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In humans, abnormalities of the vertebral venous system are considered rare but significant causes of radiculopathy and myelopathy. Published information on abnormalities of the canine vertebral venous system is currently lacking. Aims of this retrospective descriptive study were to characterize magnetic resonance imaging (MRI) abnormalities of the vertebral venous system in a population of sighthounds, report prevalence of vertebral venous system abnormalities within that population and explore possible clinical significance. Our hospital database was searched over the period of 2002–2013 for sighthounds with MRI studies of the vertebral column. Medical records and MRI studies for included dogs were retrieved and findings were recorded by a single observer. A total of 92 sighthounds were sampled. Eleven cases (prevalence 12%) showed abnormal enlargement of the internal vertebral venous plexus (10/11 unilaterally, 1/11 bilaterally), external vertebral venous plexus (7/11 cases unilaterally), and/or intervertebral veins (8/11 unilaterally, 2/11 bilaterally, and 1/11 unilaterally and bilaterally at different sites). The majority of the abnormalities were right sided and the most common location for abnormalities was C6/7. Of the 11 cases, nine did not have a definitive diagnosis. Seven of those nine cases had an abnormality in a neuroanatomical localization that could wholly or partly explain the clinical signs. Findings indicated that, while the prevalence of vertebral venous system abnormalities was low in this sample of sighthounds, the majority of dogs with these abnormalities had clinical signs that matched the location of the abnormalities. Further prospective research is needed to investigate potential underlying aetiologies for vertebral venous system abnormalities in dogs and clarify their clinical significance.

In humans, abnormalities of the vertebral venous system are considered rare but significant causes of radiculopathy and myelopathy. Published information on abnormalities of the canine vertebral venous system is currently lacking. Aims of this retrospective descriptive study were to characterize magnetic resonance imaging (MRI) abnormalities of the vertebral venous system in a population of sighthounds, report prevalence of vertebral venous system abnormalities within that population and explore possible clinical significance. Our hospital database was searched over the period of 2002-2013 for sighthounds with MRI studies of the vertebral column. Medical records and MRI studies for included dogs were retrieved and findings were recorded by a single observer. A total of 92 sighthounds were sampled. Eleven cases (prevalence 12%) showed abnormal enlargement of the internal vertebral venous plexus (10/11 unilaterally, 1/11 bilaterally), external vertebral venous plexus (7/11 cases unilaterally), and/or intervertebral veins (8/11 unilaterally, 2/11 bilaterally, and 1/11 unilaterally and bilaterally at different sites). The majority of the abnormalities were right sided and the most common location for abnormalities was C6/7. Of the 11 cases, nine did not have a definitive diagnosis. Seven of those nine cases had an abnormality in a neuroanatomical localization that could wholly or partly explain the clinical signs. Findings indicated that, while the prevalence of vertebral venous system abnormalities was low in this sample of sighthounds, the majority of dogs with these abnormalities had clinical signs that matched the location of the abnormalities. Further prospective research is needed to investigate potential underlying aetiologies for vertebral venous system abnormalities in dogs and clarify their clinical significance.

The article byNeumann et al. in this issue is an important contribution to the literature; one that shedsmuch light on a heretofore largely overlooked aspect of Section 114 of the 1997 Food and Drug Modernization Act (FDMA). The article describes how Section 114 has been interpreted and used by major US pharmaceutical firms with respect to the dissemination and communication of a pharmaceutical product’s economic value to health plans, formulary decision makers and similar organizations. The authors’ argument for greater clarity on the topic by the US FDA deserves to be echoed loudly, as does their appeal for flexibility with respect to its interpretation. The article, which fills a long-standing lacuna in the literature, is particularly timely, as the authors of the article emphasize, because new and evolving comparative effectiveness research (CER) legislation will potentially affect many Section 114 claims. The purpose of this commentary is to offer a larger context within which the findings and arguments of Neumann et al. might be considered: a free-market context. When new pharmaceutical regulations and policies are proposed, it is always in society’s best interest to consider the cost-benefit calculus of the proposed government intervention, and to ask the question ‘Will the new regulation lead to net social benefits relative to the benefits in the absence of the regulation?’ Alternatively, and more generally, the following question might be considered: ‘Will the regulation facilitate or impede free market forces and outcomes?’ To be certain, there are numerous circumstances, or market failures, that do indeed justify government intervention to improve upon unregulated market outcomes. Intellectual property rights established via government-enforced limited-term patents is one example; one that is a defining feature of pharmaceutical markets, and that significantly affects the industry’s structure, conduct and performance. Information, for example, themolecular structure of a new pharmaceutical or biologic, is a public good once the product is brought to market (and often much sooner). As such, in the absence of patents, this new information is non-rival and non-excludable; consumption/acquisition of this information, by any individual or organization, does not reduce its availability for consumption by anyone else. And once the information is public (published), without patents, no-one can be excluded from consuming the information. Without limited-term patents, there would be virtually no economic incentive to invest in R&D, and there would be no pharmaceutical innovation, ceteris paribus. Of course

