By Y. Finley. DeVry University.
Cyclosporine A: Cyclosporine A buy combivent 100mcg line, [R-[R* generic combivent 100mcg on-line,R*-(E)]]-cyclo-(L-alanyl-D-alanyl-N-methyl-L- leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6- octenoyl-L-α-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucine) (31. A new era in the development of immunopharmacology began with the discovery of cyclosporines. Cyclosporines are produced by mycelial mushrooms Tolypocladium inflatum, Tricoderma polysporum, and Cylindrocarpon lucidum, which are found in the ground. Cyclosporine A is the first drug to affect a specific line of protecting cells of the body. Unlike usual cytotoxics, it suppresses T-cells and acts on all cell lines simultaneously. Cyclosporine A significantly eases the ‘reception’ of transplants, and increases the possi- bility of treating autoimmune system diseases. All cyclosporines (A,B,C, … U,V,W), are oligopeptides containing 11 amino acids closed in a cyclic form. All of these are known amino acids except the first, which some- times has not been isolated from natural sources. Because of all of the hydrogen bonds, the structure of cyclosporine is quite rigid. Cyclosporine A itself and a number of other cyclosporines have been completely synthe- sized. Many structural analogs have also been synthesized, and a few patterns have been discovered in terms of their structure and activity. It is known that the activity of the drug is determined by the entire cyclic structure, and not by its separate fragments. Likewise, it is also clear, that the structure of amino acids at position 1 is an important factor of 424 31. Despite the fact that the molecule is relatively large, cyclosporine eas- ily diffuses through the cellular membrane. It is possible that there are no corresponding ‘recognizing’ receptors for cyclosporine. However, there is a cytosol cyclosporine-binding protein known as cyclophilin, which has a molecular weight of about 15,000. Cyclophilins are observed mainly in T-cells; however, they are found in other tissues, in particular, in the brain and kidneys. Since the mechanism of action of cyclosporine is still being intensively studied, it must be noted that it is not cytotoxic in the general sense of the word, because it suppresses bone marrow function. Despite the fact that cyclosporine has not been used for a long time, it is the number one drug used for transplants. Cyclosporine is also being studied as a substance for treating a number of autoimmune diseases, including diabetes, multiple sclerosis, myasthenia, rheumatoid arthritis, and psoriasis. It also has had a great effect in treating schistosomia- sis, malaria, and filariasis. Despite the fact that all of these terms are basically interchangeable, the first three—antibiotics, anti-infectious agents, and anti- microbial drugs—are generally used to describe drugs used for treating infectious dis- eases, while the term chemotherapeutic drugs is more associated with drugs used for treating cancer. Antibiotics are essentially natural compounds produced by microorganisms that are capable of inhibiting growth of pathogenic microbes, bacteria, and a few of the more sim- ple microorganisms. Semisynthetic antibiotics generally are products that are a partially chemically altered versions of antibiotics that are isolated from natural sources. Thus, antibiotics are compounds produced by microorganisms and that are able to kill or inhibit growth of bacteria and other microorganisms. This definition makes a specific distinction between antimicrobial drugs produced by microorganisms and completely syn- thetic compounds. The difference is of a completely academic nature, and today the word antibiotic is used quite often for specifying antimicrobial drugs in general. It should be noted that there are compounds produced by microorganisms with antifungal and antitu- mor action, which also are classified as antibiotics. The general concept of antimicrobial action is called selective toxicity, which entails that the growth of the infected organism is inhibited or destroyed by certain drugs without harming host cells. All of the antimicrobial drugs used in clinical practice are selectively toxic with respect to microorgansisms. High selective toxicity of antibiotics to microor- ganisms is explained by the unique qualities of the organization of microbial cells, which are principally different from mammalian cells. The nature and degree of this selectivity determines whether the given antimicrobial drug is generally non-toxic in its relationship with mammalian cells or if it just exhibits certain toxicity on certain mammalian tissues. Antimicrobial drugs exhibit antibacterial effect using one or all of the following mecha- nisms: 1. Inhibition of cell membranes synthesis in microorganisms (beta-lactam antibiotics, vancomycin, cycloserine). Inhibition of protein synthesis in microorganisms (aminoglycosides, erythromycin, clindamycin, chloramphenicol, and tetracyclines).
