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Simvastatin
Simvastatin
Simvastatin is a lactone prodrug which is metabolized after oral
ingestion to the dihydroxy open acid form which inhibits 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme which
catalyses an early rate-limiting step in the biosynthesis of cholesterol.
Chemistry
Simvastatin (synvinolin, MK-733, Zocor) (1S,3R,7S,8S,8aR)1,2,3,7,8,8a-Hexahydro-3,7-dimethyl-8-(2-[(2R,4R)-tetrahydro-4hydroxy-6-oxo-2H-pyran-2-yl]ethyl)-1-naphthyl-2,2dimethylbutanoate
C25 H3805
Molecular weight
:pKa
Solubility
in alcohol
in water Octanol/water partition
coefficient
418.6
-
freely soluble
almost insoluble
high
Simvastatin is a white crystalline powder. It is prepared by replacing
the 2-methy-butyryl side chain of lovastatin with a 2,2-dimethybutyryl group. It is not present in any combination preparations.
Pharmacology
Simvastatin is a -lactone obtained by chemical modification of
lovastatin. Hydrolysis of the lacton by esterases results in the
dyhidroxy open acid originally desigrated by the manufacturer
as L654,969, now known as Simvastatin add or SVA, which is the
active form of the compound. This active metabolite is a
competitive inhibitor of HMG-CoA reductase, a key rate-limiting
enzyme in the cholesterol biosynthetic pathway. The Ki of inhibition
of the solubil-ized HMG-CoA reductase preparation obtained
from rat liver microsomes is approximately 1 x 10-10 M. The enzyme
HMG-CoA reductase catalyses the conversion of HMG-CoA to
mevalonate.
The main mechanism of reduction of low density lipoprotein
(LDL) cholesterol is that, following inhibition of HMG-CoA reductase activity, the LDL receptor density on the liver cells is increased
(up regulation) and t h i s leads to an ircreased removal of LDL
cholesterol from the plasma and increased catabolism of LDL
cholesterol. In addition there is a reduction in the very low density
lipoprotein (VLDL) cholesterol and reduced formation of LDL from
VLDL. Inhibition of HMG-CoA reductase does not lead to a build
up of intermediary metabolites since this enzyme step is involved
early in the synthetic pathway for cholesterol. The precursor HMGCoA is readily metabolized back to acetyl CoA which participates in
many biosynthetic processes throughout the tissues of the body. Two
systems have been utilized to demonstrate that Simvastatin is an
inhibitor of cholesterol synthesis; mammalian cells grown in culture
and in vivo studies in various species.
In cultured mammalian cells simvastatin inhibited the incorporation of radiolabelled acetate into sterols with IC50 values of 20 nM or
less. In Hep-G2 cells Simvastatin inhibits cholesterol formation
from acetate in a dose-dependent fashion without inhibiting its
formation from mevalonate. HMG-CoA reductase activity was
increased and the specific binding of LDL to the cells was increased,
suggesting increased expression of the LDL receptor.1 In the rat the
drug blocked cholesterol synthesis after a single oral dose with ID50
values of less than 0.2 mg.kg-1.
Studies have been carried out in the dog to assess the effects of
Simvastatin on serum total lipoprotein cholesterol. The drug effectively lowers circulating cholesterol in this species, both in the
presence and absence of cholestyramine, whereas in rats it has no
sustained effect on cholesterol levels. In rodents in vivo other
products of the cholesterol synthetic pathway (e.g. oxysterols) inhibit
cholesterol synthesis by feed back regulation and during simvastatin
therapy this feed back is diminished or removed. The net result in the
rat is that HMG-CoA reductase activity is increased so greatly that
no fall in serum cholesterol takes place. In dogs treated with 12 g
daily of cholestyramine, cholesterol is decreased by an average of
35%. Treatment of these animals with 1 and 2 mg.kg-1 daily of
simvastatin resulted in an additional 29.1% and 37.6% decrease
respectively from the cholestyramine baseline. These effects of simvastatin are primarily on LDL cholesterol in spite of the fact that
approximately 70-80% of circulating cholesterol in the dog is in the
form of high density lipoprotein (HDL). In the cholestyramineprimed dogs, LDL cholesterol decreased by 57-72% with a 19-38%
increase in HDL.
