Hypercholesterolemia Hyperlipidemia

RUKMINI c, REDDY SASTRY c, MCPEAKP, LYNCH I (2000) Method for treating hypercholesterolemia, hyperlipidemia, and atherosclerosis. US Patent 6,126,943. 

Atherosclerosis is a progressive vascular fibroproliferative-inflammatory disease. It is triggered, maintained, and driven by risk factors such as hypercholesterolemia, hyperlipidemia, and hypertonus [28]. The characteristic clinical manifestation of atherosclerosis is the atherosclerotic lesion, developing in the vessel wall (atherosclerotic plaque). 

Hypercholesterolemia, hyperlipidemia, hypertension, rash with high doses (5 mg/day) anemia, arthralgia, diarrhea, hypokalemia, and thrombocytopenia Rare... 

Indications Hypercholesterolemia, Hyperlipidemia, Type 2 DiabetesThrombocytopenic purpura Category PPAR modulator Half-life 1-2 hours... 

Among various types of fat deposition, visceral fat type obesity is one risk factor for metabolic diseases such as diabetes mellitus, hypercholesterolemia, hyperlipidemia, hypertension, and atherosclerosis. The risk of diseases such as diabetes mellitus and coronary heart disease, as well as all-cause mortality, increases in proportion to the increase in body adipose above optimal, but intra-abdominal distribution of fat in the body is associated more closely with disease risk. 

BARs are useful in treating primary hypercholesterolemia (familial hypercholesterolemia, familial combined hyperlipidemia, type Ila hyperlipoproteinemia). 

The principal use of niacin is for mixed hyperlipidemia or as a second-line agent in combination therapy for hypercholesterolemia. It is a first-line agent or alternative for the treatment of hypertriglyceridemia and diabetic dyslipidemia. 

Excess lipid in the blood can result from primary genetic deficiencies, most of which are rare, or as a secondary consequence of another disease. Two primary hyperlipidemias, type I hypertriglyceridemia and type IIA hypercholesterolemia, are summarized in Table 1-15-2. 

Primary hypercholesterolemia or mixed hyperlipidemia Initial dose 130 mg/day Initial dose 200 mg/day Initial dose 145 mg/day Initial dose 160 mg/day... 

It is indicated as an adjunct to diet to reduce elevated total cholesterol, LDL-cholesterol and TG levels in patients with primary hypercholesterolemia, diabetic dyslipidaemia or mixed hyperlipidemia, hypertriglyceridemia, dysbetalipo-proteinemia and familial hypercholesterolemia. 

Is an indigenous drug obtained from gum guggul used for treatment of hyperlipidemia, hypercholesterolemia and hypertriglyceridemia. 

Dietary measures are initiated first—unless the patient has evident coronary or peripheral vascular disease—and may obviate the need for drugs. Patients with familial hypercholesterolemia or familial combined hyperlipidemia always require drug therapy. Cholesterol and saturated and trans-fats are the principal factors that increase LDL, whereas total fat, alcohol, and excess calories increase triglycerides. 

Reductase inhibitors are useful alone or with resins, niacin, or ezetimibe in reducing levels of LDL. Women with hyperlipidemia who are pregnant, lactating, or likely to become pregnant should not be given these agents. Use in children is restricted to selected patients with familial hypercholesterolemia or familial combined hyperlipidemia. 

In combination with a resin or reductase inhibitor, niacin normalizes LDL in most patients with heterozygous familial hypercholesterolemia and other forms of hypercholesterolemia. These combinations are also indicated in some cases of nephrosis. In severe mixed lipemia that is incompletely responsive to diet, niacin often produces marked reduction of triglycerides, an effect enhanced by marine omega-3 fatty acids. It is useful in patients with combined hyperlipidemia and in those with dysbetalipoproteinemia. It is clearly the most effective agent for increasing HDL and the only agent that may reduce Lp(a). 

Combined drug therapy is useful (1) when VLDL levels are significantly increased during treatment of hypercholesterolemia with a resin (2) when LDL and VLDL levels are both elevated initially (3) when LDL or VLDL levels are not normalized with a single agent, or (4) when an elevated level of Lp(a) or an HDL deficiency coexists with other hyperlipidemias. 

