April 2005 Archives

Vaccine Development For Infectious Diseases

Three diseases with the highest human and economic toll are malaria, TB and AIDS. Almost all malaria infections, more than 95% of new tuberculosis cases, and 95% of HIV infections occur in developing countries. The latest figures from Global Health Reporting count 39 million people worldwide infected with HIV, 300 million with acute malaria, and 15 million with TB. Treatments or prevention of these diseases are expensive, easy to abandon after ambitious pronouncements, and inevitably mired in multi-national politics. For many in public health arenas vaccinations are the most practical way to solve the problem, even if vaccine development is a scientifically challenging, long- term solution.

Public health challenges generally fall through the cracks of traditional market solutions because there is little financial motivation to solve these expensive, multi-faceted and politically cumbersome problems. This is particularly true for diseases that are present in countries in Africa and Asia. Malaria has been a killer in Africa and Asia for as long as we remember and prevention and control mechanisms have failed.

Only part of the failure is due to technology, however a vaccine offers a way to potentially cut through all the failures to stem the disease. The broad and all encompassing concept of a 'failure of the markets' occurs because for-profit pharmaceutical companies, almost exclusively based in the United States and Europe, have no incentive to research, develop drugs or treat diseases that are only prevalent in developing countries. According to one report by Medicin San Frontiers, 1393 new chemicals were developed as potential drug targets from 1977 through 1999. Of these, 13 were for "tropical diseases" (a group of diseases largely confined to tropical regions including, Dengue Fever, Cloroquine resistant Malaria, TB, Leprosy, Chagas, and others). Six of these thirteen were for military use. Drug development looks at potential profit not potential lives saved.

While vaccine development promises to circumvent a lot of entrenched problems it's susceptible to its own set of problems-- and also financing. The Wall Street Journal reports on funding initiativesin in the works that help finance infectious disease drug development in developing countries. In an April 26, 2005 article titled "Malaria Trial Could Set a Model For Financing of Costly Vaccines", the paper reports on several private/public funding collaborations to finance costly drug development. The hope is that these new financing models can "...step[] in where market mechanisms have failed".

There have been numerous proposals over the years aimed at lowering drug development costs by promoting research and collaboration between often competitive agencies. This effort is promising, according to the Wall Street Journal because it aims at two of the most problematic impediments to funding, the hesitation of drug companies to front research that they won't profit from, and the hesitation of individual countries to fund highly expensive public health initiatives for developing countries. The article highlights efforts to establish the International Finance Facility (IFF), by a group of European countries -- the US will not participate-- via government bonds:

"...floating government bonds geared specifically to supplying poor countries with available vaccines...countries go to the international bond market to obtain funds to speed up the purchase of existing...[and] new vaccines."

The Global Alliance for Vaccines and Immunizations (GAVI) also contributes to the IFF immunization project. The article describes a malaria initative for vaccine research project at GlaxoSmithKline PLC's GSK Biologicals unit in Belgium that after a long delay is now in clinical trials in Mozambique to test children using the newly developed vaccine. The effort had been abandoned due to a funding quagmire but has been revived through these collaborative funding efforts.

The second scheme being used to fund vaccine development involves "advance-purchase contracts", through which pharmaceutical companies are paid to develop medicines in advance. The idea was proposed and modeled by economist Michael Kremer. The contracts aim to motivate pharmaceutical companies to develop vaccines. It insures that the companies who bring a vaccine to fruition are reimbursed for their development efforts.

Of course, in addition to these ideas, there are others. The various alternative plans reflect the inevitable uncertainty that hovers overs any research efforts as well as dynamic politics, ever changing financial priorities, and . Senators Frist and Kerry introduced a bill in 2001 that would have allowed tax incentives for the development of infectious diseases. The Global Alliance for Vaccines and Immunization (GAVI) combines contributions from private sources such as the Gates Foundation, WHO, NGO's, and research organizations, with funds from national governments The organization strives to promote standardized resource allocation.

Of course their are concerns with the proposals. Some organizations that are involved with current prevention efforts like the Global Fund Global Fund's HIV/AIDS, TB and Malaria projects have concerns that the vaccine initiatives will distract the efforts of current prevention efforts like bednets.

Tetracycline Analogs Synthesized

One of the vexing public health challenges today is antibiotic resistance. Replicating bacteria are constantly subjected to environmental stimuli which cause them to mutate to resist antibiotics. Among other factors, the promiscuous use of antibiotics, and more rapid and frequent migration of humans who enter foreign countries hosting bacteria native to their home countries speeds the spread and evolution of new strains of bacteria. Meanwhile, the relatively slow pace of antibiotic development is outpaced. Spurred by drug resistant bacteria as well as patent expiration, new antibiotic development research struggles to catch-up with new strains of antibiotic resistant bacteria. Development is an incredibly time-consuming process that often involves the production of the antibiotic (for instance via fermentation or synthesis), then research trial and error to alter the chemical pathways to produce new structures and drug candidates.

