The acute effect of cannabis on ammonia dynamics: a potential new mechanism for THC in locomotor activity?

Effetto in acuto della cannabis sull'equilibrio dell'ammonio: Un nuovo potenziale meccanismo del THC sull'attivit\ue0 motoria

Approval rating and opinion of outpatients and general practitioners toward generic drugs: a questionnaire-based real-world study

Purpose: Generic drugs use in the Liguria region is higher than the Italian average, but lower than in other European countries. No data exist about real-life prescription and level of awareness of generic drugs. In this study, we analyzed demographic, social, economic and cultural factors that may affect the level of awareness of generic drugs and their effective use. Methods: We conducted a population survey using a structured questionnaire, administered to a sample of 8 outpatient clinics of general practitioners located in different districts of Genoa (Liguria, Italy). Multivariate logistic modeling was adopted to study the relationship between awareness/use of generic drugs and characteristics of subjects. Results: Out of 2,000 outpatients surveyed, 95% were aware of generic drugs: these were mostly females (OR =2.2, 95% CI: 1.4\u20133.6), .35 years old (OR .6.0 vs 18\u201335 years), with a high level of education (OR .4.4 vs \u201celementary sch\u201d), living in the west side of the city (OR =1.9 vs center); of these, only 59% declared that they effectively use generic drugs. Users were younger (OR =3.1, 18\u201335 years vs .65 years), with a high level of education (high school/university degree vs no title/elementary/secondary school OR =1.7), and were aware of the lower cost compared with branded drugs, and were mainly informed by pharmacists and physicians. Conclusions: Although subjects were substantially aware of the existence of generic drugs, ~40% still did not use them; doubts about their efficacy seem to be mainly driven by the idea that cheaper drugs lead to lower product quality, in term

Population pharmacokinetics and probability of target attainment of meropenem in critically ill patients

Purpose: Patients admitted to intensive care unit (ICU) with Klebsiella pneumoniae infections are characterized by high mortality. The aims of the present study were to investigate the population pharmacokinetics parameters and to assess the probability of target attainment of meropenem in critically ill patients to provide information for more effective regimens. Methods: Twenty-seven consecutive patients were included in the study. Meropenem was administered as 3-h intravenous (i.v.) infusions at doses of 1\u20132 g every 8 or 12 h. Meropenem plasma concentrations were measured by a high-performance liquid chromatography (HPLC) method, and a population pharmacokinetics analysis was performed using NONMEM software. Meropenem plasma disposition was simulated for extended (3 h; 5 h) or continuous i.v. infusions, and the following parameters were calculated: time during which free drug concentrations were above minimum inhibitory concentration (MIC) (fT > MIC), free minimum plasma concentrations above 4 7 MIC (fCmin > 4 7 MIC), probability of target attainment (PTA), and cumulative fraction of response (CFR). Results: Gender and severity of sepsis affected meropenem clearance, whose typical population values ranged from 6.22 up to 12.04 L/h (mean \ub1 standard deviation (SD) value, 9.38 \ub1 4.47 L/h). Mean Cmin value was 7.90 \ub1 7.91 mg/L, suggesting a high interindividual variability. The simulation confirmed that 88 and 97.5 % of patients achieved effective Cmin > 4 7 MIC values after 3- and 5-h i.v. infusions of meropenem 2 g  7 3/day, respectively. On the contrary, the same total daily doses reached the target Cmin > 4 7 MIC values in 100 % of patients when administered as continuous i.v. infusions. Conclusions: Several factors may influence meropenem pharmacokinetics in ICU patients. Continuous i.v. infusions of meropenem seem to be more effective than standard regimens to achieve optimal therapeutic targets

Metabolismo do hemo: as duas faces dos efeitos da acumulação de precursores e porfirinas

