FDA Reports Critical Drug Shortages

Delays put EMTs on alert for dextrose, naloxone, epinephrine.

It’s the kind of thing most people take for granted: You’re suddenly taken seriously ill—a heart attack, dehydration, asthma, shock, perhaps even a heroin overdose—and in the ambulance or the emergency room, medical professionals immediately go to work, using the right drugs and medications for the job.

Imagine lying in the back of an ambulance, in cardiac arrest, or experiencing an episode of acute schizophrenia, or turning blue from a heroin OD—and the EMTs and nurses and other medical staff have only a precariously minimal supply of what you need. You might expect such a thing in wartime, or in parts of the developing world.  But drug shortages already plague health care, and may worsen as drug suppliers run the risk of cutting back production too aggressively on vital drugs used in emergency medical procedures.

At present, according to the Food and Drug Administration (FDA), shortages exist for the following drugs, among others:

Injectable Dextrose 50%: unanticipated increased demand. Full recovery by mid-September. Used in IV solutions.

Injectable ephedrine: manufacturing delays, increased demand. Full recovery by late August. Used as a brochodilator.

Injectable epinephrine: Unanticipated increased demand. Recovery by late September. Used in the treatment of cardiac arrest, shock and anaphylaxis.

Injectable haloperidol decanoate: On back order from major suppliers, estimated recovery by November.  Used for schizophrenia.

Injectable naloxone: manufacturing delays. Recovery by mid-September. Used for heroin overdose.

Writing for the New England Journal of Medicine online, Valerie Jensen and Bob A. Rappaport demonstrate that shortages of certain drugs in sterile injectable form have been increasing. Data from the Drug Shortage Program at the FDA show that, while 35% of the drugs experiencing supply shortages in 2008 were sterile injectables, that number rose to 46% in 2009.  “Reduction in the supply of these drugs can have dramatic effects on medical practice,” they write, “ultimately keeping patients from receiving the level of care they deserve and have come to expect.”

How do these shortages happen? For perspective, the authors lay out the case history of the injectable drug propofol, a fast-acting sedative commonly used to induce and maintain sedation or anesthesia. In 2009, three pharmaceutical manufacturers serviced the market for propofol—Hospira, Teva, and APP. In October of 2009, Hospira recalled “multiple batches of its propofol owing to the presence of particulate matter in the vials.” A few weeks later, Teva issued a recall on several lots of propofol due to “possible microbial contamination.” In June of 2010, Hospira had still not returned to the market, and Teva had chosen to exit the market for good. That left a single company as sole supplier of propofol for the entire U.S.—“an unrealistic expectation, given anesthesiologists’ reliance on the drug.”

Drug shortages can occur in other ways. Producers often abandon older drugs for newer, higher margin offerings. Free market policies can and do lead to supply shortages, particularly in the case of complex injectable products with long manufacturing lead times. Such drugs are most efficiently manufactured in amounts that leave little excess supply in inventory channels. As a result, “a sudden change in either the supply of or the demand for the drug can have catastrophic clinical consequences,” the authors write.

The FDA, say the authors, “cannot require a company to start or to continue manufacturing a drug or dictate how much of a drug must be manufactured…” The free market paradox is always part of medicine: competition drives down the price of drugs, making them more affordable and accessible to patients. But if prices go too low, manufacturers may choose to stop producing a given drug, thereby limiting competition and making the drug vulnerable to supply shortages.

However, the FDA does have the authority to temporarily allow the importation of drugs certified to be of similar formulation and quality, if there is a serious shortage. In the case of propofol, the FDA allowed the importation of a similar but unapproved drug, Fresenius Propoven 1%, which is used in other countries.

Shortages of sterile injectable drugs like propofol create special hazards. For example, they are commonly used in ambulances and emergency rooms for treating shock and heart attack. We are not talking about a shortage of cotton swabs here. In addition, the FDA warns of numerous adverse effects resulting from “multiple entries into single-use vials of the drug,” a common method of dealing with shortages. The authors cite a case in a Nevada endoscopy clinic, where the practice of obtaining multiple doses from a single-dose vial “led to an outbreak of hepatitis C infection, and approximately 40,000 patients were advised to be tested for potential infection of hepatitis B, hepatitis C, and HIV.”

