Swine Flu and Glutathione Supplements

GlutathioneCould a simple dietary change that increases glutathione, or indeed supplementation with this tripeptide be all you need to boost your immune system and ward of influenza?

Evidence mounted for glutathione itself in 2000, when Emory University researchers led by Dean Jones reported that a lozenge or oral spray containing glutathione might help prevent infection with influenza. Trials in humans had not been carried out but details were reported in Free Radical Biology and Medicine and elsewhere.

If glutathione is actually effective against influenza infection, and it may well not be, then it would presumably have to be present at the infection site – mouth and nose and upper respiratory tract. No definitive clinical trials have proven efficacy one way or the other yet.

FRIEL, H., & LEDERMAN, H. (2006). A nutritional supplement formula for influenza A (H5N1) infection in humans? Medical Hypotheses, 67 (3), 578-587 DOI: 10.1016/j.mehy.2006.02.040

How to find new drugs for malaria

German researchers have used the powerful analytical technique of X-ray diffraction to home in on an important metabolic reaction used by all pathogenic bacteria and the malaria parasite. The detailed structure of the IspH enzyme active site they revealed, which resembles a shamrock in shape, and has an Fe-S cluster at its core, could offer a promising new target for novel antibiotics that might stave off bacterial resistance.

More details on the research can be found in my XRD column on SpectroscopyNOW this week. Meanwhile, I asked team leader Michael Groll of the Technische Universität München (TUM), to expand on the implications of the work.

What is the next step now that you’ve characterized the active site?

The structure allows us to perform modeling and so look for attractive ligands and putative inhibitors of the enzyme. Furthermore, we need to understand how substrates access the enzyme, docking and release. It looks like there is a major structural rearrangement, a so-called induced-fit mechanism, between the open and the closed (ligand bound) state of the IspH enzyme.

It would be interesting to get further insights into this mechanism which might allow us to get a comprehensive overview of the catalyzed specific reaction. Since the reaction of the substrate is a reduction, the FeS-cluster in the enzyme gets oxidized, we also need to understand the mechanism of enzymatic reduction of this FeS-cluster.

How might drug targets be developed for this enzyme?

Molecular modeling and high throughput screening (HTS) will be key. It would be important to get structures of various ligands including substrate and product (currently we have only modeled the substrate, which we would like to experimentally verify by the complex structure). These new compounds and structures definitely will serve as lead structures for drug development!

Surely, bacteria will simply evolve resistance to those anyway?

Yes, that can be expected. Nevertheless, it should be mentioned that most bacteria become resistant to drugs, since they create enzymes to metabolize the drug or transport it out of the bacteria — this is nothing new. For Vancomycin, it took more than 7 years to see the first resistant strains. It is definitely worth looking for IspH inhibitors as putative new antibiotics. Moreover, it is an attractive new target, because IspH exists only in bacteria, Plasmodia and some plants, and not animals, which would mean a lower risk of side-effects.

Research Blogging IconGräwert, T., Rohdich, F., Span, I., Bacher, A., Eisenreich, W., Eppinger, J., & Groll, M. (2009). Structure of Active IspH Enzyme from Provides Mechanistic Insights into Substrate Reduction Angewandte Chemie International Edition, 48 (31), 5756-5759 DOI: 10.1002/anie.200900548

Malaria Drug Fail

The BBC reports today that malaria has started to evolve resistance to the artemesinin family of drugs that are used as the world’s front-line defense against the most prevalent and deadly form of the disease.

Artemesinin emerged from a Chinese herbal medicine, Qinghaosu, where it was used as a fever treatment for generations. I remember writing about the earliest research in my New Scientist days and have watched the drug discovery process bring us to the point where a potent pharmaceutical could, it seemed, defeat the disease…

…no more. In Cambodia, at least, resistant strains of malaria have been spotted by two teams of scientists, working on separate clinical trials who reported disturbing evidence of reduced drug efficacy.

The BBC says researchers are blaming a weak public health system and poorly controlled drug use, as well as fake drugs, produced by international criminals, for the problem. But, the problem is not really socioeconomic at all – it’s natural selection in action. We present the disease with a changing environment and it evolves to fill the niche.

