By C. Kent. Teachers College. 2019.

Recent development and application of virtual screening in drug discovery: an overview order motrin in united states online. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity buy 600 mg motrin with amex. Structure and function of cytochromes P450: a comparative analysis of three crystal structures buy motrin on line. Enantioselective substrate binding in a monooxygenase protein model by molecular dynamics and docking order motrin 400 mg online. Crystal structure of cytochrome P-450cam complexed with the (1S)-camphor enantiomer. Crystal structures of ligand complexes of P450eryF exhibiting homotropic cooperativity. Automated multiple analysis of protein structures: application to homology modeling of cytochromes P450. A preliminary 3D model for cytochrome P450 2D6 constructed by homology model building. A three-dimensional protein model for human cytochrome P450 2D6 based on the crystal structures of P450 101, P450 102, and P450 108. Evidence that aspartic acid 301 is a critical substrate-contact residue in the active site of cytochrome P450 2D6. Mutations that alter aggregation, phospholipid dependence of catalysis, and membrane binding. Impact of incorporating the 2C5 crystal structure into comparative models of cytochrome P450 2D6. Residues glutamate 216 and aspartate 301 are key determinants of substrate specificity and product regiose- lectivity in cytochrome P450 2D6. Phe120 contributes to the regiospecificity of cytochrome P450 2D6: mutation leads to the formation of a novel dextro- methorphan metabolite. Influence of phenylalanine 120 on cytochrome P450 2D6 catalytic selectivity and regiospecificity: crucial role in 7-methoxy-4-(aminomethyl)-coumarin metabolism. Mammalian microsomal cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity. Ketoconazole-induced conforma- tional changes in the active site of cytochrome P450eryF. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. ConsDock: a new program for the consensus analysis of protein- ligand interactions. Binding mode prediction of cytochrome p450 and thymidine kinase protein-ligand complexes by consideration of water and rescoring in automated docking. Multiple hydrogen-bonding features of water molecules in mediating protein-ligand interactions. Principles of docking: an overview of search algorithms and a guide to scoring functions. Enhanced docking with the mining minima optimizer: acceleration and side-chain flexibility. Sensitivity of molecular docking to induced fit effects in influenza virus neuraminidase. Combined three-dimensional quantitative structure-activity relationship analysis of cytochrome P450 2B6 substrates and protein homology modeling. Computer-assisted, structure-based prediction of substrates for cytochrome P450 (Cam). Substrate docking algorithms and pre- diction of the substrate specificity of cytochrome P450(cam) and its L244A mutant. Computer-assisted design of selective imidazole inhibitors for cytochrome p450 enzymes. Electrostatic steering and ionic tethering in enzyme-ligand binding: insights from simulations. Computer simulation of molecular dynamics: methodology, applications and perspectives in chemistry. Amber, a package of computer- programs for applying molecular mechanics, normal-mode analysis, molecular- dynamics and free-energy calculations to simulate the structural and energetic properties of molecules. Dynamic conformations of flavin adenine dinucleotide: simulated molecular dynamics of the flavin cofactor related to the time- resolved fluorescence characteristics. Metabolic regio- and stereoselectivity of cytochrome P450 2D6 towards 3,4-methylenedioxy-N-alkylamphetamines: in silico predictions and experimental validation. How do substrates enter and products exit the buried active site of cytochrome P450cam? Random expulsion molecular dynamics investigation of ligand access channels and mechanisms. How do substrates enter and products exit the buried active site of cytochrome P450cam? Comparison of the dynamics of substrate access channels in three cytochrome P450s reveals different opening mechanisms and a novel functional role for a buried arginine. Improving efficiency of large ime-scale molecular dynamics simulations of hydrogen-rich systems. Single-step perturbations to calculate free energy differences from unphysical reference states: limits on size, flexibility, and character. Dramatic differences in the motions of the mouth of open and closed cytochrome P450bm-3 by molecular-dynamics simulations. Substrate access to cytochrome P450cam: a comparison of a thermal motion pathway analysis with molecular dynamics sim- ulation data. Thermodynamics of water mediating protein-ligand inter- actions in cytochrome P450cam: a molecular dynamics study. The binding and regioselectivity of reaction of (R)-nicotine and (S)-nicotine with cytochrome-P-450cam - parallel experimental and theoretical-studies. Molecular modeling of cytochrome P450 1A1: enzyme- substrate interactions and substrate binding affinities. Prediction of regiospecific hydroxylation of camphor analogs by cytochrome-P450(Cam). Prediction of regio- and stereoselectivity in the primer metabolism of carbofuran: a theoretical study. Investigation of the proton-assisted pathway to formation of the catalytically active, ferryl species of P450s by molecular dynamics studies of P450eryF. A predicted three-dimensional structure of human cytochrome P450: implications for substrate specificity. Molecular modelling of members of the P4502A subfamily: application to studies of enzyme specificity. Application of 3-dimensional homology modeling of cytochrome P450 2B1 for interpretation of site-directed mutagenesis results. Molecular modeling of cytochrome P450 2B1: mode of membrane insertion and substrate specificity. Probing the active site of cytochrome P450 2B1: metabolism of 7-alkoxycoumarins by the wild type and five site-directed mutants. Reassessment of cytochrome P450 2B2: catalytic specificity and identification of four active site residues. Site-directed mutagenesis as a tool for molecular modeling of cytochrome P450 2B1. Structure-function analysis of human cytochrome P-4502B6 using a novel substrate, site-directed mutagenesis, and molecular modeling. Metabolism of sirolimus and its derivative everolimus by cytochrome P450 3A4: insights from docking, molecular dynamics, and quantum chemical calculations. Direct interaction between substrates and endogenous steroids in the active site may change the activity of cytochrome P450 3A4. Structure-function relationships of human aromatase cytochrome P-450 using molecular modeling and site-directed mutagenesis. Construction of a model of the Candida albicans lanosterol 14-alpha-demethylase active site using the homology modelling technique.