Drug innovation relies on cumulative, path-dependent, incremental research and development (R&D). In oncology, path-dependence may not be along a single dimension, such as steadily improving efficacy or survival against a given endpoint in the same population, but innovation builds on itself. The next innovation may use a recently developed drug in a new way – e.g., a new line of therapy, or a new indication in a different population, or in combination with other drugs. Of course, in some cases, innovation on a current drug can be the development of a next generation drug. Yet, few have studied how path-dependence impacts the decisions of oncology pharmaceutical producers, consumers, and insurers/payers. This study illustrates how real options can be used to value the effects of path-dependence, that is, the additional value that incremental innovation adds when the innovation is a first step along a path to a major innovation. We show how rational pharmaceutical producers and consumers recognize...

Academic researchers, as well as pharmaceutical firms themselves, often use the Capital Asset Pricing Model (CAPM) to estimate a firm's cost of capital. But the CAPM implicitly assumes that cash flows follow a random walk. This assumption is inconsistent with our finding that large U.S.-based pharmaceutical firms' cash flow growth rates display either momentum or mean-reversion. We show that growth rate momentum implies: (1) the systematic risk of a project increases monotonically with time to maturity of the cash flows; and (2) longer duration projects require a higher cost of capital. One of the practical implications of our results is that the traditional CAPM underestimates the cost of capital for some pharmaceutical firms by as much as 2.8%. These findings are quite relevant for the policy debate about the high rates of return earned by pharmaceutical companies, which some claim are pure rents and are not necessary to attract investors. Our theoretical and empirical analysis shows that high returns are often required to compensate for the higher systematic risk of long-duration pharmaceutical cash flows.

EU countries closely regulate pharmaceutical prices, whereas the US does not. This paper shows how price constraints affect the profitability, stock returns and R&D spending of EU and US firms. Compared with EU firms, US firms are more profitable, earn higher stock returns and spend more on R&D. We tested the relationship between price regulation and R&D spending, and estimated the costs of tight EU price regulation. Although results show that EU consumers enjoyed much lower pharmaceutical price inflation, we estimated that price controls cost EU firms 46 fewer new medicines and 1680 fewer research jobs during our 19-year sample period. Had the US used controls similar to those used in the EU, we estimate it would have led to 117 fewer new medicines and 4368 fewer research jobs in the US.

As healthcare reform evolves and takes shape, comparative effectiveness research (CER) appears to be one of the central topics on the national healthcare agenda. Over the past couple of years, comparative effectiveness has been explicitly incorporated in more than ten bills. For example, the passage of the American Recovery and Reinvestment Act of 2009 authorized $US1.1 billion for CER. Comparative effectiveness, when costs are formally considered, offers the hope of efficient resource allocation within US healthcare markets. However, the future operationalization and implementation of comparative effectiveness is uncertain, and there exist potentially negative, and unintended, consequences under certain scenarios. One example, and the focus of this article, is pharmaceutical innovation. Incentives for pharmaceutical R&D could be affected if drug development costs increase as a result of firms having to bear, directly or indirectly, the costs of running larger, randomized, head-to-head comparative effectiveness trials. While this may or may not be the case with current and future comparative effectiveness legislation and its subsequent implementation, the potential consequences for pharmaceutical innovation warrant recognition. This is the purpose of the article. To achieve this goal, we develop several models of clinical trial design, drug development costs and R&D investment. By example, we shed light on the causal links between the models and the ways in which industry R&D investment can be affected.

