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1.
Ian Evans 《The Yale journal of biology and medicine》2010,83(2):97-100
The U.S. pharmaceutical industry plays a vital role in shaping the face of American healthcare. As an industry rooted in innovation, its continued evolution is inherent. With major patent expirations looming and thin product pipelines, the industry now must consider new directions to maintain growth and stability. Follow-on biologics, derived from living organisms and marketed after the patent expiration of similar therapies, represent a growing opportunity for big pharmaceutical firms, as discussed during Yale’s Healthcare 2010 conference in April. Key characteristics of follow-on biologics make them a worthwhile investment for big pharma companies: They command high prices, will likely have fewer entrants than generics due to high barriers to entry, and play to the existing strengths of big pharma firms. With the recent healthcare legislation providing the way for consistent Food and Drug Administration (FDA) regulation, the timing seems right to continue the push into this new and growing market.At a time when healthcare issues are on the mind of every American, it would serve us well to consider the future of one of the most influential players in the sector: pharmaceutical companies. National health expenditures for pharmaceutical products are hovering around 10 percent, meaning that one out of every 10 dollars that we, as a nation, spend on healthcare goes toward drugs. These drugs regulate our cholesterol levels, promote the growth of white blood cells in cancer patients, manage our restless leg syndrome, help us sleep better at night, and provide myriad other benefits to our health and well-being. Yet, for all the benefits that the pharmaceutical industry provides, it is also criticized by many for the expense of its products and the high profit margins that these products command. The growing popularity of biologics — treatments derived from living organisms, such as antibodies and interleukins — has particularly increased the price of drugs in the United States. The current price of the average biologic is more than 20 times that of a traditional, chemically synthesized small-molecule drug. There is a trade-off between high prices and innovative new therapies. Moreover, pharmaceutical companies themselves argue justifiably that prices account not only for the price of production, but also for the research and development (R&D) for that therapy as well as numerous others that did not make it all the way through the regulatory process and to the clinic.In recent years, we have witnessed the breakdown of the well-oiled innovation machinery of the traditional big pharma company. While R&D departments spent more and more (well over $1B per drug), they did not see promising results in the form of late-stage drug candidates [1]. Over time, this led to a strategic shift in portfolio management within big pharma companies toward an acquisition-heavy plan to build up their pipeline of drugs. In-house R&D projects were cut, and layoffs of scientific staff were rampant. This phenomenon continues, with 2009 bearing witness to the most mergers and acquisitions in the pharmaceutical industry to date. Industry-wide consolidation aimed to find complementary development projects and synergies in manufacturing and emerging markets. What has been the effect of all of this? The answer is not as hopeful as the pharmaceutical industry would have liked. A giant “patent cliff” still persists, referring to a number of blockbuster drugs that will go off patent over the next two years and cause a dramatic decrease in sales for big pharma firms. Without a strong pipeline to fill in the valley with new product sales, big pharma companies have begun scrambling to find new ways to generate revenue.Meanwhile, the biotech industry’s foray into therapeutics has been a wild success story. From the 1980s to the present, biologics have reshaped the face of medicine in many disease areas. The spawn of highly innovative, nimble biotech firms, biologic drugs are large, complex molecules grown in living cells rather than synthesized chemically like small molecules. For example, Enbrel is a fusion protein that acts as a tumor necrosis factor (TNF) inhibitor to stop inflammation. This drug is being widely prescribed for rheumatoid arthritis as well as psoriasis, among other indications, with sales last year reaching $5.9 billion, up 9.3 percent from 2008 [2]. Enbrel was first developed by Immunex and released in 1998. Immunex was acquired by a rival biotech firm, Amgen, in 2001 [3], and subsequent marketing of the drug in the United States was jointly undertaken by Amgen and Wyeth (now taken over by Pfizer in the mega-merger of 2009). Enbrel’s is the classic story of the modern biologic: a novel therapy developed at a small biotech firm and acquired or licensed up the food chain to feed bigger firms’ appetites for late-stage assets.Enbrel is by no means unique; there are many blockbuster biologics on the market. Like Enbrel, many of them will reach the end of their patent life soon. Enbrel’s patent expiration is set for 2012, at which time it will be exposed to potential competition from generic versions. Therefore, though there are many novel biologics therapies that can provide new ways of treating patients, there is also a huge opportunity for generic versions of biologics that did not exist even one decade ago. This opportunity is hard to quantify, but one recent estimate shows that biologics responsible for $20B in annual sales will go off patent by 2015 [4]. Unsurprisingly, small-molecule