SARS Virus Treatments
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The following example illustrates the use of carbohydrate microarray technology in an important research area. In this case, the above described eight-chamber subarray system was applied to construct a glycan array. This glycan array was then applied to identify immunogenic sugar moieties of a human cor-onavirus (SARS-CoV). SARS-CoV is a newly identified human viral pathogen that caused an outbreak of severe acute respiratory syndrome (SARS). Although substantial efforts have been made to study the etiological agent of the disease, the carbohydrate structures of SARS-CoV remain largely uncharacterized. This information is, however, very important for devising a vaccination strategy against SARS-CoV, as well as understanding the pathogenesis of SARS. To investigate this, we constructed glycan arrays to display carbohydrate antigens of defined structures and then applied these tools to detect carbohydrate-specific antibody fingerprints that were elicited by a SARS vaccine. Our rationale...
(19.25), although definitive studies confirming this effect are not yet available. These cis-acting sequences can themselves serve as response elements which enhance the activity of a nearby promoter through binding of an endogenous transcription factor or by imparting a structure to the chromatin in the vicinity of the promoter that allows enhanced access to nuclear regulatory factors (26). These later elements, known as matrix attachment regions (MARS) or scaffold-attachment regions (SARS) have also been hypothesized to delineate the boundary of transcriptionally active units within the genome and have been shown to neutralize the effects of integration location or position-dependent effects on expression of stably integrated transgenes. The elements often have little or negative effect on transient gene expression.
In the clinical arena, there are three main diagnostic applications of PCR detection of pathogens, screening specific genes for unknown mutations, and genotyping. For instance, PCR permits mutation detection and early identification of deadly infective agents like SARS, small pox, HIV, and influenza. PCR can be applied for tumor cell detection as well, mixed chimerism after bone marrow transplantation, and noninvasive prenatal screening of fetal DNA in the maternal circulation. Single-strand confor-mational polymorphism (SSCP) is one of the most widely used methods for detecting single base pair mutations. SSCP is based on the sequence-dependent intramolecular folding that is responsible for the differential migration of two single-stranded DNA molecules of identical length but dissimilar sequence on nondenaturing acrylamide gel. Finally, efficient extraction of RNA and DNA from formaldehyde fixed tissues was recently achieved and, importantly, it was shown that it is possible to...
Amantadine is effective only against influenza A it acts by interfering with the uncoating and release of viral genome into the host cell. It is well absorbed from the gastrointestinal tract and is eliminated in the urine (t' 2 3 h). Amantadine may be used orally for the prevention and treatment of infection with influenza A (but not influenza B) virus. Those most likely to benefit include the debilitated, persons with respiratory disability and people living in crowded conditions, especially during an influenza epidemic.
The incubation period is short, approx 3-6 days (maximum 10 days), and, despite the media frenzy surrounding the initial outbreak, SARS is less infectious than influenza. The following clinical case definition of SARS has been developed for public health purposes (82). A person with a history of any combination of the following should be examined for SARS
Despite the re-emergence of SARS, it is highly unlikely that a case will be encountered in the custodial setting in the near future. However, forensic physicians must remain alert for the SARS symptoms and keep up-to-date with recent outbreaks. Information can be obtained from the WHO on a daily basis from its Web site. If SARS is suspected, medical staff should wear gloves and a surgical mask when examining a suspected case however, masks are not usually available in custody. Anyone suspected of SARS must be sent immediately to the hospital, and staff who have had prolonged close contact should be alerted as to the potential symptoms.
Examination of the structure-activity relationships (SARs) of several of the classic stimulants provides not only an understanding of the development of other drugs, but provides important clues as to the underlying mechanisms involved in interaction with the target protein(s). The following sections will hopefully illustrate both of these points.
