Trends in Nonfatal Overdose Rates Due to Alcohol and Prescription and Illegal Substances in Colombia, 2010‒2021.

Objectives. To examine drug overdoses in Colombia by type of substance, sex, age, and intent using data from a health surveillance system from 2010 to 2021. Methods. We characterized data by year, type of substance, and sociodemographic variables. We calculated age-adjusted overdose rates by substance type, sex, age groups, and intent. We used Poisson regression models to examine trend differences across sex and age groups. Results. Age-adjusted rates of drug overdoses increased from 8.51 to 40.52 per 100 000 during 2010 to 2021. Men, compared with women, had higher overdose rates for every substance, except for opioids and psychotropics. Drug overdose rates involving cannabis and stimulants increased steadily until 2017 but decreased afterward. Overdose rates involving psychotropic medication increased greatly during 2018 to 2021, mainly because of intentional overdoses in young women. Conclusions. Overdoses involving illegal drugs decreased in recent years in Colombia; however, the continuous increase in intentional psychotropic overdose rates highlights the need for prevention efforts to curb this trend. Health surveillance systems are an important tool that can guide overdose prevention efforts in countries with limited data resources. (Am J Public Health. 2024;114(11):1252-1260. https://doi.org/10.2105/AJPH.2024.307786).

The rise in mortality due to intentional self-poisoning by medicines in Brazil between 2003 and 2022: relationship with regional and global crises.

In recent years, suicide rates in Brazil have increased, but little is known about the temporal behavior and characteristics of suicides due to intentional self-poisoning by medicines. The aim of the present study was to provide an overview of sociodemographic characteristics and place of death related to suicide due to intentional self-poisoning by medicines, to evaluate the trend of mortality rates in Brazil between 2003 and 2022, and its relationship with regional and global crises. Ecological time series study with data from the Mortality Information System of the Brazilian Ministry of Health, related to individuals aged 10 years and over, who committed suicides due to intentional drug overdose, in the period from 2003 to 2022. The analyses were performed in the R environment in RStudio. Between 2003 and 2022, there was a predominance of deaths in women (55.5%), individuals aged 30-49 years (47.2%), of White race/color (53.2%), occurring in health facilities (67.0%), using drugs or unspecified substances (40.4%); a higher concentration in the southern region (22.8%) and a positive trend in mortality rates due to intentional drug overdose, especially from 2016 onwards. A rise of 264% was observed in the comparison of 2022 and 2003. A peculiar sociodemographic profile was observed in the victims of intentional self-poisoning by medicines and a positive temporal trend in mortality rates, especially in a period marked by regional and global crises.

Narcanazo: Community Activation of Antiracist Epidemiology.

The Latinx (Hispanic) social construct obscures differences in the overdose risk levels of groups within this category. When national data are disaggregated, stateside Puerto Rican mortality increases exponentially, so much that this community has the highest rates of overdose deaths across years. Developed by Bronx-based Puerto Ricans, Narcanazo is an empowered upstander campaign that uses local overdose data to mobilize community members as trained naloxone dispensers. This health promotion campaign was grounded in antiracist epidemiological analysis. (Am J Public Health. 2024;114(S6):S463-S466. https://doi.org/10.2105/AJPH.2024.307605) [Formula: see text].

[Liver transplantation as treatment for acetaminophen poisoning]. / Trasplante hepático como tratamiento de intoxicación por paracetamol.

Acetaminophen is a commonly used analgesic and antipyretic drug, which has experienced an increase in its consumption in recent years in our environment. There has also been an increase in the number of accidental and intentional overdoses that were treated by the health system. Its toxicity is dose-dependent and can cause fulminant liver failure, becoming one of the main reasons for liver transplantation in English-speaking countries. The case of a 28-year-old woman with a history of major depression and five previous suicide attempts, who deliberately ingested a significant amount of paracetamol tablets, is here presented. She developed fulminant liver failure and metabolic acidosis, for which she underwent an emergency liver transplant due to the severity of her condition, from which she evolved favorably. The decision to perform a liver transplant in serious cases like this and under a condition of severe psychiatric vulnerability is challenging and must be carefully considered. This particular case illustrates the importance of multidisciplinary care including psychiatric evaluation in patients with acetaminophen poisoning.

