RESUMO
Methamphetamine (METH) is a highly addictive psychostimulant with serious neurotoxic effects. Given evidence indicating that brain-derived neurotrophic factor (BDNF) is associated with addictive behaviors, this study aimed to investigate the serum level of BDNF and cognitive functions in chronic METH users and healthy participants. Thirty-seven chronic METH users and 37 healthy participants were recruited in this study. Cognitive functioning, including executive functions and working memory, were assessed using the Wisconsin Card Sorting Test (WCST) and Wechsler Memory Scale (WMS), respectively. The levels of serum BDNF were also examined using an enzyme-linked immunosorbent assay kit. METH users showed significant impairment in executive function and working memory compared to healthy participants. The serum BDNF concentrations of METH users were significantly higher than healthy participants (42 ± 13.34 ng/ml vs. 24 ± 7 ng/ml). BDNF concentration was significantly correlated with duration (r = 0.37, p = 0.02) and dose of METH use (r = 0.35, p = 0.02). Besides, the BDNF level was not associated with any subscales of WCST and WMS. These results provide further evidence regarding the role of BDNF in the pathophysiology of METH addiction. Besides, these findings suggest that increased BDNF level is not related to cognitive impairments in METH users.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/sangue , Fator Neurotrófico Derivado do Encéfalo/sangue , Cognição , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Estimulantes do Sistema Nervoso Central/toxicidade , Usuários de Drogas , Função Executiva , Humanos , Masculino , Metanfetamina/toxicidadeRESUMO
Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Amphetamine addiction may cause serious of psychotic and physical damage to humans. There is some evidence that shows that amphetamine may increase the risk of PD. Thus, this study is aimed at comparing the PD serum biomarkers between amphetamine addicts and PD patients and utilizing them as diagnostic biomarkers for the early detection of PD incidence among amphetamine addicts. In the current study, nineteen amphetamine addicts, aged <40, were recruited from the Al Amal Psychiatric hospital, Jazan, Saudi Arabia. Nineteen PD patients and 19 healthy controls, who have never taken amphetamine, were also recruited. Blood samples were withdrawn from all groups. A biomarker multiplex assay from MILLIPLEX was used to assess the levels of serum amyloid-P (SAP), complement C4, C-reactive protein (CRP), and CRP/albumin ratio in serum samples (Vitros 350® slide was used to assess the albumin). All data were statistically analyzed using one-way ANOVA. The results showed that SAP and CRP levels were significantly higher in amphetamine addicts compared to healthy controls (p = 0.0001 and p = 0.0001, respectively). The results of amphetamine addicts were comparable to PD levels. However, there are no significant differences between all studied groups concerning complement C4 level. Moreover, albumin levels were significantly decreased and CRP/Albumin ratio levels were significantly increased in amphetamine addicts (p = 0.01 and p = 0.041, respectively) in contrast with controls. These findings indicate that the increased level of these inflammatory biomarkers (SAP and CRP) in the amphetamine addicts may give a potential possibility of their serum level to be used as screening markers to detect PD development in the amphetamine addict. It may be useful to evaluate the changes in easily accessible and cost-effective parameters such as the serum CRP/albumin ratio.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/sangue , Biomarcadores/sangue , Doença de Parkinson/sangue , Adulto , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Complemento C4/metabolismo , Feminino , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Curva ROC , Albumina Sérica/metabolismo , Componente Amiloide P Sérico/metabolismoRESUMO
