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The information is extracted from the diffraction patterns through a mathematical analysis known as a Fourier series medications grapefruit interacts with order compazine cheap online. Many thousands of such calculations are required to determine the structure of a protein medicine video purchase compazine 5mg on line, and even though they are performed by computer medications bladder infections cheap compazine 5mg on-line, the process is a fairly long one symptoms dust mites best order compazine. The articles by Hauptmann and by Karle cited in the bibliography at the end of this chapter outline some of the accomplishments in the field medications with dextromethorphan safe compazine 5 mg. It is similar to X-ray diffraction in other ways: It is a long process symptoms 6 days post embryo transfer cheap compazine 5 mg mastercard, and it requires considerable amounts of computing power and milligram quantities of protein. This environment is closer to that of proteins in cells, and thus it is one of the main advantages of the method. Myoglobin: An Example of Protein Structure In many ways, myoglobin is the classic example of a globular protein. The complete myoglobin molecule consists of a single polypeptide chain of 153 amino acid residues and includes a prosthetic group, the heme group, which also occurs in hemoglobin. The myoglobin molecule (including the heme group) has a compact structure, with the interior atoms very close to each other. This structure provides examples of many of the forces responsible for the threedimensional shapes of proteins. Approximately 75% of the residues in myoglobin are found in these helical regions, which are designated by the letters A through H. Hydrogen bonding in the polypeptide backbone stabilizes the a-helical regions; amino acid side chains are also involved in hydrogen bonds. The peptide backbone and the heme group are shown overlain on the space-filling model. The interior of the protein contains almost exclusively nonpolar amino acid residues. Two polar histidine residues are found in the interior; they are involved in interactions with the heme group and bound oxygen, and thus play an important role in the function of the molecule. The presence of the heme group drastically affects the conformation of the polypeptide: the apoprotein (the polypeptide chain alone, without the prosthetic heme group) is not as tightly folded as the complete molecule. Four of the six sites are occupied by the nitrogen atoms of the four pyrrole-type rings of the porphyrin to give the complete heme group. The fifth and sixth coordination sites lie perpendicular to , and on opposite sides of, the plane of the porphyrin ring. The other histidine residue in the interior of the molecule, residue E7 (the seventh residue in helical segment E), lies on the same side of the heme group as the bound oxygen (Figure 4. This second histidine is not bound to the iron, or to any part of the heme group, but it acts as a gate that opens and closes as oxygen enters the hydrophobic pocket to bind to the heme. The E7 histidine sterically inhibits oxygen from binding perpendicularly to the heme plane, with biologically important ramifications. Several isomeric porphyrin rings are possible, depending on the nature and arrangement of the side chains. Histidine F8 (His F8) occupies the fifth coordination site of the iron (see text). Oxygen is bound at the sixth coordination site of the iron, and histidine E7 lies close to the oxygen. At first, it would seem counterintuitive that oxygen would bind imperfectly to the heme group. When carbon monoxide is forced to bind at an angle in myoglobin because of the steric block by His E7, its advantage over oxygen drops by two orders of magnitude (Figure 4. It is also important to remember that although our metabolism requires that hemoglobin and myoglobin bind oxygen, it would be equally disastrous if the heme never let the oxygen go. Thus having binding be too perfect would defeat the purpose of having the oxygencarrying proteins. Thus, the combination of both heme and protein is needed to bind O2 for oxygen storage. Denaturation and Refolding the noncovalent interactions that maintain the three-dimensional structure of a protein are weak, and it is not surprising that they can be disrupted easily. Denaturation and reduction of disulfide bonds are frequently combined when complete disruption of the tertiary structure of proteins is desired. Under proper experimental conditions, the disrupted structure can then be completely recovered. This process of denaturation and refolding is a dramatic demonstration of the relationship between the primary structure of the protein and the forces that determine the tertiary structure. For many proteins, various other factors are needed for complete refolding, but the important point is that the primary structure determines the tertiary structure. An increase in temperature favors vibrations within the molecule, and the energy of these vibrations can become great enough to disrupt the tertiary structure. At either high or low extremes of pH, at least some of the charges on the protein are missing, and so the electrostatic interactions that would normally stabilize the native, active form of the protein are drastically reduced. If a detergent is charged, it can also disrupt electrostatic interactions within the protein. Other reagents, such as urea and guanidine hydrochloride, form hydrogen bonds with the protein that are stronger than those within the protein itself. These two reagents can also disrupt hydrophobic interactions in much the same way as detergents (Figure 4. Urea is usually added to the reaction mixture to facilitate unfolding of the protein and to increase the accessibility of the disulfides to the reducing agent. If experimental conditions are properly chosen, the native conformation of the protein can be recovered when both mercaptoethanol and urea are removed (Figure 4. Experiments of this type provide some of the strongest evidence that the amino acid sequence of the protein contains all the information required to produce the complete threedimensional structure. Protein researchers are pursuing with some interest the conditions under which a protein can be denatured-including reduction of disulfides-and its native conformation later recovered. The tertiary structure of proteins is maintained by different types of covalent and noncovalent interactions. Hydrogen bonding occurs between atoms on the peptide backbone as well as atoms in the side chains. Electrostatic attractions between positively charged side chains and negatively charged side chains are also important. The tertiary structure of proteins is determined by the techniques of X-ray diffraction and nuclear magnetic resonance. Myoglobin, the first protein to have its tertiary structure determined, is a globular protein for oxygen storage. Myoglobin is a single polypeptide chain with 153 amino acids, 8 a-helical regions, and a prosthetic group called heme. The number of chains can range from two to more than a dozen, and the chains may be identical or different. Commonly occurring examples are dimers, trimers, and tetramers, consisting of two, three, and four polypeptide chains, respectively. As a result of these noncovalent interactions, subtle changes in structure at one site on a protein molecule may cause drastic changes in properties at a distant site. A classic illustration of the quaternary structure and its effect on protein properties is a comparison of hemoglobin, an allosteric protein, with myoglobin, which consists of a single polypeptide chain. The protein ribonuclease can be completely denatured by the actions of urea and mercaptoethanol. Hemoglobin Hemoglobin is a tetramer, consisting of four polypeptide chains, two a-chains, and two b-chains (Figure 4. In this case, the terms a and b have nothing to do with the a-helix and the b-pleated sheet; rather they just refer to two different polypeptide chain subunits. The a-chain is 141 residues long, and the b-chain is 146 residues long; for comparison, the myoglobin chain is 153 residues long. Many of the amino acids of the a-chain, the b-chain, and myoglobin are homologous; that is, the same amino acid residues are in the same positions. Hemoglobin (a2b2) is a tetramer consisting of four polypeptide chains (two a-chains and two b-chains). Both hemoglobin and myoglobin bind oxygen reversibly, but the binding of oxygen to hemoglobin exhibits positive cooperativity, whereas oxygen binding to myoglobin does not. Positive cooperativity means that when one oxygen molecule is bound, it becomes easier for the next to bind. A graph of the oxygen-binding properties of hemoglobin and myoglobin is one of the best ways to illustrate this point (Figure 4. When the degree of saturation of myoglobin with oxygen is plotted against oxygen pressure, a steady rise is observed until complete saturation is approached and the curve levels off. This shape indicates that the binding of the first oxygen molecule facilitates the binding of the second oxygen, which facilitates the binding of the third, which in turn facilitates