By J. Porgan. City University of Los Angeles. 2018.
The relevance of an analogue depends on the simi- Clinical trial data that are submitted for product regis- larity of the subject product and market to the new tration buy nexium 20 mg without a prescription, however nexium 40mg with visa, might only provide evidence of the therapy in question. Looking at products in the same effects on surrogate endpoints from short-term studies. Manufacturers often there have been no significant innovations in the therapy use economic models, which are generally received with area for some time or if it is an uncharted area for a scepticism by payers, to attempt to demonstrate the link pharmaceutical. In some cases, it is possible to define the between the surrogate results that are shown in clinical therapy area relatively broadly and still gain useful trials and the projected long-term outcomes from the insight. Given that, in most countries, it is not possible to vascular disease are generally viewed as having a com- raise prices once they are set, the conundrum for phar- mon ultimate aim: to reduce the risk of major adverse maceutical companies is managing the trade-off cardiovascular events. A risk-sharing strategy becoming increasingly important in providing the can be applied if there is partial evidence that a new methodological framework for quantifying the eco- product has significant value, although it might require nomic value of a new product compared with present long-term or naturalistic studies to robustly confirm therapies. Under these circumstances, the pricing authority incorporates value-based pricing into its analytical might allow the launch of the product at a premium approach and provides a reference point for quantifying price on the condition that these naturalistic studies are the differential value of a new pharmaceutical. The drug price might then be amended The pharmacoeconomic value of a new pharma- once the outcomes are known. In this way, the manufac- ceutical product is generally measured by a comparison turer has assumed part of the risk that the product of the change in total health care and other costs with will not work in the real world as projected on the the change in health outcomes that are associated basis of the clinical trial data. Changes in costs tion of risk-sharing strategies have involved treatments include the acquisition and administration costs for for multiple sclerosis in the United Kingdom and the new product compared with those for the drugs Alzheimer s disease in Italy. In both countries, the that the new therapy might replace, as well as changes authorities are paying for drug treatments only if they in the costs that are associated with treatment of the have proved effective in the patients to whom they were disease and with side effects. Also included might be administered, as demonstrated through modified forms changes in productivity-related costs and other indirect of naturalistic clinical studies. For a drug-value analysis, changes in health out- comes are most commonly measured in changes of Communicating value. Many countries now incor- Increasingly, the vehicle that is used for communicating porate a review of pharmacoeconomic evidence as the most complete picture of the differential value of a part of their assessment of whether to recommend product is a value dossier, which is aimed specifically at reimbursement or usage of a new product at the price the payer, and focuses on the clinical and economic that is requested by the manufacturer. For example, product/add product to Clinical innovation prescribers in health-care systems that are subject to formulary? In addi- Level of physician demand tion, for products in which a large proportion of the Level of patient demand/advocacy price is an out-of-pocket cost to a patient for example, lifestyle products such as erectile-dysfunction drugs Prescriber Expected clinical improvement the price sensitivity of patients is heightened and the "Should I prescribe patient perspective needs to be carefully considered in this product? As illustrated by these two examples, Personal financial impact the importance of a particular stakeholder for value esti- mation and pricing strategies tends to be proportional to their role in paying for the product. Patient Prescriber recommendation "Should I accept Therefore, the formal payer or financial gatekeeper this prescription/fill this Co-pays/out of pocket prescription? The payer, prescriber and patient can each play a role in the purchase decision for a pharmaceutical. This is advances, and what evidence they require to demon- particularly important