Mark Corson

By I. Mortis. Willamette University.

As a result of study established that the Ukrainian market has a various cosmetic goods positions order glucovance 500 line, from which 42% of positions are local products generic glucovance 400 on line, and 58% are foreign products glucovance 400. Cosmetic products volume is higher on the foreign markets in pharmacies and in stock at all. Cosmetic products is very popular among consumers because it occupies an important place in their lives. The number of objects of investigation (cases) and the number of features that characterize these objects may be very large. These tasks are the segmentation of the market, the construction of a typology of countries over a sufficiently large number of indicators, forecasting market conditions of certain goods, the definition of competitive capacity of the goods. For these tasks, important applications are cluster analysis methods — multivariate statistical procedures, data collection, containing information on a sample of objects, and then organize the objects in a relatively homogeneous group. The aim of this study is to investigate the possibility of using the method of principal component analysis to solve clustering problems in marketing research. Cluster analysis unlike most mathematical and statistical methods does not impose any restrictions on the form of these objects, and allows you to treat a variety of source data almost arbitrary nature. This is important, for example, to predict the conditions when the figures have varied views, difficult to use traditional econometric approaches. If clustering objects are represented as a point in n-dimensional feature space (n – number of features that characterize the objects), the similarity between objects is determined by the concept of distance between the points, since it is intuitively clear that the smaller the distance between objects, so they are similar. The method of calculating the distance between objects and groups of objects reflects the specificity solve applied problems. For example, the euclidean distance can be set in the case of continuous variables: 2 = ( − ) =1 178 here Xij – the value of the i-th factor in the j-th observation. Despite much research in the cluster analysis, there are a number of current problems in this area. These include, in particular, multicollinearity is often present in these marketers. The questionnaires in conducting marketing research, as a rule, contain related issues, and the data is usually multicollinearity. There is an effective method of linear transformation of the space of the explanatory variables, allowing to obtain new regressors, comfortable and effective in dealing with the prediction or recognition problems. It is based on the transition from the initial set of correlated factors X1, X2, … Xn to the new set of explanatory variables Z1, Z2, … Zn coefficients with zero covariance between: cov(Z ,i Zj) = 0, (i ≠ j). New factors (principal components) are selected so that the first principal component had the highest dispersion in the new set of variables, and the second – the dispersion, the next highest, and so on.. Thus, it becomes possible to reduce the number of explanatory variables to the first few principal components thus facilitated visualization of the original data. The method of principal components is easily implemented in a software environment R, which is controlled via the command line. For this environment, there are numerous additional modules library with open source that greatly enhance its functionality. R has great functionality, including a large range of options for data visualization. The method of principal components is well suited for market research, it allows you to create a new space of explanatory variables with zero multicollinearity, reducing the dimension of this space facilitates visualization of data. The pharmaceutical sector is an important part of the primary health system its condition depends on the overall level of the industry and the economy as a whole. However guarantee level free medical care to the patients is a problem carried out the most difficult and hardest. The availability of drugs is determined by their presence in the pharmaceutical market and economic accessibility that is to sayprice regulation and compensation of spending on medicines through compulsory health insurance. To analyze the current state of pharmaceutical care in Poland and establish a mechanism reimbursement cost of medicines. Some drugs are used to remove symptoms that are easy to identify, such as: painkillers, antipyretics, vitamins, homeopathic medicines can be bought without a prescription. Each patient is insured in Poland has the right to discount the price of the drugs. There are 4 levels of reimbursement of drugs:  100% free (bezpłatny (B) dispensed medicines used to treat severe, chronic diseases such as cancer, tuberculosis, infectious diseases, mental disorders, seizures, etc. Where the retail price is higher than the set limit for financing, the patient must pay the difference between the retail price and size limit funding. For discounted prescriptions mainly released generic drugs because their price is much lower than the original. In the case of the introduction of the first generic drug to limit the group, its price will be not more than 75% of the original drug price. At the end of patent protection, the manufacturer of the original drug should reduce the price by at least 25%, even if his group does not include any generic drag. Draws attention to the fact that the purchase of drugs can use and prescription prescribed in another country. If some medicines that prescribed in the recipe are absent, pharmacist can represcribe them for a patient, and leave the old prescription at the pharmacy. One prescription forms are allowed to issue up to 5 drugs on; the prescription valid 30 days usually. The doctor prescribes medicines in an amount such that enough for 3 months of treatment. According to statistics, the price of drugs in Poland for the last 20 years steadily increased, but still they are three times lower than in other European countries. Established, the average trade margin on drugs Poland is only 17%, and in most European countries – almost 30%.

