Unidad de práctica para optar al título de Químico Farmacéutico / Autor no autoriza el acceso a texto completo de su documento / El clonazepam y alprazolam, entre otros, pertenecen a un grupo de medicamentos denominados benzodiazepinas (BDZs), que presentan variadas propiedades farmacológicas, tales como sedantes, ansiolíticos y relajantes musculares. En el ámbito forense, dichos fármacos se utilizan de forma ilegal en delitos sexuales y hurtos, donde se convierten en las sustancias de elección para poner en estado de indefensión a las personas. También son consideradas drogas de abuso, siendo muy frecuente encontrarlas solas o asociadas a otras drogas en muchas de las muertes traumáticas, por lo tanto, es de suma importancia poder contar con una metodología analítica correctamente validada, en una institución forense, como lo es el Servicio Médico Legal (SML). De acuerdo a lo que representan estas sustancias, el presente trabajo consistió en dos tareas principales, la primera de ellas fue validar la metodología analítica por cromatografía de gases con detector de captura de electrones (GC/ECD), que actualmente es utilizada en el SML para la confirmación de clonazepam y alprazolam en muestras de individuos fallecidos, o vivos con alguna problemática legal. La matriz utilizada para la validación fue sangre, de la cual se obtuvieron las BDZs por medio de una extracción en fase sólida con columnas Oasis HLB. La segunda tarea realizada, fue implementar una metodología analítica por electroforesis capilar (EC) con detector de arreglo de diodos, para la detección de: clonazepam, alprazolam, diazepam, flunitrazepam, nitrazepam y metabolitos (7-aminoclonazepam, α-OH alprazolam, nordiazepam, oxazepam), y así poder tener una técnica instrumental alternativa a la CG/ECD, que permita identificar estas BZDs de las posibles interferencias cromatográficas

The problem with which this investigation was concerned is that of treating agoraphobia with cognitive-behavioral group therapy and cognitive-behavioral group therapy combined with the drug alprazolam (Xanax). The purpose of the research was twofold. The first goal was to determine the relative effectiveness of the two treatment conditions on phobic behavior, anxiety, and depression. A second goal was to analyze the results and make recommendations concerning each of these modalities available to agoraphobics, their families, and to treatment specialists. The research design of this study was a randomized, pretest-posttest, experimental group design. The sample (N = 15) consisted of Group I (N = 7), who received behavioral-cognitive group therapy combined with the medication alprazolam, and Group II (N = 8), who received behavioral-cognitive group therapy only. The treatment included 15, 2-hour weekly group sessions, with the addition of a brief medication evaluation prior to each group meeting for Group I. During these sessions, the subjects received information about agoraphobia in the form of brief didactic segments, treatment materials, homework assignments, group interaction, and various forms of desensitization. Based on the findings of this study, the following conclusions were drawn: 1. Multidimensional behavioral-cognitive group therapy can significantly reduce phobic avoidance, anxiety, and depression associated with agoraphobia; and 2. Multidimensional behavioral-cognitive group therapy in combination with administration of alprazolam, can significantly reduce phobic avoidance and anxiety associated with agoraphobia.

The prevalence of drugged driving has increased in the United States, and some prescription medications (e.g., zolpidem) cause impairment after the predicted duration of therapeutic action has elapsed. The aim of this study is to determine if bedtime administration of alprazolam similarly impacts driving performance the following day. Volunteers were 14 healthy adults (6 males) who completed a double-blind, double-dummy within-subjects design study examining the effects of alprazolam (0.5, 1, & 2mg), zolpidem (10mg), and placebo administered at bedtime on driving performance the following day. The positive control condition was alprazolam (1mg) administered on the test morning. Driving simulator measures, cognitive and psychomotor tasks, and questionnaires querying drug effects were collected the afternoon before drug administration and for 5.5 hours the next day and analyzed using symmetry and mixed-model approaches. The positive control was robustly impairing. Driving impairment equivalent to that seen with alcohol at the legal limit was observed up to 12.5hr after bedtime alprazolam 2mg and for 8.5hr after bedtime zolpidem 10mg. Volunteers were not fully aware of their own level of impairment. These results suggest that alprazolam used before bed may pose an as yet unrecognized public safety risk in the form of next-day drugged-driving.