Methamphetamine (METH) abuse has become a global public health problem. However, the potential mechanisms involving METH-induced metabolic disorders have thus far remained poorly understood. Metabolomics can provide a clue for the cause of apparent changes and consequently be used to investigate the METH-induced dysregulation of metabolite expression and the mechanism of metabolic disorder mechanism. This laboratory investigation included 80 METH abusers and 80 healthy people. The serum metabolites were detected and analysed by gas chromatography/time-of-flight mass spectrometry. Raw data were processed with the software MS DIAL, which includes deconvolution, peak alignment and compound identification. The data matrix was processed by univariate and multivariate analyses for significant metabolite screening with the criteria of variable importance in projection values > 1, fold change > 1.5 and the t test (p value < 0.05). Significant differences in 16 metabolites (deoxycholic acid, cholic acid, hydroxylamine, etc.) in serum were found between the METH abuse group and the control group. Energy metabolic pathways and several amino acid metabolic pathways (alanine, aspartic acid and glutamate metabolism and tryptophan metabolism) were primarily involved. Further analysis indicated that the area under the receiver operating characteristic curve (AUC) was 0.998 for these 16 metabolites. Among the metabolites, three carbohydrates (d-ribose, cellobiose and maltotriose) had an AUC of 0.975, which were determined as potential markers of abuse. We observed metabolic disturbances in METH abusers, particularly perturbation in energy metabolism and amino acid metabolism, which can provide new insights into the search for biomarkers and the mechanisms underlying the adverse effects of METH on human health.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Doenças Metabólicas/induzido quimicamente , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica/métodos , Metanfetamina/efeitos adversos , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/sangue , Biomarcadores , Estudos Transversais , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/fisiopatologia , Pessoa de Meia-Idade , Curva ROCRESUMO
BACKGROUND: Disclosure of one's sexual orientation as a sexual-minority (SM) person (i.e., being "out") may affect HIV-related health outcomes. This longitudinal study examined whether race/ethnicity moderated effects of outness on the plasma kynurenine/tryptophan (KT) ratio, a marker of dysregulated serotonin metabolism due to immune activation that predicts clinical HIV progression. METHODS: Participants were African American, Hispanic/Latino, and non-Hispanic White, methamphetamine-using SM men living with HIV (N = 97) who completed self-report scales of outness and SM stress at baseline for a randomized controlled trial of a positive affect intervention. Linear mixed modeling was used to test whether race/ethnicity and experimental condition moderated the association of baseline outness with the KT ratio at baseline, 6, 12, and 15 months controlling for SM stress, sociodemographics, HIV disease markers, and recent stimulant use. RESULTS: The interactions of outness by race/ethnicity and outness by experimental condition on the KT ratio were significant. Greater outness predicted a lower KT ratio over time in non-Hispanic White SM men, but not among SM men of color (MOC). Greater outness predicted a lower KT ratio over time for SM men in the control, but not among those in the intervention arm. CONCLUSION: Being more out may be protective for non-Hispanic White SM men, but not for their SM MOC peers. Outness mattered for participants who did not receive the positive affect intervention. Findings underscore the potentially different contexts and consequences of outness depending on SM men's race/ethnicity and whether they received a positive affect intervention. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/sangue , Transtornos Relacionados ao Uso de Anfetaminas/epidemiologia , Etnicidade/estatística & dados numéricos , Infecções por HIV/sangue , Infecções por HIV/epidemiologia , Minorias Sexuais e de Gênero/estatística & dados numéricos , Triptofano/sangue , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Estimulantes do Sistema Nervoso Central/sangue , Comorbidade , Seguimentos , Hispânico ou Latino/estatística & dados numéricos , Homossexualidade Masculina/estatística & dados numéricos , Humanos , Estudos Longitudinais , Masculino , Metanfetamina/sangue , São Francisco/epidemiologiaRESUMO