for products that are expected to strate those advances, is a crucial component of value have a large effect on the drug budget, and/or if the estimation and price planning. As stated previously, current burden of the disease is not well understood and these issues must be considered by pharmaceutical com- needs to be highlighted. The customer In addition to assessing the value for money of a new In most industry- or consumer-purchase situations, therapy, the issue of affordability is an increasingly the same person or entity initiates the purchase of a prominent focus of payers who are faced with rapidly product, uses it and pays for it. The prevailing silo the manufacturer, for the purposes of valuing and mentality in many parts of the world, in which drug pricing a product, is therefore clear. Evenin situations in has an influence over the purchase decision for a par- which robust evidence indicates that a drug will lead to ticular product, in which price will probably have a reductions in costly events elsewhere in the health-care role. Similarly, the decision of options,such as segmented patient strategies,are available a doctor to prescribe might be affected by the reim- for use in price negotiations. A Box 1 | The influence of different health-care systems on pricing discount rate of 10 12% is generally chosen in the phar- Differences in the structure of health-care funding between the United States and maceutical industry as the standard rate at which to value Europe result in different pricing environments. People choose the level of coverage that they desire,although and marketing lifecycle. In Europe,national health systems dominate and provide health care timing during drug development. These include the to all,with funding through a mixture of taxation and national insurance systems. In general, for every 5,000 mole- must typically pay almost the full list price for medicines. In this situation,the purchaser clearly has immense price is lower than the maximum feasible price from negotiating power. Drug prices in Europe are further constrained by cross-national price the market perspective, then the investment should be referencing and parallel trade between countries. These include the following: formularies in the United States are comparable along the product development timeline as new clinical to positive lists in Europe; tiered co-pays in the United States are analogous to the tiered and market data become available. Also,although pricing flexibility is presently greater in the United States,the recent turing capacity. The phenomenon of the price in one coun- the unit price and the unit production cost.
And as a result purchase nexium 40 mg without prescription, in some cases the antibi- problems nexium 20 mg, resulting in a reliance on drug promotion for otics/antibacterial drugs are used in nonbacterial infec- revenue generation. Therefore the massive promotion of tions and diseases such as viral infections like flu and medicines like antibiotics/antibacterial drugs by the phar- most especially the acute respiratory viral infections. The maceutical drug companies and medical representatives global increase in irrational antibiotics in humans and increases the volume of the medicines in the healthcare animals have resulted in increasing selection of antibiotic facilities, communities and in the public and this greatly resistant bacterial organisms that also has resulted in re- promotes the irrational drug use in both the medical and duced pharmaceutical companies investing in production veterinary practice, food industries and in agriculture of newer and effective drugs . And currently, antibiotics resistance has out- sistant bacteria that can spread globally and hence con- paced the production of new antibiotic/antibacterial drugs tributing continuously to a global health problem. The antibiotics/anti- environment leading to selection of resistant bacteria in bacterial drugs enter the environment in a complex vi- the environment. The bacterial organisms in the environment sewage or landfill daily by humans and others from ani- get exposed to sub-therapeutic antibiotic concentrations mals and food industries where they eventually enter the from excessive overuse of antibiotics and hence promot- environment causing environmental pollution and hence ing the development of antibacterial resistant mecha- affect the environmental bacterial organisms as well as nisms that spreads in many organisms in the environment. They can also af- Many resistant bacterial infections to various antibiotics/ fect the microbiota in the ecosystem leading to the dis- antibacterial drugs