En metod som kan användas för att extrahera opolära narkotika- och läkemedelssubstanser ur matriser med ett högt fettinnehåll har tagits fram. Metoden är baserad på ett extraktionsprotokoll från Livsmedelsverket (SLV K1-f4-m018.3) som används för analys av bekämpningsmedel i animaliska livsmedel. Metoden har sedan optimerats för forensiska applikationer genom att ändra olika variabler. Två av variablerna som testades var olika typer av extraktionsmedel och mängden tillsatt C18 (oktadekylsilyl)-sorbent. Experimenten visade att acetonitril som extraktionsmedel och en ökad tillsats av C18 eliminerade den största andelen av fettmolekylerna i matrisen utan att kompromissa med utbytet av den undersökta analyten. Analyterna som undersöktes var 5F-AKB48, tetrahydrocannabinol (THC) och alprazolam och den fettinnehållande matrisen utgjordes av smör. Metoden lyckades minska fetthalten i smörproverna från ca 80- till 3-5 % fett samtidigt som ett utbyte av analyterna erhölls på 70-90 %. Analyten med högst utbyte efter extraktionen var 5F- AKB48 med ett utbyte på cirka 90 %. Utbytet för alprazolam och THC blev 72- respektive 75 %. Vid extraktion med etylacetat, som var det extraktionsmedel som användes i den ursprungliga metoden (SLV K1-f4-m018.3), erhölls inga minskningar av fetthalten överhuvudtaget utan hamnade runt 80 % i samtliga analyser. När metodens kapacitet testades med ökade fetthalter visade det sig att fetthalten efter extraktionen blev lägre i de prover som hade en högre fetthalt från början. Utbytet av analyten (5F-AKB48 i detta fall) påverkades däremot inte nämnvärt av de ökade fetthalterna utan höll sig stabilt runt 85 %.

Os campos magnéticos estáticos interferem com o sistema nervoso central lesado, modificando a atividade de diferentes estruturas e recuperando o comportamento afetado pela lesão. Esse trabalho tem por objetivo investigar os efeitos dos polos magnéticos em ratos Wistar saudáveis e as repercussões comportamentais no Labirinto em Cruz Elevado (LCE) induzidas por pentilenotetrazol (PTZ) e por Alprazolam (ALP) sob o efeito da estimulação magnética. EXPERIMENTO I - Foram utilizados 107 ratos albinos Wistar, machos, pesando entre 270 - 300g. Após quatro dias da implantação de um magneto (3200 Gauss) no crânio dos animais, esses foram submetidos à avaliação comportamental no LCE. Grupos injetados receberam, via intraperitoneal, 30 mg/kg de PTZ ou salina. Os dados obtidos foram analisados por ANOVA, as significâncias foram evidenciadas pelo pós-teste de Holm Sidak com valor de P significativo<0,05. Observamos diminuição no número de entradas nos braços abertos nos grupos PN, PTZ e SMPTZ em relação ao grupo C, e um aumento nas entradas do grupo PSPTZ sobre os grupos PTZ e SMPTZ (F6, 158= 1,91). Análise etológica revelou um aumento da apresentação do comportamento espreitar nos grupos PTZ, SMPTZ, PNPTZ, PSPTZ (F6, 79= 3,51), diminuição na apresentação dos comportamentos mergulho de cabeça (F6, 79= 2,40) e levantamentos (F6, 79= 17,64) nos grupos PN, PS, PTZ, SMPTZ, PNPTZ e PSPTZ em relação ao C. EXPERIMENTO II - Participaram 79 animais mantidos nas mesmas condições experimentais que no experimento I, injetados com Alprazolam (1mg/kg - intraperitoneal) ou salina. Observamos um aumento no número de entradas nos braços abertos nos grupos ALP e SMALP em relação ao grupo C (F6, 144= 3,53). A porcentagem de entradas nos braços abertos foi maior nos grupos ALP e SMALP em relação ao C (F6, 72= 2,41), e a porcentagem de tempo nos braços abertos foi maior no PNALP, comparado com o C (F6, 72= 3,95). A análise etológica revelou um aumento na frequência dos comportamentos mergulho de cabeça (F6, 72= 10,79) e exploração da extremidade final (F6, 72= 6,00) nos grupos ALP, SMALP e PNALP em relação ao C. Para o comportamento de levantamentos (F6, 72= 4,71) também observamos um aumento da frequência desse comportamento para os grupos ALP, SMALP e PSALP em relação ao C. No experimento I, o polo Sul conseguiu antagonizar o efeito do PTZ, na variável espaço-temporal entradas nos braços abertos, além