Psychiatric disorders such as anxiety and depression precipitated by substance use occurred during both use and withdrawal. Exosomes play significant roles in biological functions and regulate numerous physiological and pathological processes in various diseases, in particular substance use disorders (SUDs) and other psychiatric disorders. To better understand the role of exosomal miRNAs in the pathology of symptoms of anxiety and depression in patients with SUDs, we first isolated circulating exosomes from heroin-dependent patients (HDPs) and methamphetamine-dependent patients (MDPs) and identified exosomal miRNAs that were differentially expressed between patients and healthy controls (HCs). Furthermore, the correlations between exosomal DE-miRNAs and symptoms of anxiety and depression which were measured using Hamilton-Anxiety (HAM-A)/Hamilton-Depression (HAM-D) Rating Scales in the participants. Notably, the expression level of exosomal hsa-miR-16-5p, hsa-miR-129-5p, hsa-miR-363-3p, and hsa-miR-92a-3p showed significantly negative correlations with HAM-A scores in both HDPs and MDPs. But all of the 4 DE-miRNAs lost significant correlations with HAM-D scores in HDPs. Functional annotation analyses showed that the target genes of the DE-miRNAs were mainly enriched for "synapse", "cell adhesion", "focal adhesion" and "MHC class II protein complex". Our study suggests that a set of circulating exosomal miRNAs were associated with anxiety and depression in SUD patients and may have clinical utility as diagnostic and prognostic biomarkers.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/sangue , Transtornos Relacionados ao Uso de Anfetaminas/epidemiologia , Ansiedade/sangue , Ansiedade/epidemiologia , MicroRNA Circulante/sangue , Depressão/sangue , Depressão/epidemiologia , Exossomos/metabolismo , Dependência de Heroína/sangue , Dependência de Heroína/epidemiologia , Adulto , Transtornos de Ansiedade/epidemiologia , Biomarcadores/sangue , Estudos de Casos e Controles , MicroRNA Circulante/genética , Análise por Conglomerados , Comorbidade , Transtorno Depressivo/epidemiologia , Feminino , Humanos , Masculino , Prognóstico , RNA-Seq/métodosRESUMO
BACKGROUND: HIV infection and methamphetamine dependence (METH) are each associated with inflammation and premature aging, but their impact on biological aging is difficult to measure. Here we examined the impact of HIV and METH on leukocyte telomere lengths (LTL), and the correlations between LTL and other aging biomarkers. METHODS: The study was a cross-sectional analysis of 161 individuals categorized by HIV and methamphetamine (METH) dependence status into four groups: HIV-METH- (n = 50), HIV-METH+ (n = 29), HIV + METH- (n = 40), and HIV + METH+ (n = 42). We analyzed the relationships of leukocyte telomere length (telomere to single copy gene [T/S] ratio) with demographic and clinical data as well as a panel of biomarkers of inflammation and endothelial activation measured in blood and cerebrospinal fluid (CSF). RESULTS: HIV and METH were independently associated with shorter T/S ratio, even after adjusting for demographics and leukocyte count (R2 = 0·59, p < 0·0001). Higher plasma C-reactive protein (p = 0·0036) and CSF VCAM-1 (p = 0·0080) were also associated with shorter T/S ratio. A shorter T/S ratio was associated with higher risk for cardiovascular disease (p < 0·0001) and stroke (p < 0·0001), worse motor functioning (p = 0·037) and processing speed (p = 0·023), more depressive symptoms (p = 0·013), and higher CSF neurofilament-light (p = 0·003). CONCLUSIONS: HIV and METH dependence were each associated with shorter telomeres. After adjusting for demographics, HIV, and METH, T/S ratio remained associated with aging-related outcomes including neurocognitive impairment, neurodegeneration, risks of cardiovascular disease and stroke. While not establishing causality, this study supports using the T/S ratio as a biomarker for estimating the impact of HIV and comorbidities on long-term health.