In cholesterol fed (0.25% of diet) rabbits 2 there was a dose
dependent inhibition of the increase in serum cholesterol over the
range 0.7 mg.kg -1 to 6 mg.kg-1.
Ancillary pharmacology studies to assess effects on organ systems
and biological parameters were conducted with L654,969. No major
changes were seen. Minor effects were noted on acid secretion and
respiratory parameters in dogs.
s
Toxicology
The oral LD50 of simvastatin in mice is approximately 3.8 g.kg-1
and in rats approximately 5 g.kg-1
Hepatic changes have been detected in several species used in
toxicity tests. In the rat these changes appeared to be due to
proliferation of the smooth endoplasmic reticulum consequent upon
induction of HMGCo-A reductase. They were reversible by mevalonate. In the rabbit a dose of 50 mg kg-1 caused a 50% mortality and
a high incidence of centrilobular necrosis in the liver and tubular
necrosis in the kidney. These changes were prevented by mevalonate
feeding. In the dogs there were elevations of transaminases without
histological changes and there were no hepatic changes in the
monkey.3 Acanthosis and hyperkeratosis in the rat forestomach and
testicular degeneration in the dog appear to be species specific
changes.
At very high doses simvastatin causes cataracts in dogs. 4 The
amounts of drug in the lenses of animals developing cataracts (< 500
mg.l-1) were low and there was no change in cholesterol content or
sterol composition in these lenses. While there is no clear correlation
between the magnitude of serum lipid-lowering and the development
of cataracts, a consistent relationship has been observed between high
serum levels of drug and cataract development with simvastatin and
related HMG-CoA reductase inhibitors. A suggested mechanism is
that high concentrations of the drug in the aqueous humor inhibit
cholesterol synthesis in the outer cortical region of the lens. There
appears to be a wide margin of safety for the human lens, based on
either dose or on plasma concentration.
At maximally tolerated doses in both the rat and the rabbit,
simvastatin produced no fetal malformations and had no effects on
fertility, reproductive function or neonatal development. Other related inhibitors of HMG-CoA, however, including the open acid
form of simvastatin (L-654,969) have produced treatment- related
skeletal malformations in the fetus. This is thought to be a result of a
decrease in the availability of mevalonic acid to the developing fetus.
In vitro and in vivo genetic toxicity tests provided no evidence of
an interaction of simvastatin or L-654,969 with genetic material.
In mouse carcinogenicity studies conducted with simvastatin at
S25
Simvastatin
Simvastatin
doses from 1 mg.kg -1 daily to 25 mg.kg -1 daily, there was no
evidence of a treatment-related incidence of tumour types in any
tissue. In similar studies in rats a statistically significant increased
incidence of thyroid follicular cell adenomas was observed in females
receiving 25 mg.kg -1 day-1 (31 times the maximum human dose). No
other statistically significant increased incidence of tumour types was
found in any tissues.
