You Can Teach an Old Drug New Tricks

Drug discovery is a laborious process.

From initial discovery of a promising target to the final medication becoming available, is an expensive, and lengthy process. At present, the costs of bringing a single new drug to market is around $1.2 billion, an amount that doubles every five years.

Aside from the cost, it takes, on average, 12 years for an experimental drug to progress from bench through FDA approval to market.

Annually, North American and European pharmaceutical industries invest more than $40 billion to identify and develop new drugs. Even so, for every 5,000 compounds that enter pre-clinical testing, only five, on average, are tested in human trials, and only one of these five receives approval for therapeutic use.

So, it’s hardly surprising that many pharmaceutical companies are choosing to take a closer look at old drugs. Last week, SRxA’s Word on Health brought you news of a host of potential new uses for aspirin.

And aspirin is not alone.  Old drugs often get a surprising second shot at life. In the past few weeks, the news has buzzed about the skin cancer drug – bexarotene – that may cure Alzheimer’s; a common antimalarial drug – hydroxychloroquine – that may help to destroy cancerand, a leukemia drug that inhibits the Ebola virus.

Then, of course, there’s the personal favorite of many women – Latisse.  Originally developed as a glaucoma treatment , it was found to have the desirable side effect of making eyelashes fuller and longer and is now FDA approved for this purpose.

Testing drugs already approved for one use to see if they can treat other conditions, can reduce time and money. Since these known drugs have already undergone toxicology and safety testing, the clinical development program can be streamlined.

Sometimes it’s pure serendipity.

Take Viagra for example. Although these days it’s the stuff of pharmaceutical industry legend , in the early 1990s, it was just a chest pain drug that wasn’t performing very well in clinical trials. So how did the little blue pill go from heart to crotch?  Pfizer was ready to call it quits when they decided to look into one unexpected but common side effect: long-lasting erections. Then came the drug patent and the rest is history.

The discovery that lithium could be used to treat manic episodes in bipolar patients was equally fortuitous. In 1949, Australian psychiatrist John Cade was injecting guinea pigs with urine extracts from schizophrenia patients to try and isolate a compound that caused mental illness. By accident he happened to use a compound with lithium – which at the time was used as a treatment for gout, as the control. Although he didn’t find the compound that caused mental illness, he did find one that treated it!

Back in 2010 we reported on the repurposing of thalidomide. Although the drug caused serious birth defects when it was launched in the 1960’s as a morning sickness pill it has since been found to be useful in reducing severe and frequent bleeding in patients with  hemorrhagic telangiectasia (HHT); in the treatment of patients with newly diagnosed multiple myeloma when taken  in combination with dexamethasone; and for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum

The National Institutes of Health (NIH) recently established The Learning Collaborative (TLC) to study how to more easily repurpose known drugs to treat rare forms of blood cancers.

TLC is a dedicated collaboration between the NIH Chemical Genomics Center (NCGC) and its Therapeutics for Rare and Neglected Diseases (TRND) program, The Leukemia & Lymphoma Society (LLS), and Kansas University Cancer Center (KUCC) to discover and develop new drug therapies for rare blood cancers. TLC is creating a pipeline of new therapies to treat leukemia from both the discovery of new treatments as well as identifying new uses for approved and abandoned drugs.  For example, Auranofin, a drug originally used for rheumatoid arthritis, is now in clinical trials for treating chronic lymphocytic leukemia.

Word on Health will continue to follow the drug recycling trend and bring you news as it breaks. In the meantime if you have noticed any beneficial side effects from the medicines you’re taking, we’d love to know.

Reckless Research Race, Results in Rising Retractions. Reform Required?

As our regular readers know, SRxA’s Word on Health loves nothing more than a good alliteration to start the day!  Although the blog post title may rank as one of our more classic tongue twisters, there is nothing amusing about the content.  As involved as we are in medical communications and peer-reviewed, scientific publishing, we are saddened to report on the rise of a recent trend of falsified research. An unsettling pattern is emerging. The rate at which articles are retracted (meaning the study was published, only to later be dubbed unfit for print — typically due to either deliberate misconduct or an honest scientific mistake) is increasing. To our knowledge, at least three scientific journals have published articles over the past two years warning of the rise in retractions and misconduct by researchers who have fudged results.

