Die Arbeit befasst sich mit Methoden der Erfassung metabolischer Funktion einer dynamischen Zellkultur in Bioreaktoren zur klinischen Verwendung als Leberunterstützungssystem. Der Fokus liegt auf der Etablierung von Tests zur Qualitätssicherung als effiziente In- Prozess Kontrollen während der Bereitstellungsphase der Zellkulturen. Weitere Ziele sind ein Beitrag zu Wirksamkeitsnachweis und zur Charakterisierung des Systems im Rahmen von Zulassungen als "Biologic". Bei der experimentellen Untersuchung unter Verwendung von Leberzellkulturen aus porcinen Organen wurden der Lidocain- MEGX Test, die Elimination von Galaktose und Sorbitol sowie die Elimination von Ammoniak und die Synthese von Harnstoff, Lactat und Albumin berücksichtigt. Dies erfolgte mittels Bolus- und Fliessgleichgewichtsuntersuchungen sowie Konzentrationsbestimmungen. Die Ergebnisse zeigten für alle Parameter einen hochsignifikanten Unterschied zu Zellfreien Bioreaktoren, sowie einen typischen Verlauf, der in eine initiale Adhäsionsphase, eine stabile Kulturphase und eine darauf folgende erweiterte Phase mit langsamer Abschwächung der Zellleistungen gegliedert werden kann. Die Parameter erwiesen sich prinzipiell alle geeignet für den Einsatz in der Qualitätssicherung der dynamischen Zellkultur. Ein kombiniertes Untersuchungsschema bestehend aus Parametern die die Integrität der Zellmembranen reflektieren, wie die Freisetzung von Enzymen, sowie metabolischen Parametern wie Lidocain, Galaktose, Sorbitol als auch Syntheseparameter, für Proteine Albumin, als Hepatozyten typische Leistungen die Synthese von Harnstoff und der Abbau von Lactat ist in der Lage einen ausreichend umfassenden Einblick in den Status der dynamischen Zellkultur zu liefern. / Objectives of this work were to find easy to handle every day quality assessment procedure for bioreactors that are intended for clinical trials, further more usefulness of these parameters in characterization and standardization of the Liver Support System. Parameters for evaluation had been: Lidocaine, Megx, Sorbitol, Galactose, Urea, Albumin and Lactate. Bolus and Continuous metabolic liver functions tests had been done, for synthesis and detoxification parameters liberation was measured by concentration. Highly significant difference between bioreactor with primary porcine liver cells and cell-free devices was shown by t-tests. Differences to other groups like infected bioreactors had been demonstrated with ANOVA. Results show typical course over the culture period that can be categorized into a initial phase of cell reorganization, a stable culture phase and an extended phase with slow decay. All parameter proved to be suitable for daily routine quality assessment in dynamic cell culture systems. The combination of parameters reflecting different specific cellular function is able to give more comprehensive insights in the status of the cell culture.

