Investigaram-se 108 pacientes, entre 20 a 85 anos, com internação no pós-operatório em unidades de recuperação cardíaca. Pacientes submetidos a procedimentos cirúrgicos e portadores de quadros infecciosos diversos - broncopneumonia, endocardite, mediastinite e sepse - causados por agentes etiológicos sensíveis à terapia com vancomicina, foram selecionados para este estudo retrospectivo. A vancomicina é um antibiótico muito utilizado, principalmente na terapia de infecções hospitalares graves, predominantemente causadas por Staphylococcus aureus, microorganismo gram positivo resistente à meticilina e oxacilina. Na primeira fase do estudo realizou-se o desenvolvimento e validação da metodologia analítica para dosagem das concentrações plasmáticas da vancomicina pela técnica de cromatografia líquida de alta eficiência (CLAE). O método consiste em simples purificação das amostras biológicas em acetonitrila e detecção em ultravioleta (UV 230 nm). Empregou-se, para a quantificação do fármaco, coluna analítica Shimpack® CLC-ODS, 150 x 6 mm, 5 µm e fase móvel constituída por tampão fosfato 0,05 M, pH 4,5, metanol e acetonitrila, na proporção 80:15:5, pH da fase móvel entre 4,0-4,5, em sistema isocrático de diluição, fluxo 0,8 ml/minuto. Solução metanólica de b-etil-hidroxiteofilina foi utilizada como padrão interno no ensaio. Na fase seguinte da investigação, coletaram-se 2 amostras de sangue de cada paciente, em níveis de pico (Css MÁX), 2 horas após o início da infusão e vale (Css MÍN), imediatamente antes da infusão subsequente, na terapia de manutenção - \"steady state\". As concentrações plasmáticas da vancomicina foram determinadas e utilizadas para estimativa dos parâmetros farmacocinéticos, por meio de modelagem cinética monocompartimental. Determinou-se a meia-vida biológica de eliminação (t(1/2)b) pelo método gráfico e calcularam-se a depuração plasmática ou ?clearance? total (ClT) e o volume de distribuição (Vd) do fármaco no organismo. Estimou-se o índice de acúmulo da vancomicina, pela razão vale/pico (V/P). Efetuou-se, na última etapa do protocolo, o estudo comparativo da cinética da vancomicina, com a população dividida em grupos, classificados de acordo com a idade, função renal, tipo de infecção e dose total diária. Utilizou-se a estatística não paramétrica para análise de significância (teste de Kruskall Wallis). A função renal é o fator determinante da farmacocinética da vancomicina e das doses da antibioticoterapia, sendo responsável pelo acúmulo do fármaco em pacientes no pós-operatório cardíaco. Idade e tipo de infecção não demonstram influência significativa na disposição cinética da vancomicina nos indivíduos estudados. / In this study, 108 patients were investigated, aged 20 to 85 years old, admitted in the intensive care units during the post-operative period. Patients submitted to surgical procedures and with several infectious - bronchopneumonia, endocarditis, mediastinitis, and sepsis - caused by agents sensitive to vancomycin therapy, were selected for this retrospective study. The vancomycin is a widely prescribed antibiotic, mainly for therapy of serious hospital infections caused by Staphylococcus aureus, gram positive microorganism resistant to meticilin and oxacilin. Firstly, the analytic methodology was developed and validated for dosage of the vancomycin plasmatic concentrations by the technique of high efficiency liquid chromatography (HPLC). The method consists of biological samples simple purification in acetonitrile and detection in ultraviolet (UV 230 nm). It was used for quantification of the drug analytical column Shimpack® CLC-ODS, 150 x 6 mm, 5 mm and mobile phase constituted by phosphate buffer 0,05 M, pH 4,5, methanol and acetonitrile, proportion 80:15:5, mobile phase pH 4,0-4,5, in isocratic dilution system, flow 0,8 ml/min. Solution of b-ethil-hydroxitheophylline in methanol was used as internal standard. In the following investigation phase, 2 blood samples from each patient were collected, at peak levels (Css MÁX - 2 hours after the infusion beginning), and at trough (Css MÍN - immediately before the subsequent infusion) in the maintenance therapy - steady state. Plasmatic vancomycin concentrations were used to estimate pharmacokinetics parameters, by monocompartimental kinetic model. Biological half-life of elimination (t(1/2)b) was determined by graphic method. The plasmatic purification or total clearance (ClT) and drug distribution volume (Vd) in the organism were calculated. It was estimated the vancomycin accumulation index, the reason trough/peak (V/P). Comparative study of vancomycin kinetics was performed with groups of patients, classified according to their age, renal function, infection type and daily total dose. Non parametric statistic were used for significancy analysis (Kruskall Wallis test). Renal function is a decisive factor of the vancomycin kinetics disposition and therapy doses, being responsible for drug accumulation in cardiac post-operative patients. Age and infection type did not demonstrate significant influence in the vancomycin pharmacokinetics in this study.