Last year Nature reported a tenfold increase in retractions over the past decade even though the number of published papers only increased by 44%. Before that, the Journal of Medical Ethics published a study in 2010 that said a rise in recent retractions was the fault of misconduct and “honest scientific mistakes.” It calculated that the number of retractions had more than tripled from 50 in 2005 to 180 in 2009.

The latest publication to highlight this issue is Infection and Immunity. In the fall of 2010, Dr. Ferric C. Fang, editor in chief of the journal made an unsettling discovery – one of his authors had doctored several papers. The journal wound up retracting six of the papers from the author, Naoki Mori of the University of the Ryukyus. It soon became clear that Infection and Immunity was hardly the only victim of Dr. Mori’s misconduct. Since then, according to the blog Retraction Watch, other scientific journals, including the International Journal of Cancer  have retracted another 24 of his papers. This was a new experience for Fang. Prior to this incident Infection and Immunity had only retracted nine articles over a 40-year period. “Nobody had noticed the whole thing was rotten,” said Fang, a professor at the University of Washington School of Medicine. Dr. Fang became curious how far the rot extended. To find out, he teamed up with a fellow editor at the journal, and before long they reached a troubling conclusion: not only that retractions were rising at an alarming rate, but that retractions were just a manifestation of a much more profound problem.

Dr. Fang’s colleague, Dr. Arturo Casadevall, said he feared that science had turned into a winner-take-all game with perverse incentives that led scientists to cut corners and, in some cases, commit acts of misconduct. Last month, in a pair of editorials in Infection and Immunity, the two editors issued a plea for fundamental reforms. While no one claims that science was ever free of misconduct or bad research, the new raft of retractions appears to be a mix of misconduct and honest scientific mistakes. Several factors are at play here, scientists say. One may be that because journals are now online, bad papers are simply reaching a wider audience, making it more likely that errors will be spotted. But other forces are more pernicious. To survive professionally, scientists feel the need to publish as many papers as possible, and to get them into high-profile journals. And sometimes they cut corners or even commit misconduct to get there. To measure this claim, Drs. Fang and Casadevall looked at the rate of retractions in 17 journals from 2001 to 2010 and compared it with the journals’ “impact factor,”  – a score based on how often their papers are cited by scientists. The higher a journal’s impact factor, the higher its retraction rate. The highest “retraction index” in the study went to one of the world’s leading medical journals, The New England Journal of Medicine.

The scramble to publish in high-impact journals may be leading to more and more errors. Each year, every laboratory produces a new crop of Ph.D.s, who must compete for a small number of jobs, and the competition is getting fiercer. In 1973, more than half of biologists had a tenure-track job within six years of getting a Ph.D. By 2006 the figure was down to 15 percent. In such an environment, a high-profile paper can mean the difference between a career in science or leaving the field. The scramble isn’t over once young scientists get a job. “What people do is they count papers, and they look at the prestige of the journal in which the research is published, and they see how many grant dollars scientists have, and if they don’t have funding, they don’t get promoted,” Dr. Fang said. “It’s not about the quality of the research.”

With all this pressure on scientists, they may lack the extra time to check their own research. Instead, they have to be concerned about publishing papers before someone else publishes the same results. Adding to the pressure, thousands of new Ph.D. scientists are coming out of China and India, countries that offer cash rewards to scientists who get papers into high-profile journals. Dr. Fang worries that the situation could be become much worse if nothing happens soon. To change the system, Fang and Casadevall say graduate students need a better understanding of science’s ground rules. They would also move away from the winner-take-all system, in which grants are concentrated among a small fraction of scientists by putting a cap on the grants any one lab can receive. A little bit of old fashioned honesty wouldn’t hurt either!

An aspirin-a-day keeps fat away

Aspirin is one of the most widely used medications in the world. A staggering 40,000 tons of it are consumed each year.

It’s also one of the oldest known medicines. First reports of its use date back to an Egyptian papyrus in 1543 BC. Hippocrates, the father of modern medicine, who lived sometime between 460 BC and 377 BC, left historical records describing the use of powder made from the bark and leaves of the willow tree to alleviate headaches, pains, and fevers. The active ingredient of this willow bark extract – salicylic acid.

