The effects of intra-accumbal administration of the nicotinic acetylcholine receptor agonist cytisine on the operant oral self-administration of ethanol were prevented by the GABAB receptor agonist baclofen in rats.

RATIONALE: Although the mesocorticolimbic dopamine (DA) system is the main neurochemical substrate that regulates the addictive and reinforcing effects of ethanol (EtOH), other neurotransmitter systems, such as the acetylcholine (Ach) system, modulate DAergic function in the nucleus accumbens (nAcc). Previously, we reported that intra-nAcc administration of the nicotinic Ach receptor agonist cytisine increased oral EtOH self-administration. GABAB receptors in the nAcc are expressed in DAergic terminals, inhibit the regulation of DA release into the nAcc, and could modulate the effects of cytisine on oral EtOH self-administration. The present study assessed the effects of intra-nAcc administration of the GABAB receptor agonist baclofen (BCF) on the impacts of cytisine on oral EtOH self-administration. METHODS: Male Wistar rats were deprived of water for 23.30 h and then trained to press a lever to receive EtOH on an FR3 schedule until a stable response rate of 80 % was achieved. After this training, the rats received an intra-nAcc injection of the nAch receptor agonist cytisine, BCF, and cytisine or 2-hydroxysaclofen, BCF, and cytisine before they were given access to EtOH on an FR3 schedule. RESULTS: Intra-nAcc injections of cytisine increased oral EtOH self-administration; this effect was reduced by BCF, and 2-hydroxysaclofen blocked the effects of BCF. CONCLUSIONS: These findings suggest that the reinforcing effects of EtOH are modulated not only by the DA system but also by other neurotransmitter systems involved in regulating DA release from DAergic terminals.

Involvement of Pre-limbic Cortex-Nucleus accumbens projections in Context-Induced alcohol seeking.

Alcohol use disorder (AUD) remains a critical public health issue worldwide, characterized by high relapse rates often triggered by contextual cues. This research investigates the neural mechanisms behind context-induced reinstatement of alcohol-seeking behavior, focusing on the nucleus accumbens and its interactions with the prelimbic cortex, employing Male Long-Evans rats in an ABA renewal model. In our experimental setup, rats were trained to self-administer 10 % ethanol in Context A, followed by extinction of lever pressing in the presence of discrete cues in Context B. The context-induced reinstatement of ethanol-seeking was then assessed by re-exposing rats to Context A or B under extinction conditions, aiming to simulate the environmental cues' influence on relapse behaviors. Three experiments were conducted: Experiment 1 utilized Fos-immunohistochemistry to examine neuronal activation in the nucleus accumbens; Experiment 2 applied the baclofen + muscimol inactivation technique to probe the functional importance of the nucleus accumbens core; Experiment 3 used Fos-immunofluorescence along with Retrobeads injection to investigate activation of neurons projecting from the prelimbic cortex to the nucleus accumbens core. Our findings revealed significant increases in Fos-immunoreactive nuclei within the nucleus accumbens core and shell during the reinstatement phase in Context A, underscoring the environment's potent effect on ethanol-seeking behavior. Additionally, inactivation of the nucleus accumbens core markedly reduced reinstatement, and there was a notable activation of neurons from the prelimbic cortex to the nucleus accumbens core in the ethanol-associated context. These results highlight the critical role of the nucleus accumbens core and its corticostriatal projections in the neural circuitry underlying context-driven ethanol seeking.

Uso de analgésicos não opioides entre estudantes de Enfermagem no Amazonas, Brasil / Uso de analgesicos no-opioides entre estudiantes de Enfermería em Amazonas, Brasil / Use of non-opioid analgesics among nursing students in the Amazonas, Brazil

Objetivo: Estimar a prevalência do uso de analgésicos não opioides para alívio da dor entre graduandos de Enfermagem. Método: Estudo transversal, realizado com 142 estudantes de Enfermagem no interior do estado do Amazonas, Região Norte do Brasil. Os dados foram coletados no segundo semestre de 2017, utilizando questionário autoaplicável. Resultados: A prevalência do consumo de analgésicos não opioides foi de 68,3%; sendo o alívio das dores de cabeça (64,9%) e dores abdominais (14,4%) os principais motivos para uso. A maioria afirmou que: a dor interfere na realização de atividades diárias (77,3%); reconhecem que os analgésicos podem fazer mal à saúde (76,3%); consumiam analgésicos por conta própria (58,8%). Ainda, 47,4% indicavam medicamentos a terceiros e 93,8% estocavam medicamentos em suas casas. Conclusão: Constatou-se elevado consumo de analgésico, destacando o uso irracional -sem prescrição de profissional. Faz-se necessário fortalecer o ensino sobre o uso racional de medicamentos entre os alunos de Enfermagem, visando minimizar os riscos desta prática.