Do threats of pharmaceutical price regulation affect subsequent research and development (R&D) spending? This study uses the Clinton administration’s Health Security Act (HSA) of 1993 as a natural experiment to study this issue. We link events surrounding the HSA to pharmaceutical stock price changes and then examine the cross-sectional relation between firms’ stock price changes and their subsequent unexpected R&D spending changes. Results show that the HSA had significant negative effects on stock prices and firm-level R&D spending. Conservatively, the HSA reduced R&D spending by about $1 billion even though it never became law.

FDA approval times have declined significantly since the enactment of the Prescription Drug User Fee Act (PDUFA) in 1992. As a result, present value expected returns to pharmaceutical RD therefore, the social benefits of PDUFA (over and above the benefits of more rapid consumer access) are likely to be substantial.

In a widely cited article, DiMasi, Hansen, and Grabowski (2003) estimate the average pre-tax cost of bringing a new molecular entity to market. Their base case estimate, excluding post-marketing studies, was $802 million (in $US 2000). Strikingly, almost half of this cost (or $399 million) is the cost of capital (COC) used to fund clinical development expenses to the point of FDA marketing approval. The authors used an 11% real COC computed using the capital asset pricing model (CAPM). But the CAPM is a single factor risk model, and multi-factor risk models are the current state of the art in finance. Using the Fama-French three factor model we find that the cost of drug development to be higher than the earlier estimate.

Objectives: This article examines racial health disparities among the elderly in Sao Paulo, Brazil. It also explores whether these disparities differ among income groups. Methods: The study follows the conceptual framework developed by LaVeist (1994). A multistage analysis and Oaxaca-Blinder decomposition are used to explore the sources of racial disparities in health. Results: White seniors report better health than Black seniors. This is the case even after controlling for baseline health conditions and several demographic, socioeconomic, and family support characteristics. Discussion: This article suggests that the two most important factors driving racial disparities in health among seniors are historical differences in rural living conditions and current income. Present economic conditions are more relevant to racial disparities among poor than among rich seniors. Racial differences in health not attributable to observable characteristics are more important when comparing individuals in the upper half of the income distribution.

In this article we describe how reimbursement cost-effectiveness thresholds, per unit of health benefit, whether set explicitly or observed implicitly via historical reimbursement decisions, serve as a signal to firms about the commercial viability of their R&D projects (including candidate products for in-licensing). Traditional finance methods for R&D project valuations, such as net present value analyses (NPV), incorporate information from these payer reimbursement signals to help determine which R&D projects should be continued and which should be terminated (in the case of the latter because they yield an NPV < 0). Because the influence these signals have for firm R&D investment decisions is so significant, we argue that it is important for reimbursement thresholds to reflect the economic value of the unit of health benefit being considered for reimbursement. Thresholds set too low (below the economic value of the health benefit) will result in R&D investment levels that are too low relative to the economic value of R&D (on the margin). Similarly, thresholds set too high (above the economic value of the health benefit) will result in inefficiently high levels of R&D spending. The US in particular, which represents approximately half of the global pharmaceutical market (based on sales), and which seems poised to begin undertaking cost effectiveness in a systematic way, needs to exert caution in setting policies that explicitly or implicitly establish cost-effectiveness reimbursement thresholds for healthcare products and technologies, such as pharmaceuticals.

In the pharmaceutical industry, costs attributed to manufacturing are a major part of a company’s total expenses. In this paper, trends in various expense and income categories of pharmaceutical companies have been analyzed with particular emphasis on manufacturing costs to gain an insight into their relationships and how they may differ among types of pharmaceutical companies such as brand name, generics, and biotechs. The study includes data published in the annual reports of leading pharmaceutical companies from 1994 to 2005. Twenty-two pharmaceutical companies were selected based on the annual revenues. The set was further divided into three groups: brand names, generics, and biotechs. The analysis shows that, between 1994 and 2005, manufacturing costs (as a percentage of total sales) are different for the three groups of companies listed above. Additionally, each group of companies differs in how savings are leveraged strategically. The data on brand-name pharmaceutical companies also indicate that there is a strong correlation between the reduction of the cost of goods sold (COGS) and the increase in R&D expenditure. This suggests the validity of Vernon’s theory that for brand-name companies, a reduction in COGS will likely have a positive impact on investments in R&D, presumably resulting in much needed innovations and future health benefits for the society.