generics firms are flocking to this space. Teva, the world’s largest generics manufacturer, has partnered with the Lonza Group to make and sell so-called follow-on biologics. These treatments are similar, but not identical, to preceding biologics whose patents expired. Meanwhile, Novartis’s generics arm, Sandoz, has increased capacity in biomanufacturing to ramp up its efforts. Big pharma itself has made motions of interest in the business of follow-on biologics, as witnessed by the dedicated division of Merck, BioVentures, established in late 2008 for the development of follow-on biologics. Interestingly, even Pfizer is testing a follow-on version of Enbrel, now in phase 2 clinical trials [5]. With a big market opportunity and a number of firms interested, follow-on biologics will surely play an important role in shaping the future of the pharma industry.For large pharmaceutical firms, what is needed is a way to diversify and mitigate risk, a way to supplement their rollercoaster sales figures year after year. Follow-on biologics may be a smart play for big pharma companies. Like their generic cousins, biologics manufacturing has strong economies of scale that big pharma firms can leverage. But unlike generics, there are higher barriers to entry because of the technical challenges of manufacturing biologics and the necessary clinical proofs of equivalency. Pharmaceutical companies already are practiced at navigating the global clinical-trials arena and should be able to exercise a significant competitive advantage in this area, especially over the existing generics manufacturers attempting a play in the follow-on biologics market. It has been estimated that the investment necessary to bring a follow-on biologic to market is eight to 10 years and will cost $100-$200M [6]. This investment of time and capital is substantial and tends to favor larger firms with significant R&D budgets. However, to put the investment into perspective, this is only one-tenth of the cost of developing a full-scale innovative pharmaceutical product and has less associated risk of failure — a proposition that the big pharma industry should find appealing. Additionally, the trend for current follow-on biologics on the market in the European Union (EU) and United States has been to use traditional detailing and marketing practices to compete with branded products. This, too, puts big pharma at a competitive advantage over other players lacking an army of detailing pharmaceutical reps, who can use their established relationships with doctors and medical personnel to promote new follow-on biologics.One counter-argument to the case for a move into follow-on biologics is that the new healthcare reform, the Patient Protection and Affordable Care Act (PPACA), passed in March of this year will harm any would-be generic biologics makers with its 12-year exclusivity for branded biologics. However, while this length of time is significantly longer than the proposed five years that generics proponents pushed for, the surety of a secure path forward through the FDA for follow-on biologics outweighs the downside of lengthy biologics exclusivity. It is reasonable to hope that within two to three years, the FDA will have functional guidelines for the regulation of this nascent market. Now more than at any other time in the past, the ambiguity associated with government regulation is manageable. And if big pharma becomes more intentional about entering the follow-on biologics market, its powerful lobby, PhRMA, could influence the way that the details of the FDA regulations are written.If the pharma industry does find the follow-on biologics market appealing and makes a bet on it for supplementary revenue, what can we expect from the patient perspective? It could mean greater access at cheaper prices, but the dynamics are much more nuanced. The economics of the small-molecule generics market likely will not be transferrable to the follow-on biologics market. High barriers to entry, high fixed costs of manufacturing, and marketing expenses will more likely manifest themselves in a market that has a small number of firms with relatively small price drops upon introduction of follow-on therapies. In small-molecule generics, the price typically decreases by about 80 percent from the original branded drug price after one year of generic competition. However, in current follow-on markets in the EU, this has not been the case. Since its introduction of biosimilars regulation in 2004, the EU has successfully introduced numerous follow-on biologics for three classes of branded drugs. The results hint at what might be expected for U.S. firms: By 2008 in Germany, biosimilars had captured an estimated 14 percent to 30 percent market share and discounted prices by 25 percent [7]. The U.S. story of follow-on biologics will likely mirror that of EU biosimilars rather than that of small-molecule generics.With healthcare legislation passed and the inevitable refocusing on bending the cost curve in healthcare expenditures, big pharma firms may be able to boost their reputation with the public as well as their bottom line with a continued push into follow-on biologics. The decreased risk of approval and steady returns will help diversify pharmaceutical companies’ volatile revenue streams, while concurrently winning favorable public opinion by promoting price reductions for some of the most expensive drugs available. The cost savings to consumers will increase access for patients as FDA regulation is finalized and more and more follow-on biologics enter the market. This could be a win-win scenario for big pharma and for patients. 相似文献
2.
