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America is a meat-and-potato culture diabetes medications for type 2 order cheap acarbose, and many Americans would view the Dole menu as fancy or exotic jurnal diabetes insipidus pdf generic acarbose 25mg mastercard. Californians may be more familiar with diverse cuisines compared with other parts of the United States diabetes diet no sugar purchase acarbose, particularly the central part of the country diabetes insipidus histiocytosis generic 50mg acarbose mastercard. Nevertheless, Dole faced a challenge in getting its employees to accept the menu changes. The pricing, presentation and, of course, taste have slowly won over most of the employees. Despite the obvious advantages of removing unhealthy foods from the workplace, it is not clear whether the Dole approach would work in a largely blue-collar, industrial setting with burly men resentful that they are forced to eat tofu. In Dole’s defence, there is nothing stopping employees from packing a lunch or visiting a nearby restaurant. Dole hopes to reduce health-care costs but also attract and retain employees with the attractive benefit of an inexpensive and pleasant canteen. Dole is working with an independent clinic to evaluate the programme’s health impact on a group of 50 volunteers. Grossman reports that employees are losing weight – sometimes without trying – and have come to view the canteen as a perk. Dole also sees itself as an industry leader and hopes to raise the standard of American workplace nutrition. Grossman, also a vegetarian, said she could count on him to support the ambitious health programme that she and her staff created. In other companies, the healthy choice might not be chosen because it is either tasteless or expensive. While most unhealthy food has been stripped from the canteen, workers do have temptations: they can eat out or bring food from home, and these choices are unlikely to be as healthy as food at the Dole canteen. Essentially, Dole uses incentives to make it impractical to maintain an unhealthy lifestyle. One worry was that the employees would reject the changes, resenting that they were being forced to eat healthy foods. Indeed, many employees grumbled at first that their favourite, unhealthy foods were gone. Union/employee perspective the Dole headquarters has no union to offer its perspective. Employees grumbled at first about being forced to eat “health food”, but most have come to appreciate the canteen. Many are losing weight, some without trying, and this has boosted the canteen’s popularity. I really look forward to my salad at lunch with the same kind of gusto that in the past I would have reserved for less healthy, higher calorie meals,” said one male employee. Other comments reflect the real ity of staying on a diet alone, such as this from a female employee, “I wasn’t doing it myself. Guatemala City, Guatemala Type of enterprise: San Pedro Diseños is a textile company founded in the early 1990s. Food solution – key point: revamped meal programme to address workers’ lack of calories and nutrients. San Pedro Diseños workers are mostly low wage earners – operators and manual workers. Most (75 per cent) come from distant parts of the country and 90 per cent have less than six years of education. Operators’ wages vary based on productivity, and are usually higher than the salary for manual workers. Workers live on the margins of poverty in rented houses in the city, often with extended family members. Several years ago the company established an occupational health and safety programme, for which it was recognized nationally. Through an initial health surveillance managers discovered the extent of poor nutrition and poor knowledge of nutrition among the workers. In essence, the workers’ health status reflected that of the nation, where 36 per cent of women of child bearing years are anaemic and the average deficiency of calories is 200 kcal per day, according to the Instituto de Nutrición para Centroamérica y Panamá. The workers at San Pedro Diseños had a typically meagre and unvaried diet of rice, beans and corn tortilla, which afforded them some calories but not the recommended intake of micronutrients. Guatemala experienced fluctuations in its food supply during the 1980s, and food availability has fallen sharply since 1995 to a current, critical level, ten years later. Approximately 60 per cent of homes do not have enough income to provide the calories and nutrients required. Since 1997, two minimum wages are needed to cover the basic food cost for a family. Child malnutrition 67 Food at work: Workplace solutions for malnutrition, obesity and chronic diseases Workers prepare tortilla in one of three kitchens, adhering to safe food-handling principles (E. Food solution the San Pedro Diseños management came to realize that the majority of workers started their day without breakfast and many didn’t have a nutritious lunch. Workers said they chose their food based on price: eating rice, beans and tortilla was the cheapest way to feel full. Most complained of a lack of money to buy food or a lack of time to prepare meals. What little they understood about