Study Probes Whether Clinical Trials Benefit Patients’ Health
A recently published report states that patients with chronic heart failure who agree to take part in clinical trials have a better prognosis than those who do not. The investigators suggest that the findings may challenge the ethical requirement of most clinical trials, which states that by choosing not to take part in a trial patients will not be disadvantaged.
The study conducted at Castle Hill Hospital, Hull, UK, involved 2332 consecutive patients who had been diagnosed with heart failure as a result of left ventricular systolic dysfunction. On their initial visit, all patients were asked whether they would be prepared to take part in a clinical research project. After a median follow-up of 55.7 months, analysis of the full group showed that 792 patients (34%) had died. However, the results demonstrated that agreeing to take part in the clinical trial strongly predicted a good outcome, in that it more than halved the risk of death.
The outcomes for patients with chronic heart failure are typically poor, with approximately 40% of patients dying within a year of diagnosis. “However,” commented Andrew Clark, lead investigator of the study “two-year mortality rate in recent trials of chronic heart failure trials has been in the order of 20%. And even in studies of very sick patients, mortality has only been 30%. So we wanted to see if taking part in a clinical trial was associated with a beneficial outcome.”
In addition, in order to investigate the effect on survival of entering a clinical trial – as opposed to merely indicating a willingness to take part – the investigators compared the survival rates following the first year to those of willing patients who were recruited and willing patients who were not.
Using multivariate modelling, the researchers showed that willingness to take part was a predictor of good outcome, independent of age, severity of left ventricular dysfunction, renal function, sodium levels, drug use and co-morbidities. In fact, other likely protective variables, such as good mobility and appropriate medication, proved not to be significant predictors in the multivariate model.
However, results from a second analysis showed that being recruited into a clinical trial was not predictive of outcome: “we found no appreciable difference in survival between those who are actually recruited to an interventional trial within the first year and those who were not” said Clark.
The investigators were unable to suggest a firm explanation for their findings; however, they have proposed that “being prepared to take part in a trial is a marker for better compliance with, and acceptance of treatment”, adding that “patients’ attitudes to their illness and its treatment are an important aspect of their care”.
Clark and his team propose that their study may explain the difference seen in the survival rates between patients monitored in clinical trials and those in everyday life: “our study contributes to the perception that heart failure trials can be unrepresentative of real life, particularly as study designs often deliberately exclude patients with an inherently poor prognosis, such as those with anemia or impaired renal function. Both these co-morbidities are common in real-life populations.”
Commenting on the implications of the study in a recent editorial, Oliver Wang and Harlan Krumholz of University of Yale, School of Medicine, USA, stated “studies are suggesting that trials may not represent typical populations. The results from Clark et al. extend our understanding about how patient preference may affect enrolment and the risk profile of the study sample.”
Sources: Clark AL, Lammiman MJ, Goode K, Cleland JGF. Is taking part in clinical trials good for your health? A cohort study. Eur. J. Heart Fail. 11(11), 1078 (2009); Wang O, Krumholz HM. Clinical trial participation: are we studying the patients we are trying to treat? Eur. J. Heart Fail. 11(11), 1021 (2009).
Protein Identified as Potential Anti-Inflammatory Target
Researchers at the University of California, Irvine, USA, have uncovered a strategy for increasing levels of a natural body lipid that helps decrease inflammation, potentially paving the way for new treatments for allergies and injuries related to the immune system.
The lipid, palmitoylethanolamide (PEA), has for some time been known as a potent anti-inflammatory agent, yet little was known about how it works. In a recently published study, Daniele Piomelli and co-workers have reported that levels of PEA are closely regulated by immune system cells. PEA also helps control the activity of these cells, whose function is to fight infection.
The team also found that PEA is deactivated by the cysteine amidase N-acylethanolamine-hydrolyzing acid amidase (NAAA), an enzyme that breaks down molecules controlling cell inflammation and is highly expressed in macrophages.
Using molecular modeling and chemical-library screening, the researchers created a novel compound, N-[(3S)-2-oxo-3-oxetanyl]-3-phenylpropanamide [(S)-OOPP], which blocks the action of NAAA. (S)-OOPP increased PEA levels in activated leukocytes and blunted responses induced by inflammatory stimuli both in vitro and in vivo. When administered to rodents subjected to spinal cord trauma, (S)-OOPP increased the levels of PEA in their immune cells, decreased inflammation and tissue damage and improved recovery of motor function.