the binding of the fourth. However, note that even though cooperative binding means that binding of each subsequent oxygen is easier than the previous one, the binding curve is still lower than that of myoglobin at any oxygen pressure. In other words, at any oxygen pressure, myoglobin will have a higher percentage of saturation than hemoglobin. The two different types of behavior exhibited by myoglobin and hemoglobin are related to the functions of these proteins. It must bind strongly to oxygen at very low pressures, and it is 50% saturated at 1 torr partial pressure of oxygen. The oxygen-binding curve of myoglobin is hyperbolic, whereas that of hemoglobin is sigmoidal. Myoglobin is 50% saturated with oxygen at 1 torr partial pressure; hemoglobin does not reach 50% saturation until the partial pressure of oxygen reaches 26 torr. In the alveoli of lungs (where hemoglobin must bind oxygen for transport to the tissues), the oxygen pressure is 100 torr. In the capillaries of active muscles, the pressure of oxygen is 20 torr, corresponding to less than 50% saturation of hemoglobin, which occurs at 26 torr. In other words, hemoglobin gives up oxygen easily in capillaries, where the need for oxygen is great. Structural changes during binding of small molecules are characteristic of allosteric proteins such as hemoglobin. Hemoglobin has different quaternary structures in the bound (oxygenated) and unbound (deoxygenated) forms. The two b-chains are much closer to each other in oxygenated hemoglobin than in deoxygenated hemoglobin. The change is so marked that the two forms of hemoglobin have different crystal structures (Figure 4. Conformational Changes That Accompany Hemoglobin Function Other ligands are involved in cooperative effects when oxygen binds to hemoglobin. Increasing H+ causes the protonation of key amino acids, including the N-terminals of the a-chains and His146 of the bchains. The protonated histidine is attracted to , and stabilized by, a salt bridge to Asp94. Actively metabolizing tissue, which requires oxygen, releases H+, thus acidifying its local environment. Hemoglobin has a lower affinity for oxygen under these conditions, and it releases oxygen where it is needed (Figure 4. The oxygenated form of hemoglobin is a stronger acid (has a lower pKa) than the deoxygenated form. In other words, deoxygenated hemoglobin has a higher affinity for H+ than does the oxygenated form. Thus, changes in the quaternary structure of hemoglobin can modulate the buffering of blood through the hemoglobin molecule itself. The presence of large amounts of oxygen in the lungs reverses the process, causing hemoglobin to bind O2. Fetal hemoglobin (Hb F) has a higher affinity for oxygen than does maternal hemoglobin, allowing for efficient transfer of oxygen from the mother to the fetus (Figure 4. Two features of fetal hemoglobin contribute to this higher oxygenbinding capacity. The subunit structure of Hb F is a2g2, where the b-chains of adult hemoglobin (Hb A), the usual hemoglobin, have been replaced by the g-chains, which are similar but not identical in structure. In the fetal hemoglobin, the g-chain has an amino acid substitution of a serine for His143. In Hb S, the -chains have a single amino acid substitution of a glutamic acid for a valine. This substitution of a nonpolar amino acid for a polar one causes the characteristic effects of the disease. The nonpolar amino acid is on the surface and leads to aggregation of the molecules through nonpolar interactions. Apply Your Knowledge Oxygen Response to pH in Hemoglobin Assume that during a 400-m running race, the pH decreases in muscle cells from 7. This means that hemoglobin will bind less oxygen at lower pH or, in other words, it will release more oxygen to the muscle cells. Myoglobin does not have a Bohr effect, however, and there is no effect caused by lowering the pH. Some proteins with multiple subunits are allosteric, which means that the subunits interact such that binding of a ligand to one subunit affects the binding of ligands to other subunits. The protein has 4 subunits, two -chains and two -chains, and it exhibits positive cooperativity. Binding of oxygen to one subunit makes it easier for oxygen to bind to other subunits. When the pH drops or when oxygen pressure is low, hemoglobin tends to release more oxygen to the tissues. When the pH is high and oxygen is plentiful, such as at the lung-blood interface, hemoglobin binds oxygen. Hemoglobin is bound to 2,3-bisphosphoglycerate, which acts as a bridge between the 4 subunits. In the absence of 2,3-bisphosphoglycerate, hemoglobin is not allosteric and behaves like myoglobin.

However medications 1-z buy compazine 5 mg online, it was later found that the sequence of the gene was very similar to that of a normal gene in eukaryotes medications ok for pregnancy order compazine paypal. Many proto-oncogenes are normal and necessary for proper growth and development in eukaryotic cells medications identification compazine 5 mg cheap. In other cases treatment jiggers cheap compazine uk, the event that causes a proto-oncogene to become an oncogene is not known treatment 5ths disease order compazine 5 mg line. Many of these genes are involved in signal-transduction pathways that affect the transcription of genes that speed up cell division medicine on time buy discount compazine 5mg. The process starts when an extracellular signal binds to a receptor on the cell membrane (see Figure 14. This receptor is a tyrosine kinase that dimerizes, and then each part phosphorylates the other. This protein, called p21ras or just Ras, is involved in about 30% of human tumors. The designation Ras comes from Rasarcoma, the original tissue in which it was discovered. Signal transduction starts when a growth factor (blue) binds to a receptor monomer (red) on the cell membrane. The receptor is a tyrosine kinase, which then phosphorylates its partner receptor. Although Ras mutations have been some of the most-studied mutations leading to cancer, we can see that Ras is found rather early in the process that ultimately leads to cell division. This enzyme enters the nucleus and phosphorylates a transcription factor called Jun. In 2002, researchers screening 20 different genes in 378 cancer samples found that the Raf gene was mutated in 70% of the malignant melanoma samples. Tumor suppressors inhibit transcription of genes that would cause increased replication. When a mutation occurs in any of these suppressors, replication and division become uncontrolled and tumors result. A 53-kDa protein designated p53 has become the focus of feverish activity in cancer research. Mutations in the gene that codes for p53 are found in more than half of all human cancers. When the gene is operating normally, it acts as a tumor suppressor; when it is mutated, it is involved in a wide variety of cancers. By the end of 1993, mutations in the p53 gene had been found in 51 types of human tumors. Normal levels of p53 protein cannot turn these genes off in cancer cells, but they could do this in normal cells. A number of factors come together in explaining the variety of diseases we call cancer. The possibility of finding new cancer therapies-and perhaps even cancer cures-is enhanced by understanding these contributing factors and how they affect each other. Viruses and Cancer the original work by Rous showed how viruses could cause cancer in certain situations. The close homology between the oncogene sequence found in some viruses with the proto-oncogene sequences in the mammalian genome has led many researchers to theorize that the oncogenes may have been of mammalian origin. In the course of the rapid mutation that occurs in retroviruses, these proto-oncogenes could be mutated to a form that is oncogenic. One of the biggest fears of using in vivo delivery techniques for human gene therapy (see Section 14. In 9 of 11 cases, the viral-gene therapy restored the immune systems of the patients. It was later found that the virus had inserted itself, in each case, near a gene that has been found to be a leukemia oncogene. This was a tragic setback in viral-gene therapy, and now many government agencies are discussing the future of such therapy. The more traditional approaches include surgeries to remove tumors, radiation and chemotherapy to kill cancerous cells, and treatment with monoclonal antibodies that target specific tumors. One of the most current focus points for research is the attempt to reactivate p53 in the cancerous tissues that have lost this function. Because this single gene was found to be the culprit in so many types of cancer, this became an obvious strategy. Clinical trials with mice have shown that in tumors that have lost p53 function, restoring p53 activity stops tumor growth and even shrinks the tumors. Remember that p53 has a two-pronged attack on tumor cells-it arrests the growth of the cell and it promotes cell death (apoptosis) of the cell. Many of the early trials involved specific delivery of an active p53 gene via gene therapy (Section 14. As has often been the case with cancer research, scientists and doctors must be very careful when tinkering with processes involved in cell growth. In