A anestesia local normalmente precede a maioria dos procedimentos odontológicos. Porém, por ser realizada por processo invasivo (injetável), muitas vezes afugentam o paciente do consultório. Portanto, a substituição do processo invasivo por não invasivo, além de inovador traria diversas vantagens a odontologia i.e., possibilitaria o aprimoramento de procedimentos rotineiros e cirúrgicos devido à provável redução de custos, submissão do paciente, facilidade de aplicação e menores riscos de contaminação e intoxicações. Neste intuito, filmes poliméricos hidrofílicos mono ou trilaminados, compostos pelo polímero mucoadesivo HPMC K100 LV, glicerol ou PEG 400 como plastificantes, e contendo os anestésicos locais cloridratos de prilocaína (PCL) e lidocaína (LCL) em diferentes proporções foram desenvolvidos. Os filmes apresentaram flexibilidade e moldabilidade adequadas, além de uniformidade de massa e teor. Tanto a massa total de fármaco nos filmes (11 - 55 mg/0,64cm2), quanto suas contribuições relativas nas misturas (0 - 100% m.m-1) modularam seus perfis e cinéticas de liberação e permeação, além das quantidades retidas no epitélio esofageal suíno. Quantidades menores dos fármacos conduziram aos maiores coeficientes de permeabilidade do LCL. O filme contendo mistura dos fármacos na proporção 1:1 (PCL:LCL) apresentou a melhor relação custo/benefício e foi escolhida para a continuidade dos estudos. O aumento na massa total de fármaco nos filmes de 12,5 para 25 mg aumentou significativamente sua força e trabalho de mucoadesão, mas reduziu sua resistência à tração e módulo de elasticidade. Os filmes apresentaram propriedades mecânicas e de mucoadesão adequadas para a finalidade proposta. A adição de camadas oclusiva (composta por Eudragit® S100 e trietil citrato como plastificante) e mucoadesiva (composta por HPMC K100 LV e policarbofil na proporção 3:1 m.m-1 e PEG 400 como plastificante) aos filmes reduziu significativamente as quantidades dos fármacos liberadas, permeadas e retidas no epitélio e, portanto, a composição e arquitetura dos patches trilaminados deve ser aprimorada de modo a favorecer a hidratação da camada de liberação. Pela primeira vez foi demonstrada a eficiência da técnica de iontoforese (1 mA.cm-2) na promoção da permeação destes fármacos em associação a partir de filmes poliméricos. Para que possa substituir a anestesia injetável (solução a 2%, equivalente a 36 mg de fármaco), a permeação dos fármacos a partir do filme mais promissor (12,5 mg de PCL:LCL 1:1, 3% m.m-1 HPMC K100LV e 30% PEG400 em função da massa de polímero mucoadesivo) deve ser aumentada em pelo menos 30 vezes. / Local anesthesia typically precedes the majority of dental procedures. However, due to be performed using an invasive process (injection), often it scares the patient out from the dentist office. Accordingly, besides its innovative character, the replacement of the painful injection by a noninvasive process might bring several advantages to the dentistry field. It might enable the improvement of routinely and surgical procedures as a function of cost saving, patient compliance, ease of application and lowering the risk of contamination and intoxication. In this pursuit, we developed hydrophilic polymeric films comprised by one or three layers, comprised by the mucoadhesive polymer HPMC K100 LV, glycerol or PEG 400 as plasticizers, and containing the local anesthetic drugs prilocaine (PCL) and lidocaine (LCL) hydrochloride in different proportions. The films showed suitable flexibility and plasticity, besides uniformities of mass and content. Both the total mass of drugs in the films (11 - 55 mg/0.64 cm2), and their relative contribution in the mixtures (0 - 100% w.w-1) have modulated their profiles and kinetics of both delivery and permeation, as well as their amount retained in the porcine esophageal epithelium. Lower drug loadings lead to an increase on the permeability coefficient of LCL. The film containing the drugs blended on a 1:1 (PCL:LCL) proportion has presented the most acceptable cost/benefit ratio. Hence, it was chosen for further investigations. Increasing the total amount of drug in the film from 12.5 to 25 mg significantly raised their force and work of mucoadhesion. On the other hand, it have decreased their tensile strength and elastic modulus. The films presented suitable mechanical e mucoadhesive properties for our purposes. Adding the mucoadhesive (comprised by HPMC K100 LV and polycarbophil at 3:1 w.w-1 and PEG400 as plasticizer) and occlusive (Eudragit® S100 and triethyl citrate as plasticizer) layers on the delivery layer has significantly decreased the amount of drug released, permeated and retained on the epithelium from the films. Thereby, both composition and architecture of the patches must be refined in order to improve the hydration of the delivery layer. For the first time it was presented the efficiency of iontophoresis (1 mA.cm-2) on the permeation enhancement of these drug in association from polymeric films. To reach the replacement of infiltrative anesthesia (2% solution, equivalent to 36 mg of drug), the amount of drug permeated from the most promising film (12.5 mg of PCL:LCL 1:1, 3% w.w-1 HPMC K100LV and 30% PEG400 as a function of the mass of mucoadhesive polymer) must be improved in at least 30 folds.