Portal blood flow (Qpv) generic 400 mg motrin with amex, which perfuses the liver is comprised of blood leaving the small intestine and other splanchnic organs such as the stomach and spleen discount 400 mg motrin. Blood flow leaving the liver (Qhv) represents the sum of hepatic arterial flow (Qha)andQpv purchase motrin 600mg online. First-pass metabolism of an orally administered substrate (S) to product (P) may occur in the enterocyte or hepatocyte discount 400 mg motrin fast delivery. The assumption that intestinal metabolism does not contribute significantly to systemic clearance is based on studies of acetaminophen, enalapril, morphine, and (À)-aminocarbovir disposition in perfused, rat small intestine [see recent review by Pang (2)], and one human study on intestinal metabolism of mid- azolam during the anhepatic phase of liver transplantation (5). The inducer was assumed to cause an equivalent change in hepatic and intestinal intrinsic clearance. The inhibitor/Ki ratio was assumed to be equivalent for inhibition of hepatic and intestinal metabolism (i. Igm may exceed the unbound portal plasma concentration during the inhibitor absorption phase or be less than the unbound portal concentration postabsorption if there is not rapid equilibrium between the intracellular and portal plasma compartments (i. This obviously makes it challenging to anticipate the quantitative effect of an inhibitor on intestinal first- pass metabolism. Saturation of Role of the Gut Mucosa in Metabolically Based Drug-Drug Interactions 477 metabolic enzymes by the substrate is generally not an issue for hepatic elimi- nation of most drugs, but may influence the extent of inhibition for intestinal metabolism as the enterocytes may face concentrations of drugs that greatly exceed those observed in plasma. Competition for the metabolic enzyme be- tween the substrate and inhibitor will decrease the overall inhibition observed. This is not the case for the intestine, where the relative magnitude of mucosal blood flow compared with the baseline mucosal intrinsic clearance and the apparent intrinsic clearance in the presence of inhibitor must be considered. When the baseline mucosal intestinal intrinsic clearance is negligible compared to mucosal blood flow (i. For example, complete inhibition of an intestinal extraction at 25% in the control state would result in a 1. The lower the mucosal extraction ratio, the more the inter- action will be defined by the liver. For interactions involving induction of intes- tinal processes, a lower limit of significance for the initial mucosal extraction is more difficult to deduce. It is possible to have a drug-drug interaction that is confined to the intestine during first-pass extraction. Another important consideration for understanding metabolically based drug-drug interactions is that the level of exposure of the liver and intestinal mucosa to an inhibitor or inducer need not be identical (as discussed above), particularly during the periabsorptive phase, when modulator concentration at the intestinal mucosa may be much greater than that in the portal blood. It is also important to recognize that the intracellular mechanism underlying an interaction (e. Consequently, the extent of induction or inhibition at each site of metabolism/transport following acute or chronic administration of an interacting drug could be quite different (e. In the remainder of this chapter, we review the characteristic features of drug interactions that involve modulation of the first-pass intestinal metabolism of orally administered drugs. A full complement of drug-metabolizing enzymes is expressed in the human intestinal epithelium. The most important phase 1 enzymes in the context of drug-drug interactions are the cytochrome P450 enzymes. The specific P450 content of microsomes isolated from mucosal epithelium of the human proximal small intestine is roughly one-sixth to one-eighth of that found in liver microsomes (8,9). Notable aspects of drug interactions involving each of the aforementioned enzyme classes will be presented in the following sections. Mucosal enzyme concentration is greatest within the duodenal and jejunal sec- tions of the small intestine and declines distally and proximally. In a later study of 20 full-length intestines and livers from organ donors, Paine et al. A villous fraction consisting of mainly mature enterocytes was isolated from the intestinal samples. In this respect, these cell lines may represent an excellent model for xenobiotic metabolism in the human colon and its role in chemical-induced mutagenesis or cytotoxicity. Although some of this extreme variability in the latter study could be the result of events pre- ceding the procurement of tissue (i. Given the inaccessibility of the intestinal site of metabolism, it is understandable that most of the in vivo evidence is indirect in nature. The usual approach is to assume that systemic clearance represents hepatic clear- ance for drugs that are extensively metabolized, and that intestinal metabolism does not contribute to systemic clearance. For most drugs that are readily released from the oral formulation and have high intestinal permeability, Fa is often assumed to be unity. The assumption that intestinal mucosa does not contribute to systemic clearance (i. However, the entire dose released from the dosage form is exposed to the mucosal enzymes during its obligatory passage through the intestinal epithelium and, thus, the more relevant comparison is the intracellular enzyme concentration and intrinsic clearance (i. In studies that offer comparative metabolic kinetics between hepatic and intestinal (duodenal or jejunal) microsomes, mean intrinsic clearance for intestinal microsomes varied from 20% to as high as 200% of that for liver microsomes; the list of drugs include cyclosporine (41), eryth- romycin (15), indinavir (44,45), irinotecan (46), lovastatin (48), midazolam (8), quazepam (50), rifabutin (51), saquinavir (53), and tacrolimus (55). For many of these drug substrates, mucosal intrinsic clearances are comparable to the cor- responding mean hepatic intrinsic clearance. Whether there will be a similar intestinal and hepatic first-pass extraction for the aforementioned drugs is more difficult to predict since intestinal first-pass extraction is dependent on a number of other factors, including total oral dose, rate of drug absorption, enzyme saturability (Km), the absorptive region, mucosal barrier permeability, and binding to blood components. For example, should the dose be high enough to cause enzyme saturation, it is possible that a drug with a high hepatic and intestinal intrinsic clearance could largely escape intestinal first-pass extraction but not hepatic extraction. Also, if the basolateral membrane represents the rate-limiting barrier to the passage of drug across the intestinal