some studies, reactivating p53 in certain laboratory animals had fatal effects as the reactivation caused a generalized cell death that went beyond the targeted tumors. Viruses Helping Cure Cancer As we have seen in this chapter, viruses come in many types and cause many diseases. Viruses can be very specific to a single cell type because they rely on a protein receptor on the cell to gain entry. Oncologists (doctors who treat cancer) have treated cancer for years with techniques such as radiation therapy and chemotherapy. These techniques attempt to target cancer cells, but, in the end, destroy other cells as well. In some sense, the goal of chemotherapy is to kill the cancer before the treatment kills the patient. The virus of choice was an adenovirus, which we saw in the section on gene therapy. The second is to have the virus ferry in a gene to the cancer cell that makes the cell more susceptible to a chemotherapy agent. One of the biggest challenges in virotherapy is to make sure the virus specifically targets the cancer cell. With this technique, the replication genes for adenovirus are placed after a promoter that is specific for a cancer cell. Therefore, the genes for enzymes that make melanin are turned on more often in skin cells than in other cells (see Figure 14. Adenovirus can be engineered to have the promoter for the melanin-producing enzyme near the genes for virus replication. In cancerous skin cells, these promoters are triggered more often, so adenovirus replicates much quicker in skin-cancer cells, killing them specifically. Similar techniques have been used to target liver-cancer cells and prostate-cancer cells. The other basic strategy is to have the virus ferry in a gene that makes the cancer cell more susceptible to chemotherapy. Inside these cells, and only in these cells, the gene carried by the virus converts an innocuous pro-drug into an anticancer drug. These viruses are sometimes called "smart viruses" for their ability to select only the cancer cells. The Biochemical Connections box on page 434 describes one other approach to fighting cancer. Viruses, such as adenovirus, are used to infect and destroy cancer cells selectively. Spikes on the adenovirus are mutated so that they recognize unique receptors on cancer cells. The adenovirus infects many cells, but it is activated to replicate only in the cancer cell. Most cancers have been linked to specific genes called oncogenes or to tumor-suppressor genes. There are many classical ways to fight cancer, such as radiation therapy and chemotherapy. Novel techniques using viruses are now being tried to target cancer cells more directly, and some of these are showing tremendous promise. This aspect of the immune system was the poor cousin to acquired immunity for decades, but has recently graduated to a much higher status because of its relationship to inflammation. Many of the processes involving macrophages and other innate immunity cell types lead to inflammation. Cancer begins with a series of genetic changes that leads to cells overreplicating and then progressing to a stage where cells break off and set up new cancerous colonies at other sites. However, the stages in development are controlled by many factors, and researchers are now realizing that invasive cancers require cells of the innate immune system. As shown in the figure, cells of the innate system can be both beneficial and detrimental to the fight against cancer. As antigen-presenting cells, dendritic cells or macrophages stimulatecells and B cells, which lead to an attack on a tumor cell. However, they also lead to an inflammatory response that leads to tumor growth through production of cytokines and growth factors. The evidence indicates that the inflammation surrounding macrophages encourages the conversion of precancerous tissue to full malignancy. This realization has led researchers to question the dogmatic search for a cancer cure. Cancer researchers have always looked for cures, but if they can treat the inflammation symptom, then they might be able to stop the progression of the disease, essentially turning cancer into a manageable long-term disease. Tumor-supporting response Activated B cell Adapt i ve Anitgencell Antibodies Ad ap ti ve Inflammatory response B cell Tumor grows In na the Tumor Ad ap tiv the immune paradox. Two arms of the immune system-the innate and the adaptive-are exquisitely well adapted for fighting pathogens, but their role in combating cancer is more paradoxical. The innate system furnishes an initial inflammatory response to a microbial insult by attacking any invading pathogen indiscriminately, whereas adaptive immunity furnishes a delayed response that hones in on a particular pathogen. But a tumor protects itself by recruiting the innate system to enhance its development. Viruses have been linked to cancer, and they can be used as delivery agents in gene therapy. One type of immunity, called innate immunity, consists of physical barriers, such as skin, and cellular warriors, such as dendritic cells. These cells are generated randomly with receptors that can be specific for an unimaginable number of antigens. When these cells encounter their specific antigens, they are stimulated to multiply, exponentially increasing the number of cells that can fight the invading organism. T cells and B cells are conditioned, in their early stages of development, not to recognize proteins from that individual. Helpercells also bind to antigenpresenting cells, but instead of destroying the cell, they stimulate B cells. Antibodies are Y-shaped proteins composed of two chains, a light chain and a heavy chain. Cancer cells can avoid apoptosis when other cells would be triggered to self-destruct. They can replicate indefinitely; normal cells can replicate only a few times before dying. Cancer cells emit chemical signals that promote blood vessel growth in their area to deliver oxygen to the cancerous tissues. They defy multiple signals that normally hold cells in place, thus traveling and thriving in other locations in the body. When these genes are mutated, the cell loses the ability to control its replication. Because more than half of the known cancers involve a mutated and nonfunctional p53 gene, restoring the activity of p53 is a focus of cancer research today. Recall Define the following: (a) virion (b)capsid (c) nucleocapsid (d)protein spike 3. Recall What is the difference between the lytic pathway and the lysogenic pathway Reflect and Apply Is there a correlation between the speed of a viral infection and its potential mortality rate Reflect and Apply If you were going to design a drug to fight a virus, what would be likely targets for the drug design Reflect and Apply Some viruses can undergo lysis or lysogeny even in the same host. Reflect and Apply Describe the relationship between the innate immunity system and the acquired-immunity system. Reflect and Apply Describe how the cells of the acquired-immunity system develop so that they do not recognize self-antigens but do recognize foreign antigens. Reflect and Apply Describe the difference between a tumor suppressor and an oncogene with respect to the actual causes of cancer. Reflect and Apply Describe the nature of p53 reactivation as a cancer-fighting strategy. Reflect and Apply What is the difference between Prima-1 and nutlins in the way they would fight cancer Reflect and Apply Describe different techniques that might restore p53 to a cell lacking it. Biochemical Connections Describe the positive and negative effects of the innate immune system on cancer cells. Biochemical Connections Explain why some researchers believe science should focus its attention on the inflammation associated with cancer progression instead of looking for a cure. Recall What types of viruses are used for gene therapy, and how are they manipulated to make them useful