Australia, like most countries, faces high and rapidly-rising drug costs. There are longstanding concerns about pharmaceutical companies inappropriately extending their monopoly position by “evergreening” blockbuster drugs, through misuse of the patent system. There is, however, very little empirical information about this behaviour. We fill the gap by analysing all of the patents associated with 15 of the costliest drugs in Australia over the last 20 years. Specifically, we search the patent register to identify all the granted patents that cover the active pharmaceutical ingredient of the high-cost drugs. Then, we classify the patents by type, and identify their owners. We find a mean of 49 patents associated with each drug. Three-quarters of these patents are owned by companies other than the drug''s originator. Surprisingly, the majority of all patents are owned by companies that do not have a record of developing top-selling drugs. Our findings show that a multitude of players seek monopoly control over innovations to blockbuster drugs. Consequently, attempts to control drug costs by mitigating misuse of the patent system are likely to miss the mark if they focus only on the patenting activities of originators. 相似文献
3.
Background
Internet-sourced drugs are often considered suspect. The World Health Organization reports that drugs from websites that conceal their physical address are counterfeit in over 50 percent of cases; the U.S. Food and Drug Administration (FDA) works with the National Association of Boards of Pharmacy (NABP) to regularly update a list of websites likely to sell drugs that are illegal or of questionable quality.Methods and Findings
This study examines drug purchasing over the Internet, by comparing the sales of five popular drugs from a selection of websites stratified by NABP or other ratings. The drugs were assessed for price, conditions of purchase, and basic quality. Prices and conditions of purchase varied widely. Some websites advertised single pills while others only permitted the purchase of large quantities. Not all websites delivered the exact drugs ordered, some delivered no drugs at all; many websites shipped from multiple international locations, and from locations that were different from those advertised on the websites. All drug samples were tested against approved U.S. brand formulations using Raman spectrometry. Many (17) websites substituted drugs, often in different formulations from the brands requested. These drugs, some of which were probably generics or perhaps non-bioequivalent copy versions, could not be assessed accurately. Of those drugs that could be assessed, none failed from “approved”, “legally compliant” or “not recommended” websites (0 out of 86), whereas 8.6% (3 out of 35) failed from “highly not recommended” and unidentifiable websites.Conclusions
Of those drugs that could be assessed, all except Viagra® passed spectrometry testing. Of those that failed, few could be identified either by a country of manufacture listed on the packaging, or by the physical location of the website pharmacy. If confirmed by future studies on other drug samples, then U.S. consumers should be able to reduce their risk by relying on credentialing agencies recommended lists and by using common sense when examining packaging and pills. 相似文献4.
Background
Little is known about the long-term drug costs associated with treating AIDS in developing countries. Brazil''s AIDS treatment program has been cited widely as the developing world''s largest and most successful AIDS treatment program. The program guarantees free access to highly active antiretroviral therapy (HAART) for all people living with HIV/AIDS in need of treatment. Brazil produces non-patented generic antiretroviral drugs (ARVs), procures many patented ARVs with negotiated price reductions, and recently issued a compulsory license to import one patented ARV. In this study, we investigate the drivers of recent ARV cost trends in Brazil through analysis of drug-specific prices and expenditures between 2001 and 2005.Methods and Findings
We compared Brazil''s ARV prices to those in other low- and middle-income countries. We analyzed trends in drug expenditures for HAART in Brazil from 2001 to 2005 on the basis of cost data disaggregated by each ARV purchased by the Brazilian program. We decomposed the overall changes in expenditures to compare the relative impacts of changes in drug prices and drug purchase quantities. We also estimated the excess costs attributable to the difference between prices for generics in Brazil and the lowest global prices for these drugs. Finally, we estimated the savings attributable to Brazil''s reduced prices for patented drugs. Negotiated drug prices in Brazil are lowest for patented ARVs for which generic competition is emerging. In recent years, the prices for efavirenz and lopinavir–ritonavir (lopinavir/r) have been lower in Brazil than in other middle-income countries. In contrast, the