USE OF ISONIAZID FOR THE TREATMENT OF HYPERLIPOPROTEINEMIA
FIELD OF THE INVENTION
The present invention relates to the use of a known drug for the prevention and treatment of hyperlipoproteinemia which can lead to heart disease.
BACKGROUND OF THE INVENTION
Hyperlipoproteinemia is a condition in which the concentration of cholesterol- and/or triacylglycerol-carrying lipoproteins in the plasma exceeds a well defined normal limit. Clinical concern arises because an elevated concentration of lipoproteins can accelerate the development of atherosclerosis, thrombosis and infarction. Numerous population studies have shown that elevated serum concentration of total cholesterol, and especially low-density lipoprotein (LDL)-cholesterol, constitutes a major risk factor for the occurrence of atherosclerotic events. It has been clearly demonstrated that lowering the concentration of cholesterol-carrying lipoproteins in plasma can diminish the risk of myocardial infarction. However, there is now well established evidence that an increase in high- density lipoprotein (HDL)-cholesterol (and thus a decrease in the LDL/HDL cholesterol ratio) also has a beneficial and protective effect against the development of atherosclerosis and its complications. It is therefore more common to use the LDL/HDL cholesterol ratio as a measure of the plasma lipid profile with respect to predisposition to heart disease.
Various therapeutic measures are currently available in order to improve plasma lipid profile. These include the administration of various
drugs which generally lower the concentration of plasma lipoproteins (Goodman and Gilman. The Pharmacological Basis of Therapeutics, Eighth Edition (1990) Pergamon Press, Inc., Maxwell House, Fairview Park, Elmsford, New York, pg. 881-894) These drugs include: (1) Fibric Acids: Aryloxyisobutyric acids and other related compounds collectively referred to as fibric acids have been found to be effective in reducing plasma concentrations of triglycerides and LDL-cholesterol. Some of these drugs have also been shown to mildly increase HDL-cholesterol. Among the better known compounds are: clofibrate, gemfibrozil, feno- fibrate, ciprofibrate, benzafibrate.
(2) HMG (hydroxymethylglutaric acid) CoA reductase inhibitors: These drugs, which are fungal-derived compounds, were found effective in lowering LDL-cholesterol and generally result in a mild increase in HDL- cholesterol. Compounds include: mevastatin, lovastatin, simvastatin, pravastatin.
(3) Nicotinic Acid: This drug decreases plasma triglycerides, LDL- cholesterol and induce a mild to moderate increase in HDL-cholesterol, but its use is limited by the frequent occurrence of serious side effects.
Most of the aforementioned drugs exert their beneficial effects mainly by reducing LDL-cholesterol. It would be advantageous to also have a drug which acts mainly to increase HDL-cholesterol without causing undue side effects,
Isoniazid, also known as isonicotinic acid hydrazide (INH), is considered to be a primary drug for the chemotherapy of tuberculosis (Goodman and Gilman, supra, pages 1146-1149). Other minor therapeutic uses which have been described for this drug include cerebellar tremor, Crohn's Disease, Huntington's Disease, Parkinson's Disease, Multiple Sclerosis and shoulder-hand syndrome. Although its precise anti-tuberculous mechanism is unknown, it was observed to act on the same hepatic enzymes as does alcohol. The latter has been shown to have the capability of increasing plasma HDL-cholesterol.
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One study (Tanalp, R. and Uzalp, B., Ankara Univ. Tip Fak. Mecm. (1978), in Chem. Abst.91(l):243k) showed an increase in blood cholesterol in rats treated with a combination of isoniazid and testosterone propionate. Another study (Manyam, B.V. in Chest 84:120 (1983)) briefly described a decrease in serum cholesterol in humans on treatment with isoniazid. A third study (Krishnamoorthy, M.S. and Karthikoyan, S. Pharmacol Res. ( 1991) 24(3):219-25) reported an increase in the levels of plasma total lipid and cholesterol in phenobarbitone sodium-pretreated rabbits after INH treatment, while treatment with INH alone did not alter the lipid levels in plasma and tissues.
Thus, there is no clear indication in the literature as to a potential use of isoniazid in treating hyperlipoproteinemia.
BRIEF SUMMARY OF THE INVENTION It is an object of the present invention to provide a drug capable of lowering the LDL/HDL plasma cholesterol ratio.
It is a further object of the present invention to provide a drug capable of increasing the HDL-cholesterol level in the plasma.
Additionally, it is an object of the present invention to provide a method of treating hyperlipoproteinemia in a mammal by drug administra¬ tion.
It has now been suφrisingly discovered that the anti-tuberculosis drug isoniazid is active in increasing the HDL cholesterol concentration in the plasma. According to one aspect of the present invention, there is provided a method for decreasing the LDL/HDL cholesterol ratio in the plasma of a mammal comprising administering isoniazid to the mammal.
Further in accordance with this aspect of the present invention, there is provided a method for decreasing the LDL/HDL cholesterol ratio in the plasma of a mammal wherein the ratio is decreased by an increase in the concentration of HDL-cholesterol in the plasma.