epithelium, the residence time of the drug substrate within the enterocytes would increase and result in a greater metabolic first-pass loss than a comparable substrate with better permeability (6,68). A number of studies have shown that induction of midazolam elimination is highly route dependent (75–77). Although systemic clearance (Cl) of midazolam was also induced by rifampin, the effect was modest by comparison; i. This rem- arkable route dependency in the induction of midazolam clearance can be explained by induction of sequential first pass at the intestinal mucosa and the liver after oral administration, whereas only hepatic extraction is operative and inducible after intravenous administration. It should also be appreciated that the increase in systemic or hepatic clearance of midazolam following rifampin is limited to some extent by the ceiling of liver blood flow, as hepatic extraction of midazolam is increased from around 0. The inductive effects at the two sites appeared not to be concordant; in fact, the extent of induction was high at either the hepatic or intestinal site, but not both. Of note, all the drugs listed for which unambiguous data are available exhibit incomplete oral bioavailability. In addition, where both intravenous and oral administration have been studied, rifampin appears to increase the extent of intestinal first-pass metabolism and decrease intestinal bioavailability substan- tially; for example, alfentanil, Fgm ¼ 0. John’s wort, a widely used herbal supplement for the treatment of mild to moderate depression, has also attracted considerable interest. John’s wort on intestinal extraction was slightly greater than that on hepatic extraction. The difference can be attributed to the much higher peak cir- culating rifampin concentrations (8 mM) (86), compared with that of hyperforin (0. There is evidence indicating that micro- somal enzyme inducers can simultaneously act as inhibitors. These investigators proposed that the inductive effect of rifampin was masked by its simultaneous inhibition of repaglinide metabolism when repaglinide clearance was assessed immediately after concurrent rifampin administration when the circulating concentration of rifampin was high. The inductive effect of rifampin was fully revealed after the washout of rifampin by 24 hours. It stands to reason that the masking of an inductive effect by simultaneous inhibition is more likely to occur with intestinal first-pass metabolism; however, supportive evidence is lacking. The interplay between induction and inhibition also means that the outcomes of interaction studies with enzyme inducers may depend on study design; that is the relative timing of the inducer and substrate administrations. Although some of the pharmacokinetic changes observed were surely the result of an interaction in the liver, it is likely that the enzyme/ transporter barrier at the intestinal mucosa was also affected by ketoconazole. These interactions can conveniently be grouped according to the mechanism of inhibition, namely those involving reversible (i. For example, in an earlier study of the interaction between ketoconazole and tirilazad, Fleishaker et al. Moreover, ketoconazole inhibited intestinal and hepatic extraction to nearly the same extent; the hepatic availability (Fh) increased from 0. It should be noted that mechanism- based inhibitors also act as competitive inhibitors.

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A white or colorless crystalline body in shining prismatic crystals; soluble in thirty-six parts of hot alcohol purchase motrin with a visa, and in alkalies; almost insoluble in water buy discount motrin 400 mg on-line. A yellowish-white crystalline body generic motrin 600mg amex, or an amorphous powder motrin 400mg visa, bitter, inodorous except a slight odor of the acetic acid; soluble in two and one- half parts of water. In white feathery, silky crystals, without odor; of an intensely bitter taste; soluble in twenty-one parts of water and in seven hundred parts of alcohol. Muriate of Morphine occurs in white needle-shaped, feathery, lustrous crystals; bitter and odorless; soluble in twenty-four parts of water and in sixty-two parts of alcohol. This is the product of the action of hydrochloric acid on a modified form Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 313 of the alkaloid morphine. It occurs as white or grayish white crystals, without odor, bitter, turning slightly green upon exposure to the air; soluble in forty-five parts of either water or of alcohol. The dose for this purpose is from one-twentieth to one-sixteenth of a grain, although one-eighth of a grain may be given. It may be given to eject bodies from the esophagus to evacuate the stomach after the injection of poisons, and in extreme asthmatic or catarrhal attacks. A field of action has developed for this remedy, outside of its influence as an emetic, which is important. One writer says that in wild delirium, sleep may be induced with this remedy, and a restful quiet. It should be given in doses of from one one-hundredth to one-thirtieth of a grain, hypodermically injected. The dose is less than the emetic dose, and yet sufficient to produce a physiological effect. It is not given until after the patient is undressed and in bed ready to go to sleep. Where it is used for its hypnotic effect alone, and the patient has not previously taken it, it might be well to beg in with a dose as small as the one one hundredth of a grain. The influence of the agent is not protracted, and in some cases it must be repeated in two or three hours. In others it produces a restfulness, which results in sleep, independent of further action of the remedy. In hysterical attacks, the agent is valuable, as it produces general quiet, and refreshing sleep. It may be used in the place of morphine and opium with those who are addicted to a habit for these drugs, and it will produce the same results. The drug is a treacherous one, and consequently dangerous, and must therefore be given with care. In very minute doses, it is given in bronchitis, where there is a deficiency of secretion, or in croup, producing relaxation and expectoration. It is given as an expectorant in cough mixtures, with good results, but its emetic influence should not be induced. One one-hundredth of a grain, repeated every two hours, will be sufficiently large dosage. It produces a Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 314 watery secretion of mucus, which is often undesirable. It should be used only with adults, as stated, as children are too susceptible to its influence. Kinnett has used it in pain from spasms of the pyloris, and others mention its influence for spasmodic pain in severe, acute stomach disorder in sthenic cases. Dice believes apomorphine given in small doses frequently repeated in the initial stage of appendicitis will prevent the development of many cases of this disease. He dissolves also a dram of sulphate magnesium in four ounces of water and gives a teaspoonful every two hours with it. Apomorphine in doses of One-thirtieth of a grain or less, frequently repeated controls some very severe cases of vomiting. In the treatment of alcoholism, this agent is given in sufficient quantity to produce mild nausea; then one-thirtieth of a grain of strychnine or other indicated stimulant is given for its influence upon the nervous system at the same time. Occurrence—An alkaloid of opium closely related to morphine, often, if not carefully prepared, containing a certain proportion of morphine. Character—White octahedral crystals, bitter, odorless, permanent, soluble in eighty parts of water and in three parts of alcohol. Physiological Action—Its influence is that of an anodyne and antispasmodic, more active as an antispasmodic than morphine and much less narcotic. It controls pain without checking secretion to as great an extent as the other alkaloids of opium. Therapy—It has a more marked influence upon pain in the abdomen and in the pelvic organs. Spasms, neuralgia and other painful conditions in these parts are well controlled by codeine. It has been given in doses of fifteen or twenty grains daily for this purpose, in some cases with permanent results. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 315 Codeine has a marked influence upon spasmodic cough. It is often given to soothe irritable conditions of the air passages and to control persistent annoying and exhausting cough. Opium is stimulant and narcotic, according to the dose and susceptibility of the patient. Infants and old people are easily poisoned by the drug, while those addicted to alcohol can take very large doses without any bad effects; and those accustomed to the drug can take a poisonous dose with impunity. In the healthy adult a moderate dose of opium stimulates all the nervous functions of the body, raises the spirits and excites intellectual action; this gives way to a condition of placidity, freedom from care, and a state of quiet enjoyment. In an hour or less, con-sciousness is lost in sleep, which may continue for eight hours or longer. On waking there is evidence of disturbance of the functions of the organism, such as nausea, vomiting, headache, constipation and diminished secretion, except that of the skin. In a dose sufficient to cause death the period of excitement is short, while the strength of the system rapidly gives way to drowsiness and apoplectic sleep. There is stertorous breathing, dusky countenance, slow pulse, nearly total insensibility, only responding slightly to violent agitation, with confusion of the mind, and an inclination to continue in a comatose state with increasing debility. After a few hours, six to twelve, according to the dose and the resisting power of the patient, the face becomes pale, the pulse from being full and strong becomes weak and thready, with cold extremities, a cool and clammy skin, a slow gasping respiration; a condition from which it is impossible to rouse the patient and death soon follows. The pulse is first slow from stimulation of the vasomotor nerve centers, and becomes rapid as these become paralyzed. The pupil is first contracted by stimulation of the oculo-motor nerves, and dilates as death approaches and these become paralyzed. With some individuals there appears to be an inherent and usually Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 316 permanent idiosyncrasy against the action of opium and morphine. These are nausea or violent vomiting, spasm of the stomach and loss of appetite, obstinate constipation or abdominal pain. In others there is nervous excitement, restlessness, headache, tremors, general distress and an increase of pain. Given under the conditions we have named as contraindications, it will often produce these phenomena; where there is an absence of idiosyncrasy, and where given under the proper conditions, the effects would be desirable. Itching of the skin, inducing an apparent miliary eruption, is one of the unpleasant effects of its use, which, like any one of the others, may be always greatly exaggerated in certain individuals. By using water as a solvent, or combining opium with ipecac or camphor, or in some cases with the bromides, these unpleasant effects can, in great measure, be overcome. It has poisoned infants while nursing, the mother either taking it as medicine or habitually. Caution—All of the effects of these agents are especially marked in infants and early childhood. The nervous system is profoundly impressed by them, and the dose, if given at all to very young babes, should be infinitesimal. Its administration can be avoided in nearly all cases with these little patients, as we have access to many agents which, while not working actively in adults, produce most satisfactorily soothing, anodyne or pain- relieving properties in childhood. Opium addiction is acquired by continued use of the agent, and is debasing and deadly in its effects.

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Antioxidants intervene at differ- ent levels of oxidative processes: (1) scavenging free radicals; (2) scavenging lipid peroxyl radicals; (3) binding metal ions; or (4) removing oxidatively dam- aged biomolecules (2) generic motrin 600 mg line. However order cheap motrin on line, the antioxidant defense in cutaneous tissues can be overwhelmed either by an increased exposure to exogenous (e order 600 mg motrin with visa. The chapter summarizes the currently available knowledge on (1) the pres- ence and physiological distribution of natural antioxidants in skin; (2) their re- sponse to oxidative environmental stressors; and (3) the photoprotective potential of topically applied antioxidants motrin 600mg overnight delivery. While most mammals are able to synthesize ascorbate from glu- cose-derived glucuronic acid, guinea pigs, monkeys, and humans lack the enzyme gulonolactase and therefore require the dietary intake of this vitamin. Dietary ascorbate is absorbed and distributed throughout the body within a few hours. The biochemical importance of vitamin C is primarily based on its reducing po- tential, as is required in a number of hydroxylation reactions. Several hydroxy- lases involved in collagen synthesis require ascorbate as a reductant (11). Due to its high reduction potential, ascorbate is an efficient scavenger of superoxide anion radicals, hydroxyl radicals, hypochlorite, singlet oxygen, thiyl radicals, and water-soluble peroxyl radicals (2,12,13). Oxidation of ascorbate results in the formation of dehydroascorbate via the ascorbyl radical, which can be recycled back to ascorbate in the presence of thiols (Fig. Please note that some of the depicted recycling mechanisms have been found in other than cutaneous systems (see ‘‘Antioxidant Properties’’). Although ascorbate is not able to scavenge lipophilic radicals directly, in the presence of vitamin E it synergistically reduces lipid peroxyl radicals by reacting with tocopheroxyl radicals. Mixtures of copper or iron salts with ascorbate are well known to stimulate lipid peroxidation in vitro (15). With the exception of pathological metal overload disease states, however, the prooxidative potential of ascorbate is not considered to be of relevance in vivo (16). Prevalence in Skin In skin, the data available on ascorbate concentrations are limited and variable due to differences in species, skin layer analyzed, and method of analysis (Table 1). Importantly, however, vitamin C is present at sig- nificant levels in both the dermis and epidermis of animals and humans. In hair- less mice, vitamin C levels are only slightly higher in the epidermis than in the dermis (5,17). In human skin, which is dependent on dietary vitamin C, the epi- dermis apparently contains approximately fivefold higher levels than the dermis (18). This difference in dermal and epidermal vitamin C levels may reflect an increased utilization in the dermis for the regulation of collagen and elastin bio- synthesis (19), or facilitated transport mechanisms for vitamin C from the dermal Antioxidant Defense Systems in Skin 149 Table 1 Physiological Levels of Ascorbate in Cutaneous Tissues Skin layer Species Concentration References Year Total skin Rat 0. The epidermis is not only more directly exposed to the environment than the underlying dermis and therefore might have a higher demand of antioxidant protection, but also requires the presence of ascorbate for efficient formation of the stratum corneum barrier (20). Isolated human stratum corneum was reported to contain only very low ascorbate levels, as compared with levels in subjacent epidermal layers (6). The latter phenomenon is most likely due to both the hydrophobicity and, due to its location, the high degree of environmental exposure of the stratum corneum. In cells, glutathione is syn- thesized from glutamate, cysteine, and glycine (22). It acts as a substrate for numerous reducing enzymes, among them glutathione peroxidase and the phos- pholipid hydroperoxide glutathione peroxidase. Therefore, the absence of gluta- thione may lead to an accumulation of lipid hydroperoxides (2). In humans, who are dependent on dietary vitamin C intake, this link remains to be clarified. However, comparing the relative levels, most studies demonstrated higher glutathione levels in the epidermis than in the dermis. Since the epidermis is more directly exposed to the environment, it seems also possible that the pathways leading to the endog- enous formation of epidermal glutathione are upregulated by chronic environ- mental factors, as was shown for glutathione peroxidase in ozone-exposed lung epithelium (26). Urate Antioxidant Properties Uric acid (deprotonated form: urate) is a small water-soluble molecule (Fig. In blood plasma, urate has been shown to be a powerful scavenger of singlet oxygen, peroxyl-, and hydroxyl radicals (28). Fur- ther studies have demonstrated that urate scavenges ozone (15) and hypochlorous acid (29). In addition to its radical-scavenging potential, urate was proposed to stabilize reduced vitamin C in serum. This stabilizing effect appears to be due to inhibition of iron-catalyzed oxidation of ascorbate, which largely results from the formation of a stable, noncatalytic urate–iron complex (30). Unlike radical- scavenging reactions, this protective effect provided by iron chelation is not asso- ciated with depletion of urate. Direct free-radical attack upon urate generates allantoin, which has therefore been proposed as a marker molecule for free-radi- cal reactions in vivo (31). Prevalence in Skin Only little data are available on urate levels in cutane- ous tissues. Thus, as found for other antioxidants, the highest cutaneous urate levels are present in epidermal tissue. Lipid-Soluble Antioxidants Vitamin E Antioxidant Properties Vitamin E is the major lipophilic antioxidant in plasma, membranes, and tissues (33). The term ‘‘vitamin E’’ collectively refers to the eight naturally occurring molecules (four tocopherols and four tocotrie- nols), which exhibit vitamin E activity. Tocotrienols differ from tocopherols in that they have an isoprenoid instead of a phytyl side chain (see Fig. In humans, α– tocopherol is the most abundant vitamin E homologue, followed by γ–tocopherol. Vitamin E is among the early recognized biological antioxidants, and its redox and free-radical chemistry are well documented (33). The major antioxidant role of vitamin E is generally considered to be the arrest of chain propagation by scavenging lipid peroxyl radicals. The initial oxidation product of tocopherol is the metastable tocopheroxyl radical (Fig. Thus, one molecule of tocopherol is able to scav- enge two peroxyl radical molecules. Since the physiological molar ratio of to- copherols to polyunsaturated phospholipids, first-line targets of oxidative attack, is less than about 1:1000 in most biological membranes, regeneration of tocoph- erol is essential for its high antioxidant efficacy in vivo. As mentioned above, several hydrophilic coantioxidants, such as ascorbate and glutathione, can regen- erate vitamin E from the tocopheroxyl radical and thus enhance the antioxidant capacity of vitamin E (14). Furthermore, there is some in vitro evidence that ubiquinol-10 protects α– tocopherol from photo-oxidation by recycling mechanisms (37). In vitro, unphys- iologically high concentrations of α–tocopherol were reported to induce prooxi- dative effects leading to acceleration of lipid peroxidation (38,39). In human skin in vivo, however, such adverse health effects have not been reported. Prevalence in Skin As demonstrated in other body tissues, α-tocopherol is the predominant vitamin E homologue in murine and human skin (Table 3) (5,6,18). In addition, γ–tocopherol is present in murine and human epidermis, dermis, and stratum corneum. The α–tocopherol/γ–tocopherol molar ratio in the human dermis and epidermis is approx. Notably, a vitamin E gradient has recently been demonstrated in human upper arm stratum corneum. The highest α–tocopherol levels were found in the lower stratum corneum, whereas the low- est levels were present in the upper layers. The α–tocopherol/γ–tocopherol ratio Antioxidant Defense Systems in Skin 153 154 Thiele et al. The α–tocopherol levels in human dermis and epidermis were sever- alfold higher than in corresponding layers of hairless mouse skin (17,18). Consis- tently, human stratum corneum contains almost tenfold higher α–tocopherol lev- els than measured in murine stratum corneum (5,6). As observed for hydrophilic antioxidants, higher vitamin E levels were found in murine and human epidermis, as compared with dermal levels.

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Clarithrom ycin 500-mg dry powder vials * Clarithromycin is a macrolide antibacterial with a broad discount 600mg motrin free shipping, mainly bacteriostatic action against many Gram-positive and order motrin 600 mg mastercard, to a lesser extent buy 600 mg motrin with mastercard, some Gram-negative bacteria buy discount motrin 400mg on-line, as well as some ‘atypicals’. Pre-treatment checks * Contraindicated in patients with known hypersensitivity to macrolide antibiotics. Dose in renal impairment: adjusted according to creatinine clearance:1 * CrCl >30--50mL/minute: dose as in normal renal function. Withdraw the required dose and add to a suitable volume of compatible infusion fluid to give a solution containing approximately 2mg/mL (e. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Fluid restriction: concentrations up to 5mg/mL have been given via a central line. Technical information Incompatible Aminophylline,ceftazidime,cefuroxime,flucloxacillin,furosemide,heparinsodium, with phenytoin sodium. Displacement Negligible value Stability after From a microbiological point of view, should be used immediately; however: preparation * Reconstituted vials may be stored at 2--8 C for 24 hours. Monitoring Measure Frequency Rationale Physical signs of Daily * Monitor patient response (e. Injection site At regular * Local tenderness and inflammation, phlebitis, pain at intervals the injection site. Development of Throughoutand * Development of severe, persistent diarrhoea may be diarrhoea up to 2 months suggestive of Clostridium difficile-associated after treatment diarrhoea and colitis (pseudomembranous colitis). Additional information Common and serious Immediate: Anaphylaxis has been reported rarely. Action in case of No known antidote; stop administration and give supportive therapy as overdose appropriate. Counselling Potential for drug interactions; explain short-term alterations in co-prescribing, e. This assessment is based on the full range of preparation and administration options described in the monograph. Clindam ycin 150mg/mL solution in 2-mL, 4-mL ampoules * Clindamycin phosphate is a semisynthetic antibiotic that is a derivative of lincomycin (a lincosamide). Pre-treatment checks * Do not give if there is known hypersensitivity to clindamycin or lincomycin. Withdraw the required dose and add to a suitable volume of compatible infusion fluid (usually 100mL NaCl 0. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Technical information Incompatible with Clindamycin phosphate is incompatible with natural rubber closures. Aminophylline, ampicillin, calcium gluconate, ceftriaxone, ciprofloxacin, doxapram, drotrecogin alfa (activated), fluconazole, magnesium sulfate, phenytoin sodium, ranitidine, tramadol. Donotrefrigerateorfreeze(crystalsmay form, which will re-dissolve at room temperature without affecting potency). Stability after From a microbiological point of view, should be used immediately; however, preparation prepared infusions may be stored at 2--8 C and infused (at room temperature) within 24 hours. Monitoring Measure Frequency Rationale Renal function Periodically if * Manufacturer’s recommendation. Signs of Throughout treatment * May result in the overgrowth of non-susceptible supra-infection or organisms -- appropriate therapy should be superinfection commenced; treatment may need to be interrupted. Additional information Common and serious Immediate: Anaphylactoid and other hypersensitivity reactions have been undesirable effects reported. Other: Diarrhoea (see monitoring above), abdominal discomfort, oesophagitis, oesophageal ulcers, taste disturbances, nausea, vomiting, jaundice, rashes. Significant * Clindamycin "effect of the following drugs: interactions non-depolarising muscle relaxants, suxamethonium. Action in case of No known antidote; stop administration and give supportive therapy as overdose appropriate. This assessment is based on the full range of preparation and administration options described in the monograph. Clodronate sodium | 167 Clodronate sodium (sodium clodronate, disodium clodronate) 60mg/mL solution in 5-mL ampoules * Sodium clodronate is a bisphosphonate with properties similar to those of the other bisphospho- nates. It inhibits bone resorption but appears to have less effect on bone mineralisation. Pre-treatment checks * Do not give to patients already receiving other bisphosphonates. Women of child-bearing potential should take contraceptive precautions during planned treatment. For multiple infusions, these are repeated daily until normo- calcaemia is achieved, or for a maximum of 7 days. Dose in renal impairment: adjusted according to creatinine clearance (see Table C3). It seems wise to give the dose as smaller multiple infusions -- no guidance exists for dose adjustment for large single infusions. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Multiple intravenous infusions Preparation and administration Clodronate sodium is incompatible with Hartmann’s and Ringer’s (which contain Ca). Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Technical information Incompatible with Clodronate sodium is incompatible with Hartmann’s and Ringer’s (which contain Ca). Stability after From a microbiological point of view, should be used immediately; however, preparation prepared infusions should be infused within 12 hours of preparation. Clodronate sodium | 169 Monitoring Measure Frequency Rationale Fluid balance Frequently during * Hydration "Ca diuresis. Additional information Common and serious Immediate: Angioedema and bronchospasm have been reported. Pharmacokinetics The half-life for elimination from plasma is 2 hours but a second phase with a half-life of 13 hours has been identified (<10% of total urinary excretion takes placeduringthisphase). Thesubstancewhichisboundtoboneisexcretedmore slowly at a rate corresponding to bone turnover. Significant drug Clodronate sodium may "levels or effect (or "side-effects) of estramustine. Advise patients with risk factors for osteonecrosis of the jaw (see pre-treatment checks) not to undergo invasive dental procedures during treatment. This assessment is based on the full range of preparation and administration options described in the monograph. Pre-treatment checks * Do not use in respiratory depression; acute pulmonary insufficiency; sleep apnoea syndrome; marked neuromuscular respiratory weakness including unstable myasthenia gravis. Intravenous injection Preparation and administration Give slowly into a large vein to reduce risk of thrombophlebitis. Inspect visually for particulate matter or discoloration prior to administration and discard if present. Withdraw the required dose and add to a suitable volume of compatible infusion fluid to give a maximum concentration of 3mg in 250mL, e. Inspect visually for particulate matter or discoloration prior to administration and discard if present. Technical information Incompatible with Sodium bicarbonate Compatible with Flush: NaCl 0. Monitoring Measure Frequency Rationale Seizure frequency and At regular intervals * Monitor for reduction in the frequency and severity severity to ensure therapeutic effect. Counselling May cause transient drowsiness -- if affected do not drive or operate machinery. This assessment is based on the full range of preparation and administration options described in the monograph.