El paracetamol es una droga analgésica y antipirética comúnmente utilizada, que ha experimentado un aumento en su consumo en los últimos años en nuestro medio. También se ha observado un incremento en el número de sobredosis accidentales e intencionales que fueron atendidas por el sistema de salud. Su toxicidad es dosis dependiente y puede causar falla hepática fulminante, convirtiéndose en una de las principales razones de trasplante hepático en países angloparlantes. Se presenta el caso de una mujer de 28 años con antecedentes de depresión mayor y cinco intentos de suicidio previos, quien ingirió deliberadamente una cantidad significativa de comprimidos de paracetamol. Desarrolló una falla hepática fulminante y acidosis metabólica, por lo que fue sometida a un trasplante hepático de emergencia debido a la gravedad de su condición evolucionando favorablemente. La decisión de realizar un trasplante hepático en casos graves como este y bajo una condición de vulnerabilidad psiquiátrica grave, es un desafío y debe considerarse cuidadosamente. Este caso en particular ilustra la importancia de la atención multidisciplinaria incluyendo la evaluación psiquiátrica en pacientes con intoxicación por paracetamol.

Trends in drug overdose deaths in Mexico (1999-2019). A national descriptive analysis and interstate comparison.

BACKGROUND: We assess trends in overdose mortality rates in Mexico from 1999 to 2019 and identify the states with the highest overdose mortality rates over time. METHODS: The analysis using mortality statistics examined deaths related to drug use. We estimated general overdose mortality rates at the national and state levels and calculated specific mortality rates associated with opioid and stimulant use using central rate estimation. We used joinpoint regression to analyse national and state-specific trends in overdose mortality from 1999 to 2019. FINDINGS: Nationally, the general overdose mortality rate increased annually by 10.49 % (p < 0.01, CI=11.4-18.9) from 2015 to 2019. The northern states of Baja California and Chihuahua were the states with the higher annual increases (18.6 %, p < 0.01, CI=4.2-29.6; and 15.6 %, p < 0.01, CI=12.9-19.7, respectively). By substance type, the national opioid-related mortality rate increased by 29.82 % per year from 2014 to 2019 (p < 0.01; CI=20.1-40.3), compared with an annual decrease of 11.43 % in the previous period (2005-2014) (p < 0.01; CI=-14.7- 8.0). Baja California was the state with the highest rise in opioid-related mortality from 2013 to 2019, with an annual increase of 15.84 % (p < 0.01; CI=1.4-32.3). Stimulant-related mortality increased by 21.79 % per year since 2013 (p < 0.01; CI=16.9-26.9), but it was not possible to calculate state-level trends. CONCLUSIONS: Drug-related mortality rates have increased in Mexico since 2015, particularly in the northern states of Baja California, Chihuahua, Sonora and Sinaloa. Improving harm reduction programmes and local surveillance of fatal and non-fatal overdoses is essential to address the silent escalation of overdose mortality.

Spatial Heterogeneity in Fatal Overdose Rate Trends in Mexican Cities: 2005-2021.

Objectives. To describe national and city-level fatal drug overdose trends between 2005 and 2021 in Mexico. Methods. We calculated fatal overdose rates at the city level in 3-year periods from 2005 to 2021 and annually at the national level for people aged 15 to 64 years in Mexico. We calculated rate differences and rate ratios for each city between periods. Results. The national fatal overdose rate was 0.53 overdose deaths per 100 000 population and was almost twice as high in urban than in nonurban areas. The national fatal overdose rate was stable over the period 2005 to 2014 and increased monotonically to a peak in 2021. Fatal overdose rates varied across cities. Cities with the 8 highest fatal overdose rates in the period were all in states along the US-Mexico border. Conclusions. Fatal overdoses have doubled over the past 15 years in Mexico. Overdose rates are particularly high and increasing in cities close to the US-Mexico border. Public Health Implications. There is a need for enhanced overdose surveillance data and coordinated harm reduction strategies, particularly in the northern border region of Mexico. (Am J Public Health. 2024;114(7):705-713. https://doi.org/10.2105/AJPH.2024.307650).

"It didn't hurt me": patients' and providers' perspectives on unsupervised take-home doses, drug diversion, and overdose risks in the provision of medication for opioid use disorder during COVID-19 in San Juan, Puerto Rico.