There are important fundamental links among the efficiency of pharmaceutical manufacturing, drug prices, and public health in the United States. This article seeks to probe these links because recent research (by academics and even the US Food and Drug Administration) suggests there are significant opportunities to improve the manufacturing processes for pharmaceuticals. Two models are developed that consider the impact of reduced manufacturing costs on pharmaceutical prices and firm profits. The two models effectively bound the range of potential future benefits from greater manufacturing efficiency and estimate that, for example, a 30% reduction in manufacturing costs will generate between $1.0 and $12.3 trillion in social value to the United States.

Previous empirical studies that have examined the links between pharmaceutical price controls, profits, cash flows, and investment in research and development (R&D) have been largely based on retrospective statistical analyses of firm- and/or industry-level data. These studies, which have contributed numerous insights and findings to the literature, relied upon ad hoc reduced-form model specifications. In the current paper we take a very different approach: a prospective micro-simulation approach. Using Monte Carlo techniques we model how future price controls in the US will impact early-stage product development decisions in the pharmaceutical industry. This is done within the context of a net present value (NPV) framework that appropriately reflects the uncertainty associated with R&D project technical success, development costs, and future revenues. Using partial-information estimators calibrated with the most contemporary clinical and economic data available, we demonstrate how pharmaceutical price controls will significantly diminish the incentives to undertake early-stage R&D investment. For example, we estimate that cutting prices by 40–50% in the US will lead to between 30 and 60% fewer R&D projects being undertaken (in early-stage development). Given the recent legislative efforts to control prescription drug prices in the US and the likelihood that price controls will prevail as a result, it is important to better understand the firm response to such a regulatory change. Copyright © 2007 John Wiley & Sons, Ltd.

1. IntroductionThe on-going public debate over prescription drug prices represents one of the most contentious issues in the history of U.S. health care politics. The commonly held perception that U.S. drug prices are "too high" has been fueled by the fact that real drug prices in the United States have been rising steadily and at a rate faster than that of the general consumer price index for over two decades. As a result, the pharmaceutical industry has come under intense criticism, with both politicians and special interest groups calling for new legislation making pharmaceuticals more affordable, either through legalized reimportation from price-regulated markets such as Canada and the European Union, or more directly through government-imposed price controls.Although these calls for legislative action are not new, the United States does appear to be, for the first time, very close to a major policy change regarding U.S. drug prices.1 The U.S. government might, like all other industrialized governments around the world, soon begin regulating drug prices.2 In addition to several reimportation bills currently on the Senate floor, proposed amendments to the recently passed Medicare Modernization Act of 2003 (MMA) also exist that will allow the U.S. government to negotiate directly with drug manufacturers for Medicare prescription drug purchases (the MMA currently has a noninterference clause), which will amount to approximately 60% of all U.S. drug purchases (Santerre, Vernon, and Giaccotto 2006).Although regulated drug prices in the United States will undoubtedly improve the public's access to today's medicines, and thus generate both cost savings and improved public health, it will simultaneously reduce firms' incentives to invest in pharmaceutical research and development (RD Miller and Frech 2002), as well as the sensitivity of R&D investment to real pharmaceutical prices (Giaccotto, Santerre, and Vernon 2005) and profits (Vernon 2004). Thus, in addition to the short-run benefits associated with lower regulated drug prices, long-run costs also arise. This is precisely the tradeoff the U.S. patent system tries to balance by awarding limited-term patents to new drug products.Even though a policy of regulated drug prices in the United States involves a tradeoff between short-run benefits and long-run costs, the former outcome often receives more attention in policy debates (Scherer 2004). Interestingly, however, efforts to quantify these short-run benefits from a rigorous economic perspective are nonexistent. Therefore, in this article, we attempt to do just that. We also compare our findings with the results from an earlier study by Giaccotto, Santerre, and Vernon (2005)--one that employed the same data and modeling techniques but that measured the economic costs of the same U.S. price control policy--in terms of reduced levels of pharmaceutical innovation. Thus, we are able to weigh the benefits of pharmaceutical price controls (in terms of consumer surplus gains) against the costs (measured in terms of forgone drug discoveries). Although these studies are retrospective in nature (out of necessity), and consider only one type of U.S. price control policy (one that requires pharmaceutical prices grow no faster than the consumer price index), the price control policy simulated is, nevertheless, similar to an actual policy enacted in 1992 for drugs purchased by the government for the Veterans Administration (VA) health system. Moreover, and for the first time, a formal cost-benefit analysis of a particular type of drug price control is possible, and this could offer new insights. …