Hansch experimentally determined the logP values of many drugs and showed the importance of these values in determining the ability of a drug to penetrate into the brain purchase combivent 100 mcg with visa. Over the past 35 years cheap 100mcg combivent fast delivery, many methods for theoretically calcu- lating logP values have been devised. The fragmental constants are determined statistically by regression analysis; they are additive, and their sum provides a reasonable value for logP. Detailed tables of the f values for various functional groups have been published by Rekker (1977) and are sometimes used in computer program algorithms that calculate logP values. Somewhat analogous to the fragmental constants are the atomic constants put forth by Ghose and Crippen (1986); these assign logP values for every atom in a molecule and then determine the logP for the overall molecule by summing these values. The energy situation at a surface differs markedly from that in a solution because special intermolecular forces are at work; therefore, surface reactions require specific consideration. In living organisms, membranes comprise the largest surface, covering all cells (the plasma membrane) and many cell organelles (the nucleus, mitochondria, and so forth). Dissolved macromolecules such as proteins also account for an enormous surface area (e. Biological membranes also (i) serve as a scaffold that holds a large variety of enzymes in proper orientation, (ii) provide and maintain a sequential order of enzymes that permits great efficiency in multistep reactions, and (iii) serve as the boundaries of cells and many tissue compartments. It is therefore apparent why the physical chemistry of surfaces and the structure and activity of surface-active agents are also of interest to the medicinal chemist. Antimicrobial detergents and many disinfectants exert their activity by interacting with biological surfaces and are important examples of surface-active drug effects. We have already discussed the hydrogen-bonding interaction of water molecules that creates clusters. The water molecules at a gas–liquid interface, however, are exposed to unequal forces, and are attracted to the bulk water of the liquid phase because no attraction is exerted on them from the direction of the gas phase. Because the dissolution of a solid is the result of molecular interaction between a solvent and the solid (which, once dissolved, becomes a solute), polar compounds capable of forming hydrogen bonds are water soluble, whereas nonpolar compounds dissolve only in organic solvents as the result of van der Waals and hydrophobic bonds. The nonpolar alkyl chains are in the nonpolar phase; the polar carboxylate head groups are in the aqueous phase. Only in this way can amphiphilic detergents, through their hydrogen bonding with water and nonpolar interaction with a nonpolar (organic) phase or with air, maintain an orientation that ensures the lowest potential energy at an interface. A classic example of such behavior is given by soap, a mixture of alkali-metal salts of long-chain fatty acids. At a higher concentration, the molecules find it more energy efficient to “remove” their hydrophobic tails from the aqueous phase and let them interact with each other, thus forming a miniature “oil drop” or nonpolar phase, with the polar heads of the soap molecules in the bulk water. At a concentration that is characteris- tic for a given individual detergent, molecular aggregates, known as micelles, are formed. The concentration at which such micelles are formed is called the critical micellar concentration, and can be determined by measuring the light diffraction of the solution as a function of detergent concentration. When soap is dispersed in a nonpolar phase, inverted micelles are formed in which the nonpolar tails of the soap molecules interact with the bulk solvent while the hydrophilic heads interact with each other. This behavior of amphiphilic molecules explains how they can disperse nonpolar particles in water: the hydrocarbon tail of the amphiphile interacts with the particle, such as an oil droplet, dirt, or a lipoprotein membrane fragment, covers the particle, and then presents its hydrophilic head groups to the aqueous phase. This patient had a seven–year history of epilepsy, well controlled with the drug phenytoin at a dose of 300 mg/day. When asked why he had stopped taking his phenytoin he stated that he had not, but had been taking the same dose for years. She stated that he took his daily dose of phenytoin every morning at breakfast and that she had witnessed his doing so, every day for the past six years. Upon questioning, it was discovered that this individual purchased his phenytoin in bottles of 1,000 capsules, in order to save money. He routinely stored this phenytoin in the basement of his home—a relatively damp and cool location—for months at a time; one week earlier he had started to use the capsules from one of these old stored bottles. When thirty “old” capsules from this recently opened bottle of 1000 capsules were weighed, all had masses in excess of 295 mg. When thirty capsules from a recently pur- chased supply of “new” phenytoin were weighed, all had masses less than 280 mg. An examination of an old capsule revealed that the contents were hardened and slightly dis- coloured. Subsequent analyses revealed that the phenytoin within the old capsules had become excessively hydrated from the ambient humidity of their storage conditions. The resulting hardened mass of drug material was less soluble within the gastrointesti- nal tract and was thus less bioavailable for absorption. Many factors can influence the bioavailability of a drug molecule following oral absorption. Damp storage conditions of the drug can cause increased molecular hydra- tion with concomitant altered solubility. When a drug molecule is crystallized using dif- ferent solvents or different conditions, the resulting change in crystal morphology can influence bioavailability and thus alter biological results. The inter- action of the drug molecule’s pharmacophore with its complementary receptor during the pharmacodynamic phase of drug action is dependent upon a geometrically precise and accurate intermeshing of two molecular fragments.
