curves obtained during exercise in the CYBEX

350.

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duction, obtained by measuring distal latency expressed by m/set (normal values: median, ~3.4 m/see; ulnar, c3.5 msec); motoneuron conduction, obtained through distal latency (median and ulnar normal values, ~4.0 m/set); conduction rate, in the segment located between the elbow and the forearm (normal values: median, ~52.0 m/set; ulnar, ~57.0 m/set); repeated stimulation test at 5 Hz, evaluation of the neuromuscular junction- 10 sequential motor potentials recorded at rest and after prolonged tetanic contraction using the ulnar nerve; and electromyographic test of the opposite muscles of the thumb and the first dorsal interosseous muscle of the hand, at rest and during maximal muscle contraction performed with a monopolar needle electrode. Laboratory

Evaluation

Serum lipid levels were measured after a 12-hour fast at times 0, 1, and 2 as follows: (1) total cholesterol (TC), using calorimetric and enzymatic methods (Merck Laboratories’ kit, Merck SA, Rio de Janeiro, Brazil); (2) triglycerides (TG), using a microenzymatic method (Abbott Laboratories’ kit, Abbott Laboratories, Abbott Park, Illinois); (3) high-density lipoprotein cholesterol (HDL-C), dosing cholesterol through the same method, after precipitation of apolipoprotein B using magnesium chloride and phosphotungstic acid; and (4) LDL-C, using Friedewald’s formula” (LDL-C = TC - [VLDL-C + HDL-Cl, where very low-density lipoprotein cholesterol (VLDL-C!) = TG/5, when TG ~400 mg/dL). Serum enzymes determinations included the following: (1) CK, using the kinetic ultraviolet test (Merck Laboratories’ kit, E. Merck, Darmstadt, Germany), as recommended by the German Clinical Chemistry Association12; (2) myocardial fraction of CK (CKMB), immunoinhibition method (Merck Laboratories’ kit, E. Merck); (3) lactate dehydrogenase (LDH), kinetic ultraviolet test (Merck Laboratories’ kit, E. Merck) as recommended by the German Clinical Chemistry Association; (4) LDH isoenzymes (LDH,, LDH2, LDH,, LDH,, and LDH,), acetate membrane overlay method for multiple samples of LDH isoenzyme; (5) alanine aminotransferase, kinetic ultraviolet test (Roche Laboratories’ kit, F. Hoffmann-La Roche AG, Basel, Switzerland); (6) aspartate aminotransferase, kinetic ultraviolet test (Roche Laboratories’ kit, F. Hoffmann-La Roche AG); and (7) gamma-glutamyltransferase, calorimetric method (Abbott Laboratories’ kit, Abbott Laboratories). Blood samples were collected, both before and after the exercises were performed at each isokinetic evaluation, to detect muscle disorders through changes in CK, LDH, and fractions. Alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase were assessed at times 0, 1, and 2. Patients were to be withdrawn from the study if muscle complaints 380

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developed or enzyme levels increased more than three times above the reference values during simvastatin therapy. All laboratory evaluations were performed at the Clinical Laboratory of the Heart Institute of Sao Paulo under the surveillance of the National Institute of Standard Technology, which is recognized by the Laboratory Standardization Panell The laboratory uses four different quality controls in each run, which are repeated and compared to determine if the results are within the limits. Statistical

Analysis

One-Sample Profile Analysis, a part of the Statistical Analysis System (SAS Institute, Cary, North Carolina), was used for comparative analysis of the values of each variable at each time of measurement. Using this method, we were able to determine the F value, which represents the Wilks statistic’s approximate value for F distribution, The paired t-test was used only to compare the values obtained through dynamometry of the CK and LDH enzymes before and immediately after exercise. P < 0.05was considered statistically significant. RESULTS

Lipids Table I shows the comparative analysis of the mean values for the different lipid fractions. Significant reductions in TC and LDL-C and nonsignificant changes in TG and HDL-C were seen. Zsokinetic Evaluation The comparative analyses of the various isokinetic variables are shown in Tables II and III. There were no significant differences between any of the variables before therapy (time 0) and at times 1 and 2. This was true for the variables during both muscle flexion and extension. Electroneuromyographic