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Drinking coffee and carbonated beverages blocks absorption of nicotine from nicotine polacrilex gum shinee symptoms order compazine 5mg on line. C Coffee + Iron compounds Coffee may possibly contribute towards the development of irondeficiency anaemia in pregnant women treatment ulcer discount compazine 5mg mastercard, and reduce the levels of iron in breast milk medicine number lookup buy compazine 5mg with mastercard. Clinical evidence In a series of studies in healthy subjects medications causing dry mouth cheap compazine 5mg without prescription, drinking 200 mL of coffee with various test meals containing radiolabelled iron resulted in a 39% to 83% reduction in the absorption of iron medicine you can take while pregnant compazine 5 mg fast delivery. No decrease was observed if the coffee was drunk one hour before the meal medications zocor order compazine online pills, but when the coffee was given one hour after the meal the reduction was the same as taking it simultaneously with the meal. Almost a quarter of the mothers were considered to have iron-deficiency anaemia (haemoglobin levels of less than 11 g/dL), compared with none among the control group of non-coffee drinkers. The coffee drinkers drank more than 450 mL of coffee daily, equivalent to more than 10 g of ground coffee. Mechanism It is suggested that polyphenolics in coffee might interfere with the absorption of iron. Note that coffee is not generally considered to be a suitable drink for babies and children, because of its effects on iron absorption. Inhibition of non-haem iron absorption in man by polyphenolic-containing beverages. Coffee + Phenylpropanolamine A case report describes mania in a patient who drank coffee and took phenylpropanolamine. Evidence, mechanism, importance and management A case report describes mania with psychotic delusions in a healthy woman (who normally drank 7 to 8 cups of coffee daily) within 3 days of her starting to take a phenylpropanolamine-containing decongestant. She recovered within one week of stopping both the coffee and the phenylpropanolamine. However, case reports have described other severe reactions with caffeine, see Caffeine + Phenylpropanolamine, page 103. Coffee + Tetracycline Coffee does not appear to affect the absorption of tetracycline. Evidence, mechanism, importance and management A study in 9 healthy subjects found that 200 mL of coffee (milk content, if any, unstated) did not significantly affect the bioavailability of a single 250-mg dose of tetracycline. Influence of liquids (coffee and orange juice) on the bioavailability of tetracycline. The influence of coffee with milk and tea with milk on the bioavailability of tetracycline. For information on the pharmacokinetics of individual flavonoids present in cola, see under flavonoids, page 186. Interactions overview Cola contains significant amounts of caffeine, therefore the interactions of caffeine, page 97, should be applied to cola, unless the product is specified as decaffeinated. By virtue of its caffeine content cola may also cause serious adverse effects if used with other drugs or herbs with similar effects, such as ephedra, page 176. Cola may reduce the bioavailability of halofantrine and increase the risk of developing hypertension. For information on the interactions of individual flavonoids present in cola, see under flavonoids, page 186. Carbonated cola beverages are acidic, and they can therefore interact with drugs by altering gastric acidity. The best example of this is that they can increase the absorption of the azole antifungal drugs ketoconazole and itraconazole. However, this mechanism is not going to be applicable to herbal medicines containing cola extracts, and these interactions are not therefore covered here. Other constituents include flavonoids from the flavanol group (such as catechin and epicatechin), amines, an anthocyanin pigment (kola red) and betaine. Use and indications the main use of cola seed is as a stimulant for depression, tiredness and poor appetite, and as a diuretic. Evidence, mechanism, importance and management There is a possibility that the effect of cola on blood pressure might differ from that of pure caffeine. There appear to be very few published studies of the effect of cola on blood pressure; however, in the Nurses Health prospective cohort studies, both sugared cola and diet cola beverages were associated with an increased risk of developing hypertension with increased intake. However, the modest hypertensive effects of the caffeine content of cola may be of importance. See Caffeine + Antihypertensives, page 99, for further discussion of the adverse effect of caffeine on blood pressure. Clinical evidence In a study in 15 healthy subjects, a single 500-mg dose of halofantrine was given alone or with cola 12. Similar reductions were seen in the major metabolite of halofantrine, N-desbutylhalofantrine. Mechanism the authors suggest that caffeine, or other consituents of cola such as catechins or tannins, may have formed a complex with halofantrine to reduce its absorption. Importance and management Evidence appears to be limited to this one study, which found a modest reduction in the bioavailabilty of halofantrine. Nevertheless, as there is the potential that this interaction could lead to malaria treatment failure, it may be prudent to advise patients to avoid taking cola during treatment with halofantrine. Note that the effects of caffeine from cola-containing herbal medicine or supplement will be additive with those of other caffeinecontaining foods or beverages. Cola + Herbal medicines Cola + Halofantrine Cola appears to moderately reduce the bioavailability of halofantrine. The caffeine content of cola suggests that it may interact with other herbal medicines in the same way as caffeine, see Caffeine + Herbal medicines; Bitter orange, page 101, and Ephedra + Caffeine, page 176. Constituents the leaves and flowers of coltsfoot contain mucilage composed of polysaccharides, which include arabinose, fructose, galactose, glucose and xylose, and the carbohydrate inulin. Flavonoids (such as rutin, isoquercetin and hyperoside), polyphenolic acids, triterpenes and sterols are present, and sesquiterpenes including bisabolene derivatives and tussilagone may also be found. All parts of the plant may contain the pyrrolizidine alkaloids isotussilagine, senecionine, senkirkine and tussilagine in variable amounts. Extracts have anti-inflammatory and antispasmodic activity and tussilagone alone has been found to be a cardiovascular and respiratory stimulant. The concentration of the most toxic pyrrolizidine alkaloid, senkirkine, is thought to be too low to cause toxicity if used infrequently, and tussilagine is unsaturated and therefore less toxic. Use and indications Coltsfoot is traditionally used in cough and cold preparations Interactions overview No interactions with coltsfoot found. For information on the pharmacokinetics of the alkaloid constituent, berberine, see under berberine, page 58. Constituents the thread-like rhizomes contain isoquinoline alkaloids, mainly berberine and coptisine. However, for the interactions of the alkaloid constituent, berberine, see under berberine, page 58. Use and indications Coptis species are used widely in Chinese medicine for 151 Cranberry Vaccinium macrocarpon Aiton (Ericaceae) C Synonym(s) and related species Large cranberry (Vaccinium macrocarpon) is the cultivated species. Constituents the berries contain anthocyanins and proanthocyanidins (mainly oligomers of epicatechin), and organic acids including malic, citric, quinic and benzoic acids. Note that, although salicylic acid does not appear as a constituent of the juice in many cranberry monographs, some studies have shown low levels of salicylates in commercial cranberry juice. The urinary levels of anthocyanins reached a maximum between 3 and 6 hours, and the recovery of total anthocyanins in the urine over 24 hours was estimated to be 5% of the amount consumed. Interactions overview Clinical studies suggest that cranberry juice and/or extracts do not affect the pharmacokinetics of ciclosporin, flurbiprofen, midazolam, tizanidine and warfarin. Cranberry juice is unlikely to affect the pharmacokinetics of nifedipine to a clinically relevant extent. Increased salicylate concentrations in urine of human volunteers after consumption of cranberry juice. Use and indications the main use of cranberries and cranberry juice is for the prevention and treatment of urinary tract infections, although they have also been used for blood and digestive disorders. Pharmacokinetics There is high absorption and excretion of cranberry anthocyanins in human urine, as shown by a study where 152 Cranberry 153 Cranberry + Ciclosporin Occasional consumption of cranberry juice does not appear to affect the bioavailibility of ciclosporin. Evidence, mechanism, importance and management In a well-controlled, single-dose study, 12 healthy fasted subjects were given a 200-mg dose of oral ciclosporin simultaneously with 240 mL of cranberry juice or water. Cranberry juice was found to have no clinically significant effect on the pharmacokinetics of ciclosporin. This study suggests that cranberry juice does not affect the absorption of ciclosporin, and that drinking the occasional glass of cranberry juice with ciclosporin should not affect ciclosporin levels. However, note that a study of regular daily cranberry juice consumption is required to also rule out an interaction affecting ciclosporin elimination, which may have a bearing on the safety of regular. Pomelo juice, but not cranberry juice, affects the pharmacokinetics of cyclosporine in humans. C Cranberry + Midazolam Limited evidence suggests that cranberry juice does not appear to affect the pharmacokinetics of midazolam. Clinical evidence In a randomised, crossover study in 10 healthy subjects, 200 mL of cranberry juice three times daily for 10 days had no significant effect on the pharmacokinetics of a single 500-microgram oral dose of midazolam taken on day 5. Cranberry + Flurbiprofen Limited evidence suggests that cranberry juice does not appear to affect the pharmacokinetics of flurbiprofen. Clinical evidence In a study in 14 healthy subjects, 230 mL of cranberry juice taken the night before, and 30 minutes before a single 100-mg dose of flurbiprofen, had no significant effect on the pharmacokinetics of flurbiprofen. Experimental evidence In an in vitro study, cranberry