Clinical pharmacology
Simvastatin lowers both total and LDL cholesterol in patients with
heterozygous familial, familial combined, familial dysbetalipoproteinemia and non-familial (non-FH) forms of hypercholesterolaemia 9
Simvastatin has been shown to reduce both normal and elevated
LDL cholesterol concentrations by 25-40% in a dose-dependent
manner with doses in the range 10-40 mg daily. Simvastatin also
causes a modest reduction (10-15%) of VLDL cholesterol and a rise
in HDL cholesterol of similar magnitude. There is a small reduction
in concentration of triglycerides in plasma. Apolipoprotein B also
falls substantially during treatment with simvastatin. Since each LDL
particle contains one molecule of apolipoprotein B, and since little
apolipoprotein B is found in other lipoproteins, this strongly suggests
that simvastatin does not merely cause cholesterol to be lost from
LDL, but also reduces the concentration of circulating LDL particles. As a result of these changes the ratio of total to HDL cholesterol
and LDL to HDL cholesterol are reduced. However, Lp(a) levels are
not reduced by treatment with this drug or other inhibitors of HMGCoA reductase 10 Female FH patients with the apoE3E3 phenotype
appear to respond better to simvastatin than male patients with the
same phenotype.11
In a study in 7 normolipidaemic volunteers given simvastatin
20 mg daily for a month, 125-I-labelled LDL and 131-I-labelled
cyclohexanedione-treated LDL were used to quantify the receptor
pathway. Simvastatin did not modify the synthetic rate of LDL-apo
B but increased the catabolic rate of the receptor-dependent pathway
and the contribution of this pathway to overall catabolism. It
appeared that the fall in LDL could be entirely explained by
enhanced fractional removal by the receptor route. 12
Simvastatin is a specific competitive inhibitor of HMG-CoA
reductase. At therapeutic doses, however, the enzyme is not completely blocked, thereby allowing biologically necessary amounts of
mevalonate to be available. Steroidogenesis is unaffected although a
small rise in ACTH levels has been noted 13 Platelet hyperreactivity in
untreated FH patients is decreased by treatment with simvastatin. 14
Pharmacokinetics
S26
Most pharmacokinetic studies with the drug have been carried out
using radioactive tracer doses supplemented by HPLC with UV
detection or FAB mass spectrometry. 15 Simvastatin is an inactive
lactone which is readily hydrolysed in vivo to the corresponding hydroxy acid, L-654,969 a potent inhibitor of HMG-CoA reductase.
In some species conversion of the lactone to the open acid occurs in
plasma but this 'lactonase' activity is not present in human plasma
and the conversion takes place, mainly in the liver. Inhibition of
HMG-CoA reductase is the basis for an assay used in pharmacokinetic studies for the -hydroxy acid metabolites (active inhibitors)
and, following base hydrolysis, active plus latent inhibitors (total
inhibitors). Both are measured in plasma following administration of
simvastatin.
When the availability of L-654,969 to the systemic circulation
following an oral dose of simvastatin was estimated using an
intravenous reference dose of L-654,969, the value was found to be
less than 5% of the dose. By analogy with the dog, simvastatin
appears to be well absorbed, and undergoes extensive first- pass
extraction in the liver, its primary site of action, with subsequent
excretion of metabolites in the bile. Availability of active drug to the
general circulation is low. Maximum plasma concentrations of
inhibitors occur 1.3-2.4 hours post-dose.
In dose-proportionality studies using doses of simvastatin of 5, 10,
20, 60, 90 and 120 mg there was no substantial deviation from
linearity of area under the curve (AUC) of inhibitors in the general
circulation with increasing dose. The plasma profile of inhibitors is
not affected when simvastatin is administered immediately before a
test meal rather than in the fasting state.
Pharmacokinetic studies of single and multiple doses of simvastatin
showed that no accumulation of drug occurs during multiple dosing
Both simvastatin and L-654,969 are highly bound to plasma
proteins (98%).
In a disposition study with 14C-labelled simvastatin, 100 mg (20 uCi)
of drug was administered as capsules (5 x 20 mg), and blood, urine and
faeces collected. 13% of the radioactivity was recovered in the urine
and 60% in the faeces. Most of the urinary and faecal radioactivity was
from metabolites, not simvastatin or the open acid. This suggests that
the drug is well absorbed but subject to extensive biliary excretion as
the drug is unlikely to be metabolised by gut flora. Less than 0.5% of
the dose was recovered in the urine as HMG-CoA reductase inhibitors
In plasma, inhibitors account for 14% and 28% (active and total
inhibitors) of the AUC of total radioactivity, indicating that the
majority of metabolites are inactive or weak inhibitors.
Tissue distribution studies 4 h after a 1 mg.kg-1 intravenous dose
in the rat showed high concentrations in intestinal contents and
moderate amounts in the liver and kidneys. In dogs given a
60 mg.kg-1 radiolabelled dose by mouth the highest concentration
4h after the dose was in bile (2389 mg equiv.1 -1) with substantial
amounts in the liver (15.6ug equiv.g -1) and kidney ( 8 . 2ug
equiv.g-1). Amounts in the lens (0.08 ug equiv.g-1) aqueous humor
and CSF were very low. Although it is not known whether simvastatin crosses the placenta or is excreted in breast milk, it seems likely
that this will occur, given the lipid solubility of the parent compound
No information is available on transfer of the active metabolites
Little simvastatin or its inhibitory metabolites is excreted in the
urine.
