New Informa Healthcare website

Informa Healthcare has moved this week the content of its 180 peer-reviewed journals to a new online delivery platform at www.informahealthcare.com.

The site combines all the Informa Healthcare journal titles listed on InformaWorld.com and InformaPharmaScience.com to help simplify the customer experience. The new site utilizes the online content management and delivery system provided by Atypon Systems, Inc. – an e-publishing solutions supplier for a number of leading information providers including JSTOR, New England Journal of Medicine and the American Chemical Society.

The Atypon system enables Informa Healthcare to integrate a comprehensive archive service dating back to 1918 giving pharmaceutical, medical and healthcare professionals one central, high-quality source of information.

The new platform offers the option of online trials, advanced searching, alerting, and single article purchases. The site also provides COUNTER-compliant reports and statistics to help subscribers analyze usage.

There will be a dual-hosting period with the InformaWorld platform, which currently hosts the medical content, through 2009 allowing for a gradual migration. Informa Healthcare will set up customer accounts in August and will notify subscribers of the change to ensure a seamless transition to the new site. Customers with journals on InformaPharmaScience.com will be automatically re-directed.

This website will also allow Informa Healthcare to implement new features and improve the layout over the next few months.

To review a list of journal titles on the new site or for more information, visit www.informahealthcare.com.

Ubiquitin - a promising target for new drug development

Where potential approaches to drug discovery are concerned, ubiquitylation might not be the first word that springs to mind. But the 2006 approval of bortezomib (Velcade) and recent research into inhibitors of the ubiquitin-proteasome pathway have raised expectations for this biological process as a target for novel treatments for a range of diseases.

A recent review article published in Expert Opinion on Therapeutic Targets, Targeting the proteasome pathway, by Yokosawa and Tsukamoto explores the emergence of the proteasome and other members in the ubiquitin–proteasome pathway as novel therapeutic targets. In a related piece in Scrip World Pharmaceutical News, Informa Analyst Ian Schofield provides his Expert View on ubiquitylation as an attractive route to novel drug design.

Yokosawa and Tsukamoto review the current understanding of the ubiquitin–proteasome pathway and describe inhibitory mechanisms for tageting it, while Schofield discusses the RUBICON network and the recent creation of the Scottish Institute for Cell Signalling, which with government funding hopes to pinpoint novel drug targets for use in designing medicines for inflammation, cancer and infectious diseases.

Read both articles at:
Expert Opinion on Therapeutic Targets and
Scrip World Pharmaceutical News

Outstanding performance for Informa Healthcare journals

Impressive growth, high world rankings and excellent impact factors demonstrate strength of Informa Healthcare’s comprehensive portfolio of highly respected publications.

LONDON – Monday, 29 June 2009 – Informa Healthcare – one of the world’s leading medical and scientific publishing groups – has announced highlights of its latest journal Impact Factor results, with impressive results across the division’s comprehensive range of titles. The company’s highly respected range of Expert Opinion titles performed notably well, with significant jumps for Expert Opinion on Biological Therapy which is up almost 20% to 3.475 and Expert Opinion on Therapeutic Targets, up more than 21% to 4.038. Expert Opinion on Investigational Drugs leads the series with a 2008 Impact Factor of 4.058 and two new titles – Expert Opinion on Drug Safety and Expert Opinion on Metabolism & Toxicology, registered sensational first ever Impact Factors of 3.073 and 3.069, respectively.

The company’s Critical Reviews in Toxicology also registered an outstanding impact factor of 7.204, up more than 40% and now ranked 2nd out of 75 journals in toxicology – with 1st place being an annual publication as compared with Critical Reviews in Toxicology’s ten issues per year.

Impact factors are a method of measuring the influence which a journal has on the scientific community. They are calculated by Thomson Reuters and are designed to indicate how many times the published articles of a journal are cited during the course of a year, providing an insight to how much ‘impact’ the journal is making on its audiences.

“Impact Factors provide us with a measure for the importance of our journals to the medical and scientific communities we serve,” explains Phil Garner, Publishing Director at Informa Healthcare. “We are delighted with the performance of our market leading titles as well as some new journals which have posted excellent first time results.”

“Our Expert Opinion range of titles – which provides in-depth analysis of the pharmaceutical R&D pipeline – has registered impressive gains across the board and first ever Impact Factors of above three for our two new titles is testament to the quality of information that goes into our journals,” says Phil. “These results give a big ‘thumbs up’ to the comprehensive, intelligent content which make these titles the definitive reference source for leading pharmaceutical scientists.”