juice inhibited flurbiprofen hydroxylation by about 44%, which was less than that of the positive control sulfaphenazole (79%). Therefore no dosage adjustment appears to be necessary if patients taking flurbiprofen wish to drink cranberry juice. Interaction of flurbiprofen with cranberry juice, grape juice, tea, and fluconazole: in vitro and clinical studies. Importance and management Although the evidence is limited to this particular study, there appears to be no need for special precautions when taking cranberry juice with midazolam. Cranberry + Nifedipine the interaction between cranberry juice and nifedipine is based on experimental evidence only. However, other pharmacokinetic parameters such as the mean residence time, volume of distribution, and elimination rate constant were not significantly affected. The patient was drinking almost 2 litres of cranberry juice daily, because of recurrent urinary tract infections, and was advised to stop drinking this. The cranberry concentrate had no effect on platelet aggregation, and had no effect on the pharmacokinetics of either R- or S-warfarin. Importance and management Evidence appears to be limited to two experimental studies. Taken on its own, this evidence suggests the possibility of a modest interaction, and therefore some caution might be warranted in patients taking nifedipine who drink cranberry juice. C Cranberry + Tizanidine Limited evidence suggests that cranberry juice does not appear to affect the pharmacokinetics of tizanidine. Clinical evidence In a randomised, crossover study in 10 healthy subjects 200 mL of cranberry juice three times daily for 10 days had no significant effect on the pharmacokinetics of a single 1-mg oral dose of tizanidine taken on day 5. In this study, the cranberry juice used was a concentrate (Kontiomehu sokeroitu karpalomehu) diluted 1 to 4 with tap water before use. Importance and management Although the evidence is limited to this particular study, there appears to be no need for any special precautions when taking cranberry juice with tizanidine. For example, the salicylate constituent of commercial cranberry juice might cause hypoprothrombinaemia. Controlled studies have not found a pharmacokinetic interaction, and only one of four studies found any evidence for an increase in warfarin effect. This might be explained if the interaction is dose dependent (in one of the cases where cranberry intake was mentioned a quantity of 2 litres daily was being consumed), or if it is product dependent. However, it could also be that there is no specific interaction, and that the case reports just represent idiosyncratic reactions in which other unknown factors. Committee on Safety of Medicines/Medicines and Healthcare products Regulatory Agency Possible interaction between warfarin and cranberry juice. Committee on Safety of Medicines/Medicines and Healthcare products Regulatory Agency Interaction between warfarin and cranberry juice: new advice. Warfarin-cranberry juice interaction resulting in profound hypoprothrombinemia and bleeding. A randomized, double-blind trial of the interaction between cranberry juice and warfarin. Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects. C Creatine N-(Aminoiminomethyl)-N-methylglycine C Types, sources and related compounds Creatine monohydrate. Use and indications Creatine supplements are taken most often to improve exercise performance and increase muscle mass. Creatine is found in foods, most abundantly in meat and fish, and is also synthesised endogenously. Excessive intake of creatine, by the use of supplements, has, very rarely, been reported to cause acute renal impairment. The maximum plasma level of creatine is reached less than 2 hours after the ingestion of doses of under 10 g, but after more than 3 hours for doses over 10 g, and may vary with the ingestion of carbohydrate, see food, page 157. Clearance of creatine would appear to be dependent on both skeletal muscle and renal function. There is an isolated report of stroke in a patient taking a creatine supplement with caffeine plus ephedra, although the role of creatine in this case is uncertain. There is a possibility that creatine supplements might complicate interpretation of serum creatinine measurement. Pharmacokinetics Creatine is distributed throughout the body, with the majority being found in skeletal muscle.

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Characterized as lands dominated by grasses rather than large shrubs or trees F Forest G Grasslands L Lacustrine "permanently flooded lakes and reservoirs symptoms rectal cancer trusted 5mg compazine, intermittent lakes and tidal lakes with salinity <= 0 medicine 79 discount compazine 5 mg on-line. For clarity symptoms influenza discount compazine 5mg visa, the length of the exposure (short medications such as seasonale are designed to purchase compazine pills in toronto, medium medicine pouch buy cheap compazine on-line, or long) and the nature of the effect end point (lethal or nonlethal) should be specified treatment narcissistic personality disorder buy compazine online. The duration of an acute aquatic toxicity test is generally 4d or less and mortality is the response measured. Can be used to define either the exposure or the response to an exposure (effect). For clarity the length of the exposure and the nature of the effect end point should be specified. Chronic exposure typically induces a biological response of relatively slow progress and long continuance. The chronic aquatic toxicity test is used to study the effects of continuous, long-term exposure to a chemical or other potentially toxic material on organisms. Generally, a life cycle is from birth until the organism reproduces (Rand and Petrocelli, 1985) A study that encompasses multiple generations of the test organism. P, F1,F2) either exposed to a toxicant during different generations or exposure to one generation and results measured in subsequent generations. With experimental animals, the period of exposure may range from a few days to 6 months. Department of Health, education and Welfare, Food and Drug Administration (1978) and the U. Method suitable for leaf-eating Lepidoptera and Coleoptera on cotton, vegetable and field crops. Office of Prevention, Pesticides, and Toxic Substances Harmonized Test Guidelines. Estimation of the Acute Lethal Toxicity of Pollutants to Marine Fish and Invertebrates. Criteria and meaning of tests for determining susceptibility or resistance of insects to insecticides. Data that has been statistically analyzed and there is a difference between all doses and control. Data that has been statistically analyzed and there is no difference between dose and control. Data that has been statistically analyzed and there is a difference between dose and control. Oral Preterm infants less than 32 weeks Postmenstrual Age: 20 to 25 mg/kg orally; then 12 to 15 mg/kg/dose every 12 hours as needed or around-the-clock. Rectal Preterm infants less than 32 weeks Postmenstrual Age: 30 mg/kg rectally; then 12 to 18 mg/kg/dose every 12 hours as needed or around-the-clock. Preterm infants greater than or equal to 32 weeks Postmenstrual Age: 30 mg/kg rectally; then 12 to 18 mg/kg/dose every 8 hours as needed or around-the-clock. Uses Fever reduction and treatment of mild to moderate pain: the decision to use acetaminophen should be weighed against the epidemiological evidence of an association between acetaminophen use and asthma, atopy, rhinoconjunctivitis, or eczema; although causality has not been established [9] [10] [11]. Routine prophylactic use of acetaminophen at the time of vaccination is not recommended because of a potential reduction in antibody response. Rare but serious skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis, have been associated with the use of acetaminophen. Use with caution in patients with hepatocellular insufficiency, severe renal insufficiency, glucose 6 phosphate dehydrogenase deficiency, chronic malnutrition, or dehydration/hypovolemia [4]. Epidemiological evidence demonstrated an association between acetaminophen use and asthma [11], rhinoconjunctivitis, eczema [10] and atopy [9]. Elimination half-life is approximately 3 hours in term neonates, 5 hours in preterm neonates greater than 32 weeks gestation, and up to 11 hours in more immature neonates. An effect compartment concentration of 10 mg/L was associated with a pain score reduction of 3. Oral/Rectal: Target concentrations above 10 mg/L are predicted in 50% of patients administered acetaminophen (30 mg/kg orally loading dose, 15 mg/kg/dose orally every 8 hours and 37. Rash, fever, thrombocytopenia, leukopenia, and neutropenia have been reported in children [5] [14] [15] [16] [17]. Serious skin reactions have been reported from patients who were rechallenged with acetaminophen and had a recurrence of a serious skin reaction [12]. Although data are limited for neonates, in children liver toxicity occurs with excessive doses [4] [5] or after prolonged administration (greater than 48 hours) of therapeutic doses. Acute liver failure occurred in an 11-month-old boy who received therapeutic doses of oral acetaminophen for a prolonged duration (10 days) [21]. Intravenous formulation available in a 100-mL glass vial containing 1000 mg (10 mg/mL). Terminal Injection Site Compatibility Acetaminophen 10 mg/mL Cimetidine 12 mg/mL, dextrose 5% in lactated Ringer solution, dextrose 5% in normal saline, dextrose 10%, dexamethasone 10 mg/mL, diphenhydramine 50 mg/mL, dolasetron 20 mg/mL, fentanyl 50 mcg/mL, granisetron 0. Drug compatibility is 10 Micormedex NeoFax Essentials 2014 dependent on multiple factors (eg, drug concentrations, diluents, storage conditions). Allegaert K, Naulaers G, Vanhaesebrouck S et al: the paracetamol concentration-effect relation in neonates. None Listed: Injectable paracetamol in children: yet more cases of 10-fold overdose. Wickens K, Beasley R, Town I et al: the effects of early and late paracetamol exposure on asthma and atopy: a birth cohort. Etminan M, Sadatsafavi M, Jafari S et al: Acetaminophen use and the risk of asthma in children and adults: a systematic review and metaanalysis. Hopchet L, Kulo A, Rayyan M et al: Does intravenous paracetamol administration affect body temperature in neonates Allegaert K, Rayyan M, De Rijdtet al: Hepatic tolerance of repeated intravenous paracetamol administration in neonates. Preterm infants greater than or equal to 32 weeks Postmenstrual Age: 20 to 25 mg/kg orally; then 12 to 15 mg/kg/dose every 8 hours as needed or around-the-clock. Term infants: 20 to 25 mg/kg orally; then 12 to 15 mg/kg/dose every 6 hours as needed or around-the-clock. Term infants: 30 mg/kg rectally; then 12 to 18 mg/kg/dose every 6 hours as needed or around-the-clock. Exercise caution when calculating the dose in milligrams and administering the dose in milliliters [6] [7] [8]. Contraindications/Precautions Intravenous formulation contraindicated in patients with severe hepatic impairment or severe active liver disease. Hypersensitivity reactions, including life-threatening anaphylaxis, have been reported [5]. Discontinue use immediately if rash or other hypersensitivity symptoms occur [12]. Neonates with pre-existing low arterial pressure may be at greater risk for hypotension [13]. Extensively metabolized in the liver, primarily by sulfation with a small amount by glucuronidation. Special Considerations/Preparation Available orally in various liquid formulations containing 32, 80, and 100 mg/mL. Inaccurate dosing may occur with rectal administration because of unequal distribution of acetaminophen in the suppositories. Allegaert K: the pharmacokinetics of intravenous paracetamol in neonates: size matters most. An absolute neutrophil count of 500 cells/mm3 or less was reported in 20% to 25% of patients receiving acyclovir compared with 5% to 7% receiving placebo; no patient had complications associated with neutropenia [4]. The mean acyclovir dose required to achieve the target peak concentration of 2 mcg/mL or greater was 1340 18 Micormedex NeoFax Essentials 2014 mg/m2/dose given every 12 hours. Long-term neurological development was normal in 7 of the 9 children; the 2 children who developed neurological impairment experienced a delay in oral therapy following completion of parenteral acyclovir therapy [14]. Resistant viral strains may emerge during long-term therapy; these patients are at high risk for progressive life-threatening disease. Prepare powder for solution by dissolving contents of 500-mg vial in 10 mL sterile water for injection. Aztreonam, caffeine citrate, caspofungin, cefepime, dobutamine, dopamine, meropenem, and piperacillin-tazobactam. References Whitley R, Arvin A, Prober C, et al: A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. Rudd C: Dosing considerations for oral acyclovir following neonatal herpes disease. Herpes Simplex Virus Infection, Chronic suppression: 300 mg/m2/dose orally 3 times a day. Oral route: take with or without food; for suspension, shake well before measuring each dose [12]. In asymptomatic neonates born to women with active herpes lesions, initiation of acyclovir is dependent on risk of transmission to the neonate [1] [2]. Starting doses were 1200 to 1600 mg/m2 every 12 hours to achieve an acyclovir peak serum concentration greater than 2 mcg/mL [13]. There was no control group; however, the authors concluded there were improved neurological outcomes in this cohort based on comparisons with historical information from other studies. The mean acyclovir dose required to achieve the target peak concentration of 2 mcg/mL or greater was 1340 mg/m2/dose given every 12 hours. Long-term neurological development was normal in 22 Micormedex NeoFax Essentials 2014 7 of the 9 children; the 2 children who developed neurological impairment experienced a delay in oral therapy following completion of parenteral acyclovir therapy [14]. Most of administered dose is excreted unchanged in urine, primarily via glomerular filtration. Serum half-life is 3 to 4 hours in patients with normal renal and hepatic function. Risk of transient renal dysfunction and crystalluria is minimized by slow infusion rates and adequate patient hydration. Special Considerations/Preparation Intravenous formulations available as solution (50 mg/mL) or as powder for solution in 500-mg and 1-g vials. A 5-mg/mL dilution may be made by adding 1 mL of 50 mg/mL concentration to 9 mL of preservative-free normal saline. Terminal Injection Site Compatibility 23 Micormedex NeoFax Essentials 2014 Amikacin, ampicillin, aminophylline, cefazolin, cefotaxime, cefoxitin, ceftazidime, ceftriaxone, chloramphenicol, cimetidine, clindamycin, dexamethasone, erythromycin lactobionate, famotidine, fluconazole, gentamicin, heparin, hydrocortisone succinate, imipenem/cilastatin, linezolid, lorazepam, magnesium sulfate, metoclopramide, metronidazole, milrinone, morphine, nafcillin, oxacillin, penicillin G, pentobarbital, piperacillin, potassium chloride, propofol, ranitidine, remifentanil, sodium bicarbonate, theophylline, ticarcillin, tobramycin, trimethoprim/sulfamethoxazole, vancomycin, and zidovudine. Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines, 2010. Sauerbrei A: Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. Singalavanija S, Limpongsanurak W, Horpoapan S et al: Neonatal varicella: a report of 26 cases. References Paret G, Steinmetz D, Kuint J et al: Adenosine for the treatment of paroxysmal supraventricular tachycardia in full-term and preterm newborn infants. Increase dose in 50 mcg/kg increments every 2 minutes until return of sinus rhythm. Adverse Effects Flushing, dyspnea, and irritability occur frequently, but usually resolve within 1 minute. Consider alternative potassium-lowering therapies for potassium levels greater than 7. Following administration every 2 hours until serum potassium dropped below 5 mmol/L (or a maximum of 12 doses), nebulized albuterol (n=8) was effective in lowering potassium levels at 4 and 8 hours when compared with placebo (saline via nebulization; n=11) [1]. Adverse Effects Tachycardia, arrhythmias, tremor, hypokalemia, and irritable behavior. Published data using the nebulized formulation of albuterol for the treatment of hyperkalemia in preterm neonates are limited to one randomized, placebo-controlled trial (n=19). Optimal aerosol dose in neonates is uncertain due to differences in aerosol drug delivery techniques. Beck R, Robertson C, Galdes-Sebaldt M, Levison H: Combined salbutamol and ipratropium bromide by inhalation in the treatment of severe acute asthma. Higher initial doses are usually no more effective and have a high incidence of adverse effects. Sample Dilution and Infusion Rate: Mix 1 ampule (500 mcg) in 49 mL of compatible solution (eg, D5W) yielding a concentration of 10 mcg/mL. Uses To promote dilation of ductus arteriosus in infants with congenital heart disease dependent on ductal shunting for oxygenation/perfusion. Apnea is seen most often in neonates weighing less than 2 kg at birth, and usually appears during the first hour of drug infusion. Monitor respiratory status throughout treatment and be prepared to intubate/resuscitate. Maximal drug effect usually seen within 30 minutes in cyanotic lesion; may take several hours in acyanotic lesions. Uncommon (1% to 5%): Seizures, hypoventilation, tachycardia, cardiac arrest, edema, sepsis, diarrhea, and disseminated intravascular coagulation. Cortical hyperostosis and 32 Micormedex NeoFax Essentials 2014 periostitis may occur with long-term (greater than 3 months) therapy. Aminophylline, ampicillin, caffeine citrate, calcium chloride, cefazolin, cefotaxime, cimetidine, clindamycin, dobutamine, dopamine, fentanyl, furosemide, gentamicin, glycopyrrolate, metoclopramide, metronidazole, nitroglycerin, nitroprusside, potassium chloride, penicillin G, tobramycin, vancomycin, and vecuronium. Adverse Effects Common (6% to 15%): Apnea (consider treating with aminophylline), hypotension, fever, leukocytosis, cutaneous flushing, and bradycardia. Hypokalemia reported with long-term therapy (greater than 20 days), especially with doses greater than 0. Gastric outlet obstruction and reversible cortical proliferation of the long bones after prolonged treatment (greater than 120 hours). Rare (less than 1%): Urticaria, bronchospasm, hemorrhage, hypoglycemia, and hypocalcemia.

