Plasma level monitoring of the major metabolites of diacetylmorphine (heroin) by the "chasing the dragon" route in severe heroin addicts

peer reviewedThe objective of the present study was to verify if severe physical health problems frequently encountered in heroin addicts and the concomitant use of alcohol and legal or illegal drugs other than heroin influenced the pharmacokinetics of the major metabolites of heroin. We conducted a 90 minutes follow-up of the plasma concentrations of the pharmaceutical heroin, named diacetylmorphine (DAM), in patients recruited in a DAM assisted treatment centre. TADAM (Traitement Assisté par DiAcétylMorphine) aimed to compare the efficacy of heroin-assisted treatment (HAT) compared with methadone maintenance treatment (MMT) for heroin users considered as treatment resistant patients and who have severe physical and mental health problems. Eleven patients were recruited. Blood samples were collected at baseline and 15, 45 and 90 minutes after DAM administration. All patients received DAM by the "chasing the dragon" route. Plasma samples were analyzed by a previously described ultra-high pressure liquid chromatography coupled to tandem mass spectrometry (UHPLC/MS-MS) method. A principal component analysis (PCA) was performed and 8 metabolite concentrations ratios were calculated to evaluate the influence of various factors (DAM dose, patient pathologies, concomitant use of medications, methadone, street heroin, alcohol and cocaine) on heroin metabolite pharmacokinetics. It seemed to be not affected by the DAM dose, patient pathologies and the concomitant use of medications, methadone, street heroin and alcohol. Cocaine use was the only parameter which showed differences in heroin pharmacokinetics

Homologous Transcription Factors DUX4 and DUX4c Associate with Cytoplasmic Proteins during Muscle Differentiation

Hundreds of double homeobox (DUX) genes map within 3.3-kb repeated elements dispersed in the human genome and encode DNA-binding proteins. Among these, we identified DUX4, a potent transcription factor that causes facioscapulohumeral muscular dystrophy (FSHD). In the present study, we performed yeast two-hybrid screens and protein co-purifications with HaloTag-DUX fusions or GST-DUX4 pull-down to identify protein partners of DUX4, DUX4c (which is identical to DUX4 except for the end of the carboxyl terminal domain) and DUX1 (which is limited to the double homeodomain). Unexpectedly, we identified and validated (by co-immunoprecipitation, GST pull-down, co-immunofluorescence and in situ Proximal Ligation Assay) the interaction of DUX4, DUX4c and DUX1 with type III intermediate filament protein desmin in the cytoplasm and at the nuclear periphery. Desmin filaments link adjacent sarcomere at the Z-discs, connect them to sarcolemma proteins and interact with mitochondria. These intermediate filament also contact the nuclear lamina and contribute to positioning of the nuclei. Another Z-disc protein, LMCD1 that contains a LIM domain was also validated as a DUX4 partner. The functionality of DUX4 or DUX4c interactions with cytoplasmic proteins is underscored by the cytoplasmic detection of DUX4/DUX4c upon myoblast fusion. In addition, we identified and validated (by co-immunoprecipitation, co-immunofluorescence and in situ Proximal Ligation Assay) as DUX4/4c partners several RNA-binding proteins such as C1QBP, SRSF9, RBM3, FUS/TLS and SFPQ that are involved in mRNA splicing and translation. FUS and SFPQ are nuclear proteins, however their cytoplasmic translocation was reported in neuronal cells where they associated with ribonucleoparticles (RNPs). Several other validated or identified DUX4/DUX4c partners are also contained in mRNP granules, and the co-localizations with cytoplasmic DAPI-positive spots is in keeping with such an association. Large muscle RNPs were recently shown to exit the nucleus via a novel mechanism of nuclear envelope budding. Following DUX4 or DUX4c overexpression in muscle cell cultures, we observed their association with similar nuclear buds. In conclusion, our study demonstrated unexpected interactions of DUX4/4c with cytoplasmic proteins playing major roles during muscle differentiation. Further investigations are on-going to evaluate whether these interactions play roles during muscle regeneration as previously suggested for DUX4c

DUX4c Is Up-Regulated in FSHD. It Induces the MYF5 Protein and Human Myoblast Proliferation

Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disease linked to contractions of the D4Z4 repeat array in 4q35. We have previously identified a double homeobox gene (DUX4) within each D4Z4 unit that encodes a transcription factor expressed in FSHD but not control myoblasts. DUX4 and its target genes contribute to the global dysregulation of gene expression observed in FSHD. We have now characterized the homologous DUX4c gene mapped 42 kb centromeric of the D4Z4 repeat array. It encodes a 47-kDa protein with a double homeodomain identical to DUX4 but divergent in the carboxyl-terminal region. DUX4c was detected in primary myoblast extracts by Western blot with a specific antiserum, and was induced upon differentiation. The protein was increased about 2-fold in FSHD versus control myotubes but reached 2-10-fold induction in FSHD muscle biopsies. We have shown by Western blot and by a DNA-binding assay that DUX4c over-expression induced the MYF5 myogenic regulator and its DNA-binding activity. DUX4c might stabilize the MYF5 protein as we detected their interaction by co-immunoprecipitation. In keeping with the known role of Myf5 in myoblast accumulation during mouse muscle regeneration DUX4c over-expression activated proliferation of human primary myoblasts and inhibited their differentiation. Altogether, these results suggested that DUX4c could be involved in muscle regeneration and that changes in its expression could contribute to the FSHD pathology

Heroin

peer reviewedSummary : Heroin (or diacetylmorphine), a depressant of the nervous central system, is a semi-synthetic opiate. Its main adverse effect, respiratory depression, can lead to death, especially after an intravenous injection. By loss of tolerance, an overdose can be lethal following heroin use after a period of abstinence (voluntary or not). Mortality rate among heroin users is between 1 and 3%. Addiction, following a regular and continuous use, occurs in less than a quarter of persons who ever tried heroine. Heroin addicts often present with different problems (for instance, a criminal behaviour), without any obvious link with addiction. For a fraction of the addicts, addiction becomes a chronic relapsing disease, requiring a long term maintenance substitution therapy. However, relapses and sometimes continuous heroin use are frequent. For treatment resistant and severe heroin addicts, heroinassisted treatment can be a solution. Despite the numerous available therapies, heroin is considered to be the drug with the most negative effects on the user.Projet TADAM, un projet pilote de traitement assisté par diacétylmorphin

Projet TADAM: Conclusions scientifiques et recommandations

Projet TADAM, un projet pilote de traitement assisté par diacétylmorphin

Le traitement assisté par héroïne a montré plus d'efficacité que le traitement par méthadone

Background: A fraction of patients receiving methadone treatment pursues their use of street heroin. In Switzerland, a new treatment with prescribed diacetylmorphine (pharmaceutical heroin) was developed to help these heroin addicts resistant to methadone treatment to decrease their street heroin use. In this heroin-assisted treatment (HAT), diacetylmorphine is prescribed to severe heroin user and diacetylmorphine is administered by patients under the supervision of nurses in a specific centre. Six randomised controlled trials compared HAT to methadone treatment: in Switzerland, The Netherlands, Spain, Germany, Canada and United- Kingdom. HAT showed better efficacy than methadone. Patients used less street heroin, their health improved and their criminal behaviour decreased. A new trial assessed in Belgium the feasibility and efficacy of this treatment compared to methadone treatment. Methods: The TADAM (Treatment Assisted by Diacetylmorphine) was an open label randomised controlled trial developed on the Swiss model of HAT developed in 1994. Main inclusion criteria were 5 years of heroin addiction, (almost) daily use of street heroin and a previous attempt of methadone treatment. As in the Dutch experiment, patients could choose to inhale or to inject diacetylmorphine in the new HAT centre. HAT was stopped after 12 months and the best available treatment was offered to the patient. The research team assessed subjects every three months with standardised questionnaires (EuropASI, MAP-HSS, SCL-90-R) and questions on involvement in a criminal milieu. We completed our reported data with toxicological analysis and criminal proceedings. Results: 74 subjects were randomised in the trial: 36 in the experimental group and 38 in the control group. According to the primary efficacy criterion, the experimental group counted at least 30% more responders than the control group after 3 months (p<0.05), 6 months (p<0.05) and 9 months (p<0.01). At the 12 month assessment, the number of responders was still higher in the experimental group but the difference (11%) was no more significant (p=0.35). At the 12 month assessment, the condition of patients in the experimental group worsened compared to the 9 month assessment. This effect was not seen in the control group were patients could continue their methadone treatment after the 12 months. Conclusion: As in other countries, HAT is an effective treatment for severe heroin addicts resistant to methadone treatment. However, a predetermined duration of 12 month counteracts the efficacy of this treatment

