Scripps Research Institute

Gabapentin Treatment for Alcohol Dependence.

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A Randomized Clinical Trial

Importance  Approved medications for alcohol dependence are prescribed for less than 9% of US alcoholics.

Objective  To determine if gabapentin, a widely prescribed generic calcium channel/γ-aminobutyric acid–modulating medication, increases rates of sustained abstinence and no heavy drinking and decreases alcohol-related insomnia, dysphoria, and craving, in a dose-dependent manner.

Design, Participants and Setting  A 12-week, double-blind, placebo-controlled, randomized dose-ranging trial of 150 men and women older than 18 years with current alcohol dependence, conducted from 2004 through 2010 at a single-site, outpatient clinical research facility adjoining a general medical hospital.

Interventions  Oral gabapentin (dosages of 0 [placebo], 900 mg, or 1800 mg/d) and concomitant manual-guided counseling.

Main Outcomes and Measures  Rates of complete abstinence and no heavy drinking (coprimary) and changes in mood, sleep, and craving (secondary) over the 12-week study.

Results  Gabapentin significantly improved the rates of abstinence and no heavy drinking. The abstinence rate was 4.1% (95% CI, 1.1%-13.7%) in the placebo group, 11.1% (95% CI, 5.2%-22.2%) in the 900-mg group, and 17.0% (95% CI, 8.9%-30.1%) in the 1800-mg group (P = .04 for linear dose effect; number needed to treat [NNT] = 8 for 1800 mg). The no heavy drinking rate was 22.5% (95% CI, 13.6%-37.2%) in the placebo group, 29.6% (95% CI, 19.1%-42.8%) in the 900-mg group, and 44.7% (95% CI, 31.4%-58.8%) in the 1800-mg group (P = .02 for linear dose effect; NNT = 5 for 1800 mg). Similar linear dose effects were obtained with measures of mood (F2 = 7.37; P = .001), sleep (F2 = 136; P < .001), and craving (F2 = 3.56; P = .03). There were no serious drug-related adverse events, and terminations owing to adverse events (9 of 150 participants), time in the study (mean [SD], 9.1 [3.8] weeks), and rate of study completion (85 of 150 participants) did not differ among groups.

Conclusions and Relevance  Gabapentin (particularly the 1800-mg dosage) was effective in treating alcohol dependence and relapse-related symptoms of insomnia, dysphoria, and craving, with a favorable safety profile. Increased implementation of pharmacological treatment of alcohol dependence in primary care may be a major benefit of gabapentin as a treatment option for alcohol dependence.

Soure: JAMA

Anticonvulsant Promising for Alcohol Dependence.

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The anticonvulsant gabapentin, a widely prescribed anticonvulsant used to treat epilepsy and neuropathic pain, is showing promise in the treatment of alcohol dependence, new research suggests.

Results from a 12-week, randomized, placebo-controlled trial show that participants taking 1800 mg of gabapentin were twice as likely to refrain from heavy drinking and 4 times as likely to stop drinking altogether compared with participants taking placebo.

“Gabapentin’s effect on drinking outcomes is at least as large or greater than those of existing FDA-approved treatments,” lead researcher Barbara Mason, PhD, Scripps Research Institute, La Jolla, California, said in a statement.

The study was published online November 4 in JAMA Internal Medicine.

Filling a Treatment Gap

According to investigators, gabapentin has the potential to fill a large gap in the treatment of alcohol dependence. They note that of the estimated 8.5 million alcohol-dependent Americans, statistics show that only 720,000 prescriptions were filled for US Food and Drug Administration (FDA)–approved medications for alcohol dependence in 2007, most of them prescribed by psychiatrists.

Previous studies of gabapentin for alcohol-dependent persons have suggested that the drug may be safe and effective, but conclusive results have been hampered by small sample size and methodologic or dosing issues.

To provide a more definitive evaluation of the drug for alcohol dependence, the researchers conducted a 12-week, double-blind, placebo-controlled, randomized, dose-ranging trial of 150 adults with current alcohol dependence who were attending a single outpatient center.

Participants were randomly assigned to receive 900 mg/day, 1800 mg/day, or placebo. All patients received concomitant counseling.

The study’s primary outcomes included sustained abstinence and no heavy drinking, and decreases in alcohol-related insomnia, dysphoria, and craving in a dose-dependent manner.