BACKGROUND: During the COVID-19 pandemic, clinics offering medication for opioid use disorder (MOUD) needed to rapidly introduce unsupervised take-home dosing, while relapsing patients and patients unable to enter treatment faced increased risks of fentanyl-related overdose deaths and other drug-related harms. Based on a qualitative study of people who inject drugs (PWID) receiving MOUD treatment and MOUD staff in Puerto Rico, this paper documents the lived experiences of patients and providers during this period and the risk perceptions and management strategies to address substance misuse and drug diversion attributable to unsupervised take-home-dose delivery. METHODS: In-depth qualitative interviews were conducted with patients (N = 25) and staff (N = 25) in two clinics providing MOUD in San Juan, Puerto Rico, during 2022. Patients and staff were receiving or providing treatment during the pandemic, and patients reported injection drug use during the past thirty days. RESULTS: Patients were overwhelmingly male (84%), unmarried (72%), and unemployed (52%), with almost half (44%) injecting one to three times a day. Mean time in treatment was 7 years. Staff had a mean age of 46 years with more than half of the sample (63%) female. The majority of patients believed that unsupervised take-home dosing had no significant effect on their treatment adherence or engagement. In contrast, providers expressed concerns over the potential for drug diversion and possible increased risks of patient attrition, overdose episodes, and poor treatment outcomes. CONCLUSION: This study underscores the importance of insider perspectives on harm-reduction changes in policy implemented during a health crisis. Of note is the finding that staff disagreed among themselves regarding the potential harms of diversion and changes in drug testing protocols. These different perspectives are important to address so that future pandemic policies are successfully designed and implemented. Our study also illuminates disagreement in risk assessments between patients and providers. This suggests that preparation for emergency treatment plans requires enhanced communication with patients to match treatments to the context of lived experience.

The Drug Overdose Epidemic in the U.S.-Mexico Border Region: Shifts, Progression, and Community Characteristics.

OBJECTIVE: Previous studies show the reach of the current drug overdose epidemic into the U.S.-Mexico border region, albeit with a unique border-specific wave pattern compared to national waves and a delayed onset of fentanyl involvement (Wave I: 2002-2011, Wave II: 2012-2016, and Wave III: since 2017). The objective of this study is to examine the community predictors and the progression of overdose deaths across the U.S-Mexico border-specific epidemic waves. METHOD: Descriptive epidemiological profile of border communities across the unfolding of the opioid epidemic, integrated data from the CDC-WONDER multiple causes of death data set, the CDC SVI, Uniform Crime Report, and the Behavioral Risk Factor Surveillance System. Using spatially adjusted Bayes rates by border-specific epidemic waves, we provide a descriptive profile of the spatial unfolding of the drug overdose epidemic. Negative binomial regression models assessed community predictors of overdose deaths across waves. RESULTS: Spatial analysis identified moderate to steep increases in drug overdose deaths over the three waves along the border. The impact and unfolding of the epidemic in the U.S.-Mexico border region were not uniform and affecting communities with differing severity and timing. Our study also finds support for social vulnerability and community violence as predictors of overdose deaths over the current wave of the epidemic. CONCLUSION: Findings suggest that more disadvantaged U.S.-Mexico border communities may encounter increasing rates of overdose death over the coming years. Interventions need to target not only the supply side but also the underlying social root causes for sustainable overdose prevention.

Xylazine potentiates the lethal but not the rewarding effects of fentanyl in mice.