have been documented in nature and ruption of the various environmental cycling of the or- in some human pathogens. Also the discharge of antibi- ganic matter and the resistance is also transferred to ani- otic/antibacterial drugs by the pharmaceutical plants and mals and to human pathogens. They also cause alterations from the various healthcare facilities like hospitals and of the bacterial flora both in sediments and in the water industries in waste water and various water bodies have column . In this way, the wild type (non mutants) bacteria are ing to destruction of useful bacteria and selection of re- killed and the resistant mutant survives and grows. The antibiotic resistant bacte- horizontal gene transfer is another mechanism beyond rial organisms are selected from the several populations spontaneous mutation that is responsible for the acquisi- of bacteria in the environment mainly by horizontal gene tion of antibiotic resistance. The intrinsic escape from the chromosome into plasmids, transposons, or inherent or natural resistance is due to lack of target or integrons that may occur as mobile genetic elements sites or molecules for the antibiotic to bind and lack of which can be disseminated into similar or dissimilar spe- transport system for an antibiotic into the organisms cies through the process of conjugation, transduction and [43-49]. Antibiotics are chemical substances naturally produced by various species of microorganisms such as bacteria, fungi, actinomycetes and streptomy- ces that kill or inhibit the growth of other microorganisms [1-4]. Antibacterial agents or drugs are chemical substances that inhibit bacterial growth and their multiplication or directly kill bacterial organisms [1-4]. Antimicrobial agents or drugs are chemical substances that destroy various microbial agents including bacteria, viruses, fungi and protozoa organ- isms [1-4]. Golden age of antibiotics is the period when the entire antibiotics/antibacterial drug spectra were discovered and in this period almost all bacterial infections were treatable with these drugs [4,7]. Drug promotion is defined by the World Health Organization as all informational and persuasive activities by manufacturers, the effect of which is to induce the prescription, supply, purchase and/or use of medicinal drugs [15-18]. Pharmaceutical marketing or medico-marketing or pharma-marketing is the business of advertising or otherwise promoting the sale of pharmaceu- ticals or drugs [15-18]. Self-medication is the use of drugs or pharmaceutical products by the consumer to treat self recognized disorders or symptoms or the intermittent or continued use of the medication prescribed by the physicians for a chronic or recurring diseases or symptoms . Antimicrobial-resistant bacteria in the community setting (Adopted from Furuya and Lowy (2006), Nat Rev Microbiol. The various host range and are able to cross genus lines during the mechanisms of acquired resistance expressed by bacte- gene transfer. These matic alteration of the antibiotic 2) metabolic bypass of genes sometimes encode resistance factors. The use of the targeted pathway or the presence of an alternative antibiotic growth promoters in animal husbandry may pathway for the enzyme that is inhibited by the antim- increase the amount of free phage in the gastrointestinal icrobial agent 3) a mutation in the antimicrobial agent s tract that may contribute to the spread of antibiotic resis- target, which reduces the binding of the antimicrobial tance. Characteristics of different elements involved in resistance gene spread [13,50-52]. Mechanisms of resistance against different antibiotic/antibacterial drugs [44,45,47,48]. These creased emergence of resistant zoonotic bacterial dis- have promoted the emergence of resistant bacterial such eases. The lack or poor regu- rial-resistance-to-antimicrobials-From-the-Go/ArticleStan lation of the use of these drugs coupled with increased dard/Article/detail/660591 levels of corruption by various government authorities  Gottfried, J. Avoiding a Return especially in the developing countries has led to massive to the Pre-Antibiotic Age. Michigan State Uni- responding to pharmaceutical promotion a practical guide versity, East Lansing. Indian Journal of Me- teristics of patients receiving pharmaceutical samples and dical Research, 134, 281-294. Technical Reference, Promega Founda- otics and by antibiotic resistance determinants. Nature Reviews Micro- tic use among secondary school teachers and university biology, 4, 36-45. International Journal of  Encyclopdia-Britannica (2013) Antibiotic resistance: Me- Preventive Medicine, 3, 839-845.