Atheromas contain hypoxic areas which upregulate HIF1α expression, promoting angiogenesis and unstable lesion formation. Simvastatin stabilises atheromas through preventing rupture and neovascularisation. Atheromas express matrix metalloproteinase 14 (MMP14) which degrades matrix proteins and promotes neovascularisation. MMP14 is upregulated by hypoxia and contains Hypoxic-Inducible Factor (HIF) recognition sequences (5’-RCGTG-3’). My project sought to investigate if HIF1α interacts with the MMP14 promoter to enhance MMP14 expression, and whether simvastatin attenuates this effect, inhibiting angiogenesis. Immunostaining of atheromas identified MMP14 and HIF1α localisation. Protein-DNA binding assays were performed on human umbilical vein endothelial cells (HUVECs) and showed HIF1α bound to the MMP14 promoter in hypoxia, which was significantly decreased by simvastatin. To assess gene regulation, a human MMP14 promoter-firefly luciferase reporter construct was transfected into C166 endothelial cells alongside HIF-overexpression plasmids and mutations of the MMP14 promoter region at HIF recognition sequences. Overexpression of HIF1α and HIF1β increased MMP14 activity which was abolished by introducing the mutations and diminished by simvastatin in a HIF-dependent manner. Immunoblots, flow cytometry, scratch assays and bromodeoxyuridine incorporation showed HIF1α knockdown and simvastatin significantly attenuated hypoxia upregulated MMP14 expression, migration and proliferation in a HIF1α-dependent manner. Angiogenesis was assessed using in vivo sponge angiogenesis assays and ex vivo aortic ring assays cultured in hypoxia or normoxia, with or without 0.1μM simvastatin, and MMP14 inhibitor, utilising HIF1αfl/flTie1Cre+ and wildtype littermates. Simvastatin perturbed angiogenesis through decreasing MMP14 expression in a HIF1α-dependent manner. The results show hypoxia upregulates MMP14 through HIF1α interaction with the MMP14 promoter. Simvastatin attenuates MMP14 upregulation which reduces HIF1α:MMP14 promoter interaction. HIF1α knockdown and simvastatin treated HUVECs show less migration and proliferation, equivalent to that of MMP14 inhibition. Simvastatin inhibits neovascularisation in a HIF1α-dependent manner. These results suggest simvastatin may stabilise atheromas through inhibiting MMP14 driven angiogenesis which may have further implications in the treatment of atherosclerosis.