In addition to its use as an anti-inflammatory pain reliever, aspirin is also used  as an anticoagulant / antiplatelet agent  to prevent strokes and heart attacks, and to stop coronary and carotid stents from blocking and to prevent deep vein thrombosis associated with long distance travel.

Aspirin has also been theorized to reduce cataract formation in diabetic patients and three studies published last month suggest that taking an aspirin every day may significantly reduce the risk of many cancers and prevent tumors from spreading.

Now, a group of researchers from Canada, Scotland and Australia have discovered that salicylate, the active ingredient in aspirin, directly increases the activity of the protein AMP-activated protein kinase (AMPK).  AMPK is a key player in regulating cell growth and metabolism.  It is considered a cellular fuel-gauge which can be switched on by exercise and the commonly used oral anti-diabetic medication metformin.

We’re finding this old dog of aspirin already knows new tricks,” says McMaster University associate professor of medicine Dr. Greg Steinberg.  The research shows that, in contrast to exercise or metformin which increase AMPK activity by altering the cells energy balance, the effects of salicylate depend on a single amino acid.

Salicylate increases fat burning and reduces liver fat in obese mice which does not occur in genetically modified mice lacking the beta1 subunit of AMPK.

These findings are important as a large clinical trial is currently underway testing whether salsalate (a well-tolerated aspirin derivative), can prevent Type 2 diabetes.  With many recent studies showing that metformin may be important for cancer prevention the authors’ study raise the interesting possibility that aspirin may also be working in a similar manner.

While further studies are needed, the prospect that this cheap, over-the-counter drug can increase fat burning while simultaneously preventing pain, clotting problems and possibly cancer, is probably one of the best health news stories of the year.

Cure for hepatitis C gets closer

About 170 million people worldwide are estimated to have been infected with Hepatitis C.

Among them, many celebrities including: actor  Larry Hagman; Rolling Stone Keith Richards; American Idol judge Steven Tyler; Baywatch babe Pamela Anderson; stuntman Evel Knievel and “Dr Death” Jack Kevorkian.

Currently there is no cure for this bloodborne, liver destroying virus and until recently there has been no specific treatment. Although interferon injections have been used, the  flu-like symptoms and other side effects often lead patients to discontinue or delay treatment.

However, in the last two years, two new injectable treatments were approved for use and clinical trials of oral medicines demonstrate promising results.

Earlier this month Abbott Laboratories released impressive data from a small mid-stage trial combining its experimental protease inhibitor ABT-450 boosted by the antiviral drug ritonavir, along with a polymerase inhibitor and ribavirin. The combination achieved a 95% cure rate in one arm of the study.

Separately, Gilead reported results from the Electron study, showing that of 88% of the 25 patients who completed 12 weeks of treatment with GS-7977 and ribavirin, had undetectable levels of virus four weeks after completion of treatment.

And last Thursday, at a liver disease meeting in Europe, researchers released interim data showing that a combination regimen of  GS-7977 from Gilead Sciences Inc and daclatasvir  from Bristol-Myers Squibb Co led to a 100% response rate in previously untreated patients with the most common form of hepatitis C.

GS-7977 is a nucleotide polymerase inhibitor. Daclatasvir  is from a new class of drugs known as NS5A inhibitors. Both are designed to block enzymes essential to replication of the hepatitis C virus.

All 44 of the patients who had the most common and difficult to treat type of hepatitis C (Genotype 1)  had undetectable levels of the virus in their blood four weeks after completing treatment, while 40 out of 44 patients with Genotypes 2 or 3 had undetectable levels of virus at four weeks following treatment -a 91% response rate.

The experimental drugs were considered to be well tolerated with the most frequent side effects being fatigue, headache and nausea. Full results from the trial are expected later this year.

Despite these promising results the 2 companies have decided not to pursue a collaboration.  Gilead is now commencing a trial of GS- 7977 in combination with its own experimental NS5A inhibitor, while Bristol-Myers is testing its drug daclatasvir with a compound similar to GS-7977.