BACKGROUND: Fentanyl is commonly laced with xylazine. People who use this combination report heightened effects, but it also increases death risk. Although no medication has been approved to counteract overdoses produced by fentanyl and xylazine, naloxone is frequently used. This paper studies the preclinical rewarding and lethal effects of fentanyl combined with xylazine and the efficacy of yohimbine or naloxone to prevent death. METHODS: Male Swiss Webster mice were treated with (in mg/kg, i.p.) xylazine (0.3, 1, 3, or 5.6), fentanyl (0.01, 0.3, or 0.1), or 1 xylazine plus 0.01 (non-effective) or 0.1 (effective) fentanyl doses during the conditioned-place preference (CPP) test. In addition, independent groups received (in mg/kg, i.p.): xylazine (31.6, 60, 74.2, or 100), fentanyl (3.1 or 10), or both substances at two doses: 31.6 xylazine + 3.1 fentanyl, or 60 xylazine + 10 fentanyl to analyze lethal effects. We determined whether yohimbine or naloxone (each medication tested at 10 or 30mg/kg) could prevent the lethality produced by fentanyl/xylazine combinations. Female mice were also tested in key experiments. RESULTS: Xylazine neither induced CPP nor altered fentanyl's rewarding effects. In contrast, lethality was potentiated when fentanyl was combined with xylazine. Naloxone, but not yohimbine, effectively prevented the lethality of the fentanyl/xylazine combinations. CONCLUSIONS: At the doses tested, xylazine does not increase the rewarding effect of fentanyl on the CPP in male mice but potentiates the risk of fatal overdose in male and female mice. A high naloxone dose prevents death induced by coadministration of fentanyl and xylazine in both sexes.

Drug overdose deaths in Brazil between 2000 and 2020: an analysis of sociodemographics and intentionality.

OBJECTIVES: To examine drug overdose records in Brazil from 2000 to 2020, analyzing trends over time in overdoses and overall sociodemographic characteristics of the deceased. METHODS: Using data from the Brazilian Mortality Information System (Sistema de Informações sobre Mortalidade), we identified records from 2000-2020 in which the underlying cause-of-death was one of the following codes: X40-X45 (accidental poisoning), X60-X65 (intentional poisoning), or Y10-Y15 (undetermined intentionality poisoning). The Brazilian dataset included 21,410 deaths. We used joinpoint regression analysis to assess changes in trends over time. RESULTS: People who died of drug overdoses in Brazil between 2000 and 2020 had a mean age of 38.91 years; 38.45% were women, and 44.01% were identified as White. Of the overdose deaths, 44.70% were classified as intentional and 32.12% were classified as unintentional. Among the identified drugs, stimulants were the most common class. However, most records did not report which drug was responsible for death. CONCLUSION: Sociodemographic trends in overdose deaths in Brazil must guide country-specific policies. Nevertheless, data collection protocols must be improved, particularly regarding the drug used in overdoses.

Prescription amphetamines in people with opioid use disorder and co-occurring psychostimulant use disorder initiating buprenorphine: an analysis of treatment retention and overdose risk.

BACKGROUND: Attention-deficit and hyperactivity disorder (ADHD) is frequently diagnosed in patients with substance use disorders (SUDs), including opioids. There remains concern about the safety and efficacy of prescription amphetamines (PAs) and their impact on effectiveness of opioid use disorder (OUD) treatment with buprenorphine. OBJECTIVES: To assess the effect of PAs on OUD buprenorphine treatment retention and/or SUD-related emergency admission or drug-related poisonings. METHODS: We used a retrospective cohort design with a secondary analysis of data from Merative MarketScan Commercial and Multi-State Medicaid Databases from 1 January 2006 to 31 December 2016. Individuals included were aged 12-64 years, had an OUD diagnosis and were prescribed buprenorphine. Our analysis used multivariable Cox regression to evaluate the relationship between PA receipt and time to buprenorphine discontinuation. The second part focused on subsamples of buprenorphine initiators who had either (1) any SUD-related emergency admissions or (2) drug-related poisoning. These outcomes were modelled as a function of PA exposure using conditional logistic regression models as part of a within-person, case-crossover design. FINDINGS: Our sample had 90 269 patients with OUD (mean age 34.2 years (SD=11.3)) who initiated buprenorphine. Being prescribed a PA was associated with improved buprenorphine retention among individuals both with (adjusted HR (aHR) 0.91 (95% CI 0.86 to 0.97)) and without a concurrent psychostimulant use disorder (PSUD) (aHR 0.92 (95% CI 0.90 to 0.93)). CONCLUSIONS: PA use was associated with improved buprenorphine retention in people with OUD with and without co-occurring PSUD. The risks of acute SUD-related events and drug-related poisonings associated with PA use did not differ when comparing PA-using days with days without PA use. CLINICAL IMPLICATIONS: Patients with OUD on buprenorphine should receive treatment with a PA when indicated.