Other Informa Healthcare journals that have performed well are the Journal of Drug Targeting – up to 2.771, Inhalation Toxicology – up to 2.403, International Reviews of Immunology with a 37% increase to 4.935, the International Journal of Radiation Biology – up 48% to 2.178, and first ever IF’s for The Aging Male – at 2.622, and Prehospital Emergency Care at 1.248, now ranked in the top half of 13 journals in the emergency medicine category.

Informa’s Scandinavian titles also performed well: Fifteen out of twenty five registered increased impact factors and eighteen with impact factors of over 1.00. The International Journal of Pediatric Obesity registered 3.984 in just its second year, up almost 100% from 2.00 in 2000. World Journal of Biological Psychiatry was also up by more than 111% to 3.582. The division’s flagship journal, Annals of Medicine, registered an impact factor of 5.435 with some 78% of the group’s Scandinavian journals registering impact factors.

“We are justifiably proud of the performance of all of our journals,” adds Phil. “Our new titles have done very well and our established journals have continued to go from strength to strength, with an impressive number of them moving many places up in their respective rankings.”

Informa’s results, across its wide range of journals, are remarkable: The International Journal on the Biology of Stress is up to 2.952; The Journal of Protein Folding Disorders is up to 1.714; The International Journal of Audiology has an Impact Factor of 1.201; The Journal of Psychosomatic Obstetrics and Gynecology is up 67% to 1.585, and Platelets is up to 2.271 – a rise of almost 20% over last year. In addition, the Journal of Intellectual & Developmental Disability has increased to 0.902 and Pathology to 2.324.

“Our overall performance – together with the outstanding individual performances of many of our titles – ensures that Informa continues to serve as a leading force in medical and scientific publishing, providing the market with the lion’s share of must-read titles,” explains Phil.

Scholar One 'submitting agent' feature activated for Expert Opinion journals

Medical communication agencies can now submit manuscripts to Expert Opinion journals as third party, on behalf of the authors .
The name of the submitting agent will not appear in the authors' list and both the submitting agent and the corresponding author will receive emails from the editorial team regarding the manuscript.

The submitting person must now identify itself as an author or a third-party submitting agent at the first step of the submission process.

This feature has been activated for the following journals using the Scholar One submission platform:

• Expert Opinion on Pharmacotherapy
• Expert Opinion on Therapeutic Targets
• Expert Opinion on Investigational Drugs
• Expert Opinion on Biological Therapy
• Expert Opinion on Metabolism and Toxicology
• Expert Opinion on Drug Safety
  

Award winning research at the Dutch Atherosclerosis Symposium, 2009

The years to come are going to be very busy for persons working in the field of atherosclerosis and cardiovascular disease. Basic-science researchers are hot on the trail of targeted drugs that will be much more focused than available drugs, and some remarkable progress is being made. The 12th Dutch Atherosclerosis Symposium took place on March 12 and 13, 2009 and showcased some of this progress taking place in the Netherlands. I would like to briefly present 4 of the interesting research topics that received jury awards.

Exercise
Meissner et al.1 investigated the effect of exercise on cholesterol metabolism in mice either exposed to voluntary running wheel for 2 weeks or which remained sedentary. Exercise appears to increase cholesterol and bile acids turnover via specific changes in the intestine that decrease intestinal bile acid and cholesterol absorption and promote their fecal excretion. If the same holds true in humans, exercised-induced modulation of bile acids and cholesterol turnover leading to reduced plasma cholesterol levels might contribute to the beneficial effects of exercise on cardiovascular disease.

Cathepsin inhibition
The research aim of Waard et al.2 is to develop pharmaceutical therapies for abdominal aortic aneurysm to prevent surgical intervention in elderly patients. They have previously shown that cathepsins are functionally involved in collagen degradation in human aneurysm tissue. In the present study they showed that E64 (a cathepsin inhibitor) treatment resulted in a decreased number and severity of aneurysms and in a less inflammatory profile in serum in a mouse model. The inhibition of cathepsins may be therefore an attractive therapeutic approach to prevent aortic aneurysms expansion.

Microarray antigen chip
The immune system is thought to play an important role in initiation and progression of atherosclerosis. Den Dekker et al.3 aimed to explore the potential of auto-antibody profiles as a biomarker for a cardiovascular event. A generic version of the antigen microarray was used bearing over 740 proteins related to a variety of conditions including immune regulation, inflammation, angiogenesis, apoptosis and more. The antigen microarray was able to identify patients with previous myocardial infarction with a high sensitivity and specificity. In conclusion, a microarray antigen chip may be used as a novel biomarker for cardiovascular disease.