nutrition, which was often incorrect, came from television, magazines, and friends and family. Manage ment started a nutritional plan as part of an enterprise policy and outlined three main strategies: food security, social services (making sure workers can afford the food) and health (general check-ups). The basics of the new meal programme include: cooking facilities; a dining area; subsidized meals; an hour-long meal break; free sweet bread (pan dulce or 68 Canteens and cafeterias the dining area is simple but pleasant, with room for all 250 workers (E. The company’s dining room is about 120 square metres and accommodates 150 workers comfortably. During the 60-minute lunch break, workers make the short walk to one of two serving areas to purchase a meal. Some workers play sports before lunch, so the 150-seat dining area is large enough to facilitate 250 workers eating lunch at different times during the long break. Lunch contains 1,000–1,100 kcal, about half the daily requirement to perform the type of work at San Pedro Diseños. There are three or four main items on the menu each day, and this includes meat, soup, rice, fresh vegetables, salad, tortilla, pasta and a beverage. So, the total weekly cost to the workers for a decent daily meal is Q30, which is about 9 per cent of the lowest factory wage. Before 1998 the company maintained three factories in different locations, each with a small, overcrowded canteen. The new facility has space for three kitchens: two to cook meals and one to make tortillas. The kitchens each have three or four cooks who have licenses issued by the Ministry of Public Health. Possible disadvantages of food solution There are few disadvantages of the new meal programme. The San Pedro Diseños meal costs 9 per cent, but it is not clear how many workers earn only the minimum wage. The company has now recognized the need to educate the workers about nutrition and will implement a programme in the future. The cost of hiring cooks was not disclosed, but this was more expensive than hiring unlicensed, untrained cooks, a temptation in poorer nations. Workers are more productive and more satisfied; morale is higher; absenteeism and the need for rotation due to illness have fallen; and medical costs are down. Since 2001, production has increased by around 70 per cent and annual earnings have increased approximately 20 per cent. With a modest budget the company offers a canteen as impressive as the Dole canteen presented in the preceding case study. The company saves money by offering simple chairs and tables, which can be moved easily. This also gives workers sufficient time to rest, which is particularly important in the hot climate.


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It can often be diffcult to control diabetes early stages order acarbose australia distinguish the effects of alcohol and drugs from your mental health symptoms diabetes beauty treatments purchase 25mg acarbose amex. However blood sugar 61 order 25mg acarbose with visa, there are lots of things you can do to diabetes mellitus type 1 symptoms purchase genuine acarbose online manage your symptoms and increase your wellbeing. You could try using a free mood diary online, such as Mood Panda (see ‘Useful contacts’ on p. For example, if you often feel high after a late night or low when facing a deadline, it can help to recognise these patterns. You may start to notice that there is a pattern to how you feel before an episode. This could be changes in your sleeping pattern, eating patterns or appetite, or in your behaviour. Being aware that you are about to have a change in mood can help you make sure you have support systems in place and that you can focus on looking after yourself. It can also help to discuss any warning signs with family and friends, so they can help you notice changes. Having a routine can help you feel calmer if your mood is high, motivated if your mood is low, and more stable in general. Your routine could include: – day-to-day activities, like when you eat meals and go to sleep – time for relaxation or mindfulness – time for hobbies and social plans – taking any medication at the same time each day – this can also help you manage side effects and make sure that you have a consistent level of medication in your system. You can contact National Debtline for free, impartial fnancial advice (see ʽUseful contactsʼ on p. For lots of people who experience bipolar disorder, disturbed sleep can be both a trigger and a symptom of episodes. Eating a balanced and nutritious diet can help you feel well, think clearly and calm your mood. Gentle exercise, like yoga or swimming, can also help you relax and manage stress. The trick [for me] is not to be seduced by the ‘high’ and to look after [my]self – get enough sleep, good nutrition. Use your support network Friends and family the people closest to you can be really important in helping you manage your mood. Peer support Making connections with people with similar or shared experiences can be really helpful. You could try talking to other people who have bipolar disorder to share your feelings, experiences and ideas for looking after yourself. You might fnd