Experimental Drugs Reverse Arthritis in Rats Study

The science shows potential results in treating a debilitating condition.

People with osteoarthritis, or “wear and tear” arthritis, have limited treatment options: pain relievers or joint replacement surgery. Now, Salk researchers have discovered that a powerful combination of two experimental drugs reverses the cellular and molecular signs of osteoarthritis in rats as well as in isolated human cartilage cells. Their results were published in the journal Protein & Cell on January 16, 2020.

“What’s really exciting is that this is potentially a therapy that can be translated to the clinic quite easily,” says Juan Carlos Izpisua Belmonte, lead author and a professor in Salk’s Gene Expression Laboratory. “We are excited to continue refining this promising combination therapy for human use.”

Affecting 30 million adults, osteoarthritis is the most common joint disorder in the United States and its prevalence is expected to rise in coming years due to the aging population and increasing rate of obesity. The disease is caused by gradual changes to cartilage that cushions bones and joints. During aging and repetitive stress, molecules and genes in the cells of this articular cartilage change, eventually leading to the breakdown of the cartilage and the overgrowth of underlying bone, causing chronic pain and stiffness.

Previous research had pinpointed two molecules, alpha-KLOTHO and TGF beta receptor 2 (TGFβR2), as potential drugs to treat osteoarthritis. αKLOTHO acts on the mesh of molecules surrounding articular cartilage cells, keeping this extra-cellular matrix from degrading. TGFβR2 acts more directly on cartilage cells, stimulating their proliferation and preventing their breakdown.

While each drug alone had only moderately curbed osteoarthritis in animal models of the disease, Izpisua Belmonte and his colleagues wondered if the two drugs would act more effectively in concert.

“We thought that by mixing these two molecules that work in different ways, maybe we could make something better,” says Paloma Martinez-Redondo, a Salk postdoctoral fellow and co-first author of the new study.

The researchers treated young, otherwise healthy rats with osteoarthritis with viral particles containing the DNA instructions for making αKLOTHO and TGFβR2.

Six weeks after the treatment, rats that had received control particles had more severe osteoarthritis in their knees, with the disease progressing from stage 2 to stage 4. However, rats that had received particles containing αKLOTHO and TGFβR2 DNA showed recovery of their cartilage: the cartilage was thicker, fewer cells were dying, and actively proliferating cells were present. These animals’ disease improved from stage 2 to stage 1, a mild form of osteoarthritis, and no negative side effects were observed.

“From the very first time we tested this drug combination on just a few animals, we saw a huge improvement,” says Isabel Guillen-Guillen, the paper’s co-first author. “We kept checking more animals and seeing the same encouraging results.”

Further experiments revealed 136 genes that were more active and 18 genes that were less active in the cartilage cells of treated rats compared to control rats. Among those were genes involved in inflammation and immune responses, suggesting some pathways by which the combination treatment works.

To test the applicability of the drug combination to humans, the team treated isolated human articular cartilage cells with αKLOTHO and TGFβR2. Levels of molecules involved in cell proliferation, extra-cellular matrix formation and cartilage cell identity all increased.

“That’s not the same as showing how these drugs affect the knee joint in humans, but we think it’s a good sign that this could potentially work for patients,” says Martinez-Redondo.

The research team plans to develop the treatment further, including investigating whether soluble molecules of the αKLOTHO and TGFβR2 proteins can be taken directly, rather than administered through viral particles. They also will study whether the combination of drugs can prevent the development of osteoarthritis before symptoms develop.

“We think that this could be a viable treatment for osteoarthritis in humans,” says Pedro Guillen, director of the Clinica CEMTRO and co-corresponding author.

America’s Economy Outside of Unemployment and GDP

It’s rather striking that median male wages in America are 3 percent lower today than they were 40 years ago. Where the hell is the societal progress with damning statistics like that? And other stats worth mentioning are that 75 percent of Americans live paycheck to paycheck while their country’s child poverty rate is well over 20 percent. It is rather appalling that people are saying that America’s economy is booming.

As the world’s business elites trek to Davos for their annual gathering, people should be asking a simple question: Have they overcome their infatuation with US President Donald Trump?