Clinical and forensic toxicology analysts rely heavily in their daily tests on the analysis of the conventional samples (blood and urine). However, these specimens are limited in the time scale they reflect with regard to drug intake history and also in terms of drug stability within the matrices. Alternative matrices such as hair, oral fluids and dried blood spots (DBS) provide new horizons and new opportunities. Drugs incorporated within hair are very stable. Hair also provides a very long detection window, for at least one year, if not a lot longer. Oral fluids on the other hand are non-intrusive, easy to collect and much cleaner sample matrix than blood or urine. DBS also offer great drug stability, are easy to collect, faster to analyse and suitable for automated analysis. However, a number of studies are needed to assess the limits of these alternative samples in terms of the correlation of their results with the results of conventional samples and with regard to drug stability. Such studies will enable a more reliable and confident interpretation of results obtained from these matrices especially for medico-legal purposes. The main aims of this research were: to develop and validate analytical methods for detection and quantitation of drugs of use and abuse in hair, oral fluids, blood and DBS samples, to investigate the correlation between dose and drug concentration in hair, blood and oral fluids after controlled chronic drug administration, to investigate the stability of anti-psychotic drugs in DBS (from patients) stored under different conditions and the effect of addition of preservative, and to investigate the alcohol intake prevalence among Kuwaiti drug addicts and correlate these results with selfreported intake. As the majority of drugs were basic, an extraction method based on methanolic incubation was developed for detection of basic/weak basic drugs in hair. It was compared to alkaline digestion (with NaOH) followed by liquid-liquid extraction (LLE). Detection was achieved by LC-MS/MS (Sciex2000) after separation on a C18 column. When applying both methods on positive authentic hair samples the results showed that the methanolic method was capable of extracting most basic drugs in hair but only partially, while the alkaline digestion method was found to degrade V some unstable drugs like sulpiride, but was capable of fully extracting the alkaline stable drugs such as quetiapine. After development and validation of the LLE-LC-MS(Exactive) method for the analysis of anti-psychotics in blood, oral fluids and hair, an investigation was carried out on the correlation pattern between trough concentrations in those three matrices. The most significant correlation coefficients (r) found were those between blood and hair concentrations, procyclidine r=0.83 (18 subjects p=<0.001), risperidone r=0.96 (14 subjects p=<0.001), haloperidol r=0.90 (10 subjects p=<0.001), OH-risperidone r=0.24 (13 subjects p=>0.44), quetiapine r=0.28 (14 subjects p=>0.33) and chlorprothixene r=0.32 (13 subjects p=>0.32). Among the interesting results was the strong correlation found between drugs half-lives and the mean ratio of hair concentration/dose (r=0.96, p=<0.003). The stability of anti-pyschotics in DBS from patients’ samples was assessed by storing them at four different temperatures (25, 4, -20 and -80°C) with and without prior impregnation of the DBS cards with sodium fluoride. After development and validation of the LLE-LC-MS method, samples were analysed at days 0, 45, 90 and 180. Results showed good stability of all the compounds (procyclidine, quetiapine, risperidone, OH-risperidone, chlorprothixene and haloperidol) in all the different storage conditions and no significant increase or decrease in drug concentrations with sodium fluoride impregnation. Finally, after trials with five different HPLC columns, two SPE cartridges, two LLE extraction procedures and two mass spectrometer instruments, a method was developed and validated for the detection and quantitation of alcohol’s minor and specific metabolite in hair, ethyl glucuronide (EtG). The method has a limit of detection (LOD) of 3pg/mg and lower limit of quantitation (LLOQ) of 9pg/mg. This method was applied to 59 hair samples from patients at a general addiction centre and alcohol prevalence was investigated and its correlation with self-reported use was investigated.