Jensen, V., & Rappaport, B. (2010). The Reality of Drug Shortages -- The Case of the Injectable Agent Propofol New England Journal of Medicine DOI: 10.1056/NEJMp1005849

Photo Credit: http://www.thaimedicalnews

Chasing the Genes for Cocaine Addiction

Brain protein MeCP2 in the spotlight.

Dr. Edward Sellers, former director of the psychopharmacological research program at the University of Toronto’s Addiction Research Foundation once said to me: “Every cell, every hormone, every membrane in the body has got genetic underpinnings, and while many of the genetic underpinnings are similar in people, in fact there are also huge differences. So on one level, the fact that there is a genetic component to addiction is not very surprising. What is surprising is that you could ever have it show up in a dominant enough way to be something that might be useful in anticipating risk.”

If there existed a set of genes that predisposed people to alcoholism, and possibly other addictions, then these genes had to control the expression of something specific. That’s what genes did.  However, back in the 1990s, addiction researchers could not even agree on the matter of where they should be looking for such physical evidence of genetic difference. In the brain? Among the digestive enzymes? Blood platelets? A gene, or a set of genes, coding for…what? What was it they were supposed to be looking for?

What set of genes coded for addiction?

Something about modern genetic research breeds a strong jolt of excitement. There is the promise of sudden discoveries, headlines, and great leaps forward toward cures for stubborn diseases. Even the most sober scientists seem to get enthused about gene hunting. The idea of curing a disease by locating a defective gene and repairing it is one of the brightest and fondest hopes in medicine. At least 3,000 medical disorders, including diabetes, cystic fibrosis, and some forms of Alzheimer’s are inherited diseases caused by defective genes passed on from generation to generation. But the premature announcements and retractions involving genes for everything from drinking to shyness has brought a hard-won maturity to the field.

These days, the hunt for evidence of genes influencing addiction is drilling very deeply into the molecular underpinnings of neural activity, in a wide-ranging effort to sort out the variety ofgene interactions involved in the genetic propensity for alcoholism and other addictions. 

Work done at the Scripps Research Institute in Florida, funded by the National Institute on Drug Abuse (NIDA) and published in Nature Neuroscience, recently shone a spotlight on a gene responsible for making a particular protein—MeCP2—needed for normal development of nerve cells in the brain. This gene for methyl CpG binding protein 2 is best known as the gene responsible for a rare genetic brain disorder called Rett syndrome.  

Researchers at Scripps discovered that cocaine increased levels of this regulatory protein in the brains of rats. So did fluoxetine , better known as Prozac, suggesting that the serotonergic system may be involved. “At that point,” according to lead author Paul Kenny, “we wanted to know if this increase was behaviorally significant—did it influence the motivation to take the drug?” Evidently it did. The higher the levels of MeCP2 in the brain, the higher the rats’ motivation to consume cocaine. When the researchers disrupted the expression of MeCP2 with a virus, the rats showed less interest in cocaine.

This is the first evidence that MeCP2 plays some as yet unexplained role in regulating vulnerability to cocaine addiction. Earlier this summer, investigators reported in Nature that another regulatory molecule known as MiRNA-212—a type of RNA involved in gene regulation--had the opposite effect, lessening the test animals’ interest in cocaine. The balancing act between MeCP2 and MiRNA-212 may help explain “the molecular mechanisms that control the transition from controlled to compulsive cocaine intake,” according to the paper, although the mechanisms that regulate this balance are not known.

One strong piece of evidence for this regulatory feedback loop was the finding that, while MeCP2 blocked miR-212 expression, the opposite was also true. “We still don’t know what exactly influences the activity levels of MeCP2 on miR-212 expression,” according to Kenny. “Now we plan to explore what drives it—whether it’s environmentally driven, and if genetic and epigenetic influences are important.” (For more on MeCP2, check this Lab Spaces post.)

NIDA director Nora Volkow said in an NIH press release that the work on MeCP2 “exposed an important effect of cocaine at the molecular level that could prove key to understanding compulsive drug taking.”

Graphics Credit: http://www.labspaces.net/

Im, H., Hollander, J., Bali, P., & Kenny, P. (2010). MeCP2 controls BDNF expression and cocaine intake through homeostatic interactions with microRNA-212 Nature Neuroscience DOI: 10.1038/nn.2615

What is Methadone?