price of tenofovir is US$200 higher per patient per year than that reported in other middle-income countries. Despite precipitous price declines for four patented ARVs, total Brazilian drug expenditures doubled, to reach US$414 million in 2005. We find that the major driver of cost increases was increased purchase quantities of six specific drugs: patented lopinavir/r, efavirenz, tenofovir, atazanavir, enfuvirtide, and a locally produced generic, fixed-dose combination of zidovudine and lamivudine (AZT/3TC). Because prices declined for many of the patented drugs that constitute the largest share of drug costs, nearly the entire increase in overall drug expenditures between 2001 and 2005 is attributable to increases in drug quantities. Had all drug quantities been held constant from 2001 until 2005 (or for those drugs entering treatment guidelines after 2001, held constant between the year of introduction and 2005), total costs would have increased by only an estimated US$7 million. We estimate that in the absence of price declines for patented drugs, Brazil would have spent a cumulative total of US$2 billion on drugs for HAART between 2001 and 2005, implying a savings of US$1.2 billion from price declines. Finally, in comparing Brazilian prices for locally produced generic ARVs to the lowest international prices meeting global pharmaceutical quality standards, we find that current prices for Brazil''s locally produced generics are generally much higher than corresponding global prices, and note that these prices have risen in Brazil while declining globally. We estimate the excess costs of Brazil''s locally produced generics totaled US$110 million from 2001 to 2005.Conclusions
Despite Brazil''s more costly generic ARVs, the net result of ARV price changes has been a cost savings of approximately US$1 billion since 2001. HAART costs have nevertheless risen steeply as Brazil has scaled up treatment. These trends may foreshadow future AIDS treatment cost trends in other developing countries as more people start treatment, AIDS patients live longer and move from first-line to second and third-line treatment, AIDS treatment becomes more complex, generic competition emerges, and newer patented drugs become available. The specific application of the Brazilian model to other countries will depend, however, on the strength of their health systems, intellectual property regulations, epidemiological profiles, AIDS treatment guidelines, and differing capacities to produce drugs locally. 相似文献5.
We analyze the patent filing strategies of foreign pharmaceutical companies in Chile distinguishing between “primary” (active ingredient) and “secondary” patents (patents on modified compounds, formulations, dosages, particular medical uses, etc.). There is prior evidence that secondary patents are used by pharmaceutical originator companies in the U.S. and Europe to extend patent protection on drugs in length and breadth. Using a novel dataset that comprises all drugs registered in Chile between 1991 and 2010 as well as the corresponding patents and trademarks, we find evidence that foreign originator companies pursue similar strategies in Chile. We find a primary to secondary patents ratio of 1:4 at the drug-level, which is comparable to the available evidence for Europe; most secondary patents are filed over several years following the original primary patent and after the protected active ingredient has obtained market approval in Chile. This points toward effective patent term extensions through secondary patents. Secondary patents dominate “older” therapeutic classes like anti-ulcer and anti-depressants. In contrast, newer areas like anti-virals and anti-neoplastics (anti-cancer) have a much larger share of primary patents. 相似文献
6.
Yamey G 《BMJ (Clinical research ed.)》2000,320(7246):1357
The UN has reported that five multinational pharmaceutical companies would cut down HIV drug prices in the developing world. One of these drug companies is GlaxoWellcome, which has promised to reduce the price of zidovudine and lamivudine to US$2 in the poorest nations, a fifth of its price in the US. Although Peter Piot, director of the UN Program on HIV/AIDS, welcomed the companies' promises, he warned that price cuts alone will not curb the epidemic. He stated that this initiative is only one critical factor in what must become a much broader and more urgent effort to help people living with HIV/AIDS. Moreover, health and development agencies expressed concern that AIDS drugs will still be unaffordable for the vast majority of those in need in developing countries. In addition, poor countries lack the infrastructure to deliver these drugs safely and effectively. During the time of the UN announcement, US President Bill Clinton also signed an executive order allowing sub-Saharan Africa to adopt legal measures to obtain cheap HIV drugs. Meanwhile, South Africa's reaction to the offer to cut antiretroviral drug prices has been lukewarm. 相似文献
7.