A pesar del uso terapéutico de GHB y de un aumento en la percepción de su toxicidad, el conocimiento sobre los efectos fisiológicos, subjetivos y sobre el rendimiento psicomotor inducidos por el GHB en humanos era limitado. Si bien se habían descrito casos de abuso y dependencia, no se habían realizado estudios controlados evaluando el potencial de abuso de la sustancia. El objetivo más importante de este trabajo fue la caracterización de los efectos del GHB en humanos. En este contexto se pusieron en marcha una serie de estudios controlados para evaluar los efectos del GHB y su potencial de abuso. Los estudios fueron randomizados, a doble ciego, de tipo cruzado y controlados. Las variables estudiadas incluyeron constantes vitales (presión arterial, frecuencia cardiaca, temperatura oral, diámetro pupilar), efectos sobre el rendimiento psicomotor (test de sustitución de símbolos por dígitos, tarea de balance, ala de maddox) efectos subjetivos (cuestionario Addiction Research Center Inventory reducido de 49 items, 13 escalas visuales analógicas, cuestionario de valoración de efectos subjetivos de sustancias con potencial de abuso&#8208;VESSPA) y evaluación farmacocinética. En una primera fase se realizó un estudio piloto de farmacología humana de fase I, donde fueron administradas diferentes dosis de GHB sódico (40, 50, 60 y72 mg/kg) por vía oral a 8 voluntarios en una pauta de dosis ascendente. Las concentraciones de GHB en plasma, fluido oral, orina y sudor fueron analizadas mediante cromatografía de gases acoplada a espectrometría de masas. El método de detección de GHB en plasma, fluido oral y orina fue validado para su posterior uso durante los estudios. Los efectos fisiológicos, subjetivos y sobre el rendimiento psicomotor del GHB fueron evaluados simultáneamente. El GHB produjo efectos de tipo mixto estimulante y sedante, con un incremento inicial de las puntuaciones en los efectos subjetivos de euforia y"colocón", seguido de efectos moderados de tipo sedante asociados a una alteración del rendimiento psicomotor. La administración de GHB se siguió de una rápida absorción y eliminación.El estudio definitivo se realizó con la intención de confirmar los efectos fisiológicos y subjetivos del GHB y su impacto sobre el rendimiento psicomotor, así como pare evaluar su potencial de abuso en comparación con etanol y flunitrazepam, en usuarios de "Club Drugs". Con estos objetivos se evaluaron 12 voluntarios sanos con experiencia previa en el uso de GHB durante 5 sesiones experimentales. Las diferentes condiciones de tratamiento fueron, 2 dosis únicas de GHB (40 o 60 mg/kg), etanol (0.7 g/kg), flunitrazepam (1.25 mg), y placebo, todos administrados por vía oral.Todos los tratamientos activos indujeron efectos de tipo positivo relacionados con su potencial de abuso. La administración de GHB indujo efectos de tipo euforizantes y placenteros ligeramente superiores a los observados tras la administración de flunitrazepam y etanol. El perfil de efectos inducidos por el GHB fue de tipo bifásico, inicialmente de tipo estimulante&#8208;euforizante en relación con el incremento simultáneo de las concentraciones plasmáticas, seguido de un efecto de tipo sedante no relacionado con la cinética plasmática. La administración de GHB produjo asimismo efectos adversos dosis dependientes, pero sin una coincidencia intra&#8208;sujeto de efectos positivos y negativos. Las concentraciones plasmáticas de GHB y las concentraciones de etanol en sangre se correlacionaron significativamente con los efectos subjetivos estimulantes, mientras que las concentraciones plasmáticas de flunitrazepam se correlacionaron significativamente con efectos de tipo sedante. Las concentraciones plasmáticas de GHB se correlacionaron significativamente con las variables relacionadas con el potencial de abuso. En cuanto a los efectos fisiológicos, el GHB indujo un aumento significativo de la presión arterial y del diámetro pupilar, mientras el etanol indujo sus efectos prototípicos y flunitrazepam produjo una marcada sedación. GHB y flunitrazepam produjeron un empeoramiento significativo del rendimiento psicomotor (tareas de sustitución de símbolos por dígitos y del balance), mientras que el etanol únicamente indujo un leve empeoramiento de la tarea del balance.Como conclusión, a las dosis investigadas, la administración de GHB indujo efectos de tipo euforizantes y placenteros, sedación y efectos estimulantes de tipo moderado, similares a los descritos previamente por los usuarios de las sustancia. El perfil de efectos inducidos por el GHB fue de tipo bifásico, inicialmente de tipo estimulante&#8208;eufórico y relacionado con el incremento simultáneo de las concentraciones plasmáticas, seguido de un efecto de tipo sedante no relacionado con la cinética plasmática. La tolerabilidad del GHB difirió substancialmente entre los diferentes sujetos, sin coincidencia intra&#8208;sujeto de efectos positivos y negativos. La administración de GHB se sigue de una rápida