Intranasal mesenchymal stem cell secretome administration markedly inhibits alcohol and nicotine self-administration and blocks relapse-intake: mechanism and translational options.

BACKGROUND: Chronic consumption of most drugs of abuse leads to brain oxidative stress and neuroinflammation, which inhibit the glutamate transporter GLT-1, proposed to perpetuate drug intake. The present study aimed at inhibiting chronic ethanol and nicotine self-administration and relapse by the non-invasive intranasal administration of antioxidant and anti-inflammatory secretome generated by adipose tissue-derived activated mesenchymal stem cells. The anti-addiction mechanism of stem cell secretome is also addressed. METHODS: Rats bred for their alcohol preference ingested alcohol chronically or were trained to self-administer nicotine. Secretome of human adipose tissue-derived activated mesenchymal stem cells was administered intranasally to animals, both (i) chronically consuming alcohol or nicotine and (ii) during a protracted deprivation before a drug re-access leading to relapse intake. RESULTS: The intranasal administration of secretome derived from activated mesenchymal stem cells inhibited chronic self-administration of ethanol or nicotine by 85% and 75%, respectively. Secretome administration further inhibited by 85-90% the relapse "binge" intake that occurs after a protracted drug deprivation followed by a 60-min drug re-access. Secretome administration fully abolished the oxidative stress induced by chronic ethanol or nicotine self-administration, shown by the normalization of the hippocampal oxidized/reduced glutathione ratio, and the neuroinflammation determined by astrocyte and microglial immunofluorescence. Knockdown of the glutamate transporter GLT-1 by the intracerebral administration of an antisense oligonucleotide fully abolished the inhibitory effect of the secretome on ethanol and nicotine intake. CONCLUSIONS: The non-invasive intranasal administration of secretome generated by human adipose tissue-derived activated mesenchymal stem cells markedly inhibits alcohol and nicotine self-administration, an effect mediated by the glutamate GLT-1 transporter. Translational implications are envisioned.

Neurobiology of comorbid post-traumatic stress disorder and alcohol-use disorder.

Post-traumatic stress disorder (PTSD) and alcohol-use disorder (AUD) are highly comorbid in humans. Although we have some understanding of the structural and functional brain changes that define each of these disorders, and how those changes contribute to the behavioral symptoms that define them, little is known about the neurobiology of comorbid PTSD and AUD, which may be due in part to a scarcity of adequate animal models for examining this research question. The goal of this review is to summarize the current state-of-the-science on comorbid PTSD and AUD. We summarize epidemiological data documenting the prevalence of this comorbidity, review what is known about the potential neurobiological basis for the frequent co-occurrence of PTSD and AUD and discuss successes and failures of past and current treatment strategies. We also review animal models that aim to examine comorbid PTSD and AUD, highlighting where the models parallel the human condition, and we discuss the strengths and weaknesses of each model. We conclude by discussing key gaps in our knowledge and strategies for addressing them: in particular, we (1) highlight the need for better animal models of the comorbid condition and better clinical trial design, (2) emphasize the need for examination of subpopulation effects and individual differences and (3) urge cross-talk between basic and clinical researchers that is reflected in collaborative work with forward and reverse translational impact.

Propofol for Treatment of Refractory Alcohol Withdrawal Syndrome: A Review of the Literature.