Oral absorption Presystemic
metabolism
Plasma half life
Volume of distribution
Plasma protein binding
extensive
extensive
98%
The effects of liver disease on the kinetics of simvastatin are no:
known.
Concentration-effect relationship
There is insufficient data in man to establish concentration-effect
relationships.
Metabolism
Simvastatin (SV) is extensively netabolized in the liver which is also
the main site of action of the drug. 16 The paths of metabolism are
shown in Figure 1. Metabolite 1, 6'-OH-SV, is formed by
microsomal oxidation in liver. It is a major metabolite in
microsomal prepara-tions. Metabolite II is an allylic
rearrangement product of 1 with the with the 6'-OH group moving
to the 3' position and double bond rearrangement. Metabolite
IIIis a second oxidation product but with the hydroxyl group in
the 3 position of the acyl side chain. It is-formed by rat
microsomes. Metabolite IV is the triene, 6'- exomethy-lene-SV. It is
a microsomal poduct and it may be formed by a double hydrogen
abstraction catalysed by cytochrome P-450. Microsomal
metabolism of these compounds is stereoselective. 17 Formation of
simvastatin acid (SVA) ocurs as a result of the activity of
microsomal and plasma esterases.
The major metabolites pesent in human bile are the hydroxy
acid form of 3'-OH-SV, and two products of 6'-exomethylene-SV
(M-IV). 6'-COOH-SV (M-VI) and 6'-beta-CH2OH-SV (M-V). The
acid form of M-II was inactive but M-V and M-VI were active with
about 90% and 40% of the activity of SVA respectively. The main
product in plasma is simvastatin acid but the main biliary
metabolites have also been identified in plasma.
Pharmaceutics
Simvastatin is available only in tablet form.
1. Zocor (MSD, UK) tablets containing 10 mg simvastatin are
peach coloured, oval film-coated and marked 'ZOCOR 10' on
one side. Tablets containing 20 mg simvastatin are tan-coloured
oval, film-coated and are marked 'ZOCOR 20' on one side.
Simvastatin
Simvastatin
Simvastatin is currently marketed in Europe, Australia and
South Africa.
2. Acute liver disease or unexplained persistent elevations of serum
transaminases
3. Pregnancy and breast feeding
4. Women of child-bearing potential unless adequately protected
by barrier contraceptive methods
5. In patients with the homozygous form of familial
hypercholesterolaemia, in whom there is a complete absence of
LDL receptors, therapy with simvastatin is unlikely to result in
clinical benefit
6. As simvastatin has only a moderate triglyceride-lowering effect
it is not indicated where hypertriglyeridaemia is the abnormality
of most concern (i.e. hyperlipidaemia types I, IV and V).
Therapeutic use
Indications
1. Primary hypercholesterolaemia in patients who have a
cholesterol ovel in excess of 7.8 mmol.l-1.
Contraindications
1. Hypersensitivity to any component of the preparation
Fig. 1
The metabolism of simvastatin
Simvastatin
acid
II 3'Hydroxysimvastatin
6'-Hydroxymethylsimvastatin
VI Simvastatin
6'carboxylic acid
Simvastatin
Simvastatin
Mode of use
markedly elevated CPK levels occur or if myopathy is diagnosed.
Minor asymptomatic transient rises in serum transaminases may
occur soon after initiation of treatment. These do not require the
drug to be discontinued. There is no evidence of hypersensitivity.
It is recommended that liver function tests be performed before
treatment begins, every 4-6 weeks during the first 12 months of
therapy and periodically thereafter in all patients. Special attention
should be paid to patients who develop elevated serum transaminase
levels and in such patients measurements should be repeated
promptly and then performed more frequently. If the transaminase
levels show evidence of progression, particularly if they rise to three
times the upper limit of normal and are persistent, the drug should be
discontinued. Liver biopsy should be considered if elevations persist
after the drug has been stopped.