Ase that share the same tcore structure. Biochemical data obtained from testing these compounds can be used for generating structure-activity relationships (SARs), before synthetic plans are made for lead Optimization (84). In contrast, superstructure Isearches are used to find smaller molecules that jareembedded in the query (Fig.6.14).Oneprob-arises from substructure searches is &at the number of compounds identified can into the thousands. A solution to this iblem is ranking the compounds based on ity to a reference compound. Similarity hes use one or more structural descriptors ft quantifying the similarity between com-iunds in the database and in the query (85,86) . 6.15). A review of descriptors used in simi-ity searches is provided by Willett et al. (86). rond structural similarity, activity similarity
The structure-activity relationship (SAR) of a compound series is a means to relate changes in chemical diversity to the biological actiyity of the compound in uitroand in uiuo, as well as the pharmacokinetic (gut blood brain barrier transit, liver metabolic stability, plasma protein binding, etc.) and toxicological properties of the molecule (119). These SARs, when known, are frequently distinct such that changes that improve the bioavailability of a compound often decrease its activity and or selectivity. Compound optimization is thus a highly iterative and dynamic process.
While the technique of radioligand binding has been largely supplanted by activity-based assays in many high-throughput settings, it remains the gold standard for compound characterization and SAR development. It is done by measuring the RL interaction (Equation 10.1) in uitro using a radioactive ligand, R*, to bind with highly affinity and selectivity to receptor sites. The interaction of unlabeled ( cold ) ligands with the receptor competes with the radioligand, decreasing its binding. This simple technique revolutionized compound evaluation in the 1970s, allowing SARs to be determined with milligram amounts of compound in a highly cost- and resource-effective manner. At steady state, the RL* complex can either be separated out from free radioli-gand using filtration or assayed using a scintillation proximity assay.
UCSC Genome Browser (http genome.ucsc.edu ) This browser contains the reference sequence for the human, C. elegans, and C. briggsae genomes and working drafts for the mouse, rat, fugu, Drosophila, and SARS genomes. It also contains the CFTR (cystic fibro-sis) region in 13 species. The Genome Browser zooms and scrolls over chromosomes showing annotations. The Family Browser shows expression, homology, and other information on groups of genes that can be related in many ways. The Table Browser provides convenient access to the underlying database. The Blat (51) alignment tool (similar to BLAST but structured differently), which quickly maps a sequence to the genome, is also available here.
Gene finding requires the integration of many different signals promoter regions, translation start and stop context sequences, reading frame periodicities, polyadenylation signals, and, for eukaryotes, intron splicing signals, compositional contrast between exons and introns, potential differences in nucleo-some positioning signals, and sequence determinants of topological domains. The last involves the matrix (or scaffold) attachment regions (MARs or SARs), which are associated with higher-order chromosomal organization. The attachment signals may be involved in promoting transcriptional activity in vivo, and have recently been reported to be present between genes. For prokaryotes the DNA sequence also needs to allow strong compaction in a chromatin-like structure. The length of the extended DNA from a single operon corresponds to the diameter of the cell. Since all these signals to a large extent complement each other, in the sense that some may be weak when others are strong, a...
Some problems can be anticipated and should be met with adequate prophylaxis. The genome of immortals would initially encompass a small part of the human genetic pool, a fraction of the biodiversity represented by human beings. Such a pool should be expanded as quickly as possible to offset the possibility of new diseases spreading rapidly among immortals. In the absence of adequate counter measures, new diseases might wipe out the first immortals in a single pandemic.
Usually there are two classes of RNA editing the substitution conversion class and the insertion deletion class. The insertion deletion editing occurs in protozoans like Trypanosoma and Leishmania in slime molds like Physarum spp., and in some viral categories like paramyxoviruses, Ebola virus, etc. To date, the substitution conversion pathway has been observed in humans along with other mammals, Drosophila, and some plants. The RNA-editing processes are known to create diversity in proteins involved in various pathways like lipid transport, metabolism, etc., and may act as potential targets for therapeutic intervention.