Two years ago, a few rare corporate leaders were concerned about climate change, or upset at Trump’s misogyny and bigotry. Most, however, were celebrating the president’s tax cuts for billionaires and corporations and looking forward to his efforts to deregulate the economy. That would allow businesses to pollute the air more, get more Americans hooked on opioids, entice more children to eat their diabetes-inducing foods, and engage in the sort of financial shenanigans that brought on the 2008 crisis.

Today, many corporate bosses are still talking about the continued GDP growth and record stock prices. But neither GDP nor the Dow is a good measure of economic performance. Neither tells us what’s happening to ordinary citizens’ living standards or anything about sustainability. In fact, US economic performance over the past four years is Exhibit A in the indictment against relying on these indicators.

To get a good reading on a country’s economic health, start by looking at the health of its citizens. If they are happy and prosperous, they will be healthy and live longer. Among developed countries, America sits at the bottom in this regard. US life expectancy, already relatively low, fell in each of the first two years of Trump’s presidency, and in 2017, midlife mortality reached its highest rate since World War II. This is not a surprise, because no president has worked harder to make sure that more Americans lack health insurance. Millions have lost their coverage, and the uninsured rate has risen, in just two years, from 10.9% to 13.7%.

One reason for declining life expectancy in America is what Anne Case and Nobel laureate economist Angus Deaton call deaths of despair, caused by alcohol, drug overdoses, and suicide. In 2017 (the most recent year for which good data are available), such deaths stood at almost four times their 1999 level.

The only time I have seen anything like these declines in health—outside of war or epidemics—was when I was chief economist of the World Bank and found out that mortality and morbidity data confirmed what our economic indicators suggested about the dismal state of the post-Soviet Russian economy.

Trump may be a good president for the top 1%—and especially for the top 0.1%—but he has not been good for everyone else. If fully implemented, the 2017 tax cut will result in tax increases for most households in the second, third, and fourth income quintiles.

Given tax cuts that disproportionately benefit the ultrarich and corporations, it should come as no surprise that there was no significant change in the median US household’s disposable incomebetween 2017 and 2018 (again, the most recent year with good data). The lion’s share of the increase in GDP is also going to those at the top. Real median weekly earnings are just 2.6% above their level when Trump took office. And these increases have not offset long periods of wage stagnation. For example, the median wage of a full-time male worker (and those with full-time jobs are the lucky ones) is still more than 3% below what it was 40 years ago. Nor has there been much progress on reducing racial disparities: in the third quarter of 2019, median weekly earnings for black men working full-time were less than three-quarters the level for white men.

[…]

And despite Trump’s vaunted promises to bring manufacturing jobs back to the US, the increase in manufacturing employment is still lower than it was under his predecessor, Barack Obama, once the post-2008 recovery set in, and is still markedly below its pre-crisis level. Even the unemployment rate, at a 50-year low, masks economic fragility. The employment rate for working-age males and females, while rising, has increased less than during the Obama recovery, and is still significantly below that of other developed countries. The pace of job creation is also markedly slower than it was under Obama.

Again, the low employment rate is not a surprise, not least because unhealthy people can’t work. Moreover, those on disability benefits, in prison—the US incarceration rate has increased more than sixfold since 1970, with some two million people currently behind bars – or so discouraged that they are not actively seeking jobs are not counted as “unemployed.” But, of course, they are not employed. Nor is it a surprise that a country that doesn’t provide affordable childcare or guarantee family leave would have lower female employment—adjusted for population, more than ten percentage points lower—than other developed countries.

Abortion Reversal — The Dangerous Practice You’ve Probably Never Heard Of

In the United States, many more laws have been implemented that restrict or ban a woman’s ability to have an abortion. Abortion reversal is a new technique that hasn’t undergone much medical testing since the one test on it showed significant harm to the women.

Several states now require women who seek medication abortions to be provided with dubious information that the procedure could be stopped, allowing a pregnancy to continue.

But when researchers attempted to carry out a legitimate study of whether these “abortion reversal” treatments were effective and safe, they had to stop almost immediately – because some of the women who participated in the study experienced dangerous hemorrhaging that sent them to the hospital.

By passing these abortion reversal laws, “states are encouraging women to participate in an unmonitored experiment,” Creinin said.