Objetivo: Estimar la prevalencia de analgésicos no opioides para el alivio del dolor entre los estudiantes de enfermería. Método: Estudio transversal, realizado con 142 estudiantes de enfermería en el interior del estado de Amazonas, Región Norte de Brasil. Los datos se recopilaron en el segundo semestre de 2017 utilizando un cuestionario autoadministrado. Resultados: La prevalencia del uso analgésico no opioide fue del 68,3%; ser el alivio de los dolores de cabeza (64,9%) y dolor abdominal (14,4%) las principales razones de uso. La mayoría declaró que: el dolor interfiere con el desempeño de las actividades diarias (77,3%); reconocen que los analgésicos pueden dañar la salud (76,3%); consumieron analgésicos por sí solos (58,8%). Además, el 47,4% reportó medicamentos a terceros y el 93,8% dijo que almacenaba los medicamentos en sus hogares. Conclusión: Hubo un alto consumo de analgésicos, destacando el uso irracional ­sin prescripción profesional. Es necesario fortalecer la enseñanza sobre el uso racional de los medicamentos entre los estudiantes de enfermería, con el objetivo de minimizar los riesgos de esta práctica.

Objective: To estimate the prevalence of non-opioid analgesics for pain relief among nursing undergraduates. Method: Cross-sectional study, conducted with 142 nursing students in the interior of the state of Amazonas, Northern Region of Brazil. Data were collected in the second half of 2017 using a self-administe redquestionnaire. Results: The prevalence of non-opioid analgesic use was 68,3%; being the relief of headaches (64,9%) and abdominal pain (14,4%) the main reasons for use. The majority stated that: pain interferes with the performance of daily activities (77.3%); they recognize that analgesics can harm health (76.3%); they consumed analgesics on their own (58.8%). Still, 47.4% indicated medicines to third parties and 93.8% reported that they stocked medicines in their homes. Conclusion: There was a high consumption of analgesics, highlighting irrational use -without professional prescription. It is necessary to strengthen the teaching on the rational use of medicines among nursing students, aiming to minimize the risks of this practice.

Clinical usability study of a home-based self-administration transcranial direct current stimulation for primary dysmenorrhea: A randomized controlled trial.

This study tested the usability of a home-based self-administration transcranial direct current stimulation (tDCS) device designed specifically for women's health needs. This is a single center triple blinded clinical usability study for a new wireless, Bluetooth-controlled wearable tDCS device for women's health. The study aims to evaluate the usability and effective blinding of a home-based tDCS system. A total of forty-nine women of reproductive age were randomly allocated (1:1) to receive one session of active tDCS (n = 24) or sham tDCS (n = 25) over the motor and dorsolateral prefrontal cortex. Each participant self-administered one 20-minute session without supervision following guidance on a software application alone. The System Usability Scale (SUS) and the Patient Global Impression of Change (PGIC) were used to evaluate the usability of the system. Regardless of sham or active conditions, all users found the system easy to use without the support of researchers. Usability scores were considered to be "excellent" in both groups and no significant difference was found between sham and active groups showing effective blinding of the device (Active group: 93.7 (83.1-97.5); Sham group 90 (86.2-95) p = 0.79) and PGIC (Active group: 2 (1-2.75); Sham group 2 (1-2) p = 0.99) using an unpaired t-test or non-parametric statistical tests accordingly. The new Bluetooth-controlled wearable tDCS device is easy, safe to use and completely controlled by a smartphone app. This device is focused on women's health and will be tested as an alternative treatment for chronic pelvic pain and mood disturbance associated with menstrual cycles in further research.

Involvement of cortical projections to basolateral amygdala in context-induced reinstatement of ethanol-seeking in rats.