Assuntos
Envelhecimento/sangue , Transtornos Relacionados ao Uso de Anfetaminas/sangue , Infecções por HIV/sangue , Mediadores da Inflamação/sangue , Metanfetamina/efeitos adversos , Telômero/fisiologia , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/epidemiologia , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Biomarcadores/sangue , Estudos de Coortes , Comorbidade , Estudos Transversais , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
OBJECTIVE: Withdrawal symptoms are common during methamphetamine (METH) abstinence. This study aimed to explore the association between serum interleukins and withdrawal symptoms during METH abstinence. METHODS: This study recruited 120 METH users, and 94 of them completed the 2-week follow-up. Serum interleukin-1ß, 6,8,10 were tested at admission. Withdrawal symptoms were assessed by the Methamphetamine Withdrawal Questionnaire (MAWQ). RESULTS: Serum IL-8 levels were positively correlated with MAWQ scores at the 2-week endpoint (r = .257, p = .013). The variation of the MAWQ scores during the 2-week follow-up was negatively correlated with serum IL-8 levels at admission (r = -.249, p = .026). Serum IL-8 levels remained associated with the severity of METH withdrawal symptoms (ß = .363, p = .023), after adjusting for potential confounders. LIMITATIONS: This study did not include normal controls. Most patients were male and cigarette smokers. Patients were only followed up for 2 weeks, and their toxicology data were not collected. Interleukins were only measured at admission, and were tested in serum, not in the cerebrospinal fluid. CONCLUSIONS: Our study demonstrated that higher serum IL-8 levels may predict more severe withdrawal symptoms at 2 weeks after METH abstinence.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/reabilitação , Interleucina-8/sangue , Metanfetamina/efeitos adversos , Síndrome de Abstinência a Substâncias/fisiopatologia , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/sangue , Feminino , Seguimentos , Humanos , Masculino , Metanfetamina/administração & dosagem , Estudos Prospectivos , Síndrome de Abstinência a Substâncias/sangue , Inquéritos e Questionários , Adulto JovemRESUMO
OBJECTIVES: Drug abuse is one of the most severe global social and public health problems, especially in China. However, objective blood biomarkers that are easy to detect are still in great need. This study was aim to explore the expression pattern of circulating microRNAs (miRNAs) in subjects with drug addiction and test the potential of altered serum miRNAs as noninvasive diagnostic tools for drug abuse. METHODS: Serum samples were obtained from 42 heroin abusers, 42 methamphetamine (MA) abusers and 42 controls. Microarray-based miRNA analysis was first applied to screen unique serum miRNA profiles in drug abusers on a training set of serum samples from 12 heroin abusers, 12 MA abusers and 12 control subjects. The expression levels of selected candidate miRNAs were subsequently verified in individual samples of the training set and further confirmed independently in a validation set of samples from 30 heroin abusers, 30 MA abusers and 30 controls using real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: Microarray analysis identified 116 and 109 significantly altered miRNAs in heroin abusers and MA abusers, respectively. Three miRNAs, including let-7b-5p, miR-206 and miR-486-5p, were verified to be significantly and steadily increased in heroin abusers, and miR-9-3p was significantly increased in MA abusers compared with normal controls. The areas under the curve (AUCs) of the ROC curve of these miRNAs ranged from 0.718 to 0.867. CONCLUSIONS: Our study raises the possibility that the altered serum miRNAs could potentially be used as an auxiliary tool to identify individuals in drug abuse and addiction.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/sangue , Perfilação da Expressão Gênica/métodos , Dependência de Heroína/sangue , Heroína/efeitos adversos , Metanfetamina/efeitos adversos , MicroRNAs/sangue , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/genética , Biomarcadores/sangue , Feminino , Dependência de Heroína/genética , Humanos , Masculino , MicroRNAs/biossíntese , MicroRNAs/genética , Pessoa de Meia-IdadeRESUMO
Methamphetamine (MA) is the largest drug threat across the globe, with health effects including neurotoxicity and cardiovascular disease. Recent studies have begun to link microRNAs (miRNAs) to the processes related to MA use and addiction. Our studies are the first to analyse plasma EVs and their miRNA cargo in humans actively using MA (MA-ACT) and control participants (CTL). In this cohort we also assessed the effects of tobacco use on plasma EVs. We used vesicle flow cytometry to show that the MA-ACT group had an increased abundance of EV tetraspanin markers (CD9, CD63, CD81), but not pro-coagulant, platelet-, and red blood cell-derived EVs. We also found that of the 169 plasma EV miRNAs, eight were of interest in MA-ACT based on multiple statistical criteria. In smokers, we identified 15 miRNAs of interest, two that overlapped with the eight MA-ACT miRNAs. Three of the MA-ACT miRNAs significantly correlated with clinical features of MA use and target prediction with these miRNAs identified pathways implicated in MA use, including cardiovascular disease and neuroinflammation. Together our findings indicate that MA use regulates EVs and their miRNA cargo, and support that further studies are warranted to investigate their mechanistic role in addiction, recovery, and recidivism.