Fundamento: O número de pacientes acometidos por insuficiência cardíaca (IC) cresce anualmente, em razão direta do aumento da longevidade, fato que ocorre mundialmente. Patologias bucais como perda do elemento dental e periodontopatias têm sido relacionadas e apresentam alta prevalência em pacientes com IC. Estes indivíduos necessitam de atendimento odontológico. O uso de solução anestésica local com vasoconstritor para procedimentos odontológicos para esta população continua controverso, pois pode gerar riscos cardiovasculares adversos. Objetivo: Analisar dor e alterações hemodinâmicas em pacientes com insuficiência cardíaca, submetidos a procedimento odontológico sob anestesia local com ou sem epinefrina . Método: Estudo prospectivo, grupo paralelo, controlado, duplo-cego em pacientes com insuficiência cardíaca, fração de ejeção < 45%, classe funcional II e III/IV e com terapêutica otimizada foram randomizados para procedimentos odontológicos (restaurações ou extrações) usando de 1,8ml a 3,6ml solução anestésica de lidocaína a 2% sem epinefrina (LSE) ou a mesma dose de lidocaína com epinefrina 1:100.000 (LCE). Resultados: Setenta e dois pacientes (50 anos ± 10 anos, 62% do sexo masculino, portadores de IC foram alocados para LSE (n=36) ou LCE (n=36). Foram observadas diferenças significativas no desfecho primário (dor) para os grupos que receberam LSE e efetuaram extrações dentárias. Não foram observadas diferenças nos valores de pressão arterial e frequência cardíaca antes, durante e após o procedimento dental em ambos os grupos. Entretanto, quando os grupos foram analisados separadamente, a pressão arterial aumentou e a frequência cardíaca reduziuse significativamente em relação à fase basal, durante o procedimento. Conclusão: A solução anestésica local de lidocaína com epinefrina mostrou ser superior no controle da dor e segura para pacientes com insuficiência cardíaca. Tanto no grupo LSE como no LCE não ocorreram alterações significativas nos parâmetros hemodinâmicos / Background: The number of patients with heart failure (HF) increases annually over the world. Oral diseases have been related to, and have shown high prevalence among this population. These patients need dental care. Using local anesthesia with vasoconstrictor for dental treatments is still controversial in patients with HF because it may generate adverse cardiovascular effects. Goal: To analyze pain and hemodynamic changes in patients with heart failure submitted to a dental procedure under local anesthesia with or without epinephrine. Methods: Prospective, parallel group, controlled, double-blind study , with heart failure patients, ejection fraction < 45%, NYHA class II and III / IV and with optimized therapy, were randomized to dental procedures (dental extraction or restoration) using 1,8 to 3.6ml of lidocaine without epinephrine (LSE) or lidocaine with epinephrine (LCE). ( Lidocaine 2% epinephrine 1:100.000). Results: Seventy two patients (50 ± 10 years, 62% male, 27% ischemic) were allocated to LSE (n = 36) or LCE (n = 36). It was observed a significant increase in pain , among patients that had dental extractions in the LSE group in comparison to LCE. No differences were observed in blood pressure, heart rate and pain scores before, during and after dental procedures in both groups. However, blood pressure increased and heart rate significantly reduced in relation to the baseline phase during and after the procedure in both groups when they were analyzed separately. Conclusion: Lidocaine with epinephrine (LCE) has shown to be more effective for pain control in heart failure patients. Concerning hymodinamic changes there was no difference between groups with or without epinephrine, and the treatment did not cause undesirable adverse cardiovascular effects.