How agonists ease agony for heroin addicts.

It isn’t the best, the worst, or the only treatment for heroin addiction. But for many heroin addicts, it has been a way out of the circle of euphoria and dispair.

In contrast to antagonist drugs, the agonist theory is based on drugs that bind to specific sites and which mimic some of the addictive drug’s typical range of effects. For obvious reasons, this greatly reduces craving. But is it simply a replay of the historical tactic of substituting one addictive drug for another?

The most successful use of the agonist theory remains heroin’s most controversial and stigmatized treatment—methadone therapy. Back in the 1960s, researchers at Rockefeller Hospital and The Rockefeller Institute, led by Professor Vincent Dole of Rockefeller University, began a series of studies that led to the development of methadone treatment. They did it on the strength of their belief in the unfolding biological model. “Heroin addiction is a disease of the brain, with diverse physical and behavioral ramifications, and not simply due to criminal behavior, a personality disorder, or ‘weak will,’” wrote Dr. Kreek, one of the principle methadone researchers at Rockefeller.

Methadone was approved by the FDA in 1973 for medical use against heroin addiction. It is a slow-acting opiate receptor agonist, meaning that it has some of the properties of heroin and morphine. However, the buzz it provides is no real substitute for heroin or morphine, from an addict’s point of view. It was nobody’s idea of a sweet drug holiday. But why give agonist drugs to addicts at all? Isn’t that just like giving them watered-down heroin? Writing in the September 2002 issue of Nature Reviews Drug Discovery, Dr. Kreek summed up what doctors face when dealing with long-term addiction:

"Repeated ‘on-off’ exposure to a drug of abuse progressively leads to stable molecular and cellular changes in neurons, which alter the activity of neural networks that contain these neurons. This eventually results in complex physiological changes and related behaviors that characterize addiction, such as tolerance, sensitization, dependence, withdrawal, craving and stress-induced relapse. These drug-induced changes are, in part, counteradaptive, and they contribute to dysphoria and dysfunction, which promotes continued drug use through negative-reinforcement mechanisms."

Daily methadone doses of 80mg or more exert a definite blocking effect on heroin craving. And patients who use it do not suffer the same lassitude and intensity of cognitive distortions as the heroin addict. Methadone’s other strength is that it doesn’t mix well with heroin or alcohol. 

More recently, Kreek and her colleagues, in collaboration with the NIH, used PET scans to watch opioid-receptor binding occur in the living brains of methadone-maintained patients. The brain scans confirmed that methadone leaves a significant number of opioid receptors unoccupied, allowing those regions of the brain to carry out normal physiological roles.

“In methadone-maintained patients there is modest occupancy of the receptors but still a lot of available receptors for normal cognition, normal reproductive function and normal stress responsivity,” Kreek reported.

Another underreported advantage of methadone is its oral administration, thus eliminating the need for hypodermics and reducing the risk of AIDS and hepatitis from contaminated needles. Provided the dosage is right, patients can be maintained for years on methadone. One reason methadone therapy fails, say researchers, is because of inadequate dosages—but higher dosages are much harder to withdraw from.

Photo Credit: http://www.wilkeseastna.org/ 

Rehab as Punishment

Why Cambodians, Chinese, and Vietnamese shun treatment—if they can.

The term “drug rehab” usually means one of two things to Americans: Either a genuine, if not always effective, clinic for drug withdrawal, counseling, and follow-up; or else a touchy-feely form of group therapy and 12-step religiosity. What we don’t expect drug rehab to mean is beatings, forced labor, detention without appropriate treatment, or electric batons.

Start with China. A New York Times report by Andrew Jacobs documented the fate of as many as 500,000 Chinese citizens held at government-run drug rehabilitation centers. “Detentions are meted out by the police without trials, judges or appeals,” Jacobs wrote. “Created in 2008 as part of a reform effort to grapple with the country’s growing narcotics problem, the centers, lawyers and drug experts say, have become de facto penal colonies where inmates are sent to factories and farms, fed substandard food and denied basic medical care.”

