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Adapted from Witte, E. C.: Prog. Med. Chem. 11:199, 1975. aAfter having been kept standing at 4°C for 25 hours.

Adapted from Witte, E. C.: Prog. Med. Chem. 11:199, 1975. aAfter having been kept standing at 4°C for 25 hours.

type of hyperlipoproteinemia responds to some form of chemotherapy. The combined therapy may bring LDL levels back to normal.

Type III is a rare disorder characterized by a broad band of jS-lipoprotein. Like type II, it is also familial. Patients respond favorably to diet and drug therapy.

In type IV hyperlipoproteinemia, levels of VLDL are elevated. Because this type of lipoprotein is rich in triglycerides, plasma triglyceride levels are elevated. The metabolic defect that causes type IV is still unknown; this form of hyperlipid-emia, however, responds to diet and drug therapy.

Type V hyperlipoproteinemia has high levels of chy-lomicrons and VLDL, resulting in high levels of plasma triglycerides. The biochemical defect of type V hyper-lipoproteinemia is not understood. Clearance of dietary fat is impaired, and reduction of dietary fat is indicated along with drug therapy.

Clofibrate, USP. Clofibrate, ethyl 2-(p-chlorophenoxy)-2-methylpropionate (Atromid-S), is a stable, colorless to pale yellow liquid with a faint odor and a characteristic taste. It is soluble in organic solvents but insoluble in water.

Clofibrate is prepared by a Williamson synthesis, condensing ^-chlorophenol with ethyl a-bromoisobutyrate, or by the interaction of a mixture of acetone, ^-chlorophenol, and chloroform in the presence of excess potassium hydroxide. The acid obtained by either of these methods is esterified to give clofibrate. Both acid and ester are active; the latter, however, is preferred for medicinal use. Clofibrate is hydrolyzed rapidly to 2-^-chlorophenoxy-2-methylpropionic acid by esterases in vivo and, bound to serum albumin, circulates in blood. The acid has been investigated as a hypolipidemic agent. It is absorbed more slowly and to a smaller extent than is the ester. The aluminum salt of the acid gives even lower blood levels than ^-chlorophenoxy-2-methylpropionic acid.69

Clofibrate is the drug of choice in the treatment of type III hyperlipoproteinemias and may also be useful, to a lesser extent, in types IIb and IV hyperlipoproteinemias. The drug is not effective in types I and IIa.

Clofibrate can lower plasma concentrations of both triglycerides and cholesterol, but it has a more consistent clinical effect on triglycerides. It also affects lipoprotein plasma levels by enhancing removal of triglycerides from the circulation and causes reduction of VLDL by stimulating lipoprotein lipase to increase the catabolism of this lipoprotein to LDL.70 Clofibrate lowers triglyceride levels in the serum much more than cholesterol levels and decreases levels of FFAs and phospholipids. The lowering of cholesterol levels may result from more than one mechanism. Clofibrate inhibits the incorporation of acetate into the synthesis of cholesterol, between the acetate and mevalonate step, by inhibiting sn-glyceryl-3-phosphate acyltransferase. Clofibrate also regulates cholesterol synthesis in the liver by inhibiting microsomal reduction of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), catalyzed by HMG-CoA reductase. Clofibrate may lower plasma lipids by means other than impairment of cholesterol biosynthesis, such as increasing excretion through the biliary tract.

Clofibrate is tolerated well by most patients; the most common side effects are nausea and, to a smaller extent, other gastrointestinal distress. The dosage of anticoagulants, if used in conjunction with this drug, should be reduced by one third to one half, depending on the individual response, so that the prothrombin time may be kept within the desired limits.

Clofibrate (Atromid)

Gemfibrozil. Gemfibrozil, 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid (Lopid), is a congener of clofibrate that was used first in the treatment of hyperlipoproteinemia in the mid-1970s. Its mechanism of action and use are similar to those of clofibrate. Gemfibrozil reduces plasma levels of VLDL triglycerides and stimulates clearance of VLDL from plasma. The drug has little effect on cholesterol plasma levels but does cause an increase of HDL.

Gemfibrozil is absorbed quickly from the gut and excreted unchanged in the urine. The drug has a plasma half-life of 1.5 hours, but reduction of plasma VLDL concentration takes between 2 and 5 days to become evident. The peak effect of its hypolipidemic action may take up to 4 weeks to become manifest.