absorción y eliminación con una gran variabilidad inter&#8208;indiviudal. Si bien se encontraron concentraciones de GHB todas las matrices biológicas analizadas, tanto el fluido oral como el sudor no parecen convenientes para monitorizar el consumo de GHB. Los resultados sugieren un alto potencial de abuso de GHB en usuarios de "Club Drugs" y aportan los fundamentos científicos del aumento en el abuso de la sustancia en humanos. / Despite GHB therapeutic uses and the increasing concern about the toxicity of this drug, little was known about the physiologic and subjective effects and alterations in psychomotor performance induced by GHB in humans. Furthermore, a number of cases of GHB abuse and dependence have been reported, but no abuse liability studies had been performed. The main aim of this work was characterising the actual behavioural effects of GHB in humans. Within this context, a series of controlled studies to evaluate the effects of GHB and its relative abuse liability were set up. The studies were double blind, randomized, crossover and controlled. Study assessments included vital signs (BP, HR, oral temperature, pupil diameter), psychomotor performance (digit-symbol-substitution-test, balance, maddox&#8208;wing), subjective effects (a set of 13 visual analogue scales, Addiction Research Center Inventory&#8208;49 items, and Evaluation of the Subjective Effects of Substances with Potential of Abuse questionnaires), and pharmacokinetics. Firstly, a pilot pharmacology phase I study was performed where different oral doses of sodium GHB (40, 50, 60, and 72 mg/kg) were given to 8 volunteers in a dose escalation schedule. GHB concentrations in plasma, oral fluid, urine, and sweat were analyzed by gas chromatography-mass spectrometry. The method of detection of GHB in plasma, urine and oral fluid used throughout the studies was validated. Physiological effects, psychomotor performance, and subjective effects were examined simultaneously. GHB showed a mixed stimulant&#8208;sedative pattern, with initially increased scores in subjective feeling of euphoria, high, and liking followed by mild&#8208;moderate symptoms of sedation with impairment of psychomotor performance. GHB was readily absorbed after oral administration and rapidly eliminated. The final study was performed to confirm GHB&#8208;induced subjective and physiological effects, and to evaluate its relative abuse liability compared to flunitrazepam and ethanol, and its impact on psychomotor performance in 'Club Drug' users. Twelve healthy male recreational users of GHB participated in 5 experimental sessions. Drug conditions were a single oral dose of GHB (40 or 60 mg/kg), ethanol (0.7 g/kg), flunitrazepam (1.25 mg), and placebo. All active conditions induced positive effects related to their abuse potential. The administration of GHB produced euphoria and pleasurable effects with slightly higher ratings than those observed for flunitrazepam and ethanol. GHB induced a biphasic time profile with an initial stimulant&#8208;like effect related to the simultaneous rise of plasma concentrations and a latter sedative effect not related to GHB kinetics. GHB administration also induced dose&#8208;dependent mild unpleasant effects, with no within&#8208;subject coincidence of positive and negative GHB related effects. GHB plasma concentrations and ethanol blood concentrations were well correlated to subjective effects related with stimulation whereas flunitrazepam plasma concentrations were better correlated to sedative&#8208;like effects. GHB plasma concentrations were also well correlated to different VAS related to abuse potential. GHB increased blood pressure and pupil diameter. Ethanol induced its prototypical effects, and flunitrazepam produced marked sedation. GHB and flunitrazepam impaired psychomotor performance (digit symbol substitution test and balance task), whereas ethanol, at the dose tested, induced only mild effects exclusively affecting the balance task.In conclusion, at the doses tested GHB was capable of inducing euphoria, pleasurable feelings, sedation and slight stimulant&#8208;like effects as previously reported by GHB users. GHB induced a biphasic time profile with an initial stimulant&#8208;like, euphoric and pleasurable effect related to the simultaneous rise of plasma drug concentrations and ulterior sedative effect collateral to a decrease in GHB plasma concentrations. GHB tolerability highly differ between subjects with no within&#8208;subject coincidence of positive and negative GHB related effects. Following oral administration, GHB is rapidly absorbed and eliminated with high interindiviidual variability. Measurable plasma, urine, oral fluid and sweat were observed. However, oral fluid and sweat appear not to be suitable biological matrices for monitoring GHB consumption. The results suggest a high abuse liability of GHB in 'Club Drug' users, providing the scientific rationale for the increased abuse of the drug in humans.