Creinin and his colleagues detailed their concerns in a commentary in the journal Contraception, and they will publish their study in January’s edition of Obstetrics and Gynecology.

Medication abortions, which are used up to 10 weeks into a pregnancy, consist of taking two pills in sequence. The first pill in the regimen, mifepristone, loosens the pregnancy’s attachment to the uterus. The second pill, misoprostol, forces the uterus to contract to push out the pregnancy. The pills must be taken consecutively to complete the abortion, and there’s a chance the pregnancy will continue if the second pill is not taken.

A total of 862,320 abortions were provided in clinical settings in 2017, according to the Guttmacher Institute, about 39 percent of which were medication abortions. Research has shown that using these drugs is a safe way to end a pregnancy.

Some antiabortion activists and legislators claim that not taking the second pill, or giving a woman high doses of the hormone progesterone after taking mifepristone, can help stop, or “reverse,” a medical abortion.

The American College of Obstetricians and Gynecologists firmly states that “claims regarding abortion ‘reversal’ treatment are not based on science and do not meet clinical standards” and say the purported studies that underpin these antiabortion arguments lack scientific rigor and ethics.

Despite this, the claims made in these discredited studies have worked their way to antiabortion lawmakers, who in turn have put them into abortion reversal legislation that was signed by governors in North Dakota, Idaho, Utah, South Dakota, Kentucky, NebraskaOklahoma and Arkansas. The laws are currently blocked or enjoined in Oklahoma and North Dakota.

Because reliable research on these treatments is nonexistent, earlier this year, Creinin and his colleagues designed a legitimate double-blind, placebo-controlled, randomized trial that aimed to observe 40 volunteers who had already elected to have a surgical abortion.

Their goal was to see if giving progesterone to women who took the first pill in the prescribed regimen would effectively and safely halt an abortion.

After the women took the first pill in the abortion protocol, mifepristone, rather than take the second pill, misoprostol, they were either given a placebo or a dose of progesterone.

Researchers only enrolled 12 women before they had to stop the study.

Bleeding is normal during a medication abortion. But three of the women who enrolled in the UC-Davis study experienced far more serious bleeding than anyone could have anticipated when the second pill was not administered.

One woman “was so scared she called an ambulance,” while another woman startled by the amount of blood “called 911 and crawled into her bathtub”, Creinin said. A third woman who went to the emergency room needed a transfusion. One of the women had received a placebo, while two others had taken the progesterone.

Creinin and his colleagues halted the study as soon as it became clear that they could not proceed safely.

“I feel really horrible that I couldn’t finish the study. I feel really horrible that the women … had to go through all this,” Creinin said. Because the study ended prematurely, the researchers could not establish any evidence that progesterone was an effective way to stop a medication abortion.

“What the results do show, though, is that there’s a very significant safety signal” when it comes to disrupting the approved medication abortion protocol, Creinin said.

In their upcoming paper in Obstetrics and Gynecology, the researchers warn that “patients in early pregnancy who use only mifepristone may be at high risk of significant hemorrhage.”

Medical experts are so concerned about abortion reversal laws that the American Medical Association joined a lawsuit against North Dakota’s abortion reversal law, which was blocked by a federal judge in September.

The North Dakota abortion reversal law, signed by Gov. Doug Burgum (R) in March, instructed health-care providers to tell a woman “that it may be possible to reverse the effects of an abortion-inducing drug if she changes her mind, but time is of the essence” and to provide a woman with literature on how to do this. The law fails to specify what that literature would include, or what such a treatment might entail.

Some Drug Company Executives Criminally Charged in America’s Flawed Democracy

A major producer of opioids known as the Rochester Drug Cooperative has recently witnessed its executives criminally charged with illegally distributing controlled substances. With the prosecution of corporate criminals at a 20 year low in America, amidst a major wave of corporate crime — crime in the suites instead of crime in the streets — it is a notable development during the despair-ridden opioid crisis.

Much of this opioid crisis is attributable to the patent monopolies on prescription drugs, which enable American pharmaceutical companies to charge ridiculously high prices. A patent monopoly on a drug legally prevents competitors from producing or selling that drug, and the lack of governmental negotiation to rein in prices allows pharmaceutical companies to charge to a large extent whatever they want. Purdue Pharma would have had nowhere near as much incentive to market Oxycontin if it was sold at generic prices, but since they had a tremendous incentive, many communities have suffered as a result of the addictive drug.