Coronaviruses are classified on the basis of several fundamental characteristics, including nucleic acid type, a lipid envelope, and their distinctive morphology 42, 64, 79 . All members have characteristic petal-shaped proteins extending from the virion surface. Coronaviruses infect numerous vertebrate hosts including humans, chickens, pigs, and mice, causing a wide variety of disorders involving a number of different organ systems however, there are specific tropisms for the CNS, lungs, gastrointestinal tract, and liver 42,64,79 . Receptor use among the varied coronaviruses is restricted to several well-defined proteins. Human coronavirus infections result in acute enteritis as well as 15 of common colds indistinguishable from those caused by other viruses 42, 64, 79 . More recently, a human coronavirus has been indicated to be the etiologic agent for severe acute respiratory syndrome (SARS). SARS is a potentially lethal disease and is recognized as a health threat internationally...
5.1.1,2 SARs, Because it was thought that the activity of compound (10) was caused by its metabolic conversion into dapsone, intensive studies have been carried out that vary the structure of the latter to find optimal activity and to improve its low solubility. Various substitutions on the phenyl ring yielded products less active than dapsone. The only product of this type that has some clinical use is acetosulfone sodium, which contains one S02N(Na) C0CH3 group in the ortho position to the sulfone group. Its antibacterial effect seems to be caused by the unchanged drug. Substitutions in both the amino groups gave rise to products that are in general active only if they are converted metabolically into the parent dapsone.
Viruses occupy a unique space between the living and nonliving worlds. On one hand they are made of the same molecules as living cells. On the other hand they are incapable of independent existence, being completely dependent on a host cell to reproduce. Almost all living organisms have viruses that infect them. Human viruses include polio, influenza, herpes, rabies, ebola, smallpox, chickenpox, and the AIDS (acquired immunodeficiency
Alcohols have desirable properties as disinfectants and antiseptics. They are bactericidal, inexpensive, and relatively nontoxic when used topically however, they are more active against vegetative forms than against spores. Structure-activity relationships (SARs) among aliphatic alcohols have been established (36). Bactericidal activity increases as the homologous series of normal alcohols is ascended from methanol through ethanol, propanol, and so on to octanol. The phenol coefficients range from 0.026 for methanol to 21.0 for n-octanol when Salmonella typhosa is the organism. Against Pseudomonas aeruginosa, bactericidal activity of alcohols decreased in the order n-primary i-primary n-secondary tertiary (36).
On March 14, 2003, the WHO issued a global warning to health authorities about a new atypical pneumonia called SARS. The earliest case was believed to have originated in the Guandong province of China on November 16, 2002. The causative agent was identified as a new Corona virus SARS-CoV (80,81). By the end of June 2003, 8422 cases had been reported from 31 different countries, with a total of 916 deaths. Approximately 92 of cases occurred in China (including Hong Kong, Taiwan, and Macao). The case fatality rate varied from less than 1 in people younger than 24 years, 6 in persons aged 25-44 years, 15 in those aged 44-64 years, and more than 50 in persons 65 years or older. On July 5, 2003, the WHO reported that the last human chain of transmission of SARS had been broken and lifted the ban from all countries. However, it warned that everyone should remain vigilant, because a resurgence of SARS is possible. Their warning was well given because in December 2003, a new case of SARS was...
Mostly particular to developingcountries, contribute to confirm this hypothesis war, natural disaster, poverty, malnutrition, demographic changes, increasing antituberculous drug resistance, and expansion of HIV pandemic, especially in Southeast Asia. It is estimated that the global HIV-related tuberculosis cases will increase from 700,000 in 1995 to 1.4 million in 2000 (507, 532).
When it comes to intellectual property rights, governments and academic research institutions are often at odds. In this capacity, they have the potential to be significant negative stakeholders in the pharmaceutical industry. For example, consider the battle for intellectual property rights surrounding the SARS virus. As soon as the virus was identified, several pharmaceutical firms, the U.S. federal government, and researchers associated with academic laboratories in Canada and Hong Kong filed patent applications claiming ownership of the virus. The British Columbia Cancer Agency, the Centers for Disease Control (CDC) in the United States, the biotech company Combimatrix, and the University of Hong Kong's intellectual property unit, Versitech Ltd., are among the groups that vied with the pharmaceutical industry for rights to the virus. The rationale for the patent applications advanced by each applicant ranged from ensuring affordable access to the virus by academic research labs to...