Background
While there has been much discussion by policymakers and stakeholders about the effects of “secondary patents” on the pharmaceutical industry, there is no empirical evidence on their prevalence or determinants. Characterizing the landscape of secondary patents is important in light of recent court decisions in the U.S. that may make them more difficult to obtain, and for developing countries considering restrictions on secondary patents.Methodology/Principal Findings
We read the claims of the 1304 Orange Book listed patents on all new molecular entities approved in the U.S. between 1988 and 2005, and coded the patents as including chemical compound claims (claims covering the active molecule itself) and/or one of several types of secondary claims. We distinguish between patents with any secondary claims, and those with only secondary claims and no chemical compound claims (“independent” secondary patents).We find that secondary claims are common in the pharmaceutical industry. We also show that independent secondary patents tend to be filed and issued later than chemical compound patents, and are also more likely to be filed after the drug is approved. When present, independent formulation patents add an average of 6.5 years of patent life (95% C.I.: 5.9 to 7.3 years), independent method of use patents add 7.4 years (95% C.I.: 6.4 to 8.4 years), and independent patents on polymorphs, isomers, prodrug, ester, and/or salt claims add 6.3 years (95% C.I.: 5.3 to 7.3 years). We also provide evidence that late-filed independent secondary patents are more common for higher sales drugs.Conclusions/Significance
Policies and court decisions affecting secondary patenting are likely to have a significant impact on the pharmaceutical industry. Secondary patents provide substantial additional patent life in the pharmaceutical industry, at least nominally. Evidence that they are also more common for best-selling drugs is consistent with accounts of active “life cycle management” or “evergreening” of patent portfolios in the industry. 相似文献8.
Drug-target interaction (DTI) is a key aspect in pharmaceutical research. With the ever-increasing new drug data resources, computational approaches have emerged as powerful and labor-saving tools in predicting new DTIs. However, so far, most of these predictions have been based on structural similarities rather than biological relevance. In this study, we proposed for the first time a “GO and KEGG enrichment score” method to represent a certain category of drug molecules by further classification and interpretation of the DTI database. A benchmark dataset consisting of 2,015 drugs that are assigned to nine categories ((1) G protein-coupled receptors, (2) cytokine receptors, (3) nuclear receptors, (4) ion channels, (5) transporters, (6) enzymes, (7) protein kinases, (8) cellular antigens and (9) pathogens) was constructed by collecting data from KEGG. We analyzed each category and each drug for its contribution in GO terms and KEGG pathways using the popular feature selection “minimum redundancy maximum relevance (mRMR)” method, and key GO terms and KEGG pathways were extracted. Our analysis revealed the top enriched GO terms and KEGG pathways of each drug category, which were highly enriched in the literature and clinical trials. Our results provide for the first time the biological relevance among drugs, targets and biological functions, which serves as a new basis for future DTI predictions. 相似文献
9.
Sileshi Belew Mestawet Getachew Sultan Suleman Tesfaye Mohammed Habetewold Deti Matthias D'Hondt Evelien Wynendaele Zeleke Mekonnen Jozef Vercruysse Luc Duchateau Bart De Spiegeleer Bruno Levecke 《PLoS neglected tropical diseases》2015,9(9)
BackgroundThere is a worldwide upscale in mass drug administration (MDA) programs to control the morbidity caused by soil-transmitted helminths (STHs): Ascaris lumbricoides, Trichuris trichiura and hookworm. Although anthelminthic drugs which are used for MDA are supplied by two pharmaceutical companies through donation, there is a wide range of brands available on local markets for which the efficacy against STHs and quality remain poorly explored. In the present study, we evaluated the drug efficacy and quality of two albendazole brands (Bendex and Ovis) available on the local market in Ethiopia.Conclusion/SignificanceThe study revealed that differences in efficacy between the two brands of albendazole (ABZ) tablets against hookworm are linked to the differences in the in-vitro drug release profile. Differences in uptake and metabolism of this benzimidazole drug among different helminth species may explain that this efficacy difference was only observed in hookworms and not in the two other species. The results of the present study underscore the importance of assessing the chemical and physicochemical quality of drugs before conducting efficacy assessment in any clinical trials to ensure appropriate therapeutic efficacy and to exclude poor drug quality as a factor of reduced drug efficacy other than anthelminthic resistance. Overall, this paper demonstrates that “all medicines are not created equal”. 相似文献
10.
Gerhard Levy 《CMAJ》1964,90(16):978-979
The rate of gastrointestinal absorption and the physiologic availability of tolbutamide are functions of the dissolution rate of the drug in gastrointestinal fluids. This property can be modified markedly by pharmaceutical formulation factors. The in vitro dissolution rates of clinically efficacious and clinically inefficacious tolbutamide tablets have been determined, and it has been found that the former dissolved considerably more rapidly than the latter. Once diabetic patients have been “titrated” with a particular brand of tolbutamide they should not be switched to a different brand without “retitration.” There is need to establish an adequate in vitro test to assure the physiologic availability of tolbutamide from commercial tablets. 相似文献
11.