Nuclear receptor Nurr1
Bonta et al.4 have investigated the role of nuclear receptor Nurr1 in stent restenosis. They found that Nurr1 is expressed in human in-stent restenosis lesions. Nurr1 inhibits inflammatory gene expression in both macrophages and smooth muscle cells and it inhibits proliferation of smooth muscle cells. In vivo Nurr1 reduces neointima formation in mice. Small-molecule drugs have been identified that enhance the transcriptional activity of this nuclear receptor. It seems therefore that Nurr1 may be an attractive novel target for local intervention against in-stent neointima formation.

Comment
Genetics and biochemistry have now become the unchallenged leaders of cardiovascular research. New drugs to be soon perfected together with the immense progress in the invasive field will completely change the cardiology that we all knew.

By: Sandrin C. Bergheanu, MD, Dept. of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (s.c.bergheanu@lumc.nl)

References

1. Maxi Meissner et al., Department of Pediatrics, University Medical Center Groningen, The Netherlands. E-mail: M.Meissner@med.umcg.nl

2. Vivian de Waard et al. Division of Biopharmaceutics of the Leiden/Amsterdam Center for Drug Research, Leiden and Department of Medical Biochemistry, AMC, Amsterdam, The Netherlands. E-mail: v.dewaard@amc.uva.nl

3. Wijnand den Dekker et al. Molecular Cardiology Laboratory, Erasmus Medical Center Rotterdam, The Netherlands.

4. Peter Bonta et al. Department of Medical Biochemistry, Academic Medical Center Amsterdam, The Nertherlands. E-mail: P.I.Bonta@amc.uva.nl

Top 5 reasons why medical associations should maintain ties with industry

In the April 1st issue of JAMA, Rothman, et al. spelled out a proposal for controlling conflicts of interest that calls for professional medical associations (PMAs) to cut all ties with industry. PMA conferences, continuing education and practice guidelines often set the standard for patient care.

The proposal seems reactionary, albeit understandable given how quickly a handful of high-profile cases—particularly those involving failure to disclose—both blackened the eyes of science and eroded public trust.

But should a few bad apples be allowed to spoil the bunch? I say no. And here are the top 5 reasons why I propose just cutting all the bad apples loose and continuing to reap the best possible fruit.

1. Together, PMAs and industry actually do more good than harm. I could go on and on about all the good new drugs and devices have done for patient care, but we don’t have the space. I will say that I once had a 40-plus year old former patient stop me on the street to thank me for helping save his life. In my opinion, the kudos should have gone to the makers of the intra-aortic balloon pump that kept him alive while his heart recouped. Back in the day, he would never have survived that event regardless of how good the care was.

2. Industry doesn’t have as much power as you think. Industry’s power is diluted by nurses, patients and grass-roots patient advocacy groups, who together wield big clubs called prescriptive pressure and noncompliance: if a drug or device doesn’t work, nurses won’t give it, or patients won’t use it. And don’t forget the 800-lb. gorilla in the room—third-party payers—who have more power than drug and device companies over treatment guidelines and who gets what and when.

3. Industry is on the same side of the fiduciary coin as PMAs. Industry wants to save lives, too. They also want safe and ethical care. If you don’t believe that take a look at how pharma manufactures have come together to police themselves. Visit http://www.phrma.org/ and click on their outline for a revised marketing code.

4. Physicians are business people too. Physicians can’t cut ties with industry; they are industry. We like to believe that pure professionalism lies at the heart of medicine, but the drivers of treatment guidelines, namely the individual physicians and their associations, are in business. Profit isn’t a palatable word, so let’s call what they do “earning a living.” Besides, physicians can cross the line without help from the drug and device part of the industry, as evidence by anti-kickback laws that have more to do with unethical patient referrals than branded pens and notepads.

5. Together, PMAs and industry are on the ethically right path. In the Association of American Medical Colleges’ “The scientific basis of influence and reciprocity: A symposium” the authors show how self-interest can unconsciously bias even those of us who have the best of intentions, but they also demonstrate how just being reminded of an honor code stops cheating completely regardless of the amount of reward. Full transparency is a kind of honor-code reminder, and a huge step in the ethically right direction for all parties involved.

Sources:
Rothman DJ, McDonald WJ, Berkowitz CD, et al. Professional Medical Associations and their relationships with industry. JAMA 2009; 301: 1367–72
Korn D, Ehringhaus SH. Association of American Medical Colleges, The scientific basis of influence and reciprocity: A symposium. 2007. Available at: www.aamc.org/publications Association of American Medical Colleges, Industry funding of medical education: report of an AAMC task force. 2008. Available at: www.aamc.org/publications


Written by Terri Metules.