Las Porfirias son enfermedades metabólicas consecuencia de fallas en la biosíntesis del Hemo, caracterizadas por un patrón específico de acumulación y excreción de intermediarios, responsables de su patofisiología. En las Porfirias Agudas el exceso de ácido -aminolevúlico (ALA) produce una sintomatología neuroabdominal asociada al daño oxidativo por formación de especies reactivas de oxígeno (ROS), originadas por autooxidaxión del ALA. En las Cutáneas la sintomatología es producto de la acumulación de porfirinas, que como el ALA, induce la formación de ROS. Su desencadenamiento se precipita por factores endógenos (ayuno, estrés, hormonas) y/o exógenos (fármacos), en particular algunos anestésicos.Se presenta una revisión de los estudios bioquímicos y genéticos en pacientes con diferentes Porfirias obtenidos en el CIPYP, durante los últimos 38 años, que permitieron ampliar nuestro conocimiento sobre las bases moleculares de estas patologías.Se describen los logros resultantes del empleo de modelos experimentales de Porfiria, inducida farmacológica o genéticamente, que contribuyeron a la clasificación de algunas drogas como prohibidas para pacientes con Porfiria. Finalmente, las porfirinas generadoras de ROS y por ende inductoras de muerte celular tienen su aplicación para combatir infecciones por organismos hemo-deficientes como Trypanosoma cruzi y también ser utilizadas como fotosensibilizadores en la terapia fotodinámica (TFD).Porphyrias comprise a group of metabolic disorders of the heme biosynthesis pathway resulting in a specific accumulation and excretion of intermediates which are responsible for their pathophysiology. Acute porphyrias are characterized by acute neurovisceral symptoms due to the overproduction and accumulation of d-aminolevulinic acid (ALA) which leads to an oxidative damage resulting from the formation of reactive oxygen species (ROS). In cutaneous porphyrias, the symptomatology is a result of porphyrin accumulation which also induces ROS moulding. In both cases, their clinical signs are precipitated by endogenous factors (stress, hormones, low calories intake) and/or exogenous drugs, in particular some anaesthetics. A review of the biochemical and genetic results obtained from patients with different porphyrias, diagnosed at the CIPYP during the last 38 years is presented here, aimed at obtaining additional evidence about the molecular nature of these disorders. The achievements obtained from experimental porphyria models –pharmacologically or genetically induced– are also described, which contributed to the classification of some drugs as prohibited for their use in porphyric patients. Finally, as porphyrins produce ROS and therefore cellular death, they can be used to treat infections by heme-deficient organisms like Trypanosoma cruzi and also as photosensitizers in photodynamic therapy (TFD).As Porfirias são doenças metabólicas decorrentes de falhas na biossíntese do Hemo, caracterizadas por um padrão específico de acumulação e excreção de intermediários responsáveis de sua patofisiologia. Nas Porfirias Agudas, o excesso de ácido δ-aminolevulínico (ALA) produz uma sintomatologia neuroabdominal associada ao dano oxidativo por formação de espécies reativas de oxigênio (ROS), decorrentes da auto-oxidação do ALA. Nas Cutâneas a sintomatologia é produto da acumulação de porfirinas, que como o ALA, induzem a formação de ROS. Seu desencadeamento precipita-se por fatores endógenos (jejum, estresse, hormônios) e/ou exógenos (fármacos), especialmente alguns anestésicos. Apresenta-se uma revisão dos estudos bioquímicos e genéticos em pacientes com diferentes Porfirias obtidos no Centro de Investigações de Porfirias e Porfirinas (CIPYP), durante os últimos 38 anos, que permitiram ampliar o conhecimento sobre as bases moleculares destas patologias. Descrevem-se as conquistas resultantes do uso de modelos experimentais de Porfiria, induzida farmacológica ou geneticamente, que contribuíram à classificação de algumas drogas como proibidas para pacientes com Porfiria. Afinal, as porfirinas geradoras de ROS e, por conseguinte, indutoras de morte celular têm sua aplicação para combater infecções por organismos hemo-deficientes como Trypanosoma cruzi e também ser utilizadas como fotossensibilizadores na terapia fotodinâmica (TFD).Fil: Rossetti, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Buzaleh, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Parera, Victoria Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Fukuda, Haydee. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Lombardo, Maria Elisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Lavandera, Jimena Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Gerez, Esther Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Melito, Viviana Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Zuccoli, Johanna Romina. Porphyrias Research Centre; EspañaFil: Ruspini, Silvina Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Puente, Vanesa Rocío. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Diez, Berenice Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Teijo, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Cervino, Nadia Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Varela, Laura Sabina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Guolo, Marcelo Nestor. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Batlle, Alcira María del C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; Argentin

Could Smokers\u2019 Socio-Demographic and Housing Factors Affect and Influence the Choice Between Smoking Cessation Therapies?