Simvastatin should be used with caution in patients who consume
substantial quantities of alcohol.
Simvastatin is generally well tolerated and adverse effects have
usually been mild and transient in nature. Less than 2% of patients
were withdrawn from controlled clinical studies because of effects
attributable to simvastatin.
Taking all clinical studies, both controlled and uncontrolled,
adverse effects occurring with a frequency of 1% or more and
considered by the investigator as possible, probably or definitely
drug-related, were constipation, flatulence and headache. Other
adverse effects occurring in 0.5-0.9% of patients were: nausea,
dyspepsia, gastrointestinal cramps and other abdominal pains, diarrhoea and fatigue. 25
Before initiating therapy with simvastatin, secondary causes for elevated cholesterol values, such as obesity, poorly controlled diabetes
mellitus, hypothyroidism, nephrotic syndrome, obstructive liver
disease, or drug therapy, should be excluded. It is important to
determine whether increased levels of total cholesterol are due to
increased LDL cholesterol before initiating treatment. In primary
hyperalphalipoproteinaemia (elevated HDL cholesterol), serum levels
of total cholesterol may be elevated. Treatment with cholesterollowering agents in this instance is not indicated. When total cholesterol
is elevated along with marked hypertriglyceridaemia (> 5.0 mmol.l -1),
the intermediate density lipoprotein (IDL) fraction may be increased.
The efficacy of simvastatin has not been evaluated in such patients.
Prior to starting treatment with the drug, patients should be placed
on a cholesterol-lowering diet and maintained on it during treatment.
Fasting lipids should be measured and, as part of safety assessment
procedures, liver function test, plasma creatine phosphokinase and
urine microscopy should be performed.
Simvastatin is administered initially as a 10 mg dose once daily at
bed time. The maximum effect of a given dose is evident within 4
weeks. Measurement of the lipid profile and biochemical safety tests
should be repeated and, if necessary, the dose can be increased to
20 mg. The maximum recommended dose is 40 mg daily although
80 mg has been used in clinical trials. In some studies the dose has
been divided between morning and evening doses 8 and in others it
has been given once a day but there is little to be gained by twice daily
dosing or increasing the dose above 40 mg daily. Once the desired
reduction of cholesterol has been achieved the patients can be seen at
2-3 month intervals. Drug therapy should be discontinued if there is
a persistent increase greater than 3 times the upper limit of normal in
serum transaminases or marked elevated CPK (MM fraction) of
greater than ten times normal (although this test is very sensitive to
heavy physical activity).
Administration of simvastatin 10-40 mg daily is associated with a
23-38% decrease in LDL cholesterol which is similar regardless of
the patients age, sex, pretreatment LDL-cholesterol level or diagnostic
classification (familial hypercholesterolaemia, familial combined
hyperlipidaemia, polygenic hyperlipidaemia). On average a 40 mg
daily dose will bring about a 25-35% reduction in total cholesterol, a
15% increase in HDL-cholesterol and a 15-25% reduction in
triglyceride levels.18-22
Combination therapy should be considered in patients who, despite maximal doses (40 mg) of simvastatin fail to achieve target
cholesterol levels as recommended by the European Atherosclerosis
Study Group 23 or National Cholesterol Education Program Expert
Panel. 24 Simvastatin is effective alone or in combination with bile
acid sequestrants. Combination of simvastatin 40 mg daily with
cholestyramine resulted in an additional 12% reduction in cholesterol, a 9% increase in HDL and a 16% decrease in triglycerides. 19
Adverse reactions
Potentially life-threatening effects
None has been reported.
Acute overdosage
There are no data available on overdosage. No antidote is available.
General measures should be adopted, and liver function should be
monitored.
Severe of Irreversible adverse effects
Therapy with the closely associated compound, lovastatin, has been
associated with myopathy, including rare instances of severe rhabdomyolysis with secondary acute renal failure. All patients recovered
upon discontinuation of lovastatin therapy with appropriate supportive medical intervention. Myolysis has also been reported with
simvastatin (see Clinical Trials, Emmerich et al).