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/sangue , MicroRNA Circulante/sangue , Vesículas Extracelulares/metabolismo , Metanfetamina/efeitos adversos , Adulto , Biomarcadores/sangue , Feminino , Citometria de Fluxo , Humanos , Masculino , Metanfetamina/administração & dosagem , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Folate deficiency is shown to be associated with schizophrenia. Folate profile in patients with psychosis due to stimulant use has not been investigated. We aim to determine whether there is an association between serum folate level and the presence of psychosis in patients with methamphetamine (METH) use disorder. METHODS: Forty patients diagnosed with METH-use disorder were included in this cross-sectional study. Serum folate levels were measured using enzyme immunoassay technique and compared between psychotic and non-psychotic subgroups (Nâ¯=â¯25 and 15, respectively). We designed a logistic regression model to measure the extent of any association and also to adjust for potential confounders. RESULTS: We detected lower serum folate level in the psychotics [3.4 (IQRâ¯=â¯5.3)] compared to non-psychotic METH users [8.9 (IQRâ¯=â¯2.5)], pâ¯=â¯0.01. The model demonstrated that every 1-unit increase in serum folate decreases the odds of presence of psychosis by 27% (R2â¯=â¯53.5%, CI 12-64%, pâ¯=â¯0.006). The observed difference was not associated with the duration of METH use, patient's age at first METH use, or concurrent use of other substances. CONCLUSIONS: Our findings suggest that low folate level in psychotic METH users does not correlate with previously established risk factors for meth-induced psychosis such as duration of use, age of onset of using, and poly-drug use. We assume that low folate levels may play a crucial role in the pathophysiology of psychosis.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/sangue , Estimulantes do Sistema Nervoso Central/efeitos adversos , Ácido Fólico/sangue , Metanfetamina/efeitos adversos , Psicoses Induzidas por Substâncias/sangue , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Psicoses Induzidas por Substâncias/diagnóstico , Fatores de RiscoRESUMO
An enterogenic infection occurs when intestinal mucosal disruption is followed by the invasion of intestinal bacteria into the blood and distant organs, which can result in severe diseases or even death. Our previous study using Rhesus monkeys as an in vivo model revealed that methamphetamine (MA) induced intestinal mucosal barrier damage, which poses a high risk of enterogenic infection. However, how methamphetamine causes intestinal mucosal barrier damage remains largely unknown. In this study, we employed an in vitro model, and found that MA treatment could inhibit the expression of miR-181c, which directly targets and regulates TNF-α, and ultimately induces apoptosis and damages the intestinal barrier. Moreover, we measured TNF-α serum levels as well as the intestinal mucosal barrier damage indicators (diamine oxidase, d-lactic acid, and exotoxin) and found that their levels were significantly higher in MA-dependents than in healthy controls (P < 0.001). To the best of our knowledge, this is the first report evidencing that miR-181c is involved in MA-induced intestinal barrier injury via TNF-α regulation, which introduces novel potential therapeutic targets for MA-dependent intestinal diseases.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Estimulantes do Sistema Nervoso Central/efeitos adversos , Células Epiteliais/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Metanfetamina/efeitos adversos , MicroRNAs/metabolismo , Junções Íntimas/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/sangue , Transtornos Relacionados ao Uso de Anfetaminas/genética , Transtornos Relacionados ao Uso de Anfetaminas/patologia , Animais , Apoptose/efeitos dos fármacos , Translocação Bacteriana/efeitos dos fármacos , Biomarcadores/sangue , Estudos de Casos e Controles , Linhagem Celular , Impedância Elétrica , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Microbioma Gastrointestinal , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Permeabilidade , Ratos , Transdução de Sinais , Junções Íntimas/metabolismo , Junções Íntimas/patologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Adulto JovemRESUMO