Evaluation

The values of the variables measured by electroneuromyography in the median and ulnar nerves are shown in Table IV. Treatment with simvastatin did not significantly alter the values of the variables either after the first treatment period of 30 days with 10 mg/d or after the second treatment period of 30 days with 20 mg/d. 381

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Table I. Serum lipid levels (mean 2 SD) at times 0 (baseline), 1 (after 30 days of treatment with simvastatin 10 mgid), and 2 (after 30 more days of treatment with simvastatin 20 mg/d) in 15 patients with hypercholesterolemia.

lipid

Time

Mean+ SD (mmol/L)

F’

P

0.0001t

Total cholesterol

0

7.33 ? 1.07

Triglyceride

: 0

5.75 2 0.98 5.62 1.04 1.88 k 0.96

12.59

High-density lipoprotein cholesterol

: 0

1.48 * 0.60 1.59 0.71 1.31 k 0.36

1.08

0.350

Low-density lipoprotein cholesterol

: 0

1.44 + 0.35 1.32 0.39 5.22 t 1.01

0.46

0.636

:

3.47 2 0.91 3.70 0.95

14.63

0.0001t

Using single variance analysis. t Statistically significant. l

Enzymatic

Evaluation

Aspartate aminotransferase, alanine aminotransferase, and gammaglutamyltransferase values did not vary significantly over the course of the study (Table Vl. No increases in enzyme activity were large enough to require that a patient withdraw from the study. Table VI shows the mean values for CK and CKMB immediately before exercise and at the end of muscle activity. The comparisons between the mean values before exercise at times 0, 1, and 2 and the mean values after exercise at the same times are shown in Table VII. Individual analysis showed that at time 2, two patients had total CK values slightly higher than the acceptable upper limit (>80 U/L) but not high enough to require that treatment be discontinued. Values for LDH and the LDH isoenzymes are shown in Tables VIII and IX. LDH, and LDH, had increased significantly at time 2 (Table IX). Results of isokinetic and electroneuromyographic evaluations were within the normal ranges for all patients. DISCUSSION AND CONCLUSION

The isokinetic evaluation of muscle groups through computerized dynamometry represents an important contribution to the early detection of muscle function impairment. An important aspect of impairment is muscle fatigue, which can be analyzed through measurements taken after a series of standard flexion and extension exercises performed at different angular 382

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Table II. Values (mean 2 SD) of the isokinetic variables during extension of the muscles at times 0 (baseline), 1 (after 30 days of treatment with simvastatin 10 mg/d), and 2 (after 30 more days of treatment with simvastatin 20 mgid).

lsokinetic Variables

Mean + SD

Time

110.2 + 47.7 115.8 ? 43.3 112.9 2 42.0 116.4 _t 55.9 124.8 2 56.3 123.0 t 55.0 140.0 2 69.8 146.8 t 50.4 155.2 +- 72.6 14.0 ? 6.1 14.8 t 5.4 15.0 ? 6.6 935.1 t 615.9 1013.8 2 595.3 1025.5 2 652.7 1069.0 2 646.2 1052.1 * 497.3 1047.0 2 619.5 72.0 2 17.2 63.0 ? 8.5 66.6 " 16.5 114.1 + 20.0 106.1 2 12.1 109.4 t 10.1

Maximum torque (N/m) Totalwork (TW) performed(J) Maximum power(W) Torque acceleration energy(J) TW setlt (J) TW set2t (J) Enduranceratio Recoveryratio

F”

P

0.06

0.943

0.10

0.909

0.18

0.836

0.16

0.849

0.09

0.911

0.01

0.994

1.45

1.246

0.90

0.415

* Usingsinglevariance analysis. t Twenty maximal contractions atan angularvelocity of 240 "/se& followedby 100 set of rest.