The case of patent monopolies on prescription drugs such as Oxycontin is another example of the government using its power in a way that’s overall against the public interest. The government is not necessarily an evil or inefficient entity, as people sometimes believe or that propaganda might suggest. There is plenty of evidence that structured properly, the government can be a force for the common good — government-run programs such as Medicare and Social Security remain popular because they work well. The administrative overhead on Medicare is about 2 percent, while the administrative overhead on corporate health insurance is often 12 to 20 percent.

It is beneficial for much of the corporate sector if the public automatically despises the government and doesn’t pressure for public interest control of it. Unlike the corporate sector, where the boards of directors (those who run the corporations) are largely determined by top management, in a undemocratic process where one share of the corporation equates to one vote in the board of directors election, there is a built-in democratic process in the government. This built-in process of one person (rather than one share) and one vote may currently be quite dysfunctional, but it is a mechanism of democratic values nonetheless, and one of the things to be strengthened for an improved society.

About every year at least, the Bulletin of Atomic Scientists meets to discuss the most significant threats to human societies, and if necessary they adjust their famous Doomsday Clock. The Doomsday Clock measures the probability of major catastrophe by the minute hand’s closeness to midnight, and it is now 2 minutes to midnight, the closest it has ever been since 1953, when America and Russia detonated thermonuclear weapons. In 2019, the Bulletin of Atomic Scientists added a third major problem to climate change and the potential of nuclear war — the breakdown of and threats to democracy. This is significant because lively and functioning democracy offers perhaps the only way to solve many of the world’s most serious problems.

Activism that is deservedly popular (and therefore democracy-based, or majority supported) is very often how things change for the better, from worker’s rights to new government programs and movements producing a beneficial change in public consciousness. Instead of only examining problems, it’s necessary to remember that to achieve progress.

Using Chronoprinting to Cheaply Detect Food and Drug Impurities

The world has long needed this valuable sort of development to safeguard people’s health.

If we could tell authentic from counterfeit or adulterated drugs and foods just by looking at them, we could save money and lives every year, especially in the developing world, where the problem is worst. Unfortunately, the technologies that can detect what a sample is made of are expensive, energy-intensive, and largely unavailable in regions where they are needed most.

This may change with a simple new technique developed by engineers from the University of California, Riverside that can detect fake drugs from a video taken as the sample undergoes a disturbance.

If you’ve ever used online photo tools, you’ve probably seen how these tools use image analysis algorithms to categorize your photos. By distinguishing the different people in your photos, these algorithms make it easy to find all the photos of your daughter or your dad. Now, in the journal ACS Central Science, researchers report they have used these algorithms to solve a very different problem: identifying fake medicines and other potentially dangerous products.

Called “chronoprinting,” the technology requires only a few relatively inexpensive pieces of equipment and free software to accurately distinguish pure from inferior food and medicines.

The World Health Organization says that about 10 percent of all medicines in low- and middle-income countries are counterfeit, and food fraud is a global problem that costs consumers and industry billions of dollars per year. Fraudulent food and drugs waste money and jeopardize the health and lives of their consumers. But detecting fakes and frauds requires expensive equipment and highly trained experts.

William Grover, an assistant professor of bioengineering in UC Riverside’s Marlan and Rosemary Bourns College of Engineering, and Brittney McKenzie, a doctoral student in Grover’s lab, wondered if it would be possible to distinguish authentic from adulterated drugs and food by observing how they behave when disturbed by temperature changes or other causes. Two substances with identical compositions should respond the same way to a disturbance, and if two substances appear identical but respond differently, their composition must be different, they reasoned.

McKenzie designed a set of experiments to test this idea. She loaded samples of pure olive oil, one of the world’s most commonly adulterated foods, and cough syrup, which is often diluted or counterfeited in the developing world, into tiny channels on a microfluidic chip, and chilled it quickly in liquid nitrogen. A USB microscope camera filmed the samples reacting to the temperature change.