Intersections between syndemic conditions and stages along the continuum of overdose risk among women who inject drugs in Mexicali, Mexico.

BACKGROUND: Research on women who inject drugs is scarce in low- and middle-income countries. Women experience unique harms such as sexism and sexual violence which translate into negative health outcomes. The present work aims to provide insight into the experiences of women who inject drugs at the US-Mexico border to identify social and health-related risk factors for overdose to guide harm reduction interventions across the Global South. METHODS: We recruited 25 women ≥ 18 years of age accessing harm reduction and sexual health services at a non-governmental harm reduction organization, "Verter", in Mexicali, Mexico. We employed purposeful sampling to recruit women who inject drugs who met eligibility criteria. We collected quantitative survey data and in-depth interview data. Analyses of both data sources involved the examination of descriptive statistics and thematic analysis, respectively, and were guided by the syndemic and continuum of overdose risk frameworks. RESULTS: Survey data demonstrated reports of initiating injection drug use at a young age, experiencing homelessness, engaging in sex work, being rejected by family members, experiencing physical violence, injecting in public spaces, and experiencing repeated overdose events. Interview data provided evidence of stigma and discrimination toward women, a lack of safe spaces and support systems, risk of overdose-related harms, sexual violence, and the overall need for harm reduction services. CONCLUSION: Women who inject drugs in Mexicali describe experiences of violence, overdose, and public injecting. Women are particularly vulnerable in the Mexicali context, as this area faces a noticeable lack of health and social services. Evidenced-based harm reduction strategies such as safe consumption sites and overdose prevention strategies (e.g., naloxone distribution and training) may benefit this population. Evidence from local organizations could help close the gap in service provision in low-resource settings like Mexico, where government action is almost nonexistent.

Fentanyl, heroin, and methamphetamine-based counterfeit pills sold at tourist-oriented pharmacies in Mexico: An ethnographic and drug checking study.

BACKGROUND: Fentanyl- and methamphetamine-based counterfeit prescription drugs have driven escalating overdose death rates in the US, however their presence in Mexico has not been assessed. Our ethnographic team has conducted longitudinal research focused on illicit drug markets in Northern Mexico since 2018. In 2021-2022, study participants described the arrival of new, unusually potent tablets sold as ostensibly controlled substances, without a prescription, directly from pharmacies that cater to US tourists. AIMS: To characterize the availability of counterfeit and authentic controlled substances at pharmacies in Northern Mexico available to English-speaking tourists without a prescription. METHODS: We employed an iterative, exploratory, mixed methods design. Longitudinal ethnographic data was used to characterize tourist-oriented micro-neighborhoods and guide the selection of n=40 pharmacies in n=4 cities in Northern Mexico. In each pharmacy, samples of "oxycodone", "Xanax", and "Adderall" were sought as single pills, during English-language encounters, after which detailed ethnographic accounts were recorded. We employed immunoassay-based testing strips to check each pill for the presence of fentanyls, benzodiazepines, amphetamines, and methamphetamines. We used Fourier-Transform Infrared Spectroscopy to further characterize drug contents. RESULTS: Of n=40 pharmacies, one or more of the requested controlled substances could be obtained with no prescription (as single pills or in bottles) at 28 (70.0%) and as single pills at 19 (47.5%). Counterfeit pills were obtained at 11 pharmacies (27.5%). Of n=45 samples sold as one-off controlled substances, 18 were counterfeit. 7 of 11 (63.6%) samples sold as "Adderall" contained methamphetamine, 8 of 27 (29.6%) samples sold as "Oxycodone" contained fentanyl, and 3 "Oxycodone" samples contained heroin. Pharmacies providing counterfeit drugs were uniformly located in tourist-serving micro-neighborhoods, and generally featured English-language advertisements for erectile dysfunction medications and "painkillers". Pharmacy employees occasionally expressed concern about overdose risk and provided harm reduction guidance. DISCUSSION: The availability of fentanyl-, heroin-, and methamphetamine-based counterfeit medications in tourist-oriented independent pharmacies in Northern Mexico represents a public health risk, and occurs in the context of 1) the normalization of medical tourism as a response to rising unaffordability of healthcare in the US, 2) plummeting rates of opioid prescription in the US, affecting both chronic pain patients and the availability of legitimate pharmaceuticals on the unregulated market, 3) the rise of fentanyl-based counterfeit opioids as a key driver of the fourth, and deadliest-to-date, wave of the opioid crisis. It was not possible to distinguish counterfeit medications based on appearance of pills or geography of pharmacies, because identically-appearing authentic and counterfeit versions were often sold in close geographic proximity. Nevertheless, people who consume drugs may be more trusting of controlled substances purchased directly from pharmacies. Due to Mexico's limited opioid overdose surveillance infrastructure, the current death rate from these substances remains unknown.