The value of in vitro data in metabolic disease: Editorial Board member Keith Suckling comments on a review by Clapham et al.

It is not unusual to read at the end of a paper presenting new biology that the novel mechanism or process being described may be a target for pharmacological intervention. The data may well have been obtained from studies in cell culture, perhaps of an immortalised human cell line, perhaps from cells genetically manipulated, and the basic picture (given the rigours of the reviewing process) may be very convincing. But there is always a strong doubt in the reader’s mind. This is because the pathway from a novel and potentially relevant piece of biology to a new drug with demonstrated clinical value is long and hazardous. At this early stage, the relevance to human disease may be little more than a hypothesis, and data of all kinds will be required as drug discovery and development takes place to validate the target.

It has been recognised for many years that one of the major problems to address is how to develop sufficient confidence in a target or agent to allow the major financial commitment that is required to be made. We need confidence that the cell culture models are relevant to an intact animal, and that the data we obtain in a pre-clinical species has relevance to the situation in the patient. Such confidence is hard to obtain, particularly for novel biology. In this review [1], Clapham and colleagues lay out the ground for metabolic disease. Apart from offering a very clear analysis of the issues involved, they make a very useful contribution by illustrating the value of data on drug activity obtained from cell culture studies and from parallel studies in laboratory animals, both in relation to the observed effects in patients. This kind of information is not readily available: it is mostly held in the experience of specialised scientists, an asset that is all too easily lost in the major reorganisation of drug companies.

A central point in the problems clearly illustrated by Clapham et al. is the proper understanding of what a cell culture model or an in vivo model can be expected to achieve. The question has been addressed for animal models in the closely related area of dyslipidaemia [1], but, probably because the relevant data are very widely scattered in the literature, the aligning of in vitro, in vivo and human data has not been widely done. The analysis of Clapham and colleagues is a welcome example of what could be done. But we need to go further. As I have noted recently [3,4], I believe we need to be much more critical of what our models can achieve and what their limitations are. Only then, as Clapham et al. clearly illustrate, will we be able to offer a rigorous scientific foundation for the difficult investment decisions that have to be made.


1. Clapham J.C., Hallén S. (2009), Cell based in vitro and ex vivo models in metabolic disease drug discovery: nice to have or critical path?, Expert Opinion on Drug Discovery, 4: 417-428.

2. Suckling K.E. (2006), The ideal model in atherosclerosis and dyslipidaemia - does it exist? Expert Opinion on Drug Discovery 1: 507-511.

3. Suckling KE (2007), Top down meets bottom-up. The critical interface for drug discovery. International Atherosclerosis Society Commentary.

4. Suckling KE (2008) Animal research: too much faith in models clouds judgement. Nature (letter) 2008, 455, 460.

By Keith Suckling, PhD, Editorial Board member of Expert Opinion on Therapeutic Patents

Open repositories VS the Publisher

On March 18th the MIT introduced a policy requiring all scholarly articles written by its faculty members to be made freely available in an open access repository. While researchers understandably applaud the free and open dissemination of data, there are questions that should be considered with regards to the impact of a growing number of open repositories on the value added by Publishers, and how this value would be retained if in the long term the open access journal turns out to be unsustainable.

How important is the value added by the Publisher (and this is not an open access versus non-open access journal debate)? While the peer review process is certainly not without its failings, to any Publisher or Editor worth their salt, the integrity of the peer review process is paramount. To quote a previous blog post on this site, an author of a CMRO article on receiving his peer review comments said "I have never received 58 referee comments on a manuscript less than 3000 words long, but the referees' comments and the revision definitely improved the paper." An author of a recent paper submitted to Expert Opinion on Medical Diagnostics fed back "a comment about the reviewers: it was clear that they read the manuscript carefully. Regardless of whether they agreed with some of our arguments, their comments reflected readers that thought about what they read. This is how peer review is supposed to work. Excellent reviewer selection on your part, and a thorough job on theirs." Aside from assisting the author in critically reviewing their work and ultimately leading to a better paper, without the peer review process how do we ensure no dangerously inaccurate information is published that is indistinguishable from high calibre scientific research?

And it’s not just in the peer review that value is added by the Publisher. Who checks references are cited correctly and terms are not misspelled - will the institutions running their own open access repositories employ copyeditors? Who will ensure the figures are legible and of good quality – will the institutions employ production editors who lay the work out in such a way that it is easy on the eye and doesn’t give readers a headache? Will there be any independent quality check before the research is published? With a limitless amount of potentially unqualified freely available literature, how will the busy physician who only has 5 minutes in his/her day to digest the most important findings even know where to start? These are just a few of the questions that would need to be answered.