that people have misconceptions about you or have a negative image of bipolar disorder. This can be very upsetting, especially if someone who feels this way is a friend, colleague, family member or a health care professional. Show people this information to help them understand more about what your diagnosis really means. The aim of treatment should be to help you maintain stable moods and manage your symptoms well. If you are receiving a talking treatment, you might set some of these goals with your therapist. You may also want to share them with your family, friends and carer if you have one. There are several talking treatments you might be offered to help you manage your bipolar disorder in the long term. Enhanced relapse prevention/individual psychoeducation – this is a brief intervention to help you learn coping strategies. It aims to help you balance your sleep cycle, work-life balance and daily routines. What you are offered can also depend on what you and your doctor agree would be most useful for you. Your current symptoms, for example, if you are currently experiencing a manic or depressive episode. Before prescribing you any medication, your doctor should explain to you what the medication is for, and discuss any possible side effects and alternative treatment options. Lithium for bipolar disorder Lithium can be a very effective treatment for mania, but is less effective at treating severe depression. However, in these situations, people often experience repeated episodes, even with lithium treatment. Anticonvulsants for bipolar disorder There are three anticonvulsant drugs used as mood stabilisers which are licensed to treat bipolar disorder: carbamazepine (Tegretol); valproate (Depakote, Epilim) and lamotrigine (Lamictal). Lamotrigine has antidepressant effects and is licensed to treat severe depression in bipolar disorder. Antipsychotics for bipolar disorder You are most likely to be prescribed an antipsychotic if you have an episode of mania or severe depression in which you experience psychotic symptoms, such as hearing voices. The antipsychotic asenapine (Sycrest) is also licensed as a mood stabiliser for moderate to severe manic episodes in bipolar disorder. You might be offered antidepressants in combination with one of the medications described above. Note: You should always check with your doctor or pharmacist before taking any drugs together, or closely following one another, in case they could interact with each other badly. So it can be useful to make a plan for how you want to be treated, while you are well. For example, you might want to make an advance statement, or if you have a crisis team, create a crisis plan with them. Planning ahead for a crisis can also reduce the likelihood that you may need to be sectioned, as those around you will know better how to handle an emergency. This section is for friends and family who want to help someone who has bipolar disorder. Seeing someone you care about going through the moods and symptoms of bipolar disorder can be distressing. But there are lots of steps you can take to offer support, whilst also looking after your own wellbeing. Be open about bipolar disorder Being open to talking to someone about their experiences can help them feel supported and accepted. If you fnd it hard to talk about bipolar disorder or want to learn more, reading through this booklet is a positive frst step to take. Make a plan for manic episodes When your friend or family member is feeling well, try talking to them about how you can support them if they have a hypomanic or manic episode. It can be helpful to calmly discuss your feelings with them when they are feeling more stable. Most people will have some warning signs that they are about to experience an episode of mania or depression. The best way to learn what these are for your friend or family member is to talk to them. If you have noticed certain behaviours that normally happen before an episode, you can gently let them know. You can try to understand what these triggers are for your friend or family member, and how you can help avoid or manage them. Having a father with bipolar is defnitely a worry; you ride the highs and lows with them. If those around me are concerned about whether changes are symptomatic of relapse [I encourage them] to ask, not assume. You may feel very worried about your friend or family member, but making sure that you stay well will enable you to continue to offer support. Support for people with bipolar disorder and their families and National Institute for Health friends. Emotional support for anyone feeling down, experiencing distress or struggling to cope. Whether you, or someone you care about, have bipolar disorder, your strength and courage is an inspiration to us all. A special thanks to the children who inspired us to found this organization, Chris, Court, Lauren and Sam. The information compiled in this book is meant to provide useful information on the topic of Bipolar Disorder. This book is not meant to be used, nor should it be used, to diagnose or treat any medical condition. For proper diagnosis or treatment of any medical problem you must consult your own physician.

