Bio Firm Working on New Technology for E-Cigarettes

Key tobacco scientist endorses “going vape.”

Cypress Bioscience of San Diego hopes to enter the controversial and potentially lucrative market for so-called e-cigarettes, which deliver nicotine by heating it to produce an inhalable, smoke-free vapor. The company announced last week that it had acquired a $5 million license for Staccato nicotine technology—“A novel electronic multidose delivery technology designed to help people stop smoking.”

The company claims that the “the electronics embedded within the Staccato delivery system could allow for the programmed, over-time reduction in the overall daily dose of nicotine, and ultimately may lead to the better management of nicotine cravings and eventual sustained smoking cessation”

Critics of e-cigarettes have maintained that the devices were not meant to curb smoking but to enable it, by allowing smokers to circumvent no-smoking regulations. Fears have also been voiced that children might be tempted to make use of them. Makers of electronic cigarettes, primarily in Asia, have maintained that the devices are perfect for the management of nicotine cravings when smokers quit, and may have significant advantages over nicotine gums and patches.

The press release from Cypress Bioscience makes the claim explicitly: “The Staccato technology may be capable of mimicking the pharmacokinetics of smoking cigarettes through the delivery of optimally-sized nicotine particles to the deep lung. Staccato nicotine may also provide some of the psychological aspects of smoking (e.g., hand-to-mouth movement, oral inhalation) and could allow smokers to self-administer and possibly titrate to the dose to treat cravings.”

Up until now, electronic cigarettes have been opposed by the Food and Drug Administration (FDA) on the grounds that e-cigarettes were novel and untested drug delivery systems. Signaling a possible change in official attitudes, Dr. Neal Benowitz, professor of Medicine at the University of California, San Francisco--and a prominent nicotine researcher for many years--said in the Cypress Bioscience press release that a delivery device like Staccato nicotine “may be useful in addressing a pressing pharmacological problem in overcoming nicotine addiction; namely, that acute cravings during quit attempts are inadequately treated by current nicotine replacement therapies.” Dr. Benowitz called the nicotine delivery device “an advancement that the field has been waiting for.”

Cypress Bioscience said it plans to take the technology into Phase 1 clinical trials next year. The company reported a net loss of 5 cents per share in the second quarter, compared to a loss of 23 cents per share during the same period a year ago.

The Centers of Disease Control and Prevention (CDC) estimate that almost 450,000 people die annually in the U.S. from smoking. One in five deaths in the U.S. are due to smoking-related illness, according to the CDC.

Earlier posts:

Leave Cigarettes Along, Judge Tells FDA

E-Cigarettes: Another Look

Graphics Credit: http://www.ecigarettebuyer.co.uk/

Smoking and Baby Poop

Telltale metabolites in meconium.

Attention pregnant smokers: You can run, but you can’t hide. A chemical analysis of your baby’s first official poop can establish whether your infant has suffered from prenatal exposure to tobacco smoke. The higher the levels of tobacco metabolites, the more likely the mother was an active smoker.

The authors of a study published in Environmental Health found that nicotine and assorted tobacco metabolites were easily detectable in an infant’s meconium, the black, tar-like substance that comprises the first stools from newborns. In a study of 337 babies, tobacco metabolite concentrations were higher in active smokers than in non-smoking women exposed to second-hand smoke only.

The researchers say the meconium method is not superior to other methods of measurements, but suggest it may be a useful adjunct in estimating “gestational exposure to other environmental toxicants that exhibit more variability during pregnancy, especially non-persistent compounds like bisphenol A and phthalates.”

One striking aspect of the study is that the researchers found nicotine and cotinine—a common nicotine metabolite--in most of the meconium samples analyzed. 80% of the samples contained nicotine. So it is not a question of exposure, it’s a question of the degree of exposure. Should we be concerned about the lower levels of exposure registered from second-hand smoke? Apparently so, since “meconium tobacco smoke metabolites were inversely associated with birth weight,” according to Joe M. Braun and coworkers. Braun suggested that additional biomarkers for tobacco exposure were important, based on his belief that tobacco smoke exposure during pregnancy is under-reported.

This looks like a potentially useful tool for epidemiological studies that enroll women and infants at birth. More studies of this kind are needed, because prenatal tobacco smoke exposure is increasingly implicated in “adverse infant and childhood health outcomes.”

Graphics Credit: http://www.youquittwoquit.com/

Meth Use Trending Downward, Say Feds.

Big drop registered from 2004 to 2008.

The history of illegal drug use in America is a history of peaks and valleys, with various drugs gaining ascendency and popularity for various reasons at various times--even though none of them ever go away for good.

It would be foolish to say that methamphetamine use has peaked and is on its way out. However, there is at least some evidence that in the U.S., meth may be following the same recent trend line as cocaine.

SAMHSA, the Substance Abuse and Mental Health Services Administration, regularly gathers figures related to drug use through its Drug Abuse Warning Network (DAWN) and through the National Survey on Drug Use and Health.  Between 2002 and 2006, the number of people who had used meth in the past year fluctuated from 1.6 to 1.9 million users. By 2008, however, that number had decreased to 850,000, SAMHSA has concluded. As reasons, the agency cited the 2005 law limiting sales of pseudoephedrine and ephedrine, as well as “supply and demand reduction efforts,” presumably a reference to the drug war.

As for hospital visits, “admissions for primary use of methamphetamine increased steadily from 54,000 admissions in 1994 to 154,000 admissions in 2005 and then declined to 137,000 admissions in 2007.”  Emergency department visits involving methamphetamine accounted for 8% of total drug-related visits in 2004, compared to 3% of emergency department visits for drug abuse or misuse in 2008.