Ethanol is the most consumed substance of abuse in the world, and its misuse may lead to the development of alcohol use disorder (AUD). High relapse rates remain a relevant problem in the treatment of AUD. Exposure to environmental cues previously associated with ethanol intake could trigger ethanol-seeking behavior. However, the neural mechanisms involved in this phenomenon are not entirely clear. In this context, cortical projections to the basolateral amygdala (BLA) play a role in appetitive and aversive learned behaviors. Therefore, we aimed to evaluate the activation of the cortical projections from the prelimbic (PL), orbitofrontal (OFC), and infralimbic (IL), to the BLA in the context-induced reinstatement of ethanol-seeking. Male Long-Evans rats were trained to self-administer 10% ethanol in Context A. Subsequently, lever pressing in the presence of the discrete cue was extinguished in Context B. After nine extinction sessions, rats underwent intracranial surgery for the unilateral injection of red fluorescent retrograde tracer into the BLA. The context-induced reinstatement of ethanol-seeking was assessed by re-exposing the rats to Context A or B under extinction conditions. Finally, we combined retrograde neuronal tracing with Fos to identify activated cortical inputs to BLA during the reinstatement of ethanol-seeking behavior. We found that PL, but not OFC or IL, retrogradely-labeled neurons from BLA presented increased Fos expression during the re-exposure to the ethanol-associated context, suggesting that PL projection to BLA is involved in the context-induced reinstatement of ethanol-seeking behavior.

A dual mechanism fully blocks ethanol relapse: Role of vagal innervation.

Previous studies showed that vagotomy markedly inhibits alcohol self-administration. Present studies hypothesised that vagotomy significantly adds to the inhibition of alcohol relapse induced by drugs that reduce the alcohol-induced hyperglutamatergic state (e.g., N-acetylcysteine + acetylsalicylic acid). The alcohol relapse paradigm tested gauges the elevated alcohol intake observed in animals that had consumed ethanol chronically, were subjected to a prolonged alcohol deprivation and are subsequently allowed ethanol re-access. Ethanol-drinker rats (UChB) were exposed to 10% and 20% ethanol and water concurrently for 4 months, were alcohol deprived for 14 days and were thereafter allowed re-access to the ethanol solutions. An initial binge-like drinking episode is observed upon ethanol re-access, followed by a protracted elevated ethanol intake that exceeds the predeprivation intake baseline. Prior to ethanol re-access, animals were (i) administered N-acetylcysteine (40 mg/kg/day) + acetylsalicylic acid (15 mg/kg/day), (ii) were bilaterally vagotomised, (iii) were exposed to both treatments or (iv) received no treatments. The initial binge-like relapse intake and a protracted elevated ethanol intake observed after repeated ethanol deprivations/re-access cycles were inhibited by 50%-70% by the administration of N-acetylcysteine + acetylsalicylic acid and by 40%-70% by vagotomy, while the combined vagotomy plus N-acetylcysteine + acetylsalicylic acid treatment inhibited both the initial binge-like intake and the protracted ethanol intake by >95% (p < 0.001), disclosing a dual mechanism of ethanol relapse and subsequent inhibition beyond that induced by either treatment alone. Future exploration into the mechanism by which vagal activity contributes to ethanol relapse may have translational promise.

Effectiveness of self-managed medication abortion with accompaniment support in Argentina and Nigeria (SAFE): a prospective, observational cohort study and non-inferiority analysis with historical controls.