disso, a estimulação magnética polo Norte, mimetizou o efeito do PTZ. No experimento II, ambos os polos magnéticos antagonizaram o efeito ALP na variável espaço-temporal entradas nos braços abertos. As variáveis etológicas também revelaram um antagonismo da resposta ALP, pelo polo Norte e pelo polo Sul. Dessa maneira, esse trabalho mostra através da análise comportamental no LCE que os campos magnéticos podem interferir de maneira distinta com as modificações no comportamento de ratos injetados com PTZ ou ALP / Static magnetic fields interfere with the injured central nervous system, modifying the activity of different structures and recovering the behavior affected by the lesion. The objective of this study was to investigate the effects of magnetic poles on healthy Wistar rats and the behavioral repercussions of the Penzolenotetrazole (PTZ) and Alprazolam (ALP) induction on the Elevated Plus-Maze (EPM) under the effect of magnetic stimulation. EXPERIMENT I - 107 male Wistar rats weighing between 270 and 300 g were used. After four days of implantation of a magneto (3200 Gauss) in the cranium of the animals, they were submitted to behavioral evaluation in the EPM. Injected groups received intraperitoneally 30 mg / kg of PTZ or saline. The data were analyzed by ANOVA, the significance was evidenced by the Holm Sidak post-hoc with a significant P value <0.05. We observed a decrease in the number of entrance open arms in the PN, PTZ and SMPTZ groups compared to group C, and an increase in the PSPTZ group on PTZ and SMPTZ groups (F6, 158 = 1.91). Ethological analysis showed an increase in the peeking out behavior in the PTZ, SMPTZ, PNPTZ, PSPTZ groups (F6, 79 = 3.51) and a decrease in the performance of the head dipping behavior (F6, 79= 2.40), and of rearing in PS, PTZ, SMPTZ, PNPTZ and PSPTZ in relation to C (F6, 79= 17.64). EXPERIMENT II - Participated 79 animals maintained in the same experimental conditions as in experiment I, injected with Alprazolam (1mg / kg - intraperitoneal) or saline. We observed an increase in the number of entrance into open arms in the ALP and SMALP groups compared to group C (F6, 144 = 3.53). And the percentage of open arms entries was higher in the ALP and SMALP groups than C (F6, 72 = 2.41), and the percentage of open arms time spented was higher in PNALP, compared to C (F6, 72 = 3.95). The ethological analysis revealed an increase in the frequency of head dipping behaviors (F6, 72 = 10.79) and end-arm activity (F6, 72 = 6.00) in the groups ALP, SMALP and PNALP in relation to C. Already for the rearing (F6, 72 = 4.71), we also observed an increase in the frequency of this behavior for the ALP, SMALP and PSALP groups in relation to C. In the experiment I, the South pole was able to antagonize the PTZ effect, as reported for the space-time variable in the open arms, besides the North pole magnetic stimulation, mimics the PTZ effect. In the experiment II, both magnetic poles antagonize the ALP effect in the space-time variable in the open arms. The ethological variables also revealed an antagonism of the ALP response, by the North and South poles. Thus, this work shows through the behavioral analysis in the EPM that the magnetic fields can interfere in a different way with the modifications in the behavior of injected rats with PTZ or ALP

Os campos magnéticos estáticos interferem com o sistema nervoso central lesado, modificando a atividade de diferentes estruturas e recuperando o comportamento afetado pela lesão. Esse trabalho tem por objetivo investigar os efeitos dos polos magnéticos em ratos Wistar saudáveis e as repercussões comportamentais no Labirinto em Cruz Elevado (LCE) induzidas por pentilenotetrazol (PTZ) e por Alprazolam (ALP) sob o efeito da estimulação magnética. EXPERIMENTO I - Foram utilizados 107 ratos albinos Wistar, machos, pesando entre 270 - 300g. Após quatro dias da implantação de um magneto (3200 Gauss) no crânio dos animais, esses foram submetidos à avaliação comportamental no LCE. Grupos injetados receberam, via intraperitoneal, 30 mg/kg de