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According to another aspect of the present invention, isoniazid is administered in combination with a hypolipidemic drug. The combination of the two drugs results in a lowering of the LDL/HDL ratio and enables utilizing lower doses of each of the individual drugs, thus minimizing drug specific side effects.
According to yet another aspect of the present invention, there is provided a use of isoniazid in the preparation of a pharmaceutical composi¬ tion capable of decreasing the LDL/HDL cholesterol ratio in the plasma of a mammal.
DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT
The effect of isoniazid in increasing the plasma HDL cholesterol concentration was demonstrated in the following clinical study. Nine apparently healthy individuals (six males and three females) were treated (because of suspected tuberculosis) with 300 mg/day of oral isoniazid for 6 months. Total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycer¬ ides were determined in serial blood tests taken at baseline, after 3 and 6 months of treatment, and 3 months after termination of the treatment (for which there are currently results for only 4 patients). The tests were carried out using kits (Boehringer Mannheim) based on an enzymatic hydrolysis method which measure triglycerides and cholesterol and HDL. Total cholesterol was calculated according to the Friedwald equation (Friedwald, Y. et al. Clin. Chem.. 18:499-502 (1972)). The results are presented in Tables I-IV:
Table I: HDL-Cholesterol (mg/dl)
3 month Post-
Patient Age Sex Initial 3 months 6 months treatment
1 69 F 69 71 69
2 58 F 40 44 50 42
3 22 M 56 54 59 ...
4 17 F 62 97 98 65
5 58 M 53 44 62 52
6 50 M 68 72 92 ...
7 73 M 40 39 54 ...
8 38 M 57 74 71 ...
9 43 M 47 52 62 49
Tabie II: LDL-Cholesterol (mg/dl)
3 months Post-
Patient Initial 3 months 6 months treatment
1 103 113 105
132 125 155 42
3 76 62 92
4 82 84 90 98
5 144 123 152 162
6 80 95 109
7 134 110 120
8 151 121 117
9 99 88 95 129
Table III: Total Cholesterol (mg/dl)
3 month Post-
Patient Initial 3 months 6 months treatment
1 209 201 195
228 225 260 234
3 145 125 164
4 159 194 199 179
5 226 191 240 240
6 162 194 231
7 229 188 207
8 245 212 191
9 183 163 201 196
Table IV: Triglycerides (mg/dl)
3 months Post-
Patient Initial 3 months 6 months Treatment
1 184 158 165
2 280 281 275 428
3 66 47 64
4 74 66 54 79
5 144 121 128 131
6 71 133 151
7 276 194 161
8 185 85 64
9 161 116 95 129
The results are summarized in Table V:
Table V
parameter measured baseline 6 months p values (n=9) (n=9)
HDL-cholesterol 55±11 69±16 0.005
LDL-cholesterol 111±29 115±24 NS total cholesterol 198±37 210±29 NS triglycerides 160±82 129±70 0.165
NS - not significant
It may be seen that a significant increase in plasma HDL-cholesterol trom 55+11 mg% at baseline to 69±16 mg% at 6 months (p=0.005) was attained. No significant changes were observed in the other parameters.
This clinical study was later broadened to encompass 15 patients. The HDL-cholesterol level was measured at the baseline and after 3 and 6 months of treatment. The results are summarized in Table VI:
Table VI: HDL-cholesterol (mg/dl)
months of baseline post-treatment p values treatment (n=15) (n=15)
3 53+11 61±19 0.048
6 53±11 65+18 0.002
It can be seen that a significant increase in HDL-cholesterol was obtained with isoniazid treatment already after three months. Thus it can be seen that the administration of isoniazid results in a decrease in the LDL/HDL cholesterol ratio by increasing the HDL-cholesterol concentration.
The ratio can be further decreased by administering a hypolipidemic drug, which decreases the concentration of LDL cholesterol, in combination with isoniazid. Such drugs include fibric acids such as clofibrate, gem- fibrozil, fenofibrate, ciprofibrate and bezafibrate; HMG CoA reductase inhibitors such as mevastatin, lovastatin, simvastatin and pravastatin; and nicotinic acid.
A pharmaceutical composition can be prepared for decreasing the LDL/HDL cholesterol ratio in the plasma of a mammal which comprises isoniazid together with a pharmaceutically acceptable excipient. Such excipients include for example amylan, acacia, tragacanth, sodium stearate glycolate, elcema, talc and calcium stearate. As discussed above, various hypolipidemic drugs can be included in the composition. The composition is preferably in an oral form. Typical doses of isoniazid are in the range of
10-300 mg accumulated dose. In the event that isoniazid is administered together with hypolipidemic drugs, the dose can be reduced.
The use of isoniazid in the treatment of hyperlipoproteinemia can provide a major contribution to the primary and secondary (post cardiovas¬ cular event) prevention of cardiovascular events, including myocardial infarction, cerebrovascular disease and peripheral vascular disease.
It will be appreciated by persons skilled in the art that the present invention is not limited to what has been thus far described, but rather the scope of the present invention is limited only by the following claims: