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Note that cheap fluoxetine 10mg, except for the π-ring normal projections cheap fluoxetine 20 mg with mastercard, all features are positioned in one plane order fluoxetine 10 mg visa. The pharmacophore score was defined as the number of pharmacophoric features in the molecule that match pharmacophore centers in the model, from which the root mean square distance between the feature centers in molecule and pharmacophore is subtracted. These indices are calculated as follows: each property is transformed into a desirability function that expresses how well criteria are met. Desirability functions have a value ranging from zero to one, where zero (0) indicates that criteria are violated and one (1) that all criteria are entirely satisfied The function displays a gradual rise between zero and one, the shape of which can vary (linear in this study), to express improvement and to steer evolution towards satisfying the criteria. Desirability functions are either one- sided or two-sided, depending on whether maximization of a value is required or whether the value should be within a specified target range. The individual desirability functions are combined into a desirability index by multiplication. These values where then inverted (one minus the desirability value) and combined into the final desirability index that was used as objective. Pareto selection is a method to select the set of best solutions of a problem with multiple (conflicting) objectives. The best or non-dominated solutions are those for which no 194 Multi-Objective Evolutionary Ligand Design other solution is superior in all properties. The non-dominated solutions form the Pareto front and have the characteristic that it is not possible to improve on one property without degrading another property. Removing the solutions on the first Pareto front will expose the second Pareto front, removing those will expose the third, etc. From the top-ranked structures, diverse subsets were selected using dynamic peak 34 identification, or ‘niching’, whereby the best molecules are grouped in niches based on a similarity measure such as fingerprint distance. Niching starts by assigning the best molecule from the Pareto selection as the first niche center. The second best molecule is compared to this niche center and if the fingerprint distance is within a set minimum known as the niche radius, it is assigned to the niche; if it falls outside the niche radius, it will be the niche center of the second niche. If the maximum number of molecules per niche is reached, the niche with the second best niche center is considered, then the third, and so on. If the molecule falls not within any of the niches and the maximum number of niches is reached, it is discarded. This process continues until all molecules are processed or all niches have the maximum number of molecules. The remaining molecules were grouped by scaffold and ordered by pharmacophore score. To keep only novel candidates for further synthesis, molecules containing ring systems or scaffolds also found in adenosine receptor ligands were removed. Single rings and fragments without heteroatoms were removed; the rest of the fragments was used for filtering. This final pruning process yielded a collection of novel scaffolds presented in Figure S1. Subsequently our chemists searched for possible routes of synthesis and availability of starting materials. Chemical shifts are reported in δ (ppm) and the following abbreviations are used: s = singlet, d = doublet, dd = double doublet, dt = double triplet, t = triplet, td = triple doublet, m = multiplet, br = broad. Subsequently, the reaction mixture was cooled and poured into water to precipitate the desired compound. Suzuki-Miyaura cross-coupling reaction between 2-(N,N- diisopropylcarboxamido)phenylboronic acid and 2-amino-3-bromopyridine under microwave conditions was performed to obtain 2-(2-aminopyridin-3-yl)-N,N- diisopropylbenzamide, with subsequent cyclization affords the entitle compound 2. Upon completion the reaction mixture was poured into water and the product was extracted with ethyl acetate. The resulting solid was recrystallized from ethanol 1 yielding the desired compound. Compounds 3a-3k were synthesized under microwave conditions, which is further detailed in the Supporting Information. The reaction mixture was allowed to reach room temperature and stirred for additional 4 h. The precipitate was filtered and washed with cold dichloromethane yielding the corresponding semicarbazide. Subsequently, the reaction mixture was filtered and the ethanol was removed under vacuo yielding the corresponding cyclohexanecarboxaldehyde N-phenylsemicarbazone. All compounds made were tested in radioligand binding assays to determine their affinities at the human adenosine A1, A2A, A2B, and the A3 receptors. Filters were washed three times with ice-cold buffer and placed in scintillation vials. Filters were washed three times with ice-cold buffer and placed in scintillation vials. This study was performed within the framework of the Dutch Top Institute Pharma, project number: D1-105. Adenosine receptor antagonists: Translating medicinal chemistry and pharmacology into clinical utility. Chemogenomic data analysis: Prediction of small-molecule targets and the advent of biological fingerprints. Analysis of Pharmacology Data and the Prediction of Adverse Drug Reactions and Off-Target Effects from Chemical Structure. Applications of Support Vector Machines in Chemistry Reviews in Computational Chemistry 2007, 23, 291.

It interferes with the chlo- ride-binding cotransport system (Na+-K+-2Cl−symporter) and halts salt transport in this segment cheap fluoxetine 20 mg with visa. The drug also inhibits calcium and magnesium reabsorption in the ascending limb by eliminating the transepithelial potential difference generic fluoxetine 10mg online. Dosing Neonates buy fluoxetine 20 mg on line, premature: Oral (poor bioavailability): doses of 1 to 4mg/kg/dose once or twice daily have been used Intramuscular (I. Adults: Oral: initial, 20 to 80 mg/dose; increase in increments of 20 to 40 mg/dose at intervals of 6 to 8 hours; usual maintenance dose interval is once or twice daily; may be titrated up to 600 mg/day for severe edematous states I. Diuretic Medications 121 interval, 6 to 12 hours; for acute pulmonary edema, the usual dose is 40 mg I. The peak effects occur within 1 to 2 hours and the duration of action is 6 to 8 hours. After oral dosing, 45 to 65% of the drug is absorbed and the protein binding is 98%. The hepatic metabolism of the drug is minimal and the half-life is approximately 30 minutes. Also reported are dizziness, urticaria, hypokalemia, nausea,pancreatitis, headaches, photosensitivity, diarrhea, dehydration, and anemia. There is increased ototoxicity with aminoglycosides and ethacrynic acid; and drugs affected by potassium depletion, such as digoxin. There is increased anticoagulation by warfarin; decreased glucose tolerance may increase requirements of oral antidiabetic agents; and there is decreased lithium excretion with furosemide administration. Poisoning Information Symptoms of furosemide overdose may include weakness, muscle cramps, fatigue, dizziness, fainting, confusion, irregular pulse, dry mouth, dehydration, 122 D. Decontamination using activated charcoal is recommended and other treatment is supportive and symptomatic. It interferes with the chloride- binding cotransport system (Na+-K+-2Cl− symporter) and halts salt transport in this segment. The drug also inhibits calcium and magnesium reabsorption in the ascending limb by eliminating the transepithelial potential difference. The drug undergoes partial hepatic metabolism, with the majority of the drug eliminated as the parent molecule or as a metabo- lite in the urine. Monitoring parameters: serum electrolytes, renal function, blood pressure Contraindications: anuria or increasing azotemia Warnings/Adverse Effects Warning: loop diuretics are potent agents. The injectable formulation of this drug con- tains benzyl alcohol and large amounts (>99 mg/kg/d) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates. In vitro animal studies have shown that benzoate, a metabolite of benzyl alcohol, displaces bilirubin from protein binding sites. In vitro studies using pooled sera from critically ill neonates have also shown bumetanide to be a potent displacer of bilirubin. Use with caution in patients with previous hypersensitivity reactions to sulfonamides or thiazides. Adverse effects that may occur with bumetanide use include hypotension, chest pain, dizziness, headache, encephalopathy, vertigo, and potential rashes. Other effects may include urticaria, hypokalemia, nausea, pancreatitis, photosensitivity, diarrhea, dehydration, and decreased uric acid excretion. Hyponatremia, hypochloremia, arthritic pain, metabolic alkalosis, hypercal- ciuria, agranulocytosis, thrombocytopenia, hyperuricemia, and cramps have also been reported. There is increased ototoxicity when bumetanide is used with aminoglycosides and ethacrynic acid; and drugs affected by potassium depletion, such as digoxin. With bumetanide administration, there is decreased glucose tolerance with antidiabetic agents; and decreased lithium excretion. Poisoning Information Symptoms of bumetanide overdose may include acute and profound water loss, volume and electrolyte depletion, dehydration, reduction of blood volume, and 124 D. Kazmerski circulatory collapse with a possibility of vascular thrombosis and embolism. Electrolyte depletion may be manifested by weakness, dizziness, mental confu- sion, anorexia, lethargy, vomiting, and cramps. Decontamination using activated charcoal is recommended and other treatment is supportive and symptomatic. It may also be used in the treatment of hypertensive patients1 alone or in combination with other antihypertensive medications. Mechanism of Action Torsemide is a loop diuretic and functions through inhibition of reabsorption of sodium and chloride from the ascending loop of Henle. It interferes with the chlo- ride-binding cotransport system (Na+-K+-2Cl− symporter) and halts salt transport in this segment. The drug also inhibits calcium and magnesium reabsorption in the ascending limb by eliminating the transepithelial potential difference. Titrate up to maximum dose of 200 mg/day Hypertension: 5mg once daily initially, then increase to 10mg once daily, if needed, after 4 to 6 weeks Pharmacokinetics Rapidly absorbed; bioavailability, 80 to 90%. The half- life of torsemide is normally 2 to 4 hours, but is increased to 7 to 8 hours in cirrhosis. Monitoring parameters: serum electrolytes, renal function, blood pressure Contraindications: anuria 5. Diuretic Medications 125 Precautions/Adverse Effects Warning: loop diuretics are potent agents.

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The comparative fine ceral leishmaniasis and their induction by experimental poly- structure and surface glycoconjugate expression of three life clonal B-cell activation order 10 mg fluoxetine visa. Vesicular stomatitis virus Indiana glycoprotein clonal activation: a pitfall for vaccine design against infectious as a T-cell-dependent and – independent antigen discount 20mg fluoxetine mastercard. The nucleocapsid of hepatitis B virus paradigm of pathogenesis and protection hold for New World is both a T-cell-independent and a T-cell-dependent antigen cheap fluoxetine 20 mg online. Antibody-mediated protection against intracellular tion by a T-cell independent type 2 antigens as an integral part pathogens. T cell independent anti- donovani amastigotes: antibody facilitation of alternate comple- gens. Leishmaniases of the New World: current receptor is required to sustain infection in murine cutaneous concepts and implications for future research. Biochem Biophys Res Commun 2000; role of the Leishmania major ribosomal protein S3a homologue 273:793–8. Interaction of Leishmania gp63 with cellular receptors for fibro- Nature 1997; 388:900–3. Cloning and characterization of two mouse genes mechanism of parasite control and evasion. Cytotoxicity of human serum for Leishmania Biochem Biophys Res Commun 1999; 260:273–9. In vitro growth of Leishmania amazonensis promastigotes resistant to pentamidine is dependent on interactions among strains. Apoptosis in a unicellular eukaryote (Trypanosoma cruzi): implications for the evolutionary origin and role of programmed cell death in the control of cell proliferation, differentiation and survival. Leishmania mexicana cysteine proteinase-deficient mutants have attenuated virulence for mice and potentiate a Th1 response. Localized mucosal leishmaniasis due to Leishmania (Leishmania) infantum: clinical and microbiologic findings in 31 patients. Canine leishmaniasis: clinical, parasitological and entomological follow-up after chemotherapy. The biogenesis and properties of the parasitophorous vacuoles that harbour Leishmania in murine macrophages. Mitochondrial release of apoptosis-inducing factor occurs downstream of cytochrome c release in response to several proapoptotic stimuli. Studies on control of visceral leishmaniasis: impact of dog control on canine and human visceral leishmaniasis in Jacobina, Bahia, Brazil. Latex agglutination test for the detection of urinary antigens in visceral leishmaniasis. Trypanothione as a target in the design of antitrypanosomal and antileishmanial agents. Treatment of visceral leishmaniasis with pentavalent antimony and interferon gamma. Natural killer cell behavior in lymph nodes revealed by static and real-time imaging. Axenic cultivation and partial characterization of Leishmania braziliensis amastigote-like stages. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. Mannose-coated liposomal hamycin in the treatment of experimental leishmaniasis in hamsters. Drug delivery system: targeting of pentamidines to specific sites using sugar grafted liposomes. Leishmaniasis in Bahia, Brazil: evidence that Leishmania amazonensis produces a wide spectrum of clinical disease. Resistance to pentamidine in Leishmania mexicana involves exclusion of the drug from the mitochondrion. Molecular and cellular effects of hexadecylphosphocholine (Miltefosine) in human myeloid leukaemic cell lines. Development of a natural model of cutaneous leishmaniasis: powerful effects of vector saliva and saliva preexposure on the long-term outcome of Leishmania major infection in the mouse ear dermis. The interaction of Alba, a conserved archaeal chromatin protein, with Sir2 and its regulation by acetylation. Silent infection of bone marrow-derived dendritic cells by Leishmania mexicana amastigotes. Selective impairment of protein kinase C isotypes in murine macrophage by Leishmania donovani. Efficacy and tolerability of miltefosine for childhood visceral leishmaniasis in India. Macrophage complement and lectin-like receptors bind Leishmania in the absence of serum. Epidemiological surveys confirm an increasing burden of cutaneous leishmaniasis in north-east Brazil. Transcriptional silencing in yeast isassociated with reduced nucleosome acetylation. Efficient transcriptional silencing in Saccharomyces cerevisiae requires a heterochromatin histone acetylation pattern. Role of the Leishmania surface protease gp63 in complement fixation, cell adhesion, and resistance to complement-mediated lysis. Conserved linkage groups associated with large-scale chromosomal rearrangements between Old World and New World Leishmania genomes. A policy for leishmaniasis with respect to the prevention and control of drug resistance. Correlation between enhanced oxidative metabolism and leishmanicidal activity in activated macrophages from healer and nonhealer mouse strains.

The risk the malingerer takes must be evaluated in terms of the importance of the goal of resistance and the possible effectiveness of alternative modes of resistance and evasion open to him buy fluoxetine 20 mg free shipping. The risks involve both the damage the captor may inflict upon him and the possibilities of a real and lasting personality disorder resulting from his simulation order 10mg fluoxetine. To the best of our knowl- Executive Publisher edge generic 10 mg fluoxetine amex, these procedures reflect currently accepted practice. For individual applications, all recommen- Editorial Director dations must be considered in light of the patient’s clinical David Moreau condition and, before administration of new or infrequently Clinical Director used drugs, in light of the latest package-insert information. No part of it may be repro- Editors duced, stored in a retrieval system, or transmitted, in any form or by any means—electronic, mechanical, photocopy, record- Margaret Eckman, Diane Labus ing, or otherwise—without prior written permission of the Copy Editors publisher, except for brief quotations embodied in critical arti- Kimberly Bilotta (supervisor), Jane Bradford, cles and reviews and testing and evaluation materials provid- Shana Harrington, Lisa Stockslager, ed by publisher to instructors whose schools have adopted its accompanying textbook. Ruhf Indexer Barbara Hodgson Library of Congress Cataloging-in-Publication Data Clinical pharmacology made incredibly easy!. Joseph Health Services Assistant Professor of Clinical Pharmacy North Providence, R. Philadelphia College of Pharmacy University of the Sciences in Philadelphia Glen E. Farr, PharmD Professor of Clinical Pharmacy & Associate Dean Suzzanne Tairu, PharmD University of Tennessee College of Pharmacy Clinical Specialist Knoxville The Medical Affairs Company/Consultant for Pfizer Kennesaw, Calif. Here’s why this book is so terrific: It will teach you all the important things you need to know about clinical pharmacology. We’ll be there to explain key concepts, provide important care reminders, and offer reassurance. Oh, and if you don’t mind, we’ll be spicing up the pages with a bit of humor along the way, to teach and entertain in a way that no other resource can. Joy 1 Fundamentals of clinical pharmacology Just the facts In this chapter, you’ll learn: ♦ pharmacology basics ♦ routes by which drugs are administered ♦ key concepts of pharmacokinetics ♦ key concepts of pharmacodynamics ♦ key concepts of pharmacotherapeutics ♦ key types of drug interactions and adverse reactions. Pharmacology basics This chapter focuses on the fundamental principles of pharmacol- ogy. It discusses basic information, such as how drugs are named and how they’re created. It also discusses the different routes by Read on to find which drugs can be administered. This involves three main areas: pharmacokinetics (the absorption, distribution, metabolism, and excretion of a drug) pharmacodynamics (the biochemical and physi- cal effects of drugs and the mechanisms of drug ac- tions) pharmacotherapeutics (the use of drugs to pre- vent and treat diseases). Drugs have a specific kind of nomenclature—that is, a drug can go This is confusing! The symbol ® after the trade name indicates that the name is registered by and restricted to the drug manufacturer. To avoid confusion, it’s best to use a drug’s generic name be- cause any one drug can have a number of trade names. In 1962, the federal government mandated the use of official names so that only one official name would represent each drug. The official names are listed in the United States Pharmacopeia and National Formulary. Family ties Drugs that share similar characteristics are grouped together as a pharmacologic class (or family). Where drugs come from Traditionally, drugs were derived from natural sources, such as: • plants • animals • minerals. Today, however, laboratory researchers use traditional knowl- edge, along with chemical science, to develop synthetic drug sources. One advantage of chemically developed drugs is that they’re free from the impurities found in natural substances. In addition, researchers and drug developers can manipulate the molecular structure of substances such as antibiotics so that a slight change in the chemical structure makes the drug effective against different organisms. The first-, second-, third-, and fourth- generation cephalosporins are an example. Subsequent- about any substance ly, harmful substances often found their way into the mixture. As the understanding of plants as drug sources became more sophisticated, researchers sought to isolate and intensify active components while avoiding harmful ones. Power plant The active components consist of several types and vary in char- acter and effect: • Alkaloids, the most active component in plants, react with acids to form a salt that can dissolve more readily in body fluids. Examples of volatile oils, which readily evapo- rate, include peppermint, spearmint, and juniper. The drugs obtained from animal sources include: • hormones such as insulin • oils and fats (usually fixed) such as cod-liver oil • enzymes, which are produced by living cells and act as cata- lysts, such as pancreatin and pepsin • vaccines, which are suspensions of killed, modified, or attenuat- ed microorganisms. The mineral sources are used as they occur in nature or are combined with other ingredi- ents. In the near future, traditional barnyard animals might also be small, or- That’s an unusual ganic pharmaceutical factories. Examples of drugs produced in the laboratory include thyroid hormone (natural) and ranitidine (synthetic). Recombinant deoxyribonucleic acid research has led to other chemical sources of organic compounds. For example, the re- ordering of genetic information has enabled scientists to develop bacteria that produce insulin for humans. How drugs are administered A drug’s administration route influences the quantity given and the rate at which the drug is absorbed and distributed.

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As with all spectroscopic techniques discount 20mg fluoxetine amex, it can be used to identify and study chemicals buy 10 mg fluoxetine fast delivery. Infrastructure: The basic physical and organizational structures needed or the operation of a society or enterprise generic 10mg fluoxetine with amex, or the services and facilities neces- sary for an economy to function. It can be generally defned as the set of interconnected structural elements that provide the framework supporting an entire structure of development. The term typically refers to the technical structures that support a society, such as roads, bridges, water supply, sew- ers, electrical grids, telecommunications, and so forth. Innovator drug: Generally the pharmaceutical product that was frst au- thorized for marketing (normally as a patented product) on the basis of documentation of effcacy, safety, and quality according to requirements at the time of the authorization. It includes inventions, literary and artistic works, symbols, names, images, and designs used in commerce. Lifestyle drug: A term commonly applied to medications that treat non-life- threatening and nonpainful conditions such as baldness, impotence, wrin- kles, erectile dysfunction, or acne, which the speaker perceives as either not medical problems at all or as minor medical conditions relative to others. Linear barcode: One-dimensional barcodes made up of lines and spaces of various widths, creating specifc patterns. These patterns represent stock- keeping unit numbers and batch numbers, which can be easily and quickly read by computer scanners. Low- and middle-income countries: Countries with a gross national income per capita of less than $12,475. Manufacturing dossier: An entire collection of records and documents that a manufacturer holds for a particular product, which is generally submit- ted to a regulatory authority as part of a marketing authorization request. Marginal cost: The change in total cost that arises when the quantity pro- duced changes by one unit. Market authorization: An offcial document issued by the competent drug regulatory authority for the purpose of marketing or free distribution of a product after a satisfactory evaluation for safety, effcacy, and quality. Mass spectrometer: An instrument used to measure the precise masses and relative amounts of atomic and molecular ions. In order to measure the characteristics of individual molecules, a mass spectrometer converts them to ions so that they can move and be manipulated by external electric and magnetic felds. The molecules of interest are frst introduced into the ionization source of the mass spectrometer, where they are frst ionized to acquire positive or negative charges. The ions then travel through the mass analyzer and arrive at different parts of the detector according to their mass-to-charge ratio. After the ions make contact with the detector, usable Copyright © National Academy of Sciences. The computer displays the signals graphically as a mass spectrum showing the relative abundance of the signals according to their mass-to-charge ratio. Mass spectrometry: An analytical technique that measures the mass-to- charge ratio of charged particles. It can provide both qualitative (structure) and quantitative (molecular mass or concentration) information on analyte molecules after their conversion to ions. This technique is used for deter- mining masses of particles, for determining the elemental composition of a sample or molecule, and for elucidating the chemical structures of mol- ecules, such as peptides and other chemical compounds. Medicines registration: A system that subjects all pharmaceutical products to premarketing evaluation, marketing authorization, and postmarketing review to ensure that they conform to required standards or quality, safety, and effcacy established by national authorities. The outcome of the medi- cines registration process is the issuance or the denial of a pharmaceutical product marketing authorization or license. Medicrime Convention: The frst international treaty established by the Council of Europe against counterfeit medical products and similar crimes involving threats to public health. The Convention makes it an offense to manufacture counterfeit medical products; supply, offer to supply, and traffc counterfeit medical products; falsify documents; manufacture or sup- ply medicinal products without proper authorization; and market medical devices that do not comply with conformity requirements. Microfuidics: The science and technology of systems that process or ma- nipulate small amounts of fuids, using channels with dimensions of tens to hundreds of micrometers. Microscopy: The technical feld of using microscopes to examine samples and objects that cannot be seen with the unaided eye. Monograph: A written set of assessment methods and standards that are used to defne an acceptable or compliant article (e. Monographs are used to help control the quality of pharmaceutical, dietary supplement, and food ingredient products. It may be used to identify or quantify organic com- pounds by measuring the absorption of near infrared light by chemical bonds in organic materials. Nonprobability sample: Also called a nonrandom sample, wherein the se- lected units have an unknown probability of being selected. Nonprobability samples cannot be used to infer from the sample to the general population. Any generalizations obtained from a nonprobability sample must be fltered through one’s knowledge of the topic being studied. Nosocomial infections: An infection whose development is favored by a hospital environment, such as one acquired by a patient during a hospital visit or one developing among hospital staff. Such infections include fungal and bacterial infections and are aggravated by the reduced resistance of individual patients. They are Australia, Austria, Belgium, Canada, Chile, Czech Republic, Denmark, Es- tonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Israel, Italy, Japan, Korea, Luxembourg, Mexico, the Netherlands, New Zealand, Norway, Poland, Portugal, Slovak Republic, Slovenia, Spain, Sweden, Swit- zerland, Turkey, the United Kingdom, and the United States. Opportunity cost: The cost of an action measured in terms of the value of the next best alternative action.

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Identifying a crystal from its projected reciprocal lattice geometry is order 10mg fluoxetine visa, thus buy 20 mg fluoxetine with visa, frequently equivalent to finding the 2D data points of the experimental plot within the theoretical lattice-fringe fingerprint plot generic 10mg fluoxetine fast delivery. Figure 9 shows the theoretical lattice-fringe fingerprint plot for the mineral rutile for a 0. Screw axes and glide planes result in systematic absences of reflections in 2D projections of the reciprocal lattice geometry and are revealed in “kinematic lattice-fringe fingerprint plots” by missing rows [compare Figs. The so-called “Gjønnes and Moodie dynamically forbidden reflections” (83) are shown in dynamical lattice-fringe fingerprint plots [Fig. The other type of system- atic absences of reflections in 2D projections of reciprocal lattice geometries, which are due to 3D Bravais lattice centerings, results in systematic absences of entire rows in lattice-fringe fingerprint plots independent of the “kinematic” or “dynamic” type of these plots. While there are two data points in lattice-fringe fingerprint plots for reflections with different spacings, the crossing of two symmetrically reflections results in just one data point (because the latter possess by symmetry the same spacing). All of the resolvable lattice fringes and reflections up to the appropriate resolution will be included for a certain crystal Structural Fingerprinting of Nanocrystals in the Transmission Electron Microscope 295 Lattice-fringe fingerprint plot for rutile; Ti O2 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 0 3. Note the (Gjønnes and Moodie) dynamically forbidden reflections, for example, in the case of rutile in the exact [001] orientation, are included in the (two-beam) dynamic diffraction limit plot. Note the characteristically different distribution of the two-dimensional data points in both plots and that the abscissas are on different length scales. Structural Fingerprinting of Nanocrystals in the Transmission Electron Microscope 297 structure into these plots. The appearance of lattice-fringe fingerprint plots is, thus, both crystalline material and reciprocal space resolution specific (Figs. Figure 10(A) shows a theoretical lattice-fringe fingerprint plot that has been calculated for vanadium oxide nanotubes, a crystalline material that did not give a characteristic X-ray powder diffraction fingerprint (Fig. Due to the rather large unit cell dimensions of the vanadium oxide nanotubes (29), an older transmission electron microscope with a very modest Scherzerb resolution of 0. A modern analytical transmission electron microscope with a Scherzerb resolution of 0. Figure 10(B) shows a theoretical lattice-fringe fingerprint plot for the min- eral pseudo-brookite, for which a characteristic X-ray powder diffraction fingerprint was shown as Figure 1. From the comparison of Figures 10(A) and 10(B), one can conclude that lattice-fringe fingerprinting works for both types of crystalline mate- rials, those that do not (Fig. An initial search in a database of theoretical lattice-fringe fingerprints that is based on the 2D positions of data points in lattice-fringe fingerprint plots alone may result in several candidate structures. In the following steps, the search can be made more discriminatory both by trying to match crystallographic indices to the 2D positions and by determining the projected symmetry. Because one will always project along one zone axis, all indices of the reflec- tions must be consistent with a certain family of zone axes. As far as the lattice- fringe fingerprint plots are concerned, this follow-up search is equivalent to assign- ing crystallographic indices to the 2D data points. Each (vertical) column of data points in a lattice-fringe fingerprint plot corresponds to one family of reflections (net planes). Discrete points on a second x-axis in a lattice-fringe fingerprint plot can, therefore, be labeled with the respective Miller indices, , of a family of reflections. Each (horizontal) row of data points in a plot such as Figures 9 and 10, on the other hand, belongs to a family of zone axes. Discrete points on a second y-axis of such a plot can, thus, be labeled with the respective Miller indices, , of a family of zone axes. The cross product of the Miller indices of two data points from two different columns (representing two different reciprocal spacings) that are also located within the same row (representing one interfringe angle) gives the zone axis symbol, = × . While each family of reflections will show up only once on such a second x-axis, the same family of zone axis symbols may be showing up multiple times on such a second y-axis. Guided by the added 298 Moeck and Rouvimov Miller indices for columns and rows on such a lattice-fringe fingerprint plot, kine- matically forbidden reflections can be easily identified (in kinematical diffraction limit plots). Higher orders of a family of net planes {nh,nk,nl} possess an (n times) integral multiple of the spatial frequency of that family. Such higher orders of families are also easily spotted in a lattice-fringe fingerprint plot because their “columns” look identical. This is because the respective higher order net planes will intersect other net planes at precisely the same interfringe angles as those net planes from a lower order. Within the error bars and especially in lattice-fringe fingerprint plots for a very high microscope resolution, it is possible that families of net planes or zone axes coincide on the second x-ory-axis. There are also cases in which the net plane spacings of two different families are exactly the same, for example, and or and in the cubic system. While the respective data points will be located in a lattice-fringe fingerprint plot in the same column, they will most likely possess different interfringe angles, that is, will be located in different rows. Because all interfringe angles between identically indexed reflections are the same in the cubic system, space group information can be extracted straightforwardly from lattice-fringe fingerprint plots (in the kinematic diffraction limit) of cubic crystals. More elaborate lattice-fringe fingerprint plots may contain in the third and fourth dimension information on structure factor phases and amplitudes. Possibly, in a fifth dimension, histograms of the probability of seeing crossed lattice fringes in an ensemble of nanocrystals may be added to both types of lattice-fringe fingerprint plots and may facilitate the structural fingerprinting of an ensemble of nanocrys- tals. The equations for calculating such probabilities for an ensemble of randomly oriented nanocrystals are given in Ref. Instead of employing higher dimensional spaces, one could also stick to 2D displays such as Figures 9 and 10 and simply add to selected data points sets of numbers that represent additional information (e.

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A recorded prescriptions were for primidone 10 mg fluoxetine otc, but statistically significant decrease in incidence 25% of patients had no records of prescriptions was observed for cancer of the urinary bladder discount 20mg fluoxetine otc. Smoking informa- [The strengths of this study were adequate tion was surveyed among living controls discount fluoxetine 10 mg line, but not follow-up and case ascertainment. Te relative risk was close to unity for linkage study among 3727 ofspring of women use of primadone and cancer of the liver and from the Filadelfa cohort who were alive as of biliary tract (Olsen et al. Mothers of 2 of when repeated excluding Torotrast-exposed the 14 children with cancer had taken primidone patients. Limitations size of the cohort was relatively large and case included incomplete information on exposure to ascertainment and follow-up were adequate, primidone (with respect to duration of use; drug this study was not considered to be inform- exposure information was collected only during ative because the fndings were not reported the patient’s stay in hospital) and on potential specifcally for primidone, and few cancers were confounders, and small numbers of exposed observed in the cohort. Cancer in Experimental Animals of males at the highest dose, in which survival was less than that of controls. In males, there was In one study of carcinogenicity, groups of 50 also a signifcant positive trend in the incidence male and 50 female B6C3F1 mice (age, 5–6 weeks) of follicular cell adenoma of the thyroid in mice were given diets containing primidone (purity, receiving pyrimidone, with a signifcant increase > 99%) at a concentration of 0 (control), 300, 600, in incidence in the group receiving the highest or 1300 ppm for 104–105 weeks. Tere was an increased incidence in folli- was equivalent to average daily doses of approx- cular cell hyperplasia of the thyroid in males and imately 0, 30, 65, or 150 mg/kg body weight (bw) females receiving pyrimidone. Primidone caused a signifcant increase O in the incidence of follicular cell adenoma of the Phenylethylmalonamide Phenobarbital thyroid in males receiving the intermediate dose. In the extended evaluations involving additional Compiled by the Working Group step sections of the kidney in males, there was a 4. Mechanistic and Other (a) Pharmacokinetics of single doses Relevant Data Baumel et al. Two of the subjects had been done; peak concentration of unchanged primidone on a daily dose of primidone (750 mg in divided (mean Cmax, 41. Mean elimination half- of 750 mg in this study, peak serum concentra- life was 19. Te elimination epileptic patients who had been receiving a half-life ranged from 17 to 25 hours in drug-free constant dose of primidone for at least 2 months. Tere Data were compared in two groups: 10 elderly was no evidence for a glucuronide conjugate. Te rate of metab- group, than the young (575 ± 206 mg/day olism to phenobarbital showed wide variation and 422 ± 115 mg/day, respectively). In the (25-fold) among children, which, although not elderly and young, respectively, the mean half- infuencing the overall elimination rate constant life of primidone was 12. Differences between phenytoin had no detectable efect on half-life the two groups were not statistically significant, or serum concentrations of phenobarbital. Of indicating that half-life and total clearance of the total primidone daily dose, approximately primidone were unaltered in elderly patients. Te administered primidone was studied in 12 chil- shortest half-lives for primidone (8–11 hours) dren (age, 7–14 years) undergoing long-term were detected in two neonates whose mothers (> 3 months) treatment for epilepsy, and were had been treated with phenytoin in addition to assumed to be in steady state. Serum concentrations and elimina- were taking primidone only, and eight were tion rates varied among neonates, and during the also taking phenytoin. Mean recovery of the adminis- neonatal metabolism of primidine, and rate of tered dose in the urine within 24 hours was 92% 196 Primidone elimination increased afer a few days in some increase or decrease in pharmacologically active babies (Nau et al. Primidone is frequently used in combi- Analyses of maternal milk of four of the nation with such substrates (e. Because of breastfeeding, all compounds faster, and total body clearance was increased, were also detected in neonatal blood (Nau et al. In a study of seven neonates, whose mothers were treated for epilepsy throughout (iii) Liver disease pregnancy, the shortest half-lives for primidone Te disposition of a single oral dose of 500 mg were reported in two neonates whose mothers of primidone was studied in seven patients with had been treated with both phenytoin and prim- acute viral hepatitis and in seven healthy subjects idone (Nau et al. Afer oral adminis- plasma concentrations of primidone (at most tration of primidone (at a dose of 50 mg/kg bw), doses and time points) were consistently higher 198 Primidone (approximately double) and half-lives greater (b) Chromosomal damage (two- to fvefold) in females than in males. Additional in-vitro plasma of female rats at 15 and 30 minutes, and studies showing no induction of sister-chro- plasma concentrations of phenobarbital, for a matid exchange in Chinese hamster ovary cells, given dose, were consistently higher in males or chromosomal aberration in human lympho- than in females. In studies in which rodents were exposed to phenobarbital in vivo, no covalent binding to 4. Phenobarbital did side-efects included nausea, vomiting, dizzi- not increase the frequency of sperm-head abnor- ness, ataxia, and somnolence, and caused early malities in mice, but spermatogonial germ-cell discontinuation of treatment. Further increases in the toin were associated with statistically signif- frequency of chromosomal aberration were found cantly lower incidences of intolerable side-efects in liver foci cells of mice treated with phenobar- than were primidone or phenobarbital. Although tions that were below the reference range when the majority of the test results were negative, the compared with untreated patients and controls. Primidone caused a decrease three large cohort studies of patients with of pteroylpentaglutamates in the liver to less than epilepsy. El-Masri & Portier (1998) carcinogenesis attributable to phenobarbital in have suggested that there is wide inter-individual mice have been reported. Typically, these investi- variation in the metabolic profle of primidone, gations exploited comparison between strains of which may indicate the presence of people who mice that were variously sensitive and resistant produce greater amounts of primidone metabo- to phenobarbital-induced hepatocarcinogen- lites than the general population, and who are esis. Diferences in epigenetic female mice, feed containing primidone caused control (e. Primidone also caused a signifcant increase in the incidence of hepatoblastoma and of thyroid 5. Primidone also caused a small Primidone is a synthetic drug that was used but signifcant increase in the incidence of renal commonly as an oral anticonvulsant, begin- tubule adenoma or carcinoma (combined) in ning in the 1950s. Tere was no signifcant increase in the predominantly for the treatment of essential incidence of any neoplasm in female rats. Te limited to two case–control studies reporting data on genetic toxicity for primidone in tradi- on several types of cancer nested in a cohort of tional assays are limited in scope and amount, epileptic patients in Denmark.