Fundamento: O número de pacientes acometidos por insuficiência cardíaca (IC) cresce anualmente, em razão direta do aumento da longevidade, fato que ocorre mundialmente. Patologias bucais como perda do elemento dental e periodontopatias têm sido relacionadas e apresentam alta prevalência em pacientes com IC. Estes indivíduos necessitam de atendimento odontológico. O uso de solução anestésica local com vasoconstritor para procedimentos odontológicos para esta população continua controverso, pois pode gerar riscos cardiovasculares adversos. Objetivo: Analisar dor e alterações hemodinâmicas em pacientes com insuficiência cardíaca, submetidos a procedimento odontológico sob anestesia local com ou sem epinefrina . Método: Estudo prospectivo, grupo paralelo, controlado, duplo-cego em pacientes com insuficiência cardíaca, fração de ejeção < 45%, classe funcional II e III/IV e com terapêutica otimizada foram randomizados para procedimentos odontológicos (restaurações ou extrações) usando de 1,8ml a 3,6ml solução anestésica de lidocaína a 2% sem epinefrina (LSE) ou a mesma dose de lidocaína com epinefrina 1:100.000 (LCE). Resultados: Setenta e dois pacientes (50 anos ± 10 anos, 62% do sexo masculino, portadores de IC foram alocados para LSE (n=36) ou LCE (n=36). Foram observadas diferenças significativas no desfecho primário (dor) para os grupos que receberam LSE e efetuaram extrações dentárias. Não foram observadas diferenças nos valores de pressão arterial e frequência cardíaca antes, durante e após o procedimento dental em ambos os grupos. Entretanto, quando os grupos foram analisados separadamente, a pressão arterial aumentou e a frequência cardíaca reduziuse significativamente em relação à fase basal, durante o procedimento. Conclusão: A solução anestésica local de lidocaína com epinefrina mostrou ser superior no controle da dor e segura para pacientes com insuficiência cardíaca. Tanto no grupo LSE como no LCE não ocorreram alterações significativas nos parâmetros hemodinâmicos / Background: The number of patients with heart failure (HF) increases annually over the world. Oral diseases have been related to, and have shown high prevalence among this population. These patients need dental care. Using local anesthesia with vasoconstrictor for dental treatments is still controversial in patients with HF because it may generate adverse cardiovascular effects. Goal: To analyze pain and hemodynamic changes in patients with heart failure submitted to a dental procedure under local anesthesia with or without epinephrine. Methods: Prospective, parallel group, controlled, double-blind study , with heart failure patients, ejection fraction < 45%, NYHA class II and III / IV and with optimized therapy, were randomized to dental procedures (dental extraction or restoration) using 1,8 to 3.6ml of lidocaine without epinephrine (LSE) or lidocaine with epinephrine (LCE). ( Lidocaine 2% epinephrine 1:100.000). Results: Seventy two patients (50 ± 10 years, 62% male, 27% ischemic) were allocated to LSE (n = 36) or LCE (n = 36). It was observed a significant increase in pain , among patients that had dental extractions in the LSE group in comparison to LCE. No differences were observed in blood pressure, heart rate and pain scores before, during and after dental procedures in both groups. However, blood pressure increased and heart rate significantly reduced in relation to the baseline phase during and after the procedure in both groups when they were analyzed separately. Conclusion: Lidocaine with epinephrine (LCE) has shown to be more effective for pain control in heart failure patients. Concerning hymodinamic changes there was no difference between groups with or without epinephrine, and the treatment did not cause undesirable adverse cardiovascular effects.

