Skip to main content

Diabetes Drug May Be Effective in Treating Addiction


Exenatide (Ex-4), a glucagonlike peptide-1 (GLP-1) receptor agonist currently used in the management of type 2 diabetes, could effectively treat drug addiction, including cocaine dependence, new research shows.
Investigators at Vanderbilt University in Nashville, Tennessee, found that mice pretreated with the drug seemed to enjoy cocaine less, spending less time in the treatment chamber following cocaine introduction, compared with mice that were not pretreated with Ex-4.
"We know that the GLP-1 receptor affects the dopaminergic system and when dopamine neurotransmission is impaired, it leads to hedonic feeding and obesity," study investigator Aurelio Galli, PhD, professor of molecular physiology and biophysics and the Vanderbilt Brain Institute, told Medscape Medical News.
"So providing animals with a GLP-1 agonist activates the GLP-1 receptor and decreases interest in highly palatable food, and we found it also works to decrease the craving for cocaine."
The study was published online October 23 in a letter to the editor in Molecular Psychiatry.
Reduced Reward
GLP-1 is released in response to food intake and acts both peripherally and centrally to regulate feeding behavior.
Emerging data suggest that peptides such as GLP-1 may also be involved in drug reward and thus could serve as a therapeutic target for the treatment of psychostimulant addiction.
GLP-1 receptors are expressed in a number of regions in the brain that are part of the reward circuit that makes drugs like cocaine addictive, said Dr. Galli.
Because drug reward and hedonic feeding behavior use overlapping brain circuitry and mechanisms, "we hypothesized that the GLP-1R [GLP-1 receptor] agonist Ex-4 would reduce the rewarding effects of cocaine," the investigators write.
Using conditioned place preference, a test in which an animal is placed into 1 of 2 separate compartments of a test chamber, mice consistently migrated to the test chamber in which they received a pleasurable injection of cocaine.
However, when researchers pretreated mice with Ex-4, the animals appeared to enjoy the drug less, spending less time in the treatment chamber containing cocaine.
The rewarding effects of cocaine were attenuated in mice pretreated with Ex-4, regardless of the pretreatment dose. In addition, the researchers found no evidence of negative side effects or addiction to Ex-4 treatment.
The authors caution that additional research is needed to verify dosing structure and to determine whether these findings extend to other psychostimulants.
However, if results from future studies are positive, there may be significant clinical implications.
"What we have demonstrated is that a brain mechanism already known to be therapeutic for the treatment of diabetes also appears to be implicated in at least certain types of drug addiction," study coauthor Gregg Stanwood, PhD, assistant professor of pharmacology and an investigator within the Vanderbilt Kennedy Center and Vanderbilt Brain Institute, said in a release.
"We found that this drug...that is already used for the medical management of diabetes reduces the rewarding effects of cocaine in animals. We suspect that this is a general mechanism that will translate to additional drugs of abuse, especially other stimulants like amphetamine and methamphetamine."
Repurposing Drugs
Nigel Greig, PhD, from the National Institute on Aging in Baltimore, Maryland, told Medscape Medical News that he and his team have been working on the GLP-1 receptor drugs in the diabetes field for many years.
More recently, a number of investigators have been repurposing these drugs for neurological disorders, mostly notably Alzheimer's and Parkinson's disease. They are currently in clinical trials to assess the drugs' potential as neuroprotective and neurotrophic agents.
"This is the first strong scientific evidence that the same drugs may be repurposed for the treatment of drug abuse, and I think the findings are very intriguing and they are worth following up," said Dr. Greig.
The authors and Dr. Greig have disclosed no relevant financial relationships.

