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Now these molecules can be produced in genetical- ly modified cells that carry the hereditary information for pro- ducing the human protein buy generic albuterol 100 mcg. Main avenues of research 41 In addition discount 100mcg albuterol amex, new findings from basic research now allow thera- peutic proteins to be coupled with non-protein components to improve their efficacy and duration of action. Since the substance is produced mainly in the kidneys, patients with renal damage are prone to develop anemia. Those affected – often dialysis patients – generally feel weak and tired, because their red blood cells no longer carry sufficient supplies of oxygen to the body. Since the early 1990s recombinant erythropoietin has replaced time-consuming, costly and risky blood transfusions, previous- ly the standard treatment for anemic patients. Because the hor- mone is a glycoprotein (see illustration), it cannot be produced in bacterial or yeast-cell cultures: the erythropoietin molecule has several carbohydrate side chains that slow its breakdown in the body but also modify its intrinsic bioactivity. These side chains can be attached to proteins only by the synthe- Erythropoietin: the molecule sising apparatus found in carbohydrate chain mammalian cells. For this reason, only mammalian cells can be used to produce complex therapeutic pro- teins. In renal clinical trials untreated anemic patients can ex- perience a correction of their anemia with one injection twice a month. Patients who are in maintenance can be managed with a single monthly injection whether they have reached end stage renal disease (chronic kidney disease stage 5) or not (typically chronic kidney disease stages 3 and 4). Less frequent adminis- trations reduce the oscillation in hemoglobin levels outside the optimal range of hemoglobin as defined by best practice guide- lines, which is often seen with existing short-acting compounds (epoetin, darbepoetin). Such excursions are associated with ad- verse events and considered to contribute to further deterio- ration of cardiac and renal functions. It is believed that less fre- quent administrations represent a significant gain in quality of life for patients but also allow overworked nephrologists and nurses to concentrate on the other serious medical conditions affecting many of these patients such as hypertension, diabetes, chronic heart failure and obesity. The principle of Improved efficacy of proteins can be achieved pegylation: Pegasys with the help of specific modifications. It is essential to select the proper moiety that will confer Main avenues of research 43 to the active protein the de- A pegylated protein: Pegasys sired properties. The choice of linker is also very impor- tant as its rigidity (or lack thereof) will influence the ultimate properties of the new medicine. Roche has successfully applied this principle to develop a drug for the treatment of hepati- tis C and B. In this method the drug is enveloped in one or two highly branched molecules of polyethylene glycol. It has been used for de- cades for treating hepatitis C, a widespread infection which causes inflammation of the liver. To date no treatment exists that is able to eradicate the hepatitis C virus from the body. As a result, drug levels in the patients’ blood- stream undergo significant fluctuations in a two-day rhythm, giving rise to side effects and limit efficacy. It is also considered that fluctuation is instrumental promoting the appearance of resistant viruses. Thanks to a carefully selected pegylation with the appropriate bond with the protein,Pegasys is broken down much more slow- ly than simple interferon and therefore remains active in the body longer. This has several advantages for patients: Firstly, Pegasys only has to be given once weekly. Secondly, the dose does not have to be adjusted gradually – at least not to the same degree – according to the patient’s age, hepatic status and renal function, a time-consuming process. Thirdly, interferon levels in the bloodstream are subject to less fluctuation, making the side effects more tolerable and improving patient compliance. First approved in 2002, Pegasys quickly became the internation- al market leader in the hepatitis C sector. The drug was also the first pegylated therapeutic protein in the world to be approved for the treatment of chronic hepatitis B. A new drug class: Therapeutic antibodies form a relatively new therapeutic antibodies drug class that was only made possible by modern biotechnology. These Y-shaped proteins bear on their two short arms two identical regions that recognise a specific foreign structure. The long stem of the molecule interacts with other components of the immune sys- tem, which then initiate destruction of the intruders. In 1972 César Milstein and Georges Köhler, who later received the Nobel Prize, found a way to produce copies of identical antibody molecules in unlimited amounts. Within a few years these so-called monoclonal antibodies had revolutionised bio- logical research, allowing any desired molecule to be reliably identified and marked. However, it took more than 20 years for monoclonal antibodies to find widespread use in therapy. Not until the late 1990s did researchers succeed in exploiting the specificity of monoclonal antibodies for therapeutic purposes.