Despite its widespread use, little research has been undertaken on the use of progestogen-only injectable contraceptives by South African women. This thesis is comprised of two sections. Section 1 provides the first comprehensive description of injectable contraceptive use among rural South African women. It includes an analysis of the contraceptive method mix, prevalence of injectable contraceptive use, discontinuation patterns and reported side effects. A comparison of depot medroxyprogesterone acetate (DMPA) versus norethisterone oenanthate (NET-EN) focuses on utilization patterns and costs. The second section gives an account of the pharmacokinetics of DMPA including the first ever population analysis. A cross-sectional, community-based household survey was undertaken in the Hlabisa sub-district of KwaZulu-Natal, South Africa. Interviews were held during 1998 and 1999, with 848 randomly selected women (aged 15-49 years) and with 14 focus groups. There was a heavy reliance on injectable contraceptives which were used by 74% of women practising contraception. By contrast, the condom was the current method of only 4%. The injectable method was the most commonly used method among teenagers. However, in most cases, contraceptive use appeared to commence only after the first pregnancy. Slightly more NET-EN (54%) than DMPA (46%) was used, with younger women more likely to use NET-EN than DMPA (p=0.001). No significant differences in self-reported side effects were found between current users of the two injectables. Health workers played an important role in women's decisions to use the injectable, and in product selection, with NET-EN being recommended for younger women on the basis of concerns about method reversibility. While some women used injectables for long periods of time, discontinuation rates at two years were high, most commonly due to menstrual disturbances. Many side effects were reported by users of both DMPA and NET-EN, with amenorrhoea the most common, experienced by 63% of current injectable users. Heavy bleeding was most commonly reported by previous users (38%). Vaginal wetness was also common, mentioned by 18% and 29% of current and previous users respectively. Utilisation patterns of the two injectable products (DMPA and NET-EN) were analysed by means of a Pareto analysis of injectables issued from four South African provincial pharmaceutical depots over three financial years (1997/8, 1998/9 and 1999/2000). Injectables accounted for a substantial share of total state expenditure on drugs. While more DMPA than NET-EN was issued, NET-EN distribution from two depots increased over the period of analysis, even though DMPA was the cheaper option. The pharmacokinetic analysis was undertaken amongst DMPA users routinely attending family planning services in three Durban clinics in 1996. Medroxyprogesterone acetate levels at the end of the dosing interval were analysed for 94 women. In addition a population pharmacokinetic analysis of 291 serum levels from 111 DMPA users was undertaken. This involved the use of Non Linear Mixed Effect Modelling (NONMEM) to fit the data and determine the pharmacokinetic parameters, apparent clearance (CLIP) and apparent volume of distribution (VIP), and to estimate the influence of covariates on CLIP and VIP (where P is the bioavailability). The final model estimates for CLIP and VIP were 1080 (95% confidence interval: 994, 1166) litres/day and 86200 litres (95% confidence interval: 68246, 104154) respectively. No significant relationships were found between the covariates tested and CLIP and VIP. Concerns raised in the literature about the influence of weight or ethnicity on the pharmacokinetics of DMPA were shown to be unfounded. In the context of South Africa's HIV epidemic, the heavy reliance on injectable contraceptives, which offer no protection against HIV, should be addressed by expanding the contraceptive method mix to include barrier methods such as the female condom. Health providers are influential in contraceptive decision-making and should be encouraged and supported to redress the dependence on the injectable method alone, taking into account the need of many for dual protection against HIV and unwanted pregnancy. Provider counseling should also focus on adherence to dosing regimens, improving continuation rates, and should provide appropriate advice for women complaining about vaginal wetness with injectable use. Promotion of one injectable product over another to younger women is not appropriate. Since DMPA is the cheaper product, provider training about the rational use of injectable contraceptives should include cost considerations. / Thesis (Ph.D.)-University of Natal, 2003.