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Interactions overview Policosanol has antiplatelet effects medications names order genuine compazine line, which may be additive with other antiplatelet drugs medications you should not take before surgery purchase compazine 5 mg online, and could theoretically increase the risk of bleeding in patients taking anticoagulants medicine 8 discogs buy compazine american express. Policosanol may also enhance the blood pressure-lowering effects of some antihypertensives treatment 5th metatarsal fracture purchase compazine master card. Pharmacokinetics Policosanol did not alter the metabolism of phenazone 323 324 Policosanol Policosanol + Anticoagulants the interaction between policosanol and anticoagulants is based on a prediction only medications 7 rights generic 5 mg compazine mastercard. Experimental evidence Policosanol 200 mg/kg did not prolong the bleeding time of warfarin 200 micrograms/kg given for 3 days in rats medicine 44175 5mg compazine visa. Policosanol + Beta blockers Policosanol appears to increase the blood pressure-lowering effects of beta blockers. Clinical evidence In a randomised study in patients (aged 60 to 80 years) taking beta blockers, the addition of policosanol 5 mg tablets daily (titrated to a dose of 2 to 4 tablets) found that the average blood pressure was reduced from about 141/83 mmHg to 131/81 mmHg after one year, and 126/79 mmHg after 3 years. The efficacy of policosanol was not reduced and adverse effects were actually slightly lower in the policosanol group. Importance and management Policosanol increased the blood pressure-lowering effects of beta blockers and the clinical study suggests that the effect is gradual and beneficial. It therefore appears that, as with other conventional antihypertensives, policosanol may increase the effects of the beta blockers and so some caution is warranted, but no adverse effects such as first-dose hypotension would be expected. P Policosanol + Antiplatelet drugs Policosanol has antiplatelet effects, which may be additive with those of other antiplatelet drugs. Clinical evidence In a randomised study, four groups, each containing 10 or 11 subjects, were given placebo, policosanol 20 mg daily, aspirin 100 mg daily or both drugs together, for 7 days. Adrenaline-induced platelet aggregation was reduced in the group given aspirin and policosanol by about 35% more than in the group given aspirin alone: the effects of aspirin and policosanol were approximately additive. Furthermore, collagen-induced platelet aggregation was reduced in the group given aspirin and policosanol by about 10% more than in the group given aspirin alone. Importance and management the concurrent use of two conventional antiplatelet drugs is not uncommon, and so concurrent use of policosanol and aspirin need not be avoided. However, because platelet aggregation was reduced significantly, and a bleeding event was experienced, caution is perhaps warranted when taking policosanol supplements with aspirin or any other antiplatelet drug. Comparative study of policosanol, aspirin and the combination therapy policosanol-aspirin on platelet aggregation in healthy volunteers. Policosanol + Nifedipine Policosanol does not appear to affect the blood pressurelowering effects of nifedipine. Clinical evidence A 3-year study, primarily designed to assess the safety and efficacy of policosanol in patients taking beta blockers, included 28 patients taking calcium-channel blockers (unnamed). Importance and management There appears to be no reason to avoid taking policosanol supplements with nifedipine. However, additive blood pressurelowering effects seem possible, see beta blockers, page 324. Policosanol + Sodium nitroprusside the interaction between policosanol and sodium nitroprusside is based on experimental evidence only. Experimental evidence A study found that the antiplatelet and hypotensive effect of sodium nitroprusside was greater in rats that had been pre-treated with a single 200-mg/kg oral dose of policosanol, than in animals that had not received policosanol. Policosanol reduces vascular resistance and has been shown to enhance the blood pressure-lowering effects of other antihypertensives. Importance and management the clinical significance of this finding is unclear, but bear it in mind in case of an unexpected response to treatment. P Policosanol + Phenazone (Antipyrine) the information regarding the use of policosanol with phenazone (antipyrine) is based on experimental evidence only. Experimental evidence A study in dogs found that the pharmacokinetics of an intravenous dose of phenazone 10 mg/kg were not affected by oral treatment with policosanol, 25 mg/kg daily for 21 days. Constituents the main constituents of prickly ash bark include the isoquinoline alkaloids magnoflorine, laurifoline, nitidine, chelerythrine, tambetarine and candicine. Various natural coumarins, tannins, lignans, including sesamin and asarinin, resins and volatile oil are also present. It is also used to treat toothache and fevers, and is used as a flavouring agent in food and drink. Because of doubts about the toxicity of the alkaloids that it contains (which are said to have hypotensive, anti-inflammatory and neuromuscular blocking activity), some sources do not recommend its use. The bark is mainly used as an antirheumatic, analgesic and carminative, and is believed to possess Interactions overview No interactions with prickly ash found. Traditionally, they were used to treat tapeworm infection (cucurbitin has anthelmintic effects), but more recently they have begun to be more widely used to treat benign prostatic hyperplasia. P Constituents Pumpkin seeds contain a fixed oil, the predominant fatty acids of which are linoleic, oleic, palmitic and stearic. There is a high sterol content with cholestanol and lathostanol derivatives present, and vitamin E, particularly gammatocopherol. The seeds also contain a number of cucurbitacins such as cucurbitin, the type and concentration depending on growth and variety. Note that Pycnogenol is a trademark for the extract from the bark of the French maritime pine which grows in the southern coastal area of France. Clinical studies indicate that it can be effective in the treatment of chronic venous insufficiency, cardiovascular disorders, asthma, vascular retinopathies and inflammatory conditions such as systemic lupus erythematosus. Constituents Pycnogenol is a standardised water extract of the bark of French maritime pine, containing a range of flavonoid polyphenols and procyanidins, including catechin, and, to a lesser degree, epicatechin. Other constituents are polyphenolic monomers, which include taxifolin, ferulic acid, benzoic acid and cinnamic acid, and their glycosides. For information on the pharmacokinetics of individual flavonoids present in pycnogenol, see under flavonoids, page 186. Interactions overview Pycnogenol only modestly increases the antiplatelet effects of aspirin. For information on the interactions of individual flavonoids present in pycnogenol, see under flavonoids, page 186. Use and indications Pycnogenol is used for a wide variety of disease states and is 328 Pycnogenol 329 Pycnogenol + Antiplatelet drugs the interaction between pycnogenol and antiplatelet drugs is based on experimental evidence only. Pycnogenol dissolved in water did not affect platelet inhibition caused by aspirin. Therefore concurrent use seems likely to be safe, although this needs confirmation in clinical studies. The use of pycnogenol with other antiplatelet drugs does not appear to have been studied. Does pycnogenol intensify the efficacy of acetylsalicylic acid in the inhibition of platelet function Constituents Pygeum bark contains phytosterols including beta-sitosterol and beta-sitostenone, pentacyclic triterpenes based on oleanolic and ursolic acids, and ferulic esters. For further information on the pharmacokinetics of the specific isoflavones genistein, daidzein and biochanin A, see isoflavones, page 258. Constituents Red clover flowers contain isoflavones, to which they may be standardised. The major isoflavones are biochanin A and formononetin, with small amounts of genistein and daidzein and others, and their glycoside conjugates. Other constituents include