Fundam Clin Pharmacol

BACKGROUND: Due to its psychoactive effects, ketamine has become a drug used for non-medical purpose. OBJECTIVES: To assess the latest trends in ketamine use among people with substance use disorder and to characterize its clinical complications using complementary health data sources of the French Addictovigilance Network. METHODS: First, we extracted all reports involving ketamine from 2012 to 2021 from the database of the OPPIDUM program (i.e., a multicentric program conducted in collaboration with hundreds of substance abuse treatment facilities that collects data on drugs used by subjects with substance use disorders). We described the reports globally and the changes from 2012 to 2021. Second, we extracted all cases involving ketamine from July 2020 to December 2022 from the French National Pharmacovigilance Database (BNPV). We identified the cases related to ketamine use among people with substance use disorder and described them. RESULTS: There was a 2.5-fold increase in the number of ketamine users with substance use disorder in the OPPIDUM program, from 35 (0.7%) subjects in 2012 to 89 (1.7%) subjects in 2021. There was an increase in the proportion of subjects who were daily users, had distress upon discontinuation, and presented addiction. There were 238 cases related to ketamine use among people with substance use disorder in the French National Pharmacovigilance Database from July 2020 to December 2022. Among them, 94 (39.5%) cases involved ketamine use disorder, 20 (8.4%) cases involved urinary tract and kidney symptoms, and 13 (5.5%) cases involved hepatobiliary symptoms. CONCLUSION: The trend observed over 10 years reflects the growth in ketamine use among people with substance use disorder, although it does not allow to estimate the rates of non-medical use of ketamine in the general population. Ketamine-induced uropathy and cholangiopathy are reported in ketamine users with substance use disorder, especially in case of repeated and/or prolonged use of high doses

rs11886868 and rs4671393 of BCL11A associated with HbF level variation and modulate clinical events among sickle cell anemia patients

International audienceAims: Fetal hemoglobin (HbF) modulates the phenotype of sickle cell anemia (SCA) by inhibiting deoxy sickle hemoglobin (HbS) polymerization. HbF genes are genetically regulated, and the level of HbF and its distribution among sickle erythrocytes is highly variable. Herein, we aimed to determine whether two functional polymorphisms of BCL11A are implicated in the variation of HbF and clinical events in SCA Tunisian patients. Material and methods: The studied population consisted of 148 SCA patients with SS phenotype. The group of patients was divided into two subgroups according to the threshold point of %HbF which is 15%. Genotyping of rs11886868 and rs4671393 was performed using PCR/Sequencing. To test for trait association with the candidate SNPs, genotype and allele frequencies between `group who had %HbF 15' (controls) were compared using Pearson's chi-square test (compare 2, version 1.02). The association of each genotype and the combined genotype with complications was performed by logistic regression test. Results: Our findings showed that the majority of patients carried genotype CT of rs11886868 and genotypes AG and GG of rs4671393 present HbF level < 15%. RR = 0.08, RR = 0.176, and RR = 0.189, respectively. The results showed a significant association between the alleles T of rs11886868 and G of rs4671393 and %HbF < 15% with P = 0.016; RR = 0.39 and P = 8.9 x 10(-3): RR = 0.567, respectively. Interestingly, the C allele of the rs11886868 and the A allele of the rs46713939 were associated with an ameliorated phenotype in patient's SCA. The combination of the genotypes GG and CT explains more phenotypic variance than the sum of the two BCL11A SNPs taken individually

Genetic link with cholelithiasis among pediatric SCA Tunisian patients: Examples of UGT1A1, SLCO1A2 and SLCO1B1

International audienceAims and background: Hyperbilirubinemia is often observed in chronic hemolysis and results in the formation of pigment cholelithiasis that could be increased by the presence of defected enzymes involved in the bilirubin metabolism. Indeed, this is the first report that interested in the study of polymorphisms in genes encoded for enzymes involved in the bilirubin metabolism: rs 4149056 of SLCO1B1 and rs4149000 of SLCO1A2 in combination with rs8175347 and rs887829 of UGT1A1 in order to find a correlation between the polymorphisms studied and the presence of gallstones in a population of sickle cell anemia (SCA) pediatric Tunisians. Material and methods: Our study involved 102 unrelated Tunisian subjects. All SCA patients are children (less than 16 years old) and were characterized by hyperbilirubinemia and 52 of them have cholelithiasis. The polymorphisms of the candidate genes were analyzed for all subjects by PCR/sequencing. Genotype and allele frequencies between cases and controls were compared using Pearson's chi-square test with a significance threshold of P < 0.05 (compare 2, version 1.02). Results: The novelty of this report is that children carrying the combined genotype of the rs studied: (TA7TA7)/TT/TC/GA have a higher risk to develop gallstones (P = 0.0027, RR = 18.27 (20.0061-915.28)). Conclusion: Altogether our data provide the implication of UGT1A1 and SLCO1A2 in sickle cell anemia-related cholelithiasis

Phenotypic and molecular genetic analysis of Pyruvate Kinase deficiency in a Tunisian family