Results showed that gabapentin significantly improved the rates of abstinence and no heavy drinking with rates of 4.1% (95% confidence interval [CI], 1.1% – 13.7%) in the placebo group, 11.1% (85% CI, 5.2% – 22.2%) in the 900-mg group, and 17.0% (95% CI, 8.9% – 30.1%) in the 1800-mg group.

Further, the investigators report that the no-heavy-drinking rate was 22.5% (95% CI, 13.6% – 37.2%) in the placebo group, 29.6% (95% CI, 19.1% – 42.8%) in the 900-mg group, and 44.7% (95% CI, 31.4% – 58.8%) in the 1800-mg group.

In addition, the results showed that the drug significantly reduced cravings, depression, and sleeplessness. The researchers report that gabapentin had a favorable safety profile with no reports of serious adverse events.

According to Dr. Mason, gabapentin offers several potential advantages over the 3 other FDA-approved medications for alcohol dependence. It is “the only medication shown to improve sleep and mood in people who are quitting or reducing their drinking, and it’s already widely used in primary care ― that’s an appealing combination,” she said.

Broader Access to Treatment

In an accompanying editorial,Edward V. Nunes, MD, writes that the finding that gabapentin prevents relapse in alcohol-dependent patients is “an important development.”

“This well-designed and well-powered trial replicates the positive findings of several previous smaller trials,” Dr. Nunes writes.

He notes that a large proportion of alcohol-dependent patients presenting to family physicians fall into the mild to moderate range of alcohol dependence, which further suggests “the strong potential for gabapentin in the treatment of alcohol dependence in primary care.”

Acting director of the National Institute on Alcohol Abuse and Alcoholism, Kenneth R. Warren, PhD, said, “Gabapentin adds to the list of existing medications that have shown promise in treating alcohol dependence. We will continue to pursue research to expand the menu of treatment options available for alcoholism in the hopes of reaching more people.”

Eat More, Weigh Less: Worm Study Provides Clues to Better Fat-Loss Therapies for Humans

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Scientists at The Scripps Research Institute (TSRI) have discovered key details of a brain-to-body signaling circuit that enables roundworms to lose weight independently of food intake. The weight-loss circuit is activated by combined signals from the worm versions of the neurotransmitters serotonin and adrenaline, and there are reasons to suspect that it exists in a similar form in humans and other mammals.

“Boosting serotonin signaling has been seen as a viable strategy for weight loss in people, but our results hint that boosting serotonin plus adrenaline should produce more potent effects—and there is already some evidence that that’s the case,” said TSRI Assistant Professor Supriya Srinivasan, who was principal investigator for the study, published online before print on October 10, 2013 by the journal Cell Metabolism.

Serotonin signaling, which can be increased artificially by some diet and antidepressant drugs, has long been known to reduce weight. Until recently, scientists assumed that it does so largely by suppressing appetite and food intake. However, Srinivasan reported in 2008—while she was a postdoctoral fellow at the University of California, San Francisco—that serotonin changes food intake and fat levels via separate signaling pathways. “We could make the animals we studied lose fat even as they ate more,” she said. Her experiments were conducted on C. elegansroundworms, whose short lifespans and well-characterized nervous systems make them a preferred species for quick-turnaround lab studies. Indeed, other researchers soon found that serotonin’s food-intake-suppressing and weight-loss effects are separable in mammals, too.

Now with her own laboratory at TSRI, Srinivasan has been examining the C. elegans weight loss circuitry in more detail. In the new study, Srinivasan and her colleagues, first author Research Assistant Tallie Noble and graduate student Jonathan Stieglitz, used a series of gene-blocking experiments to identify some of the circuit’s key elements.

Their most surprising discovery was that serotonin isn’t the sole driver of this weight-loss pathway, but works in concert with another neurotransmitter, octopamine—the C. elegans version of adrenaline (also called epinephrine) in mammals. “That was a very interesting finding, especially since other studies suggest that these two neurotransmitters tend to oppose each other’s functions,” said Noble.

The team mapped out a self-reinforcing network of serotonin and octopamine-producing neurons in the worms that send the lose-weight signal to the body. This network includes a set of serotonin-sensitive neurons known as URX neurons, which have access to the worm circulatory system and apparently release a still-to-be-identified signaling molecule. The downstream result of this signal, the researchers found, is a boost in the production of a key enzyme in the worm intestine. The enzyme, known as adipocyte triglyceride lipase 1 (ATGL-1), literally cuts fat molecules in a way that leads to their further metabolic breakdown. ATGL-1 also has a very similar counterpart in mammals.

