Effect of NK104, a New Hydroxymethylglutaryl Coenzyme Reductase Inhibitor, on Low Density Lipoprotei

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Effect of NK-104, a New Hydroxymethylglutaryl-
Coenzyme Reductase Inhibitor, on Low- Density
Lipoprotein Cholesterol in heterozygous Familial
HypercholesterolemiaThe American Journal of
Cardiology Volume 85(2) 15 Jan 2000 pp.178-83
Presented By Leslie Wattkis
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Introduction

• Significance cardiovascular disease
• Morbidity and mortality
• Approximately 2 million people
• Prevention
• Risk factor age, sex
• Modification, Lipid, Life style
• Diabetes's Hypertension

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Background

• Multiple studies conducted
• Lowering of Cholesterol
• Scandinavian Smivastatin (4S)
• West of Scotland Coronary Prevention (Woscops)
• Stastins smivastatin,privastatin, atrostatin
• Ctochrome p450
• Cholesterol LDL, HDL
• 3-Hydroxyl-3-methlyglutary (HMG-Coa)

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NK-104 structure
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Purpose

• Show efficacy of NK-104
• Concerning Low density Lipoprotein (LDL)
• Adverse effect of Coadministering drugs
• High density lipoprotein (HDL)
• Reduction in triglyceride levels
• Drug safety therapy in 16 Wk study
• In heterozygous familial hypercholesterolemia
• Show NK-104 alternation for patent modification
  therapy
• Indepence of cytochrome p450 pathway

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Study protocol

• National Cholesterol Education program (NCEP)
• Set diet protocol
• Calorie intake
• Between 1600 and 2,220 depend on weight and body
  height
• Cholesterol intake
• Less than 200 mg/day
• saturated fatty acid less than 7
• Total daily fat intake was less than or 30
• Placebo period less than 4 wks in 2 patients
• Serum Levels of alpoprotein

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Method

• Study Population
• 30 patients ( 15 female and 15 male)
• Ages between 38-64 an mean of 51
• Inclusion
• Hypercholesterolemia (gt230 mg/dl) with
• Tendon xanthoma or 1st degree relative of
  heterozygous
• Exclusion
• none

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Cont

• Coronary artery disease (CAD) 30 of the study
  group
• Impaired glucose intolerance 17
• Glycohemoglobin levels (HgA1C) lt7
• 19 patient received only NK-104 and 11 got
  Nk-104 with other drugs.

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Cont

• Dosage of NK-104
• Given at evenings
• 0-8 wk 2mg and 8-16 wk 4mg NK-104
• Blood sample
• post overnight fast

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Results

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ResultsNK-104 therapy

• Low density Lipoprotein (LDL)
• Decreased 40 post 8 wk tx 48 at 16wk from
  baseline
• Serum Levels
• Decreased 30 post 8 wks and 37 post 16 wks
• High Density Lipoprotein
• No significant change
• Non-HDL cholesterol
• Decreased 36 8 wk 45 _at_ 16 wk
• Triglyceride
• 2mg no change 4mg 23 from baseline

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NK-104 and LDL
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Cholesterol comparison
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Triglyceride Comparison
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No Adverse reaction
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Rationale

• Aspartate aminotransferase (AST)
• Alanine Aminotranseferase (ALT)
• Liver enzyme assist in p450 pathway
• Lacate Dehyrogenase (LDH)
• Creatine Kinase (CK)

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Conclusion

• No Evidence of side effect
• High probability it hardly enters cytchrome p450
  pathway
• Good LDL inhibitor
• Need more study
• Not enough data for clinical application
• Did not use placebo or double blind study

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Reference

• Arkemena, Baker et al JAMA 1996 275 p.128-133
• Hoogerbrugge N .Effect of Atrostatin J internal
  Medcine1998244143-147
• Sakasshantia.K Toyota et al Areneim-For/Drug Res
  1997.904-909
• Tatami, R Et al circulation 1981 641174-1184