BACKGROUND: Preclinical studies suggest that the non-selective phosphodiesterase inhibitor, Ibudilast (IBUD) may contribute to the treatment of methamphetamine (METH) use disorder through the attenuation of METH-induced inflammatory markers such as adhesion molecules, sICAM-1 and sVCAM-1, and cytokines, IL-6 and TNF-α. OBJECTIVE: The present study aimed to test whether treatment with IBUD can attenuate peripheral markers of inflammation during a METH challenge in an inpatient clinical trial of 11 patients. METHODS: This trial followed a randomized, within-subjects crossover design where participants received a METH challenge, during which five participants were treated with placebo then with IBUD, while the remaining six participants were treated with IBUD prior to placebo. Mixed effects regression modeled changes in peripheral markers of inflammation-sICAM-1, sVCAM-1, TNF-α, IL-6, MIF, and cathepsin D-by treatment condition, with measurements at baseline, 60â¯min post-METH infusion, and 360â¯min post-METH infusion. RESULTS: While on placebo, sICAM-1, sVCAM-1, and cathepsin D significantly increased by 60â¯min post-METH infusion, while IL-6 significantly increased 360â¯min post-METH infusion. Treatment with IBUD significantly reduced METH-induced levels of sICAM-1, sVCAM-1, and cathepsin D at 60â¯min post-METH infusion. CONCLUSIONS: Our findings demonstrate that IBUD attenuated acute pro-inflammatory effects of METH administration, which may have implications for treatment of METH use disorder.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/sangue , Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/sangue , Metanfetamina/efeitos adversos , Piridinas/uso terapêutico , Adulto , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/efeitos adversos , Estudos Cross-Over , Feminino , Humanos , Infusões Intravenosas , Masculino , Metanfetamina/administração & dosagem , Pessoa de Meia-Idade , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Piridinas/farmacologiaRESUMO
BACKGROUND: Methamphetamine use disorder continues to be inadequately treated, but improvements are being made in the field of immunotherapeutics, including vaccines, which could provide new options for treatment. Cocaine and nicotine vaccines have been tested clinically, but have yet to elicit the necessary antibody concentrations required to be effective. Methamphetamine vaccines have been tested in multiple nonclinical models and appear promising. Improved adjuvants have the potential to further stimulate the immune system to reach effective levels of antibodies. Previously, the methamphetamine vaccine IXT-v100 was administered with GLA-SE, a toll-like receptor 4 agonist, in mice to produce higher levels of antibodies than when it was administered with two other widely used adjuvants, Alhydrogel and Sigma Adjuvant System. METHODS: The purpose of this research was to evaluate IXT-v100, given in combination with the adjuvant GLA-SE, to determine its efficacy in antagonizing methamphetamine disposition in a rat pharmacokinetic study. Additional rat studies were conducted to compare the ability of IXT-v100 manufactured with greater hapten densities to elicit higher antibody levels. RESULTS: As expected based on prior studies with anti-methamphetamine monoclonal antibodies, the antibodies resulting from vaccination with IXT-v100 altered methamphetamine pharmacokinetics by increasing serum concentrations and extending the half-life. Furthermore, intentional variations in the ratio of components during manufacturing led to production of vaccines with higher hapten densities. The higher hapten densities resulted in production of antibodies that maintained the ability to bind methamphetamine with high affinity. CONCLUSIONS: The results support continued development of IXT-v100 for the treatment of methamphetamine use disorder.
Assuntos
Formação de Anticorpos/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/sangue , Glucosídeos/administração & dosagem , Lipídeo A/administração & dosagem , Metanfetamina/sangue , Vacinação/tendências , Adjuvantes Imunológicos/administração & dosagem , Transtornos Relacionados ao Uso de Anfetaminas/sangue , Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Animais , Formação de Anticorpos/fisiologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/farmacocinética , Relação Dose-Resposta a Droga , Masculino , Metanfetamina/administração & dosagem , Metanfetamina/farmacocinética , Ratos , Ratos Sprague-Dawley , Vacinas/administração & dosagem , Vacinas/sangueAssuntos
Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico por imagem , Hemorragia dos Gânglios da Base/induzido quimicamente , Encefalopatias/induzido quimicamente , Encéfalo/efeitos dos fármacos , Imageamento por Ressonância Magnética , Metanfetamina/efeitos adversos , Tomografia Computadorizada por Raios X , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/sangue , Hemorragia dos Gânglios da Base/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encefalopatias/sangue , Encefalopatias/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Paralisia Facial/induzido quimicamente , Paralisia Facial/diagnóstico por imagem , Humanos , Masculino , Metanfetamina/sangue , Paresia/induzido quimicamente , Paresia/diagnóstico por imagemRESUMO
