Internation Marketing Assignment Example | Topics and Well Written Essays - 2250 words

Internation Marketing - Assignment Example While retail stores and other associated channels provide arenas where final transactions take place and consumption begin, the impact of retailing activities on customer demand has largely been ignored in the theory of marketing, with few exceptions such as the late Hollander whose research has continuously proved to be of great contribution to market researchers. Hollander argued that the fundamental of market theory was aimed at understanding how retailers have acted (and still act) as consumption modifiers and gatekeepers. Likewise, Hunt noted in 1983 that marketing study involves the study of exchange behavior and institutional frameworks through which exchange occur. Hunt’s view was that the study should be a fundamental marketing explanda. Within the marketing arena, slow knowledge change on retailing has been achieved. This however should be the case considering the numerous technological and socio-cultural advancements the world continues to witness every passing moment. One exception for the slowness is the historic nature of most marketing research activities. Hollander noted that much study was a historical or highly â€Å"anecdotal†. The call for response to Hollanders challenge was echoed by Alexander in 1997. In Alexanda’s perspective, the importance of retailing and marketing to modern business development cannot be underestimated. Much action needs to be taken in ensuring that theories and frameworks that are developed are beneficial to the growing business world. One area that is of great concern is the issue of ethnocentricity in business and especially in international marketing although it has not been incorporated in previously formulated theories. From the facts discussed above, it is noted that marketing managers and market researchers often fail to take into consideration ethnocentrism in their conceptual frameworks, practice and

Genetic Polymorphism Governing the CYP2D6 Cytrochrome

Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome P450 Enzyme Subfamily in Drug Metabolism I. Abstract The decoding of the human genome has opened up an immense opportunity for further research in designing treatment plans that can be more personalized. The composition of a persons genome varies amongst individuals and also within populations. Individual responses to drug are inherited. The clinical implication of inter-individual variations is implicit in Cytochrome P450 enzymes that are prominent in drug metabolism. Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes. The Cytochrome P450 enzymes have been subjected to numerous evolutionary pressures over time, consequently producing various isoforms. The frequency of variant alleles can alter the pharmacokinetic parameters of the drug, especially of a drug with a narrow therapeutic index. These alleles can either have heightened responses to certain drugs causing toxicity or show very low compliance leading to therapeutic failure. Specifically, CYP2 D6 is known to vary tremendously amongst different ethnic groups. Polymorphism of drug metabolizing enzymes such as CYP2D6 can severely affect the clinical outcome in regards to drug response. CYP2D6 gene is shown to have 74 variant alleles, when expressed in homozygous or heterozygous manners give rise to four distinct phenotypes. In this new era of genomic advancements, there is much hope to decipher variations pertaining to drug metabolism and gear the focus towards individualized medicine. Patient selection can be drastically improved by the employment of genotyping. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Sir William Osler (1849-1919) documented that variability is the law of life, and as no two faces are the same, no two bodies are alike, and no two individuals react alike, and behave alike under the abnormal conditions we know as disease. II. Personalized Medicine and Pharmacogenomics A. Pharmacogenomics The human genome project has it made possible for researchers to comprehend the complexity of biological pathways involved in disease states and focus on variations amongst individuals in regards to drug regimens (Ginsburg and Willard, 2009). The pharmacokinetic aspect of the bodys way of dealing with the drug such as adsorption, distribution, metabolism and elimination of the substrate factors into the variability of individual drug response (Kroemer and Meyer zu Schwabedissen, 2010). The pharmacogenetic variation in absorption and elimination are quite rare compared to the variation seen in drug elimination (Nebert, 1999). According to Nebert et al. (2004) Clinical pharmacology is any particular response seen after a drug is administered. However, this phenotypical drug response is rather ambiguous and has various biological and environmental influences as illustrated in Fig.1, which can lead to a gradient in drug efficacy and toxicity (D. R. Nelson et al., 2004). The phenomenon of genetic variability causing different reactions to drugs has been recognized for awhile as seen in Fig 2 but only recently has the idea become prevalent (March, 2000). In 1902, Sir Archibold Garrard regarded enzymes as vital endogenous biochemical substances required for detoxification in alkaptonuria (Hood, 2003). Sir Archibold Garrard later exemplified the enzyme deficit leading to adverse drug reactions as in born errors of metabolism (Hood, 2003). An inherited difference in tasting ability of phenylthiocarbamide was first discovered by a chemist, Arthur Fox in 1931. Arthur Foxs finding in 1931 on genetic variability was considered a breakthrough finding in the field of pharmacogenetic (Hood, 2003). During World War II, the antimalarial drug such as primaquine showed differing results in Caucasian soldiers compared to the African American soldiers; African American soldiers showed greater occurrences of hemolytic anemia when administered drug (March, 2000). Metabolism as a conce pt became prevalent in mid 19th century when scientists began to decipher the excretory metabolites of consumed substances (Nebert and Vesell, 2004). Pharmacogenomics, the term coined in 1995, focuses on a persons genetic composition, gene and respective gene products, and illustrates how this variability affects drug metabolism (Nebert and Vesell, 2004)(Maria Almira Correia, 2009). The two major aspects of pharmacogenomics are a) To recognize the genes that are affected in a disease state; and b) To focus on the variant alleles that alter our response to the drugs (Wolf, Smith, and Smith, 2000). Figure 1 Factors influencing individual drug response. Reprinted from Pharmacology, pharmacogenetics, and pharmacoepidemiology: three Ps of individualized therapy By S. Dawood , 2009, Cancer Investigation, 27, 809-815 Figure 2 Favism is implicit in certain population that consume fava beans A Greek philosopher Pythagoras first noted this phenomenon that was later found to be associated with acute hemolytic anemia in people who consume the legumes. These people have deficiency in glucose-6-phospahte dehydrogenase and can show altered response to antimalarial drug Reprinted from Pharmacogenomics: the promise of personalized medicine by Hood Emily, 2003, Environ Health Perspect.; Aug;111(11):A581-9. Pharmacogenomics encompasses the whole human genome, DNA, RNA and the associated gene products involved in the study of drug metabolism, drug transport, target proteins (receptor, ion channels, enzymes) and links these gene products to their affects on xenobiotics (Mini and Nobili, 2009). A drug that exhibits reduced efficacy does not always correlate with reduced levels of toxicity since remedial values and noxious side effects of a drug are often exerted via diverse biochemical pathways (Mini and Nobili, 2009). The study of pharmacogenomics, therefore, has vital therapeutic value because most disease states entail some sort of drug treatment (Kroemer and Meyer zu Schwabedissen, 2010). The study of genomics is now made it possible to predict safety, toxicity and efficacy of drugs and opt for a personalized treatment plan by targeting variant alleles (Dawood, 2009). The empirical notion of patients with a certain disease state reacting to drugs homogenously is flawed (Dawood, 2009). This conviction, however, does not account for genetic variation, which unfortunately leads to over 40% of patients either getting the incorrect drug or wrong dosage of the drug (Bordet, Gautier, Le Louet, Dupuis, and Caron, 2001). A Meta analysis study done in 1994, estimated that more than 2 million patients hospitalized in the US had fatalities related to adverse drug reactions (Lazarou, Pomeranz, and Corey, 1998). These results concluded that in 1994, the 106,000 fatalities associated with adverse drug effects ranked between fourth to sixth leading causes of death in the US(Lazarou et al., 1998). Regardless of strict and regulated standards for drug efficacy and prevention of toxicity, adverse drug reactions are prominent and a drug is never equivalently effective on a general population (Roses, 2000). Financially, neither the patients and/or the health insurance companies find it feasible to pay for drugs that are either ineffective or cause adverse effects (Roses, 2000). If a patient has blunted ability to metabolize a drug that is administered to them in normal doses this could easily lead to mortality due to toxic levels of the exogenous substance left in the system (Hood, 2003). Patients react to drugs in a heterogeneous manner compared to the notion of homogenous efficacy, which is particularly imminent in chemotherapeutic drugs (Dawood, 2009). Most chemotherapeutic drugs have narrow therapeutic index and any variability in metabolism of this drug can lead to adverse drug reaction (Dawood, 2009). The approach employed currently often leads to therapeutic failure and waste of time leading to expensive health care costs and valuable time (Hood, 2003). Therapeutic failure related to drug metabolism in diseases such as cancer, psychiatric disorders, and hypertension can be severely detrimental if the drugs do not take effect due to the presence of variantions in enzymes leading to high and low metabolizers (Hood, 2003). Although, genetic variability alon e does not account for all the adverse effects of drugs seen in a patient, pinpointing the altered gene can be beneficial in tailoring a more precise therapy that involves less adverse effects (Hood, 2003). Therefore, understanding the complex interaction of individuals with their environment and underlying genetic variation will allow for a gradual shift from one drug fits all perception to an embodiment of individualized medicine (Dawood, 2009). B. Individualized Medicine Individualized medicine encompasses many attributes such as clinical, genetic, and environmental factors all intertwined in a complex meshwork affecting a disease state (Ginsburg and Willard, 2009). Thorough understanding of these various attributes can aid in development of personalized treatment plans and medication types/dosages leading to an effective patient care, reduction in drug toxicity and increase in drug efficacy (Ginsburg and Willard, 2009). The ultimate goal of the drug is to have the most efficacious and least toxic effect on the patient (Dawood, 2009). However, clinical variables such as drug-drug interaction and metabolism of drug and drug transport show pronounced differences accounting for toxicity (Dawood, 2009). The statistics reveal that a certain drug is known to produce therapeutic effect only in 30% of the patients, whereas 30% of the patient show little or no advantageous effect to the drug, 10% are shown to have only deleterious effects (Maitland-van der Zee, de Boer, and Leufkens, 2000). For example if a patient is on an antidepressant, which usually take two weeks to take effect, predicting drug response for patients with a variant allele is advantageous in regards to predicting efficacy (Kirchheiner and Seeringer, 2007). Predicting drug response poses just as many challenges as do the study of inherited diseases related to genes (McCarthy and Hilfiker, 2000). The variant gene products involved in drug me tabolism are related to regulation at the level of gene expression, post translational modification and drug-drug interaction, all of which affects individual responses to xenobiotics (McCarthy and Hilfiker, 2000).Typically, drug doses are determined by body surface area and for certain group of individuals the systemic exposure is presumed to be homogenous if the surface area is similar The surface area is mainly determined based on height and weight (Dawood, 2009). The variation however stems not necessarily from differences in physical factors but rather from discrepancy in drug metabolism and drug clearance (Galpin and Evans, 1993). Although, systemic monitoring for drugs with low therapeutics indicies has been employed, it still is not