Symptomatic adverse effects
Myopathy should be considered in any patient with diffuse myalgias,
muscle tenderness and/or marked elevations of creatine phosphokinase. Transient increases associated with heavy or unaccustomed
physical activity are not a reason for cessation of treatment but
patients should be asked to report promptly any unexplained muscle
pain, tenderness or weakness. Simvastatin should be discontinued if
Interference with clinical pathology tests No
information is available.
High risk groups
Neonates
Studies to show safety and effectiveness in neonates have not been
carried out.
Breast milk. It is not known whether simvastatin or its metabolites are excreted in human milk. Simvastatin should be avoided
during lactation.
Children
Studies to show safety and effectiveness in children have not been
carried out.
Pregnant women
The active metabolite, simvastatin acid was shown to produce fetal
malformations in the offspring of pregnant rats. There are no data
available for the use of simvastatin in pregnant women. Therefore,
the drug is contraindicated for use in pregnancy. An interval of one
month should elapse between the end of simvastatin therapy and
planned conception.
The elderly
Although experience in elderly patients is relatively limited, efficacy
using standard doses appears similar to that seen in the population as
a whole. There is no apparent increase in the frequency of clinical or
laboratory adverse findings.
Concurrent disease
Renal insufficiency. Because simvastatin does not undergo signiticant renal excretion, modifications of dosage should not be
necessary in patients with renal insufficiency.
Liver disease. The drug is contraindicated in patients with liver
disease.
Drug interactions
Potentially hazardous interactions
Coumarin derivatives. The administration of simvastatin appeared to slightly enhance the anticoagulant effect of warfarin mean
changes in prothrombin time less than two seconds) in normal
volunteers maintained in a state of low therapeutic anticoagulation
The clinical importance of these findings for fully anticoagulated
patients receiving concomitant chronic therapy with simvastatin is
unknown. In patients taking anticoagulants, prothrombin time
should be determined prior to starting therapy with simvastatin and
then monitored at the intervals usually recommended for patients on
coumarin anticoagulants.
Simvastatin
Simvastatin
In clinical studies, simvastatin was used concomitantly with  -_
blockers, calcium channel blockers, diuretics and non-steroidal antiinflammtory drugs (NSAIDs) without evidence of clinically significant adverse interactions.
Other significant interactions
Walker J F 1989 Simvastatin: the clinical profile. American Journal
of Medicine 87: 44S-46S Todd PA, Goa K L 1990 Simvastatin: a
review of its pharmacological
properties and therapeutic potential in hypercholesterolaemia.
Drugs 40: 583-607
Potentially useful interactions
No information yet available.
References
Clinical trials
No outcome trial results are available. Many short term studies on
hypercholesterolaemic patients have been undertaken.
1. Jones PH 1990 Lovastatin and simvastatin prevention studies.
American Journal of Cardiology 66: 39B-43B
An outline of the design of two proposed outcome trials.
2 Emmerich J, Aubert I, Bauduceau B et al 1990 Efficacy and safety of
simvastatin (alone or in association with cholestyramine). A 1-year
study in 66 patients with type II hyperlipoproteinaemia. European
Heart Journal 11: 149-155
The effects and safety of simvastatin were investigated alone or in
combination with cholestyramine in 66 patients with hypercholesteralaemia, in a 1-year open study.
In type IIa hypercholesterolaemia (n = 41), the association was
more effective than simvastatin used alone in lowering total cholesterol (37% vs 29%) and LDL-cholesterol (45% vs 37%). In type IIb
hypercholesterolaemia (n = 23), combined treatment did not appear
more effective than simvastatin used alone. The most serious
sideas myolysis in two patients.