The race for a cure seems to be well and truly on…and whoever comes first the real winners will be the people already infected.

Solved! The Mystery of the Stones

Kidney stones strike an estimated 1 million Americans each year.

Those who have experienced them say it is among the most excruciating pain known to man (or woman).

Now, new research provides evidence to explain why some people are more prone to develop the condition than others. The discovery by scientists at Washington University School of Medicine in St. Louis opens the door to finding effective drug treatments and a test that could assess a person’s risk of kidney stones.

Now, we finally have a more complete picture detailing why some people develop kidney stones and others do not,” says Jianghui Hou, PhD, assistant professor of medicine. “With this information, we can begin to think about better treatments and ways to determine a person’s risk of the condition, which typically increases with age.”

Although the research was in mice, the new findings will help scientists to understand the root causes of kidney stones in patients because their kidneys function the same way as ours.

Most kidney stones form when the urine becomes too concentrated, allowing minerals such as calcium to crystallize and stick together.  Diet plays a role – not drinking enough water or eating too much salt (which binds to calcium) increases the risk of stones.

But genes are also partly to blame. A common genetic variation called claudin-14 has recently been linked to a 65% increased risk of kidney stones.

In the new study, the researcher demonstrated how alterations in the gene’s activity influence the development of stones.  Typically, the claudin-14 gene is not active in the kidney. Its expression is dampened by two snippets of RNA, that essentially silence the gene.  When claudin-14 is idled, the kidney’s filtering system works like it’s supposed to. Essential minerals in the blood pass through the kidneys and are reabsorbed back into the blood, where they are transported to cells to carry out basic functions of life.

But when people eat a diet high in calcium or salt and don’t drink enough water, the small RNA molecules release their hold on claudin-14 and the subsequent increase in the gene’s activity prevents calcium from re-entering the blood.  Without a way back to the bloodstream, excess calcium passes into the urine. Too much calcium in the urine leads to the development of stones in the kidneys or bladder.

Then when a large stone gets stuck in the bladder, ureter or urethra the flow of urine is blocked and the characteristic intense pain, that can reduce even the most mild-mannered man to a cursing, foul-mouthed monster, develops.

People with the common, genetic variation in claudin-14 lose the ability to regulate the gene’s activity, increasing the risk of kidney stones.

The results of this research lead to the hope that drugs that will keep the activity of claudin-14 in check can be developed.  Additionally, it may be possible to develop a diagnostic test to measure levels of the claudin-14 protein excreted in urine. Elevated levels would indicate an increased risk of stones, and people could take steps to prevent stones by modifying their diet.

Many genes likely play a role in the formation of kidney stones,” Hou says. “But this study gives us a better idea of the way one of the major players work. Now that we understand the physiology of the condition, we can start to think about better treatments or even ways to prevent stones from developing in the first place.”

For the million or so sufferers and their loved ones we guess that day can’t come soon enough.

A Question of Health

As we’ve said before, and will doubtless say again – the more patients become more actively involved in their own health, the better the outcome.

So we were pleased to learn of a new public education initiative from the U.S. Agency for Healthcare Research and Quality (AHRQ), which encourages patients to have more effective two-way communication with their doctors and other clinicians.

The “Questions are the Answer,” campaign features a website packed with helpful advice and free educational tools for doctors and patients. Among the offerings:

  • A 7-minute video featuring real-life patients and clinicians who give firsthand accounts on the importance of asking questions and sharing information. The video has been designed for use in a patient waiting room area and can be set to run on a continuous loop
  • A brochure, titled “Be More Involved in Your Health Care: Tips for Patients,” that offers helpful suggestions to follow before, during and after a medical visit
  • Notepads to help patients prioritize the top three questions they wish to ask during their medical appointment.

In addition, the site has a series of patient and clinician videos in showing how simple questions can help you take better care of yourself, feel better, and get the right care at the right time. In one of these, Rachelle Toman, M.D., Ph.D., a family physician from Washington D.C., says if you are happy to ask your doctor and grocery store clerk a question, then why not your healthcare provider?

Patients need to come forth with questions, and providers need to be open about asking their patients questions, and asking their patients to ask questions,” she continues.