Speaking to Future Medicinal Chemistry about the significance of his team’s findings, Daniele Piomelli said “our work shows that the bioactive lipid amide, PEA, is an important regulator of the inflammatory response, and that blocking PEA degradation in tissues causes profound anti-inflammatory effects in animals. Our results come soon after another study, by the University of Nottingham, UK, which has shown that PEA levels are dramatically decreased in inflamed tissues of people suffering from arthritis (osteoarthritis or rheumatoid arthritis). These two sets of findings are very consistent and point to an important role for PEA in inflammation.”
Researchers at the Drug Discovery and Development unit of the Italian Institute of Technology and the University of California, Irvine, will continue to work together to identify clinical candidates targeting the PEA/NAAA mechanism. The collaboration, which will include medicinal chemists and pharmacologists at the Universities of Urbino and Parma, Italy, will also aim to validate NAAA as an anti-inflammatory target and optimize several lead compounds that have already been identified.
Source: Solorzano C, Zhu C, Battista N et al. Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation. Proc. Natl Acad. Sci. USA DOI: 10.1073/pnas.0907417106 (2009) (Epub ahead of print).
The Heat is on for New Pain Therapies
A product that contains prescriptionstrength capsaicin (8%), the active component in chili peppers, has recently been recently approved by the US FDA for the treatment of postherpetic neuralgia (PHN), a nerve pain that follows the outbreak of shingles.
The product, Qutenza™, was developed by the US firm NeurogesX and marks the company’s first FDA approval. The patch received EMEA approval in May 2009.
Shingles is caused by the same virus that causes chicken pox, the varicella zoster virus. After chicken pox, the virus lies dormant in the nerve tissue, usually without causing further problems, however it can reappear, most commonly in individuals over the age of 50, especially those who have a weakened immune system.
Commenting on the newly approved product, Lynn Webster from Lifetree Clinical Research, said “PHN can be an excruciatingly painful condition that can affect many aspects of a patient’s quality of life. Qutenza may provide a unique treatment option that works at the site of the pain and may be useful as a treatment option in combination with existing therapies.”
Current treatments for PHN include anticonvulsants, antidepressants and opiates, which can cause systemic side effects. Qutenza is applied to areas of the skin where pain is present, targeting pain nerves. After a single 1-hour treatment clinical studies have shown that the pain can be reduced for up to 12 weeks. A maximum of four patches can be used, with repeated treatment every 3 or more months depending on the pain experienced.
The product may have further potential applications, having also been investigated for the treatment of HIV distal sensory polyneuropathy and diabetic neuropathy.
Source: NeurogesX, Inc. press release: http://ngsx.client.shareholder.com/releasedetail.cfm?ReleaseID=424559
Uncovering the Structure of the HIV Coat
A recent study from the University of Pittsburgh School of Medicine, PA, USA, has used a combination of NMR and cryo-EM to analyze the structure of the HIV capsid protein, an essential component in the life cycle of the virus. The findings could contribute to the development of new strategies for blocking HIV infection.
The capsid protein encases the genome of the HIV virus. The protein, and in particular the interfaces where one protein connects to another, is vital for the correct assembly and disassembly of the HIV coat, which assists viral infectivity.
Speaking to Future Medical Chemistry, Peijun Zhang, co-author of the study, explained “knowing what the HIV capsid protein looks like and how the capsid is built will allow scientists to rationally design therapeutic compounds that affect assembly and function of the HIV capsid.”
The group employed direct imaging using cryo-EM and the high resolution of NMR to enable determination of both the overall shape and atomic details of the capsid’s assembly. “These structural studies, combined with mutagenesis and functional assays, allowed us to identify interfaces of functional importance that previously went unrecognized.”
The team found that the interfaces connecting the capsid proteins provide the flexibility to dismantle the coat efficiently after viral entry into the host and assemble it again when new viruses leave the cell. “If we replace a few of the pivotal stitches in the seam by mutation, the resulting viruses are less infectious or even non-infectious. The capsid, and therefore the virus, can no longer function properly” said Angela Gronenborn, Director of the University of Pittsburgh Center for HIV Protein Interactions and member of the research group.
The findings identify the capsid as a vital target for future HIV therapeutics. “We are currently working on molecules that interfere with the HIV capsid assembly/disassembly, as well as the host cell factors that potentially restrict HIV infection through interaction with the HIV capsid.” said Zhang.
Source: Byeon IJ, Meng X, Jung J et al. Structural convergence between Cryo-EM and NMR reveals intersubunit interactions critical for HIV-1 capsid function. Cell 139(4), 780–790 (2009).