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Anticipation and Entrainment However managing diabetes and pregnancy order generic acarbose line, in light of the above anticipation ‘Synchronization bandwidth’ of entrainment related metabolic disease ruminants acarbose 25mg, a question is then arisen as approximately 30 milliseconds is one of the to diabetes mellitus diagnostic criteria generic 25mg acarbose amex what degree is entrainment a conscious results of the analysis of entrainment in case process and how far is it from being an study 3 diabetes signs and symptoms tagalog purchase cheap acarbose on-line. How far can this method attest the learning take place without violating the linkage between synchrony and entrainment cultural and musical characteristic of the phase memorization processing in oral culture? This is a computer modes of anticipation – but in the sense of metaphor – the kind of digital computer that planning. Within the context of sensory motor symbolized the brain in early phase of coordination, he is referring to an experiment cognitive science – and it stands in sharp performed at the Juilliard School of Music, in contrast to ‘self-organization’ that is central to which musicians were asked to syncopate with dynamical system theory, that seems to be the an auditory stimulus (repeated tones), than preferred platform in this target article. And switching to a synchronized state with the fact that a timekeeper activates this pattern increasing frequency of the repetitions. In at a specific moment as part of its evolving in other words: performing a transition from an time does not mean that the pattern computes anti-phase to a phase with the metronome. Additionally, he compared the magnetic field of the left side of the brain during these two perception-action tasks – syncopation and synchronization – pointing out to an interesting phenomenon, paradoxical in its nature because we would expect just the opposite: apparently, there seems to exist an inverse correlation between strong brain periodicity in anti-phase. One possible explanation for this seems to be that syncopation is more difficult to perform, since it demands the attention of not only anticipating where the next beat is (as is the case in synchronization), but also estimating the temporal location of the in between beats point – a task which increases attention load. Consequently to Kelso’s experiment, it seems that stimulus rate is not necessarily an influencing factor, or at least is not in direct correlation with the degree of brain state coherence. In view of the above, and returning for a moment to the entrainment process identified in case study 3, I think that it would be interesting to make an experiment basing solely on data of case study 3, in order to detect brain states during the transition from pre-entrainment mode to in-entrainment mode and within each of the modes, as presented in Fig. Summarizing, I think one needs to establish a precise and coherent framework for further discussion and investigation the subject of synchronization and entrainment within cognitive ethnomusicology research. It should include clarification of certain ambiguities and consider some questions arising from the study of entrainment, for example: Authors’ response: In Time With the Music 70 respective roles, without favouring one over the Authors’ response to the other. This is why entrainment theory seems able commentaries to avoid the cognitivistic bias (‘consciousness bias’: only what is conscious is real) dominant in Writing on entrainment phenomena can many a discipline dealing with human behaviour indeed seem, at times, like little more than and contributing much to the stating the obvious, and yet a serious attempt to ethnological/scientific divide, as we are explain real life entrainment phenomena in reminded, for example, by Balasa’s musical behaviour throws up numerous, often commentary. For entrainment theory any bodily unexpected complexities that are yet to be implementation of interacting processes is real, unravelled. The commentaries on our target no matter whether it is consciously experienced article have helped us to get a little closer to or not. It was fascinating to read the very lines of the cognitivistic body/mind divide, different responses of such a diverse group of creates a confusion of terms: it suggests that scholars and we are grateful for all critical and ‘cognitive entrainment’ is a type of entrainment thoughtful remarks and suggestions received, distinguishable from other types of entrainment, which have helped to clarify and advance the when in fact it is defined as ‘feeling of discussion and debate on the issue. Some synchrony’, referring only to the awareness of a important themes have emerged from these process of synchronization, not a specific type of commentaries on which we have organized our synchrony or mode of entrainment. Our reply focuses on areas where we object to introducing ‘cognitive entrainment’ as a feel that our intention and position was