velocities. In hypercholesterolemic patients receiving simvastatin therapy, isokinetic evaluation was used to detect impairment of the muscles of the lower limbs after two 30-day treatment periods with two different dosages of simvastatin. Even after receiving the increased dosage of simvastatin (20 mg/d) for 30 days, no significant changes were seen in muscle performance. There was no significant decrease in the total work performed in either set of 20 repetitions of an exercise, indicating no increased muscle fatigue during intensive anaerobic activity. Although vastatin-induced myopathy occurs rarely, our findings are significant, since several clinical studiesle7 have indicated that functional changes in muscle fibers occur without detectable clinical or enzymatic expression. In experimental trials with rats using doses of different vastatins comparable to the doses of simvastatin we used, Smith et al demonstrated progressive dose-related muscle fiber changes. When similar doses were used, no significant difference was seen in the distribution of the different vastatins in the skeletal muscles of the rats.14 Thus the effects of the drugs on skeletal muscles seem to be dependent on their plasma concentration, and a low mean plasma concentration appears not to influence muscle activity. 383

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Table III. Values (mean i SD) of the isokinetic variables during flexion of the muscles at times 0 (baseline), 1 (after 30 days of treatment with simvastatin 10 mg/d), and 2 (after 30 more days of treatment with simvastatin 20 mg/d).

lsokinetic Variables

Time

Mean + SD 56.8 59.8 60.4 66.4 69.1 73.4 75.1 85.1 83.0 7.3 7.7 7.6 436.2 501.4 564.4 612.0 569.5 597.5 102.6 84.6 71.3 126.2 131.5 116.8

Maximum torque (N/m) Total work (TW) performed (J) Maximum power (W) Torque acceleration energy (J) TW set it (J) TW set 2t (J) Endurance ratio

2

Recovery ratio

* 21.9 ” 26.6 2 23.5 + 31.2 r 35.1 + 37.0 * 47.9 IL 44.9 * 52.8 * 2.5 2 3.2 2 2.5 + 395.5 + 440.7 * 435.7 * 512.0 * 418.1 r+_510.1 + 42.4 + 65.4 2 58.5 2 29.4 lr 81.8 2 41.4

F’

P

0.10

0.909

0.11

0.926

0.18

0.840

0.09

0.917

0.34

0.712

0.03

0.976

1.17

0.321

0.25

0.781

* Using single variance analysis. t Twenty maximal contractions at an angular velocity of 240 “/set, followed by 100 set of rest

Our investigation did not demonstrate any myopathic or neuropathic dysfunction of the neuromuscular junction. On electroneuromyographic evaluation, drug-related adverse effects on the neuromuscular junction would appear as decreased motor potentials during the repeated stimulation test, reflecting the exhaustion of the neuromuscular junction. However, this was not observed in any patient. It is important to note that at the end of the second treatment period, in which patients received simvastatin 20 mg/d for 30 days, CK values for two patients (108 and 127 U/L) were slightly above the allowable limit; however, neither of them showed any impairment of muscle function during the tests. While an increase in enzymatic activity is likely to precede functional change, this hypothesis requires further study. In addition, a comparison before and after exercise at times 0, 1, and 2 did not reveal that muscle activity had any influence on total CK or CKMB. Thus we concluded that simvastatin did not cause an increase in the release of muscle enzymes as a result of muscle work, even though exercise itself may cause a two- to threefold increase in these enzymes.15 Although exercise has no influence on total LDH, we found that it did intervene in LDH, and LDHz fractions after 30 days of treatment with 384

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Table IV. Values (mean + SD) obtained by electroneuromyograpby of sensitive latency, motor latency, and motor neuroconduction in the ulnar and median nerves at times 0 (baseline), 1 (after 30 days of treatment with simvastatin 10 mg/d), and 2 (after 30 more days of treatment with simvastatin 20 mg/d).

Mean 2 SD (m/see)

Time

P

F’

Mediannerve Sensitive latency

0

3.212 0.47

Motorlatency

: 0

3.18 3.21k + 0.31 1.27 3.45r 0.54

0.03

1.967

Motorneuroconduction

: 0

3.41+ 0.30 3.25 0.50 55.76lr4.68

0.77

0.468

:

55.472 55.69 5 5.01 2.94

0.02

0.981

0

3.042 0.30

Motorlatency

: 0

3.03* 3.02 2 0.28 2.612 0.34

0.02

0.983

Motorneuroconduction

: 0

2.81 1.78k t 0.32 0.25 65.50k 6.49

1.82

0.175

:

61.38 64.465 2 4.03 5.21

2.29

0.114

Ulnar newe Sensitive latency

* Usingsingle variance analysis.

simvastatin 20 mg/d. Because these LDH fractions reflect muscle changes, the greater plasma concentration of simvastatin may have facilitated the release of the fractions during intensive muscle activity. We were not able to locate a reference to research evaluating the influence of simvastatin on LDH fractions. Further study in this area is indicated.