The authors evaluated all available evidence on the use of propofol as an adjuvant for the treatment of resistant alcohol withdrawal syndrome (AWS) in comparison to other therapies. A comprehensive PubMed search (1966-December 2015) was conducted using the search terms propofol, alcohol withdrawal, and drug therapy. Articles were cross-referenced for other citations. Clinical studies, case series, and case reports published in the English language assessing the use of propofol in adult patients for treatment of AWS were reviewed for inclusion. Propofol is a sedative-hypnotic that exerts its actions through agonism of GABAA receptors at a different binding site than benzodiazepines and reduces glutamatergic activity through N-methyl-d-aspartase (NMDA) receptor blockade. Dosages from 5 to 100 µg/kg/minute reduced AWS symptoms with frequent development of hypotension and requirement for mechanical ventilation. Patients on propofol often experienced longer durations of mechanical ventilation and length of stay, which may be attributed to more-resistant cases of AWS. When propofol was compared with dexmedetomidine as adjuncts in AWS, both agents showed similar benzodiazepine- and haloperidol-sparing effects. Dexmedetomidine was associated with more numerical rates of bradycardia, while propofol was associated with more numerical instances of hypotension. Dexmedetomidine was used more frequently in nonintubated patients. The available data assessing the utility of propofol for AWS exhibited significant heterogeneity. Propofol may be useful in a specific population of patients with AWS, limited to those who are not clinically responding to first-line therapy with benzodiazepines. Specifically, propofol should be considered in patients who are refractory to or not candidates for other adjuvant therapies, patients already requiring mechanical ventilation, or those with seizure activity or refractory delirium tremens. In severe, refractory AWS, adjuvant therapy with propofol may be considered but requires further research to recommend its use either preferentially or as monotherapy.

Reducing physical restraint use in alcohol withdrawal patients: a literature review.

Alcohol withdrawal patients experience symptoms ranging from mild anxiety and disorientation to severe agitation and hallucinations. The most critical of these patients are treated in intensive care units. Physical restraints are often required to maintain patient safety until symptoms resolve. The use of physical restraints is contradictory to nursing values and is unsupported by evidenced-based literature. A literature review was conducted to see what, if any, alternatives have been tested to improve patient care for this complicated patient population.

Assessment of alcohol withdrawal in Native American patients utilizing the Clinical Institute Withdrawal Assessment of Alcohol Revised Scale.

BACKGROUND: The Clinical Institute Withdrawal Assessment of Alcohol Revised (CIWA-Ar) is a commonly used scale for assessing the severity of alcohol withdrawal syndrome in the acute setting. Despite validation of this scale in the general population, the effect of ethnicity on CIWA-Ar scoring does not appear in the literature. The purpose of our study was to investigate the validity of the CIWA-Ar scale among Native American patients evaluated for acute alcohol detoxification. METHODS: A case series of all patients seen for alcohol withdrawal at an Acute Drug and Alcohol Detoxification facility was conducted from June 1, 2011, until April 1, 2012. The CIWA-Ar scores were recorded by trained nursing staff on presentation to Triage Department and every 2 hours thereafter. At our institution, a score of 10 or greater indicates the need for inpatient hospital admission and treatment. Ethnicity was self-reported. Age, sex, blood alcohol concentration, blood pressure, and pulse were recorded on presentation and vital signs repeated every 2 hours. Patients were excluded from the study if other drug use was noted by history or initial urine drug screen. A multivariate logistic regression model was utilized to identify statistically significant variables associated with admission to the inpatient unit and treatment. The relationship of CIWA-Ar scores and ethnicity was compared using analysis of variance. RESULTS: A total of 115 whites, 45 Hispanics, and 47 Native Americans were included in the analysis. Native Americans had consistently lower CIWA-Ar scores at 0, 2, 4, and 6 hours than the other 2 ethnic groups (P = 0.002). In addition, Native Americans were admitted to the hospital less often than the other 2 groups for withdrawal (P < 0.001). CONCLUSIONS: The CIWA-Ar scale may underestimate the severity of alcohol withdrawal syndrome in certain ethnic group such as Native Americans. Further prospective studies should be undertaken to determine the validity of the CIWA-Ar scale in assessing alcohol withdrawal across different ethnic populations.

Systematic review of interventions for children with Fetal Alcohol Spectrum Disorders.