distinct category, we do agree with Pearl that a insufficiently clear in the original presentation, clear distinction needs to be made between the and where we feel the need to supply additional feeling of what happens and the actual physical information about current developments in processes. As the comments of Pearl, Sweers, entrainment research, as well as areas where we Lucas and Allgayer-Kauffmann affirm, feeling take a view different from those expressed in the and appearance to the observer of synchrony and comments. Conscious states and socio Scope cultural interpretations, however, should not be As Pearl points out in his commentary, confounded with synchronization itself. What our target article is partly an attempt to set entrainment theory offers is, in our view, a ethnographic and empirical/scientific approaches chance to analyze how these appreciations and to music research on an equal footing. Moreover, evaluations can, in turn, become factors we think that in addition to complementing influencing entrainment. The entrainment theory is a kind of ‘open theory’ that generally accepted distinction between self supplies basic principles and procedures, but entrainment and other forms of entrainment only leaves it to the respective disciplines to apply concerns the organizational level (entrainment them to specific systems, identify the oscillatory within or between organisms, bodies, etc). The entrainment may be based on physical forms of theory permits understanding of certain interactions that do not and cannot exist if phenomena of human behaviour (entrainment) in entrainment takes place between different bodies terms of the bodily realizations of the underlying or organisms. The principal entrainment oscillatory processes, and there is no a priori mechanisms and phenomena, however, hold in distinction between conscious and unconscious both cases. On the contrary, entrainment theory is unique to musical entrainment (Bispham), it will able to deal with both and acknowledge their be up to music researchers to establish this by Authors’ response: In Time With the Music 71 analysing specific realizations of entrainment in structures might induce different styles of musical context. Until such uniqueness is attention, which in turn may be associated with proven, we remain wary of a hypothetically different kind of experiences, deserves further distinct classification for musical entrainment. Here it is important for us to assert that shifts and (limited) fluctuations of the phase entrainment is precisely concerned with the differences are a general feature of dimension of time: We do not think this synchronizing dynamical systems, not just of necessarily precludes for example its application human behaviour. The defining criterion for to studies of timbre or pitch, which are both phase locking is that the phase differences temporal phenomena, but any entrainment between processes stay smaller than a certain studies concerning timbre and pitch would be value. On the other hand, entraining stimuli interacting forces, and the noise components do not necessarily have to be acoustic ones; they involved. Despite these fluctuations, the could also be visual or tactile (although "synchronization bandwidth" or degree of entrainment to acoustic stimuli may have synchronization can nevertheless be described in characteristic that distinguish it from other quantitative terms. We have given some the second point is that conceiving examples of entrainment to non-acoustic stimuli "synchronization bandwidth" as something in the target article, and Allgayer-Kaufmann‘s ambiguous or imprecise misses the essential marching band offers an additional one. In all point that the ‘bandwidth’ or degree of cases, however, what matters is that we are synchronization informs us about important dealing with temporal relationships of two or features of the interaction between two more autonomous processes. This limitation to oscillatory processes: the weaker the interaction the temporal domain is at the same time the or the more noise it contains, the broader the conceptual strength of the theory. For example, after all, is no more than an interpretive and familiarity with a certain style of music can explanatory model that can be applied to certain affect the degree of synchronization. Its explanatory the variance of the phase differences) in response power may be great, but it is not, and we do not to this music and the response variability may intend that it be taken for, a theory of everything represent the factor ‘familiarity with the music’. If necessary, this bandwidth can also easily be Allgayer-Kaufmann also brings up a described in quantitative terms, for example in couple of other ideas that might be explored terms of dispersion around mean values. One is the role of memory and its use to Furthermore, synchronization – as defined predict likely changes in musical periodicities – above, i. The idea that listeners may have necessarily constant – is not just contrasted with learned enough