Non-Fatal Opioid Overdose and Abuse Visits to a University Hospital Emergency Department in Puerto Rico, 2009-2018.

OBJECTIVE: The objective was to describe opioid-use trends (2009-2018) at a university hospital emergency department (ED) in metropolitan San Juan, Puerto Rico. METHODS: The ED database of the University of Puerto Rico - Dr. Federico Trilla Hospital provided the data for the study. RESULTS: Non-fatal opioid overdoses surged 7.5-fold, increasing from 12.1 (±2.5) per 100,000 ED encounters for 2009 through 2016 to 91.2 (±8.7) per 100,000 ED encounters for 2017 through 2018 (P < .0001). Starting in summer 2017, the surge reached its peak in October after two major hurricanes. The opioid-related ED cases comprised 15.8% from 2009 through 2016, increasing to 67% in 2017 through 2018. Prior to October 2015, multiple drugs were mentioned in 65% of the opioid-related cases, decreasing to 37% of the total cases, thereafter. Cocaine was reported in combination with opioids in 53% of all opioid-related cases from August 2009 through September 2015, decreasing to 21% from October 2015 through December 2018, cannabis in 15 % and 10%, respectively, and alcohol in 10% and 6%, respectively. Amphetamines were mentioned once in combination with opioids. The overall male:female ratio for all opioid-related cases was 6.3 (rate: 8.8). CONCLUSION: The data show an increase in opioid-toxicity cases in the area served by the above-named hospital beginning in mid-2017. Opioid-related cases overwhelmingly involved male patients. More work is needed to establish islandwide trends.

Changes in Opioid and Benzodiazepine Poisoning Deaths After Cannabis Legalization in the US: A County-level Analysis, 2002-2020.

BACKGROUND: Cannabis legalization for medical and recreational purposes has been suggested as an effective strategy to reduce opioid and benzodiazepine use and deaths. We examined the county-level association between medical and recreational cannabis laws and poisoning deaths involving opioids and benzodiazepines in the US from 2002 to 2020. METHODS: Our ecologic county-level, spatiotemporal study comprised 49 states. Exposures were state-level implementation of medical and recreational cannabis laws and state-level initiation of cannabis dispensary sales. Our main outcomes were poisoning deaths involving any opioid, any benzodiazepine, and opioids with benzodiazepines. Secondary analyses included overdoses involving natural and semi-synthetic opioids, synthetic opioids, and heroin. RESULTS: Implementation of medical cannabis laws was associated with increased deaths involving opioids (rate ratio [RR] = 1.14; 95% credible interval [CrI] = 1.11, 1.18), benzodiazepines (RR = 1.19; 95% CrI = 1.12, 1.26), and opioids+benzodiazepines (RR = 1.22; 95% CrI = 1.15, 1.30). Medical cannabis legalizations allowing dispensaries was associated with fewer deaths involving opioids (RR = 0.88; 95% CrI = 0.85, 0.91) but not benzodiazepine deaths; results for recreational cannabis implementation and opioid deaths were similar (RR = 0.81; 95% CrI = 0.75, 0.88). Recreational cannabis laws allowing dispensary sales was associated with consistent reductions in opioid- (RR = 0.83; 95% CrI = 0.76, 0.91), benzodiazepine- (RR = 0.79; 95% CrI = 0.68, 0.92), and opioid+benzodiazepine-related poisonings (RR = 0.83; 95% CrI = 0.70, 0.98). CONCLUSIONS: Implementation of medical cannabis laws was associated with higher rates of opioid- and benzodiazepine-related deaths, whereas laws permitting broader cannabis access, including implementation of recreational cannabis laws and medical and recreational dispensaries, were associated with lower rates. The estimated effects of the expanded availability of cannabis seem dependent on the type of law implemented and its provisions.