Ok, I’m playing devil’s advocate a little here. I do not envisage a world where the peer-reviewed journal ceases to exist, but the open access model of publishing is widely debated, both in terms of quality and sustainability. So what is the future of publishing? Even if the open access, pay to publish model is viable in the long term, does the scientific community agree to paying to publish all of their work in the future, rather than pay to read the work of others? The fact is, publishing a journal is a costly business and the money has to come from somewhere. Publishers are accused of placing scientific research behind ‘commercial barriers’, but surely the same argument could be applied to the pay to publish model. Is it fair that only authors with funding can afford to have it published? Will this lead to a bias in the literature towards sponsored research, not even so much through the choices of the Editor, but through the fact that only authors who can pay can publish? Or is there an alternative, free to publish, free to read, sustainable model for open access publishing that still maintains high standards of peer review and editorial quality?

While Publishers undoubtedly need to take steps to ensure the advancement of science through the widest possible dissemination of research, with respect to the whole principal of open access, how do we do this for free? Surely someone, somewhere has to pay something?

In summary:

• How important is value added by the Publisher?
• How will high calibre research be distinguished?
• How will the reader filter the wealth of freely available literature?
• Does the scientific community want to pay to publish all of their work in the future?
• Could this lead to bias in the literature?
• What if the pay to publish model doesn't work?
• Is there an alternative, free to publish, free to read, sustainable model for open access publishing that still maintains high standards of peer review and editorial quality?

By Anna Heinink, Publisher, Expert Opinion

Informa Pharmaceutical Science’s policy on NIH-funded research can be found here http://www.informapharmascience.com/page/resources/authors#nihfundedresearch

Expert Opinion on Therapeutic Patents and Journal of Medical Economics selected for indexing in MEDLINE

Informa Pharmaceutical Science is delighted to announce that Expert Opinion on Therapeutic Patents (EOTP) and the Journal of Medical Economics (JME), have been selected for indexing in MEDLINE.

A widely used bibliographic database compiled and maintained by the US National Library of Medicine, MEDLINE is freely accessible via the PubMed search engine. It is worth noting that the decision by MEDLINE to index or not a journal is based on a review by the Literature Selection Technical Review Committee upon application. The main criteria for selection, which go beyond sound science and thorough peer review, are listed here.

We are very pleased by this decision which will deservedly increase the visibility of JME and EOTP articles.

Reuben’s Research: A Pain In The Analgesia

Research on multimodal analgesia took a hit when one of its leading proponents, Scott S. Reuben, MD – aka the Medical Madoff - was caught fudging his data. Baystate Medical Center’s internal review board launched a full-fledged investigation into Reuben’s work last May when he appeared to be conducting studies on humans without approval. The investigation, completed in January, uncovered some 21 published articles—dating as far back as 1996—in which Reuben made up some or all of the data. Baystate's chief academic officer is quoted as saying that in many cases, "there was no clinical trial because there were no patients." Whew!

At least it looks like nobody got hurt. But the incident raises questions in our industry that beg for answers:

Where Were The Peer Reviewers? In my opinion, that’s an unfair question some people are asking. Peer reviewers, and editors for that matter, can only work with the data they’re given. We can’t be expected to show up on every study site to make sure a prospective author’s data is pure before we decide to accept it for publication.

Why did it take 13 years to catch him? We can only speculate on why it took so long to uncover Reuben’s fraud, but it may have been because, like the Piltdown Man, nobody was taking his research all that seriously—nobody else could replicate his findings. Replication, albeit slow, is the surest way to keep fraud in check.

What was Industry’s role? Outside of partially funding some of Reuben’s research—and there’s nothing inherently wrong with that--Pfizer is not suspected of any wrongdoing. However, Reuben’s relationship with Pfizer, at least in the papers I was able to fully access, was not properly disclosed in most cases.

Would full disclosure have mattered? I think so. Knowing the financial ties an author has to a study’s sponsor alerts readers to the potential for biased results.

What Can Be Done About It? Reuben’s case is every Editor’s worst nightmare. Patient care is ultimately affected by erroneous data. While CMRO has never published a Reuben paper, something like this could happen to us. But rest assured that we are doing everything within our power to prevent such a thing from happening.

All CMRO articles undergo such a stringent peer review process that caused one author recently to say, “I have never received 58 referee comments on a manuscript <3000 words long, but the referees' comments and the revision definitely improved the paper.” We will also be introducing new measures soon to stay at the forefront of ethical publishing - keep your eyes open for more news soon.