Pharmacoeconomic analyses employ a wide range of techniques and methods to help societies allocate scarce health-care resources wisely, fairly, and efficiently. Techniques such as dynamic optimization and optimal control, however, have yet to be exploited by this field. Although control theory has a long history in mathematical biology and disease management, its application to economic costs in these disciplines has not yet been explored. Pharmacoeconomics therefore may offer a particularly promising starting point because of the emphasis this field places on the economic perspective. Although challenges may exist to implementing these techniques in practice (at least in some settings), there will nevertheless be value to considering the dynamic perspective these techniques offer, which requires thinking more critically about the optimal allocation of scare health-care resources over time. Therefore, our article serves as a primer to introduce this dynamic perspective from an economic standpoint within the context of two examples of treating of hyperlipidemia.

The pharmaceutical industry's core business is the innovation, development and marketing of new drugs. Pharmacogenetic (PG) testing and technology has the potential to increase a drug's value in many ways. A critical issue for the industry is whether products in development should be teamed with genetic tests that could segment the total population into responders and non-responders. In this paper we use a cost-effectiveness framework to model the strategic decision-making considerations by pharmaceutical manufacturers as they relate to drug development and the new technology of PG (the science of using genetic markers to predict drug response). In a simple, static, one-period model we consider three drug development strategies: a drug is exclusively developed and marketed to patients with a particular genetic marker; no distinguishing among patients based on the expression of a genetic marker is made (traditional approach); and a strategy whereby a drug is marketed to patients both with and without the genetic marker but there is price discrimination between the two subpopulations. We developed three main principles: revenues under a strategy targeting only the responder subpopulation will never generate more revenue than that which could have been obtained under a traditional approach; total revenues under a targeted PG strategy will be less than that under a traditional approach but higher than a naive [corrected] view would believe them to be; and a traditional [corrected] approach will earn the same total revenues as a price discrimination strategy, assuming no intermarket arbitrage. While these principles relate to the singular (and quite narrow) consideration of drug revenues, they may nevertheless partially explain why PG is not being used as widely as was predicted several years ago when the technology first became available, especially in terms of pharmaceutical manufacturer-developed tests.

This paper evaluates the impact of Colombia's subsidized health insurance program (SUBS) on medical care utilization. Colombia's SUBS program is a demand-side subsidy intended for low-income families, where the screening of beneficiaries takes place in decentralized locations across the country. Due to the self-selection problems associated with non-experimental data, we implement Propensity Score Matching (PSM) methods to measure the impact of this subsidy on medical care utilization. By combining unique household survey data with community and regional data, we are able to compute propensity scores in a way that is consistent with both the local government's decision to offer the subsidy, and with the individual's decision to accept the subsidy. Although the application of PSM using these rich datasets helps to achieve a balance between the treatment and control groups along observable dimensions, we also present instrumental variable estimates to control for the potential endogeneity of program participation. Using both methods, we find that Colombia's subsidized insurance program greatly increased medical care utilization among the country's poor and uninsured. This evidence supports the case for other Latin American countries implementing similar subsidy programs for health insurance for the poor.

This paper argues theoretically and shows empirically that pharmaceutical R&D spending increases with real drug prices, after holding constant other determinants of research and development (R&D). Specifically, an estimated elasticity suggests that a 10 percent increase in the growth of real drug prices is associated with nearly a 6 percent increase in the growth of R&D intensity. Simulations that are based on our multiple‐regression model indicate that the capitalized value of pharmaceutical R&D spending would have been about 30 percent lower if the federal government had limited the rate of growth in drug price increases to the rate of growth in the general consumer price index during the period 1980–2001. Moreover, the results suggest that a drug price control regime would have resulted in 330–65 fewer new drugs, representing over one‐third of all actual new drug launches brought to the global market during that time period.