《The Western journal of medicine》1962,97(2):128-129
The Consumer Price Index (CPI) of the Bureau of Labor Statistics is an index which measures the price changes of 300 goods and services. Among these 300 items are several which reflect price changes for selected health care and medical care services. These comprise the medical care index and physician fee index, depending on what services are being measured.The Physician Fee Index is based upon charges for five procedures rendered by physicians: Appendectomy, tonsillectomy, obstetrical delivery, home visits and office visits.Although the CPI takes into account quality changes in the prices for various goods, it is unable to do so for services, particularly physicians'' services.The difficulty in measuring the “cost” of quality of medical care overstates price increases in the physician fee and medical care indexes. 相似文献
12.
Objectives
The UK government has noted the public health importance of food prices and the affordability of a healthy diet. Yet, methods for tracking change over time have not been established. We aimed to investigate the prices of more and less healthy foods over time using existing government data on national food prices and nutrition content.Methods
We linked economic data for 94 foods and beverages in the UK Consumer Price Index to food and nutrient data from the UK Department of Health''s National Diet and Nutrition Survey, producing a novel dataset across the period 2002–2012. Each item was assigned to a food group and also categorised as either “more healthy” or “less healthy” using a nutrient profiling model developed by the Food Standards Agency. We tested statistical significance using a t-test and repeated measures ANOVA.Results
The mean (standard deviation) 2012 price/1000 kcal was £2.50 (0.29) for less healthy items and £7.49 (1.27) for more healthy items. The ANOVA results confirmed that all prices had risen over the period 2002–2012, but more healthy items rose faster than less healthy ones in absolute terms:£0.17 compared to £0.07/1000 kcal per year on average for more and less healthy items, respectively (p<0.001).Conclusions
Since 2002, more healthy foods and beverages have been consistently more expensive than less healthy ones, with a growing gap between them. This trend is likely to make healthier diets less affordable over time, which may have implications for individual food security and population health, and it may exacerbate social inequalities in health. The novel data linkage employed here could be used as the basis for routine food price monitoring to inform public health policy. 相似文献13.
目的 了解武汉市公立医院的药品相对价格水平,揭示药品市场现存的问题。方法 选择全国市场销售排名前100位的药品全部纳入研究样本,收集武汉市12家公立医院和14家零售药房的药品价格数据,对定量资料进行统计分析,对公立医院间及其与零售药房间的药品价格进行差异性比较。结果 公立医院的药品均价高于零售药房同商品名药品的均价;公立医院间同商品名的药品均价差异不显著,但同通用名的药品价格差异有较大的波动性。结论 进一步建立健全药品监管制度,加快削弱公立医院的垄断地位,严格药品招标采购管理,建立健全国家基本药物制度。 相似文献
14.
15.
Background
Manufacturers justify the high prices for orphan drugs on the basis that the associated R&D costs must be spread over few patients. The proliferation of these drugs in the last three decades, combined with high prices commonly in excess of $100,000 per patient per year are placing a substantial strain on the budgets of drug plans in many countries. Do insurers spend a growing portion of their budgets on small patient populations, or leave vulnerable patients without coverage for valuable treatments? We suggest that a third option is present in the form of a cost-based regulatory mechanism.Methods
This article explores the use of a cost-based price control mechanism for orphan drugs, adapted from the standard models applied in utilities regulation.Results and conclusions
A rate-of-return style model, employing yardsticked cost allocations and a modified two-stage rate of return calculation could be effective in setting a new standard for orphan drugs pricing. This type of cost-based pricing would limit the costs faced by insurers while continuing to provide an efficient incentive for new drug development.16.