BACKGROUND: Clinical trials have established the high effectiveness and safety of medication abortion in clinical settings. However, barriers to clinical abortion care have shifted most medication abortion use to out-of-clinic settings, especially in the context of the COVID-19 pandemic. Given this shift, we aimed to estimate the effectiveness of self-managed medication abortion (medication abortion without clinical support), and to compare it to effectiveness of clinician-managed medication abortion. METHODS: For this prospective, observational cohort study, we recruited callers from two safe abortion accompaniment groups in Argentina and Nigeria who requested information on self-managed medication abortion. Before using one of two medication regimens (misoprostol alone or in combination with mifepristone), participants completed a baseline survey, and then two follow-up phone surveys at 1 week and 3 weeks after taking pills. The primary outcome was the proportion of participants reporting a complete abortion without surgical intervention. Legal restrictions precluded enrolment of a concurrent clinical control group; thus, a non-inferiority analysis compared abortion completion among those in our self-managed medication abortion cohort with abortion completion reported in historical clinical trials using the same medication regimens, restricted to participants with pregnancies of less than 9 weeks' gestation. This study was registered with ISCRTN, ISRCTN95769543. FINDINGS: Between July 31, 2019, and April 27, 2020, we enrolled 1051 participants. We analysed abortion outcomes for 961 participants, with an additional 47 participants reached after the study period. Most pregnancies were less than 12 weeks' duration. Participants in follow-up self-managed their abortions using misoprostol alone (593 participants) or the combined regimen of misoprostol plus mifepristone (356 participants). At last follow-up, 586 (99%) misoprostol alone users and 334 (94%) combined regimen users had a complete abortion without surgical intervention. For those with pregnancies of less than 9 weeks' gestation, both regimens were non-inferior to medication abortion effectiveness in clinical settings. INTERPRETATION: Findings from this prospective cohort study show that self-managed medication abortion with accompaniment group support is highly effective and, for those with pregnancies of less than 9 weeks' gestation, non-inferior to the effectiveness of clinician-managed medication abortion administered in a clinical setting. These findings support the use of remote self-managed models of early abortion care, as well as telemedicine, as is being considered in several countries because of the COVID-19 pandemic. FUNDING: David and Lucile Packard Foundation. TRANSLATIONS: For the Arabic, French, Bahasa Indonesian, Spanish and Yoruba translations of the Article see Supplementary Materials section.

Cocaine-induced increases in motivation require 2-arachidonoylglycerol mobilization and CB1 receptor activation in the ventral tegmental area.

A wide body of evidence supports an integral role for mesolimbic dopamine (DA) in motivated behavior. In brief, drugs that increase DA in mesolimbic terminal regions, like cocaine, enhance motivation, while drugs that decrease DA concentration reduce motivation. Data from our laboratory and others shows that phasic activation of mesolimbic DA requires signaling at cannabinoid type-1 (CB1) receptors in the ventral tegmental area (VTA), and systemic delivery of CB1 receptor antagonists reduces DA cell activity and attenuates motivated behaviors. Recent findings demonstrate that cocaine mobilizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the VTA to cause phasic activation of DA neurons and terminal DA release. It remains unclear, however, if cocaine-induced midbrain 2-AG signaling contributes to the motivation-enhancing effects of cocaine. To examine this, we trained male and female rats on a progressive ratio (PR) task for a food reinforcer. Each rat underwent a series of tests in which they were pretreated with cocaine alone or in combination with systemic or intra-VTA administration of the CB1 receptor antagonist rimonabant or the 2-AG synthesis inhibitor tetrahydrolipstatin (THL). Cocaine increased motivation, measured by augmented PR breakpoints, while rimonabant dose-dependently decreased motivation. Importantly, intra-VTA administration of rimonabant or THL, at doses that did not decrease breakpoints on their own, blocked systemic cocaine administration from increasing breakpoints in male and female rats. These data suggest that cocaine-induced increases in motivation require 2-AG signaling at CB1 receptors in the VTA and may provide critical insight into cannabinoid-based pharmacotherapeutic targets for the successful treatment of substance abuse.

Psychosis induced by abuse of ayahuasca: a case report / Psicosis inducida por el abuso de la ayahuasca: un caso clínico

A B S T R A C T Ayahuasca is a psychotropic infusion prepared by boiling the bark of Amazonian plants and has many psychopharmacological effects not fully understood. Some of those effects are used as treatment for different diseases. However, the side effects of ayahuasca, including ayahuasca-induced psychosis, are an important issue. Here we report the case of a patient who had a psychotic episode after taking ayahuasca and who was successfully treated with antipsychotic medication. Given the current spread of ayahuasca consumption in developed societies, the present case highlights the need for better understanding and regulation of the social-legal condition of ayahuasca and the need for further research. Additionally, psycho-education seems advisable in order to create awareness of the potential risks of the use of ayahuasca.

RESUMEN La ayahuasca es una bebida psicotrópica preparada a través de la cocción de plantas de la cuenca amazónica que tiene muchos efectos psicofarmacológicos no del todo estudiados. Algunos de esos efectos son usados como tratamiento de diversas patologías. Sin embargo, existen efectos secundarios de la ayahuasca que deben ser tenidos en cuenta, entre ellos psicosis inducida por ayahuasca. Reportamos un caso de un paciente que, tras autoadministración de ayahuasca, presentó un episodio psicótico y que fue satisfactoriamente tratado con antipsicóticos. Dada el uso cada vez más frecuente de ayahuasca en las sociedades desarrolladas, el caso actual resalta las necesidades de entender, regular e investigar el uso de la ayahuasca. Además, crear conciencia de los potenciales riesgos del uso de ayahuasca a través de la psicoeducación debería ser implementado.