PTZ ou salina. Os dados obtidos foram analisados por ANOVA, as significâncias foram evidenciadas pelo pós-teste de Holm Sidak com valor de P significativo<0,05. Observamos diminuição no número de entradas nos braços abertos nos grupos PN, PTZ e SMPTZ em relação ao grupo C, e um aumento nas entradas do grupo PSPTZ sobre os grupos PTZ e SMPTZ (F6, 158= 1,91). Análise etológica revelou um aumento da apresentação do comportamento espreitar nos grupos PTZ, SMPTZ, PNPTZ, PSPTZ (F6, 79= 3,51), diminuição na apresentação dos comportamentos mergulho de cabeça (F6, 79= 2,40) e levantamentos (F6, 79= 17,64) nos grupos PN, PS, PTZ, SMPTZ, PNPTZ e PSPTZ em relação ao C. EXPERIMENTO II - Participaram 79 animais mantidos nas mesmas condições experimentais que no experimento I, injetados com Alprazolam (1mg/kg - intraperitoneal) ou salina. Observamos um aumento no número de entradas nos braços abertos nos grupos ALP e SMALP em relação ao grupo C (F6, 144= 3,53). A porcentagem de entradas nos braços abertos foi maior nos grupos ALP e SMALP em relação ao C (F6, 72= 2,41), e a porcentagem de tempo nos braços abertos foi maior no PNALP, comparado com o C (F6, 72= 3,95). A análise etológica revelou um aumento na frequência dos comportamentos mergulho de cabeça (F6, 72= 10,79) e exploração da extremidade final (F6, 72= 6,00) nos grupos ALP, SMALP e PNALP em relação ao C. Para o comportamento de levantamentos (F6, 72= 4,71) também observamos um aumento da frequência desse comportamento para os grupos ALP, SMALP e PSALP em relação ao C. No experimento I, o polo Sul conseguiu antagonizar o efeito do PTZ, na variável espaço-temporal entradas nos braços abertos, além disso, a estimulação magnética polo Norte, mimetizou o efeito do PTZ. No experimento II, ambos os polos magnéticos antagonizaram o efeito ALP na variável espaço-temporal entradas nos braços abertos. As variáveis etológicas também revelaram um antagonismo da resposta ALP, pelo polo Norte e pelo polo Sul. Dessa maneira, esse trabalho mostra através da análise comportamental no LCE que os campos magnéticos podem interferir de maneira distinta com as modificações no comportamento de ratos injetados com PTZ ou ALP / Static magnetic fields interfere with the injured central nervous system, modifying the activity of different structures and recovering the behavior affected by the lesion. The objective of this study was to investigate the effects of magnetic poles on healthy Wistar rats and the behavioral repercussions of the Penzolenotetrazole (PTZ) and Alprazolam (ALP) induction on the Elevated Plus-Maze (EPM) under the effect of magnetic stimulation. EXPERIMENT I - 107 male Wistar rats weighing between 270 and 300 g were used. After four days of implantation of a magneto (3200 Gauss) in the cranium of the animals, they were submitted to behavioral evaluation in the EPM. Injected groups received intraperitoneally 30 mg / kg of PTZ or saline. The data were analyzed by ANOVA, the significance was evidenced by the Holm Sidak post-hoc with a significant P value <0.05. We observed a decrease in the number of entrance open arms in the PN, PTZ and SMPTZ groups compared to group C, and an increase in the PSPTZ group on PTZ and SMPTZ groups (F6, 158 = 1.91). Ethological analysis showed an increase in the peeking out behavior in the PTZ, SMPTZ, PNPTZ, PSPTZ groups (F6, 79 = 3.51) and a decrease in the performance of the head dipping behavior (F6, 79= 2.40), and of rearing in PS, PTZ, SMPTZ, PNPTZ and PSPTZ in relation to C (F6, 79= 17.64). EXPERIMENT II - Participated 79 animals maintained in the same experimental conditions as in experiment I, injected with Alprazolam (1mg / kg - intraperitoneal) or saline. We observed an increase in the number of entrance into open arms in the ALP and SMALP groups compared to group C (F6, 144 = 3.53). And the percentage of open arms entries was higher in the ALP and SMALP groups than C (F6, 72 = 2.41), and the percentage of open arms time spented was higher in PNALP, compared to C (F6, 72 = 3.95). The ethological analysis revealed an