Quantitative systems pharmacology Model to characterize valproic acid-induced hyperammonemia and the effect of L-carnitine supplementation.

Valproic acid (VPA) is a short-chain fatty acid widely prescribed in the treatment of seizure disorders and epilepsy syndromes, although its therapeutic value may be undermined by its toxicity. VPA serious adverse effects are reported to have a significant and dose-dependent incidence, many associated with VPA-induced hyperammonemia. This effect has been linked with reduced levels of carnitine; an endogenous compound involved in fatty acid's mitochondrial ß-oxidation by facilitation of its entrance via the carnitine shuttle. High exposure to VPA can lead to carnitine depletion causing a misbalance between the intra-mitochondrial ß-oxidation and the microsomal ω-oxidation, a pathway that produces toxic metabolites such as 4-en-VPA which inhibits ammonia elimination. Moreover, a reduction in carnitine levels might be also related to VPA-induced obesity and lipids disorder. In turn, L-carnitine supplementation (CS) has been recommended and empirically used to reduce VPA's hepatotoxicity. The aim of this work was to develop a Quantitative Systems Pharmacology (QSP) model to characterize VPA-induced hyperammonemia and evaluate the benefits of CS in preventing hyperammonemia under both chronic treatment and after VPA overdosing. The QSP model included a VPA population pharmacokinetics model that allowed the prediction of total and unbound concentrations after single and multiple oral doses considering its saturable binding to plasma proteins. Predictions of time courses for 2-en-VPA, 4-en-DPA, VPA-glucuronide, carnitine, ammonia and urea levels, and for the relative change in fatty acids, Acetyl-CoA, and glutamate reflected the VPA induced changes and the efficacy of the treatment with L-carnitine. The QSP model was implemented to give a rational basis for the L-carnitine dose selection to optimize CS depending on VPA dosage regime and to assess the currently recommended L-carnitine rescue therapy after VPA overdosing. Results show that a L-carnitine dose equal to the double of the VPA dose using the same interdose interval would maintain the ammonia levels at baseline. The QSP model may be expanded in the future to describe other adverse events linked to VPA-induced changes in endogenous compounds.

Quercetin and resveratrol are associated with the downregulation of TNFalpha/NF-kB/inos axis-mediated acute liver injury in rats induced by paracetamol poisoning / La quercetina y el resveratrol están asociados con la regulación decreciente de la lesión hepática aguda mediada por el eje TNF-alfa/NF-kB/inos en ratas inducida por envenenamiento con paracetamol

SUMMARY: Paracetamol (known as acetaminophen, or APAP) poisoning causes acute liver damage that can lead to organ failure and death. We sought to determine that APAP overdose can augment tumor necrosis factor-alpha (TNF-α)/ nuclear factor kappa B (NF-kB)/induced nitic oxide synthase (iNOS) axis-mediated hepatotoxicity in rats, and the anti-inflammatory polyphenolic compounds, quercetin (QUR) plus resveratrol (RES) can ameliorate these parameters. Therefore, we induced acute hepatotoxicity in rats using APAP overdose (2 g/kg, orally) and the protective group of rats were treated with 50 mg/kg QUR plus 30 mg/kg RES for one week before APAP ingestion. Animals were killed at day 8. APAP poisoning caused the induction of hepatic tissue levels of TNF-α, NF-kB, and iNOS, which were significantly (p<0.05) decreased by QUR+RES. QUR+RES, also inhibited liver injury biomarkers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, a link between liver injury and TNF-α /NF-kB / iNOS axis mediated hepatotoxicity was observed. Thus, the presented data backing the conclusion that intoxication by paracetamol increases TNF-α / NF-kB / iNOS axis -mediated hepatotoxicity, and is protected by a combination of quercetin and resveratrol.