Prediction of ethanol self-administration in pre-weanling, adolescent, and young adult rats.

Alcohol (ethanol) use is almost normative by late adolescence, in most western countries. It is important to identify factors that distinguish those who progress from alcohol initiation to sustained use of the drug, from those that keep a controlled pattern of drinking. The factors precipitating this transition may change across development. This study analyzed associations between behavioral endophenotypes and ethanol intake at three developmental periods. Exp. 1 measured ethanol drinking at postnatal day 18, via an intraoral infusion procedure, in male or female pre-weanling rats screened for anxiety response in the light-dark box test and for distance traveled in a novel open field. Exp. 2 measured, in juvenile/adolescent or young adult rats, the association between shelter seeking, exploratory/risk-taking behaviors, anxiety or hedonic responses, and ethanol intake. Ethanol intake in pre-weanlings was explained by distance traveled in a novel environment, whereas anxiety responses, measured in the multivariate concentric square field apparatus (MSCF), selectively predicted ethanol intake at adolescence, but not at adulthood. Those juvenile/adolescents with lower mean duration of visit to areas of the MSCF that evoke anxiogenic responses exhibited heightened ethanol intake. These findings suggest that the association between anxiety and ethanol intake may be specifically relevant during adolescence.

Social isolation at adolescence: a systematic review on behaviour related to cocaine, amphetamine and nicotine use in rats and mice.

Adolescence is known for its high level of risk-taking, and neurobiological alterations during this period may predispose to psychoactive drug initiation and progression into more severe use patterns. Stress is a risk factor for drug consumption, and post-weaning social isolation increases drug self-administration in rodents. This review aimed to provide an overview of the effects of adolescent social isolation on cocaine, amphetamine and nicotine use-related behaviours, highlighting the specific period when animals were submitted to stress and these drugs. We wondered if there was a specific period during adolescence that isolation stress would increase drug use vulnerability. A total of 323 publications from the Scopus, Web of Science and PubMed (Medline) electronic databases were identified using the words "social isolation" and "adolescence" and "drug" or "cocaine" or "amphetamine" or "nicotine", resulting in 24 articles after analyses criteria following the PRISMA statement. The main points raised were social isolation during adolescence increased cocaine self-administration, amphetamine and nicotine locomotor activity. We did not observe a pattern of a specific moment during the adolescent period that could lead to an increased vulnerability to drug use. The precise conditions under which adolescent social stress alters drug use parameters are complex and likely depend on several factors.

Innate gut microbiota predisposes to high alcohol consumption.

Gut microbiota is known to be transferred from the mother to their offspring. This study determines whether the innate microbiota of rats selectively bred for generations as high alcohol drinkers play a role in their alcohol intake. Wistar-derived high-drinker UChB rats (intake 10-g ethanol/kg/day) administered nonabsorbable oral antibiotics before allowing access to alcohol, reducing their voluntary ethanol intake by 70%, an inhibition that remained after the antibiotic administration was discontinued. Oral administration of Lactobacillus rhamnosus Gorbach-Goldin (GG) induced the synthesis of FGF21, a vagal ß-Klotho receptor agonist, and partially re-invoked a mechanism that reduces alcohol intake. The vagus nerve constitutes the main axis transferring gut microbiota information to the brain ("microbiota-gut-brain" axis). Bilateral vagotomy inhibited rat alcohol intake by 75%. Neither antibiotic treatment nor vagotomy affected total fluid intake. A microbiota-mediated marked inflammatory environment was observed in the gut of ethanol-naïve high-drinker rats, as gene expression of proinflammatory cytokines (TNF-α; IL-6; IL-1ß) was significantly reduced by nonabsorbable antibiotic administration. Gut cytokines are known to activate the vagus nerve, while vagal activation induces pro-rewarding effects in nucleus accumbens. Both alcoholics and alcohol-preferring rats share a marked preference for sweet tastes-likely an evolutionary trait to seek sweet fermented fruits. Saccharin intake by UChB rats was inhibited by 75%-85% by vagotomy or oral antibiotic administration, despite saccharin-induced polydipsia. Overall, data indicate that the mechanisms that normally curtail heavy drinking are inhibited in alcohol-preferring animals and inform a gut microbiota origin. Whether it applies to other mammals and humans merits further investigation.