Efficacy of the treatmement assisted by diacetylmorphine (pharmaceutical heroin)

peer reviewedBefore implementing the TADAM project in Belgium (a heroin-assisted treatment trial), our research team studied the trials in other countries. Since 1994, six randomised controlled trials have been developed using the same treatment model of heroin-assisted treatment (HAT). Each trial concluded that HAT had more efficacy than methadone treatment. We analysed those trials in order to find on which levels patients in a HAT treatment are expected to improve. Improvements appeared after at least six months on the level of street heroin use, (physical and mental) health and criminal behaviour. In the longer term, the continuation of treatment had positive but limited effects on the social level. Due to his higher cost, this treatment should remain a second-line treatment for this special target group: severe heroin addicts, using continuously street heroin in spite of a methadone treatment.En préalable au projet belge TADAM (un essai clinique de traitement assisté par diacétylmorphine), notre équipe de recherche a étudié les essais cliniques réalisés à l’étranger. Depuis 1994, six études contrôlées randomisées ont été développées sur le même modèle de traitement par diacétylmorphine. Chacune de ces études a conclu à l’efficacité supérieure de ce traitement par rapport au traitement par méthadone. Sur base de ces études, nous avons cherché à définir les principaux effets positifs de ce traitement pour les patients. Les améliorations se sont manifestées après au moins six mois au niveau de la consommation d’héroïne de rue, de la santé (physique et mentale) et du comportement délinquant. A plus long terme, les patients ont montré des améliorations limitées au niveau social. Néanmoins, compte tenu de son coût élevé, ce traitement devrait rester un traitement de deuxième ligne pour le groupe cible spécifique des personnes sévèrement dépendantes de l’héroïne qui continuent à consommer de l’héroïne de rue quotidiennement malgré un traitement par méthadone.Projet TADAM, un projet pilote de traitement assisté par diacétylmorphin

Heroin-Assisted Treatment as a treatment of criminal behaviour?

Background: TADAM, a randomised controlled trial of heroin-assisted treatment, will begin in Liège, Belgium, in 2010. This trial will compare two groups of patients: one in a heroin-assisted treatment and the other in oral methadone treatment. In this new medical treatment, the criminal behaviour of the patients will also be assessed. It is one of the three efficacy criteria. Why? Methodology: We based our presentation on papers published on heroin-assisted treatment concerning changes in criminal behaviour. Results: Heroin-assisted treatment of treatment resistant heroin addicts has been successfully tested in six countries: Switzerland, The Netherlands, Spain, Germany, Canada and United-Kingdom. Each country has also assessed the criminal behaviour before and after the treatment with better results for heroin-assisted treatment than for methadone treatment. Conclusion: HAT seems a good way to treat criminal behaviour of a group: severely heroin addicts who already tried other treatments.TADA

Searches for dark matter in the center of the earth with the IceCube detector

Several models predict that dark matter is constituted of Weakly Interacting Massive Particles (WIMPs). Such particles would be attracted by the gravity of massive astronomical objects such as black holes, stars, and the Earth. WIMPs can lose energy through scattering with matter and become trapped in the gravitational field of these objects. They can then annihilate or decay resulting in production of Standard Model particles. The neutrinos thus created will escape, as they pass through ordinary matter almost unaffected. This contribution describes the search for WIMPs accumulated in the center of the Earth using the IceCube neutrino observatory located at the geographic South Pole. Results from the analysis with one year of IceCube data from 2011 will be presented along with the sensitivity for several additional years of data.SCOPUS: cp.pSCOPUS: cp.pinfo:eu-repo/semantics/publishe

Etude de faisabilité du traitement assisté par heroine à Liège en Belgique

A new heroin-assisted treatment, TADAM, has begun in Liège, Belgium. With the number of methadone patients (n=2046) in 2007, we estimated the geographical distribution of methadone treatments in the province of Liège, of heroin addicts and of potential participants for TADAM. The methadone treatments were unequally distributed. Some urban areas showed a signifi cant number of heroin addicts: more than 14/1000 of the population aged 15-64. As a conclusion, the trial is appropriately targeted to those high-density addiction areas.Un nouveau traitement assisté par diacetylmorphine (TADAM) a débuté à Liège en 2011. Grâce au nombre de patients en traitement par méthadonde (n=2046) en 2007, nous avons estimé la distribution géographique des patients en traitement par methadone dans la province de Liège ainsi que le nombre de personnes dépendantes de l’héroïne et le nombre de participants potentiels pour l’étude TADAM. Des zones urbaines de la province montraient un nombre signifi catif de personnes dépendantes de l’héroïne : plus de 14/1000 sur la population agée de 15 à 64 ans. En conclusion, l’expérimentation TADAM est correctement dirigée vers une zone à forte concentration de personnnes dependantes à l’héroïne