efficient enough to prevent therapeutic failure (Nebert and Vesell, 2004). II. Genetic Polymorphism A. Introduction Genetic polymorphism is the variation in allele that is present at a locus and occurs in more than 1% of the population (Phillips, Veenstra, Oren, Lee, and Sadee, 2001). The allele is considered a mutation when it occurs in less than 1% of the population (Mini and Nobili, 2009). The human genome is 3 billion base pair long and the variation in one nucleotide sequence in the DNA occurs in every 100-300 bases (Hood, 2003). Single nucleotide polymorphism (SNP) is the most extensively studied genetic polymorphism, which accounts for most of the variation in drug metabolism (Schmith et al., 2003). The human genome has over 1.4 million single nucleotide polymorphisms 60, 000-100,000 is associated with drug effects ((Dawood, 2009)(Schmith et al., 2003). These SNP can gives rise to polygenic gene variants that can alter the pharmacokinetic and the pharmacodynamic portfolio of a drug leading to innate deviation in metabolism (W. E. Evans and McLeod, 2003). The gene loci that encodes for prote ins involved in drug metabolism are inherently shown to have about 47-61% polymorphism, which in turn correlates to the immense differences in substrate breakdown (Nebert, 1999). Genes that have SNPs in the coding region usually change the amino acid sequence of the protein whereas the SNP in the regulatory region are known to control the concentration of the proteins (McCarthy and Hilfiker, 2000). An exogenous substance relays its effect by interacting either on the cell membrane, cytoplasm or in the plasma (Mini and Nobili, 2009). However, a substance that is known to be efficacious in most individuals can cause detrimental effects in some if they are homozygous for the variant alleles as seen in Fig 3. This variation can affect any of the compartment of interaction a drug asserts its effects (Mini and Nobili, 2009). These alterations can manifest into phenotypes that can cause adverse effects by enhancing or inhibiting normal physiological activity (Mini and Nobili, 2009). The hu man genome project has simplified the identification of roughly 100,000 SNPs in the human genome, which can be employed to acquire accurate information on individual drug responses (Schmith et al., 2003). A haplotype is regarded as a blueprint in which not one but many SNP occur on the same chromosome (Hood, 2003). Although a single SNP may cause altered response to drugs, it is more likely the combination of SNPs on a single chromosome that may play a role in drug metabolism leading to polygenic phenotype (Hood, 2003). In the near future, clinical trials might be required to incorporate genotyping for potential drugs. The cost of genotyping for clinical trials has been predicted to cost approximately 1 million dollars (McCarthy and Hilfiker, 2000). Even though the additional cost to the trial is of concern, the overall end results might provide valuable information on drug metabolism amongst different ethnic groups, which would be beneficial in the long run. Characterization of genes of enzymes involved in drug metabolism are shown to have considerable variations; about 3 to 10 variant alleles are considered to be of the common type and over 12 to 100 variant alleles that are uncommon and occur rarely (Nebert and Vesell, 2004). Initially, when the Human Genome Project was undertaken, there was little concern about the difference in sequencing of chromosome amongst different ethnic groups (Nebert, 1999). Most scientists at the time believed there would be no substantial discrepancy between chromosomes of an individual who is of an Asian descent compared to an individual of European descent (Nebert, 1999). Graham and Smith in the 1999 study showed that there is significant variation in drug metabolism amongst individuals of different ethnic backgrounds, which effects the pharmacokinetic variability of the enzyme that are involved in drug metabolism (Graham and Peterson, 1999)(Maitland-van der Zee et al., 2000). Recent study on Asian, White s and Blacks showed that different ethnic populations differ in the frequency of alleles of a gene and this variant can result in altered drug responses (Limdi et al., 2010). The functional consequence on drug metabolism of the variant allele depends on the extension of mutation and frequency of occurrence in an individual subgroup (Maitland-van der Zee et al., 2000). To establish an accurate overall picture of variant alleles in different ethnic subgroups, an extensive SNP genotyping is needed, with an average group size of 1000 individuals in each subgroup (Nebert, 1999). The information derived from this can then be utilized for an extensive genotype-phenotype linkage study (Nebert, 1999). Figure 3 Polymorphism affecting the concentration of a drug leading to toxic doses and low efficacy in individuals who are homozygous for the variant gene. Reprinted from Pharmacogenetics: implementing personalized medicine By Enrico Mini; Stefania Nobili, Clinical Cases in Mineral and Bone Metabolism 2009; 6(1): 17-24 B. Adverse Drug Reaction Drug-drug interactions are common when numerous drugs are ingested simultaneously (Wolf et al., 2000). These drug-drug interactions can induce or inhibit enzymes in the common pathway of metabolism causing adverse effects (Oesch, 2009). An individual who has reduced ability to metabolize a substrate can easily accumulate the drug if an alternative route is not accessible (Oesch, 2009). The pharmacokinetic differences in individuals can cause poor metabolizers to have increased amounts of systemic exposure to the drug and fast metabolizers having less than normal amounts resulting in therapeutic failure or even toxicity. (Bailey, Bondar, and Furness, 1998). Comprehending this inherited genetic variability in drug metabolism can herald a new era in individualized therapy (Dawood, 2009)(Oesch, 2009)(Wolf et al., 2000). Study of pharmacogenomics allows for ways to reduce adverse drug reactions by identifying the nature of the drug, reaction to the drug and metabolic targets of the drug ( Phillips et al., 2001). All of the above can be utilized to create an extensive biomarker, which can then be employed by physicians to make appropriate dosing changes for individuals with variant alleles (Ginsburg, Konstance, Allsbrook, and Schulman, 2005). Alternatively, if reducing the dose is not a viable option, physicians can alter the treatment to include drugs that can by pass the deficient biochemical pathway (Ginsburg et al., 2005; Phillips et al., 2001). In order to utilize genotyping as a beneficial tool, physicians need to quantify variant drug responses to the specific gene unambiguously (Nebert, 1999). It is imperative that the candidate locus that is affected by the drug is identified and positive tests are employed for the variant alleles (Holmes et al., 2009). The Genetic polymorphism plays a major role in drug efficacy and also in adverse drug reactions (Dawood, 2009). Pharmacogenomic studies are hard to conduct because the variation in drug metabolism is only known after the administration of the exogenous substance, as compared to inherited diseases which have clear family linkage (McCarthy and Hilfiker, 2000). It is highly unlikely that an entire family would be prescribed a certain drug at the same time so the variation in the allele is only known under clinical trials (McCarthy and Hilfiker, 2000). SNP profiling can be beneficial if it can predict the drug response in patients and the demographics of people affected (McCarthy and Hilfiker, 2000). For example, a study by Drazen in 1999 showed that variation in ALOX5 was correlated 100% of the time with patients being non-receptive to an antiasthmatic drug (Drazen et. al, 1999). However, the prevalence of the non-variant gene in ALOX5 occurs in only 6-10 % of the patients; therefore, for a drug to be efficacious, the percent frequency of variant allele needs to be determined (Drazen et. al, 1999;McCarthy and Hilfiker, 2000). The major questions to be addressed then is how prevalent is the variant gene? How often are patients in a certain demographic group prescribed a drug that can cause adverse effects (Maitland-van der Zee et al., 2000)? A potential drug is marketed and distributed worldwide, however, most of the clinical trials are never encompass a broad range of population and most polymorphisms go undetected (McCarthy and Hilfiker, 2000). The clinical trials mainly consist of the Caucasian population in America and Europe, but a wider range of population is needed to pinpoint major variation amongst different ethnic groups (McCarthy and Hilfiker, 2000). Consequently, polymorphisms that are relevant in certain populations need to be studied and the target must be to address variant genes that are prevalent in drug metabolism (Maitland-van der Zee et al., 2000). Currently, there is little to no information on most of the drugs that are already in the market regarding genetic variability in drug metabolism (Maitland-van der Zee et al., 2000). In the future, potential drugs should include such population based studies in their clinical trials so fewer drugs would conform to one drug fits all motto (Maitland-van der Z ee et al., 2000). Polymorphism profiling can have major implication in drug safety because a drug that poses adverse effects on a large subgroup could be restricted from being launched into the market (Ginsburg et al., 2005). Genotyping can permit physicians to detect different polymorphism in individuals and allow them to create drug regimens that are not only efficacious but pose least toxic effects (Oesch, 2009). Preferential genotyping by clinicians for variant alleles could drastically reduce drug related adverse effects and in turn will be economically feasible and productive in the long run (March, 2000; Nebert and Vesell, 2004). Patient selection could be drastically improved by employment of genotyping. C. When is Genotyping Appropriate? Most drug targets are not key candidates for genotyping (Kirchheiner and Seeringer, 2007). The blood sample is collected from the patient after a day or two of administration of the drug. Therefore, drugs that require an immediate attention to dose adjustment or drugs that have a high therapeutic index may not be feasible for genotyping (Kirchheiner and Seeringer, 2007). In addition drugs that are metabolized via more than one overlying biochemical pathway pose extreme difficulties in pinpointing the variant allele and do not benefit from genotyping. However there are enzymes that have variant alleles such as the Cytochrome P450 enzymes which metabolize drugs such as warfarin, morphine, tamoxifen etc. and this polymorphism can lead to altered response to a drug (Kirchheiner and Seeringer, 2007). Adjusting the dose based on plasma level concentration of the drug is not always adequate for these patients (Dawood, 2009). Genotyping in these cases can lead to increased efficacy by identi fication of polymorphism, which can reduce the costly and time-consuming dose adjustment period. For example, CYP2D6 is a major enzyme involved in the breakdown of antidepressants. The therapeutic effects of antidepressants are only seen after a few weeks of treatment (Kirchheiner and Seeringer, 2007). Therefore, if a patient is a poor metabolizer they will accumulate the drug vs. a person who is an ultra rapid metabolizer, who will show no therapeutic value. In the case of antidepressants, genotyping for the CYP2D6 polymorphism may be beneficial prior to the start of therapy. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Pharmacogenetic disciplines if employed in pharmaceutical industry can aid in development of drugs that cater to the individual; this will allow for prospective drugs to be well suited for fewer people in comparison to drugs that assert mediocre efficacy in a vast group of individual. Food and Drug administration in 2004 permitted the employment of Chip technology known as AmpliChip by Rosche for identification of variant genes in the Cytochrome P450 pathway (http://www.roche-diagnostics.us/press_room/2005/011105.htm); (Ginsburg et al., 2005) Companies like Genelex Corporation of Seattle, Washington and Gentris are now enabling pharmaceutical companies and patients respectively to utilize Cytochrome P450 genotype profiling for CYP 2D6, CYP 2C9 and CYP2C19 enzymes (Hood, 2003). The marriage of genetics and medicine is going to become promine nt in the years to come and by the year 2020 pharmacogenomics will become a vital tool utilized to market drugs. The information derived from these test will allow patients to be on customized designer drugs(Collins and McKusick, 2001), allow physicians to set appropriate prescription amount for initial dosing and establish monitoring system for individuals with variant alleles (Tweardy and Belmont, 2009). III Cytochrome P450 Enzyme A. Background Variant alleles that lead to functional changes of gene product can have therapeutic consequences. These alleles can either have heightened responses to certain drugs causing toxicity or show none to very low compliance (Wolf et al., 2000). Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes (CYP) (Wolf et al., 2000). Cytochrome P450 enzymes are involved in metabolism of over 60% of drugs currently in the market today (Hood, 2003). Polymorphisms in the CYP enzymes are known to alter the pharmacokinetic aspects of exogenous substances affecting mainly the biotransformation of the substance (Kirchheiner and Seeringer, 2007). Polymorphism of the Cytochrome P450 enzyme was first discovered in relation to debrisoquine, a hypertension-correcting drug (March, 2000). Bob Smith, of Imperial College in London ingested debrisoquine and experienced severe hypotension after administration. In addition, his blood levels showed 20 fold decreased levels of drug metabolite compared to his colleagues (March, 2000; Nebert 1997). In 1988, Gonzalez and his group characterized and showed that the gene product that was causing the altered response to debrisoquine as CYP2D6; it was also found to be a liver microsomal enzyme. The cloning of this microsomal enzyme was the first look at genetic polymorphism at the molecular level (Gonzalez et al., 1988; Mini and Nobili, 2009). The study by Gonzales et al. and his group paved way for further studies geared to identify genetic polymorphism in a population that linked variant genes to alteration in drug metabolism and drug response (Mini and Nobili, 2009). Cytochrome P450s are mainly found in endoplasmic reticulum and in the mitochondria of a cell, and are copious in the liver (Porter and Coon, 1991). The CYP enzymes consist of about 49 genes that function primarily in drug metabolism (Maitland-van der Zee et al., 2000; Porter and Coon, 1991). In humans the CYP enzymes are major constituents in metabolism of fatty acids, prostoglandins, steroids and xenobiotics (Graham and Peterson, 1999). Daily diet intake of mammals consists of many natural products such as terpenes, steroids, and alkoloids and the CYP enzymes are major catalysts in the biotransformation and breakdown of these exogenous substances (Guengerich, 1991). Cytochrome P450 enzymes comprise of a super family of gene that encompass proteins predominantly involved in metabolizing of xenobiotics as well as endogenous substrates such as steroids, fatty acids, prostaglandins and arachidonate metabolites as shown in Table 1, therefore genetic polymorphism in the CYP enzymes can lead to many health related risks such as hypertension and cancer (Graham and Peterson, 1999; Jiang et al., 2005; Mayer et al., 2005). CYP enzymes are monooxygenases that catalyze non-specific oxidations of many substrates (Guengerich, 1991), (Porter and Coon, 1991). The synthetic exogenous substrates of t he cytochrome enzymes range to approximately 200,000 entities, which can all have complex interplay amongst each other in inducing or inhibiting the various isoforms of the CYP enzymes (Porter and Coon, 1991). These enzymes however are capable of catalyzing novel substrates as well and therefore one cannot cap an upper limit on the number of possible potential substrates (Porter and Coon, 1991). Therefore, the evolutionary advantage in the immensity of the CYP isoform is a crucial survival tool for our cultivating environment as well as our dynamically changing physiological system. Table 1. Exogenous and endogenous substrates of Cytochrome P450 enzymes The substrate for the CYP enzymes are just as diverse for endogenous substance as they are for exogenous substances. The CYP enzymes are prominent catalytic enzymes involved in biotransformation of various substances. Reprinted from Miniereview: Cytochrome P450 By Todd D. Porter and Minor J. Coon, The Journal of Biological Chemistry, 1991; 266(21): 13649-13472 The rates of catalyzation of the CYP enzymes are relatively slow and this can provide further explanation into their pivotal role in drug disposition (Guengerich, 1991). In addition, most of the CYP enzymes are involved in rate-limiting steps of drug metabolism and this is a key determinant of the in vivo kinetics of the drug (Pelkonen, 2002). CYP enzymes are key players in the systemic exposure of a drug and the time period a drug can assert its action (Brockmoller, Kirchheiner, Meisel, and Roots, 2000). The CYP enzymes are involved in either forming the active metabolite of the drug from a prodrug or in metabolizing the drug into inactive by-products,both of which can influence the functional temporal aspect of a drug (Brockmoller et al., 2000). Metabolites created by the CYP enzymes can also be toxic; exerting their own mutagenic and allergenic effects (Brockmoller et al., 2000). The FDA requires pharmaceutical companies to identify on the product brochure one of twenty CYP enzyme s that are involved in the biotransformation of the drug (Brockmoller et al., 2000). Interactions of different drugs concerning CYP enzymes are good predictor of drug-drug interaction, therefore marketed drugs are required to indicate the CYP enzyme involved in biotransformation of the drug on the product information (Andersson, 1991)(Brockmoller et al., 2000). However, this information does not include the polymorphism prominent within these CYP enzymes. The need for such information is crucial since these enzymes are notorious for genetic polymorphism (Brockmoller et al., 2000). Functional variations in the CYP enzymes are known to show a gradient in efficacy and variation in the quantity of the substrate present in the subject (Maitland-van der Zee et al., 2000; Wolf et al., 2000). Allelic variants causing poor, fast and ultrarapid metabolizing enzymes have been identified in most of the CYP enzymes. Most of the CYP enzymes in the liver show some degree of polymorphism (Anzenbach erova et al., 2000). B. Cytochrome Gene Family Evolution CYP enzymes are ubiquitous as they are found in every domain of living organism from Bacteria, Archaea and Eukarya and known to have originated from an ancestral gene approximately three and half billion years ago. The modern cytochrome probably originated with the Prokaryotes 1.5 billion years before the prevalence of atmospheric oxygen (Graham and Peterson, 1999; Nebert and Gonzalez, 1987; Werck-Reichhart and Feyereisen, 2000). In early eukaryotes, these enzymes not only maintained membrane veracity but also were primarily involved in the biosynthesis of endogenous hydrophobic substances such as fatty acids, cholesterol (Nebert and Gonzalez, 1987). The CYP mutilgene family diverged again 900 hundred million years later giving rise to enzymes predominantly involved in biosynthesis of steroids (Nebert and Gonzalez, 1987). This expansion lead to the another divergence of the two most important mammalian CYP families implicit in drug and carcinogen metabolizing enzymes currently known as CYP1 and CYP2 gene family (Nebert and Gonzalez, 1987). Finally, 400 million years ago dramatic expansion ensued primarily in CYP2, CYP3 and CYP4 families (Nebert and Gonzalez, 1987). This current expansion correlates to the time frame when aquatic animals merged onto the terrestrial land and were exposed to many hydrocarbon-based combustion material in the environment along with toxic plant products in their diet (Gonzalez and Nebert, 1990; D. R. Nelson and Strobel, 1987) The generation of this multigene family is due to the multiple mechanistic changes over time that reflect the complexity and diversity of the CYP enzymes. Most of the changes are related to lack of intron conservation (Werck-Reichhart and Feyereisen, 2000), exon shuffling (Doolittle, 1985; Patthy, 1985), expression of redundant genes (Anderson et al., 1981; Barrell, Air, and Hutchison, 1976), alternative splicing, frame shit mutations and RNA editing (Andreadis, Gallego, and Nadal-Ginard, 1987; Atkins, Weiss, Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome P450 Enzyme Subfamily in Drug Metabolism I. Abstract The decoding of the human genome has opened up an immense opportunity for further research in designing treatment plans that can be more personalized. The composition of a persons genome varies amongst individuals and also within populations. Individual responses to drug are inherited. The clinical implication of inter-individual variations is implicit in Cytochrome P450 enzymes that are prominent in drug metabolism. Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes. The Cytochrome P450 enzymes have been subjected to numerous evolutionary pressures over time, consequently producing various isoforms. The frequency of variant alleles can alter the pharmacokinetic parameters of the drug, especially of a drug with a narrow therapeutic index. These alleles can either have heightened responses to certain drugs causing toxicity or show very low compliance leading to therapeutic failure. Specifically, CYP2 D6 is known to vary tremendously amongst different ethnic groups. Polymorphism of drug metabolizing enzymes such as CYP2D6 can severely affect the clinical outcome in regards to drug response. CYP2D6 gene is shown to have 74 variant alleles, when expressed in homozygous or heterozygous manners give rise to four distinct phenotypes. In this new era of genomic advancements, there is much hope to decipher variations pertaining to drug metabolism and gear the focus towards individualized medicine. Patient selection can be drastically improved by the employment of genotyping. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Sir William Osler (1849-1919) documented that variability is the law of life, and as no two faces are the same, no two bodies are alike, and no two individuals react alike, and behave alike under the abnormal conditions we know as disease. II. Personalized Medicine and Pharmacogenomics A. Pharmacogenomics The human genome project has it made possible for researchers to comprehend the complexity of biological pathways involved in disease states and focus on variations amongst individuals in regards to drug regimens (Ginsburg and Willard, 2009). The pharmacokinetic aspect of the bodys way of dealing with the drug such as adsorption, distribution, metabolism and elimination of the substrate factors into the variability of individual drug response (Kroemer and Meyer zu Schwabedissen, 2010). The pharmacogenetic variation in absorption and elimination are quite rare compared to the variation seen in drug elimination (Nebert, 1999). According to Nebert et al. (2004) Clinical pharmacology is any particular response seen after a drug is administered. However, this phenotypical drug response is rather ambiguous and has various biological and environmental influences as illustrated in Fig.1, which can lead to a gradient in drug efficacy and toxicity (D. R. Nelson et al., 2004). The phenomenon of genetic variability causing different reactions to drugs has been recognized for awhile as seen in Fig 2 but only recently has the idea become prevalent (March, 2000). In 1902, Sir Archibold Garrard regarded enzymes as vital endogenous biochemical substances required for detoxification in alkaptonuria (Hood, 2003). Sir Archibold Garrard later exemplified the enzyme deficit leading to adverse drug reactions as in born errors of metabolism (Hood, 2003). An inherited difference in tasting ability of phenylthiocarbamide was first discovered by a chemist, Arthur Fox in 1931. Arthur Foxs finding in 1931 on genetic variability was considered a breakthrough finding in the field of pharmacogenetic (Hood, 2003). During World War II, the antimalarial drug such as primaquine showed differing results in Caucasian soldiers compared to the African American soldiers; African American soldiers showed greater occurrences of hemolytic anemia when administered drug (March, 2000). Metabolism as a conce pt became prevalent in mid 19th century when scientists began to decipher the excretory metabolites of consumed substances (Nebert and Vesell, 2004). Pharmacogenomics, the term coined in 1995, focuses on a persons genetic composition, gene and respective gene products, and illustrates how this variability affects drug metabolism (Nebert and Vesell, 2004)(Maria Almira Correia, 2009). The two major aspects of pharmacogenomics are a) To recognize the genes that are affected in a disease state; and b) To focus on the variant alleles that alter our response to the drugs (Wolf, Smith, and Smith, 2000). Figure 1 Factors influencing individual drug response. Reprinted from Pharmacology, pharmacogenetics, and pharmacoepidemiology: three Ps of individualized therapy By S. Dawood , 2009, Cancer Investigation, 27, 809-815 Figure 2 Favism is implicit in certain population that consume fava beans A Greek philosopher Pythagoras first noted this phenomenon that was later found to be associated with acute hemolytic anemia in people who consume the legumes. These people have deficiency in glucose-6-phospahte dehydrogenase and can