Active-site-directed inhibition of asparagine N-glycosyltransferases with epoxy-peptide derivatives order 400 glucovance with amex. Inhibition of telomerase activity by a cell-penetrating peptide nucleic acid construct in human melanoma cells order glucovance 500 free shipping. Primary structure of a potent endogenous dopa-containing inhibitor of phenol oxidase from Musca domestica cheap glucovance 400 on-line. Regulation of tyrosinase synthesis and its processing in the hair follicular melanocytes of the mouse during eumelanogenesis and phaeome- lanogenesis. Topical application of a protein kinase C inhibitor reduces skin and hair pigmentation. Solid-phase synthesis of kojic acid-tripeptides and their tyrosi- nase inhibitory activity, storage stability, and toxicity. Discovery and characterization of a nonphosphorylated cyclic peptide inhibitor of the peptidylprolyl isomerase, Pin1. The prolyl isomerase Pin1 regulates amyloid precursor protein pro- cessing and amyloid-beta production. Membrane permeable cyclic peptidyl inhibitors against human Peptidylprolyl Isomerase Pin1. Conformationally locked isostere of phosphoSer-cis-Pro inhibits Pin1 23-fold better than phosphoSer-trans-Pro isostere. Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Potent and selective inhibition of human immunodefciency virus type 1 transcription by piperazinyloxoquinoline derivatives. Long-term treatment with novel glycogen synthase kinase-3 inhibitor improves glucose homeostasis in ob/ob mice: molecular char- acterization in liver and muscle. Intraneuronal delivery of protein kinase C pseudosubstrate leads to growth cone collapse. Evidence of zeta protein kinase C involvement in polymor- phonuclear neutrophil integrin-dependent adhesion and chemotaxis. Docking sites on substrate proteins direct extracellular signal-regulated kinase to phosphorylate specifc residues. A protein kinase C translocation inhibitor as an isozyme-selective antagonist of cardiac function. Protein kinase C-epsilon is responsible for the protection of preconditioning in rabbit cardiomyocytes. C2 region-derived peptides inhibit translocation and function of beta protein kinase C in vivo. Most people’s general impression of peptides is that they are large molecules that are easily digested by proteases. These two important draw- backs mean that peptides are often considered as being less stable with low oral bioavailability. Consequently, administration by injection is often required, and the peptides are readily inactivated by peptidases and cleared from the body. Moreover, they have a relatively higher risk of immunogenic effects when compared with small drug molecules. Owing to their relatively larger size and often hydrophilic nature, sol- ubilization, and the delivery of peptide drugs across membranes become challenges. Cost-wise, the synthesis of peptide drugs is often considered more expensive if one associates cost with molecular size. Viewed from the opposite side, where a detriment is reinterpreted as a beneft, pep- tide drugs hold several key advantages over small drug molecules. Therefore, peptide drugs are expected to be very potent because when compared to small drug molecules, peptide drugs have high activity and high specifcity due to very few unspecifc bindings to nontargeted sites. On the same line of reasoning, pep- tide drugs would have fewer drug–drug interactions, although, as previously stated, they have an increased risk of immunogenic effects. Considering that peptide drugs are large molecules composed mainly of natural amino acids with high target speci- fcity and are easily degraded by peptidases, peptide drugs would in theory exhibit lower toxicity than small drug molecules. Likewise, considering that peptide drugs have diffculty crossing membranes, they are less likely to accumulate in tissues and thus have a lower risk of adverse drug reactions over time. The sheer largeness of peptide drugs also means that they are more biologically and chemically diverse. In actual practice, however, peptide drugs are often used to derive small nonpep- tide drug molecules. Doing so offers the benefts from both classes and the fne line that differentiates between a peptide drug and small drug molecule becomes faded. Indeed, after a lengthy process of rational drug design where residues are changed from natural amino acids to nonnatural amino acids then to nonamino acids, it becomes rather challenging at times to classify if a drug is peptide or nonpeptide. Although we would like to classify a nonpeptide drug as a compound that does not possess any amino acid, out of respect for the developers of the drugs, in this chapter, we will keep the nonpeptide or peptide assignments that the drug developers have chosen, and will thus avoid any debate over semantics. We will focus on success- ful stories of peptide-derived drugs that are processed by enzymes. We will try to be as up-to-date as possible in the information that we provide at the time that this chapter is being written. It should be noted that, in this chapter, most comparisons done between differ- ent drugs are restricted to our own personal viewpoint; because of legal reasons and personal pride, the drug developers would claim originality to their own discoveries. Hence, we would like the readers to read with an open mind and come up with their own interpretations of the information that we provide.