Srinivasan and her colleagues plan in future work to identify the long-range molecular signal that boosts ATGL-1 production and to better delineate the serotonin-octopamine network that produces the signal. Eventually, they would like to map out the corresponding fat-loss network in a closer evolutionary relative of humans, such as the mouse.

However, Srinivasan noted that the human experience with weight-loss drugs already hints that mammals may have such a fat-loss circuit. Serotonin-plus-adrenaline boosting therapies, the most prominent of which was fenfluramine-phentermine (“fen-phen”), have tended to do better at cutting weight than serotonin-boosting therapies alone. Unfortunately, the serotonin-boosting elements of these compounds have often been blamed for cardiovascular side effects—fenfluramine, for example, was banned by the FDA in 1997—but in principle, future combination therapies could be designed to avoid producing such side effects.

“We wonder if boosting not just serotonin but serotonin plus a little bit of adrenaline is the real key to more potent weight loss,” Srinivasan said.

Scripps Research Institute Scientists Invent a Better Way to Make Antibody-Guided Therapies

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Chemists at The Scripps Research Institute (TSRI) have devised a new technique for connecting drug molecules to antibodies to make advanced therapies.

Antibody-drug conjugates, as they’re called, are the basis of new therapies on the market that use the target-recognizing ability of antibodies to deliver drug payloads to specific cell types—for example, to deliver toxic chemotherapy drugs to cancer cells while sparing most healthy cells. The new technique allows drug developers to forge more stable conjugates than are possible with current methods.

“A more stable linkage between the drug molecule and the antibody means a better therapy—the toxic drug is less likely to fall off the antibody before it’s delivered to the target,” said Carlos F. Barbas III, the Janet and Keith Kellogg II Chair at TSRI.

Barbas and two members of his laboratory, Research Associates Narihiro Toda and Shigehiro Asano, report the finding in the chemistry journal Angewandte Chemie, where their paper was published recently online ahead of print and selected as a “hot” contribution.

A Popular Approach with Limitations

The new method for making more stable antibody-drug conjugates comes as the first generation of these powerful therapies are entering the market. Two such conjugates are now in clinical use. Brentuximab vedotin (Adcetris®), approved by the FDA in 2011, has shown powerful effects in clinical trials against otherwise treatment-resistant lymphomas. It uses an antibody to deliver the cell-killing compound monomethyl auristatin E to cells that bear the CD30 receptor, a major marker of lymphoma. The other conjugate, ado-trastuzumab emtansine (Kadcyla®), approved just this year for metastatic breast cancer, delivers the toxic compound mertansine to breast cancer cells that express the receptor HER2.

The success of these antibody-drug conjugates and the broad potential of the technology have made them popular with drug companies, particularly those trying to develop new anticancer medicines. “The current development pipeline is full of antibody-drug conjugates,” says Barbas.

Yet the chemical method that has been used to make these conjugates has significant limitations. The method involves the use of compounds derived from maleimide, which can be easily added to small drug molecules. The maleimide molecule acts as a linker or bridge, making strong bonds with cysteine amino acids that can be engineered into an antibody protein. In this way, a single antibody protein can be tagged with one or more maleimide-containing drug molecules. The main problem is that these maleimide-to-cysteine linkages are susceptible to several forms of degradation in the bloodstream. When such a cut occurs, the disconnected “payload” drug-molecule—typically a highly toxic compound—is liable to cause unwanted collateral damage to the body, like a “smart bomb” gone astray. This instability of current maleimide-based conjugates probably accounts for at least some of their considerable toxicity.

A more stable linkage would mean less toxicity and higher efficacy for antibody-drug conjugates, and for the past several years research chemistry laboratories around the world have been looking for a way to achieve this.

Improved Linkages

Now Barbas and his colleagues appear to have found one in the form of a novel Thiol-Click reaction. In their new paper, they have described a way to make improved linkages using compounds based on methylsulfonyl-substituted heterocycles instead of maleimides. “This method turns out to enable more stable linkages to an antibody protein, as well as more specific linkages, so the drug attaches to the right place on the right protein,” said Barbas.

Coincident with the report of the new linking compounds in Angewandte Chemie, the chemical supplier Sigma-Aldrich Corporation will begin selling the compounds, so that pharmaceutical companies can start working with them to make more stable antibody-drug conjugates. Under a recent agreement (see http://www.scripps.edu/news/press/2013/20130718sigma.html), Sigma-Aldrich markets new chemical reagents from Barbas’s and several other TSRI laboratories as soon as the papers describing them are released.