Interoception and alcohol addiction: Vagotomy induces long-lasting suppression of relapse-type behavior.

Drug addictions are chronic mental disorders characterized by compulsive drug seeking and drug use, despite their negative consequences. It is a priority to find therapeutic alternatives to prevent relapse, as there are still no treatments that can ensure abstinence. One of the neural systems implicated in the appearance of the states of discomfort that motivate relapse is the interoceptive system, which oversees our internal body states. However, less attention has been given to the peripheral components of the interoceptive system and their role in addictions. Within these pathways, the vagus nerve represents one of the main visceral afferents of the interoceptive system. We hypothesized that the interruption of visceral afferent pathways would decrease the motivational effects of the drug, thereby either decreasing or preventing drug cravings. To test this idea, we used rats of a high-alcohol-drinking line and measured the effect that vagus nerve resection had on the relapse-like alcohol drinking, expressed as the alcohol deprivation effect, a phenomenon that has been linked to addiction-related events such as alcohol cravings. We found that even though vagotomy completely eliminates the effect of alcohol deprivation, it has no impact on water consumption or animal weight. These results give us valuable information about the relationship between the autonomic nervous system and alcohol use disorders and allow us to propose new clinical research that might have translational options.

Aspirin and N-acetylcysteine co-administration markedly inhibit chronic ethanol intake and block relapse binge drinking: Role of neuroinflammation-oxidative stress self-perpetuation.

Chronic alcohol intake leads to neuroinflammation and cell injury, proposed to result in alterations that perpetuate alcohol intake and cued relapse. Studies show that brain oxidative stress is consistently associated with alcohol-induced neuroinflammation, and literature implies that oxidative stress and neuroinflammation perpetuate each other. In line with a self-perpetuating mechanism, it is hypothesized that inhibition of either oxidative stress or neuroinflammation could reduce chronic alcohol intake and relapse. The present study conducted on alcohol-preferring rats shows that chronic ethanol intake was inhibited by 50% to 55% by the oral administration of low doses of either the antioxidant N-acetylcysteine (40 mg/kg/d) or the anti-inflammatory aspirin (ASA; 15 mg/kg/d), while the co-administration of both dugs led to a 70% to 75% (P < .001) inhibition of chronic alcohol intake. Following chronic alcohol intake, a prolonged alcohol deprivation, and subsequent alcohol re-access, relapse drinking resulted in blood alcohol levels of 95 to 100 mg/dL in 60 minutes, which were reduced by 60% by either N-acetylcysteine or aspirin and by 85% by the co-administration of both drugs (blood alcohol: 10 to 15 mg/dL; P < .001). Alcohol intake either on the chronic phase or following deprivation and re-access led to a 50% reduction of cortical glutamate transporter GLT-1 levels, while aspirin administration fully returned GLT-1 to normal levels. N-acetylcysteine administration did not alter GLT-1 levels, while N-acetylcysteine may activate the cystine/glutamate transport xCT, presynaptically inhibiting relapse. Overall, the study suggests that a neuroinflammation/oxidative stress self-perpetuation cycle maintains chronic alcohol intake and relapse drinking. The co-administration of anti-inflammatory and antioxidant agents may have translational value in alcohol-use disorders.

Trends in list prices, net prices, and discounts of self-administered injectable tumor necrosis factor inhibitors.