Mri Method Developed to Examine Small Changes in Brain Volume
A collaborative study conducted by researchers at the University of California School of Medicine, USA, and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) has used MRI to develop a sensitive method to quantify small structural changes in cortical and subcortical brain regions, potentially improving diagnosis and monitoring of Alzheimer’s disease.
The method employed two MRI brain scans taken over several months to allow the rate of change in subregional cerebral volume to be measured. The study involved 129 patients with Alzheimer’s disesase (AD), 299 patients with mild cognitive impairment and 169 healthy controls. From these data the team were able to calculate which regions would be most useful in clinical trials to measure the response to disease-modifying agents.
Commenting on the significance of using MRI, the study’s co-author, James Brewer, said “the technique is extremely powerful, because it allows a researcher to examine exactly how much brain-volume loss has occurred in each region of the brain, including cortical regions, where we know the bad proteins of AD build up.”
Currently available methods, such as measuring global brain volume loss and cognitive testing, lack sensitivity in early disease diagnosis. “We are particularly excited to use the techniques in new clinical trials, but also to re-examine old clinical trial data where global measures of brain shrinkage were applied. These new findings suggest that such global measures are less sensitive than regional measures for detecting the changes specific to AD – the changes these drugs are targeting.”
Evaluating the impact the study may have on AD therapeutic strategies, co-author Anders Dale, said “loss of volume in the hippocampus is a consistent finding when using MRI, and is a reliable predictor of cognitive decline. We have now, however, developed and validated imaging biomarkers to not only track brain atrophy, but distinguish the early stages of AD from changes related to normal aging.”
The Alzheimer’s Disease Neuroimaging Initiative was launched in 2004 by the NIH and involves researchers at 58 locations across Canada and the USA. Its aim is to use MRI and positron emission tomography scans with biomarkers to detect the onset and development of AD, with a view to improving current therapies and diagnosis.
Sources: Holland D, Brewer JB, Hagler DJ et al. Alzheimer’s Disease Neuroimaging Initiative. Subregional neuroanatomical change as a biomarker for Alzheimer’s disease. Proc. Natl Acad. Sci. USA DOI: 10.1073/pnas.0906053106 (2009) (Epub ahead of print).
Novel Target Uncovered for Preventing Colon Cancer
A team at the Karolinska Institute, Sweden, has identified a new way of tackling colon cancer, by focusing on the differences between cancer cells and the body’s stem cells.
Molecular signal pathways that stimulate the division of stem cells are often the same as those active in tumor growth. This, therefore, limits the possibility of treating cancer as anticancer drugs also frequently adversely affect the body’s healthy cells, notably stem cells.
Recently, a study conducted by a team led by Jonas Frisén looked at an exception that might present a new strategy for treating colon cancer.
The researchers focused on EphB receptors, a group of signal proteins that stimulate the division of stem cells in the intestine and can contribute to the formation of polyps, which can carry a risk of cancer. Interestingly, EphB receptors also prevent the polyps from growing unchecked and becoming cancerous.
Signaling proteins driving the proliferation of stem and progenitor cells are often encoded by proto-oncogenes. EphB receptors represent a rare exception.
The researchers have shown that two separate signal pathways, one of which stimulates cell division and the other that restrains the cells’ ability to become cancerous, are controlled independently by the receptor EphB2.
On the basis of this, the team identified the drug imatinib as being able to inhibit the first signal pathway, while leaving the other, protective, pathway unaffected.
Speaking to Future Medicinal Chemistry about the implications of his team’s findings, Frisén said “The research is basic in nature and does not have any immediate relevance for patients. However, it increases our understanding of how cell division is regulated in the intestinal epithelium and in tumors. Moreover, it identifies Glivec as a candidate drug for treating colon tumors.”
Imatinib has so far proved to inhibit cell division in intestinal tumor cells in vitro and in mice. The substance is a component of the drug Glivec, which also has applications in the treatment of particular forms of leukaemia. Whether it can also be used to treat adenoma and colon cancer in humans is yet to be confirmed.
The researchers plan to further investigate the basic mechanisms of the signaling pathway controlled by the receptor EphB2, as well pursue work in animal models.
Sources: Genander M, Halford MM, Xu N et al. Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression. 139(4), 679–692 Cell (2009); For an discussion with the inventor of imatinib: Interview with Jürg Zimmermann, Global Head of Oncology & Exploratory Chemistry at Novartis. Future Med. Chem. 1(8), 1395–1398 DOI: 10.4155/FMC.09.115 (2009).