It has been a long-standing tradition in China and Russia to send addicts to labor camps, along with political dissidents. Change has been promised in China, but thus far there is no evidence of the new community-based rehabilitation the government has proposed. “In China,” said one addict, “to be a drug addict is to be an enemy of the government.”

In Cambodia, according to a report in The Nation by Joseph Amon, the director of health and human rights for Human Rights Watch, police have rounded up men, women, and children in “street sweeps” and placed them in detention facilities without legal consultation. As in China, writes Amon, treatment in Cambodian rehab facilities “consists of military drills, hard labor and forced exercise. Detainees are forced to work and exercise to the point of collapse, even when they are sick and malnourished. These centers offer no medically appropriate treatment such as cognitive behavioral therapy, psycho-social support (counseling, for example) or opiate substitution therapy. As one former detainee explained, his centre was ‘not a rehab centre but a torture centre.’”

The government of Cambodia routinely denies the charges. As Amon argues, “Individuals who use drugs do not forfeit their human rights, and the Cambodian government should not create detention centers that are exempt from the protections afforded to all. “

In Vietnam, 600 addicts broke out of a state-run rehabilitation center in Haiphong and made a run for it. According to Foreign Policy magazine, they were fleeing a similar collection of “treatment” options such as beatings and years of illegal detention in the government’s 100 drug facilities. Along with Malaysia and Thailand, and Laos, Vietnam has opted for “get-tough” policies over evidence-based treatment. Even worse, the policies themselves resemble the practices inflicted on southern chain gangs in early 20th Century American prison farms.

The irony of the great Vietnamese rehab escape is that the patients may have much better luck on the outside. Amon of Human Rights Watch reports that Haiphong “is one of three [cities] in Vietnam that is piloting the use of methadone to manage opiate addiction, the preferred approach in most developed countries.”

Photo Credit: http://www.hrw.org/

Mixing up the Medicine: What Alcohol Doesn’t Go With

Drug/Drink interactions are no joke. 

--Mixing alcohol with certain antibiotics, like Furozone and Flagyl, can lead to headache, nausea, vomiting, and even convulsions.

--Chronic alcohol consumption increases the risk of liver damage from surgical anesthetics like Ethrane and Fluothane.

--Alcohol decreases the effectiveness of Inderal, a common medication used to control blood pressure.

--Continued high levels of alcohol activate the enzymes that metabolize Tylenol and other forms of acetaminophen into compounds that can impair the functions of the liver.  In older persons, the combination markedly increases the risk of gastric bleeding.

Get your exercise, eat your vegetables—and don’t mix alcohol with a list of common medications about as long as your arm. Unfortunate but true. But let’s face it—people cut corners on this matter all the time. People like to drink.  With 70 percent of the adult population consuming alcohol at least occasionally, and more than 10 percent consuming it on a daily basis, the 14 billion prescriptions doctors write annually, accounting for more than 2,800 prescription drugs (plus another 2,000 over-the-counter medications) means that the “concurrent use” of booze and pills is inevitable (figures from NIAAA).

But it’s my job to be the wet blanket, and soldier on, and present my readers with a list of common drugs, which, if any of my readers are taking them regularly, means they should not be getting their drink on.

What is actually going on when alcohol and prescription drugs interact? The amount of drug that reaches its site of action is known as its availability. Alcohol can have a direct effect on a drug’s availability and hence its effectiveness. Alcohol in acute doses—a drink now and then, or a few drinks over several hours—can increase a drug’s availability by competing for the same set of enzymes of metabolization. This increases the chances of harmful side effects. Alcohol in chronic doses—long-term heavy drinking—can have the opposite effect, decreasing a drug’s availability and effectiveness by activating metabolizing enzymes, even in the absence of alcohol.

I have edited the list to eliminate low-risk, trivial, or commonly understood interactions. Most people, for example, know that drinking seriously on top of prescription sedatives, opiates and other painkillers, or anti-anxiety medications like Xanax and Valium, is universally understood to be a risky venture. That particular combination is how lots of people stop breathing, permanently.

Having glossed those categories, we move on to a blizzard of other restrictions for daily drinkers, some very serious, some less so. They have been culled from the University of Rochester’s excellent University Health Service site,  and from publications available at the website for the National Institute on Alcohol Abuse and Alcoholism (NIAAA). An extensive list of references can be found at NIAAA’s Alcohol Alert.