Nuts have their molds; nuts grown in the ground (peanuts) are especially moldy because the earth is so full of mold spores cheap 100mcg combivent otc. But the wind carries these spores high up into trees purchase combivent 100mcg free shipping, and even up to the stratosphere. This is why aflatoxin, for instance, is found not just in your cereal, bread and pasta but in nuts, maple syrup, orange juice, vinegar, wine, etc. It is not in dairy products or fresh fruit and vegetables, provided you wash the outside. Evidently the system of wrapping baked goods in plastic keeps moisture trapped and starts the molding process. In spite of adding mold inhibitors, American bread-stuff is far inferior to Mexican baked goods in which I do not find aflatoxin! Here is some good news for cooks: if you bake it yourself, adding a bit of vitamin C to the dough, your breads will be mold free for an extended period (and rise higher). And without a taste or smell to guide you, how would you know to stop eating the moldy peanut butter or spaghetti? Boiling for many minutes at a higher temperature or baking does kill them (but not ergot, another mold) and also de- stroys aflatoxin they produced and left in the food. I suppose it acts a lot like the bisulfite; chemically destroying the mold toxin molecules. Eradicating Aflatoxin Simply sprinkling vitamin C over roasted nuts is not effec- tive because the molds have penetrated the surface. Zearalenone Zearalenone, an anabolic and uterotrophic metabolite, is fre- quently found in commercial cereal grains and in processed foods and feeds, and is often reported as causative agent of naturally occurring hyperestrogenism and infertility in swine, 18 poultry and cattle. I find nearly every breast cancer case shows a too-high estrogen level for years before the cancer is found! And what is the effect on men and boys of eating an estrogen-like mycotoxin in their daily diet? This female hormone could have a drastic effect on the maturing process even in small amounts. Myelotoxicity toxicity resulting from exogenous estro- gens evidence for bimodal mechanism of action. The main zear sources I have found so far are popcorn, corn chips, and brown rice. But it was absent in fresh corn, canned corn, corn tortillas, and white rice, making me wonder how it gets in our processed corn products. Ergot toxicity could explain “Jekyll and Hyde” behavior in children, commonly attributed to “allergies”. In fact, the mechanism, inability by the liver to keep up with detoxification, fits well into the “allergic” concept. If your child has undesirable behavior, try going off the moldy food suspects for three weeks (cold cereals, nuts and nut butters, store bought breads and baked goods, syrups). Perhaps some of the bizarre behavior and speech of intoxication is really due to the mold-alcohol combination. By delaying alcohol detoxifi- cation, the mold could even be responsible for deaths “due to” alcoholism. If bizarre behavior shows up, such as saying mean and cruel things, expressing unusual, irrational thoughts, feeling emo- 20 Canada allows one ergot grain per 300 grains of #3 or #4 wheat. Try this diet on yourself if you have a temper or crying spells or frequent colds! Dead portions of the liver cannot regenerate as they otherwise would after a toxic encounter! This leads to pancreas damage, invites pancreatic fluke infestation, and typically results in diabetes. If you are a potato lover fix your own so you can peel them and remove any gray parts. T-2 Toxin T-2 toxin is a mold I have found in all cases of high blood pressure and kidney disease. It is present on dried peas and beans but it can be detoxified in 5 minutes by adding vitamin C to the water they are soaked in. Rinse millet in vitamin C water before cooking, or add vitamin C to the cooking water. Elderly people are more easily poisoned than others; their hemorrhages show up as strokes and purple blotches on the skin. It is particularly hazardous since the mold that produces it can actually grow in your intestine in patches. Mix it with home made preserves, honey, marmalade, not very homogene- ously so the bright colors and individual flavors stand out in contrast. Having three or four such spreads in the refrigerator will give your children the right perspective on food— homemade is better.
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