Spironolactone is used both individually as well as in combination with thiazides order albuterol 100 mcg otc, since it lowers kaliuresis caused by thiazide diuretics purchase albuterol 100mcg on line. It is used for edema syndrome caused by chronic cardiac insuffi- ciency, liver cirrhosis, hyperaldosteronism, and hypokalemia caused by other diuretics. This undergoes nitrosation by reacting it with nitric acid, which results in the 21. It exhibits the same approximate effect as spirono- lactone; however, it does not competitively bind with aldosterone receptors. Its action does not have an effect on secretion of aldosterone or its antagonists, which are a result of direct action on renal tubules. This potassium sparing diuretic causes a moderate increase in excretion of sodium and bicarbonate ions in urine, and it raises excretion of potassium and ammonia ions. This drug is recommended in combination with other diuretics for treating edema caused by usual reasons such as circulatory insufficiency, cirrhosis of the liver, and nephrotic syndrome. Amyloride is rarely used individually—as a rule it is used in combination with thiazides or loop diuretics. It is mainly used in combination with thiazide diuretics for cardiac insufficiency and hypertension, especially in cases where it is necessary to prevent hypokalemia. Hypertension is a syndrome characterized by elevated arterial blood pressure that depends on a number of factors. Some of the main factors that determine arterial blood pressure are parameters of heart rate, volume, viscosity, and electrolytic contents of circu- lating blood. Moreover, various medical schools themselves determine what an acceptable value is. The etiology of 90–95% of cases of this disease are unknown, and these cases are referred to as primary or essential hypertension; treatment is of a palliative nature that is directed to lowering sys- tolic and diastolic blood pressure, and in general, effectively permitting control of a patient’s arterial blood pressure over a long period of time. During such treatment, antihy- pertensive agents can be directed at various sections of physiological systems that regulate arterial blood pressure. The remaining 5–10% of cases of hypertension originate because of stenosis of renal arteries or constriction of the aorta, Cushing’s syndrome, and pheochromocytosis. Hypertension originating from these latter conditions is called secondary hypertension. Lowering arterial blood pressure can be accomplished by affecting vascular smooth musculature using hydralazine, diazoxide, minoxidil, sodium nitroprusside, diuretics, and calcium channel blockers, which relax vascular smooth musculature, thus lowering both systolic and diastolic blood pressure. H-cholinoblockers (ganglioblockers) such as mecamylamine and trimethaphan act on autonomic ganglia to reduce blood pressure. Lowering arterial blood pressure by acting on the adrenergic system can be accom- plished by stimulating α-adrenoreceptors (clonidine, guanabenz, guanacin, and methyl- dopa), which leads to a reduction of sympathetic impulses to vessels and the heart, thus reducing cardiac output and heart rate, which consequently lowers arterial blood pressure; blocking α1-adrenoreceptors (prazosin, terazosine), the main importance of which is dilat- ing peripheral vessels, which leads to reduced blood pressure; blocking β-adrenoreceptors (propranolol, athenolol, nadolol, and others), which reduce cardiac output and peripheral resistance of vessels, resulting in lower blood pressure. Antihypertensive Drugs Lowering blood pressure can also be done by acting on the renin–-angiotensin system by using angiotensin-converting enzyme (cartopril, enalapril). Diuretics can act on the kidneys and arterioles for the purpose of lowering blood pressure. Finally, calcium channel blockers can act on smooth musculature in order to lower blood pressure (vera- pamil, diltiazem, and nifedipine). Antihypertensive drugs can be divided into eight classes based on the mechanism of action: diuretics, β-adrenoblockers, centrally acting sympatholytics, peripherally acting sympatholytics, calcium channel blockers, myotropic hypotensive drugs, angiotensin-con- verting enzyme inhibitors, and calcium channel activators. Depending on the severity of the hypertension, treatment with