increase in the frequency of head dipping behaviors (F6, 72 = 10.79) and end-arm activity (F6, 72 = 6.00) in the groups ALP, SMALP and PNALP in relation to C. Already for the rearing (F6, 72 = 4.71), we also observed an increase in the frequency of this behavior for the ALP, SMALP and PSALP groups in relation to C. In the experiment I, the South pole was able to antagonize the PTZ effect, as reported for the space-time variable in the open arms, besides the North pole magnetic stimulation, mimics the PTZ effect. In the experiment II, both magnetic poles antagonize the ALP effect in the space-time variable in the open arms. The ethological variables also revealed an antagonism of the ALP response, by the North and South poles. Thus, this work shows through the behavioral analysis in the EPM that the magnetic fields can interfere in a different way with the modifications in the behavior of injected rats with PTZ or ALP

Darbo tikslas: Optimizuoti plonasluoksnės chromatografijos ir efektyviosios skysčių chromatografijos metodikas, tinkamas alprazolamo, kodeino ir paracetamolio kokybiniam įvertinimui. Tyrimo objektas ir metodai: Optimizuojant PC metodiką, analizuoti etaloniniai 0,2 mg/ml koncentracijos alprazolamo, kodeino, paracetamolio trichlormetaniniai tirpalai ir jų mišinys. Tirpiklių sistemoms buvo naudoti etanolis, trichlormetanas, eteris, 25% amonio hidroksidas, acetonas, izobutanolis. Dėmių ryškinimui naudota UV šviesos (254nm; 365nm) lempa arba Dragendorfo reagentas (modifikuotas pagal Munjė). Optimizuotos metodikos pritaikytos tiriant trichlormetaninius darbinius tirpalus, pagamintus iš vaistinių preparatų „Xanax“, „Paracetamolis Sanitas“ ir „Ultracod“. Siekiant pritaikyti ESC metodiką tiriamųjų junginių analizei, buvo tirti etaloniniai 0,1 mg/ml koncentracijos alprazolamo, kodeino ir paracetamolio metanoliniai tirpalai bei jų mišinys. Medžiagų atskyrimui ir identifikavimui naudotas chromatografas Waters 2695 su fotodiodų matricos detektoriumi Waters 996 (210 – 400 nm bangų ilgio diapazonas). Chromatografavimui naudoti metanolis, 3% acto rūgšties vandeninis tirpalas. Optimizuota ESC metodika pritaikyta tiriant metanolinius darbinius tirpalus, pagamintus iš vaistinių preparatų „Xanax“, „Ultracod“ ir „Solpadeine“. Rezultatai ir išvados: Tinkamiausios tirpiklių sistemos alprazolamo, kodeino ir paracetamolio mišinio kokybiniam vertinimui PC metodu – TS-D (trichlormetanas: acetonas:... [toliau žr. visą tekstą] / Aim: To optimize thin-layer chromatography and high-performance liquid chromatography methods for alprazolam, codeine, paracetamol and their mixture qualitative analysis. Object and methods: For TLC method optimization alprazolam, codeine, paracetamol and their mixture stock solutions (0,2 mg/ml) in trichlormetan were analysed. For mobile phase were used: ethanol, trichlormetan, ether, 25% ammonia hydroxide, acetone, isobutanol. For spots development were used UV light lamp (254nm; 365nm) or Dragendorff reagent (modified by Munje). Optimized methods were tried with pharmaceutical products “Xanax”, “Paracetamolis Sanitas” and “Ultracod” solutions. For HPLC method optimization alprazolam, codeine, paracetamol and their mixture stock solutions (0,1 mg/ml) in methanol were analysed. Chromatograph Waters 2695 with photo diode array detector Waters 996 (210-400 nm wave length) were used for qualitative determination. Analysis was made by using methanol and 3% acetic acid aqueous solution. Optimized method was applied in analysis of pharmaceutical products “Xanax”, “Ultracod” and “Solpadeine” solutions. Results: The best mobile phases for alprazolam, codeine and paracetamol mixture qualitative analysis using TLC is TS-D (trichlormetan: acetone: concentrated ammonia hydroxide (55:40:5)) and TS-F (trichlormetan: ether: isobutanol: concentrated ammonia hydroxide (50:30:15:5)). TS-D and TS-F mobile phases are suitable for examined substances qualitative analysis in mixture and... [to full text]

Thesis (Ph. D.)--Uniformed Services University of the Health Sciences, 2005. / Typescript (photocopy).