By Terri Metules, US Deputy Managing Editor, Current Medical Research and Opinion

Further Reading

Good publication practice guidelines for medical communications agencies: a MedComm perspective Bareket-Samish et al. CMRO 2009;25(2):453-61

Working with compliance - the role of healthcare communications agencies Cairns & Yarker CMRO 2008; 24(5): 1371-78

International Society for Medical Publication Professionals (ISMPP) Position Statement Norris et al. CMRO2007 23(8): 1837-40

Phospholipases may not be targets of choice for medicinal chemistry, but two inhibitors are now in clinical development for atherosclerosis

By Editorial Board member Dr Keith Suckling

Phospholipases do not appear high on the list of major druggable target types. There are significant challenges in medicinal chemistry to provide specificity and in enzymology to generate data that can support chemistry for reactions that take place at a lipid-water interface at which active concentrations of compounds are difficult to define. So it is perhaps surprising that there are now two phospholipase inhibitors in clinical development for the treatment of atherosclerosis - surprising because of the chemical challenges but also because the final proof of efficacy in patients requires extended outcome studies in around 16,000 subjects.

The first of these compounds is darapladib (GSK) for which Phase 2 results were presented last year [1]. Darapladib inhibits the enzyme known as lipoprotein-associated phospholipase A2. As the name suggests, this phospholipase is found in the circulation associated with LDL and is thought to catalyse the hydrolysis of oxidised phospholipids. The products of the hydrolysis promote the expression of adhesion molecules on the artery wall and chemokines in macrophages and so promote the development of the vulnerable plaque. Inhibition of this process would therefore be expected to be of benefit and recent studies in a pig model support this concept [2] and some of the Phase 2 data are consistent with it too. This mechanism would be expected to have a similar overall effect on the pathogenesis of atherosclerosis to a chemokine receptor antagonist, for example CCR2. Importantly this approach does not reduce plasma LDL, and is not expected to.

Other forms of phospholipase have been implicated in atherogenesis in recent years and in particular those known as secretory phospholipases [3], of which the Group V enzymes have been of particular interest. Animal data also supports a role for these enzymes in atherogenesis [4], but the mechanism is different. In this case the phospholipase modifies HDL and LDL particles making the former less able to support reverse cholesterol transport and the latter more susceptible to oxidation. Very recently Phase 2 data have been reported of the effects of an sPLA2 inhibitor, varespladib (A-002, Anthera Pharmaceuticals) [5]. This compound inhibits a range of sPLA2 s (sPLA2-IIa>sPLA2-X>sPLA2-V) and, in contrast to darapladib, does have an effect on plasma LDL concentration and also on hsCRP. Recent animal data are consistent with an effect of varespladib on atherogenesis in the mouse [6]

It is important to recognize that the effects of these two phospholipase inhibitors on the process of atherogenesis are quite different and as a result, at least in Phase 2, they require different end points to be studied. If this is not borne clearly in mind there is a danger of serious confusion amongst non-experts. In this respect we should no more talk about phospholipase inhibitors as a class than we might about PPAR agonists: there are so many differences. Nevertheless, for both mechanisms, it is necessary to show that they improve outcomes in patients, and at this point the differences are not important. A large outcome study is beginning for darapladib (STABILITY) with around 15,000 patients [7].

By Keith Suckling, PhD, Editorial Board member of Expert Opinion on Investigational Drugs

Reference List

1. Serruys P.W., Garcia-Garcia H.M., Buszman P., Erne P., Verheye S., Aschermann M., Duckers H., Bleie O., Dudek D., Botker H.E. et al. (2008). Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 118: 1172-1182.
2. Wilensky R.L., Shi Y., Mohler E.R., III, Hamamdzic D., Burgert M.E., Li J., Postle A., Fenning R.S., Bollinger J.G., Hoffman B.E. et al. (2008). Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med 14: 1059-1066.
3. Kimura-Matsumoto M., Ishikawa Y., Komiyama K., Tsuruta T., Murakami M., Masuda S., Akasaka Y., Ito K., Ishiguro S., Morita H. et al. (2008). Expression of secretory phospholipase A2s in human atherosclerosis development. Atherosclerosis 196: 81-91.
4. Boyanovsky B., Zack M., Forrest K., and Webb N.R. (2009). The Capacity of Group V sPLA2 to Increase Atherogenicity of ApoE-/- and LDLR-/- Mouse LDL In Vitro Predicts its Atherogenic Role In Vivo. Arterioscler Thromb Vasc Biol ATVBAHA.
5. Rosenson RS, Hislop C, McConnell D, Elliot, M, Stasiv U, et al. (2009). Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study): a phase II double-blind, randomised, placebo-controlled trial. Lancet 373: 649-658.
6. Fraser H., Hislop C., Christie R.M., Rick H.L., Reidy C.A., Chouinard M.L., Eacho P.I., Gould K.E., and Trias J. (2009). Varespladib (A-002), a Secretory Phospholipase A2 Inhibitor, Reduces Atherosclerosis and Aneurysm Formation in ApoE-/- Mice. J Cardiovasc Pharmacol.53, 60-65
7. GSK Press release: http://www.gsk.com/media/pressreleases/2008/2008_pressrelease_10144.htm