Recent human population increase has been enabled by a massive expansion of global agricultural production. A key component of this “Green Revolution” has been application of inorganic fertilizers to produce and maintain high crop yields. However, the long-term sustainability of these practices is unclear given the eutrophying effects of fertilizer runoff as well as the reliance of fertilizer production on finite non-renewable resources such as mined phosphate- and potassium-bearing rocks. Indeed, recent volatility in food and agricultural commodity prices, especially phosphate fertilizer, has raised concerns about emerging constraints on fertilizer production with consequences for its affordability in the developing world. We examined 30 years of monthly prices of fertilizer commodities (phosphate rock, urea, and potassium) for comparison with three food commodities (maize, wheat, and rice) and three non-agricultural commodities (gold, nickel, and petroleum). Here we show that all commodity prices, except gold, had significant change points between 2007–2009, but the fertilizer commodities, and especially phosphate rock, showed multiple symptoms of nonlinear critical transitions. In contrast to fertilizers and to rice, maize and wheat prices did not show significant signs of nonlinear dynamics. From these results we infer a recent emergence of a scarcity price in global fertilizer markets, a result signaling a new high price regime for these essential agricultural inputs. Such a regime will challenge on-going efforts to establish global food security but may also prompt fertilizer use practices and nutrient recovery strategies that reduce eutrophication. 相似文献
17.
Max Hayman 《The Western journal of medicine》1964,101(4):266-271
18.
In the context of polypharmacology, an emerging concept in drug discovery, promiscuity is rationalized as the ability of compounds to specifically interact with multiple targets. Promiscuity of drugs and bioactive compounds has thus far been analyzed computationally on the basis of activity annotations, without taking assay frequencies or inactivity records into account. Most recent estimates have indicated that bioactive compounds interact on average with only one to two targets, whereas drugs interact with six or more. In this study, we have further extended promiscuity analysis by identifying the most extensively assayed public domain compounds and systematically determining their promiscuity. These compounds were tested in hundreds of assays against hundreds of targets. In our analysis, assay promiscuity was distinguished from target promiscuity and separately analyzed for primary and confirmatory assays. Differences between the degree of assay and target promiscuity were surprisingly small and average and median degrees of target promiscuity of 2.6 to 3.4 and 2.0 were determined, respectively. Thus, target promiscuity remained at a low level even for most extensively tested active compounds. These findings provide further evidence that bioactive compounds are less promiscuous than drugs and have implications for pharmaceutical research. In addition to a possible explanation that drugs are more extensively tested for additional targets, the results would also support a “promiscuity enrichment model” according to which promiscuous compounds might be preferentially selected for therapeutic efficacy during clinical evaluation to ultimately become drugs. 相似文献
19.
Henrik G. Dohlman 《The Journal of biological chemistry》2015,290(32):19469-19470
Over the past half-century, The Journal of Biological Chemistry has been the venue for many landmark publications on the topic of G protein-coupled receptors (GPCRs, also known as seven-transmembrane receptors). The GPCR superfamily in humans is composed of about 800 members, and is the target of about one-third of all pharmaceuticals. Most of these drugs target a very small subset of GPCRs, and do so by mimicking or competing with endogenous hormones and neurotransmitters. This thematic minireview series examines some emerging trends in GPCR drug discovery. The first article describes efforts to systematically interrogate the human “GPCR-ome,” including more than 150 uncharacterized “orphan” receptors. The second article describes recent efforts to target alternative receptor binding sites with drugs that act as allosteric modulators of orthosteric ligands. The third article describes how the recent expansion of GPCR structures is providing new opportunities for computer-guided drug discovery. Collectively, these three articles provide a roadmap for the most important emerging trends in GPCR pharmacology. 相似文献
20.
Noor Hasima Bharat B Aggarwal 《International Journal of Biochemistry and Molecular Biology》2012,3(4):328-351
In spite of major advances in oncology, the World Health Organization predicts that cancer incidence will double within the next two decades. Although it is well understood that cancer is a hyperproliferative disorder mediated through dysregulation of multiple cell signaling pathways, most cancer drug development remains focused on modulation of specific targets, mostly one at a time, with agents referred to as “targeted therapies,” “smart drugs,” or “magic bullets.” How many cancer targets there are is not known, and how many targets must be attacked to control cancer growth is not well understood. Although more than 90% of cancer-linked deaths are due to metastasis of the tumor to vital organs, most drug targeting is focused on killing the primary tumor. Besides lacking specificity, the targeted drugs induce toxicity and side effects that sometimes are greater problems than the disease itself. Furthermore, the cost of some of these drugs is so high that most people cannot afford them. The present report describes the potential anticancer properties of curcumin, a component of the Indian spice turmeric (Curcuma longa), known for its safety and low cost. Curcumin can selectively modulate multiple cell signaling pathways linked to inflammation and to survival, growth, invasion, angiogenesis, and metastasis of cancer cells. More clinical trials of curcumin are needed to prove its usefulness in the cancer setting. 相似文献