El envenenamiento por paracetamol (conocido como acetaminofeno o APAP) causa daño hepático agudo que puede provocar una insuficiencia orgánica y la muerte. El objetivo de este trabajo fue determinar si la sobredosis de APAP puede aumentar la hepatotoxicidad mediada por el eje del factor de necrosis tumoral alfa (TNF-α)/factor nuclear kappa B (NF-kB)/óxido nítico sintasa inducida (iNOS) en ratas, y si el polifenólico antiinflamatorio compuesto por quercetina (QUR) más resveratrol (RES) pueden mejorar estos parámetros. Por lo tanto, inducimos hepatotoxicidad aguda en ratas usando una sobredosis de APAP (2 g/kg, por vía oral). El grupo protector de ratas se trató con 50 mg/ kg de QUR más 30 mg/kg de RES durante una semana antes de la ingestión de APAP. Los animales se sacrificaron el día 8. El envenenamiento con APAP en el tejido hepático provocó la inducción de niveles de TNF-α, NF-kB e iNOS, que se redujeron significativamente (p<0,05) con QUR+RES. QUR+RES, también inhibió los biomarcadores de daño hepático, la alanina aminotransferasa (ALT) y el aspartato aminotransferasa (AST). Además, se observó una relación entre la lesión hepática y la hepatotoxicidad mediada por el eje TNF-α /NF-kB/iNOS. Por lo tanto, los datos presentados respaldan la conclusión de que la intoxicación por paracetamol aumenta la hepatotoxicidad mediada por el eje TNF-α /NF-kB / iNOS, y está protegida por una combinación de quercetina y resveratrol.

Sobre dias em que me senti sem ar: desassossegos do pesquisar / On days when i felt breathless: unrest of search / Sobre días que me sentí sin aliento: disurbios de investigación

Resumo Conceitos como o de alteridade, encontro de saberes, polifasia cognitiva, o princípio de familiaridade e de representações sociais operaram na complexa tarefa de compreender como os encontros entre profissionais e usuários sustentavam e/ou transformavam as práticas de acolhimento. Entretanto, a experiência da minha pesquisa de doutorado me levou a questionar os próprios conceitos utilizados da Teoria das Representações Sociais. Ao final do ensaio, após discutir aspectos teórico-metodológicos, o princípio de familiaridade e a questão da tensão e dos afetos nas representações sociais, espero evidenciar como o movimento provocado pelo encontro com usuários e profissionais de uma Rede de Atenção Psicossocial levou-me a questionar pontos essenciais da teoria: o papel domesticador das representações, a forma ainda estática de evidenciar os fenômenos, a separação entre um sujeito que representa e o objeto representado e a dificuldade em usar suas ferramentas conceituais para acompanhar processos me fazem repensar meu lugar e minha função de pesquisador.

Abstract Concepts such as alterity, encounter of knowledge, cognitive polyphasia, the principle of familiarity and the very concept of social representations operated in the complex task of understanding how the encounters between professionals and users supported and / or transformed user embracement practices. However, the experience of my doctoral research led me to question the very concepts used in the Theory of Social Representations. At the end of the essay, after discussing theoretical and methodological aspects, the principle of familiarity and the issue of tension and affects in social representations, I hope to show how the movement caused by the encounter with users and professionals of a Psychosocial Care Network, led me to question essential points of the theory: the domesticating role of representations, the still static way of showing phenomena, the separation between a subject that represents and the object represented and the difficulty in using their conceptual tools to accompany processes makes me rethink my place and role as a researcher.

Resumen Conceptos como la alteridad, el encuentro de saberes, la polifasia cognitiva, el principio de familiaridad y el concepto mismo de representaciones sociales operaron en la compleja tarea de comprender cómo los encuentros entre profesionales y usuarios apoyaron y / o transformaron las prácticas de acogimiento. Sin embargo, la experiencia de mi investigación doctoral me llevó a cuestionar los propios conceptos utilizados en la Teoría de las Representaciones Sociales. Al final del ensayo, después de discutir aspectos teóricos y metodológicos, el principio de familiaridad y el tema de tensión y afectos en las representaciones sociales, Espero mostrar cómo el movimiento provocado por el encuentro con usuarios y profesionales de una Red de Atención Psicosocial, me llevó a cuestionar puntos esenciales de la teoría: el rol domesticador de las representaciones, la forma todavía estática de mostrar los fenómenos, la separación entre un sujeto que representa y el objeto representado y la dificultad para utilizar sus herramientas conceptuales para acompañar procesos, me hace repensar mi lugar y rol como investigador.