A anestesia local normalmente precede a maioria dos procedimentos odontológicos. Porém, por ser realizada por processo invasivo (injetável), muitas vezes afugentam o paciente do consultório. Portanto, a substituição do processo invasivo por não invasivo, além de inovador traria diversas vantagens a odontologia i.e., possibilitaria o aprimoramento de procedimentos rotineiros e cirúrgicos devido à provável redução de custos, submissão do paciente, facilidade de aplicação e menores riscos de contaminação e intoxicações. Neste intuito, filmes poliméricos hidrofílicos mono ou trilaminados, compostos pelo polímero mucoadesivo HPMC K100 LV, glicerol ou PEG 400 como plastificantes, e contendo os anestésicos locais cloridratos de prilocaína (PCL) e lidocaína (LCL) em diferentes proporções foram desenvolvidos. Os filmes apresentaram flexibilidade e moldabilidade adequadas, além de uniformidade de massa e teor. Tanto a massa total de fármaco nos filmes (11 - 55 mg/0,64cm2), quanto suas contribuições relativas nas misturas (0 - 100% m.m-1) modularam seus perfis e cinéticas de liberação e permeação, além das quantidades retidas no epitélio esofageal suíno. Quantidades menores dos fármacos conduziram aos maiores coeficientes de permeabilidade do LCL. O filme contendo mistura dos fármacos na proporção 1:1 (PCL:LCL) apresentou a melhor relação custo/benefício e foi escolhida para a continuidade dos estudos. O aumento na massa total de fármaco nos filmes de 12,5 para 25 mg aumentou significativamente sua força e trabalho de mucoadesão, mas reduziu sua resistência à tração e módulo de elasticidade. Os filmes apresentaram propriedades mecânicas e de mucoadesão adequadas para a finalidade proposta. A adição de camadas oclusiva (composta por Eudragit® S100 e trietil citrato como plastificante) e mucoadesiva (composta por HPMC K100 LV e policarbofil na proporção 3:1 m.m-1 e PEG 400 como plastificante) aos filmes reduziu significativamente as quantidades dos fármacos liberadas, permeadas e retidas no epitélio e, portanto, a composição e arquitetura dos patches trilaminados deve ser aprimorada de modo a favorecer a hidratação da camada de liberação. Pela primeira vez foi demonstrada a eficiência da técnica de iontoforese (1 mA.cm-2) na promoção da permeação destes fármacos em associação a partir de filmes poliméricos. Para que possa substituir a anestesia injetável (solução a 2%, equivalente a 36 mg de fármaco), a permeação dos fármacos a partir do filme mais promissor (12,5 mg de PCL:LCL 1:1, 3% m.m-1 HPMC K100LV e 30% PEG400 em função da massa de polímero mucoadesivo) deve ser aumentada em pelo menos 30 vezes. / Local anesthesia typically precedes the majority of dental procedures. However, due to be performed using an invasive process (injection), often it scares the patient out from the dentist office. Accordingly, besides its innovative character, the replacement of the painful injection by a noninvasive process might bring several advantages to the dentistry field. It might enable the improvement of routinely and surgical procedures as a function of cost saving, patient compliance, ease of application and lowering the risk of contamination and intoxication. In this pursuit, we developed hydrophilic polymeric films comprised by one or three layers, comprised by the mucoadhesive polymer HPMC K100 LV, glycerol or PEG 400 as plasticizers, and containing the local anesthetic drugs prilocaine (PCL) and lidocaine (LCL) hydrochloride in different proportions. The films showed suitable flexibility and plasticity, besides uniformities of mass and content. Both the total mass of drugs in the films (11 - 55 mg/0.64 cm2), and their relative contribution in the mixtures (0 - 100% w.w-1) have modulated their profiles and kinetics of both delivery and permeation, as well as their amount retained in the porcine esophageal epithelium. Lower drug loadings lead to an increase on the permeability coefficient of LCL. The film containing the drugs blended on a 1:1 (PCL:LCL) proportion has presented the most acceptable cost/benefit ratio. Hence, it was chosen for further investigations. Increasing the total amount of drug in the film from 12.5 to 25 mg significantly raised their force and work of mucoadhesion. On the other hand, it have decreased their tensile strength and elastic modulus. The films presented suitable mechanical e mucoadhesive properties for our purposes. Adding the mucoadhesive (comprised by HPMC K100 LV and polycarbophil at 3:1 w.w-1 and PEG400 as plasticizer) and occlusive (Eudragit® S100 and triethyl citrate as plasticizer) layers on the delivery layer has significantly decreased the amount of drug released, permeated and retained on the epithelium from the films. Thereby, both composition and architecture of the patches must be refined in order to improve the hydration of the delivery layer. For the first time it was presented the efficiency of iontophoresis (1 mA.cm-2) on the permeation enhancement of these drug in association from polymeric films. To reach the replacement of infiltrative anesthesia (2% solution, equivalent to 36 mg of drug), the amount of drug permeated from the most promising film (12.5 mg of PCL:LCL 1:1, 3% w.w-1 HPMC K100LV and 30% PEG400 as a function of the mass of mucoadhesive polymer) must be improved in at least 30 folds.

