Brunella Occupati

Histamine release from rat mast cells induced by metabolic activation of polyunsaturated fatty acids into free radicals

Polyunsaturated fatty acids (PUFA: arachidonic and linoleic acid) release histamine from isolated purified rat serosal mast cells only in the presence of oxidizing systems such as phenobarbital-induced rat liver microsomes, prostaglandin-H-synthetase (PHS) or soybean lipoxygenase. The release of mast cell histamine by activated PUFA has a long time-course and the electron microscopical features are consistent with an exocytotic secretion in the case of arachidonic acid and cell lysis in the case of linoleic acid. The phenomenon is associated with a significant increase in malonyldialdehyde (MDA) and conjugated diene generation, suggesting a relationship between histamine release and membrane lipid peroxidation. The secretion of histamine was inhibited by anti-free radical interventions such as D-mannitol, reduced glutathione and alpha-tocopherol. Some cyclooxygenase and lipoxygenase inhibitors, cimetidine and carnitine derivatives, are differentially active in the inhibition of mast cell histamine release by activated arachidonic acid. These results suggest that free radical derivatives of PUFA, generated by metabolic activation, trigger mast cell histamine release.

Methadone Dose Adjustments, Plasma R-Methadone Levels and Therapeutic Outcome of Heroin Users: A Randomized Clinical Trial

Aims: We aimed to improve the retention in treatment and therapeutic outcome of methadone maintenance treatment (MMT) patients by adjusting the oral methadone dose in order to reach a “target” plasma R-methadone level (80–250 ng/mL). Methods: A multicenter randomized controlled trial was organized. Results: The intention-to-treat statistical analysis showed that repeated dose adjustments performed in order to obtain therapeutic plasma R-methadone levels did not improve retention in treatment of heroin-dependent patients. However, patients having plasma methadone levels in the “target range” at the beginning of the study had a better retention in treatment than controls. Furthermore, patients succeeding in keeping plasma R-methadone target levels (per protocol analysis) remained in treatment and improved their social scores better than controls. Conclusion: Although the primary endpoint of this study was not demonstrated, a post hoc and a per protocol analysis suggested that patients in MMT with plasma R-methadone concentrations in the target range have a better therapeutic outcome than controls.

Histamine release by free radicals: The relationship with the signal transduction system

In isolated rat serosal mast cells exposed to free radical-generating systems, the release of histamine was associated with a significant increase in malonyldialdehyde (MDA) production suggesting a relationship between histamine release and membrane lipid peroxidation. Under these circumstances, an increase in cytosolic calcium was observed, uncoupled with any stimulation of inositol phospholipid (PtdIns) breakdown. The data suggest similarities between the release of histamine induced by calcium ionophores and by free radical-generating systems.

Efficacy of high-frequency (15 Hz) repetitive transcranial magnetic stimulation (rTMS) of the left premotor cortex/dorsolateral prefrontal cortex in decreasing cocaine intake (the MagneTox study): A study protocol for a randomized placebo-controlled pilot trial

BACKGROUND Cocaine use disorder (CUD) is very common and has psychological and physical consequences. Patients with CUD present hypoactivity of the prefrontal cortical area. Thus, excitatory repetitive transcranial magnetic stimulation (rTMS) targeting the premotor cortex/dorsolateral prefrontal cortex (PMC/DLPFC), given its ability to increase prefrontal area excitability and to modulate cortico-limbic activity, could result in a decrease in cocaine intake. METHODS We designed a protocol for a monocentric, randomized, double-blind, placebo-controlled, parallel-group pilot trial, with the principal aim of assessing the efficacy of rTMS on the reduction of cocaine intake. Patients with CUD will be recruited according to inclusion and exclusion criteria, and then randomized to undergo active or sham rTMS. Our rTMS protocol will consist of 15 days of 15Hz rTMS targeting the left PMC/DLPFC. Toxicological and psychiatric assessments, urine drug tests, the Cocaine Craving Questionnaire (CCQ) and the Visual Analogic Scale (VAS) will be used to assess changes from baseline in cocaine intake and craving, mood and quality of life. DISCUSSION Only a few studies have evaluated the efficacy of rTMS for CUD treatment in humans, with limitations concerning small sample size, short treatment duration, different rTMS protocols and the absence of a placebo-controlled group. Our study will attempt to overcome these shortcomings and will provide data that can be used for future larger studies of non-invasive left PMC/DLPFC stimulation as a treatment for CUD.

P057. Prophylaxis with low-dose methadone in patients affected by daily refractory headache and medication-overuse headache: a prospective cohort study (METACEF study)

Results Since May 3, 2012 up to January 8, 2015, we enrolled 24 patients (18 females, 6 males; average age, 48 years) who were considered eligible to be treated with methadone. Nine patients dropped out because of adverse drug reactions (n=4, mean time of drop-out 7 days) or treatment ineffectiveness (n=5, mean time of drop-out 6 months). Six patients completed the 12-month treatment. After 1-year follow-up they still reported daily headache, however, they showed an impressive decrease of analgesic and/or antimigraine drug consumption (from 147.7 medications per month ± SD 124 to 8.5 medications per month ± SD 6.1) and a significant decrease of visual analogic scale (VAS) pain intensity (from 5.8 ± SD 2.6 to 2.8 ± SD 2.1). These patients were treated with daily methadone doses ranging from 5 mg to 60 mg; methadone dosages were safe and well tolerated. Conclusions In patients affected by daily refractory headache and medication-overuse headache, who are exposed to the risk of serious side effects due to prolonged analgesic and/or antimigraine treatment, prophylaxis with low-dose methadone therapy seems to represent an effective therapeutic option. Written informed consent to publication was obtained from the patient(s).