3. Stein E, Kreisberg R, Miller V, Mantell G, Washington L, Shapiro D
R 1990 Effects of simvastatin and cholestyramine in familial and
nonfamilial hypercholesterolemia. Multicenter Group I. Archives of
Internal Medicine 150: 341-345
Simvastatin was compared with cholestyramine in a randomized
open 12-week multi centre study of 251 patients with familial or
confamilial hypercholesterolemia. Simvastatin, 20 mg and 40 mg
daily, produced mean reductions in total cholesterol of 26% and
33%, respectively, and reductions in low-density lipoprotein
choles-trol level of 32% and 40%. Cholestyramine resin, 4 to 12 g
twice daily, reduced total cholesterol and low-density lipoprotein
choles-erol levels 15% and 21%, respectively. High-density
lipoprotein cholesterol levels were increased 8% to 10% by all
treatments. Plasma triglyceride levels were moderately decreased by
simvastatin treatment, while triglyceride levels increased with
cholestyramine treatment. Simvastatin was better tolerated than
cholestyramine, which caused many gastrointestinal tract side
effects. No patient had serious drug-related adverse event.
Tikkanen M J, Bocanegra T S, Walker J F, Cook T 1989 Comparison
of low-dose simvastatin and gemfibrozil in the
patient of elevated plasma cholesterol. A multicenter safety. The
Simvastatin Study Group. American Journal of Medicine 87(4A):
47S-53S
his was a 12-week, randomized, double-blind, multicentre study to
compare the efficacy and safety of simvastatin and gemfibrozil in
290 patients with primary hypercholesterolemia. Patients were
stratified to those with initial LDL cholesterol level less than 195
mg daily and stratum II with initial LDL at least 195 mg daily.
Simvastatin as given as a dose of 5 to 20 mg once daily, gemfibrozil
in a constant dosage of 600 mg twice daily. Simvastatin reduced
LDL cholesterol levels by 26 and 34 percent in strata I and II,
respectively. The corresponding reductions brought about by
gemfibrozil were 18 and percent. Both were well tolerated.
General review articles
Father V M. Thompson G R 1990 HMG CoA reductase inhibitors
as lipid-lowering agents: five years experience with lovastatin and
an appraisal of simvastatin and pravastatin. Quarterly Journal of
Medicine 74: 165-75
alker J F, Shapiro D R 1990 Hydroxymethylglutaryl coenzyme A
reductase inhibitors as monotherapy in the treatment of hypercholesterolemia. American Journal of Cardiology 65: 19F-22F
1. Nagata Y, Hidaka Y, Ishida F, Kamei T 1990 Effect of simvastatin (MK-733) on
the regulation of cholesterol synthesis in Hep G2 cells. Biochemical Pharmacology
40: 843-850
2. Ishida F, Watanabe K, Sato A et al 1990 Comparative effects of simvastatin
(MK-733) and pravastatin (CS-514) on hypercholesterolemia induced by
cholesterol feeding in rabbits. Biochimica Biophysica Acta 1042: 365-373
3. Gerson R J, MacDonald J S, Alberts A W et al 1989 Animal safety and toxicology
of simvastatin and related hydroxy-methylglutaryl-coenzyme A reductase
inhibitors. American Journal of Medicine 87: 28S-38S
4. Gerson R J, MacDonald J S, Alberts A W et al 1990 On the etiology of
subcapsular lenticular opacities produced in dogs receiving HMG-CoA reductase
inhibitors. Experimental Eye Research 50: 65-78
5. Mol M J T M, Erkelens D W, Gevers-Leuven J A, Schouten J A, Stalenhoef A
1986 Effects of synvinolin (MK 733) on plasma lipids in familial
hypercholesterolaemia. Lancet 2: 936-939
6. Hagemenas F C, Pappu A S, lllingworth D R 1990 The effects of simvastatin on
plasma lipoproteins and cholesterol homeostasis in patients with heterozygous
familial hypercholesterolaemia. European Journal of Clinical Investigation 20:
150-157
7. Molgaard J, Von Schencer H, Olsson A G 1988 Effects of simvastatin on plasma
lipid, lipoprotein and apolipoprotein concentrations in hypercholesterolaemia.