Put simply, questions allow doctors to take better care of you.

Are you ready to become an active member of your health care team and get your questions answered?

Drugs That Can Land You in the Emergency Room

It’s midnight at the fire station and a call goes out for a patient who has overdosed. In addition to an ambulance and medic unit, police are dispatched.  As we stage for the police, to ensure that the scene is safe, we speculate as to what we’re going to encounter. Will the patient be conscious? What sort of emotional distress has driven them to this? Is it a serious attempt or a cry for help?  Will there be weapons?

As we mentally run through all types of scenarios, it’s doubtful that many of us have considered that our patient will be an 82 year old great grandmother armed with nothing more than her reading glasses and the remote control.

But increasingly that’s what we might find.  As Americans live longer, we have an increasingly frail population suffering from a greater number of chronic conditions, taking more medications than ever before. Among adults 65 years of age or older, 40% take 5 – 9 medications and 18% take 10 or more.

This type of polypharmacy is associated with an increased risk of adverse events. Older adults are nearly seven times as likely as younger persons to have adverse drug events that require hospitalization.

According to a recent article in the New England Journal of Medicine blood thinners and diabetes drugs cause most of the unintentional overdoses that lead to emergency hospitalization in older patients.

Researchers reviewed the records of 100,000 hospitalization events due to major drug side effects in people aged 65 and above from a representative sample of 58 hospitals.  Almost half, (48%) of adverse drug event (ADE)-related hospitalizations occurred in patients older than 80.

The drugs they looked at included prescription and over-the-counter medications, vaccines, and dietary supplements.

Adverse events were categorized as allergic reactions, undesirable pharmacologic or idiosyncratic effects at recommended doses, or unintentional overdoses.  Other effects included problems due to medication-delivery methods (e.g., choking) and vaccine reactions. Visits for intentional self-harm, drug abuse, therapeutic failures, and drug withdrawal were excluded.

Shockingly, just four medications accounted for more than two-thirds of emergency hospitalizations:

Given that emergency hospitalizations caused by ADEs result in significant morbidity and enormous costs it’s not surprising that decreasing harm to patients and reducing costs by preventing re hospitalizations is a goal of the $1 billion federal initiative Partnership for Patients.

Achieving a 20% reduction by the end of 2013 may sound ambitious, but in fact there are a number of simple steps that we can take.

  1. Make sure that everyone taking medications has an up-to-date list, including all prescribed drugs as well as vitamins, herbs, and OTC medicines. Copies of the list should be kept in their wallet and should be shared with all doctors they see so that the potential for drug interactions can be assessed and avoided.
  2. Alert your loved ones that blood thinners and diabetic medicines account for 50% of hospitalizations due to ADEs. Blood thinners and diabetes medications should be regularly monitored by the primary care physician.
  3. Encouraging medication compliance can lengthen a person’s lifespan. Too many times patients stop their medications due to a comment made by a well-meaning friend who has  read something on the Internet. Often the doctor is not informed and the patient may not understand the positive effects of the medication or the dangers of stopping them suddenly.
These small measures may not only save the life of your elderly loved-ones, but they may also  reduce your Word on Health bloggers’ middle of the night 911 dispatches.

There’s a Shot for That

On May 14, 1796 Edward Jenner injected fluid from the cowpox blisters on the hands of dairymaid Sarah Nelmes, into James Phipps, an 8-year-old boy.  Jenner hoped the fluid from the cowpox lesion would somehow inoculate the boy against the smallpox scourge which at the time was killing over 400,000 Europeans a year. His hunch proved correct.

Today vaccines save 3 million lives per year worldwide. By training the human immune system to recognize and ward off dangerous pathogens, vaccines can protect against disease for decades, or even for a lifetime. Preventive vaccines work by introducing harmless microbial chemical markers, known as antigens, which resemble the markers on living microbes. The antigens train the immune system to recognize and destroy those microbes should they ever appear in the body. By injecting cowpox antigens into Phipps bloodstream, Jenner primed his immune system to attack the similar smallpox virus.