Methamphetamine (METH) is a widely consumed psychostimulant drug; its acute toxic effects in brain and liver are well known, furthermore, there is some evidence in regard to its DNA damaging properties in humans. Therefore, we studied the impact of the drug on genomic stability in human derived hepatoma (HepG2) cells, which reflect the activation/detoxification of drugs better than other cell lines. Furthermore, experiments with human buccal derived cells (TR146) were conducted as the drug is consumed orally. Induction of DNA damage in both cell types with doses reflecting the exposure in abusers was found in single cell gel electrophoresis (SCGE) assays (which detect single and double strand breaks as well as apurinic sites). Furthermore, induction of micronuclei (formed as a consequence of structural and numerical chromosomal aberrations) and formation of nuclear buds resulting from gene amplifications was detected. Additional experiments with lesion-specific enzymes showed that the drug causes oxidation of purines and pyrimidines, indicating that its genotoxic effects may be due to oxidation of the DNA. Our findings support the assumption that the drug may cause adverse health effects (such as cancer and infertility) in long-term users which are causally related to DNA damage.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/sangue , Aberrações Cromossômicas , Ensaio Cometa/métodos , Dano ao DNA , DNA/efeitos dos fármacos , Metanfetamina/toxicidade , Mutagênicos/toxicidade , Linhagem Celular , Citocinese/efeitos dos fármacos , DNA/metabolismo , DNA-Formamidopirimidina Glicosilase/metabolismo , Relação Dose-Resposta a Droga , Endodesoxirribonucleases/metabolismo , Células Hep G2 , Humanos , Metanfetamina/administração & dosagem , Testes para Micronúcleos , Mutagênicos/administração & dosagem , Oxirredução , Testes de Toxicidade AgudaRESUMO
This work extends the understanding of how toxic exposures to amphetamine (AMPH) adversely affect the immune system and lead to tissue damage. Importantly, it determines which effects of AMPH are and are not due to pronounced hyperthermia. Whole blood messenger RNA (mRNA) and whole blood and serum microRNA (miRNA) transcripts were identified in adult male Sprague-Dawley rats after exposure to toxic AMPH under normothermic conditions, AMPH when it produces pronounced hyperthermia, or environmentally-induced hyperthermia (EIH). mRNA transcripts with large increases in fold-change in treated relative to control rats and very low expression in the control group were a rich source of organ-specific transcripts in blood. When severe hyperthermia was produced by either EIH or AMPH, significant increases in circulating organ-specific transcripts for liver (Alb, Fbg, F2), pancreas (Spink1), bronchi/lungs (F3, Cyp4b1), bone marrow (Np4, RatNP-3b), and kidney (Cesl1, Slc22a8) were observed. Liver damage was suggested also by increased miR-122 levels in the serum. Increases in muscle/heart-enriched transcripts were produced by AMPH even in the absence of hyperthermia. Expression increases in immune-related transcripts, particularly Cd14 and Vcan, indicate that AMPH can activate the innate immune system in the absence of hyperthermia. Most transcripts specific for T-cells decreased 50-70% after AMPH exposure or EIH, with the noted exception of Ccr5 and Chst12. This is probably due to T-cells leaving the circulation and down-regulation of these genes. Transcript changes specific for B-cells or B-lymphoblasts in the AMPH and EIH groups ranged widely from decreasing ≈ 40% (Cd19, Cd180) to increasing 30 to 100% (Tk1, Ahsa1) to increasing ≥500% (Stip1, Ackr3). The marked increases in Ccr2, Ccr5, Pld1, and Ackr3 produced by either AMPH or EIH observed in vivo provide further insight into the initial immune system alterations that result from methamphetamine and AMPH abuse and could modify risk for HIV and other viral infections.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/sangue , Anfetamina/administração & dosagem , Febre/sangue , Golpe de Calor/sangue , MicroRNAs/sangue , RNA Mensageiro/sangue , Anfetamina/farmacologia , Animais , Biomarcadores/sangue , Febre/induzido quimicamente , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
3-Methylmethcathinone (3-MMC or metaphedrone) is a synthetic cathinone, recently introduced in the market of the new psychoactive substances (NPS), initially to replace mephedrone (4-methylmethcathinone or 4-MMC), and rapidly widespread among drug users. 3-Methylmethcathinone is legally controlled in many countries, but is still easily available for purchase from websites, and frequently found in recreational settings. Most toxicological data on this drug come from human case reports of intoxications. Thus, further investigation on their pharmacological and toxicological properties is necessary to evaluate its potential harmful effects. The present work provides a review on the available data about 3-MMC legal status, chemistry, patterns of use, prevalence, biological effects, toxicokinetics, toxicity and factors affecting stimulant/toxicological effects.