BACKGROUND: Children with Fetal Alcohol Spectrum Disorders (FASD) may have significant neurobehavioural problems persisting into adulthood. Early diagnosis may decrease the risk of adverse life outcomes. However, little is known about effective interventions for children with FASD. Our aim is to conduct a systematic review of the literature to identify and evaluate the evidence for pharmacological and non-pharmacological interventions for children with FASD. METHODS: We did an electronic search of the Cochrane Library, MEDLINE, EMBASE, PsychINFO, CINAHL and ERIC for clinical studies (Randomized controlled trials (RCT), quasi RCT, controlled trials and pre- and post-intervention studies) which evaluated pharmacological, behavioural, speech therapy, occupational therapy, physiotherapy, psychosocial and educational interventions and early intervention programs. Participants were aged under 18 years with a diagnosis of a FASD. Selection of studies for inclusion and assessment of study quality was undertaken independently by two reviewers. Meta-analysis was not possible due to diversity in the interventions and outcome measures. RESULTS: Twelve studies met the inclusion criteria. Methodological weaknesses were common, including small sample sizes; inadequate study design and short term follow up. Pharmacological interventions, evaluated in two studies (both RCT) showed some benefit from stimulant medications. Educational and learning strategies (three RCT) were evaluated in seven studies. There was some evidence to suggest that virtual reality training, cognitive control therapy, language and literacy therapy, mathematics intervention and rehearsal training for memory may be beneficial strategies. Three studies evaluating social communication and behavioural strategies (two RCT) suggested that social skills training may improve social skills and behaviour at home and Attention Process Training may improve attention. CONCLUSION: There is limited good quality evidence for specific interventions for managing FASD, however seven randomized controlled trials that address specific functional deficits of children with FASD are underway or recently completed.

Género y barreras de accesibilidad al tratamiento en pacientes adictos al alcohol de la Comunidad Valenciana / Gender and accessibility barriers to treatment in alcohol abuse patients in the Autonomous Region of Valencia

Introducción: el objetivo principal del presente estudio fue la identificación de los motivos que retrasan el acceso de los pacientes dependientes de alcohol de la Comunidad Valenciana a centros específicos de tratamiento. Método: fueron entrevistados 563 pacientes de Unidades de Conductas Adictivas y Unidades de Alcohología. Se les administró una encuesta sobre tratamientos previos en otros centros y sobre barreras que retrasan el acceso al tratamiento en centros ambulatorios específicos. Se realizó un análisis descriptivo de los ítems y se utilizó la t de student y el test de ANOVA con prueba de Scheffé. Resultados: el 59,7% de los entrevistados manifestaba haber solicitado previamente tratamiento en algún centro no especializado en drogodependencias por alguna molestia física o psíquica que actualmente considera relacionada con el consumo de alcohol o drogas y que en su momento no atribuyó al mismo, o por el propio consumo de sustancias (42,8%). Los servicios más consultados fueron Atención Primaria y Especializada, presentando las mujeres una mayor demanda de tratamiento en los Centros de Salud Mental (p<0,05). La barreras de tratamiento más importantes estaban incluidas en el eje “no conciencia de enfermedad ni problemas asociados” que obtuvo la mayor puntuación media (2,2; dt=0,6). Las mujeres presentaban puntuaciones medias más elevadas en los ejes “estigmatización y respuesta del entorno” y “factores intrínsecos al tratamiento”. Conclusiones: existen diferencias intergénero en las barreras que retrasan el acceso a tratamiento. Es necesario elaborar protocolos de intervención adaptados al género de los pacientes para utilizar en centros de Atención Primaria y de Salud Mental y que permitan disminuir las barreras de accesibilidad al tratamiento

Introduction: this study aimed at identifying the factors that contribute to delaying the access of alcohol abuse patients to specific treatment centres in the Autonomous Region of Valencia (Spain). Method: 563 patients from Addictive Behaviours Units (UCA) and Alcohology Units (UA) were interviewed. A survey was conducted which included items on previous requested treatment in other centres and on barriers of accessibility to treatment in specific ambulatory centres. A descriptive analysis and t-student and ANOVA with Scheffé post-hoc tests were carried out. Results: 59.7% of respondents said they had requested previous treatment in non-specific resources due to physical or psychical trouble that they now relate to their alcohol use although they did not do so at the time, in addition to being motivated by their own alcohol abuse (42.8%). The most attended resources were Primary Care and Specialist Unit Care. Women showed a higher demand for treatment in Mental Health Services (p<0,05). The most important treatment barriers were included in the axis “unawareness of illness and related problems” (2.2; dt=0,6). Women obtained higher scores in the axes “stigmatisation and environment response” and “treatment intrinsic factors”. Conclusions: gender differences in barriers that delay access to treatment do exist. It is necessary to build genderadapted intervention guidelines to be used in Primary Care and Mental Health services to reduce the accessibility barriers to treatment