As always, it is important to remember that most drug-related emergency room visits involve the use or overuse of more than one drug at a time. This changes the picture substantially, in some cases. For example, fully one-third of methamphetamine-related emergency department visits involve “methamphetamine combined with two or more other drugs,” the report discloses. A quarter of the visits also involved the use of alcohol. In 6 out of ten cases, the subjects were treated and released.

One optimistic but puzzling thought the report offers is that some improvements may be attributable to a growing awareness that “treatment providers and researchers have demonstrated that methamphetamine addiction—which once was thought untreatable—can be effectively addressed.”

I am not sure what SAMHSA means when it states that meth addiction was once considered untreatable—I am not aware of any substance addiction which cannot be “effectively addressed,” at least some of the time. And while I am always a bit wary of widespread number gathering, any indication of a decreasing interest in speed is always good news. Furthermore, if there is growing awareness that addiction to meth can be tackled successfully, just like addiction to any other drug, so much the better.

Photo Credit: SAMHSA

Psychedelics Back in the Spotlight

But will it be any different this time?

Two papers on the use of psychedelics for the treatment of mood disorders surfaced last week in the prestigious journals Science and Nature. The articles have garnered a great deal of publicity, especially the results having to do with the effect of ketamine on depression. I cannot pretend to offer more insightful coverage than the posts and articles listed below have already done, but I do think it’s profitable to take a closer look at the Nature piece by Franz X. Vollenweider and Michael Kometer. This paper looked at both dissociative anesthetics, like PCP and ketamine, AND “classical hallucinogens,” like psilocybin and LSD.

Traditionally, LSD has been thought of as a relentlessly serotonin-active drug, while ketamine was more actively involved with NMDA and other glutamate receptors. There is accumulating evidence, the researchers believe, that a common mechanism undergirds the operations of both kinds of psychedelics. “Despite their different primary modes of action,” they write, “classical hallucinogens and dissociative anesthetics both modulate glutamatergic neurotransmission in the prefrontal-limbic circuitry that is implicated in the pathophysiology of mood disorders.”

It’s worth noting that Vollenweider and Kometer maintain that almost all depressed patients relapse within two weeks after a single dose of ketamine. In studies of patients with advanced cancer, say the authors, psilocybin improves mood just as effectively, and lasts longer, than ketamine.

While there are significant differences between the subjective effects of ketamine and LSD, there is also “a set of overlapping psychological experiences.” The two trips are different, but not completely different—they share effects such as distortion of perception, visual and auditory hallucinations, a sense that the boundaries of self have softened, and often an ecstatic experience or sense of profound unity. The serotonin-glutamate connection leads the authors to assert that “classical hallucinogens are potent modulators of prefrontal network activity that involves a complex interaction between the serotonin and glutamate systems in prefrontal circuits.”

Alternately, these drugs can trigger a classic “bad trip” in certain users--time, place, circumstance, and innate biology depending.  As the authors put it: “The same hallucinogen might produce a pleasurable loss of ego boundaries combined with feelings of oneness or might lead to a more psychotic ego dissolution that involves fear and paranoid ideation.”

And there you have it: In the case of psychedelics, there are certain extenuating factors which may forever limit the use of these substances for therapeutic purposes. The primary problem is that the drugs are clinically unreliable. With psychedelics, it is always, in a sense, the Lady or the Tiger.  “The strongly dissociative effects of ketamine may limit clinical use despite its reported efficacy,” the researchers conclude. Which is, I think, putting it mildly--and which brings the authors to suggest that pharmacology-assisted psychotherapy might require some tweaks.

Specifically, the hunt is now on for psychedelics that are, well, less psychedelic. In the same way that pharmacologists seek to dial down the euphoric effects of pain medication to lessen the chances for black market abuse, researchers are now looking for ways to tone down the mental fireworks often associated with the use of ketamine, LSD, or psilocybin, on the assumption that these represent nothing but unwanted side effects, rather than the core of the experience that alleviates depression, OCD, and addiction—at least for awhile. These drugs are among the most powerful mind-altering compounds on the planet. So good luck with that project. Studying the behavioral effects of these drugs in the first place is a bit like trying to pin down a writhing fire hose with a pair of tweezers.

Curing or successfully treating chronic ailments like depression and addiction with a power psychoactive medication is both an old and an exciting idea. The Nature opinion piece also documents studies, beginning in the 1960s, which showed that psilocybin and LSD were effective treatments for Obsessive-Compulsive Disorder (OCD).  Other studies have shown alleged successes using low-dose ketamine for heroin addiction. And some of the earliest LSD studies of all showed impressive results when LSD and psychotherapy were combined as a treatment for alcoholism.

 By 1965, the authors claim, there were more than 1,000 published clinical studies on the therapeutic effects of psychedelics.  But many, if not most, of the early studies were marred by procedural problems, lack of control groups, and the fact that researchers from a dozen different disciplines, representing a dozen different experimental methods, predictably emphasized different kinds of experiential results.  The authors suggest that novel neuroimaging techniques combined with an increased understanding of molecular mechanisms of action mean that it will be different this time. If the only real result of the ketamine studies is increased funding for research on psychedelic drugs after a long hiatus, that is still progress, and it’s long overdue.

Resources

David Biello, Scientific American

Maia Szalavitz, New Scientist

and MSN Health and Fitness

Scicurious at Neurotic Physiology

Neuroskeptic at Neuroskeptic

Eugene Rubin, Psychology Today

Jonah Lehrer at Frontal Cortex

Photo Credit: http://cherished79.wordpress.com/

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/