show altered response to antimalarial drug Reprinted from Pharmacogenomics: the promise of personalized medicine by Hood Emily, 2003, Environ Health Perspect.; Aug;111(11):A581-9. Pharmacogenomics encompasses the whole human genome, DNA, RNA and the associated gene products involved in the study of drug metabolism, drug transport, target proteins (receptor, ion channels, enzymes) and links these gene products to their affects on xenobiotics (Mini and Nobili, 2009). A drug that exhibits reduced efficacy does not always correlate with reduced levels of toxicity since remedial values and noxious side effects of a drug are often exerted via diverse biochemical pathways (Mini and Nobili, 2009). The study of pharmacogenomics, therefore, has vital therapeutic value because most disease states entail some sort of drug treatment (Kroemer and Meyer zu Schwabedissen, 2010). The study of genomics is now made it possible to predict safety, toxicity and efficacy of drugs and opt for a personalized treatment plan by targeting variant alleles (Dawood, 2009). The empirical notion of patients with a certain disease state reacting to drugs homogenously is flawed (Dawood, 2009). This conviction, however, does not account for genetic variation, which unfortunately leads to over 40% of patients either getting the incorrect drug or wrong dosage of the drug (Bordet, Gautier, Le Louet, Dupuis, and Caron, 2001). A Meta analysis study done in 1994, estimated that more than 2 million patients hospitalized in the US had fatalities related to adverse drug reactions (Lazarou, Pomeranz, and Corey, 1998). These results concluded that in 1994, the 106,000 fatalities associated with adverse drug effects ranked between fourth to sixth leading causes of death in the US(Lazarou et al., 1998). Regardless of strict and regulated standards for drug efficacy and prevention of toxicity, adverse drug reactions are prominent and a drug is never equivalently effective on a general population (Roses, 2000). Financially, neither the patients and/or the health insurance companies find it feasible to pay for drugs that are either ineffective or cause adverse effects (Roses, 2000). If a patient has blunted ability to metabolize a drug that is administered to them in normal doses this could easily lead to mortality due to toxic levels of the exogenous substance left in the system (Hood, 2003). Patients react to drugs in a heterogeneous manner compared to the notion of homogenous efficacy, which is particularly imminent in chemotherapeutic drugs (Dawood, 2009). Most chemotherapeutic drugs have narrow therapeutic index and any variability in metabolism of this drug can lead to adverse drug reaction (Dawood, 2009). The approach employed currently often leads to therapeutic failure and waste of time leading to expensive health care costs and valuable time (Hood, 2003). Therapeutic failure related to drug metabolism in diseases such as cancer, psychiatric disorders, and hypertension can be severely detrimental if the drugs do not take effect due to the presence of variantions in enzymes leading to high and low metabolizers (Hood, 2003). Although, genetic variability alon e does not account for all the adverse effects of drugs seen in a patient, pinpointing the altered gene can be beneficial in tailoring a more precise therapy that involves less adverse effects (Hood, 2003). Therefore, understanding the complex interaction of individuals with their environment and underlying genetic variation will allow for a gradual shift from one drug fits all perception to an embodiment of individualized medicine (Dawood, 2009). B. Individualized Medicine Individualized medicine encompasses many attributes such as clinical, genetic, and environmental factors all intertwined in a complex meshwork affecting a disease state (Ginsburg and Willard, 2009). Thorough understanding of these various attributes can aid in development of personalized treatment plans and medication types/dosages leading to an effective patient care, reduction in drug toxicity and increase in drug efficacy (Ginsburg and Willard, 2009). The ultimate goal of the drug is to have the most efficacious and least toxic effect on the patient (Dawood, 2009). However, clinical variables such as drug-drug interaction and metabolism of drug and drug transport show pronounced differences accounting for toxicity (Dawood, 2009). The statistics reveal that a certain drug is known to produce therapeutic effect only in 30% of the patients, whereas 30% of the patient show little or no advantageous effect to the drug, 10% are shown to have only deleterious effects (Maitland-van der Zee, de Boer, and Leufkens, 2000). For example if a patient is on an antidepressant, which usually take two weeks to take effect, predicting drug response for patients with a variant allele is advantageous in regards to predicting efficacy (Kirchheiner and Seeringer, 2007). Predicting drug response poses just as many challenges as do the study of inherited diseases related to genes (McCarthy and Hilfiker, 2000). The variant gene products involved in drug me tabolism are related to regulation at the level of gene expression, post translational modification and drug-drug interaction, all of which affects individual responses to xenobiotics (McCarthy and Hilfiker, 2000).Typically, drug doses are determined by body surface area and for certain group of individuals the systemic exposure is presumed to be homogenous if the surface area is similar The surface area is mainly determined based on height and weight (Dawood, 2009). The variation however stems not necessarily from differences in physical factors but rather from discrepancy in drug metabolism and drug clearance (Galpin and Evans, 1993). Although, systemic monitoring for drugs with low therapeutics indicies has been employed, it still is not efficient enough to prevent therapeutic failure (Nebert and Vesell, 2004). II. Genetic Polymorphism A. Introduction Genetic polymorphism is the variation in allele that is present at a locus and occurs in more than 1% of the population (Phillips, Veenstra, Oren, Lee, and Sadee, 2001). The allele is considered a mutation when it occurs in less than 1% of the population (Mini and Nobili, 2009). The human genome is 3 billion base pair long and the variation in one nucleotide sequence in the DNA occurs in every 100-300 bases (Hood, 2003). Single nucleotide polymorphism (SNP) is the most extensively studied genetic polymorphism, which accounts for most of the variation in drug metabolism (Schmith et al., 2003). The human genome has over 1.4 million single nucleotide polymorphisms 60, 000-100,000 is associated with drug effects ((Dawood, 2009)(Schmith et al., 2003). These SNP can gives rise to polygenic gene variants that can alter the pharmacokinetic and the pharmacodynamic portfolio of a drug leading to innate deviation in metabolism (W. E. Evans and McLeod, 2003). The gene loci that encodes for prote ins involved in drug metabolism are inherently shown to have about 47-61% polymorphism, which in turn correlates to the immense differences in substrate breakdown (Nebert, 1999). Genes that have SNPs in the coding region usually change the amino acid sequence of the protein whereas the SNP in the regulatory region are known to control the concentration of the proteins (McCarthy and Hilfiker, 2000). An exogenous substance relays its effect by interacting either on the cell membrane, cytoplasm or in the plasma (Mini and Nobili, 2009). However, a substance that is known to be efficacious in most individuals can cause detrimental effects in some if they are homozygous for the variant alleles as seen in Fig 3. This variation can affect any of the compartment of interaction a drug asserts its effects (Mini and Nobili, 2009). These alterations can manifest into phenotypes that can cause adverse effects by enhancing or inhibiting normal physiological activity (Mini and Nobili, 2009). The hu man genome project has simplified the identification of roughly 100,000 SNPs in the human genome, which can be employed to acquire accurate information on individual drug responses (Schmith et al., 2003). A haplotype is regarded as a blueprint in which not one but many SNP occur on the same chromosome (Hood, 2003). Although a single SNP may cause altered response to drugs, it is more likely the combination of SNPs on a single chromosome that may play a role in drug metabolism leading to polygenic phenotype (Hood, 2003). In the near future, clinical trials might be required to incorporate genotyping for potential drugs. The cost of genotyping for clinical trials has been predicted to cost approximately 1 million dollars (McCarthy and Hilfiker, 2000). Even though the additional cost to the trial is of concern, the overall end results might provide valuable information on drug metabolism amongst different ethnic groups, which would be beneficial in the long run. Characterization of genes of enzymes involved in drug metabolism are shown to have considerable variations; about 3 to 10 variant alleles are considered to be of the common type and over 12 to 100 variant alleles that are uncommon and occur rarely (Nebert and Vesell, 2004). Initially, when the Human Genome Project was undertaken, there was little concern about the difference in sequencing of chromosome amongst different ethnic groups (Nebert, 1999). Most scientists at the time believed there would be no substantial discrepancy between chromosomes of an individual who is of an Asian descent compared to an individual of European descent (Nebert, 1999). Graham and Smith in the 1999 study showed that there is significant variation in drug metabolism amongst individuals of different ethnic backgrounds, which effects the pharmacokinetic variability of the enzyme that are involved in drug metabolism (Graham and Peterson, 1999)(Maitland-van der Zee et al., 2000). Recent study on Asian, White s and Blacks showed that different ethnic populations differ in the frequency of alleles of a gene and this variant can result in altered drug responses (Limdi et al., 2010). The functional consequence on drug metabolism of the variant allele depends on the extension of mutation and frequency of occurrence in an individual subgroup (Maitland-van der Zee et al., 2000). To establish an accurate overall picture of variant alleles in different ethnic subgroups, an extensive SNP genotyping is needed, with an average group size of 1000 individuals in each subgroup (Nebert, 1999). The information derived from this can then be utilized for an extensive genotype-phenotype linkage study (Nebert, 1999). Figure 3 Polymorphism affecting the concentration of a drug leading to toxic doses and low efficacy in individuals who are homozygous for the variant gene. Reprinted from Pharmacogenetics: implementing personalized medicine By Enrico Mini; Stefania Nobili, Clinical Cases in Mineral and Bone Metabolism 2009; 6(1): 17-24 B. Adverse Drug Reaction Drug-drug interactions are common when numerous drugs are ingested simultaneously (Wolf et al., 2000). These drug-drug interactions can induce or inhibit enzymes in the common pathway of metabolism causing adverse effects (Oesch, 2009). An individual who has reduced ability to metabolize a substrate can easily accumulate the drug if an alternative route is not accessible (Oesch, 2009). The pharmacokinetic differences in individuals can cause poor metabolizers to have increased amounts of systemic exposure to the drug and fast metabolizers having less than normal amounts resulting in therapeutic failure or even toxicity. (Bailey, Bondar, and Furness, 1998). Comprehending this inherited genetic variability in drug metabolism can herald a new era in individualized therapy (Dawood, 2009)(Oesch, 2009)(Wolf et al., 2000). Study of pharmacogenomics allows for ways to reduce adverse drug reactions by identifying the nature of the drug, reaction to the drug and metabolic targets of the drug ( Phillips et al., 2001). All of the above can be utilized to create an extensive biomarker, which can then be employed by physicians to make appropriate dosing changes for individuals with variant alleles (Ginsburg, Konstance, Allsbrook, and Schulman, 2005). Alternatively, if reducing the dose is not a viable option, physicians can alter the treatment to include drugs that can by pass the deficient biochemical pathway (Ginsburg et al., 2005; Phillips et al., 2001). In order to utilize genotyping as a beneficial tool, physicians need to quantify variant drug responses to the specific gene unambiguously (Nebert, 1999). It is imperative that the candidate locus that is affected by the drug is identified and positive tests are employed for the variant alleles (Holmes et al., 2009). The Genetic polymorphism plays a major role in drug efficacy and also in adverse drug reactions (Dawood, 2009). Pharmacogenomic studies are hard to conduct because the variation in drug metabolism is only known after the administration of