Assuntos
Metanfetamina/análogos & derivados , Psicotrópicos/farmacologia , Psicotrópicos/intoxicação , Transtornos Relacionados ao Uso de Anfetaminas/sangue , Interações Medicamentosas , Humanos , Drogas Ilícitas/química , Drogas Ilícitas/farmacologia , Drogas Ilícitas/intoxicação , Metanfetamina/química , Metanfetamina/farmacologia , Metanfetamina/intoxicação , Estrutura Molecular , Psicotrópicos/química , Medicamentos Sintéticos/química , Medicamentos Sintéticos/farmacologia , Medicamentos Sintéticos/intoxicação , Temperatura , Distribuição TecidualRESUMO
Some evidence suggested that malondialdehyde (MDA) as a marker of oxidative stress played an important part in modulating the activities of depression. Methamphetamine (METH) dependence often lead to depression that may associate with MDA. In this study, our purpose was to explore the association between serum MDA levels and depression during METH withdrawal. 179 METH-dependent patients were recruited in this study and 144 (80.4%) finished the assessment. We measured serum MDA at 532 nm spectrophotometrically at admission. The short form of the Beck Depression Inventory (BDI-13) was used to evaluate depression symptoms. Patients were identified to have depression symptoms with the BDI score ≥ 8. As a result, 89 (61.8%) of the remaining 144 METH-dependent patients were identified to have depression symptoms. Patients with depression symptoms showed significantly higher serum MDA levels than non-depression patients (3.42 ± 1.60 nmol/ml vs. 2.43 ± 1.25 nmol/ml; p < 0.001). After controlling for potential confounding variables in our logistic model, serum MDA levels were independently associated with the development of depression during early METH withdrawal (OR =1.952, 95% CI, 1.414-2.694, p < 0.001). Furthermore, our study found a positive association between Beck Depression Inventor (BDI) score in early METH abstinence and serum MDA levels (r =0.185; p = 0.026). Our results indicated that higher serum MDA levels were related to higher risk of depression symptoms during early METH withdrawal.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/sangue , Estimulantes do Sistema Nervoso Central/efeitos adversos , Depressão/sangue , Malondialdeído/sangue , Metanfetamina/efeitos adversos , Síndrome de Abstinência a Substâncias/sangue , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico , Biomarcadores/sangue , Depressão/diagnóstico , Feminino , Humanos , Masculino , Síndrome de Abstinência a Substâncias/diagnóstico , Adulto JovemRESUMO
Methamphetamine is a popular psychostimulant worldwide which causes neurotoxicity and neuroinflammation. Although previous studies have characterized potential associations between addictive drugs and fasting blood glucose, the influence of methamphetamine on the blood glucose is still largely unknown. The present study was designed to investigate the change of fasting blood glucose of methamphetamine abusers and to confirm the impairment of liver and kidney. Fasting blood glucose was significantly decreased in methamphetamine abusers and in a high-fat diet mouse model with methamphetamine treatment discontinuation. Serum level of ALT, creatine kinase and creatinine were increased in methamphetamine abusers. Serum level of ALT and AST were increased in a high-fat diet mouse model after methamphetamine injection, but there was no significant difference in the anatomy of the liver and kidney in high-fat diet treated mice with or without methamphetamine. The levels of ALT and creatinine were also increased in the methamphetamine abusers. This study demonstrated that the level of glucose was decreased in methamphetamine abusers and in high-fat diet-fed mice after methamphetamine treatment discontinuation. The effect of methamphetamine on the levels of blood glucose may provide the evidence that methamphetamine abusers should be keep energy balance due to the low blood glucose.