No description available.

No description available.

The use of the oral route of administration for the treatment of young children with antibiotics can at times be problematic since, factors such as nausea, vomiting, taste and/or smell, in addition to the challenges associated with the administration of suspensions, may contribute to poor patient compliance. In such cases, the use of the rectal route of administration may be appropriate. Therefore, suppositories containing 250 mg azithromycin (AZI) were manufactured and assessed for potential as an antibiotic suppository dosage form. Suppositories, containing AZI dihydrate were manufactured by the fusion method, using different grades of PEG, Witepsol® and Suppocire® bases. The rate and extent of AZI release was evaluated using USP apparatus I, and samples were analyzed using a validated HPLC method. Differences in the rate and extent of AZI release were observed with the greatest amount of AZI being released from PEG formulations. The rate and extent of AZI release from formulations manufactured using fatty bases were influenced by physicochemical properties, such as melting rate and hydroxyl value, of the bases. In addition drug partitioning appeared to favor the lipid phase and had a negative impact on AZI release characteristics. Two different formulation approaches were used in an attempt to increase the rate and extent of AZI release from fatty base formulations. The use of surfactants significantly increased AZI release from formulations manufactured with fatty bases with high hydroxyl values. The use of urea or Povidone K25 in combination with AZI as a physical mixture or solid dispersion did not increase the rate and extent of AZI release from the fatty suppositories, to any significant extent. The mechanism of drug release was evaluated using several mathematical models, including the Higuchi, Korsmeyer- eppas, Zero and, First order models. In addition, in vitro dissolution profiles were characterized by the difference and similarity factors, f1 and f2 and by use of the Gohel similarity factor, Sd. AZI release kinetics were best described by the Higuchi and Korsmeyer-Peppas models and the values of the release exponent, n, revealed that drug release was a consequence of the combined effects of AZI diffusion, rate of melting of the base and partitioning of the drug which can be considered to be anomalous release.

Investigaram-se 108 pacientes, entre 20 a 85 anos, com internação no pós-operatório em unidades de recuperação cardíaca. Pacientes submetidos a procedimentos cirúrgicos e portadores de quadros infecciosos diversos - broncopneumonia, endocardite, mediastinite e sepse - causados por agentes etiológicos sensíveis à terapia com vancomicina, foram selecionados para este estudo retrospectivo. A vancomicina é um antibiótico muito utilizado, principalmente na terapia de infecções hospitalares graves, predominantemente causadas por Staphylococcus aureus, microorganismo gram positivo resistente à meticilina e oxacilina. Na primeira fase do estudo realizou-se o desenvolvimento e validação da metodologia analítica para dosagem das concentrações plasmáticas da vancomicina pela técnica de cromatografia líquida de alta eficiência (CLAE). O método consiste em simples purificação das amostras biológicas em acetonitrila e detecção em ultravioleta (UV 230 nm). Empregou-se, para a quantificação do fármaco, coluna analítica Shimpack® CLC-ODS, 150 x 6 mm, 5 µm e fase móvel constituída por tampão fosfato 0,05 M, pH 4,5, metanol e acetonitrila, na proporção 80:15:5, pH da fase móvel entre 4,0-4,5, em sistema isocrático de diluição, fluxo 0,8 ml/minuto. Solução metanólica de b-etil-hidroxiteofilina foi utilizada como padrão interno no ensaio. Na fase seguinte da investigação, coletaram-se 2 amostras de sangue de cada paciente, em níveis de pico (Css MÁX), 2 horas após o início da infusão e vale (Css MÍN), imediatamente antes da infusão subsequente, na terapia de manutenção - \"steady state\". As concentrações plasmáticas