Now, medical scientists are taking Jenner’s ideas in a whole new direction. By exploiting a growing understanding of the immune system they are developing therapeutic vaccines targeting established diseases rather than trying to prevent them.

Last spring, the FDA approved Provenge, a personalized immunotherapy that activates a patient’s own immune cells to target and attack advanced prostate cancer. To make the Provenge prostate cancer vaccine, biochemists at Seattle’s Dendreon Corporation extract a sample of a patient’s own immune cells and bathe them in a chemical soup of prostate cancer antigens that are chemically linked to a cytokine that screams, “Attack this!”.  The activated immune cells are then injected back into the patient’s body to spread the call to arms.

While Provenge was the first of the new generation of therapeutic vaccines, it’s certainly not the last. BCC Research has identified 113 therapeutic vaccines in development, many of which are already in human trials. They even go so far as to estimate that the market for therapeutic vaccines will have an annual growth rate of 115% and reach an estimated $2.9 billion in 2014.

Other cancer vaccines are among the front runners. With a near-endless supply of patients willing to undergo novel treatments, cancer researchers have been among the most aggressive in experimenting with therapeutic vaccination. The Cancer Vaccine Collaborative is working on treatments that target multiple cancer antigens, which should trigger a more aggressive immune response and increase the odds of defeating tumors. All of which is good news for the 1.5 million Americans diagnosed with cancer each year.

While cancers cause a proliferation of diseased cells, some autoimmune diseases, cause the cells of the immune system to turn against healthy tissues. In diabetes, for example, the immune system attacks insulin-making pancreatic beta cells.

In multiple sclerosis, it’s the myelin sheaths that are designed to protect the nerves that come under attack.

Autoimmune vaccines hold the promise of shutting down these attacks. One promising approach boosts T-regulatory cells, a subgroup of the white blood cells. At the University of Calgary’s Diabetes Research Centre in Alberta, immunologist Pere Santamaria has attached a cocktail of antigens from pancreatic beta cells to synthetic iron oxide nanoparticles. This stimulates the development of T-regulatory cells into killer T cells that destroy the immune cells which cause the serial killer like autoimmune attack.

Santamaria’s team recently tested his vaccine in diabetes-prone mice. It restored normal blood sugar and insulin levels in animals that already had diabetes and prevented or slowed its onset in young mice that had not yet developed the disease. The team is now readying the vaccine for human trials and is designing related vaccines to treat other autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease.

If effective, such therapeutic vaccines could help the three million Americans with type 1 diabetes and the 400,000 people diagnosed with multiple sclerosis. Vaccines against dust mites and asthma are also in the works.

Some of the new therapeutic vaccines are actually designed to attack the body, albeit in a selective way. A new experimental heart-disease vaccine takes aim at unwanted biochemicals within the body, specifically low-density lipoprotein (LDL), better known as bad cholesterol. When large quantities of LDL cholesterol circulate through the bloodstream, it can be deposited on artery walls, leading to a buildup of plaque and triggering inflammation. Anti-cholesterol vaccines encourage the immune system to attack LDL and remove plaques. Scientists have also discovered that the vaccine lowers blood pressure and protects against the rupture of aneurysms, at least in mice.

Clinical trials in humans are expected to start later this year and if successful could help to prevent the 800,000+ deaths per year from cardiovascular disease.

Even more people could be helped by an anti-obesity vaccine. Nearly 75 million adults are classified as obese in the United States. Researchers are working on a vaccine that targets ghrelin – a gastrointestinal hormone that appears to stimulate appetite.

Others, are looking at vaccines to prevent addiction to cocaine, methamphetamines, opiates and nicotine.

It is too soon to know how and when these vaccines will come to market or how effective they will be, but it’s clear that therapeutic vaccines are coming and will be used against a host of the most prevailing public health issues of the 21st century.

20/20 on the Vanishing American Hospital

Most Americans are born in hospitals. Hospitals also provide care during many other intimate and extraordinary circumstances in our lives – serious injuries, severe sickness and mental breakdown. Hospitals are also, by and large where we go to die.

As such, hospitals serve as a cornerstone of our communities and our very existence.

According to the American Hospital Association, there are 5,754 registered hospitals in the U.S. In 2011, almost 37 million people were admitted to a hospital in the U.S. – that’s more than 1:10 people.