Introduction: The published data suggest that interventions which combine pharmacotherapy and behavioural support increase success rates of smoking cessation compared to minimal intervention or usual care; however, a standardized behavioural psychotherapy programme has not been assessed yet. Our main aim was to assess if socio-demographic and housing characteristics of smokers attending an Italian smoking cessation centre, could have influenced the choice between varenicline therapy and psychological support only. Our secondary aims were: i) to evaluate the 6-month abstinence rates (ARs), confirmed by comparing exhaled air carbon monoxide concentrations, in smokers according to whether they took varenicline or received only psychological support; ii) to assess the most frequently reported adverse drug reactions (ADRs) by the varenicline group, mainly focusing on psychiatric events; iii) to evaluate the differences between men and women with regard to specific varenicline-related ADRs. Method: 142 smokers were enrolled; all of them received the same psychological support programme. They were evaluated by a team of clinical experts, who advised them to opt for either one quitting method or the other; then the smokers chose themselves a treatment option of either varenicline plus psychotherapy (VAR: 78 patients) or psychotherapy alone (PSY: 64 patients). Results: Socio-demographic and psychological characteristics of patients have significantly influenced the treatment choice; the 6-month ARs were 35.9% versus 10.9% (p<0.01) in those using varenicline versus psychotherapy, respectively; 57.7% of the patients reported at least one adverse event. Conclusion: The analysis of socio-demographic factors and psychological characteristics of patients seems to be necessary to offer them the most effective therapy in order to achieve good abstinence rates. Therefore, this study confirms the data about the efficacy and safety of varenicline. Our screening methods and exclusion criteria seem to be valid aids to achieving good therapeutic outcomes with a low risk of occurrence of severe psychiatric events

Study on the Role of ABCB1 and Glutathione S-transferase Gene Variants in the Association of Porphyria Cutanea Tarda and Human Immunodeficiency Virus Infection

Porphyrias are a group of metabolic disorders due to alterations in heme biosynthesis. Porphyria Cutanea Tarda (PCT) is a hepatic cutaneous Porphyria resulting from an acquired or inherited deficiency of Uroporphyrinogen decarboxylase. Triggering factors are involved in the onset of this disease. In Argentina, PCT is strongly associated to infection with human immunodeficiency virus (HIV); however, whether the onset of this disease is associated with HIV infection and/or the antiretroviral therapy has not been determined. Our investigation was focused to study the involvement of genetic variants in the development of Porphyrias. In this work, the aim was to evaluate the role of ABCB1 and GST genetic variants in the association between PCT and HIV. This article summarized the main reports about the role of drug metabolism in the onset of PCT, in particular those related with cytochrome P-450 gene variants. Moreover, we extensively described our results about the involvement of ABCB1 transporter and Glutathione S-transferases (GSTs) variants in the association PCT-HIV. We focused our investigation on the ABCB1 gene variants: Exon 12 (rs1128503, NM_000927.5: c.1236C>T), exon 21 (rs2032582, NM_000927.5: c.2677G>T/A) and exon 26 (rs1045642, NM_000927.5: c.3435C>T), that affect drug efflux. The genotypification of GSTT1 null, GSTM1 null and GSTP1 (rs1695, NM_000852.4: c.313A>G), gene variants that alter activity, modifying xenobiotics levels was also analyzed. The high frequency of c.3435C>T (PCT and PCT-HIV) and c.1236C>T (PCT) suggested that the onset of PCT was not specifically related to HIV infection or antiretroviral therapy for these variants. c.2677G>T/A frequencies in the PCT-HIV patients were higher compared with the other groups, suggesting that a mechanism involving antiretroviral therapy had a role in this association. PCT-HIV patients also had a high frequency of GSTT1 null and low frequency for GSTM1 null variants; thus, the genetic basis for PCT onset may involve a combination between the absence of GSTT1 and the presence of GSTM1. When the gene variants studied were analyzed in a whole, PCT-HIV patients had more risk alleles than Controls, PCT or HIV groups. In conclusion, genes encoding for proteins involved in the flow and metabolism of xenobiotics may influence the PCT-HIV association, providing novel insights into the molecular basis of the association between PCT and HIV.Fil: Pagnotta, Priscila Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Melito, Viviana Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Lavandera, Jimena Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Ciencias Biológicas; ArgentinaFil: Buscalia, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Parera, Victoria Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Rossetti, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Zuccoli, Johanna Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Buzaleh, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; Argentin