clovamides, coumestrol, and the natural coumarins medicagol and coumarin. Interactions overview It has been suggested that red clover may interact with anticoagulants, but evidence for this is largely lacking. Potential interactions of isoflavone constituents of red clover are covered under isoflavones; see antibacterials, page 260, digoxin, page 261, fexofenadine, page 261, paclitaxel, page 261 and tamoxifen, page 262. Trifolium pratense isoflavones in the treatment of menopausal hot flushes: a systematic review and meta-analysis. Use and indications Red clover was traditionally used for skin conditions, such as eczema and psoriasis. For the theoretical possibility that broad-spectrum antibacterials might reduce the metabolism of the isoflavone constituents of red clover, such as daidzin, by colonic bacteria, and so alter their efficacy, see Isoflavones + Antibacterials, page 260. For the possibility that high-dose biochanin A, an isoflavone present in red clover, might increase digoxin levels, see Isoflavones + Digoxin, page 261. For the possibility that high-dose biochanin A, a major isoflavone in red clover, has been shown to slightly decrease fexofenadine levels in rats, see Isoflavones + Fexofenadine, page 261. Red clover + Anticoagulants the interaction between red clover and anticoagulants is based on a prediction only. Evidence, mechanism, importance and management Some reviews list red clover as having the potential to increase the risk of bleeding or potentiate the effects of warfarin,1 based on the fact that red clover contains natural coumarins. With melilot, page 290, which has a high content of coumarin, the action of moulds on the herb can result in the formation of an active anticoagulant, dicoumarol, from the coumarin, and bleeding disorders have occurred in animals fed spoiled hay containing melilot. There appears to be no published evidence of haemorrhagic disorders in animals fed red clover silage or hay. Note that mouldy red clover hay has caused poisoning in animals, but this is because of mycotoxins such as slaframine. However, there is one case report of spontaneous subarachnoid haemorrhage in a 53-yearold woman, which was attributed to a herbal supplement containing red clover, and also wild yam, black cohosh, Chinese angelica, raspberry leaf, agnus castus, Siberian ginseng, partridge berry and nettle leaf, which she had been taking for 4 months. However, of the constituents in this preparation, Chinese angelica has been associated with bleeding events, see Chinese angelica + Warfarin and related drugs, page 131. Taken together, the evidence suggests that no special precautions are likely to be required when red clover supplements are used with anticoagulants. Multifocal and recurrent subarachnoid hemorrhage due to an herbal supplement containing natural coumarins. For the possibility that biochanin A and genistein present in red clover might markedly increase paclitaxel levels, see Isoflavones + Paclitaxel, page 261. Note that paclitaxel is used intravenously, and the effect of biochanin A on intravenous paclitaxel does not appear to have been evaluated. Data relating to the use of the isoflavone constituents of red clover, such as biochanin A, daidzein and genistein, with tamoxifen are covered under Isoflavones + Tamoxifen, page 262. Constituents Red vine leaf contains a range of polyphenolics, mainly flavonoids, proanthocyanins and anthocyanins. The red colour is due to the anthocyanins, which are mainly glucosides of malvidin, but also of delphinidin, cyanidin and pertunidin. See under flavonoids, page 186, for information on the individual flavonoids present in red vine leaf, and see under resveratrol, page 335, for the pharmacokinetics of resveratrol. For information on the interactions of flavonoids, see under flavonoids, page 186, and for the interactions of resveratrol, see under resveratrol, page 335. Use and indications Red vine leaf extract is used both internally and externally to 334 Resveratrol Types, sources and related compounds Resveratrol is a polyphenol present in most grape and wine products and is the compound largely credited with providing the health benefits of red wine. However, the concentration is very variable between foods and supplements, so it is difficult to evaluate the clinical relevance of the available information. An in vitro study reports that resveratrol had no significant effect on the metabolism of diclofenac and only weakly inhibited the metabolism of (S)mephenytoin. An in vitro study also found that resveratrol moderately inhibited the metabolism of paclitaxel; however, the clinical relevance of this is unclear. Resveratrol, a red wine constituent, is a mechanism-based inactivator of cytochrome P450 3A4. It is said to have antioxidant properties and antiplatelet effects, and is therefore promoted as having benefits in a variety of cardiovascular diseases, including atherosclerosis. It also has some oestrogenic and anti-inflammatory activity, and is under investigation in the prevention and treatment of cancer, because it appears to reduce cell proliferation. Although there are no in vivo data available, it seems unlikely that resveratrol will affect the metabolism of diclofenac and therefore no dosage adjustments are likely to be needed if they are given together. Liquid chromatography/ tandem mass spectrometric determination of inhibition of human cytochrome P450 isozymes by resveratrol and resveratrol-3-sulfate. Resveratrol + Anticoagulant or Antiplatelet drugs the interaction between resveratrol and anticoagulants or antiplatelet drugs is based on experimental evidence only. Experimental evidence An ex vivo study using samples of platelet-rich plasma from 50 highrisk cardiac patients taking aspirin found that resveratrol significantly reduced platelet aggregation in response to collagen and adrenaline (epinephrine) in the samples taken from aspirin-resistant patients, but only had a minimal effect in those taken from aspirinsensitive patients. This effect may be additive to the effects of other drugs with antiplatelet effects. Importance and management Although there appears to be a plethora of in vitro studies to support the antiplatelet role of resveratrol, there is a lack of clinical data in humans. Therefore it is difficult to confirm if a clinically significant enhancement of antiplatelet effects would occur in patients taking resveratrol with antiplatelet drugs. Concurrent use need not be avoided (indeed combinations of antiplatelet drugs are often prescribed together), but it may be prudent to be aware of the potential for increased bleeding if resveratrol is given with other antiplatelet drugs such as aspirin and clopidogrel. Patients should discuss any episode of prolonged bleeding with a healthcare professional. Drugs that enhance antiplatelet effects may also increase the risk of bleeding in patients receiving anticoagulants such as warfarin. Clinically, the use of an antiplatelet drug with an anticoagulant should generally be avoided in the absence of a specific indication. However, if concurrent use is felt desirable it would seem sensible to warn patients to be alert for any signs of bruising or bleeding, and report these immediately, should they occur. Resveratrol inhibits aggregation of platelets from high-risk cardiac patients with aspirin resistance. Low concentrations of resveratrol potentiate the antiplatelet effect of prostaglandins. Resveratrol + Mephenytoin the information regarding the use of resveratrol with mephenytoin is based on experimental evidence only. Experimental evidence An in vitro study using human liver microsomes found that resveratrol only weakly inhibited the metabolism of (S)-mephenytoin. Although there are no in vivo data available, it seems unlikely that resveratrol will affect the metabolism of mephenytoin and therefore no dosage adjustments are likely to be needed if they are given together. Resveratrol + Diclofenac the information regarding the use of resveratrol with diclofenac is based on experimental evidence only. Experimental evidence An in vitro study using human liver microsomes found that Resveratrol 337 Resveratrol + Paclitaxel the interaction between resveratrol and paclitaxel is based on experimental evidence only.

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