Pyruvate Kinase (PK) deficiency is the most frequent red cell enzymatic defect responsible for hereditary non-spherocytic hemolytic anemia. The disease has been studied in several ethnic groups. However, it is yet an unknown pathology in Tunisia. We report here, the phenotypic and molecular investigation of PK deficiency in a Tunisian family. This study was carried out on two Tunisian brothers and members of their family. Hematological, biochemical analysis and erythrocyte PK activity were performed. The molecular characterization was carried out by gene sequencing technique. The first patient died few hours after birth by hydrops fetalis, the second one presented with neonatal jaundice and severe anemia necessitating urgent blood transfusion. This severe clinical picture is the result of a homozygous mutation of PKLR gene at exon 8 (c.1079G>A; p.Cys360Tyr). Certainly, this research allowed us to correlate the clinical phenotype severity with the identified mutation. Moreover, this will help in understanding the etiology of unknown anemia in our country

Association of rs1319868, rs1567811 and rs8041224 of gene with infection among sickle cell anemia Tunisian patients

Background and aimSickle cell anemia (SCA) is characterized by variable patterns of clinical expression. Polymorphisms linked to different genes have been associated with specific complications of the disease. Herein, we focused on the study of the association of 4 polymorphisms of Insulin like Growth Factor 1 receptor (IGF1R) gene with infections, which are the major cause of death in SCA.Material and methodsThis study involved 116 sickle cell patients among whom 58 SS have the same confirmed infectious phenotype. Allele-Specific PCR was performed for the study of rs1319868, whereas the PCR/sequencing method was carried out for rs1567811, rs2872060 and rs8041224.ResultsThe results showed that rs1319868 and rs1567811 were associated with a decreased risk of infection among SS patients (p=0.038, RR=0.54; p=0.044, RR=0.56, respectively). Interestingly, the combination of different genotypes showed the association of the genotype GT of rs1319868 and the genotype CC of rs8041224 with further decreased infection risk in SCA (p=0.028, RR=0.04).ConclusionThese significant associations of IGF1R SNPs with infection suggest that this gene could play an important role in the immune function in SCA

Augmentation des complications sanitaires graves lors de l’usage non-médical du protoxyde d’azote en France

International audienc

Augmentation des surdoses et décès en lien avec la consommation de méthadone durant la crise sanitaire liée au COVID-19 en 2020

International audienceDue to the risk of overdoses increase especially with methadone, a reinforced monitoring has been set up by the French Addictovigilance Network following the first lockdown related to coronavirus disease 2019 (COVID-19). In this context, we managed a specific study to analyze overdoses related to methadone in 2020 compared to 2019. We analyzed methadone-related overdoses which occurred in 2019 and 2020 from two sources: DRAMES program (deaths with toxicological analysis) and the French pharmacovigilance database (BNPV) (overdoses that did not lead to death). Data from DRAMES program in 2020 show methadone as the first drug involved in deaths as well as an increase in deaths: in number (n=230 versus n=178), in proportion (41% versus 35%) and number of deaths per 1000 exposed subjects (3.4 versus 2.8). According to BNPV, the number of overdose increased in 2020 compared to 2019 (98 versus 79; i.e., 1.2-fold increase) particularly during several target periods: first lockdown, end of lockdown/summer period and second lockdown. In 2020, a higher number of cases were observed in April (n=15) and May (n=15). Overdoses and deaths occurred in subjects enrolled in treatment programs or not (naïve subjects/occasional users who obtained methadone from street market or family/friends). Overdoses resulted from different factors: overconsumption, multiple drug use with depressants drugs or cocaine, injection, consumption for sedative, recreational purposes or voluntary drug poisoning. All these data show an increase of morbidity and mortality related to methadone during COVID-19 epidemic. This trend has been observed in other countries.Une surveillance renforcée a été mise en place par le réseau français d’addictovigilance à la suite du premier confinement lié au (COVID-19), en raison du risque d’augmentation des surdoses, notamment avec la méthadone. Dans ce contexte, une étude a été mise en place pour décrire les surdoses liées à la méthadone en 2020 au regard de l’année 2019. Les surdoses liées à la méthadone ont été analysées selon deux sources : le dispositif DRAMES (décès avec analyses toxicologiques) et la base nationale de pharmacovigilance (BNPV) pour les surdoses non fatales. D’après les données DRAMES, la méthadone est toujours la première substance impliquée dans les décès en 2020 avec une augmentation des décès : en nombre ( = 230 en 2020 versus = 178 en 2019), en proportion (41 % versus 35 %) et en nombre de décès pour 1000 sujets exposés (3,4 versus 2,8). D’après la BNPV, le nombre de surdoses a augmenté en 2020 par rapport à 2019 (98 versus 79 ; soit multiplié par 1,2) en particulier durant certaines périodes cibles : premier confinement, déconfinement/période estivale et deuxième confinement. En 2020, le nombre le plus important de surdoses a été observé en avril ( = 15) et mai ( = 15). Les surdoses sont survenues chez des consommateurs de méthadone dans le cadre d’un protocole de soins ou en dehors (sujets naïfs/consommateurs occasionnels ayant obtenu la méthadone via le marché de rue ou l’entourage). Les surdoses résultent de différents facteurs : surconsommation, polyconsommation avec d’autres dépresseurs ou cocaïne, injection, consommation à des fins sédatives, récréatives ou intoxication médicamenteuse volontaire. L’ensemble de ces données montre une augmentation de la morbi-mortalité liée à la méthadone pendant l’épidémie de COVID-19 en 2020. Ce phénomène a été également constaté dans d’autres pays