antihyperten- sive drugs proceeds strategically in a specific order. It is understood that this order should be flexible and open to alternative ways, but a few general principles must be adhered to. Diuretics, β-adrenoblockers, or small doses of angiotensin-converting enzyme inhibitors should be used first for minor hypertension to lower blood pressure. In treating weak and moderate hypertension, it is recommended to use β-adrenoblockers, angiotensin- converting enzymes inhibitors, clonidine, guanabenz, guanfacine, methyldopa, prazosin, terazosin, calcium channel blockers, or reserpine. In moderate to severe hypertension, it is recommended to use hydralazine and large doses of angiotensin-converting enzyme inhibitors. Finally, in urgent cases of hypertension, it is recommended to use sodium nitroprusside, diazoxide, trimethaphan, or labetalol. A universally accepted principle of antihypertension therapy is the simultaneous use of several drugs that act on the primary regions controlling arterial blood pressure, and it is generally recommended to use a combination of diuretics, adrenoblockers, angiotensin- converting enzyme inhibitors, or calcium channel blockers. The molecular mechanism of diuretics acting as antihypertensive agents is not com- pletely clear; however, use of diuretics causes a significant increase in the amount of water and electrolytes excreted in urine, which leads to a reduction in the volume of extracellular fluid and plasma. This in turn leads to a reduction of cardiac output, which is the main parameter responsible for a drop in arterial blood pressure and venous blood return. Cardiac output is gradually restored, but the hypotensive effect remains, possibly because of the reduced peripheral resistance of vessels. It is also possible that diuretics somehow lower vascular activity of noradrenaline and other factors of pressure in the organism.

Halogenated aliphatic hydrocarbons (carbon tetra- chloride albuterol 100mcg sale, chloroform cheap 100mcg albuterol, trichloroethylene, tetrachloroethylene) are extensively used as industrial solvents, cleaning agents, and degreasing agents. The environment also con- tains many insecticides, including chlorinated hydrocarbons (chlorophenothanes, ben- zene hexachlorides, cyclodienes, toxaphenes), carbamates (aminocarb, carbofuran, isolan, pyramat), organophosphorus compounds (diazinon, malathion, parathion), and botanical insecticides (rotenone, pyrethrum). In addition to insecticides, various herbi- cides with “agrotech” applications also pollute our environment, including chlorophe- noxy herbicides (2,4-dichlorophenoxyacetic acid) and bipyridyl herbicides (paraquat). The treatment of acute exposure to these various toxins is typically nonspecific and involves removing the victim from the contaminated environment, coupled with general supportive measures. The toxic effects of low-level, long-term exposure to these agents have yet to be fully determined. Toxicity from inorganic pollutants and heavy-metal intoxication is also a significant public health concern. Lead poisoning is probably the oldest environmental disease in the world; it is credited with the downfall of the Roman Empire. Although lead has been removed from gasoline and paint, it still lurks as an environmental contaminant. Lead serves absolutely no useful purpose in the human body; no safe limit for exposure to lead exists. In recent years, arsenic has received widespread commercial application in the manufacture of electronic semiconductors, cotton desic- cants, and wood preservatives. In addition, arsenic leached from natural mineral deposits can contaminate groundwater; arsenic in the drinking water in the Ganges delta region of India has emerged as one of the world’s largest environmental health prob- lems. In the 1950s, an epidemic of neurologic disease occurred in the Japanese fishing village of Minamata. The chelating agent possesses several binding sites (ligands) that act to complex and “inactivate” the heavy metal ion. The rational design of chelating agents as antidotes requires a careful consideration of acid–base chemistry. Metal ions are Lewis acids, while the chelating agents or ligands are Lewis bases. The concepts of hardness and softness may be used to describe systematically the interaction between them.