Table V. Values (mean 2 SD) of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) at times 0 (baseline), 1 (after 30 days of treatment with simvastatin 10 mg/d), and 2 (after 30 more days of treatment with simvastatin 20 mg/d).

Enzyme

l

Time

Mean k SD

F’

P

ALT (U/L)

0

9.73-c2.15

AST (U/L)

: 0

12.33 11.132 ? 3.79 5.92 13.0* 3.35

1.44

0.248

GGT (U/L)

: 0

17.3k 4.96 14.0 13.24 13.782 9.04

1.09

0.248

:

12.46? 15.28 + 21.99 12.13

0.37

0.695

Usingsingle variance analysis. 385

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Table VI. Values (mean 2 SD) of creatine kinase (CK) and myocardial fraction of CK (CKMB) at times 0 (baseline), 1 (after 30 days of treatment with simvastatin 10 mgid), and 2 (after 30 more days of treatment with simvastatin 20 mg/d).

l

Mean+ SD

Time

Enzyme

W/L)

F*

P

CK

0

53.2 t 22.6

CKMB

: 0

76.3 + 61.0 5 27.4 71.5 6.0 2 2.7

0.97

0.387

:

5.5 2 2.6 6.1 2.8

0.01

0.991

Usingsingle variance analysis.

Research somewhat similar to ours was carried out by Roust et a1.16 Five healthy volunteers received lovastatin 40 mg for 30 days, and another five received placebo for the same period. They then exercised on the treadmill (14 ’ fall, 3 km/h speed) for 1 hour. After a crossover period of more than 30 days of treatment, subjects performed the same treadmill exercise a second time. The CK was determined before and 8, 24, 48, 72, 120, and 144 hours after exercise. The authors found that even with intensive muscle activity, the subjects who received lovastatin 40 mg/d did not have enzymatic changes higher than those who received placebo.16 To determine the effect of lovastatin and exercise on serum CK activity, Thompson et all7 measured CK levels before and after treadmill exercise. Pre-exercise CK levels and average CK response to exercise did not differ before and after lovastatin treatment, although in two men CK levels increased 24 hours after exercise. Thus it appears that the unusual muscle manifestations reported in patients treated with vastatins may reflect individual responses to drug concentrations in muscle; these concentrations do not necessarily reflect

Table VII. Mean pre-exercise and postexercise values of creatine kinase (CK) and myocardial fraction of CK (CKMB) at times 0 (baseline), 1 (after 30 days of treatment with simvastatin 10 mg/d), and 2 (after 30 more days of treatment with simvastatin 20 mgid). Enzyme

Time

Mean Prr;yrcise

Mean Postexercise W/L)

t

P

CK

0

53.2

64.4

1.05

0.303

CKMB

: 0 :

76.3 61.0 6.0 5.5 6.1

71.1 63.6 5.4 6.2 6.0

0.23 0.24 0.76 0.10 1.06

0.819 0.805 0.451 0.299 0.920

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Table VIII. Values (mean ? SD) of serum lactate dehydrogenase (LDH) and LDH isoenzymes (LDH,-LDH,) at times 0 (baseline), 1 (after 30 days of treatment with simvastatin 10 mgid), and 2 Wer 30 more days of treatment with simvastatin 20 mgid).

Enzyme

Time

LDH

0

160.3 k 39.4

LDH,

: 0

162.7 2 35.2 163.2 26.6 35.9 k 12.4

LDH,

: 7

LDH,

:

37.5 2 33.9 t 48.5 5 50.4 k 51.1 t 39.5 2

LDH,

: 0

LDH,

l

0.03

0.970

0.38

0.686

0.16

0.856

39.5 5 43.4 2 11.2 11.6 15.7 2 6.4

0.50

0.612

: 0

16.9 5 17.2 + 4.5 6.7 16.0 k 6.4

0.27

0.767

:

18.6 17.4 k t 5.2 7.8

0.44

0.646

9.8 11.6 13.7 15.7 11.5 14.1

Using singlevariance analysis.