the exogenous substance, as compared to inherited diseases which have clear family linkage (McCarthy and Hilfiker, 2000). It is highly unlikely that an entire family would be prescribed a certain drug at the same time so the variation in the allele is only known under clinical trials (McCarthy and Hilfiker, 2000). SNP profiling can be beneficial if it can predict the drug response in patients and the demographics of people affected (McCarthy and Hilfiker, 2000). For example, a study by Drazen in 1999 showed that variation in ALOX5 was correlated 100% of the time with patients being non-receptive to an antiasthmatic drug (Drazen et. al, 1999). However, the prevalence of the non-variant gene in ALOX5 occurs in only 6-10 % of the patients; therefore, for a drug to be efficacious, the percent frequency of variant allele needs to be determined (Drazen et. al, 1999;McCarthy and Hilfiker, 2000). The major questions to be addressed then is how prevalent is the variant gene? How often are patients in a certain demographic group prescribed a drug that can cause adverse effects (Maitland-van der Zee et al., 2000)? A potential drug is marketed and distributed worldwide, however, most of the clinical trials are never encompass a broad range of population and most polymorphisms go undetected (McCarthy and Hilfiker, 2000). The clinical trials mainly consist of the Caucasian population in America and Europe, but a wider range of population is needed to pinpoint major variation amongst different ethnic groups (McCarthy and Hilfiker, 2000). Consequently, polymorphisms that are relevant in certain populations need to be studied and the target must be to address variant genes that are prevalent in drug metabolism (Maitland-van der Zee et al., 2000). Currently, there is little to no information on most of the drugs that are already in the market regarding genetic variability in drug metabolism (Maitland-van der Zee et al., 2000). In the future, potential drugs should include such population based studies in their clinical trials so fewer drugs would conform to one drug fits all motto (Maitland-van der Z ee et al., 2000). Polymorphism profiling can have major implication in drug safety because a drug that poses adverse effects on a large subgroup could be restricted from being launched into the market (Ginsburg et al., 2005). Genotyping can permit physicians to detect different polymorphism in individuals and allow them to create drug regimens that are not only efficacious but pose least toxic effects (Oesch, 2009). Preferential genotyping by clinicians for variant alleles could drastically reduce drug related adverse effects and in turn will be economically feasible and productive in the long run (March, 2000; Nebert and Vesell, 2004). Patient selection could be drastically improved by employment of genotyping. C. When is Genotyping Appropriate? Most drug targets are not key candidates for genotyping (Kirchheiner and Seeringer, 2007). The blood sample is collected from the patient after a day or two of administration of the drug. Therefore, drugs that require an immediate attention to dose adjustment or drugs that have a high therapeutic index may not be feasible for genotyping (Kirchheiner and Seeringer, 2007). In addition drugs that are metabolized via more than one overlying biochemical pathway pose extreme difficulties in pinpointing the variant allele and do not benefit from genotyping. However there are enzymes that have variant alleles such as the Cytochrome P450 enzymes which metabolize drugs such as warfarin, morphine, tamoxifen etc. and this polymorphism can lead to altered response to a drug (Kirchheiner and Seeringer, 2007). Adjusting the dose based on plasma level concentration of the drug is not always adequate for these patients (Dawood, 2009). Genotyping in these cases can lead to increased efficacy by identi fication of polymorphism, which can reduce the costly and time-consuming dose adjustment period. For example, CYP2D6 is a major enzyme involved in the breakdown of antidepressants. The therapeutic effects of antidepressants are only seen after a few weeks of treatment (Kirchheiner and Seeringer, 2007). Therefore, if a patient is a poor metabolizer they will accumulate the drug vs. a person who is an ultra rapid metabolizer, who will show no therapeutic value. In the case of antidepressants, genotyping for the CYP2D6 polymorphism may be beneficial prior to the start of therapy. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Pharmacogenetic disciplines if employed in pharmaceutical industry can aid in development of drugs that cater to the individual; this will allow for prospective drugs to be well suited for fewer people in comparison to drugs that assert mediocre efficacy in a vast group of individual. Food and Drug administration in 2004 permitted the employment of Chip technology known as AmpliChip by Rosche for identification of variant genes in the Cytochrome P450 pathway (http://www.roche-diagnostics.us/press_room/2005/011105.htm); (Ginsburg et al., 2005) Companies like Genelex Corporation of Seattle, Washington and Gentris are now enabling pharmaceutical companies and patients respectively to utilize Cytochrome P450 genotype profiling for CYP 2D6, CYP 2C9 and CYP2C19 enzymes (Hood, 2003). The marriage of genetics and medicine is going to become promine nt in the years to come and by the year 2020 pharmacogenomics will become a vital tool utilized to market drugs. The information derived from these test will allow patients to be on customized designer drugs(Collins and McKusick, 2001), allow physicians to set appropriate prescription amount for initial dosing and establish monitoring system for individuals with variant alleles (Tweardy and Belmont, 2009). III Cytochrome P450 Enzyme A. Background Variant alleles that lead to functional changes of gene product can have therapeutic consequences. These alleles can either have heightened responses to certain drugs causing toxicity or show none to very low compliance (Wolf et al., 2000). Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes (CYP) (Wolf et al., 2000). Cytochrome P450 enzymes are involved in metabolism of over 60% of drugs currently in the market today (Hood, 2003). Polymorphisms in the CYP enzymes are known to alter the pharmacokinetic aspects of exogenous substances affecting mainly the biotransformation of the substance (Kirchheiner and Seeringer, 2007). Polymorphism of the Cytochrome P450 enzyme was first discovered in relation to debrisoquine, a hypertension-correcting drug (March, 2000). Bob Smith, of Imperial College in London ingested debrisoquine and experienced severe hypotension after administration. In addition, his blood levels showed 20 fold decreased levels of drug metabolite compared to his colleagues (March, 2000; Nebert 1997). In 1988, Gonzalez and his group characterized and showed that the gene product that was causing the altered response to debrisoquine as CYP2D6; it was also found to be a liver microsomal enzyme. The cloning of this microsomal enzyme was the first look at genetic polymorphism at the molecular level (Gonzalez et al., 1988; Mini and Nobili, 2009). The study by Gonzales et al. and his group paved way for further studies geared to identify genetic polymorphism in a population that linked variant genes to alteration in drug metabolism and drug response (Mini and Nobili, 2009). Cytochrome P450s are mainly found in endoplasmic reticulum and in the mitochondria of a cell, and are copious in the liver (Porter and Coon, 1991). The CYP enzymes consist of about 49 genes that function primarily in drug metabolism (Maitland-van der Zee et al., 2000; Porter and Coon, 1991). In humans the CYP enzymes are major constituents in metabolism of fatty acids, prostoglandins, steroids and xenobiotics (Graham and Peterson, 1999). Daily diet intake of mammals consists of many natural products such as terpenes, steroids, and alkoloids and the CYP enzymes are major catalysts in the biotransformation and breakdown of these exogenous substances (Guengerich, 1991). Cytochrome P450 enzymes comprise of a super family of gene that encompass proteins predominantly involved in metabolizing of xenobiotics as well as endogenous substrates such as steroids, fatty acids, prostaglandins and arachidonate metabolites as shown in Table 1, therefore genetic polymorphism in the CYP enzymes can lead to many health related risks such as hypertension and cancer (Graham and Peterson, 1999; Jiang et al., 2005; Mayer et al., 2005). CYP enzymes are monooxygenases that catalyze non-specific oxidations of many substrates (Guengerich, 1991), (Porter and Coon, 1991). The synthetic exogenous substrates of t he cytochrome enzymes range to approximately 200,000 entities, which can all have complex interplay amongst each other in inducing or inhibiting the various isoforms of the CYP enzymes (Porter and Coon, 1991). These enzymes however are capable of catalyzing novel substrates as well and therefore one cannot cap an upper limit on the number of possible potential substrates (Porter and Coon, 1991). Therefore, the evolutionary advantage in the immensity of the CYP isoform is a crucial survival tool for our cultivating environment as well as our dynamically changing physiological system. Table 1. Exogenous and endogenous substrates of Cytochrome P450 enzymes The substrate for the CYP enzymes are just as diverse for endogenous substance as they are for exogenous substances. The CYP enzymes are prominent catalytic enzymes involved in biotransformation of various substances. Reprinted from Miniereview: Cytochrome P450 By Todd D. Porter and Minor J. Coon, The Journal of Biological Chemistry, 1991; 266(21): 13649-13472 The rates of catalyzation of the CYP enzymes are relatively slow and this can provide further explanation into their pivotal role in drug disposition (Guengerich, 1991). In addition, most of the CYP enzymes are involved in rate-limiting steps of drug metabolism and this is a key determinant of the in vivo kinetics of the drug (Pelkonen, 2002). CYP enzymes are key players in the systemic exposure of a drug and the time period a drug can assert its action (Brockmoller, Kirchheiner, Meisel, and Roots, 2000). The CYP enzymes are involved in either forming the active metabolite of the drug from a prodrug or in metabolizing the drug into inactive by-products,both of which can influence the functional temporal aspect of a drug (Brockmoller et al., 2000). Metabolites created by the CYP enzymes can also be toxic; exerting their own mutagenic and allergenic effects (Brockmoller et al., 2000). The FDA requires pharmaceutical companies to identify on the product brochure one of twenty CYP enzyme s that are involved in the biotransformation of the drug (Brockmoller et al., 2000). Interactions of different drugs concerning CYP enzymes are good predictor of drug-drug interaction, therefore marketed drugs are required to indicate the CYP enzyme involved in biotransformation of the drug on the product information (Andersson, 1991)(Brockmoller et al., 2000). However, this information does not include the polymorphism prominent within these CYP enzymes. The need for such information is crucial since these enzymes are notorious for genetic polymorphism (Brockmoller et al., 2000). Functional variations in the CYP enzymes are known to show a gradient in efficacy and variation in the quantity of the substrate present in the subject (Maitland-van der Zee et al., 2000; Wolf et al., 2000). Allelic variants causing poor, fast and ultrarapid metabolizing enzymes have been identified in most of the CYP enzymes. Most of the CYP enzymes in the liver show some degree of polymorphism (Anzenbach erova et al., 2000). B. Cytochrome Gene Family Evolution CYP enzymes are ubiquitous as they are found in every domain of living organism from Bacteria, Archaea and Eukarya and known to have originated from an ancestral gene approximately three and half billion years ago. The modern cytochrome probably originated with the Prokaryotes 1.5 billion years before the prevalence of atmospheric oxygen (Graham and Peterson, 1999; Nebert and Gonzalez, 1987; Werck-Reichhart and Feyereisen, 2000). In early eukaryotes, these enzymes not only maintained membrane veracity but also were primarily involved in the biosynthesis of endogenous hydrophobic substances such as fatty acids, cholesterol (Nebert and Gonzalez, 1987). The CYP mutilgene family diverged again 900 hundred million years later giving rise to enzymes predominantly involved in biosynthesis of steroids (Nebert and Gonzalez, 1987). This expansion lead to the another divergence of the two most important mammalian CYP families implicit in drug and carcinogen metabolizing enzymes currently known as CYP1 and CYP2 gene family (Nebert and Gonzalez, 1987). Finally, 400 million years ago dramatic expansion ensued primarily in CYP2, CYP3 and CYP4 families (Nebert and Gonzalez, 1987). This current expansion correlates to the time frame when aquatic animals merged onto the terrestrial land and were exposed to many hydrocarbon-based combustion material in the environment along with toxic plant products in their diet (Gonzalez and Nebert, 1990; D. R. Nelson and Strobel, 1987) The generation of this multigene family is due to the multiple mechanistic changes over time that reflect the complexity and diversity of the CYP enzymes. Most of the changes are related to lack of intron conservation (Werck-Reichhart and Feyereisen, 2000), exon shuffling (Doolittle, 1985; Patthy, 1985), expression of redundant genes (Anderson et al., 1981; Barrell, Air, and Hutchison, 1976), alternative splicing, frame shit mutations and RNA editing (Andreadis, Gallego, and Nadal-Ginard, 1987; Atkins, Weiss,