Pharmacodynamics Rising risk Asparaginase and pegaspargase capitalize on the biochemical dif- Asparaginase and peg- ferences between normal cells and tumor cells cheap 500 glucovance otc. Deprived of their supply of asparagine glucovance 400 cheap, the tumor The risk of a reaction ris- cells die cheap glucovance 500 amex. Pharmacotherapeutics Hypersensitivity re- Asparaginase is used primarily in combination with standard actions may also occur. Without If allergic… asparaginase, Pegaspargase is used to treat acute lymphocytic leukemia in pa- I’m finished! Concurrent use of asparaginase with prednisone or vincristine in- creases the risk of toxicity. Adverse reactions to Pharmacokinetics procarbazine After oral administration, procarbazine is well absorbed. Late-onset bone marrow suppression is the most Metabolism and excretion common dose-limiting Procarbazine is metabolized rapidly in the liver and must be acti- toxicity associated with vated metabolically by microsomal enzymes. Respiratory excretion of the drug occurs pneumonitis (lung in- as methane and carbon dioxide gas. Pharmacodynamics An inert drug, procarbazine must be activated metabolically in the A bad start liver before it can produce various cell changes. Pharmacotherapeutics Procarbazine is used in the treatment of Hodgkin’s disease, lym- Gut reactions phoma, and brain cancer. So • Taken with meperidine, it may result in severe hypotension and watch out for death. When your neck is on the line Hydroxyurea is also used for solid tumors and head and neck cancer. Metabolism and excretion About one-half of the dose is metabolized by the liver to carbon dioxide, which is excreted by the lungs, or to urea, which is ex- creted by the kidneys. Adverse Divide and conquer reactions to Hydroxyurea kills cells in the S phase of the cell cycle and holds hydroxyurea other cells in the G1 phase, where they’re most susceptible to irra- diation. Treatment with hydroxy- urea leads to few ad- Pharmacotherapeutics verse reactions. Those that do occur include: Hydroxyurea is used to treat selected myeloproliferative disor- ders. It may produce temporary remissions in some patients with • bone marrow suppres- metastatic malignant melanomas as well. These drugs exhibit anticancer activity as well as activity against condylomata acuminata (soft, wartlike growths on the skin and mucous membrane of the genitalia caused by a virus). The three types of interferons are: alfa interferons derived from leukocytes beta interferons derived from fibroblasts (connective tissue cells) gamma interferons derived from fibroblasts and lympho- cytes. Metabolism and excretion Alfa interferons are filtered by the kidneys, where they’re degrad- ed. Interferons Pharmacodynamics can put a stop to viral Although their exact mechanism of action is unknown, interferons replication. When bound, they initiate a sequence of intracellular events that includes the induction of certain enzymes. Running interference This process may account for the ability of interferons to: • inhibit viral replication • suppress cell proliferation • enhance macrophage activity (engulfing and destroying mi- croorganisms and other debris) • increase cytotoxicity of lymphocytes for target cells. Pharmacotherapeutics Alfa interferons have shown their most promising activity in treat- ing blood malignancies, especially hairy cell leukemia. Interfering in these areas as well… Alfa interferons also demonstrate some activity against chronic Adverse myelogenous leukemia, malignant lymphoma, multiple myeloma, melanoma, and renal cell carcinoma. Alfa concerns • Alfa interferons increase the risk of kidney failure from The most common ad- interleukin-2. Pharmacotherapeutics Aldesleukin is used to treat metastatic renal cell carcinoma. These in- clude: • pulmonary congestion Altretamine and difficulty breathing Altretamine is a synthetic cytotoxic antineoplastic drug that’s • anemia, thrombocy- used as palliative treatment for patients with ovarian cancer. Pharmacotherapeutics Altretamine is used as palliative treatment of persistent or recur- ring ovarian cancer after first-line therapy with cisplatin or an alkylating drug-based combination. Drug interactions Altretamine has a few significant interactions with other drugs. Concomitant therapy with cimetidine may increase altretamine’s half-life, increasing the risk of altretamine toxicity. Metabolism and excretion Bone marrow Paclitaxel is metabolized primarily in the liver with a small suppression is also amount excreted unchanged in urine. Pharmacodynamics When other treatments fail, don’t Paclitaxel and docetaxel exert their chemotherapeutic effect by give up! Try paclitaxel disrupting the microtubule network essential for mitosis and oth- to treat metastatic er vital cellular functions. Pharmacotherapeutics Paclitaxel is used when first-line or subsequent chemotherapy has failed in treating metastatic ovarian cancer as well as metastatic breast cancer. Head, neck, and below The taxanes may also be used for treating head and neck cancer, prostate cancer, and non–small-cell lung cancer. Cultural considerations with docetaxel use Adverse reactions to Clinical trials of docetaxel in Japanese and Other results showed fewer incidences of American patients with breast cancer re- fluid retention, neurosensory effects, muscle paclitaxel and vealed significant differences in the incidence pain, infection, and development of anemia in docetaxel of adverse effects between the two cultures. The study also indicat- During clinical trials, ed that Japanese patients are more likely to The results 25% or higher of patients develop fatigue and weakness than are Ameri- Japanese women were more likely to develop experienced these ad- can women. How- verse reactions to pacli- ever, the Japanese women in this study were Putting it into a plan taxel: less likely than the American patients (6% ver- These results are important to consider when • bone marrow suppres- sus 29. Docetaxel Adverse reactions to do- Quick quiz cetaxel include: • hypersensitivity reac- tions 1. What’s the major adverse reaction that’s common to all alky- • fluid retention lating drugs? Bone marrow suppression is a common adverse re- • numbness and tingling action to all alkylating drugs.