about likely processes in musical a-synchrony. In-between these two states we find performances to mean that prediction is at least a zone where the dynamics of phase differences as important as tracking in the entrainment is intermittent: epochs of relative stability of process is a topic not developed greatly in our phase differences. Likewise, the point made by region of intermittent synchronization, often Clarke, with reference to the work of M. Jones encountered in the interaction of processes that and co-workers, that different rhythmic are not strictly periodic, is probably of special Authors’ response: In Time With the Music 72 interest for musicologists dealing with non harmonic, noisy periodic, and non-periodic periodic and free rhythms. The short theoretical example indicating one possible great challenge is to determine the onset of approach for dealing with non-periodic intermittent synchronization, especially if movements. Individual these oscillators must have some features that phase measurements, such as applied by BenZvi, correspond to the frequency and/or phase of are obviously inadequate. One of sufficient number of phase difference the features shared by periodic and chaotic measurements, these can be tested for instance movements is the recurrence of events. The time against an equal distribution or random walk between corresponding events is fixed for distribution, and it is possible to detect even periodic oscillators and constantly changing and relative weak and noisy synchronization. Where the fiddler is accompanied by Kaufmann) and ‘non-periodic movements’ may a periodic (quasi-periodic) drum beat, we have constitute an essential component of musical two series of return times (changes in the performances (Clarke). Mathematically this involves the oscillators these are but a special case of same procedure of calculating the relative phase autonomous oscillators that can entrain and are as we have demonstrated in our case studies. Entrainment only difference is that the period length of one of research is concerned with quasi-periodic the movements (bow arm) is not constant. Furthermore, since Lou possibilities for analysing the phase relationship: Pecora’s work on chaotic transmitters and with reference to the non-periodic arm receivers in communications (Pecora and movement or to the quasi-periodic drum beats. For both cases, if there is synchronization non-periodic – systems can entrain and between the two movements this would show up synchronize. Both frequency and phase in the measurement of the phase differences; for synchronization of chaotic oscillators have been our example the phase difference between the described. During the last two corresponding return time points for the bow decades synchronization and entrainment would be stable around a certain minimal value. In our target article we as they allow for synchronization and integration already made reference to studies indicating in spatially distributed populations of neurons. In Autonomous neuronal oscillations seem to addition, Steven Strogatz (2003), has given structure and guide behaviour, perception, several some telling descriptions indicating how cognition and even consciousness (Schwender, the concept of synchronizing non-periodic 1994), and evidence indicates that oscillatory oscillators can be applied to music making and processes form the basis of timing mechanisms dance. With this in mind, it seems reasonable to for sensorimotor synchronization (Mates et al. The analyses of the pattern performances may very well show phase synchronization with in our case study 1 are compatible with the other oscillatory processes like foot movements, assumption that neural (relaxation) oscillators are singing or the rhythm of accompanying the ‘timer’ for the periodic performance of the instruments. They are, however, clearly (submitted) have recently forwarded evidence for incompatible with the assumption, which Clarke significant – though noisy phase seems to imply we are making, of a computer synchronization in listeners’ tapping responses to clock cum counter for basic time quanta: the alap, the non-metered, largely non-periodic temporal analysis indicates that the Kpegisu and section of Hindustani raga performances. Gama rhythms are organized at the pattern level Listeners’ responses showed recurring, and not at the level of the smallest units or intermittent epochs of phase stabilization that individual events (Windsor), and can be relate to temporal structures of the music. We are interpreted as the repeated sequential execution therefore confident that a major part, if not all, of of a recalled or re-activated pattern. Our idea possible timing mechanisms as a distraction from was to present ethnomusicologists, who are the main focus of our paper, which is the use of generally not familiar with methods of time entrainment to understand behaviour. However, series analysis, with some of the analytical limiting entrainment research to the behavioural methods useful in entrainment research.