This is due to the sudden decrease in the blood pressure of the brain arteries purchase motrin 400mg mastercard, which results in a temporary decrease of blood flow to the brain discount motrin line. The same hydrostatic factors operate also in the veins purchase motrin 400 mg overnight delivery, and here their effect may be more severe than in the arteries motrin 600 mg fast delivery. When a person stands motionless, the blood pressure is barely adequate to force the blood from the feet back to the heart. Thus when a person sits or stands without muscular movement, blood gathers in the veins of the legs. This increases the pressure in the capillaries and may cause temporary swelling of the legs. Hormones are molecules, often proteins, that are produced by organs and tissues in different parts of the body. They are secreted into the blood stream and carry messages from one part of the body to another. Hormones affecting the heart are produced in response to stimuli such as need for more oxygen, changes in body tempera- ture, and various types of emotional stress. These small vessels that receive blood from the arteries have an average diameter of about 0. The walls of the arterioles contain smooth muscle fibers that contract when stimulated by nerve impulses and hormones. The con- traction of the arterioles in one part of the body reduces the blood flow to that region and diverts it to another. Since the radius of the arterioles is small, con- striction is an effective method for controlling blood flow. Poiseuille’s equation shows that if the pressure drop remains constant, a 20% decrease in the radius reduces the blood flow by more than a factor of 2 (see Exercise 8-5). A stress-induced heart condition called stress cardiomyopathy (broken heart syndrome) has only recently been clearly identified by Western medicine. The syndrome occurs most frequently after a sudden intense emotional trauma such as death in the family, an experience of violence, or extreme anger. The symptoms are similar to an acute heart attack, but the coronary arteries are found to be normal and the heart tissue is not damaged. It has suggested that the condition is triggered by an excessive release of stress-related hormones called chatecholamines. During the period of flow, the velocity of the blood is about three times as high as the overall average value calculated in Exercise 8-6. The kinetic energy in the smaller arteries is even less because, as the arteries branch, the overall area increases and, therefore, the flow velocity decreases. For example, when the total flow rate is 5 liter/min, the blood velocity in the capillaries is only about 0. The kinetic energy of the blood becomes more significant as the rate of blood flow increases. For example, if during physical activity the flow rate increases to 25 liter/min, the kinetic energy of the blood is 83,300 erg/cm3, which is equivalent to a pressure of 62. This energy is no longer neg- ligible compared to the blood pressure measured at rest. In healthy arteries, the increased velocity of blood flow during physical activity does not present a problem. During intense activity, the blood pressure rises to compensate for the pressure drop. Assuming a Reynold’s number of 2000, the critical velocity for the onset of turbulence in the 2-cm-diameter aorta is, from Eq. But as the level of physical activity increases, the flow in the aorta may exceed the critical rate and become turbulent. In the other parts of the body, however, the flow remains laminar unless the passages are abnormally constricted. Laminar flow is quiet, but turbulent flow produces noises due to vibrations of the various surrounding tissues, which indicate abnormalities in the circu- latory system. These noises, called bruit, can be detected by a stethoscope and can help in the diagnosis of circulatory disorders. In the United States, an estimated 200,000 people die annually as a consequence of this disease. In arteriosclerosis, the arterial wall becomes thickened, and the artery is narrowed by deposits called plaque. Sixty to seventy percent is considered severe, and a narrowing above 80% is deemed critical. If, for example, the radius of the artery is narrowed by a factor of 3, the cross-sectional area decreases by a factor of 9, which results in a nine-fold increase in velocity. The increased kinetic energy is at the expense of the blood pressure; that is, in order to maintain the flow rate at the higher velocity, the potential energy due to pressure is converted to kinetic energy. For example, if in the unobstructed artery the flow velocity is 50 cm/sec, then in the constricted region, where the area is reduced by a factor of 9, the velocity is 450 cm/sec. Because of the low pressure inside the artery, the external pressure may actually close off the artery and block the flow of blood. When such a blockage occurs in the coronary artery, which supplies blood to the heart muscle, the heart stops functioning. Stenosis above 80% is considered critical because at this point the blood flow usually becomes turbulent with inherently larger energy dissipation than is associated with laminar flow. As a result, the pressure drop in the situa- tion presented earlier is even larger than calculated using Bernoulli’s equation. Further, turbulent flow can damage the circulatory system because parts of the flow are directed toward the artery wall rather than parallel to it, as in laminar 112 Chapter 8 The Motion of Fluids flow. The blood impinging on the arterial wall may dislodge some of the plaque deposit which downstream may clog a narrower part of the artery. If such clogging occurs in a cervical artery, blood flow to some part of the brain is interrupted causing an ischemic stroke. The artery has a specific elasticity; therefore, it exhibits certain springlike prop- erties. Specifically, in analogy with a spring, the artery has a natural fre- quency at which it can be readily set into vibrational motion. Deposits of plaque cause an increase in the mass of the arterial wall and a decrease in its elasticity. As a result, the natural frequency of the artery is significantly decreased, often down to a few hundred hertz. The plaque- coated artery with its lowered natural frequency may now be set into resonant vibrational motion, which may dislodge plaque deposits or cause further dam- age to the arterial wall. We will now compute the power generated by the heart to keep the blood flowing in the circulatory system. Therefore, as shown in Exercise 8-10, the power output of the right ventricle is 0. While in fact the systolic blood pressure rises with increa- sed blood flow, in these calculations we have assumed that it remains at 120 torr. Both abnormally high and abnormally low blood pressures indicate some disorders in the body that require medical attention. High blood pres- sure, which may be caused by constrictions in the circulatory system, certainly implies that the heart is working harder than usual and that it may be endan- gered by the excess load. Blood pressure can be measured most directly by inserting a vertical glass tube into an artery and observing the height to which the blood rises (see Fig. This was, in fact, the way blood pressure was first measured in 1733 by Reverend Stephen Hales, who connected a long ver- tical glass tube to an artery of a horse. Although sophisticated modifications of this technique are still used in special cases, this method is obviously not satisfactory for routine clinical examinations. Routine measurements of blood pressure are now most commonly performed by the cut-off method. Although this method is not as accurate as direct measurements, it is simple and in most cases adequate. In this technique, a cuff containing an inflatable balloon is placed tightly around the upper arm. The balloon is inflated with a bulb, and the pressure in the balloon is monitored by a pressure gauge.