Drug-drug interactions in oncology: from mechanisms to patient perception

Drug-drug interactions in oncology represent a highly problematic issue to resolve. The events that give rise to clinically significant drug-drug interactions are inherently driven by cancer patients that are often being medicated by more than one drug. Polypharmacy in oncology can result in alterations of chemotherapeutic pharmacokinetic profiles via multiple mechanisms affecting the pharmacodynamics of drugs that are closely related to their pharmacokinetic profiles. In their review article,Mani and colleagues critically analyze the mechanisms by which drug-drug interactions in oncology alter pharmacokinetics and also explore the emerging field of transcriptional control of enzyme/transporter action and its impact on altered drug clearance. Adding another layer of complexity to drug-drug interactions in oncology is the patient’s perception of the definition of a “drug”. Cancer patients undergoing treatment with chemotherapeutics who also consume over-the-counter medications, herbal remedies or supplements without informing their physician run the risk of unknowingly exposing themselves to potentially dangerous drug-drug interactions. In her Editorial article, Professor Marie Hanigan highlights the dangers of patients taking treatment advice from unreliable sources or misinterpretation of the scientific literature and calls for a more in-depth inquiry by the physician into the consumption of non-prescription medicines and other supplements by cancer patients. Professor Hanigan describes the lack of knowledge and confusion among cancer patients regarding the dangers of drug-drug interactions and addresses the challenges facing this large and complex field.

Finding and using patents for a bibliographical search

Patents are a valuable source of scientific information as well as business intelligence. In the case of the pharmaceutical industry, they provide early insights in a company's research programs and potential drug candidates. However, data contained in patents is often partial, biased and lacks the general objectiveness and perspective of peer-reviewed articles.
This laid the ground for Expert Opinion on Therapeutic Patents, which proposes critical reviews and analyses of patents (and articles) claiming the discovery of therapeutic compounds.

While authors have no problem at all compiling articles and data from the scientific literature, searching for patents often proves a hurdle. Here is an attempt at helping. A selection of databases and interfaces are briefly described.

Very much like for conventional scientific literature, several web-based interfaces propose search functionalities and access to patent databases. They are available to anyone and there is no need to be an IP professional to understand them. They may be free or require subscription. Search engines vary and it is recommended to read the instructions. However, they usually are obvious and easy enough to use, being not that different from Pubmed or Web of Science for example.
As ever, the selection of keywords is key to a successful search. Try several related or synonymous keywords. Also check if the search engine supports wildcard or truncated searches. The wildcard characters usually are *, ? and #. Boolean combinations and restricting searches to titles or abstracts can be necessary when a search returns too many irrelevant results.
In medicinal chemistry, searching for the molecular target is probably the best bet.

Researchers with access to SciFinder, Thomson Patents or Delphion for example will find these resources useful. Others can try:

• European Patent Office, which contains applications from most countries. You can save searches and save most original PDF files through the 'Save Full Document' link in the 'Original Document' tab.
  
• US Patent and Trademark Office, for US patents (an image can be downloaded)
• World Intellectual Property Organization proposes international patents applications. PDF and zipped TIFF images can be downloaded.
  
• Free Patents Online, for US, EU and some Japanese patents, as well as documents from the WIPO database. Powerful search engine (including a chemical search option) and access to the PDF files upon free registration.
• Google Patents, PDF available.

Patents filed in some countries, such as New Zealand and South Korea, are only accessible via their national patent offices (cf. links). However, chances are that these patents are also filed as WIPO patents.

I hope this demystifies patent searches.

Profile: Dr Micheal A. Morse

Dr Morse is a regular and invaluable contributor to Expert Opinion on Biological Therapy, having joined the Editorial Board in 2000 and accepting the position of Editor-in-Chief in 2007. He is currently Associate Professor of Medicine at Duke University, and is a G.I. Oncologist at Duke Comprehensive Cancer Center, where his clinical expertise lies in the treatment of gastrointestinal and hepatic malignancies, and malignant melanoma.