BACKGROUND: List prices of tumor necrosis factor (TNF) inhibitors drastically increased during the last decade, but previous research has shown that half of these increases were offset by rising manufacturer discounts. It remains unclear to what extent manufacturers' discounts have offset increases in list prices of each self-administered injectable TNF inhibitor. Evaluating trends in net prices and discounts at the product level will be paramount in understanding the role of competition in the biologic market. OBJECTIVES: To (a) describe product-level changes in net prices of each self-administered injectable TNF inhibitor available in 2007-2019 and (b) quantify to what extent manufacturer discounts have offset increases in list prices. METHODS: We obtained 2007-2019 pricing data for etanercept, adalimumab, certolizumab, and golimumab from the investment firm SSR Health, which uses company-reported sales to estimate net prices and discounts for brand products manufactured by publicly traded companies. For each drug and year, we calculated annual costs of treatment for patients with rheumatoid arthritis based on list and net prices and discounts in Medicaid and other payers. RESULTS: From 2007-2019, list prices of etanercept and adalimumab increased by 293% and 295%, respectively; however, discounts offset 47% and 45% of these increases, leading to net price increases of 171% and 203%. List prices of golimumab and certolizumab increased by 183% and 182%, respectively, but with discounts offsetting 58% and 59% of these increases, net prices increased by 103% and 109%. Net prices of golimumab started to decrease after 2016, while net prices of adalimumab and certolizumab experienced their first drop in 2019. Across the study period, discounts in Medicaid and in other payers increased, respectively, from 21% to 85% and 6% to 32% for etanercept; from 26% to 88% and 19% to 35% for adalimumab; from 28% to 63% and 22% to 46% for golimumab; and from 29% to 83% and 27% to 47% for certolizumab. CONCLUSIONS: Despite growing manufacturer discounts, net prices of self-administered injectable TNF inhibitors still increased at a mean annual rate of 9.6% in 2007-2019. This led to net prices tripling for adalimumab and more than doubling for etanercept, golimumab, and certolizumab. DISCLOSURES: This study was funded by the Myers Family Foundation. Hernandez is funded by the National Heart, Lung and Blood Institute (grant number K01HL142847). Funding sources had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Hernandez has served on Pfizer's scientific advisory board. The other authors have nothing to disclose.

El VOT: una opción atractiva en la administración del tratamiento de la tuberculosis / Video Observed Treatment, an attractive option for the administration of tuberculosis therapy

Resumen El VOT (video observed treatment) es la autoadministración de la terapia certificada mediante registro de imágenes en video y podría constituir para algunos pacientes una alternativa complementaria al DOT (directly observed treatment) en la administración del tratamiento ambulatorio de la Tuberculosis en Centros de Salud Primarios. Existen evidencias internacionales en que la estrategia VOT mejora la adherencia al tratamiento, empodera a los pacientes, reduce los costos para pacientes y el sistema de salud y ahorra el tiempo dedicado por los pacientes al traslado a centros de terapia. La disponibilidad masiva de teléfonos portátiles con capacidad de trasmitir videos en la población de Chile podría permitir realizar una investigación piloto de VOT.

VOT (Video Observed Treatment) is a video certificated self-administration of therapy and could be complementary to DOT (Directly Observed Treatment) for the administration of ambulatory tuberculosis treatment at Primary Health Centers. Reviewed international experience and evidence indicates that VOT improves treatment adherence, empowers patients, reduces health system costs and saves patient's transfer time to Therapy Centers. Given the high penetration of smartphones with videocall software in the Chilean population, the pre-requisites are provided to consider a VOT pilot research in Chile.

Automedicación y autoprescripción / Self-medication and self-prescription

Resumen La automedicación y la autoprescripción son acciones de los pacientes; la primera como elemento del autocuidado que involucra medicamentos de venta libre y la segunda como una violación a la ley de salud, pues comprende medicamentos que solo pueden expenderse con receta. Todos los inconvenientes que se han atribuido a la automedicación en realidad lo son de la autoprescripción.

Abstract Self-medication and self-prescription are actions undertaken by patients; the former, as an element of self-care that involves over-the-counter drugs, and the latter, as a violation of the Statute of Health, since it includes drugs that can only be dispensed with a medical prescription. All the drawbacks that have been attributed to self-medication are actually associated with self-prescription.

[Self-applied sphenopalatine ganglion block for postdural puncture headache: four case reports]. / Bloqueio do gânglio esfenopalatino autoaplicado para cefaleia pós­punção dural: relato de quatro casos.

BACKGROUND AND OBJECTIVES: The Sphenopalatine Ganglion Block (SGB) is an effective, low-risk treatment option for Postdural Puncture Headache (PDPH) refractory to conservative management. CASE REPORT: This report presents four complex cases of patients with headache related to low cerebrospinal fluid pressure. Three of them were successfully treated with the application of local anesthetic topical drops through the nasal cavity. CONCLUSION: The novel approach described in this report has minimal risks of discomfort or injury to the nasal mucosa. It is quick to apply and can be administered by the patient himself.