Temperamento, carácter y trastornos de la personalidad. Aplicación del TCI-R a una muestra de consumidores de drogas en tratamiento y su relación con el MCMI-II / Temperament, character, and personality disorders. Results of TCI-R administration in a sample of drug-addicts in treatment and its relation with MCMI-II

Objetivo: Estudiar los resultados de aplicación de la versión española del TCI-R en una muestra de sujetos que inician tratamiento por consumo problemático de sustancias. Explorar las relaciones entre las puntuaciones del TCI-R y las escalas de trastornos de la personalidad del MCMI-II. Material y método: Se administran el TCI-R y el MCM-II a una muestra de 316 sujetos que inician tratamiento por abuso/dependencia de heroína,cocaína, alcohol o cannabis, en un centro público de tratamiento ambulatorio del Ayuntamiento de Madrid. Resultados: La versión española del TCI-R ofrece adecuadas propiedades psicométricas. Existe una amplia concordancia entre los instrumentos de Cloninger y Millon en la caracterización de los trastornos de personalidad. Bajas puntuaciones en Autodirección y Cooperatividad, junto con elevada Autotrascendencia, sugieren existencia de un trastorno de personalidad. Las diversas combinaciones de los cuatro rasgos temperamentales informan del tipo de trastorno presente. Conclusiones: La versión española del TCI-R es un instrumento fiable y válido para el estudio de los trastornos de personalidad en sujetos adictos. Ambos instrumentos, TCI-R y MCMI-II, presentan indudable utilidad para una caracterización dimensional de los trastornos del Eje II

Objective. The results of the administration of the Spanish version of the TCI-R were examined in a sample of subjects undergoing treatment for substance addiction. The relationships between the TCI-R scores and the MCMI-II personality disorders scales were explored. Material and method: The TCI-R and MCMI-ii were administered to a sample of 316 subjects who had begun treatment for heroin, cocaine, alcohol or cannabis abuse/dependency in a public outpatient treatment centre in Madrid in Spain. Results: the Spanish version of the TCI-R provides suitable psychometric properties. There is a broad concordance between the Cloninger and Millon instruments on the characterisation of personality disorders. Low scores in self-directedness and cooperativeness, together with high self-transcendence, suggest the existence of a personality disorder. The different combinations of the four temperatmental traits provide information on the specific disorder. Conclusions: the Spanish version of the TCI-R appears to be a reliable and valid instrument for the study of personality disorders in addicts. Both instruments, the TCI-R and the MCMI-II, offer undoubted utility inthe dimensional characterisation of Axis II disorders

Estudio neuropsicológico de alcohólicos crónicos durante la fase inicial de desintoxicación: datos preliminares / Neuropsychological assessment of chronic alcoholism patients early during detoxication: preliminary data

El alcohol es la droga que más implicaciones sociales y sanitarias crea en España. Se estima que hasta el 75% de los alcohólicos presentan alteraciones neuropsicológicas como consecuencia del consumo de alcohol, en áreas como las capacidades visoperceptivas, visoconstructivas, mnésicas, ejecutivas, de abstracción y solución de problemas. Estudios recientes han destacado la relación existente entre los déficit cognitivos y el pronóstico y eficacia de los programas de tratamiento en esta población. Se presenta un estudio preliminar cuyo objetivo es conocer la afectación de distintas funciones cognitivas en las fases iniciales de la abstinencia (12-16 días) al inicio de un programa de intervención. Se realizó una evaluación neuropsicológica de una muestra de 15 participantes alcohólicos crónicos en abstinencia y 15 controles. Se aplicaron pruebas para obtener una evaluación cognitiva extensa que abarcase distintas competencias. Atención, memoria, habilidades visoperceptivas, visocontructivas y funciones ejecutivas (flexibilidad mental e inhibición de respeuestas automáticas, fluidez verbal de categorías fonéticas, asignación de recursos atencionales para el procesamiento de la información). Los sujetos alcohólicos mostraron, en comparación con el grupo control, alteraciones en el control atencional, velocidad de procesamiento de la información, inhibición de respuestas automáticas, función visuoespacial y memoria visual