McKenzie and Grover wrote software that converts the video to a bitmap image. Because the image showed how the sample changed over time, the researchers called it a “chronoprint.”

The team then used image analysis algorithms to compare different chronoprints from the same substance. They found that each pure substance had a reliable chronoprint over multiple tests.

Next, they repeated the experiment with samples of olive oil that had been diluted with other oils and cough syrup diluted with water. The adulterated samples produced chronoprints that were different from the pure samples. The difference was so big, so obvious, and so consistent the researchers concluded that chronoprints and image analysis algorithms can reliably detect some types of food and drug fraud.

“The significant visual differences between the samples were both unexpected and exciting, and with them being consistent we knew this could be a useful way to identify a wide range of samples,” McKenzie said.

Grover said their technique creates a powerful new connection between chemistry and computer science.

“By basically converting a chemical sample to an image, we can take advantage of all the different image analysis algorithms that computer scientists have developed,” he said. “And as those algorithms get better, our ability to chemically identify a sample should get better, too.”

The researchers used liquids in their experiments but note the method could also be used on solid materials dissolved in water, and other types of disturbance, such as heat or a centrifuge, could be used for substances that don’t react well to freezing. The technique is easy to learn, making highly trained experts unnecessary. Chronoprinting requires hobbyist-grade equipment and software downloadable for free from Grover’s lab website, putting it well within reach of government agencies and labs with limited resources.

Video on how this chronoprinting works: https://youtu.be/qbyE68qD2Zo

Drug Price Gouging in Generics

General info on prescription drugs and generic drug price gouging.

Martin Shkreli managed to make himself a household name a few years back. His claim to fame stemmed from the decision by Turing Pharmaceuticals, a company he founded and controlled, to acquire the rights to produce Daraprim. He then raised the price of the drug by 5,000 percent.

This was very bad news for the people who were dependent on the drug. Daraprim is an anti-parasitic drug that is often taken by people with AIDS to keep them from getting opportunistic infections. People with AIDS who are being successfully treated with Daraprim are not going to want to experiment with alternatives.

Daraprim was already a 60-year-old drug at the time Turing acquired it and had long been available as a generic. This meant that other manufacturers could in principle come into the market and compete with Turing’s inflated price.

Shkreli made the bet that no other drug company would take advantage of this opportunity, because even for a generic drug, there are still substantial costs for entry. Since the market for Daraprim was small, a new entrant would be unlikely to recover these costs if Turing pushed the price back down somewhere near its original level. While Daraprim was his biggest “success,” Shkreli was trying this strategy with a number of other drugs before the Justice Department put him out of business with unrelated charges of securities fraud.

Shkreli’s days of price gouging in the generic drug world may be over, but he established a model that other ambitious entrepreneurs are likely to follow. Close to 40 percent of generic drugs have only a single manufacturer. This is partly a result of the failure of anti-trust policy to stem a wave of mergers in the industry. It is also a result of the fact that many drugs simply have very limited markets where it is difficult to support multiple producers.

Most generic producers have not tried to follow the Shkreli model and jack up prices of drugs that people need for their health or even their lives, but some have. The soaring price of insulin is one important example, EpiPen, the asthma injector, is another. Both involve well-known treatments that have long been used, but the limited number of suppliers has allowed for huge price increases in recent years.

This is the context for the public drug-manufacturing corporation being proposed in a bill by Senator Elizabeth Warren and Representative Jan Schakowsky. The idea is that the federal government should create manufacturing capacity (which could be privately licensed) that would allow it to quickly enter a market to compete with the next Martin Shkreli.

If a company tries to jack up its prices by an extraordinary amount, it would find itself soon competing with a government manufacturer that is selling the same drug for the cost of production, plus a normal profit. This is a great strategy, since simply the existence of this capacity should be sufficient to discourage the next Shkreli.

There will be little money in jacking up the price of a drug by 5,000 percent if it quickly results in the disappearance of their market. This should encourage the generic industry to keep its prices in line.

It is important to note a key difference between the generic industry and brand industry. The brand pharmaceutical companies, like Pfizer and Merck, could argue that they need high prices to pay for research. These companies hugely exaggerate their research costs and downplay the extent to which high profits just mean more money for shareholders, but they actually do research.