Disease Mongering or Medicalization

medicalizationThe medicalization of many social facets of our lives, multitasking pharmaceuticals and disease mongering are problems we should face head on.

The overlap between business ethics and medical ethics represent a moral minefield. Nowhere more so than in the domain of newly recognised and previously untreated disorders, syndromes and diseases, among them social anxiety disorder, non-physiological erectile dysfunction, aging, fibromyalgia, adult attention deficit hyperactivity disorder (ADHD), restless leg syndrome and female sexual dysfunction.

And for those who only read this far, my take away message is not to claim that such conditions are not real to those who suffer from them. Indeed, I actually suffer from irritable legs syndrome (as does my dad). It’s very real, very uncomfortable, and a real problem especially when it hits in a crowded and stuffy theatre with no option to take a hot bath or go for a jog to alleviate the unscratchable symptoms. Personally, I would love to have some way to make it stop when it gets bad and if that were a once a week pill, so be it.

Diagnoses can be very real and finding effective treatments certainly worthwhile, but it is the interests of patients that should be served and not purely those of pharma industry shareholders when a condition is medicalized.

Some observers have suggested that the process of medicalization, in which issues and problems have migrated into the scientific realm coincides with the demise of traditional values. They suggest that this migration may involve less of an improvement in understanding our biology and more of a change in social attitudes and terminology, with people suffering ambiguous symptoms and their advocates essentially feeding the beast.

This is sometimes no bad thing if it means previously unrecognised medical problems can be treated on the basis of scientific evidence rather than so-called received wisdom. However, medicalization is more often than not considered disease mongering. Writing in IJBGE, Geoffrey Poitras of the Simon Fraser University, in Vancouver, British Columbia, Canada, points out that there are two threads to the process of medicalization.

The first is social medicalization, which he describes as a form of social control in which individuals and their problems are taken into the fold of the medical establishment and can be manipulated. “One unexplored aspect of medicalization is associated with recreational drug use, from Valium to Viagra, threatening to ‘scientifically’ engineer various forms of drug addiction under the guise of medical treatment,” Poitras told Sciencebase.

The second thread is economic medicalization, the “transformation of the process for doing clinical trials into exercises that are motivated more as marketing vehicles than needed R&D.” This, he adds, is driven by the pharmaceutical companies and by the medical profession which benefits financially from the need to recruit patients into trials for fledgling disorders.

Another aspect of economic medicalization concerns the multitasking of drugs, more formally known as off-label prescription usage. Having gone through costly R&D, there is an economic incentive to find additional applications for any given approved drug.

Market researcher Megann Willson does lots of work interviewing physicians so finds medicalization an interesting concept. She points out that plain old garden variety depression in women now has a secondary indication called “premenstrual dysphoric disorder”. In that case, she asks, “Is the disorder truly latent or did we create a new indication and then find what we want to find?” She says that in Canada, “the acceptance or approval of a new drug indication is governed as much by reimbursement formulae as it is by whether there’s a good health rationale.”

Similarly, another area of female health that has been medicalized is post-partum depression, says Torr-Brown. “The real solution may be to increase socialization options for mothers with newborns,” she says, “Also, not sending them home after 24 hours at the hospital might help. In countries where there is good support for new mothers, post-partum depression is almost unheard of. We put it down to hormones, but in reality it may be the sense of being alone in the face of an overwhelming new challenge in caring for a new born.”

But, as alluded to earlier, there can be a positive side to medicalization from the individual’s point of view, suggests health strategist Christopher Ervin. “There is a potential good,” he says, “with hopes that people become more aware of their bodies and the functioning of the systems.” However, he also points out that people will begin to consider the human body as a perfect machine, and that any ailment can be instantly fixed with a pill. “I think [medicalization] will raise unrealistic expectations of the healthcare system to ‘cure’ people,” he adds, “Also it will absolve people from making efforts to care for themselves and better manage their health independently.”