Electrophysiological properties and projections of lateral hypothalamic parvalbumin positive neurons.

Cracking the cytoarchitectural organization, activity patterns, and neurotransmitter nature of genetically-distinct cell types in the lateral hypothalamus (LH) is fundamental to develop a mechanistic understanding of how activity dynamics within this brain region are generated and operate together through synaptic connections to regulate circuit function. However, the precise mechanisms through which LH circuits orchestrate such dynamics have remained elusive due to the heterogeneity of the intermingled and functionally distinct cell types in this brain region. Here we reveal that a cell type in the mouse LH identified by the expression of the calcium-binding protein parvalbumin (PVALB; LHPV) is fast-spiking, releases the excitatory neurotransmitter glutamate, and sends long range projections throughout the brain. Thus, our findings challenge long-standing concepts that define neurons with a fast-spiking phenotype as exclusively GABAergic. Furthermore, we provide for the first time a detailed characterization of the electrophysiological properties of these neurons. Our work identifies LHPV neurons as a novel functional component within the LH glutamatergic circuitry

Activation of a lateral hypothalamic-ventral tegmental circuit gates motivation.

Across species, motivated states such as food-seeking and consumption are essential for survival. The lateral hypothalamus (LH) is known to play a fundamental role in regulating feeding and reward-related behaviors. However, the contributions of neuronal subpopulations in the LH have not been thoroughly identified. Here we examine how lateral hypothalamic leptin receptor-expressing (LHLEPR) neurons, a subset of GABAergic cells, regulate motivation in mice. We find that LHLEPR neuronal activation significantly increases progressive ratio (PR) performance, while inhibition decreases responding. Moreover, we mapped LHLEPR axonal projections and demonstrated that they target the ventral tegmental area (VTA), form functional inhibitory synapses with non-dopaminergic VTA neurons, and their activation promotes motivation for food. Finally, we find that LHLEPR neurons also regulate motivation to obtain water, suggesting that they may play a generalized role in motivation. Together, these results identify LHLEPR neurons as modulators within a hypothalamic-ventral tegmental circuit that gates motivation

Molecular and electrophysiological characterization of LH^PV neurons.

<p>(A) Detection of <i>Kv3</i>.<i>1</i>, <i>Kv3</i>.<i>2</i>, and <i>Hcn2</i> subunit genes by RT-qPCR analysis after harvesting the cytoplasm from single LH^PV neurons. Representative amplification plot displayed. Note that cells were <i>Pvalb</i>⁺/<i>Vglut2</i>⁺/<i>Vgat</i>⁻. (B) Relative abundance of <i>Kv3</i>.<i>1</i>, <i>Kv3</i>.<i>2</i>, and <i>Hcn2</i> in single LH^PV neurons. Box plots show mean (×), median, quartiles (boxes), and s.e.m. (whiskers). Cycle threshold (Ct), relative abundance values, and sample sizes are explained in Methods. (C) Representative firing pattern of a fast-spiking LH^PV neuron that displays spike frequency accommodation and amplitude attenuation during large depolarizing current injections (500 pA, 500 ms pulses). Note decreases in firing frequency and amplitude during the last 100 ms of the pulse. Dotted line denotes resting membrane potential (V_rmp = –63 mV). (D) Firing rate of LH^PV neurons in response to current injection (<i>I–f</i> curves) during 500 ms pulses. The red/gray dots show the average firing rate of the LH^PV neurons and the standard deviation is indicated by the black vertical bar (<i>n</i> = 34).</p

Electrophysiological properties of LH^PV neurons.

<p>Electrophysiological properties of LH^PV neurons.</p