This study focused on 12 to 16-year-olds whose brains were scanned using special functional magnetic resonance imaging (fMRI) prior to the onset of drinking, and then again three years later. About half of this group transitioned into heavy drinking over the 3-year period. However, when imaged before they began drinking, this cohort already showed less fMRI response in regions of the brain previously linked to heavy drinking.
“Interestingly, this study showed that teens who initially showed less activation in certain brain areas were at greater risk for becoming heavy drinkers over the next three years,” said principal investigator Susan Tapert, PhD, professor of psychiatry at UC San Diego School of Medicine and VA San Diego Healthcare System.
Over time, adolescents who initiated heavy drinking exhibited less efficient processing of information.
“That’s the opposite of what you’d expect, because their brains should be getting more efficient as they get older,” said lead researcher Lindsay M. Squeglia, PhD of UC San Diego Department of Psychiatry.
Once this group began drinking heavily – defined by episodes of consuming four or more drinks on an occasion for females, and five or more drinks for males – their brains already started showing the patterns previously seen in heavy drinkers: more activity in certain areas of the brain as they tried to perform a memory test. These brain areas included the parietal lobe (which helps process spatial information), and frontal lobe (the portion of the brain involved in, among other things, short-term memory tasks, planning, and organization).
“At the point these teens began drinking heavily, the fMRI data revealed greater parietal and frontal activity during a spatial working memory task in heavy drinkers versus light drinkers, despite equivalent performance on the tasks and after considering their brain activation patterns before drinking started,” said Squeglia.
The study’s findings add to evidence that heavy episodic drinking during adolescence may be followed by subtle alterations in brain functioning. But the research also points to neural response patterns that could indicate a risk factor for future substance use.
“Our results suggest there could be a pre-existing vulnerability, and could provide clues to the biological origins of problem drinking,” said Squeglia.
Additional contributors to the study include Reagan R. Wetherill, PhD, UC San Diego; and Carmen Pulido, PhD, Joanna Jacobus, PhD, and Gregory G. Brown, PhD, UC San Diego and VA San Diego Healthcare.
The study was funded by grants from the National Institute of Alcohol Abuse and Alcoholism, part of the National Institutes of Health (#F31 AA18940, R21 AA019748 and R01 AA13419).
Debra Kain, 619-543-6163, [email protected]
August 7, 2012
A glass a day of grapefruit juice lets patients derive the same benefits from an anti-cancer drug as they would get from more than three times as much of the drug by itself, according to a new clinical trial. The combination could help patients avoid side effects associated with high doses of the drug and reduce the cost of the medication.
Researchers at the University of Chicago Medicine study the effects that foods can have on the uptake and elimination of drugs used for cancer treatment. In a study published in August in Clinical Cancer Research, they show that eight ounces a day of grapefruit juice can slow the body’s metabolism of a drug called sirolimus, which has been approved for transplant patients but may also help many people with cancer.
Patients who drank eight ounces a day of grapefruit juice increased their sirolimus levels by 350 percent. A drug called ketoconazole that also slows drug metabolism increased sirolimus levels by 500 percent.
“Grapefruit juice, and drugs with a similar mechanism, can significantly increase blood levels of many drugs,” said study director Ezra Cohen, MD, a cancer specialist at the University of Chicago Medicine, “but this has long been considered an overdose hazard. Instead, we wanted to see if grapefruit juice can be used in a controlled fashion to increase the availability and efficacy of sirolimus.”
Grapefruit juice’s pharmaceutical prowess stems from its ability to inhibit enzymes in the intestine that break down sirolimus and several other drugs. The effect begins within a few hours of what the researchers refer to as “grapefruit juice administration.” It wears off gradually over a few days.
Cohen and colleagues organized three simultaneous phase-1 trials of sirolimus. Patients received only sirolimus, sirolimus plus ketoconazole, or sirolimus plus grapefruit juice. They enrolled 138 patients with incurable cancer and no known effective therapy.
The first patients started with very low sirolimus doses, but the amounts increased as the study went on, to see how much of the drug was required in each setting to reach targeted levels, so that patients got the greatest anti-cancer effect with the least side effects.
The optimal cancer-fighting dose for those taking sirolimus was about 90 mg per week. At doses above 45 mg, however, the drug caused serious gastrointestinal problems, such as nausea and diarrhea, so patients taking sirolimus alone switched to 45 mg twice a week.
The optimal doses for the other two groups were much lower. Patients taking sirolimus plus ketoconazole, needed only 16 mg per week to maintain the same levels of drug in the blood. Those taking sirolimus plus grapefruit juice, needed between 25 and 35 mg of sirolimus per week.
“This is the first cancer study to harness this drug-food interaction,” the authors note.
No patients in the study had a complete response, but about 30 percent of patients in the three trials had stable disease, meaning a period when their cancers did not advance. One patient receiving grapefruit juice had a partial response — significant tumor shrinkage — that lasted for more than three years.
Although ketoconazole produced a slightly stronger drug-retention effect, grapefruit juice has the advantage that it is non-toxic, with no risk of overdose. “Therefore,” the authors wrote, “we have at our disposal an agent that can markedly increase bioavailability (in this study by approximately 350%) and, critically in the current environment, decrease prescription drug spending on many agents metabolized by P450 enzymes.”
Sirolimus was the first of a series of drugs, known as mTOR inhibitors, that were developed to prevent rejection of transplanted organs but that also have anti-cancer effects. As the first of its class, it was also the first to come off patent, making it less costly. “Further cost savings,” the authors suggest, could be realized “by combining the drug with agents that inhibit its metabolism.”
Because different people produce varied amounts of the enzymes that break down sirolimus, the effect of grapefruit juice can vary, but tests of enzyme levels may be able to predict how an individual patient will respond.
“The variation in potency of the grapefruit juice itself may be far greater than the variation in the enzymes that break down sirolimus,” Cohen said. An early version of the study used canned grapefruit juice, generously donated by a Chicago-based grocery chain. But tests of the product found it lacked the active ingredients. So the researchers shifted to a frozen concentrate product supplied by the Florida Department of Citrus.
This study was supported by the National Institutes of Health — and not by a pharmaceutical company. Dose-finding studies are “not necessarily profitable” for drug makers, the authors note, especially if the study results in lower recommended doses after the drug has been approved and priced.
Additional authors of this study include Kehua Wu, Christine Hartford, Masha Kocherginsky, Yuanyuan Zha, Anitha Nallari, Michael Maitland, Kammi Fox-Kay, Kristin Moshier, Larry House, Jacqueline Ramirez, Samir Undevia, Gini Fleming, Thomas Gajewski and Mark Ratain of the University of Chicago, and Kimberly Eaton of the University of Texas Medical School at Houston.
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