Medical lawyer David Marshall agrees that the relabelling of any ‘normal’ human condition as a ‘medical problem’ is controversial. The label premenstrual dysphoric disorder is a case in point in which some observers suggest that it results from a patriarchal medical profession hoping to medicalize the menstrual cycle to justify marketing pharmaceuticals to treat the disorder, he explains. “This requires us to make a distinction based on supposed motives. If there is such a thing, pure medical research is engaged in the dispassionate search for a better understanding of human biology. As an incidental by-product of this better understanding, new forms of treatment or cure may emerge,” Marshall adds.

Big pharma exists to make big profits and this leads research down avenues where no competitor drugs exists. “The absence of drugs is often because the ‘problems’ are not considered medical,” suggests Marshall, “So, for example, major drug companies have spent several billion dollars trying to produce weight loss drugs when, arguably, excess weight is a lifestyle choice not a disorder (the confusion arising because hypertension and cardiovascular disease are co-morbidities to obesity).”

“In principle, the identification of a new disease or disorder is good for those that suffer without treatment because it offers hope,” adds Marshall, “But the creation of a new disease or disorder for the purpose of marketing a drug is only benefiting the pharmaceutical industry.”

So is medicalization a menace? In Norway, ADHD is “treated” by starting children at school later in Norway rather than prescribing Ritalin. Is normal sadness, through reclassification as a major depressive disorder, stifling the creativity often associated with melancholy? And, what is the true nature of the therapeutic options for people labelled mentally ill?And, what about the medicalization of childhood?

Sheryl Torr-Brown offers a useful perspective from 20 years experience in the industry. “I think [medicalizatio] is probably neither a good nor bad thing but somewhere in between,” she told Sciencebase, “If there is genuine reason to believe that the quality of life can be improved by the medicalization (and thus potentially treatment) of a previously latent condition, then it can be good.”

However, she points out that the very definition of quality-of-life has to be questioned. This is a controversial area in an age of rampant pill-popping with the expectation of instant fixes with no side effects. “Is ADHD a treatable condition, or a variant of human personality that confers advantage in systems less inclined to conformity and control than ours,” she asks.

“In that vast grey zone called healthcare, where along the spectrum between a true latent or rare disorder, a psycho-social behaviour variant or just a kink in the system does it necessitate pharmaceutical intervention,” asks Ervin.

It’s worth repeating, pharma companies enjoy increased profits because of medicalization, but that does not mean that we should not be treating previously latent disorders. Quality of life might be improved for countless individuals with new treatments whether pharmacological, physical or psychological. We should all think more critically about our options, although that can be difficult for some people simply not trained in critical thinking. “I think if individuals were able to think critically about their options, medicalization would be workable,” adds Torr-Brown. After all, your particular take on the human condition may one day be recognised as a disorder by the medical profession, but it remains your choice as to whether take the medicine.

Research Blogging IconPoitras, G. (2009). Business ethics, medical ethics and economic medicalization International Journal of Business Governance and Ethics, 4 (4) DOI: 10.1504/IJBGE.2009.023789

Rx Reviews Redux

A new(ish) website has launched that aims to provide unbiased patient-generated data on the benefits of 7000 prescription medications and their side-effects.

Rateadrug.com hopes to do for pharma products what dooyoo and ciao do for gadgets by bringing the crowd to the debate. Patients can anonymously rate and review any of the prescription drugs they take and view other people’s experiences for free.

“All information on this site is unique, community data that is not biased by pharmaceutical or corporate objectives,” says spokesman Jack Dowd. He adds that, “The site provides patients with truly independent survey results about the risks and benefits of their medications. The more people that start using the site to rate their prescription medications (a quick 5-minute survey), the greater this resource will become.”

Using a prescription drug appropriate to your condition and your genetics can have significant, and often life-saving benefits, but with physicians particularly in the UK and a few other places emphasising how patients should help manage their own illness it is important to know what problems may arise or whether asking for a different prescription might actually be better for them.

Not all medications hit everyone in the same way, because of various factors including your SNPs (single nucleotide polymorphisms), that affect your body’s enzyme and receptor activity. “What’s effective and side-effect free for one person might not be the best drug for someone else, yet most harried doctors prescribe the same drug for 90% of their patients with similar conditions – regardless of individual sensitivities,” the site’s developers say. They hope that Rateadrug will prevent the next Vioxx from happening.