Meg Bogins The Women Troubadours Essay -- Meg Bogin Women Troubadours

Meg Bogin's The Women Troubadours What is Bieiris de Romans’ speaker seeking from the woman, Maria, about whom Bieiris writes? More generally, what are female troubadours as a whole seeking from their loves, and their craft? Meg Bogin, in her The Women Troubadours, asserts that â€Å"their poems were addressed to women†¦ to whom they vowed eternal homage and obedience. In exchange for their prostration, the troubadours expected to be ennobled, enriched, or simply made ‘better’† (Bogin, 9). Is the poetry of female troubadours less about the women being addressed and more about the troubadours themselves? By performing a close textual analysis of Bieiris de Romans’ poem to Maria, I hope to elucidate some possible answers to these questions. The poem opens with Bieiris’ speaker addressing her subject as â€Å"Lady Maria.† Rather than merely employing the woman’s first name, or utilizing a possessive phrase such as â€Å"my love† or â€Å"my Maria,† the speaker addresses her as â€Å"lady.† This implies a certain bestowal of respect upon her subject, and is potentially also a means to convey an understanding on the speaker’s part that this Maria has not yet consented to be hers. Next, the speaker proceeds to enumerate copious qualities that she finds pleasing in Maria. She begins by praising Maria’s â€Å"merit and distinction.† By â€Å"distinction† we can safely assume that the speaker refers to a pleasing reputation that Maria has cultivated within society, and possibly also the speaker’s own opinion that Maria is able to be distinguished as superior to other women. The term â€Å"merit,† however, is relatively ambiguous. By â€Å"merit,† the speaker could be indicating one or many qualities, including, but not limited to, virtue, achievement, a... ...g female companion, who will comply with her wishes and desires. Thus, Maria, judging from the qualities attributed to her in the poem, seems a perfect target for Bieiris’ speaker’s affections. Bieiris also appears to have created a speaker who is more concerned with being given the ability to express her desires than with the woman about whom those desires are expressed. Maria seems to be utilized as somewhat of a passive vessel about whom Bieiris can write and express herself in a literary fashion. The desire that Bieiris succeeds in expressing, then, is less one for Maria in particular and more one for composing lyric poetry in general. As a troubadour, Bieiris most likely avidly seeks patronage. Thus Maria is less of a goal to achieve and more a means to a different end: composing poetry for the sake of procuring a reputation, and obtaining financial gain.

Globalization of multinational activities: meaning and debate Essay

There are many definition of the globalization. For example, the International Monetary fund consider globalization of multinational activities as â€Å"the growing economic interdependence of countries worldwide through increasing volume and variety of cross-border transactions in goods and services, free international capital flows, and more rapid and widespread diffusion of technology†. (Dowling 2005) There is one more definition given by the International forum on Globalization. According to it globalization is â€Å"the present worldwide drive toward a globalized economic system dominated by supranational corporate trade and banking institutions that are not accountable to democratic processes or national governments†. (Wright 2001) But first of all globalization promotes cultural diversity and division of labor. Immanuel Wallerstein stresses that globalization of business can’t be understood separately from historical events. Lots of definition ensue the debates concerning roles of governments, companies and individuals in increasing national welfare in the context of globalization. Globalization of multinational activities has not only economic aspect but also political, cultural and technological, because they are closely connected with each other. It means that changes in one aspect are followed by changes in others. These aspects of globalization are considered key points to people’s quality of life and social benefits. (Debrah 2004) The economic aspect of impact involves trade, migration and investment opportunities. Globalization of international trade suggests more available access to goods and services which were never seen before. Due to this process people are able nowadays to buy a wide range of services and goods. International investments take place through foreign direct investments. It means that multinational organizations invest directly the assets in foreign companies or investments take place by purchasing and selling the financial assets of other foreign companies. Due to globalization independent migration suggests that individuals can find employment in spheres where the companies have labor shortages. But free migration is criticized, because it can lead to destruction of native industry and loss of jobs. International investments are also criticized, because if to accept such financial scheme the country can loose economic sovereignty and â€Å"may be forced to set policies that are contrary to its citizen’s interests or desires†. What is more important is that international companies investing in country or company can receive too much economic and political power. It is admitted by critics that migration is like exploitation of workers from other countries. (Baolian 2004) The political impact of globalization is creation of international rules and institution to deal with trade, human rights and international environment. New global institutions for regulating multinational activities are World Trade Organization, Euro currency and North American Free Trade Agreement, etc. central question is if government can control the economic activity of world companies. Globalization is also characterized by cultural global ties i. e. new ideas and concepts about trade and media throughout the world. However global cultural ties are not always favorable as they may cause constrains for companies. One more point about globalization of business is the significant change of technologies, transport and communication. Nowadays transportation costs have been reduced significantly because of technological advances which make foreign markets freer for trade. It was counted that billions of dollars in different kinds of assets and/or currencies are exchanged every day with the help of electronic means. It is seen that globalization spreads the developing and appearing of new multinational activities es. (Baolian 2004) Globalization: impact on multinational activities Globalization is sometimes described as the main cause of disturbances and changes in the world. Actually the term â€Å"globalization† is the shelter for collective effect and the changes. Globalization is the total changes taken place in the factories or storefronts which are seen in the spheres of economy, multinational activities and lifestyles. It is a matter of fact that this process was caused by four significant forms of capital flows throughout the global economy and multinational activities’ spheres. It is necessary to mention these four important capital flows: 1. Human capital involving the processes of immigration, emigration, migration and/deportation. 2. Financial capital including debts, equity, aids, credits, lending. 3. Resource capital means resources of energy, lumber, different minerals resources and metals. 4. Power capital suggests security forces, armed forces and different alliances and unions among countries (Wright 2001) It was mentioned that most difficulties and stresses confronted in the general affairs of multinational activities and interactions between them can be revealed in the four mentioned capital flows. It means that globalization has great influence on these flows and is able to direct them. Globalization also affects telecommunication and travel modes and they have become cheaper. As the result they have become accessible to more people, domestic and international companies. As for cultural and political friction they â€Å"can thus be explained as arising from the difference in opinion between two or more parties about the origination, treatment, timing, ownership or value of one or more of the capital flows†. (Wright 2001) The impact of globalization is constant and inevitable. And the process of globalization was inevitable. And there appears a question: why? The main reasons of such globalization influence in the word are: advantages of low labor costs need of vertical and horizontal division of labor, great number of untapped markets, and legislation in foreign countries. It is seen that the mentioned points provide international companies with lots of profitable opportunities. It is a common knowledge that globalization of multinational activities is first of all significant expansion of regional and international markets, international laws, cultures and values. It is possible to say that globalization describes the expansion of politics from narrower area (local, regional, national) to broader horizon of international area and thus the whole planet. It is obvious that the impact of globalization is really great and considerable. Due to the globalization processes occurring in the world international and domestic markets become now standardized, mostly because they are interacting, influencing and in such a way combining with ex-rivals from different parts of the world. (Sparrow 2004) Globalization is positive, because there is an increasing competitiveness of multinational activities. Nowadays the national markets are too saturated and companies need new flied of action on a larger scale. The next fact is that globalization of business aims at gaining economies of large scale. It means that investments, administration, production of goods and services, marketing and advertising will be equally distributed among many countries. As the result the expansion costs will be significantly reduced. The last point witness for globalization is that nowadays consumers have globalized preferences and product markets have to correspond. It means that international markets have to be also global. (Sparrow 2004) Globalization of multinational activities and economy was enabled by the series of factors. Highly developed technology gives the possibility for computing power to reduce the costs of transactions and information gathering. This push is intensified by the Internet, because it is global and rather cheap. Modern communications provide the access to available information in the whole world. The importance of communication and Internet has significantly increased, because they are useful for people’s communication. It is a matter of fact that the barriers to international trade and business are falling and becoming more standardized. The important forces were GATT (General Agreement on Trade and Tariffs) and WTO (World Trade Organization). Due to globalization many countries deliberately reduced their trade barriers, removed barriers to direct foreign investments, and liberalized trade control. Governments of many countries believe that such measures will promote and assist national welfare, economic growth and developing of multinational activities. It is necessary to notice international finances and rapid capital flows. Nowadays technology developments assist banks and other financial establishments in funding foreign expansion, setting new affiliated offices and providing investment opportunities in the whole world. (Dowling 2004) The possibilities of the globalization are: 1. To set economies of large scale, because Internet and communications are global by nature and they are cheaper than other media. 