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The shoots of some plants such as honeysuckle twist to the right (clockwise) whereas the shoots of others such as bindweed twist to the left (anticlockwise) buy 600 mg motrin with mastercard. The doomed marriage of these two plants was the subject of the classic song "Misalliance" by Flanders and Swann buy motrin 400 mg line. In fact the Latin name of the ubiquitous climbing plant Common Ivy is Hedera helix buy 600mg motrin otc, which itself means twisting purchase cheapest motrin and motrin. The soft curly tendrils of clinging plants such as grape vines and beans however, can have their helices reversed when the tendril touches a support. This so-called "tendril perversion" fascinated Charles Darwin and he wrote about it at length in his book "The Movements and Habits of Climbing Plants". When the tendril starts to curl and tighten up, since neither the stem nor the support can rotate, the total twist in the tendril cannot change. Therefore, as the tendril curls on itself, the coils of the spiral are reversed at some point and the two opposite spirals are separated by a small straight segment. This phenomenon can be likened in the modern sense to a coiled telephone cable, which is first completed extended, untwisted and then slowly released. There are many examples of handedness in synthetic molecules as well all right handed- try looking on the labels of toiletries, household chemicals and medicines when you go shopping. Left-handed (or negatively-refracting) materials turn out to transform space for electromagnetic fields and their vacuum fluctuations [2,10]. Philbin, Quantum levitation by left-handed metamaterials, New Journal of Physics 9, 254 (2007). Philbin, Quantum optics of spatial transformation media, Journal of Optics A (in press). Full, Evidence for van der Waals adhesion in gecko setae, Proceedings of the National Academy of Sciences 99, 12252 (2002). Boersma, A maritime analogy of the Casimir effect, American Journal of Physics 64, 539 (1996). Casimir, On the attraction between two perfectly conducting plates, Proceedings of the Royal Netherlands Academy of Arts and Sciences, B51, 793 (1948). Capasso, Quantum Mechanical Actuation of Microelectromechanical Systems by the Casimir Force, Science 291, 1941 (2001). Philbin, General relativity in electrical engineering, New Journal of Physics 8, 247 (2006). Pendry, Negative Refraction Makes a Perfect Lens, Physical Review Letters 85, 3966 (2000). Roukes, Quantum physics: Casimir force changes sign, Nature 419, 119 References 1. Researches on the molecular asymmetry of natural organic products, English translation of French original, published by Alembic Club Reprints (Vol. On the rotation of plane of polarisation of electric waves by a twisted structure, Proc. The Cure For All Cancers Including Over 100 Case Histories of Persons Cured Plus two revolutionary electronic circuits, one to diagnose and monitor progress, the other to zap parasites and bacteria! The cause is a certain parasite, for which I have found evidence in every can- cer case regardless of the type of cancer. So lung cancer is not caused by smoking, colon cancer is not caused by a low- roughage diet, breast cancer is not caused by a fatty diet, retinal blastoma is not caused by a rare gene, and pancreatic cancer is not caused by alcohol consumption. The dis- covery of the cause and cure of all cancers has stood the test of time and here it is! You may not have time to read this entire book first if you have cancer and are scheduled for surgery, chemotherapy or radiation treatment. You may wish to skip the first pages which describe how a parasite and a solvent cause cancer to develop. Go directly to the instructions on eliminating the parasite with herbs (Cancer Curing Recipe, page 19) or with electricity (Zapping Parasites, page 30). It does not matter how far progressed the cancer is— you can still stop it immediately. After you have stopped the cancer, you can turn your atten- tion to getting well (Part 2). Read the case histories to see how easy it is to stop even terminal cancers (Part 3). But if you do not wish to make your doctor angry, you could follow her or his wishes, too. Be careful not to lose any vital anatomical parts in surgery, though, because you may need them later when you are healthy! They have no way of knowing about the true cause and cure of cancer since it has not been published for them. I chose to publish it for you first so that it would come to your attention faster. The opinions expressed herein are based on my scientific research and on specific case studies involving my clients. Be advised that every person is unique and may respond differently to the treatments described in this book. Again, remember that we are all different and any new treatment should be applied in a cautious, common sense fashion. The treatments outlined herein are not intended to be a re- placement or substitute for other forms of conventional medical treatment. I have indicated throughout this book the existence of pol- lutants in food and other products. Complete instructions for building and using this device are contained in this book. The Syncrometer is more accurate and versatile than the best existing testing methods. However at this point it only yields positive or negative results, it does not quantify. The chance of a false positive or a false negative is about 5%, which can be lessened by test repetition. It is in the public interest to know when a single bottle of a single product tests positive to a serious pollutant. If one does, the safest course is to avoid all bottles of that product entirely, which is what I repeatedly advise. These recommendations should be interpreted as an intent to warn and protect the pub- lic, not to provide a statistically significant analysis. It is my fervent hope that manufacturers use the new electronic tech- niques in this book to make purer products than they ever have before. If he had not made a slide of Fasciolopsis buskii in his student years and if he had not stored his slides carefully for three decades, finally to loan them to me in a generous offer, none of these discoveries would have been made. Thanks are also due to his wife, Linda, for her patience and willingness to listen to new ideas. Another special thank you goes to my son, Geoffrey, whose sugges- tions, computer expertise, help with instrumentation, and edit- ing were indispensable and very much appreciated. In 1996, the collaboration with Patricia Connolly Gorzen made possible our discovery of dental toxins and better dental practices. This led directly to improved survival opportunity for many terminally ill patients. The Witch Doctor, Medicine Man and Woman, Herbalist and Clinician are all alike in this respect. They wish to keep in- formation surrounding illness and wellness to themselves and away from the common person so that a profession of medicine can grow and become lucrative. The modern medical profession overlooks informa- tion on prevention; it tries to make self-help and simple treat- ments illegal. This seems inappropriate, especially where communicable or wide-spread illness is involved. This example is taken from a text on herbology: This [bath] is a safe and sane procedure and will prove most beneficial to those who are obese and desire to reduce safely. In combination with the internal treatment with decoction of Fucus, this course is worth considerable to very stout people, and should not be sold too cheaply. It is a grave mistake to put this scientific treatment in the same class as the many advertised nostrums on the market. If any do make this mistake, he will lose his client who 1 will straight away go to a drugstore for supplies. I believe hostage-holding of the sick is im- moral, fundamentally unethical, and needs to be stopped.

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