Yet despite all this history, hospitals are in the midst of massive and disruptive change.

Even knowing this, SRxA’s Word on Health was shocked to read an article suggesting that by 2020 one in three hospitals will close or reorganize into an entirely different type of health care service provider.

Writing on KevinMD.com, a leading physician voice blog, authors David Houle and Jonathan Fleece suggest that that there are four significant forces and factors are driving this inevitable and historical shift.

First, America must bring down its crippling health care costs. The average American worker costs their employer $12,000 annually for health care benefits and this figure is increasing more than 10 percent every year. U.S. businesses cannot compete in a globally competitive market place at this level of spending. Federal and state budgets are getting crushed by the costs of health care entitlement programs, such as Medicare and Medicaid. Given this cost problem, hospitals are vulnerable as they are generally regarded as the most expensive part of the delivery system for health care in America.

Second, statistically speaking hospitals are just about the most dangerous places to be in the United States. Three times as many people die every year due to medical errors in hospitals as die on our highways — 100,000 deaths compared to 34,000.

The Journal of the American Medical Association reports that nearly 100,000 people die annually in hospitals from medical errors. Of this group, 80,000 die from hospital acquired infections, many of which can be prevented. Given the above number of admissions that means that 1 out of every 370 people admitted to a hospital dies due to medical errors.

In other words, hospitals are very dangerous places.  It would take about 200 747 airplanes to crash annually to equal 100,000 preventable deaths. Imagine the American outcry if one 747 crashed every day for 200 consecutive days in the U.S. The airlines would stand before the nation and the world in disgrace.

Currently in our non-transparent health care delivery system, Americans have no way of knowing which hospitals are the most dangerous. We simply take uninformed chances with our lives at stake.

Third, hospital customer care is abysmal. Recent studies reveal that the average wait time in American hospital emergency rooms is approximately 4 hours. Name one other business where Americans would tolerate this low level of value and service.

Fourth, health care reform will make connectivity, electronic medical records, and transparency commonplace in health care. This means that in several years, and certainly before 2020, any American considering a hospital stay will simply go on-line to compare hospitals relative to infection rates, degrees of surgical success, and many other metrics. Isn’t this what we do in America, comparison shop? Our health is our greatest and most important asset. Would we not want to compare performance relative to any health and medical care the way we compare roofers or carpet installers? Inevitably when we are able to do this, hospitals will be driven by quality, service, and cost — all of which will be necessary to compete.

So hospitals are about to enter the open competitive marketplace. And as we know there will be winners and losers.  According to Houle and Fleece a third of today’s hospitals will fall into the latter category.

Will your hospital be among them?  Let us know what you think.

Of Mice and Men…and Mental Health

One in five Americans suffers a major depressive episode in their lifetime. Twenty-eight per cent will develop an anxiety disorder, such as post-traumatic stress, phobias, obsessions, or compulsions. Another 15% will fall prey to alcoholism or drug addiction. If you gather 100 people from any square mile on earth, odds are that one will have autism or schizophrenia.

Just about everything we know about drug treatments for psychiatric disorders we learned from mice.  Just how the mouse became our avatar is part tradition and part biological accident. In the past, rats were traditionally used to test experimental drugs. Rats are small enough to be affordable but big enough to make their brains easy to dissect. And they are smarter than mice. You can swiftly teach a rat to solve a maze, for instance, and then test whether your new drug has a side effect of making rats forgetful.

However, rats missed the knockout revolution of the late 1980s. Knockout technology allows researchers to silence, or knock out, individual genes.

With mice, researchers can insert altered DNA in a mouse stem cell, insert the cell in a newly fertilized egg, and insert the egg in a surrogate mother. That egg might develop as a normal mouse or a knockout. The offspring born with knocked-out genes are mated for a few generations to create a pure strain. Once the geneticists perfected these procedures, mice almost instantly assumed the lead role in modeling human mental malfunctions.