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Pioneer biologic drugs are covered by more and varied patents than small-molecule branded 139 Panelists explained the number of patents per biologic product, including platform patents, is substantial, resulting in significant ”stacking” of patents (or royalties) compared to the small-molecule patent estates. Biberstein, Senior Vice President, Alkermes) at 2; Patent Reform Act of 2007: Hearing on H. Patent cases between pioneer manufacturers reveal that patents such as process, manufacturing, and 146 method of use claims can be infringed by a branded competitor. There is no evidence that the patents claiming the compound or molecule of pioneer biologic drugs have been designed around more frequently than those claiming small-molecule drug products. There are a variety of ways to draft claims broadly 147 enough to cover the types of drug structure variations expected in follow-on biologics. For example, patent claims reciting the amino acid sequence of a biologic drug compound or molecule can encompass not only the specific sequence, but also a broad genus of structurally and/or functionally related variants through the use of “percent identity claims. The effect of these claims is that the patent covering the 150 pioneer biologic drug can be broader than the actual product. Comment (1/9/09) at 9; Momenta Comment (9/30/08) at 6-7; Wyeth Comment (9/30/08) at 4. Thomas, Toward a Theory of Marketing Exclusivities at 32-33 (2009) (forthcoming) (“Biotechnology products may commonly be defined through multiple techniques, including their structure, chemical or physical characteristics, and method of preparation, that in combination are capable of providing a potent shield against would-be competitors. Moreover, a patent claim may encompass uses not anticipated by the inventor and therefore not described in the patent. The scope of drug compound or molecule patents depends on the claim language and patent prosecution. Although it is true that alleged competitors have been found not to infringe drug compound claims because of the way in which the claims were 152 construed, it is equally true that biotechnology drug product claims have been construed so that accused products have been found to infringe even when they have 153 varied from the patentee’s corresponding product. For example, a pioneer manufacturer recently obtained a permanent injunction after a finding that its patents 154 were infringed by a competitor that had altered the patented molecule slightly. Competing branded 156 manufacturers have been doing just that since the early days of biotechnology patents. The purpose of the required patent disclosures is to assist rival firms to design around patents so that they can develop non-infringing products to compete with the patented 157 discovery and thus spur greater innovation. In sum, continued reliance on the patent system to stimulate biotechnology innovation is well-justified. The next two sections summarize these views and the need for a 12 to 14-year exclusivity period. Panelists’ and Commenters’ Views on the Likely Effects of a Branded Exclusivity Period Pioneer manufacturers suggested that a 12 to 14-year branded exclusivity period 158 provides certainty about recoupment when R&D investment decisions are made. To calculate the recoupment amount, pioneer manufacturers rely on an economic model (the “Nature model”) that calculates the time it takes for a manufacturer to recover 160 fully its investment to develop and commercialize a typical biologic drug. Some commenters have concluded that the Nature model supports a branded exclusivity period 161 between 12. Pioneer manufacturers suggested that a branded exclusivity period substantially 162 shorter than 14 years would be disastrous for innovation and patients. In addition, R&D would shift away from new treatments for diseases, thus depriving the public of much needed treatments 158 Phillips at 100-01 (“[I]f there is no chance to recoup the capital outlay, then the investment won’t be made. Although one panelist questioned why, if the exclusivity period were short, the pioneer manufacturer could not raise prices to make up for any shortfall in revenue and 167 thus not be any worse off. However, another panelist explained that the “the key driver of prices will be if you’re in a market where there’s competition or anticipated 168 competition. Instead, a 14-year branded exclusivity period may simply reduce the pace of 169 innovation. One commenter predicted that if the branded exclusivity period were that long then branded manufacturers would engage in minor product enhancement strategies 170 which would multiply the costs of expanding monopoly protection. Brand companies can, and routinely do, make relatively minor changes to their existing products in order to restart their monopoly-protection clocks. Panelists’ and Commenters’ Views on the Need for Branded Exclusivity to Incentivize Incremental Innovation the panelists and commenters also examined how the existence and length of an exclusivity period could affect incremental innovation. Pioneer manufacturers explained that there likely would not be incremental innovation without recoupment to recover 172 these investments. In this context, participants used the term “incremental innovation” to refer to actions such as the discovery of a new indication for a previously 173 approved product, or an improved formulation for