da vancomicina foram determinadas e utilizadas para estimativa dos parâmetros farmacocinéticos, por meio de modelagem cinética monocompartimental. Determinou-se a meia-vida biológica de eliminação (t(1/2)b) pelo método gráfico e calcularam-se a depuração plasmática ou ?clearance? total (ClT) e o volume de distribuição (Vd) do fármaco no organismo. Estimou-se o índice de acúmulo da vancomicina, pela razão vale/pico (V/P). Efetuou-se, na última etapa do protocolo, o estudo comparativo da cinética da vancomicina, com a população dividida em grupos, classificados de acordo com a idade, função renal, tipo de infecção e dose total diária. Utilizou-se a estatística não paramétrica para análise de significância (teste de Kruskall Wallis). A função renal é o fator determinante da farmacocinética da vancomicina e das doses da antibioticoterapia, sendo responsável pelo acúmulo do fármaco em pacientes no pós-operatório cardíaco. Idade e tipo de infecção não demonstram influência significativa na disposição cinética da vancomicina nos indivíduos estudados. / In this study, 108 patients were investigated, aged 20 to 85 years old, admitted in the intensive care units during the post-operative period. Patients submitted to surgical procedures and with several infectious - bronchopneumonia, endocarditis, mediastinitis, and sepsis - caused by agents sensitive to vancomycin therapy, were selected for this retrospective study. The vancomycin is a widely prescribed antibiotic, mainly for therapy of serious hospital infections caused by Staphylococcus aureus, gram positive microorganism resistant to meticilin and oxacilin. Firstly, the analytic methodology was developed and validated for dosage of the vancomycin plasmatic concentrations by the technique of high efficiency liquid chromatography (HPLC). The method consists of biological samples simple purification in acetonitrile and detection in ultraviolet (UV 230 nm). It was used for quantification of the drug analytical column Shimpack® CLC-ODS, 150 x 6 mm, 5 mm and mobile phase constituted by phosphate buffer 0,05 M, pH 4,5, methanol and acetonitrile, proportion 80:15:5, mobile phase pH 4,0-4,5, in isocratic dilution system, flow 0,8 ml/min. Solution of b-ethil-hydroxitheophylline in methanol was used as internal standard. In the following investigation phase, 2 blood samples from each patient were collected, at peak levels (Css MÁX - 2 hours after the infusion beginning), and at trough (Css MÍN - immediately before the subsequent infusion) in the maintenance therapy - steady state. Plasmatic vancomycin concentrations were used to estimate pharmacokinetics parameters, by monocompartimental kinetic model. Biological half-life of elimination (t(1/2)b) was determined by graphic method. The plasmatic purification or total clearance (ClT) and drug distribution volume (Vd) in the organism were calculated. It was estimated the vancomycin accumulation index, the reason trough/peak (V/P). Comparative study of vancomycin kinetics was performed with groups of patients, classified according to their age, renal function, infection type and daily total dose. Non parametric statistic were used for significancy analysis (Kruskall Wallis test). Renal function is a decisive factor of the vancomycin kinetics disposition and therapy doses, being responsible for drug accumulation in cardiac post-operative patients. Age and infection type did not demonstrate significant influence in the vancomycin pharmacokinetics in this study.

<p>Artemisia Afra, a popular South African traditional herbal medicine is commonly administered as a tea infusion of the leaves. However, clinical trials proving it safety and efficacy are lacking mainly due to the absence of good quality dosage forms and credible placebos for the plant. The objectives of this study were to prepare a standardized preparation of the plant leaves and freeze-dried aqueous extract powder of the leaves, in a tea bag dosage form and to design and prepare credible placebos for these plant materials.</p>