Nonimmunologic or mechanical barriers include gastric acid secretions and proteolytic enzymes generic nexium 40mg on-line. These digest proteins into molecules that are less antigenic generic nexium 20 mg otc, either by reducing the size (14) or by altering the structure ( 4,14), as described below in the section on tolerance. Other physical barriers include peristalsis, mucus production, and mucus secretion. The gut epithelium itself provides a barrier against significant macromolecular absorption (15). Physical factors that increase the rate of absorption are alcohol ingestion and decreased gastric acid secretion. Increased acid production and food ingestion both decrease the rate of absorption ( 16). Dimeric secretory IgA accounts for most of the increase in IgA production and serves to bind proteins, forming complexes and thereby decreasing the rate of absorption ( 21). For the macromolecules that do get absorbed as intact antigens approximately 2% ( 19) there is the development of oral tolerance. Tolerance is an immunologic unresponsiveness to a specific antigen, in this case food proteins ( 23). Both the local and systemic immune system appear to play a significant role in the development of oral tolerance ( 22), although the exact mechanisms are not well understood. The processing of antigens by the gut into a nonallergenic or tolerogenic form is important ( 24). This has been reported in studies of mice fed ovalbumin, which is immunogenic when administered parenterally. Within 1 hour after ingestion, a form similar in molecular weight to native ovalbumin was recovered from the serum. This tolerogenic form of ovalbumin induced suppression of cell-mediated responses but not antibody responses to native ovalbumin in recipient mice ( 24). This intestinally processed ovalbumin is distinct from systemic antigen processing ( 24). Mice that were first irradiated were unable to process the ovalbumin into a tolerogenic form. Food hypersensitivity is the result of a loss of or lack of tolerance, the cause of which is likely multifactorial. Until recently some of this immaturity was thought to lead to increased absorption of macromolecules from the gut of infants, but studies now indicate that this is not likely ( 30,31). The importance of local IgA is further supported by the finding of an increase in incidence of food allergy associated with IgA deficiency ( 36). Mast cells that play a significant role in the food allergy reaction also appear to play a role in the maturation of the gut associated with weaning (40), a process affected by the mucosal immune system. This is evidenced by inhibition of small intestinal maturation and decreased numbers of intraepithelial lymphocytes with the addition of cyclosporine A ( 41). It has been noted that there is an increase in systemic antibody production, generally food-specific IgM, and IgG in patients with inflammatory bowel disease and celiac disease ( 36). However, the significance of these antibodies is not known because the patients often tolerate these foods well ( 42,43). Food-specific antibodies are also found in normal individuals, although usually of lower level ( 42). Any disruption of the immunologic or nonimmunologic barriers could alter the handling of antigen and lead to an increased production of systemic antibodies. In individuals with genetic predisposition to atopy, this could lead to IgE production and resultant food hypersensitivity reactions on reexposure ( 45). Many more human studies need to be performed in order to elucidate the mechanisms. The glycoprotein in food is the component that is most implicated in food allergies. Glycoproteins that are allergenic have molecular weights of 10,000 to 67,000 daltons. They are water soluble, predominantly heat stable, and resistant to acid and proteolytic digestion ( 46). Although many foods are potentially antigenic, the vast majority of food allergies involve only a few foods ( 47). The combined results of double-blind placebo-controlled food challenges performed in the United States (primarily in children) showed that eight foods were responsible for 93% of reactions (39). The prevalence of specific allergens may vary for different countries, depending on exposure patterns. Allergens found commonly in children but not in adults (eggs, soy, milk and wheat) are usually outgrown with strict elimination for 1 or more years (48), although evidence of IgE antibodies may persist ( 49). Those with histories of severe reactions may take longer to develop clinical tolerance, up to several years (48,50). The others [peanuts ( 51), tree nuts, crustacea (52), and fish (53)] tend to be lifelong and thus are common to both populations.
One can see that the contribution new developments from which nuclear medicine of nuclear physics to hadrontherapy has been enor- will beneft nexium 40 mg visa. In this regard buy nexium 40mg with amex, exploitation of new In applying nuclear physics in medicine, con- technologies in the nuclear physics research will structive interaction with physicians is central. The main point of Te answers to these questions are various and this chapter is to emphasise how nuclear phys- require some consideration and are addressed to ics research has always been involved in medical some extent in this booklet. Developments in medical imaging parallel advances in instrumentation for nuclear physics experiments, sharing methods, In the footsteps of the alchemists techniques, and manufacturers. Emphasis is given Paracelsus, a famous alchemist and medicus of to the interplay of detector design and simulation the early 16th century stated: Many have said