Fenofibrate. Fenofibrate, 2- [4-(4-chlorobenzoyl)phe-noxy]-2-methylpropanoic acid 1-methylethyl ester (Tricor), has structural features represented in clofibrate. The primary difference involves the second aromatic ring. This imparts a greater lipophilic character than exists in clofibrate, resulting in a much more potent hypocholesterolemic and triglyceride-lowering agent. Also, this structural modification results in a lower dose requirement than with clofibrate or gemfibrozil.

Dextrothyroxine Sodium, USP. Dextrothyroxine sodium, o-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-d-tyro-sine monosodium salt hydrate, sodium d-3,3',5,5'-tetraiodo-thyronine (Choloxin), occurs as a light yellow to buff powder. It is stable in dry air but discolors on exposure to light; hence, it should be stored in light-resistant containers. It is very slightly soluble in water, slightly soluble in alcohol, and insoluble in acetone, chloroform, and ether.

The hormones secreted by the thyroid gland have marked hypocholesterolemic activity along with their other well-known actions. The finding that not all active thyroid principles possessed the same degree of physiological actions led to a search for congeners that would cause a decrease in serum cholesterol levels without other effects such as angina pectoris, palpitation, and congestive failure. d-Thyroxine resulted from this search. At the dosage required, however, l-thyroxine contamination must be minimal; otherwise, it will exert its characteristic actions. One route to optically pure (at least 99% pure) d-thyroxine is the use of an l-amino acid oxidase from snake venom, which acts only on the l-isomer and makes separation possible.

The mechanism of action of d-thyroxine appears to be stimulation of oxidative catabolism of cholesterol in the liver through stimulation of 7-a-cholesterol hydroxylase, the rate-limiting enzyme in the conversion of cholesterol to bile acids. The bile acids are conjugated with glycine or taurine and excreted by the biliary route into the feces. Although thyroxine does not inhibit cholesterol biosynthesis, it increases the number of LDL receptors, enhancing removal of LDL from plasma.

Use of thyroxine in the treatment of hyperlipidemias is not without adverse effects. The drug increases the frequency and severity of anginal attacks and may cause cardiac arrhythmias.

d-Thyroxine potentiates the action of anticoagulants such as warfarin or dicumarol; thus, the dosage of the anticoagulants used concurrently should be reduced by one third and then, if necessary, further modified to maintain the prothrom-bin time within the desired limits. Also, it may increase the dosage requirements for insulin or oral hypoglycemic agents if used concurrently with them.

Cholestyramine Resin, USP. Cholestyramine (Cuemid, Questran) is the chloride form of a strongly basic anion-exchange resin. It is a styrene copolymer with divinylbenzene with quaternary ammonium functional groups. After oral ingestion, cholestyramine resin remains in the gastrointestinal tract, where it readily exchanges chloride ions for bile acids in the small intestine, to be excreted as bile salts in the feces. Cholestyramine resin is also useful in lowering plasma lipids. The reduction in the amounts of reabsorbed bile acids results in increased catabolism of cholesterol in bile acids in the liver. The decreased concentration of bile acids returning to the liver lowers the feedback inhibition by bile acids of 7-a-hydroxylase, the rate-limiting enzyme in the conversion of cholesterol to bile acids, increasing the breakdown of hepatic cholesterol. Although biosynthesis of cholesterol is increased, it appears that the rate of catabolism is greater, resulting in a net decrease in plasma cholesterol levels by affecting LDL clearance. The increase of LDL receptors in the liver that occurs when its content of cholesterol is lowered augments this biochemical event.

Cholestyramine resin does not bind with drugs that are neutral or with amine salts; acidic drugs (in the anion form) could be bound, however. For example, in animal tests, absorption of aspirin given concurrently with the resin was depressed only moderately during the first 30 minutes.

Cholestyramine resin is the drug of choice for type Ila hyperlipoproteinemia. When used in conjunction with a controlled diet, it reduces ^-lipoproteins. The drug is an insoluble polymer and, thus, probably one of the safest because it is not absorbed from the gastrointestinal tract to cause systemic toxic effects.

Colestipol Hydrochloride. Colestipol (Colestid) is a high-molecular-weight, insoluble, granular copolymer of tetraethylenepentamine and epichlorohydrin. It functions as an anion-exchange, resin-sequestering agent in a manner similar to that of cholestyramine resin. Colestipol hydrochloride reduces cholesterol levels without affecting triglycerides and seems to be especially effective in the treatment of type II hyperlipoproteinemias.

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