The journal Science (subscription) published research developments by authors Charest MG. et al; "A Convergent Enantioselective Route to Structurally Diverse 6-Deoxytetracycline Antibiotics", in its April 15, 2005 issue. The article describes experimental processes to produce multiple analogs of tetracycline that can then be tested against various bacterial strains for antibiotic effectiveness. A simpler description of the results can be found here at Chemical and Engineering News. The method for synthesizing tetracycline is noteworthy. The yields from the Myers Lab research are very small, but the analogs produced are ones that cannot be made via typical semi-syntheses. Some of these analogs show promise against resistant strains of bacteria, however the preliminary results will need to be explored more painstakenly before scientists find drug worthy candidates.

Alimentary, My Dear

You are what you eat, but who gets to say what that is? Should you be allowed the freedom to ingest vitamins and supplements as you see fit? Or does the FDA have a say? How about an international body via a collectively agreed upon Codex Alimentarius?

In Salt Lake City a U.S. District judge ruled that the Federal Drug Administration's 2003 ban on ephedra was too broad. The suit, brought by Nutraceutical International of Park City, Utah, challenged the removal of all ephedra products on the market, on the premise that the FDA had not shown any danger for low dose (less than 10 milligrams) ephedra products. It also questioned whether the FDA had the jurisdiction to demand that dietary supplements prove their safety, as is demanded of pharmaceutical drugs. Here is one reaction to the ruling:

"The court provided a very rational decision that the amount of an ingredient must be considered when evaluating the safety of that ingredient," said Michael McGuffin, president of the American Herbal Products Association. McGuffin said the ruling should not be misinterpreted as permission to put high-dose ephedra products like Metabolife 356 back on the shelves. The decision is narrowly focused on the low-dose product sold by Nutraceutical, he said.

However Public Citizen, a Washington watchdog group, takes a different side. The group fought to have ephedra banned for years. Among many informational documents available on their website is an article by Sidney Wolfe, M.D. published in the April 18, 2003 issue of Science magazine, that details arguments for banning ephedrine alkaloids, posted here at the Public Citizen website. The article lists some health risks linked to over-the-counter (OTC) drugs containing ephedra alkaloids and ephedrine. It criticizes the FDA for dawdling rather than banning these substances in the light of multiple ephedra linked deaths, and notes the multi-million dollar political lobbying efforts employed by some of the ephedra products companies.

There are obvious incentives on the part of for-profit companies to challenge the FDA's authority and scope. However vitamins and supplements comprise a multi-billion dollar industry that is largely unregulated and certainly many OTC supplements can be dangerous if misused. Many others are unstudied and potential toxicity is undetermined.

Should someone be overseeing products on behalf of public safety? Should the FDA be regulating the manufacture and sale of herbs, minerals and vitamins or perhaps an international body such as the World Health Organization. There is support, concern and confusion about the Codex Alimentarius, whose level of jurisdiction over vitamins and minerals (potentially US nutrient industry) is currently being debated. Participating in this important public debate is elementary, after all, it's your body.

Hyponatremia: Marathoners- Imbibing in Water, Running out of Steam, Dying???

Science reporting by the media often adds to public confusion rather than advances understanding. Research can be a puzzle with hundreds or millions of pieces, many unknown. Science reporting tends to pull out one piece of the puzzle, focus on the weird shape, the color, the edges, then often inexplicably bestow that piece with front-page significance. Building blocks of previous studies are often ignored and the complexity of trying to fit the pieces together is sacrificed for the eye-catching title.

On the front page today, (Thursday April 14, 2005) the New York Times reports "Study Cautions Runners to Limit Intake of Water" The subject of the NYT article is the research study, "Hyponatremia among Runners in the Boston Marathon", recently published in the New England Journal of Medicine (NEJM). Hyponatremia is low sodium concentration in the blood (about <135mmol/L) caused by overhydration, drinking too many fluids.

The NEJM is appropriately specific about the results, in short: hyponatremia is a risk for a very small percentage of athletes who are generally less well trained and who over-consume water and symptomatically gain weight while running. The study significantly adds to 40 years of studies on hydration. Importantly, it supports various recent studies showing that overhydration can be dangerous. This is important. Runners shouldn't drown themselves in water - literally. The study warns that more than 3 liters in 26.2 miles is excessive.