greater safety or convenience. This commenter explained “that at the time a novel biologic is approved, little may be known of what that drug can do or of what can 174 be achieved in connection with its biological target. Another commenter explained that some extension of exclusivity for the pioneer product is necessary to effectively incentivize the development of new indications for, or other improvements to, existing products. He suggested that if additional branded exclusivity is granted, that the initial period be kept shorter to encourage the pioneer manufacturer to 177 engage in the post-approval R&D. Innovation benefits due to branded competition include a race among firms attacking an unmet medical need or investigating a promising therapy that results in increased dissemination of scientific knowledge, and a 178 greater chance of developing a breakthrough product to benefit consumers. The social value of the cumulative effects of incremental innovations can often exceed those of the 179 original breakthrough. Branded competitors also enhance their products to differentiate them from their competitors. Automatic substitution of generic drugs distorts this product enhancement dynamic such that branded manufacturers are incentivized to change their products in minor ways to defeat 180 automatic substitution. Actual Pioneer Drug Manufacturer Exclusivity Can Inform the Length of a Branded Exclusivity Period the head start that first-in-class branded products already experience against second-in-class products can inform the length of a branded exclusivity period for biologics. A subsequent branded competitor obtains limited benefits from the regulatory approval occasioned by the first-in-class product because its R&D efforts have been 181 proceeding on a parallel path with those of the first-in-class manufacturer. The head start of the first-in-class drug product has decreased over the last three decades as the average lead time of the first-in-class product shrank from 8. Although this study examined pharmaceutical products primarily, it included several biologic drugs as well. The generic drug approval process under Hatch-Waxman results in branded manufacturers enjoying 183 approximately 11 to 13 years of de facto exclusivity prior to a generic drug entry. Indeed, this length of time is attributable mainly to patent protection and patent 184 restoration. Given that the patent portfolios for biologic products are likely to include patents owned by third party entities, this time could be 188 substantially extended. Exclusivity Periods Have Been Used When Patent Protection Has Been Insufficient to Incentivize and Reward Innovation Congress has implemented exclusivity periods to encourage the development of new and innovative drug products when the drug molecule is in the public domain, and 189 therefore not patentable. For example, the Hatch-Waxman Act provides a five-year exclusivity period to incentivize the development of new chemical entities. In other instances, Congress has implemented an exclusivity period when market based pricing has not provided sufficient incentive to develop drug products for target populations. For example, 6-months of marketing exclusivity periods are awarded upon the showing of safety and effectiveness for children. A seven-year marketing exclusivity period is awarded to manufacturers of drug products that treat diseases affecting less than 191 200,000 persons in the United States. See Robert Rogoyski, the Orphan Drug 44 Central to each of these exclusivities is a public policy trade-off: a restriction on competition is provided in return for a development of a new drug product or new use of an existing product. A 12 to 14-year exclusivity period, however, departs sharply from this basic trade-off, because it does not spur the creation of a new product or indication. The drug has already been incentivized through patent protection and market-based pricing. To the extent that there are new biologic molecules that cannot obtain patent protection, an exclusivity period may be warranted. Because there is no evidence about the lack of patentability of new biologic products, nor that market forces have been insufficient to incentivize their development, the Commission has not recommended a length of an exclusivity period. The potential harm posed by a 12 to 14-year exclusivity period is that firms will direct scarce R&D dollars toward developing low-risk clinical and safety data for drug products with previously proven efficacy rather than toward new inventions to address unmet medical needs. In addition, a 12 to 14-year branded exclusivity period could undermine the patent system’s disclosure function as pioneer manufacturers rely on trade secrets rather than patents to protect their inventions. Because the patent system requires public disclosure, it promotes the dissemination of scientific and technical information that would not occur but for the grant of a patent. The ability to design around is prevalent for patent claims covering the formulation or dosage of drug products, product-by-process claims, and process claims – all of which currently protect pioneer biologic products. To the extent that the branded exclusivity period replaces the need for the patent, the scientific community loses the disclosure of inventions that occurs when patents are granted and published, and innovation could be harmed.

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