and reconstruction models. A point of major focus of alchemy, that it is for the making of gold is quality control in hadrontherapy. For me such is not the aim, but to also briefy describes some applications in medical consider only what virtue and power may lie imaging of mass spectrometry, which is playing an in medicines. Today, 500 years afer Paracelsus, we may diferent strategies for producing isotopes for med- therefore conclude: Many have said of nuclear ical use. Indeed radionuclides are the essential fuel physics, that it is for the making of new gold that is driving all nuclear medicine applications. For With few exceptions the required radionuclides us such is not the only aim, but also to con- are not present in natural decay chains, so have to sider what virtue and power may lie in these be produced by artifcial transmutation driven by for medicine. It is important to stress that advances in Tis report is organised into three chapters: the production of new radioactive isotopes come the frst on hadrontherapy, the second on medical out of accelerator and research reactor centres that imaging and the third on radioisotope production. On the other hand the infuence of new In general, accelerator and research reactor techniques and of particular improvements in centres play a key role in education and training each of these topics on the others is well stressed of scientists and technical personnel for nuclear in the three chapters. As a fnal remark it is worth noting that the booklet is not intended to be a position paper. Rather, it gives an updated overview of how fun- damental nuclear physics research (in its broadest sense) has had and will continue to have an impact on developments in medicine. As with previous Framework Programmes, it is important to be engaged in and committed to nuclear physics pro- jects within Horizon 2020 that will enhance the mutual roles of fundamental and applied nuclear research. Tese reports have shown has grown into an advanced, cutting-edge clini- the very strong interface between physics, biol- cal modality. More than 10,000 instruments, which have had a large impact on our have been treated with heavier ions, generally car- healthcare systems. Various companies are now ofering turn-key on hadrontherapy gives an updated view on the solutions for medical centres. Te benefts of hadrontherapy are based both In 1946, accelerator pioneer Robert Wilson laid on physical (better ballistic accuracy) as well as the foundation for hadrontherapy with his article in biological reasons (especially for heavy ions), result- Radiology about the therapeutic interest of protons ing in more accurate and efcient irradiation of for treating cancer . Today, cancer is the second the tumour, thereby reducing the dose to the sur- highest cause of death in developed countries. Its rounding healthy tissue and thus leading to a lower treatment still presents a real challenge. Clinical interest in hadron therapy Pion therapy worldwide resides in the fact that it delivers precision treatment Vancouver 1979 1994: 367 patients of tumours, exploiting the characteristic shape of Villigen 1980 1993: 503 patients the Bragg curve for hadrons, i. While Proton therapy Villigen X-rays lose energy slowly and mainly exponentially 1974: Ocular treatments 72 MeV as they penetrate tissue, charged particles release passive beam spread more energy at the end of their range in matter 1996: deep seated tumours 230 MeV ring the Bragg peak. Te Bragg peak makes it possible cyclotron to target a well-defned region at a depth in the Active beam delivery: horizontal magnetic body that can be tuned by adjusting the energy of defection the incident particle beam, with reduced damage to Vertical: patient shif the surrounding healthy tissue. Te dose deposition Depth: degrader is so sharp that new techniques had to be developed to treat the whole target. To allow 1999 Dubna full fexibility in patient treatment, the accelerator Sweden: should be coupled to an isocentric beam delivery 1989 Uppsala system called gantry. By the end of the 1980s it ofcially launched an ambitious programme became clear that there was no clinical beneft to to extend its cancer treatment replacing the patients and that a cost-efective treatment was not old synchrocyclotron with a 250MeV proton possible because of the high cost of pion production. Proton therapy 2012 Launch of the project France Hadron for was already active in Russia, but it was not yet very research and creation of infrastructures popular in Western Europe. State-of-the-art techniques borrowed from parti- Mnchen: cle accelerators and detectors are increasingly being Rinecker proton project proposal February 2002 used in the medical feld for the early diagnosis and 2013: 1500 patients treatment of tumours and other diseases; medical Austria: MedAustron: doctors and physicists are now working together May 1993 Austron project was proposed: and are able to discuss global strategies. Hadrontherapy is a feld in its At present the synchrotron is installed and infancy and in a clinical research phase with great patient treatment is expected in 2 years potential. Te cyclotron has been used tor of FermiLab, at that time working at Harvard for fast neutron radiotherapy and proton therapy of University. He realised that by exploiting the high eye melanoma and is still used (2013) for treatment of dose deposit (Bragg peak) at the end of the particle ocular tumours. It was the frst dedicated clinical duce a dose distribution that is highly conformal facility equipped with three rotating gantries.
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