European Heart Journal 9: 541-555
8. Stuyt P M, Mol M J, Stalenhoef A F, Demacker P N, Van 't Laar A 1990
Simvastatin in the effective reduction of plasma lipoprotein levels in familial
dysbetalipoproteinemia (type III hyperlipoproteinemia). American Journal of
Medicine 88: 42N-45N
9. Bard J M, Luc G, Douste Blazy P et al 1989 Effect of simvastatin on plasma
lipids, apolipoproteins and lipoprotein particles in patients with primary
hypercholesterolaemia. European Journal of Clinical Pharmacology 37: 545-550
10. Kostner G M, Gavish D, Leopold B, Bolzano K, Weintraub M S, Breslow J L
1989 HMG CoA reductase inhibitors lower LDL cholesterol without reducing
Lp(a) levels. Circulation 80: 1313-1319
11. De Knijff P, Stalenhoef A F, Mol M J 1990 Influence of apo E polymorphism on
the response to simvastatin treatment in patients with heterozygous familial
hypercholesterolemia. Atherosclerosis 83: 89-97
12. Malmendier C L, Lontie J F, Deleroix C, Magot T 1989 Effect of simvastatin on
receptor-dependent low density lipoprotein catabolism in normocholesterolemic
human volunteers. Atherosclerosis 80: 101-109
13. Mol M J, Stalenhoef A F, Stuyt P M, Hermus A R, Demacker P N, Van 'T Laar
A 1989 Effects of inhibition of cholesterol synthesis by simvastatin on the
production of adrenocortical steroid hormones and ACTH. Clinical
Endocrinology Oxford 31: 679-689
14. Schror K, Lobel P, Steinhagen Thiessen E 1989 Simvastatin reduces platelet
thromboxane formation and restores normal platelet sensitivity against
prostacyclin in type IIa hypercholesterolemia. Eicosanoids 1989, 2: 39-45
15. Vickers S, Duncan C A, Chen I W, Rosegay A, Duggan D E 1990 Metabolic
disposition studies on simvastatin, a cholesterol-lowering prodrug. Drug
Metabolism and Disposition 18: 138-145
16. Vickers S, Duncan C A, Vyas K P et al 1990 In vitro and in vivo
biotransformation of simvastatin, an inhibitor of HMG CoA reductase. Drug
Metabolism and Disposition 18: 476-483
17. Vyas K P, Kari P H, Pitzenberger S M 1990 Regioselectivity and stereoselectivity
in the metabolism of HMG-CoA reductase inhibitors. Biochemical Biophysical
Results and Communication 166: 1155-1162
18. Simons L A, Nestel P J, Calvert G D, Jennings G L 1987 Effects of MK-733 on
plasma lipid and lipoprotein levels in subjects with hypercholesterolaemia. Medical
Journal of Australia 147 (2): 65-68
19. Mol M J, Stuyt P M, Demacker P N, Stalenhoef A F 1990 The effects of
simvastatin on serum lipoproteins in severe hypercholesterolaemia. Netherlands
Journal of Medicine 36: 182-190
20. Antonicelli R, Onorato G, Pagelli P, Pierazzoli L, Paciaroni E 1990 Simvastatin in
the treatment of hypercholesterolemia in elderly patients. Clinical Therapeutics 12:
165-171
21. Bach LA, Cooper M E, O'Brien R C, Jerums G 1990 The use of simvastatin, an
HMG CoA reductase inhibitor, in older patients with hypercholesterolemia and
atherosclerosis. Journal of the American Geriatric Society:38: 10-14
22. Schulzeck P, Bojanovski M, Jochim A, Canzler H, Bojanovski D:1988
Comparison between simvastatin and bezafibrate in effect on plasma lipoproteins
and apolipoproteins in primary hypercholesterolaemia. Lancet 1: 611-613
23. European Atherosclerosis Society Study Group 1988 The recognition and
management of hyperlipidaemia in adults: A policy statement of the European
Atherosclerosis Society. European Heart Journal 9: 571-600
24. The Expert Panel. Report of the National Cholesterol Education Program Expert
Panel on detection, evaluation, and treatment of high blood cholesterol in adults.
Archives of Internal Medicine 148: 36-69
25. Stalenhoef A F, Mol M J, Stuyt PM 1989 Efficacy and tolerability of simvastatin
(MK-733). American Journal of Medicine 87: 39S-43S
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