--Other antibiotics  that may be responsible for adverse effects, according to the NIAAA, includes Acrodantin, Flagyl, Grisactin, Nizoral, Nydrazid, Seromycin, and Tindamax (all trade names).

--Cardiovascular medication that can cause possible problems if combined regularly with alcohol include Coumadin and Nitroglycerin which may become less effective, while blood pressure meds like Catapres, Lopressor, Accupril, and several others may lead to dizziness and fainting.  The NIAAA also notes potential reductions in the therapeutic effects of reserpine, methyldopa, hydralizine, and guanethidine.

--Allergies/cold medications react with alcohol in the usual way—increased drowsiness, and possible dizziness, particularly in the elderly. Drugs containing diphenhydramine, like Benadryl, or chlorpheniramine, like Tylenol Cold and Flu, can prove substantially more sedating with alcohol.

--The anti-ulcer medications Tagamet and Zantac “increase the availability of a low dose of alcohol under some circumstances.”

--Thorazine, a common antipsychotic, can lead to “fatal breathing difficulties” when combined with alcohol, according to the NIAAA.

--The anti-seizure drug Dilantin may not control epileptic seizures as effectively in chronic drinkers.

There are others, too many to list here. But if you are a chronic drinker—and you know who you are—don’t be so quick to dismiss the variously-worded DO NOT MIX WITH ALCOHOL warnings if you find them on your pill bottles.

Photo Credit:  http://www.doitnow.org/

Swipe, Smile, Breathe: Wine Vending Machines in the USA.

Move by Pennsylvania supermarkets sparks controversy.

Pennsylvania, one of the last few states in the nation where liquor sales are state-controlled, has kicked off a plan to sell wine in grocery stores via vending machines. Consumers would need a valid I.D., a matching picture taken by an onsite video camera, and a puff of breath in the direction of a no-touch air sensor to complete the purchase.

Whether you consider this a convenient or a cumbersome way to buy your bottle of Chianti for the evening’s meal, many Pennsylvanians seem supportive, according to news reports, if only because it saves them a trip to a state-run liquor outlet. Grocery stores cannot sell wine off the shelf under the rules of the Pennsylvania Liquor Control Board (PLCB).

Japan and Europe have beer vending machines, but the two prototype machines now in Pennsylvania are believed to be the first supermarket wine kiosks in the U.S.

A spokesman for the ISSU, the union representing state liquor store managers, complained that “cigarettes are banned from being sold in vending machines in Pennsylvania supermarkets and yet Americans’ number one drug of choice will now be vended only in Pennsylvania by the PLCB.”

Putting it a bit more directly, the union’s vice president, David Wanamaker, said: “Alcohol is not a Red Box DVD—it is the most abused drug in every town, city and state in the USA.”

Keith Wallace, president of the Wine School of Philadelphia, had other objections. “The process is cumbersome and assumes the worst in Pennsylvania’s wine consumers—that we are a bunch of conniving underage drunks,” he told Kathy Matheson of The Associated Press.  Liquor board members, he added, “are clearly detached from reality of they think these machines offer any value to the consumer.”

And the CEO of the Wine and Spirits Wholesalers of America, presumably with a straight face, chipped in with concerns about the machine’s ability to prevent sales to minors.

One of the major drawbacks is that the kiosk is not really a genuine vending machine, but rather a large box full of wine bottles, attached to a camera, with a live person at the other end—a state employee in Harrisburg who approves each and every remote sale only after verifying a visual match with the photo I.D.

The wine vending machines represent “a technology kludge for bad laws,” and “an attempt to solve the age-old problem of underage drinking with new technology” according to Damon Brown at BNET.

Brown offers 3 suggestions:

--Facial recognition software—“A much more reasonable solution for the vending machines than a person sitting on the other end of a camera.”

--Program tweaks—“Japan now gives out magnetic strips that, when placed on IDs, allow customers to confirm their identity… Pennsylvania has spent money on the machines, but hasn’t come up with an elegant solution to identity.”

--Just change the law—Most state allow wine sales in grocery stores, and the earth hasn’t cleaved in twain.  This Rube Goldberg-style contraption, as the store managers union has characterized it, has yet to prove that it is worth the money.