“Improved antibody–drug conjugate technologies are a top-priority research area in the pharmaceutical industry and exactly the type of fundamental research issue that our partnership with Scripps will continue to address,” said Amanda Halford, vice president of academic research at Sigma-Aldrich.

Although linking drug molecules to target-homing antibodies is the best-known therapeutic application of the new method, Barbas emphasized its broad relevance. “It should be useful for many types of protein conjugation,” he said. These include the conjugation of proteins to fluorescent beacon molecules for laboratory experiments, as well as the linkage of drug compounds to polyethylene glycol molecules—“pegylation”—to slow their clearance from the body and thus keep them working longer.

Scientists Detail Critical Role of Gene in Many Lung Cancer Cases.

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Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown that a well-known cancer-causing gene implicated in a number of malignancies plays a far more critical role in non-small cell lung cancer, the most common form of the disease, than previously thought.

These findings establish the gene as a critical regulator of lung cancer tumor growth. This new information could turn out to be vital for the design of potentially new therapeutic strategies for a group of patients who represent almost half of non-small cell lung cancer cases.

In the study, published online ahead of print by the journal Cancer Research, the scientists found that presence of known oncogene Notch 1 is required for survival of cancer cells. In both cell and animal model studies, disabling Notch 1 leads to a rise in cancer cell death.

“While Notch signaling has emerged as an important target in many types of cancer, current methodologies that target that pathway affect all members of the Notch family, and this has been associated with toxicity,” said Joseph Kissil, a TSRI associate professor who led the study. “We were able to identify Notch 1 as the critical oncogene to target, at least in a common form of lung cancer.”

The new findings show that Notch1 is required for initial tumor growth, as it represses p53, a well-known tumor suppressor protein that has been called the genome’s guardian because of its role in preventing mutations. The p53 protein can repair damaged cells or force them to die through apoptosis — programmed cell death.

Using animal models, the study shows that inhibition of Notch1 signaling results in a dramatic decrease in initial tumor growth. Moreover, disruption of Notch 1 induces apoptosis by increasing p53 stability — substantially increasing its biological half-life, for example.

These findings provide important clinical insights into the correlation between Notch1 activity and the poor prognosis of non-small cell lung cancer patients who carry the non-mutated form of the p53 gene. “If you look at lung cancer patient populations, Notch signaling alone isn’t a prognostic indicator, but if you look at p53-positive patients it is,” Kissil said.

Source: http://www.sciencedaily.com

IGT ups risk for abnormal retinal vascular reactivity CVD.

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Researchers in the United Kingdom have found a link between impaired glucose tolerance and microvascular and macrovascular function, as well as a direct association between retinal microcirculatory changes and established plasma markers for cardiovascular disease.

Sunni R. Patel, PhD, a postdoctoral fellow at University Health Network in Toronto and former researcher for the Vascular Research Laboratory and Ophthalmic Research Group at the School of Life and Health Sciences at Aston University in Birmingham, United Kingdom, and colleagues conducted a study involving 60 age- and sex-matched white European adults, 30 with IGT and 30 with normal glucose tolerance.

Patients with IGT had higher blood pressure values (P<.001), fasting triglyceride levels and triglyceride-to-HDL ratios (P<.001) vs. patients with normal glucose tolerance. According to data, blood glutathione levels were lower (reduced glutathione, P<.001; glutathione disulfide, P=.039; and total glutathione, P<.001), whereas plasma von Willebrand factor was increased in patients with IGT when compared with the control group (P=.014).

Moreover, patients with IGT displayed higher intima-media thickness in the right (P=.017) and left carotid arteries (P=.005) and larger brachial artery diameter (P=.015). Patients with IGT also had lower flow-mediated dilation percentage (P=.026) and glyceryl trinitrate-induced dilation (P=.012) than healthy control patients.

“The results of our pilot study suggest that IGT individuals demonstrate signs of early vascular dysfunction as measured by functional (at macro- and microcirculatory levels) and circulatory markers. Moreover, in addition to a relationship between functional macro- and microvascular parameters, there appears to be a direct correlation between the observed retinal microcirculatory changes and established plasma markers for CVD risk,” the researchers wrote.

Due to these observations, researchers wrote that there should be a possible emphasis on early CV screenings and interventions for those with a prediabetes diagnosis, including those with IGT.

“Retinal vascular imaging could emerge as a possible future option for individual risk stratification in diseased patients but also in individuals at risk for metabolic and CV pathologies,” the researchers wrote.

Source: Endocrine Today.