Table IX. Mean pre-exercise and postexercise values of lactate dehydrogenase (LDH) and LDH isoenzymes (LDH,-LDH,) at times 0 (baseline), 1 (after 30 days of treatment with simvastatin 10 mg/d), and 2 (after 30 more days of treatment with simvastatin 20 mg/d).

Enqme

Time

LDH

0

LDH,

1

2 0

1

Mean Pre-exercise (U/L)

Mean Postexercise NJ/u

160.3 162.7 163.2 35.9 37.5

t

P

1.57

182.4 173.8 176.7 42.7 34.9

?!i 1.27 0.68

0.127 0.353 0.173 0.23 0.51

% E

38.2 56.5 55.9 52.8

2.22 1.33 2.80 1.61

0.46' 0.218 0.141

39:5 %Z

43.7 40.0

0.12 0.35 0.80

%!' 0.735

15:7

E

2.22

%!

LDH2

2 0 1

LDH3

;

LDH4

: 0

LDHS

$

1E 16.0

18.3 19.5 22.2

0.62 1.07 %I

0.547 0.302 0.020'

:

1;::

21.5 19.5

0.74

0.472 0.056

1

* Statistically significant (P < 0.05). 387

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different plasma concentrations. This hypothesis is based on experimental data in rats.14 Acknowledgment This study was supported by a research grant from Merck, Sharp & Dohme, S&o Paulo, Brazil. References.

1. Tobbert J. Efficacy 1988;62:28&34J.

and long term adverse effects pattern of lovastatin.

Am J Cardiol.

2. Bradford R, Shear GL, Chremos AN, et al. Expanded clinical evaluation of lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8,245 patients with moderate hypercholesterolemia. Arch Intern Med. 1991; 1515:43-49. 3. Mantel1 G, Burke T, Staggers Cardiol. 1990;66:llb-15b.

J. Extended

clinical

safety profile of lovastatin.

Am J

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safety, and

6. Yoshino G, Matsushita M, Iwai M, et al. Two-year study on the effect of pravastatin on plasma lipoprotein and apolipoprotein concentrations in hypercholesterolemic patients. Curr Ther Res. 1989;46:144-152. 7. Jones PH. Lovastatin 43B.

and simvastatin

8. Davies GS. A compendium Publishers; 1985.

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of isokinetics

studies. Am J Cardiol. 1990;66:39B-

in clinical usage. 2nd ed. La Crosse, WI: S & S

9. Report of National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Arch Intern Med. 1988;148:3669. 10. The Fifth Report of the Joint National Committee on Detection, Evaluation, ment of High Blood Pressure. Arch Zntern Med. 1993;153:154-183. 11. Friedewald lipoprotein 499-502.

and Treat-

WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density in plasma without use of preparative ultracentrifuge. Clin Chem. 1972;18:

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fur Klinische

Chemie. 2 Klin Chem U Klin Biochem.

13. Current status of blood cholesterol measurements States. A report from Laboratory Standardization Education Program. Clin Chem. 1988;1:193-201. 14. Smith PF, Eydelloth

RS, Grossman

1970;8:658.

in clinical laboratories of United Panel of the National Cholesterol

SJ, et al. HMG-CoA

reductase

inhibitor-induced

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myopathy in the rat: Cyclosporine A interaction and mechanism study. J Pharmacol Exp Ther. 1991;257:1225-1235. 15. Tikkanen MJ. Use of HMG-CoA reductase inhibition in clinical practice. Lipid Rev. 1992;6:1-5. 16. Roust CS, Curry SC, Guidry JR. Lovastatin use and muscle damage in healthy volunteers undergoing eccentric muscle exercise. West J Med. 1991;154:198-200. 17. Thompson PD, Gadaleta PA, Yurgalevitch S, et al. Effects of exercise and lovastatin on serum creatinine kinase activity. Metabolism. 1991;40:1333-1336.

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