Photo Credit: http://wduqnews.blogspot.com

Cannabis Receptors and the “Runner’s High”

Maybe it isn't endorphins after all.

What do long-distance running and marijuana smoking have in common? Quite possibly, more than you’d think. A growing body of research suggests that the runner’s high and the cannabis high are more similar than previously imagined.

The nature of the runner’s high is inconsistent and ephemeral, involving several key neurotransmitters and hormones, and therefore difficult to measure. Much of the evidence comes in the form of animal models. Endocannabinoids—the body’s internal cannabis—“seem to contribute to the motivational aspects of voluntary running in rodents.” Knockout mice lacking the cannabinioid CB1 receptor, it turns out, spend less time wheel running than normal mice. 

A Canadian neuroscientist who blogs as NeuroKuz suggests that “a reduction in CB1 levels could lead to less binding of endocannabinoids to receptors in brain circuits that drive motivation to exercise.” NeuroKuz speculates on why this might be the case. Physical activity and obtaining rewards are clearly linked. The fittest and fleetest obtain the most food. “A possible explanation for the runner’s high, or ‘second wind,’ a feeling of intense euphoria associated with going on a long run, is that our brains are stuck thinking that lots of exercise should be accompanied by a reward.”

In 2004, the British Journal of Sports Medicine ran a research review, “Endocannabinoids and exercise,” which seriously disputed the “endorphin hypothesis” assumed to be behind the runner’s high. To begin with, other studies have shown that exercise activates the endocannabinoid system.

“In recent years,” according to the authors, “several prominent endorphin researchers—for example, Dr Huda Akil and Dr. Solomon Snyder—have publicly criticised the hypothesis as being ‘overly simplistic,’ being ‘poorly supported by scientific evidence’, and a ‘myth perpetrated by pop culture.’” The primary problem is that the opioid system is responsible for respiratory depression, pinpoint pupils, and other effects distinctly unhelpful to runners.

The investigators wired up college students and put them to work in the gym, and found that “exercise of moderate intensity dramatically increased concentrations of anandamide in blood plasma.” The researchers break the runner’s high into four major components. Exercise, they say, “suppresses pain, induces sedation, reduces stress, and elevates mood.” Some of the parallels with the cannabis high are not hard to tease out: “Analgesia, sedation (post-exercise calm or glow), a reduction in anxiety, euphoria, and difficulties in estimating the passage of time.”

There are cannabinoid receptors in muscles, skin and the lungs. Intriguingly, the authors suggest that unlike “other rhythmic endurance activities such as swimming, running is a weight bearing sport in which the feet must absorb the ‘pounding of the pavement.’” Swimming, the authors speculate, “may not stimulate endocannabinoid release to as great an extent as running.” Moreover, “cannabinoids produce neither the respiratory depression, meiosis, or strong inhibition of gastrointestinal motility associated with opiates and opioids. This is because there are few CB1 receptors in the brainstem and, apparently, the large intestine.”

A big question remains: What about running and the “motor inhibition” characteristic of high-dose cannabis? (An inhibition that may make cannabis useful in the treatment of movement disorders like tremors or tics.) Running a marathon is not the first thing on the minds of most people after getting high on marijuana.  The paper maintains, however, that at low doses, “cannabinoids tend to produce hyperactivity,” at least in animal models. The CB1 knockout mice were abnormally inactive, due to the effect of cannabinoids on the basal ganglia. Practiced, automatic motor skills like running are controlled in part by the basal ganglia. The authors predict that “low level skills such as running, which are controlled to a higher degree by the basal ganglia than high level skills, such as basketball, hockey, or tennis, may more readily activate the endocannabinoid system.”

The authors offer other intriguing bits of evidence. Anandamide, one of the brain’s own cannabinoids, “acts as a vasodilator and products hypotension, and may thus facilitate blood flow during exercise.” In addition, “endocannabinoids and exogenous cannabinoids act as bronchodilators” and could conceivably facilitate breathing during steady exercise. The authors conclude: “Compared with the opioid analgesics, the analgesia produced by the endocannabinoid system is more consistent with exercise induced analgesia.”

Photo Credit: http://www.madetorun.com/