Die Therapie der HIV Infektion besteht aus Kombination mehrerer antiretroviraler Substanzen und birgt ein erhöhtes Risiko an Arzneimittelwechselwirkungen. Das bekannte Problem der Virusresistenz kann zudem durch Enzyminduktion begünstigt werden. Das Ziel der vorliegenden Arbeit lag in Untersuchungen zu Einflüssen der Virustatika auf die Expression von Cytochrom P450 Enzymen: 1A1, 1B1, 3A4 sowie der P-Glykoproteins (MDR1) an immortalisierten Zellsystemen. Die Protease Inhibitoren Indinavir, Nelfinavir, Ritonavir und Saquinavir induzierten die Regulation der mRNA Expression über den Aryl-Kohlenwasserstoff-Rezeptor (AhR) und den Pregnan-X-Rezeptor (PXR) dosisabhängig und signifikant. Die Nukleosidischen Reverse Transkriptase Inhibitoren Zalcitabin, Zidovudin und Lamivudin sowie der Nicht-Nukleosidische Inhibitor Nevirapin zeigten induktive Eigenschaften nur für die AhR Zielgene CYP1A1 und CYP1B1. Amprenavir und Efavirenz aktivierten die PXR-Regulation. Die möglichen Auswirkungen der Induktion der untersuchten Gene wurden ausführlich diskutiert. Die molekularen Grundlagen der interindividuell variierenden Aktivität von CYP3A wurden in einer Probandenstudie untersucht. Es wurden die mRNA Expression in den Leukozyten, die Aktivität des Enzyms und einige bekannte Polymorphismen unter Einwirkung von Rifampicin untersucht und diskutiert. / The therapy of HIV infection requires a combination of several antiretroviral substances accompanying risk factors for drug-drug interactions. Moreover, virus resistance can be promoted by enzyme induction caused by antiretroviral drugs. The aim of the study was to investigate the influences of antiretroviral substances on the expression of cytochrome P450 enzymes: 1A1, 1B1, 3A4 and p-glycoprotein (MDR1) using immortalized cell systems. The protease inhibitors indinavir, nelfinavir, ritonavir and saquinavir induced significantly the regulation of mRNA expression through the aryl hydrocarbon receptor (AhR) and the pregnane-x-receptor (PXR) in a concentration-dependent manner. The nucleoside reverse transcriptase inhibitors zalcitabine, zidovudine and lamivudine and the non-nucleoside reverse transcriptase inhibitor nevirapine showed inductive properties only for the AhR target genes CYP1A1 and CYP1B1.Amprenavir and efavirenz activated the PXR target genes. Potentially effects of the described induction are discussed. In a second part of the work, the molecular mechanisms of the individual varying activity of the CYP3A enzyme were investigated applying an in vivo study. CYP3A4 mRNA expression and rifampicin mediated induction in leucocytes were correlated with systemic enzyme activity under induction and known polymorphisms.