A side project of Rateadrug is involving pre-med students through the PreMed Prescription Rating and Experience Program (PREPP) where the students help senior citizens become more proactive with their drug intake by reporting their experiences through Rateadrug.com.

The site blurb suggests you use the reviews together with your doctor’s advice and FDA disclosures to achieve the best possible outcome for your (or your loved ones) medical condition. Of course, spammers and corporate shills will be readying themselves to distort the results in their favour, unless preventative measures are put in place. “To prevent spam and ensure a real person is taking each survey we require email verification where the user has to click on a link that we email to them,” Dowd told Sciencebase, “We also flag accounts that submit more than one rating for a specific drug. We’re committed to providing quality, real-user data and will continue to ensure that our results are not skewed by spam or anyone trying to influence the results of a specific drug.”

The site also drops a cookie on to your machine so that it knows how many people log in from a specific computer or IP address. If it looks like there are a lot of ratings for the same drug from the same IP address, they will flag those ratings for manual checking.

I asked Dowd to expand on how they are addressing security and validity issues. “At the moment we receive 20 or fewer ratings per day, and carefully review each one,” adds Dowd, “As the volume increases significantly it will become more difficult to impact and distort results – real ratings should outweigh any attempts to skew ratings. But, we will do our best to prevent this type of tampering.”

“Right now, we have a database of over 7000 drugs, but only about 300 have been rated and reviewed by users/patients,” he adds. Dowd and his colleagues hope that as more people find out about this site, the numbers will grow. “Our intention is to provide real ratings by real people and will do everything we can to assure this as we progress,” he told me.

According to CEO Mark Deuitch, RateADrug is currently hoping to get large numbers of patients to review the cholesterol-lowering statin drugs Lipitor, Lescol, Mevacor, Pravachol, and Zocar, anti-depressants such as Lexapro, Prozac, Effexor, Paxil, Zoloft, and Pristiq, and drugs used to treat insomnia including Ambien, Lunesta, Sonata, Rozerem, and Benzodiazepines.

In related news from the UK’s National Health Service: Drug reference information in the British National Formulary will become a key element of the new NHS Evidence portal due to be launched in April 2009. As a result, responsibility for provision of this information for the NHS will transfer from the Department of Health to the National Institute for Health and Clinical Excellence (NICE), as part of the development of NHS Evidence.

Drug Design on the Playstation

Serious drug design researchers are apparently hacking their PS3 machines to turn them into drug discovery workhorses. At least that’s according to my alma mater New Scientist magazine. It’s the kind of catchy subject they cover and is a classic from Mike Nagle.

The PS3 console uses a Cell chip, made by IBM, Sony and Toshiba, which is composed of a CPU and eight slave processors that run on Linux. According to NS, this chip is prized by chemists and physicists alike because the same kind of calculations it uses to produce the stunning, high-quality PS3 graphics for gaming are just about the same those needed to simulate reactions between particles, ranging from the molecular to the astronomical (apparently, you can do black holes with it too).

But, when we say they’re hacking the PS3, it’s not like these scientists are just plugging in a data cable and running their lab. According to NS, University of Massachusetts astrophysicist Gaurav Khanna has actually strung together 16 PS consoles to simulate the gravity waves that to occur when two black holes collide. While University of Illinois chemist Todd Martinez is running particle simulations on a Playstation, with 1000 atoms (a small protein in other words) that can be done 130 times faster than on an ordinary PC.

It’s all quite twee really, what with the surgeons cannibalizing their Wii consoles to do virtual operations and chemists latching on to the power of virtual world Second Life too. One can almost imagine the response of the peer review panels as the grant applications start to roll in with instrumentation inventories listing costs for 32 PS3 consoles, 20 Wii controllers, a couple of PSPs, and a dozen iPhones. The real test will come though if they can get away with tacking on a few copies of World of Warcraft and Nintendogs Labrador Retriever & Friends.

Multitasking drugs

RU486 structure

An issue I have written about for the Nature drug discovery site is the re-marketing of pharmaceutical products for uses other than the original one for which a drug was developed. The latest example is the emergence of the so-called “morning after” pill RU486 as a rapid-acting antidepressant (it has already found use in treating certain cancers and psychotic depression).

