Metolazone is a thiazide-like diuretic marketed under the brand names Zytanix, Metoz, Zaroxolyn, and Mykrox. It is primarily used to treat congestive heart failure and high blood pressure. Metolazone indirectly decreases the amount of water reabsorbed into the bloodstream by the kidney, so that blood volume decreases and urine volume increases. This lowers blood pressure and prevents excess fluid accumulation in heart failure. Metolazone is sometimes used together with loop diuretics such as furosemide or bumetanide, but these highly effective combinations can lead to dehydration and electrolyte abnormalities. It was patented in 1966 and approved for medical use in 1974. Medical uses
One of the primary uses of metolazone is for treating edema (fluid retention) associated with congestive heart failure (CHF). In mild heart failure, metolazone or another diuretic may be used alone, or combined with other diuretics for moderate or severe heart failure. In addition to preventing fluid buildup, the use of metolazone may allow the patient to relax the amount of sodium restriction that is required. Although most thiazide diuretics lose their effectiveness in kidney failure, metolazone remains active even when the glomerular filtration rate (GFR) is below 30–40 mL/min (moderate chronic kidney disease). This gives it a considerable advantage over other thiazide diuretics, since renal and heart failure often coexist and contribute to fluid retention.Metolazone may also be used in kidney disease, such as chronic kidney disease or the nephrotic syndrome. Chronic kidney disease causes excess fluid retention that is often treated with diet adjustments and diuretics.
A parent with 35 repeats would be considered normal and would not exhibit any symptoms of the disease. However, that parents offspring would be at an increased risk of developing Huntingtons compared to the general population, as it would take only the addition of one more CAG codon to cause the production of mHTT (mutant HTT), the protein responsible for disease. Huntingtons very rarely occurs spontaneously; it is almost always the result of inheriting the defective gene from an affected parent. However, sporadic cases of Huntingtons in individuals who have no history of the disease in their families do occur. Among these sporadic cases, there is a higher frequency of individuals with a parent who already has a significant number of CAG repeats in their HTT gene, especially those whose repeats approach the number (36) required for the disease to manifest. Each successive generation in a Huntingtons-affected family may add additional CAG repeats, and the higher the number of repeats, the more severe the disease and the earlier its onset. As a result, families that have had Huntingtons for many generations show an earlier age of disease onset and faster disease progression. Non-trinucleotide expansions
The majority of diseases caused by expansions of simple DNA repeats involve trinucleotide repeats, but tetra-, penta- and dodecanucleotide repeat expansions are also known that cause disease. For any specific hereditary disorder, only one repeat expands in a particular gene. Mechanism
Triplet expansion is caused by slippage during DNA replication or during DNA repair synthesis.