Alcohol is the drug with the most social and heatlh assocated consequences inSpain. It is estimated that up to 75% of alcoholic patients presents neuropsychological deficit related to their alcohol consumption. These difficulties appear to involve visuoperceptual and visuoconstructional skills, memory, executive functions, abstraction and problem solving. Recent studies have shown the relationship between cognitive deficit and the prognosis and efficacy of the rehabilitation programmes in this population. This preliminary study evaluates the cognitive dysfunctions inthe earliest phases of the abstinence period (12-16 days) at the begining of a rehabilitation programme. A neuropsychological assessment was given to 15 chronic alcoholic patients in abstinence and 15 control subjects. Different tests were applied to these subjects in order to obtain a comprehensive cognitive profile. Several functions were assessed: attention, memory, visoperceptual and visuoconstructional skills, and executive functions. The alcoholic participants showed a poorer performance in tests related to attention control, performance speed, automatic response inhibition, visuospatial function and visual memory in comparison with the control group

[Alcohol-related amnesia ("blackout") in broader perspective]. / Alkoholové "okénko" v sirsích souvislostech.

Alcohol-related amnesia ("blackout") is a common even in people who are not alcohol dependent. The average duration of simple alcohol-induced amnesia in our alcohol dependent male patients was almost 8 hours (7.96, SD=23.96). Alcohol-induced amnesia is considered to be a risk factor for long-term impairment of cognitive functions, if alcohol abuse continues. On the other hand cognitive functions in alcohol dependent persons who abstain from alcohol often improve remarkably because of reorganisation and restoration of neuronal networks. This process can be enhanced by vitamin B1, appropriate treatment of withdrawal syndrome, memory training, coping with stress and depression (relaxation techniques can be used), balanced life-style, and nootropic drugs. Alcohol-related amnesia often motivates alcohol dependent patients to overcome their problem, especially if it is appropriately used in psychotherapy.

[A case of alcoholic multiple nervous system degeneration].

Chronic ethyl alcohol abuse is associated with different types of neurological involvement. We report a 51-year-old woman with alcoholic encephalopathy, neuropathy and autonomic dysfunction. After the alcohol abuse of about thirty years, gait disturbance, dysphagia and dysarthria progressively worsened. We thought that the disease was caused by poor nutrition due to chronic alcohol abuse and vitamin B1, B12 deficiency. Her neurological symptoms and signs improved after discontinuation of alcohol and nutritional treatment.

Coma induced by intoxication.

Clinicians in the emergency department are often confronted with coma patients due to poisoning. A systematic general approach involving early consultation with a neurologist is of paramount importance. A high index of suspicion, a systematic first assessment already in the prehospital phase and early stabilisation of vital functions are the essential first steps. Specific antidotes like hypertonic glucose and thiamine are part of a "coma cocktail". The opiate antagonist naloxone should be used only when clinically indicated and in a titrated way. Flumazenil should only be used with caution and in restricted cases. Clinical neurological evaluation and technical investigations like CT-scan and laboratory tests should make part of a careful diagnostic plan. Toxicological tests deserve their place in the diagnostic work up of a coma patient with suspected poisoning. Knowledge of the possibilities of the toxicology lab and optimal communication with the clinical toxicologist is important for optimal patient care.

Alcohol-related brain damage--the concerns of the Mental Welfare Commission.

Scottish mental health legislation permits 'guardianship' for certain mentally impaired individuals, which imposes a requirement on place of residence, access and attendance at specified services for treatment and rehabilitation. The use of guardianship for alcohol-related brain damage increased steeply in the years 1993-1998. Possible explanations include: (1) increased prevalence or diagnosis of these conditions; (2) reduction of hospital beds; (3) a trend towards diminishing family and social support; (4) increased social work involvement in caring for such individuals; (5) increased consideration of the use of guardianship; (6) new private residential services; (7) lack of interest in the condition by existing services. There have been legal and clinical concerns about such individuals under guardianship relating to quality of ongoing clinical assessment, need for specific treatment and for the management of associated psychiatric illness, issues over control of drinking and control of personal finances, uncertainty over the use of restraint, and need for programmes helping the individual's progress towards independent living.