These days, you won’t find more mentally ill mice per square mile anywhere than in Bar Harbor, Maine. Mice with anxiety, depression, autism, learning disabilities, anorexia or schizophrenia – they all congregate here. Name an affliction of the human mind, and you can probably find its avatar on this sprucy, secluded island built for America’s richest and most powerful families — including the Rockefellers, the Fords, the Vanderbilts, the Carnegies, the Astors and the Morgans.

The imbalanced mice are kept under the strictest security, in locked wards at the Jackson Laboratory, a nonprofit biomedical facility internationally renowned for its specially bred deranged rodents.

There are no visiting hours, because strangers fluster the mice and might carry in contagious diseases. The animals are attended only by highly qualified caregivers.

But, accurately reproducing a human mental illness in the tiny brain of a mouse is still hugely challenging. The basic structure of a mouse brain is mostly analogous to a human brain.  They have a hippocampus, we have a hippocampus; they have a prefrontal cortex, we have a prefrontal cortex, albeit one that is much larger. We even share about 99% of their genes. But no one would mistake you for a mouse. The mouse is a nocturnal animal with poor eyesight, adapted to fear predators that strike from above. Mice are fundamentally alarmed by light, open spaces, and sudden movements. It is no surprise then, that they manifest depression and anxiety differently than humans do, if they manifest such ailments at all.

You cannot mimic an entire human psyche in a mouse or a rat,” says 
Jacqueline Crawley, a behavioral neuroscientist at the National Institutes of Health (NIH) “Mice aren’t a one-to-one correspondence to humans. But they are better than zero.”

Disorders like depression and schizophrenia are each linked to hundreds of genes. No one gene is likely to make much difference. But genes are only one part of the story. Other clues to human mental health can be found in the neural circuits of mouse brains. By tracing the wiring that connects one brain region to the next, researchers hope to develop more precisely targeted medications.

Many vintage psychiatric drugs, such as Valium, Ritalin, and antipsychotics, were stumbled upon rather than tailor-made to solve a problem. As a result, they are too broad.  They affect more than one type of receptor, on more than one kind of nerve cell, in more than one part of the brain. Many patients decide the cure is not worth the many side effects.

Mice may be the best models we have of psychiatric disorders, but best does not mean great, or even decent. Gerald Dawson, founder and chief scientific officer of P1Vital, a pharmaceutical consulting firm in the United Kingdom, had his heart broken by the mouse mismatch. In the late 1990s, Dawson set out to eliminate the drowsiness from anxiety drugs.The class of drugs he wanted 
to modify, benzodiazepines such as Valium, Xanax, Ativan, and Klonopin, target the GABAa system.

As with most neurotransmitters, the GABAa system is so evolutionarily ancient that it has diversified to serve many purposes. Hence, the brain has six different GABAa receptor types, presumably to perform six different jobs. Dawson had a suspicion that the sleepiness side effect originated from just one of those six receptors. If he could determine which one, corporate chemists could design a molecule that would avoid activating it. He began to make mice.

One by one, he manipulated the receptor genes, breeding a new line of mice each time. With each new strain, he would administer a tiny dose of Valium. If the animals grew drowsy, he knew he had not yet knocked out the right receptor. Knocking out receptor 1 made little difference. Receptor 3 proved too hard to knock out. Receptor 5 seemed to account for the amnesia that people (and mice) experience when they take anxiety drugs. Targeting receptor 2, Dawson identified a chemical that reduced a mouse’s startle response—a measure of anxiety—without impairing its ability to balance. Success!

Or, so he thought. “When these compounds went into humans, they turned out to be just as sedating as the original drugs.”

Dawson blames the mice. “There’s not enough predictability in animal research.”

But, for all Dawson’s frustration with mice, the rodents did yield a couple of interesting drug leads.

That receptor 5 implicated in the amnesia side effect?  An experimental chemical that blocked its action created temporary geniuses: Mice on it were whizzes in the Morris water maze. A drug company is testing the compound to treat people with Down syndrome. And in the process of trying to eliminate drowsiness, Dawson and his team homed in on one of the chemical switches that cause mammals to go to sleep. Ambien locks onto that switch associated with receptor 1.

So, despite the problems, mice remain the undisputed top animal for research on mental health therapies.

Which just goes to show that mice, like us, have minds of their own.