Despite the validity of the health concern, New York Times coverage of the study reads like a sensational press release for Harvard. As with most scientific studies, the article by itself is not revelatory, the evidence has been in for a while. Medical colleges have been setting up tents at the ends of marathons and publishing the same results for years. Baylor medical college published a study in January, 2003 in the Clinical Journal of Sport Medicine (Hew et al) that found hyponatremia to be a concern. Indeed the current Harvard study liberally references other studies. This fact doesn't diminish the report because it's important to be able to repeat results. But the way the New York Times presents the research can be misleading:

"Before this study, we suspected there was a problem," said Dr. Marvin Adner, the medical director of the Boston maraton, which is next Monday, "but this proves it."

The NEJM study adds to the growing body of research, but doesn't "prove" it. However there is something about hyponatremia and the increasing number of slow runners:

"As more slow runners entered long races, doctors began seeing athletes stumbling into medical tents, nauseated, groggy, barely coherent and with their blood severely diluted. Some died on the spot."

Doctors now diagnose the condition in extremely high numbers says the NYT:

"New research involved 488 runners in the 2002 marathon. The runners gave blood samples before and after the race. While most were fine, 13 percent of them - or 62 - drank so much that they had hyponatremia, or abnormally low blood sodium levels. Three [NYT added this in later edition?] were in danger of dying."

Unlike the New York Times, New England Journal of Medicine study's authors didn't mention "dying". Although several deaths have tragically occurred in marathons, fewer then 1:50,000 runners die in marathons, and most of these deaths are due to cardiovascular failure. None of the racers in this study died, though coincidentally and tragically one person did die that year. No one has died in the Boston Marathon since.

Who was in danger of "dying" as the Times so dramatically reported? The New England Journal of Medicine reported that 3 runners had "critical hyponatremia". The NEJM study does not associate any specific permanent perils or death rates with any sodium concentration, so it's unclear which levels of hyponatremia are how dangerous, but "critical hyponatremia" is a medical term used for sodium concentrations of below 120mmol/L, which are potentially fatal. Different investigators can use slightly different terms but higher (more normal) levels of sodium are commonly referred to as "low" and "moderate" or "severe" hyponatremia. Apparently the other 59 of 62 runners who had hyponatremia were in less serious though unspecified states of hydration.

The New York Times indicates that ALL runners with hyponatremia will recover if they receive prompt medical intervention of intravenous sodium infusions:

"Hyponatremia can be treated, Dr. Noakes said. A small volume of a highly concentrated salt solution is given intravenously and can save a patient's life by pulling water out of swollen brain cells."

So then did 62 of 488, or 12.7% ("13%") of the racers require intravenous therapy? Extrapolated to the population of Boston Marathon runners in 2004, that would mean 2159 of 17,000 who ran required intravenous therapy. This seems misleading. That many people couldn't be so severely sick without the hospitals (and probably media) being well aware of the problem.

Perhaps only the 3 most seriously affected hyponatremic runners required intervenous therapy? But something's not right. In 2004 only 11 of 17,000 runners self reported and were diagnosed with hyponatremia. It's unknown how serious these self-reported cases were, but this is ten times less (11 of 17,000 = .06%) then the .6% reported in the study. None of the 2004 Boston Marathon racers died.

It is clear then, that the "critical" status of the cohort of 3 identified in the original study can not be extended to the entire cohort of 62 who had clinically identifiable but less serious conditions. But it is not clear how many athletes are affected in races since the percentage of affected runners in the NEJM study didn't seem to be reflected at actual marathons.

The New York Times article could give many athletes the wrong idea about the dangers of over-hydration. While it is certainly a condition to guard against, dehydration is a more common occurrence. Most racers who self-report at medical stations do so for dehydration. Dehydration leads to decreased blood flow which limits the perspiration process that dissipates heat and prevents heatstroke. Dehydration loss of more then 2% of the body weight can be problematic and lead to performance detriments. While the doctor cited in the Times article knows no case of death in marathon runners due to dehydration, this does not hold for military training and sports camps.

Appropriate hydration is highly individualistic and depends on physiology, level of training, outside temperature and diet among other things. The NYT article concludes that slower runners should not over-drink;

"Elite athletes are not drinking much, and they never have." Dr. Noakes said. The lead female marathon runner in the Athens Olympics, running in 97-degree heat drank just 30 seconds of the entire race."

While is true, the statement underemphasizes the physiological changes that occur during training that lead to the elite athlete being able to run with with less water.

The most news-worthy result if the Harvard study in New England Journal of Medicine is that hyponatremia happens. This is important for both runners and doctors who are treating distressed runners because it alerts both groups to the potential of this condition. However the emphasis of the New York Times article on the high prevalence of the condition and the danger of dying exaggerates the results of the study to provide an article that is shocking enough to appear on the front page of the paper.

