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.

Ethanol Toxicity During Brain Development: Alterations of Excitatory Synaptic Transmission in Immature Organotypic Hippocampal Slice Cultures.

BACKGROUND: The developing brain is particularly vulnerable to alcohol: Drinking during pregnancy can lead to a number of physical, learning, and behavioral disorders in the newborn. It has been demonstrated that immature and mature brain tissues display a differential sensitivity to ethanol (EtOH) toxicity and that cerebral structure and function are diversely impaired according to the stage of synaptic maturation. METHODS: Rat organotypic hippocampal slice cultures were exposed for 7 days to EtOH (100 to 300 mM) after 2 days (immature) or 10 days (mature) of culture in vitro; EtOH was then removed from the medium, and 24 hours later, slices were analyzed by fluorescence microscopy, Western blotting, electrophysiology, and electron microscopy to explore the molecular mechanisms of EtOH toxicity in the developing hippocampus. RESULTS: EtOH withdrawal elicited a selective CA1 pyramidal cell injury in mature slices, but not in immature slices. A significant increase in the expression of pre- and postsynaptic proteins in mature slices revealed that slice maturation is presumably associated with the development of new synapses. Incubation with chronic EtOH for 7 days and its removal from the medium induced a significant decrease in GluA1 and GluA2 expression levels; a significant reduction in the expression of synaptophysin and GluN2A was observed only after EtOH withdrawal. Whole-cell patch-clamp recordings showed that incubation with EtOH for 7 days induced a significant decrease in spontaneous excitatory postsynaptic current (sEPSC) frequency in CA1 pyramidal cells of immature slices and a trend toward a decrease in sEPSC amplitude. Electron microscopy revealed a disorganization of neurotubuli in immature slices after chronic exposure to EtOH. CONCLUSIONS: These results indicate that prolonged incubation with EtOH and its subsequent withdrawal from the medium induce an impairment of excitatory synaptic transmission and possibly an incorrect formation of neuronal circuits in developing hippocampus in vitro, which is suggestive of mechanisms that may lead to mental retardation in fetal alcohol spectrum disorders.

Clinical manifestations and analytical reports for MDPHP acute intoxication cases.

MDPHP is a synthetic cathinone (SC) belonging to α-pyrrolidinophenone derivatives. It is a central nervous system stimulant and may induce hallucinations, paranoia, tachycardia, hypertension, chest pain, and rhabdomyolysis. In literature, a few cases of intoxication have been reported. In the present study, 17 cases of MDPHP intake were described including the analytical findings and clinical manifestations. MDPHP was quantified by liquid chromatography-tandem mass spectrometry in blood (range 1.26-73.30 ng/mL) and urine (range 19.31-8769.64 ng/mL) samples. In three cases the presence of α-PHP was observed. In one case, MDPHP was the only detected substance. Concomitant use of MDPHP with other substances, particularly psychostimulants, was common and it was difficult to describe the peculiar clinical characteristics of this SC. Most of the symptoms overlapped those expected, some of them were unusual and all of them particularly severe thus inducing the research of NPS in laboratory tests. We demonstrated the presence of psychiatric, neurological, and respiratory symptoms, as well as the possible presence of rhabdomyolysis and cardiotoxicity associated with the use of MDPHP. ED admissions were also more frequent in patients with addiction problems. In some cases, MDPHP intake required intensive supportive care. A multidisciplinary approach, including specialist consultation, is recommended for patients showing challenging features. Moreover, we demonstrated that the adoption of advanced analytical techniques, i.e., liquid chromatography-tandem mass spectrometry, is necessary to detect these molecules. Further studies are needed to understand MDPHP intake patterns and associated symptoms. It is essential to raise awareness in addiction treatment centers and among potential users, especially young people, and chemsex addicted.

Prognostic value of dobutamine stress echocardiography in octogenarians.

The prognostic value of dobutamine stress echocardiography (DSE) for risk stratification of patients aged ≥ 80 years is not clearly defined. A follow-up of 3 ± 2 years for major cardiac events and all-cause mortality was obtained in 227 patients, age ≥ 80 years, who underwent DSE for known or suspected coronary artery disease. Stress function index (SFI), calculated as the ratio of peak wall motion score index to left ventricular ejection fraction, was analyzed both as continuous variable and categorized using the mean value of 5 as the cut-off. Only 95 patients (42%) of this group underwent a cycloergometer exercise stress test (EST). During DSE 118 patients developed inducible ischemia; SFI was 4.9 ± 2.6 and 60 subjects showed a value higher than 5. EST gave a positive result in 12 patients and a negative result in 8 patients; it was inconclusive for inadequate increase in heart rate in 75 (79%) subjects. Advanced age (HR: 1.184/year, 95% CI: 1.073-1.306, p = 0.001) and SFI ≥ 5 (HR: 2.682, 95% CI: 1.429-5.035, p = 0.002) were independent predictors of all-cause mortality; advanced age (HR: 1.252/year, 95% CI: 1.064-1.473, p = 0.007), SFI ≥ 5 (HR: 3.181, 95% CI: 1.174-8.621, p = 0.02) and presence of left bundle branch block (HR: 3.060, 95% CI: 1.057-8.862, p = 0.039) independently predicted an increased occurrence of major cardiac events. No parameter derived from EST showed an independent prognostic role. DSE showed a significant prognostic value in octogenarians, both for all-cause mortality and major cardiac events.