Objectives: This study examines the degree to which therapeutic class accounts for variability in drug development costs. It also scrutinizes how sales levels vary across the associated therapeutic classes for those drugs that have reached the marketplace. Data and Methods: A stratified random sample of 68 investigational drugs that first entered clinical testing anywhere in the world from 1983 to 1994 was selected from the pipelines of 10 pharmaceutical firms. Clinical period cost data were obtained for these compounds by phase. The sample consisted both of drugs that failed in testing and drugs that obtained marketing approval. We grouped the drugs by therapeutic category. Clinical period costs per approved new drug (inclusive of failures) were obtained for the analgesic/anesthetic, antiinfective, cardiovascular, and central nervous system (CNS) therapeutic classes. Worldwide sales profiles for new drugs approved in the United States from 1990 to 1994 over a 20-year product life cycle were computed base...

A series of chiral non-racemic 5,5- and 5,6-bicyclic lactams is prepared from (R)-phenylglycinol. These are isomerised on treatment with aluminium trichloride in 1,2-dichloroethane to give spiro lactams in high yield and >3:1 diastereoselectivity. From four structures determined by X-ray crystallography, it follows that spiro indenes are formed preferentially with retention of configuration at the spiro carbon atom and spiro naphthalenes with inversion.

Spiro 2-pyrrolidin-5-ones were obtained from N-substituted succinimides by a two-step procedure, involving 5- or 6-endo-trig cyclisation of N-acyliminium ion intermediates with a tethered aromatic π-nucleophile.

Background: Because pharmaceutical price controls fall outside the domain of historical experience in the US, standard retrospective statistical analyses of firm- and/or industry-level data are not appropriate for studying the long-run impact of price controls on pharmaceutical innovation. Simulation modeling, however, can be used to address this issue.

Pyrido[2′,3′:3,4]pyrrolo[2,1-a]isoindole, -isoquinoline and -benz[c]azepine derivatives are obtained by heating in polyphosphoric acid (PPA) appropriate hydroxy lactam precursors derived from pyridine-2,3-dicarboximides. The stereoselectivity of ring closure is rationalised by considering the development of A(1,3) strain in the cyclisation step from N-acyliminium ion intermediates.

The tetracyclic advanced intermediates 6, 8 and 9 obtained from L-tryptophan via a cis-selective Pictet–Spengler reaction and a Dieckmann–Thorpe cyclisation are used in a range of new approaches to polycyclic monoterpenoid indole alkaloids such as ajmaline and suaveoline. Structural modifications designed to facilitate a key intermolecular addition to C15 (ajmaline numbering) are described, followed by two intramolecular routes based on the addition of a suitable carbon fragment to a remote nitrogen atom prior to bond formation at C15.

Under UV irradiation, propan-2-ol adds to the CC bond of maleimides 4 to give 2-(1-hydroxy-1-methylethyl)succinimides 5 in 25–70% yield. Cyclohexanol adds in the same way to give 2-(1-hydroxycyclohexyl)succinimides 6. Several trace by-products are identified by GC-MS analysis and their formation accounted for.

This report models how the evolving field of pharmacogenomics, the science of using genomic markers to predict drug response, may impact drug development times, attrition rates and costs. While there still remains an abundance of uncertainty around how pharmacogenomics will impact the future landscape of pharmaceutical and biological R&D, we identify several likely outcomes. We conclude pharmacogenomics (as defined in this context) has the potential to significantly reduce both expected drug development costs via higher probabilities of technical success, shorter clinical development times and smaller clinical trials. Our conclusions are, of course, accompanied by numerous caveats.

The homologous nitrile 13 derived from L-tryptophan undergoes a modified Pictet–Spengler reaction with methyl propynoate, under conditions of kinetic control, to afford the cis-tetrahydro-β-carboline 15a (cis∶trans = 77∶23). After protection, Dieckmann–Thorpe cyclisation to the bridged keto nitrile 20 proceeds in 90% yield. Simple functional group modifications via the alcohol 21a and nitrile 22 (structures confirmed by X-ray crystallography) allow convergence with the tetracyclic α,β-unsaturated aldehyde 10, which is an advanced intermediate for the synthesis of a range of bridged indole alkaloids.

This study examines the relationships between firm size, R&D costs and output in the pharmaceutical industry. Project–level data from a survey of 12 US–owned pharmaceutical firms on drug development costs, development phase lengths and failure rates are used to determine estimates of the R&D cost of new drug development by firm size. Firms in the sample are grouped into three size categories, according to their pharmaceutical sales at the beginning of the study period. The R&D cost per new drug approved in the US is shown to decrease with firm size, while sales per new drug approved are shown to increase markedly with firm size. Sales distributions are highly skewed and suggest that firms need to search for blockbuster drugs with above–average returns. The results are consistent with substantial economies of scale in pharmaceutical R&D, particularly at the discovery and preclinical development phases.