RU486, mifepristone, is a steroidal hormone similar in chemical structure to progesterone. It inhibits the progesterone receptor and so is termed an ‘antiprogestin’, its effect is to induce abortion.

This week New Scientist reports on how RU486 might work as an antidepressant:

“The hormone treatment is based on earlier findings that stress plays a major part in triggering and prolonging depression. Stress hormones appear to damage a part of the brain called the hippocampus. The region is susceptible because it is particularly rich in hormone receptors, allowing it to regulate ongoing hormone release,” the magazine says.

Google Pharmacy Phake

google pharmacy

You know how keen Google is to expand it’s breadth? Well, how about this, it seems it’s swapped the oo in it’s logo for some ooh-la-la, in the shape of two blue diamonds stamped Pfizer.

Before you rush to get stocked up on tamiflu and viagra, however, check out The Register article on Google Pharmacy which reveals it to be a front for a fake drugs seller. How do they know it’s a fake seller, well they claim to be able to provide generic versions of dozens of drugs that are not yet off-patent, that’s how.

The spam that arrived advertising Google Pharmacy stated: “We’ve just launched a pharmaceutical interfaces for Google, as well as several new features for the people buying pills and using pharmaceutical interfaces”. Poor grammar aside, you just can rest assured that it was definitely not the real thing right from the start. Or, could you?

According to an unrelated article on WebProNews, the sponsored Googlads that appear when you search for the likes of “Vicodin” or “Oxycontin” are not necessarily from fully legitimate companies either. Some of these sites, which appear above and to the side of search results in the popular search engine, are selling direct drugs that usually require a doctor’s prescription.

Carmen Catizone, executive director of the National Association of Boards of Pharmacy, is according to WebProNews, talking with Google about a third-party service that will help them differentiate between rogue and legitimate pharmacies.

It will be interesting to see whether that works out, or whether the pharma spammers and scammers will simply find a way around it.

Disease Mongering

I was a bit tardy covering the recent conference on disease mongering, but to make up for it have posted a new poll on the SciScoop site to give visitors a chance to voice their opinion.

A conference held April 11-13, in Newcastle, Australia, raised some serious questions about the motives of the pharmaceutical industry. The patents on drugs for old-fashioned diseases that were originally making a $1billion a year are almost all expired and new avenues of research under the umbrella of biotech have yet to make the same level of return for other diseases. As such, there is a feeling among some observers that “new” conditions, such as restless legs syndrome, attention deficit hyperactivity disorder (ADHD), and sexual dysfunction are being hyped by the industry as the serious ills of our time that need new (lucrative) treatments. Is this the case or can we simply not do without the chemical fix of those repeat prescriptions? A collection of freely accessible essays on the subject of disease mongering is available on the PLOS Medicine site.

Visit SciScoop to vote in the poll and help us answer the question – “Are we drug company puppets?”

Vioxx Drugs Okay?

Researchers at Imperial College London and Queen Mary, London, are suggesting that drugs related to the withdrawn Vioxx may still be the best drugs for treating arthritis.

They argue that although Vioxx and related drugs have been associated with an increased risk of heart attack and stroke, the same might also be true for the more conventional non-steroid anti-inflammatory drugs (NSAIDs).

Jane Mitchell and her colleagues have reviewed the medical literature on the use of NSAIDs and Vioxx-like drugs and are convinced that despite the cardiovascular side-effects of certain COX-2 drugs they could still be the drug of choice for certain patients without cardiovascular risk factors, especially if they cannot tolerate NSAIDs because of the gastric side effects of those drugs.

It’s all about benefit-risk management (BRM) which sounds a little like marketing jargon, but underpins a much more effective attitude to medicine than holistically abandoning effective drugs.

Regardless of the status of Vioxx and its analogues there is much imminent movement in the pharmaceutical industry as the likes of GlaxoSmithkline vie for pole position in the market for the successor to COX-2 inhibitors. Of course, if Mitchell and her colleagues are right, then, the generic NSAID manufacturers could take another nice chunk of that market before it’s even opened up.