2. Multinational activities are more credible and people believe if it is successful in many countries, its quality is good as well. 3. It is easier and quicker to introduce new production line with global international brand. The main strategies of international globalization are to consolidate comparative advantage, to develop honest competency, to develop global way of thinking, to globalize competency of international companies and to integrate countries. But it is known that the demand of globalization is to think globally, but to act locally. It is a matter of fact that international organizations used to deal with restricted markets and it is hard for them to deal with new global perspectives. New global economy tries to get rid of static organization and to change them by new organization more suited for new globalized economy and new globalized world. (Sparrow 2004) â€Å"Over the course of the past decade, in many countries (especially in the developed world), savers have increasingly diversified their portfolios to include foreign financial assets (foreign bonds, equities, loans), while borrowers increasingly turn to foreign sources of funds, along with domestic ones. While flows of this kind to developing countries also rose sharply in the 1990s, they have been much more volatile than either trade or FDI flows, and have also been restricted to a narrower range of ’emerging market’ countries. † (Sparrow 2004) It is a matter of fact that the number of international transactions dramatically increased during last decades. Economies of many countries became internationalized as their GNP increased due to international exchange of goods and services. It was mentioned that â€Å"increasing economic integration among nations, some scholars argue, has dramatically reduced the barriers between national economies, undermining the autonomy of national governments†. (Dowling 2004) The positive and negative sides of globalization Globalisation has caused many problems for business executives and the government. However, many people support this process. The supporters of globalisation state that globalisation is inevitable and can’t be stopped anyhow. They even argue that globalization can make the world rich. Speaking about four factors of production (labour, land, entrepreneur and capital) we can’t but mention that in the process of globalisation two or three factors must cross the borders. If a company invests in another country, it will receive dividends from that country. There is a flow of these factors of production through multinational corporations. Modern companies try to respond to the emerging open market opportunities, and for the aim of winning better market share and higher profits, have to pay their attention to the globalization and the need for creating large multinational corporations. A bright example of such changes may be represented by the German Hoechst chemical company, which at the beginning of the year 2000, admitting the rapidly changing positions on the chemical market and understanding the new accents on the global cooperation and production, decided to take this step and create a new structure. Through the 2001 and 2002 it has sold twelve of its businesses in Germany for being no more profitable, and has bought four new pharmaceutical firms outside Europe. Hoechst in Europe was the pioneer of such drastic changes in the multinational management trends. Though the Hoechst’s labor force in Germany was decreased almost twice, it became possible to increase the sales over the US continent from 6 to 33 percent of the market share by the end of 2002. These actions could be viewed as an example of new innovative approach to the company’s management. On the other hand, and as Mockler (2002) puts it, ‘such actions were contributing to unrest and uncertainty in Europe’. (p. 12) The topic of multinational management should be discussed though the real life examples and it would be appropriate to note a company which was able to master the issues of multinational management. The talk will be about GE, a company which is now one of the most advanced and highly innovative corporations in relation to management approaches and structures. Its ex-CEO Jack Welch is known all over the world for having put the quality of the company management, and thus the quality of its operations to another, much higher level. Understanding the huge perspective of the global company through the period of Welch’s being GE’s CEO he has implemented one of the most prominent and successful management systems in the world. His main idea was to work though the principle of ‘creative destruction’, which was later used by other multinational companies. (Rugman & Verbeke 2003, p. 29) ‘The objective of the GE’s management strategy was to stretch the potential of the firm, even though this firm was very large. To fulfill these tasks it was necessary to apply the abilities of defining strategic guidelines which channel and stimulate innovative and entrepreneurial actions without inhibiting often unstructured individual initiative’. (Mockler 2002, p. 15) GE has become the multinational company with the ability to adapt to the changes and to implement the latest innovations into its operations. Welch understood the necessity of these innovations, and meeting these challenges, the company turned them into its assets. GE is one of the brightest examples of the multinational companies, which were able to adapt to the rapidly changing technologies and management theories. As the core problem of the multinational corporations is to work through different cultures and traditions, which is almost impossible at times, the role of management must not be underestimated in relation to such global structures. Management provides such company with clear structure, understanding of problems and challenges and gives the clear picture of its market position. GE made it possible for each worker to understand his role in contributing into the general process of management. Namely management has made this company one of the most successful in the recent years. The opponents of globalization argue that globalisation does not bring back more returns as the returns that go out. They argue that for example, a company likes British Telkom, which went abroad because of internal problems with its multinational business. However, these examples can’t spoil positive judgment about globalization. We have many examples of companies that were on the virtue of collapsing but now they are performing very well after going international. Why do others think that globalisation is not useful? In this article â€Å"Will globalisation make you happy† Wright R. (2000) argued that globalisation makes human beings happy but unfortunately they are pursuing things such as power and money which does not bring everlasting happiness. He asks the question, â€Å"does money bring happiness? †. Wright writes that survey carried out in many countries, both rich and poor and confirms that poor relationships are the source of unhappiness and there is no happiness in richness. In the same survey, it was found that a nation is fairly comfortable with a standard of living that is lower than what the average human being thinks. Changing of Employee relations Also a lot of needs appear concerning the changing of employee behaviour in order to provide effective employee relations. There a lot of important work to be implemented by managers and employees itself. (Harris et al) Most people work and live in familiar environment, in the surroundings we were brought up or places similar to this. Accordingly, people that we meet, work with and entertain, are similar to us, due to the fact that they have the same ethnic context, similar viewpoints and religion, the same framework of values, and the same language, that we speak. (Harris et al) Effective changes of behavior starts with detailed interpreting the terms under which the individual is involved into behavior that needs to be changed. It is necessary to understand his motivation in these or that circumstances. Understanding these aspects will make the process of motivating the person easier and predictable. For instance, many supervising managers suppose that speaking foreign languages during working process is the evidence of employee’s laziness, disrespect and desire to detract from the work. But in fact many employees use another language while attempting to perform some information related to their work more accurately. Sometimes it may be the evidence of stress or tiredness, or just an attempt to make the process of communication faster. (Harris et al) One important aspect of making successful cross-cultural interrelations is to be considered. Building up mutual understanding and successful communication demands self-assessment. Each employee should clearly understand and evaluate the styles he or she uses in various situations, and to what degree. (Harris et al) Ability to appreciate other people is significant for successful cross-cultural communication and cooperation. Each person should be aware that it is important to find time to pay attention to other people, to understand and evaluate their style and behavior. For instance, within a definite firm, manager staff members may represent a wide range or personal styles: â€Å"with regard to completing reports, one team leader may require pages of details, and the other leader wants only bullet points of information†. (Harris et al, p. 89) As regards to such peculiarities, cultural and language differences do not matter. Professional manager should realize that the problems of cross-cultural relations affect many spheres of business and economy, for instance, marketing, both domestic and international. It is necessary to take into consideration that, for instance, USA culture consists not only of native culture. Foreign culture of the state is made up not only by foreign citizens. American citizens now may have foreign origin, for instance, Indian, Chinese, Canadian, Australian or Russian. That is why understanding foreign cultures is important for the workers in any sphere, even if they deal with domestic consumers and companies. For those who have business relations with foreign customers of companies such skill is compulsory. The process of globalization and changing conditions of the world market made all spheres of business and finance a cross-cultural phenomenon, which demands that managers on all levels must be aware of cultural differences and means of establishing successful relations to succeed in the market. (Harris et al)

History of Motion

Prior to Copernicus’ heliocentric model, the Ptolemaic system was, with the assistance of the Roman Catholic Church, the prevailing astronomical model of the universe in Europe leading up to the 16th Century. A geocentric model, it stated that Earth was the stationary centre of the universe, and used a system of epicycles and deferents (when a planet revolved in a small circle, and this small circle revolved in a bigger circle) were used to describe anomalies such as the retrograde motion of planets. Equants (a point which the centre of a planet’s epicycle moved at a uniform velocity) were used to approximate where planets would be at a certain time. Even though the Ptolemaic model had various defects, as astronomers assumed that all the planets revolved at a uniform rate, planets revolved in perfect circles, and didn’t explain the retrograde motion of planets that it was formulated to do; it was still widely accepted by Western society for the next 1400 years. Nicolaus Copernicus (19 February 1473 – 24 May 1543) was Renaissance mathematician and astronomer who formulated the heliocentric model of the universe. Copernicus formulated a heliocentric model whilst studying in Lidzbark-Warminski in around 1508, now modern day Poland, after he was dissatisfied with the geocentric models of Ptolemy and Aristotle. Using astronomical observations and mathematical, Copernicus refined his ideas and published De revolutionibus orbium coelestium. This book outlines Copernicus’ 5 key ideas on motion, such as: 1. Planets do not revolve around one fixed point. 2. The Earth is the centre of the Moon’s orbit. 3. The sun is the centre of the universe, and all celestial bodies revolve around it. 4. Stars are stationary, and only appear to move because the Earth is itself moving. 