Monogenic dyslipoproteinemias can generally be grouped into five categories (1) hypertriglyceridemia with an increase in chylomicrons and the clinical sign of pancreatitis, (2) mixed hyperlipidemia with an increase in chylomicron and VLDL remnants and an increased risk of premature atherosclerosis, (3) hypercholesterolemia with an increase in LDL and an increased risk for premature atherosclerosis, (4) hypoalphalipoproteinemia with low HLD and an increased risk for premature atherosclerosis, and (5) hypolipoproteinemia with a decrease in VLDL and LDL, which may lead to neurological disease. 

After binding, the LDL-receptor complex is internalized by endocytosis. [Note A deficiency of functional LDL receptors causes a significant elevation in plasma LDL and, therefore, of plasma cholesterol. Patients with such deficiencies have type II hyperlipidemia (familial hypercholesterolemia) and premature atherosclerosis. The thyroid hormone, T3, has a positive effect on the binding of LDL to its receptor. Consequently, hypothyroidism is a common cause of hypercholesterolemia.]... 

VLDL in the plasma is converted to LDL—a much smaller, denser particle. Apo CM and apo E are returned to HDLs, but the LDL retains apo B-100, which is recognized by receptors on peripheral tissues and the liver. LDLs undergo receptor-mediated endocytosis, and their contents are degraded in the lysosomes. A deficiency of functional LDL receptors causes type II hyperlipidemia (familial hypercholesterolemia). The endocytosed cholesterol inhibits HMG CoA reductase and decreases synthesis of LDL receptors. Some of it can also be esterified by acyl CoAxholesterol acyltransferase and stored. 

Hyperlipidemia associated with antipsychotic drugs has been reviewed (SEDA-29, 64). Haloperidol and the atypical antipsychotic drugs ziprasidone, risperidone, and aripiprazole would be associated with lower risks of hyperlipidemia, whereas chlorpromazine, thioridazine, and the atypical drugs quetiapine, olanzapine, and clozapine would be associated with higher risks. However, severe clozapine-induced hypercholesterolemia and hypertriglyceridemia has been reported in a patient taking clozapine (55). 

Hypertriglyceridemia due to sirolimus often does not respond to dosage reduction or hypolipidemic drugs. After liver transplantation (n — 6), significant hyperlipidemia improved after withdrawal of sirolimus (1070). The incidence of sirolimus-associated hyperlipidemia is up to 44%. After liver transplantation, there was hypercholesterolemia in 15% and hypertriglyceridemia in 10% of recipients. Sirolimus in combination with tacrolimus... 

Hyperlipidemia (mainly hypercholesterolemia) is a regular part of nephrotic syndrome (K13, W6). Serum levels of cholesterol are often markedly elevated, usually above 10 mmol/L. However, in severely malnourished patients, normal or even decreased serum cholesterol level can be found. Serum levels of triacylglyc-erols fluctuate, from normal values to markedly elevated values (mainly in patients with proteinuria higher than 10 g/24 hr). There is a variable increase in plasma concentrations of very low density lipoproteins (VLDL, they correlate negatively with serum albumin level), intermediate-density lipoproteins (IDL), andLDL however, plasma concentrations of HDL are usually normal (J3). Levels of lipoprotein(a) [Lp(a)j are also increased (W4). Remission of nephrotic syndrome or decrease of proteinuria may result in the decrease of plasma concentrations of Lp(a) (G2). Concentration of free fatty acids in serum is commonly decreased because they are normally bound to albumin and albumin is lost into the urine. The activity of lecithin cholesterol acyltransferase (LCAT) is usually decreased. 

In the pathogenesis of nephrotic hyperlipidemia, both increased production and impaired catabolism of lipoproteins were demonstrated to play a role. Pathogenic mechanisms may be different in nephrotic patients with isolated hypercholesterolemia and in patients with combined hypercholesterolemia and hypertriglyceridemia (V6). 

V6. Vega, G. L., Toto, R. D., and Grundy, S. M., Metabolism of low density lipoproteins in nephrotic dyslipidemia Comparison of hypercholesterolemia alone and combined hyperlipidemia. Kidney Int. 47,579-586 (1995). 

Hausmann D, Johnson JA, Sudhir K, et al. Angiographically silent atherosclerosis detected by intravascular ultrasound in patients with familial hypercholesterolemia and familial combined hyperlipidemia correlation with high density lipoproteins, J Am Coll Cardiol I 996 27 1 562-1 570. 

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