Comments

Post a Comment

Popular posts from this blog

Missing Data Lead FDA Panel to Vote Against Rivaroxaban for ACS May 23, 2012 (Updated May 24, 2012) (Silver Spring, Maryland) — The missing data issues plaguing the ATLAS ACS 2 TIMI 51 trial of the factor Xa inhibitor rivaroxaban (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) have prevented the drug from earning the endorsement of the FDA Cardiovascular and Renal Drugs Advisory Committee. At its May 23 meeting, the panel voted six to four (with one abstention) against recommending that the FDA approve rivaroxaban for reducing the risk of thrombotic cardiovascular events in patients with acute coronary syndrome or unstable angina in combination with aspirin, aspirin plus clopidogrel, or ticlopidine. Janssen's application is based on the results of the ATLAS ACS 2 phase 3 and the ATLAS ACS TIMI 46 phase 2 trial. The placebo-controlled ATLAS ACS 2 showed rivaroxaban reduced the risk of both all-cause and cardiovascular mortality while increasing the risk of bleeding and intracranial hemorrhage, but the studies were hindered by early patient withdrawals and missing data. We Don't Know What We're Missing Based on the ATLAS ACS 2 results, FDA reviewer Dr Karen Hicks recommended approval of rivaroxaban for the requested indications except all-cause mortality. However, another FDA reviewer, Dr Thomas Marciniak, was adamant that the trial results are not interpretable because about 12% of the patients had incomplete follow-up, far higher than the 1% to 1.5% differences in the end-point rates between rivaroxaban and placebo. A total of 1294 subjects discontinued the trial prematurely, and the company was only able to contact 183, of which 177 were confirmed to be alive. Because of the patient dropouts, the company adopted a "modified intention-to-treat analysis," whereby patients were observed for 30 days after randomization or the global end date for the trial, instead of observing all the patients until the end of the trial as the FDA originally suggested. Marciniak criticized the sponsor's efforts to follow the patients and said that three patient deaths not counted in the modified intention-to-treat analysis may just be the "tip of the iceberg." Because the percentage of patients whose ultimate vital status remains unknown is much greater than the reported differences in mortality rates, the claimed mortality benefits are not reliable. The majority of the panel sided with Marciniak. For example, Dr Sanjay Kaul (University of California, Los Angeles) voted "no" because "there was enough uncertainty in the quality and robustness of the data that dissuaded me from voting yes. . . . The 'missingness' of the data doesn't invalidate it, but it certainly makes it hard to infer [the conclusion]." Dr Steven Nissen (Cleveland Clinic, OH) said that the decision to use the modified intention-to-treat analysis had a "profound impact" on the interpretability of the data. "It's saying we don't care what happens after 30 days, [and] that colored the trial in ways we couldn't recover from." Given the risk of major bleeding, "I want to see better evidence that this strategy of adding an Xa inhibitor or a direct thrombin inhibitor or something else to a good antiplatelet agent is robustly better for the patient," Nissen said. He recommends that the companies run a new trial of the 2.5 twice-daily dose of rivaroxaban using a strict intention-to-treat approach, but, he said, "I don't expect the death benefit to be too robust." Several panelists said they were concerned that the patients who dropped out of the trial were disproportionately likely to have a bleeding event, which led them to quit the trial, or a "protopathic" event, as statistician Dr Scott Emerson (University of Washington, Seattle) put it. "We're worried that an impending event is what is changing their behavior. We see that all the time in clinical trials--that regularly measured end points do not pick up [all of] the events," he said. He said that since the company was only able to contact 183 of the over 1200 patients who dropped out, it is possible that the dropouts skew the outcomes comparison of the trial. "Differential event rates after dropout are the number-one thing we're afraid of, so you have to explore it" in a statistical sensitivity analysis of the potential impact of these unknown outcomes. "It would not surprise me if, at the end of the day, these data did not hold up under a proper sensitivity analysis," he said. "What I want to know is, among the people who had events, how differential was the follow-up, but I can tell you by just looking at it, there was a very slightly different amount of follow-up of the people in the treatment arm. But I don't know whether everyone in the treatment arm was cured and they were trekking in the Himalayas and everyone in the placebo arm went home to die. I don't know that that's not the case." Dr Maury Krantz (University of Colorado, Denver) voted in favor of approval but said he does not know how rivaroxaban would perform in general clinical practice, especially when used with aspirin and clopidogrel. "I felt very much torn by this. This isn't a simple paradigm shift. It means going to triple therapy, which is really a three-headed monster in many ways. I think that what you're going to see in practice, if this is not done carefully with the proper labeling and secondary studies, is really dramatic magnification of bleeding and perhaps minimization of the efficacy benefit."

May 23, 2012   (Updated May 24, 2012)  (Silver Spring, Maryland)  —  The missing data issues plaguing the  ATLAS ACS 2 TIMI 51   trial of the factor Xa inhibitor  rivaroxaban  (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) have prevented the drug from earning the endorsement of the  FDA  Cardiovascular and Renal Drugs Advisory Committee. At its May 23 meeting , the panel voted six to four (with one abstention) against recommending that the FDA approve rivaroxaban for reducing the risk of thrombotic cardiovascular events in patients with acute coronary syndrome or unstable angina in combination with aspirin, aspirin plus  clopidogrel , or  ticlopidine . Janssen's application is based on the results of the ATLAS ACS 2 phase 3 and the  ATLAS ACS TIMI 46   phase 2 trial. The placebo-controlled ATLAS ACS 2 showed rivaroxaban reduced the risk of both all-cause and cardiovascular mortality while increasing the ri...
Post a Comment
Read more

Antidepressants Linked to Higher Diabetes Risk in Kids

Pediatric patients who use antidepressants may have an elevated risk for type 2 diabetes, the authors of a new study report. In a retrospective cohort study of more than 119,000 youths 5 to 20 years of age, the risk for incident type 2 diabetes was nearly twice as high among current users of certain types of antidepressants as among former users, Mehmet Burcu, PhD, and colleagues report in an article  published online October 16 in  JAMA Pediatrics . The risk intensified with increasing duration of use, greater cumulative doses, and higher daily doses of these antidepressants. The findings point to a growing need for closer monitoring of these products, including greater balancing of risks and benefits, in the pediatric population, the authors caution. They undertook the study because, despite growing evidence of an association between antidepressant use and an increased risk for type 2 diabetes in adults, similar research in pediatric patients was scarce. "To our know...
Post a Comment
Read more

Contact Precautions May Have Unintended Consequences

Contact precautions, including gloves, gowns, and isolated rooms, have helped stem the transmission of hospital pathogens but have also had some negative consequences, according to findings from a new study. Healthcare worker (HCWs) visited patients on contact precautions less frequently than other patients and spent less time with those patients when they did visit, report Daniel J. Morgan, MD, from the University of Maryland School of Medicine and the Veterans Affairs (VA) Maryland Health Care System, Baltimore, and colleagues. Moreover, patients on contact precautions also received fewer outside visitors. "Less contact with HCWs suggests that other unintended consequences of contact precautions still exist," Dr. Morgan and coauthors write. "The resulting decrease in HCW contact may lead to increased adverse events and a lower quality of patient care due to less consistent patient monitoring and poorer adherence to standard adverse event prevention methods (such...
Post a Comment
Read more