Dr Morse’s research focuses on developing strategies to activate T cell responses against tumors by immunizing patients with dendritic cell based vaccines. His group has continued to develop modifications to these vaccines, including loading with antigen in the form of peptides, mRNA, viral vectors and maturing dendritic cells with cytokines. Most recently, they have focused on genetically altering the expression of co-stimulatory and adhesion molecules, and have also identified preliminary data which suggests that it may be important to activate antibody responses as well as T cells in order to initiate immune-mediated destruction of tumors. The group is also working on other methods of modulating immune response, including anti-CTLA4 antibodies and strategies that interfere with inhibitory molecules such as PDL1. Further areas of research include other anti-cancer therapies to weaken the tumor’s ability to impair immune response, including combinations of cancer vaccines along with chemotherapy, radiotherapy, and targeted therapies.

Dr Morse has contributed many papers to Expert Opinion on Biological Therapy during his time on the Editorial Board, including his recent papers listed below:

Countering tumor-induced immunosupression during immunotherapy for pancreatic cancer
Michael A Morse Joseph Robert Hall, Janet MD Plate
Expert Opinion on Biological Therapy, Mar 2009, Vol. 9, No. 3, Pages 331-339.

Update on anti-CTLA-4 antibodies in clinical trials
Lee F Langer, Timothy M Clay, Michael A Morse
Expert Opinion on Biological Therapy, Aug 2007, Vol. 7, No. 8, Pages 1245-1256.

Vascular endothelial growth factor and immunosupression in cancer: current knowledge and potential for new therapy
Benjamin F Johnson, Timothy M Clay, Amy C Hobeika, H Kim Lyerly, Michael A Morse
Expert Opinion on Biological Therapy, Apr 2007, Vol. 7, No. 4, Pages 449-460.

In vitro evaluation of immunotoxicity

Recommended in 2000 by EMEA's Committee of Proprietary Medicinal Products,the in vitro assessment of immunotoxic risk for drug candidates is an integral part of preclinical safety screenings. Indeed, immunosuppression, immunostimulation, hypersensitivity and autoimmunity are adverse effects that can be elicited by (bio)pharmaceuticals.
A number of assays, available from CROs and reagent companies, can be used to test the effects of drugs, whether intended or not, on the various players of cell-mediated immunity. In a technical article to be published in the April issue of Expert Opinion on Drug Discovery, Dr Maria Fuggetta critically reviews a selection of these assays and suggests how enhanced methodologies can improve the identification of immunological hazard.

‘JUPITER’ and the risk of heart disease

Statins are blockbuster drugs taken by millions around the world. Results from the ‘JUPITER’ clinical trial[1] indicate that these cholesterol-lowering agents could decrease the risk of heart disease even for persons with low cholesterol levels; meaning that millions more could benefit from popping a statin pill…

But could they really? What indicators and risk factors dictate the prescription of statins? How should vascular risk be measured? And what are the factors that count towards this risk? An Editorial in the January 2009 issue of CMRO discusses the JUPITER study and explores these interesting themes.

The trial suggests that hsCRP, a protein associated with inflammation, can be used to identify subjects without vascular disease who should receive statins despite a low or intermediate calculated risk. The CMRO editorial highlights the fact that risk assessment needs to be re-examined, and discusses the role of hsCRP-testing in what the authors call risk stratification. The authors also feel that guidelines (and clinical practice) may need changing if indeed statins do have a much wider role in preventing vascular disease than was previously thought.

Of course, if relatively healthy persons (‘low or intermediate risk’) are to be prescribed statins, then there are terrific cost implications too. The authors of the editorial remark that this is all the more so if the benefits observed from taking Crestor (used in the JUPITER trial) can not be reproduced by cheaper, generic statins.

At the heart of the ongoing scientific debate, the fundamental question remains: do statins have a convincing role in primary prevention of heart disease? Read the editorial (an open access article) here find out what the authors think.

[1] JUPITER: Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin

Impact of predictive pharmacokinetics

The implementation of studies aiming at predicting ADME properties at preclinical drug discovery stages has been central in the effort to reduce attrition rates.
In a clear and authoritative article reviewing the development, over the past three decades, of Discovery Metabolism and Pharmacokinetics research, Dr Summerfield analyses the key elements which moved the field forward and anticipates how new paradigms, such as translational medicine and systems thinking, will push it further.
He concludes that, although the predictive metabolism and pharmacokinetics approach already proved successful, a strong impact on drug pipelines will only be achieved when pharmacodynamics and toxicology are integrated in a similar way to drug discovery programmes.
The article will be available in the March issue of Expert Opinion on Drug Discovery