The New York Times misconstrues the significance and results of the study. It's not clear whether this is entirely the New York Times' doing or whether the study's authors are complicit in overstating the problem and leading us to believe that this is new research, perhaps for self-promotion.

Inaccurate media portrayal of research leads to the perception that science itself is wishy-washy. Although we always need to be attentive to new research, the media exaggeration of research studies only undermines the aims of research to improve public health. The actual results aim at correcting an imbalance in *popular* though not *expert* advice. Doctors, exercise physiologists and trainers have long advocated balanced hydration.

Scope Creep: The Police Want a Piece of You

The New Scientist asks "Will DNA profiling fuel prejudice?" The article contemplates the power of the England and Wales National DNA Database (NDNAD):

"Launched on 10 April 1995, NDNAD holds DNA profiles from almost 3 million people...."From an investigator's perspective it's a powerful tool," says Paul Stickler of Sussex police. In a typical month, the database churns out hits for 15 murders, 45 rapes and sexual offences and 2500 car, theft and drug crimes. With DNA evidence, the average crime clear-up rate increases from 24 per cent to 43 per cent."
...but notes the scope and increased growth of the profiling tools:
"In 2001, new legislation allowed the retention of profiles from suspects acquitted in court, and on 4 April last year police were given the authority to collect DNA from any person arrested on suspicion of a "recordable offence". These are people who may never have been charged, let alone convicted."

The trend for this type of vast personal data collection by authorities is growing in the US too. The contentious "Justice For All Act" was passed in October of 2004. California voters also passed Proposition 69 last fall. Voters were apparently convinced that the law would prevent criminals from cavorting about- crime would be thwarted. The law, like England's, allows DNA from anyone arrested to be stored in the database, whether or not they are subsequently charged with a crime.

These databases have proven privacy risks. People have been falsely connected to crimes they did not commit with DNA samples or data that is misread or mishandled. The data can be used for invasive racial and medical profiling, or be sold to private concerns who would misuse the data. The American Civil Liberties Union of Northern California lists two such indiscretions:

Darpa- An Even More Realist Agenda

A couple of weeks ago we reported on the changing focus of the NIH's microbial research funding priorities from basic to defense related research. Apparently, this is also a (less intuitive) trend at the Defense Advanced Research Projects Agency at the Pentagon (Darpa). Although Darpa has long been focused on research for military applications, this New York Times article details how the "blue-sky" funding of the past couple of decades is being curbed. The recent research agenda increasingly excludes the types of basic research that have resulted in the broad applications of research like the the Internet, the technologies behind say- Google, Intel, Xerox Parc, and Apple, not to mention a myriad of computer applications of the past few decades. The cuts affect research and researchers the following ways:

"University researchers...assert that Darpa has shifted a lot more work in recent years to military contractors, adopted a focus on short-term projects while cutting support for basic research, classified formerly open projects as secret, and placed new restrictions on sharing information."
"within a relatively steady budget for computer science research that rose slightly from $546 million in 2001 to $583 million last year, the portion going to university researchers has fallen from $214 million to $123 million."

Other restrictions have been imposed also. Leonard Kleinrock, a University of California, Los Angeles professor associated with the development Arpanet, recently refused Darpa funding that demanded that all the researchers involved in a particular grant be American citizens.

The article reports that the shift is seen by some as "necessary to prepare the nation for a long battle against elusive enemies", while others are alarmed, as it affects their labs, their students, and the flow of newly emerging technologies.

Stem Cell Research in Massachusetts

The Massachusetts Senate passed a bill on Wednesday that would allow human cells to be cultured for stem cell research. The bill passed by 10-2. On Thursday the House of Representatives version of the bill passed by 117 to 37, a vote wide enough to repel the Governor's veto of the bill, which requires 53 votes.

Mitt Romney, a Republican (as usual) governor in the largely Democratic state, vigorously lobbied against the bill, most recently in a radio campaign. Romney is against cloning embryonic stem cells via somatic cell nuclear transfer because that is for the creation of "new human life". However, in apparently nuanced and rather opaque position against embryonic stem cell research, he is not opposed to stem cells created from cells leftover from in-vitro fertilization. Romney conceded defeat on the Massachusetts measure, but added:

"I think you're going to see at the national level an interest in legislation which limits the creation of new embryos though cloning," Romney said. ''So I think you're going to see a national effort to define the boundaries of ethics, and I hope that proceeds."

There is speculation that Romney is polishing his resume for a prospective presidential run in 2008.

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