HIV infection is a chronic infection with a variable course. The HIV pandemic has spread to every country in the world and has infected 59 million persons worldwide. It is estimated that more than 20 million people have died from AIDS and its complications. HIV disease is caused by the human retroviruses. HIV-1 and HIV-2. HIV-1 is more common worldwide, whereas HIV-2 has been reported in western Africa. Europe. South America, and Canada.
Important SARs in all the CAA series (and also QSAR for a limited number of compounds) have been established and therefore some fundamental conclusions on an improved general strategy for CAAs design can be drawn. An efficient CAA molecule should incorporate two main structural elements (1) at least one moiety able to shuttle protons between the enzyme active site and the external medium (generally an amino group or a NH imidazole ring), preferably with a pKa value of 6 to 8, and (2) additional polar moieties that ensure a tight binding to the enzyme, of arylsulfonyl, carboxamido, ureido thioureido or substituted pyridinium type. The substitution pattern of such a parent scaffold is an efficient tool for fine-tuning both the energy of binding of the activator molecule to the protein and the pKa of the proton-transferring group, and hence for modulating the intensity of the activating properties. A certain type of in vitro or ex vivo isozyme specificity has also been identified for...
Many drugs when an influenza epidemic swept through the laboratory and altered liver tests and created many adverse events. Placebo use does add data, but without placebos you will have difficulty interpreting data. Did those patients really have drug-induced bizarre dreams, trouble thinking, and penile erections Avoid exsanguinating a patient with unnecessary samples after a placebo dose, but do blind everyone appropriately. Blind the switch from placebo to active drug often subjects anticipate adverse events at this moment.
8 During the influenza pandemic of 1918 a physician to a big factory in a Swedish town prescribed an antipyretic powder containing phenacetin, phenazone (both NSAIDs) and caffeine. Survivors of the epidemic thought they felt fitter and reinvigorated during convalescence if they took the powder and they continued to take it after recovery. Consumption increased and many families 'could not think of beginning the day without a powder. Attractively wrapped packages of powder were often given as birthday presents'. Deaths from renal insufficiency rose in the 'phenacetin town', but not in a similar Swedish town, and in the decade of 1952-61 they were more than 3 times as many. An investigation was resisted by the factory workers to the extent that there was an organised burning of a questionnaire on powder-taking. It was eventually discovered that most of those who used the powders did so, not for pain, but to maintain a high working pace, from 'habit', or to counter fatigue (an effect...
The outstanding antituberculous activity of isoniazid in experimental infections, confirmed by the clinical trials, stimulated the study of chemical modifications of this simple molecule. At least 100 analogs were prepared, but structural changes caused a reduction in or loss of activity. Among the modified forms that retained appreciable activity, the N2-alkyl derivatives should be mentioned. In particular the N2-isopropyl derivative (iproniazid, 23), was found to be active in vivo. Extensive clinical trials proved the therapeutic effectiveness of iproniazid and revealed its psychomotor stimulant effect, caused by the inhibition of monoamine oxidase (176). Use of iproniazid in the treatment cf tuberculosis or of psychotic and neurotic depression was discontinued because of the
As mentioned before, the discovery of isoniazid was the consequence of research based on the weak antitubercular activity of nicotinamide. This lead was pursued in various directions, and among the earliest modifications, thioisonicotin-amide (26) (194-196) seemed to have the in-
Compounds with other substitutions on the pyrazine nucleus or other carboxamido heterocycles were found to be inactive or less active than pyrazinamide. The only active analog developed because of its potential superiority over pyrazinamide was morphazinamide (N-morpholinomethylamide of pyrazinoic acid, 30) (204). Interest in this drug ceased when it was ascertained that the activity and toxicity parallel those of pyrazin-amide, to which morphazinamide is converted in vivo (205). Some pyrazinoic acid esters (206) and some N-pyrazinylthyoureas (207) were found to be more active in vitro against