Conventional electroencephalographic (EEG) analysis techniques do not use the phase information from the Fourier analysis.This study used a new technique of EEG analysis, bispectral analysis, which measures interfrequency phase relationships in the EEG. Using a reference database, and a process of multivariate discriminant analysis, we developed a univariate bispectral variable, the bispectral index (BIS). This study was designed to test the efficacy of BIS in predicting movement to incision during either an isoflurane/alfentanil anesthetic or a propofol/alfentanil anesthetic technique. Fifty consenting patients were randomized to two groups; one received isoflurane/alfentanil and the other, propofol/alfentanil for anesthesia. EEG was recorded using a microcomputer system and the data were analyzed off-line. Hemodynamic variables were also recorded. After skin incision, each patient was observed carefully for 2 min to detect purposeful movement. A significant difference was found between the BIS values for movers versus nonmovers within each of the two treatment groups (P

Fifty-six million prescriptions were dispensed for antipsychotics in the USA in 2010, at an estimated cost of $16.1 billion, and 90% of these were for atypical antipsychotics (IMS Institute for Healthcare Informatics: The use of medicines in the United States: review of 2010). Co-prescription of two (or more) antipsychotics or so-called polypharmacy is estimated from 2 to >50% depending on the population surveyed. Antipsychotic polypharmacy is of considerable importance from multiple perspectives such as its sheer volume, quality and safety of care, and cost. There is much variability in this practice based on age group, primary and co-morbid diagnoses, practice setting, health insurance status, etc. A thorough understanding of the associated factors is necessary to know what drives and maintains polypharmacy practice

Dehydration of 6,7-dihydro-7-hydroxy-6-(α-methylbenzyl)-7-phenylpyrrolo[3,4-b]pyridin-5-one 4b on treatment with acid is accompanied by rearrangement, first to 6,7-dihydro-7-phenyl-7-[(E)-2-phenylethenyl]pyrrolo[3,4-b]pyridin-5-one 10 and then to 2,3-dihydro-3-phenylspiro[indene-1,7′(6′H)-pyrrolo[3,4-b]pyridin]-5′-ones 9a, b. Crystal structures of two rearranged products 9a and 10 are reported.

Responsible public policy must be informed public policy. This is particularly true with respect to the regulation and governance of the global pharmaceutical industry; an industry that has bestowe...

Dehydration of 6,7-dihydro-7-hydroxy-6-(α-methylbenzyl)-7-phenylpyrrolo[3,4-b]pyridin-5-one 4b on treatment with acid is accompanied by rearrangement, first to 6,7-dihydro-7-phenyl-7-[(E)-2-phenylethenyl]pyrrolo[3,4-b]pyridin-5-one 10 and then to 2,3-dihydro-3-phenylspiro[indene-1,7′(6′H)-pyrrolo[3,4-b]pyridin]-5′-ones 9a, b. Crystal structures of two rearranged products 9a and 10 are reported.

Under conditions of kinetic control, the cis-diastereoselectivity of the Pictet-Spengler reaction between tryptophan esters and aldehydes can be controlled by varying the size of the ester group; the reaction proceeds in essentially quantitative yield with most aldehydes when conducted in chloroform in the presence of molecular sieves.

The β-keto-nitrile 2, which is an advanced intermediate for the synthesis of several indole alkaloids, is composed of a mixture of enol/keto tautomers, and of diastereoisomers; nevertheless, reduction with sodium borohydride yields essentially a single diastereoisomer 3.

When the homologated nitrile 11 derived from L-tryptophan undergoes a modified Pictet–Spengler reaction with methyl propynoate, the resulting cis-tetrahydro-β-carboline 12a is ideally functionalised for cyclisation to the bridged ketonitrile 14; simple functional group modification via the nitrile 15(structure confirmed by X-ray crystallography) allow convergence with the tetracyclic α,β-unsaturated aldehyde 10, which is an advanced intermediate for the synthesis of a range of bridged indole alkaloids.