5. Earth moves in a sphere around the sun, causing sun’s year movement. Copernicus’ De revolutionibus orbium coelestium was banned by the Roman Catholic Church, but when the ban was lifted in the 17th Century, the scientific community immediately expanded and refined his work. This suggests that the Roman Ca tholic Church held an enormous amount of power and dictated everyday life, and as a result, people became hungry for knowledge they could not acquire as a result of the Church’s censorship of new and modern ideas. Galileo Galilei. Prior to Galileo’s study of falling objects, Aristotle stated that heavy objects would fall faster than lighter ones in direct proportion to weight, and that objects do not retain their velocity and naturally slow down even when no force is acted upon the object. Galileo Galilei (15th February 1564 – 8th January 1642) was an Italian physicist, mathematician, astronomer and philosopher. Studying free-fall, Galileo dropped 2 balls, both of the same material but different masses, from the top the Leaning Tower of Pisa to demonstrate that the mass of the object was independent from its time of descent. The balls fell at the same time, contradicting Aristotle’s widely accepted teachings. Galileo, whose works on motion are linked to the discovery of inertia, and proposed that a falling body, regardless of weight or material, would fall with a uniform acceleration in a vacuum, and that the object would retain their velocity unless another force, such as friction, acts on the object. Galileo also derived the kinetic law for the distance covered during a uniform acceleration from start to finish: d ? t 2 (distance travelled is proportional to square of time period). Galileo was convicted of heresy as a result of his revolutionary scientific works and was put under house arrest for the rest of his life. Despite his imprisonment, he still expanded and published his works. The Church was a tyrannical figure in society, who imprisoned those who went against their scientifically flawed ideals, but their censorship of such scientific material such as the works Copernicus only inspired people like Galileo to expand their ideas and develop their own ideas. Sir Isaac Newton. The Church’s repression of Galileo prevented him from expanding his revolutionary ideas of inertia, and Aristotle’s scientifically incorrect theories were still the prevailing ideas of motion, including the belief that the speed of a falling body was dependent on the mass of the object, and that inertia was non-existent and that an object need to be constantly applied with force in order to keep moving. Sir Isaac Newton (25 December 1642 – 20 March 1727) was an English physicist and mathematician who formulated the 3 Laws of Motion. . If the net force is zero, then the velocity of the object is constant. 2. The net force on an object is equal to its rate of change. 3. For every action there is an equal and opposite re-action. Newton’s Law of Universal Gravitation states that every point mass in the universe attracts every other point mass with a force directly proportional to the product of their masses and inversely proportional to the s quare of the distance between them. The greater the mass, the greater the attrition. This is shown in the formula: Newton was knighted by Queen Anne in April 1705. This suggests that the Church’s attitudes towards scientific progression had changed, and instead of supressing it as it did with Copernicus and Galileo, it was recognised as great achievement, and this scientific progression led to many discoveries that would contribute to the world we live in today. Albert Einstein’s Theory of Special Relativity. Albert Einstein’s Theory of Special Relativity, published in 1905, is a theory of measurement that only applies to uniform velocities. According to his theory, Einstein states that all motion is relative and every concept involving space and time are also relative, therefore there is no constant point of reference to measure motion. Example: a ball falling from the mast of a ship would appear to an observer standing on the ship’s deck as falling straight down. However, to a person standing in the distance, the ball would appear as if it followed a curved trajectory. If asked which trajectory the ball followed considering both people’s perspectives, Einstein’s Theory of Special Relativity states that they are both right and wrong, as there must be a measurement of motion, but there cannot because there is no constant point of reference to measure motion. Albert Einstein’s Theory of General Relativity. Einstein’s Theory of General Relativity, published in 1916, states that every object causes a distortion in space-time and the larger the object, the further space bends. This distortion in space-time is felt as gravity or inertia, therefore meaning that gravity is the product of mass bending space-time geometry. Example: a large body lay at the centre of a trampoline. A marble rolling around the edge of the trampoline would spiral inward toward the body. The body being a large object bends space-time geometry, resulting in gravity and pulling the marble towards itself.

The Next Industrial Revolution

The Next Industrial Revolution The Next Industrial Revolution depicts the ideas of Michael Braungart and William McDonough in their attempts to transform the relationship between business and the environment or nature. The two have worked with the leading corporations such as Nike and Ford in redesigning their products, processes and buildings to meet the environmental needs. The two observe that a beneficial economic growth must conform to nature’s rule.Advertising We will write a custom essay sample on The Next Industrial Revolution specifically for you for only $16.05 $11/page Learn More The idea is to present beneficial economic growth by taking care of nature. Therefore, The Next Industrial Revolution depicts economic scenarios that inspire business people to consider environmental matters seriously. Likewise, they must also realign their current institutions and businesses to conform to the rule of nature and reconsider the current business actions, consumers, and the public to enhance a new and a sustainable relationship with nature (Sarandon 2002). Authors of Green to Gold, Esty and Winston note â€Å"the economy and the environment deeply intertwine with each other† (Esty and Winston 11). This is the same idea the movie presents. The authors explore some of the paradigm shift in successful companies and how these companies are shifting their methods of conducting business and environmental relations. At the same time, they also highlight how organisations are focusing profit growth, and cost reduction, increasing market share with the environmental sustainability. Modern corporations face several challenges in relation to sustainability of the environment. Consequently, firms have begun to implement environmental changes in their value chains. These changes include customers demands for environmental friendly products, responses to depletion of resources, concerns for waste disposals, safeguarding of brand names, and reduce the cost associated with the environmental lawsuits. Modern organizations must meet the varied demand of their customers in order to keep their position in the marketplaces. This calls for responsibility not only for corporate firms, but also for end-users of their products. Organizations of today must adopt a strategy of sustainability to guide their success. As both Esty and Winston and the film depict, organizations must put their business and environment their top priorities. Thus, the top management of firms must formulate such policies for employees to adopt. Henry Ford clearly demonstrated this principle through his writings that â€Å"You must get the most out of the power, out of the material, and out of the time†. These principles created lean and clean operating procedures in Ford Motors. Top management must also resist any attempts to block changes that enhance environmental sustainability. A company’s stand on environmental conservation may damage its reputation among stakeh olders and possibly attract lawsuit from environmentalists. Therefore, Gold to Green and The Next Industrial Revolution encourage organizations to adopt sustainable strategies in their pursuit for business.Advertising Looking for essay on business economics? Let's see if we can help you! Get your first paper with 15% OFF Learn More The Next Industrial Revolution shows that organizations that have adopted environmental protection strategies are constantly redesigning their services and products, and supply chains to fit the needs of nature. Therefore, sustainability becomes a part of organizational culture, and promotional strategies meant to drive revenue growth. Organizations that have adopted nature demands as a part of their corporate culture have found new markets and increased their business revenue. In other words, environmental sustainability efforts have created new markets, and new consumers that constantly need environmental friendly products. Thes e firms also save resources in terms of efficiency, waste reduction, product design, risk reduction, and cut in expenses but ultimately increase their revenues and profit. Marketing conditions such as environmental policies, ever increasing costs of energy and raw material, growing global population and intensive use of limited resources influence the conditions of contemporary companies in production of goods and services. In addition, factors such as globalization, rapid developments in IT, products innovations and evolving market requirements control companies decisions on productions regarding environmental sustainability. Sustainable developments focus on how companies can meet the demands of today’s consumer without interfering with the future generations. The concept of green solutions emanates from the ecological changes and processes that have occurred in the economy and society. Sustainable economy requires innovative products and processes in value chains and netwo rks linked to the natural environment. Sustainable development follows the value chain from the product manufacturer to customer and proceeds up to the final stage of disposal of products and handling of materials in the processes of lifecycles. Decisions regarding the planning and design of products and processes form part of the integrated value chain in sustainable development. This implies that technical, economic and ecological perspectives must be incorporated into one approach. An organization, which ignores incorporating its green agenda in its marketing strategy, does not have the interests of its stakeholders. This is because by creating social and environmental values, sustainability marketing strives to create and increase consumers’ values. The idea of sustainability marketing focuses on consumers’ needs and wants. Companies try to develop sustainable products to provide solutions to modern customers through products value, prices, distributions, and promo tion to the target groups. Organizations must reconsider current actions of businesses, consumers, and the public to enhance a new, sustainable relationship with nature. This will create a situation whereby organizational prosperity will continue, and economic activities will increase. Sustainability or eco-efficiency aims at changing organizations from consuming and wasting trends witnessed in the past into a system that inculcate environmental concerns, consumers’ needs, and economic. Most organizations consider sustainability as the business strategy for change.Advertising We will write a custom essay sample on The Next Industrial Revolution specifically for you for only $16.05 $11/page Learn More Environmental pundits have stressed the importance of sustainability for organizations that want to remain competitive, successful and sustainable. In fact, some analysts predict that it would be impossible for some organizations to conduct business if t hey do not respond to the rules of nature. Organizations must add value by consuming fewer resources, release low amount of wastes, and sustain the environment. Past trends indicate that sustainability is gaining recognition among industries. A number of organizations are increasingly committing themselves to sustaining the environment such as Walt Disney, UPS, and Johnson Johnson, among others. Most of these organizations adopt the using and recycling methods to sustain nature. This trend is also gaining acceptance in both homes and workplaces because it has both eco-friendly and economic advantages. Reduction in energy consumptions, resource use, pollution, and wastes will translate into economic benefits for the value chains. This sense of eco-efficiency and sustainability of the environment has reduced fearful concerns for the future. Organizations and the public admire sustainability as a well-intended idea. However, the challenge is that is sustainability a life-long strategy for a success. Therefore, organizations that focus primarily on the profits may have challenges in implementation of a sustainability agenda into their corporate cultures. We are relying on organizations that caused the problem to bring changes in environmental conservation. These industries will slowly and persistently continue depleting resources, and make environmental conservation efforts illusions. Esty, Daniel and Andrew Winston. Green to Gold: How Smart Companies Use Environmental Strategy to Innovate, Create Value, Build Competitive Advantage. New Haven, CT: Yale University Press, 2006. Print. The Next Industrial Revolution. Dir. William McDonough and Michael Braungart. Perf. Susan Sarandon. Earthome Productions, 2002. Film.Advertising Looking for essay on business economics? Let's see if we can help you! Get your first paper with 15% OFF Learn More