By contrast, the generic industry is not researching new drugs. They are manufacturing drugs that have been developed by others. In this sense they can be thought of like a company that manufacturers paper plates or shovels. They need a normal profit to stay in business, nothing more.

For this reason, the Warren-Schakowsky proposal is very much the right type of remedy for excessive prices in the generic drug industry. At the same time, we have to recognize that generic drugs are the smaller part of the problem with high drug prices.

Although generics account for almost 90 percent of prescriptions, they account for only a bit more than a quarter of spending on prescription drugs. The story of drugs costing tens or hundreds of thousands of dollars a year is almost entirely a story of brand drugs with high prices as a result of patent monopolies or related protections.

This will require a larger fix, likely along the same lines, with the government paying for research and allowing new drugs to be sold as generics. But the Warren-Schakowsky bill is a huge first step in bringing drug costs down and ensuring that people will not find themselves suddenly at the mercy of the next Martin Shkreli.

Hundreds of Supplements Tainted With Hidden Drugs

This is why people should use caution when taking supplements, and it also shows the risk of inadequate corporate oversight. Unlike pharmaceutical drugs, the American supplement industry is barely regulated at all.

The labels promise miracles: Fast Weight Loss! Eliminates Hunger! Burns Calories!

Now new research highlights how hundreds of brands of dietary supplements deliver so much kick from a modest blend of vitamins and herbs. The answer is many labels leave out one important ingredient: a hidden payload of pharmaceutical drugs and experimental chemicals.

A new analysis of 10 years of FDA records reveals that from 2007 to 2016, almost 750 dietary supplements were found to be contaminated with secret doses of totally unregulated drugs, including prescription medicines, banned and unapproved chemicals, and designer steroids.

Over 20 percent of these offending products contained more than one unapproved drug ingredient, and numerous contained a cocktail of clandestine chemicals – in two cases, as many as six unlisted ingredients.

For a US$35 billion industry patronised by about half of American adults, it’s possible this data could be just the tip of the iceberg, too.

“The drug ingredients in these dietary supplements have the potential to cause serious adverse health effects owing to accidental misuse, overuse, or interaction with other medications, underlying health conditions, or other pharmaceuticals within the supplement,” researchers from the California Department of Food and Agriculture, Sacramento, explain in their paper.

Given that supplement use is associated with some 23, 000 ER visits and 2,000 hospitalisations in the US each year, it’s clear we’re looking at a big problem here, but what’s even more shocking than the brazen selling of these illicit additives is how tame and toothless the FDA’s official actions were.

Of 746 products identified as adulterated by the FDA, just 360 (48 percent) were subsequently recalled, leaving more than half of the contaminated supplements available for sale.

“The agency’s failure to aggressively use all available tools to remove pharmaceutically adulterated supplements from commerce leaves consumers’ health at risk,” writes general internist Pieter Cohen from Harvard Medical School in a commentary on the new research.

Many of the tainted supplements analysed in the study contained sildenafil (the active ingredient of Viagra) to boost their powers of sexual enhancement. Another erectile dysfunction drug, tadalafil, was also common.

Other chemicals included hidden antidepressants, a withdrawn weight loss drug called sibutramine, and undeclared anabolic steroids or steroid-like substances.

It’s been argued however that since almost 75 percent of the offending supplements were sold online or through international mail order, they don’t represent the ‘mainstream’ of the supplements industry.

“These come from dark corners of the internet,” president of the Natural Products Association, Daniel Fabricant, told the San Francisco Chronicle.

“They’re not what you get at your health food store.”

Still, given that none of these products are actually subjected to the same stringent tests reserved for pharmaceutical drugs, it’s possible any supplement could contain anything – which is why Cohen advises choosing products that only contain a single ingredient and avoiding products that purport to offer spurious, medical-sounding benefits.

Why? Because as this research shows, many supplements turn out to be medicine after all – only it’s an unknown drug, potentially a banned one, and there’s no way of measuring your dose.

“If the company is saying it works like Viagra or you’re going to gain muscle like you’re on steroids – that’s not a supplement. That’s a drug,” Fabricant says.

“Dietary supplements are meant to maintain health, not to take 30 minutes before sex.”

The findings are reported in JAMA Network Open.