O objetivo deste estudo foi comparar a eficácia anestésica da articaína 4%, da lidocaína 2%, ambas associadas à epinefrina 1:100.000, e da bupivacaína 0.5%, associada à epinefrina 1:200.000, durante pulpectomia em pacientes com pulpite irreversível em molares inferiores. Cento e cinco voluntários do Setor de Urgência da Faculdade de Odontologia da Universidade de São Paulo receberam, aleatoriamente, 3,6mL de um dos anestésicos locais para o convencional bloqueio do nervo alveolar inferior (BNAI). No caso de falha do BNAI, foram administrados 3,6mL da mesma solução como injeção complementar no ligamento periodontal. O sinal subjetivo de anestesia do lábio, a presença de anestesia pulpar e ausência de dor durante a pulpectomia foram avaliados, respectivamente, por indagação ao paciente, por meio do aparelho estimulador pulpar elétrico (pulp tester) e por uma escala analógica verbal. A análise estatística foi realizada por meio dos testes Qui-quadrado, Kruskal Wallis e Razão de Verossimilhanças. Foi adotado nível de significância de 0,05 (P <= 0,05). Todos os pacientes reportaram anestesia no lábio após o BNAI. A lidocaína apresentou valores superiores (42,9%) para a anestesia pulpar após o BNAI e após a injeção no ligamento periodontal (61,5%). A bupivacaína apresentou valores superiores para a analgesia (80%) após o BNAI e a lidocaína (92,3%) após a injeção no ligamento periodontal. Após a falha do BNAI, a dor na câmara pulpar foi a mais frequente para articaína e lidocaína e na dentina para a bupivacaína e após a falha da injeção no ligamento periodontal, a dor foi similar para articaína nas diferentes regiões; câmara, canal e dentina; para a bupivacaína foi mais frequente na dentina e para a lidocaína no canal. No entanto, essas diferenças não foram estatisticamente significantes. Portanto as três soluções anestésicas locais se comportam de forma semelhante e não apresentam efetivo controle da dor no tratamento da pulpite irreversível em molares inferiores. / The aim of this study was to compare the anesthetic efficacy of 4% articaine and 2% lidocaine both associated with 1:100,000 epinephrine and 0.5% bupivacaine associated with 1:200,000 epinephrine in patients with irreversible pulpitis of the mandibular molars during a pulpectomy procedure. One hundred and five volunteers from the Emergency Center of the School of Dentistry at University of São Paulo randomly received 3.6 mL of local anesthetic as a conventional inferior alveolar nerve block (IANB). The subjective signal of lip numbness, pulpal anesthesia and the absence of pain during the pulpectomy procedure were, respectively, evaluated by questioning the patient, stimulation using an electric pulp tester and a verbal analogue scale. Statistical analysis was performed using the chi-square test, Kruskal Wallis and likelihood rations. The level for significance of differences was P <= .05. All patients reported the subjective signal of lip numbness after the application of either IANB. Lidocaine showed higher values for pulpal anesthesia after the IANB (42.9%) and after injection in the periodontal ligament (61.5%). Bupivacaine presented higher values for analgesia after the IANB (80,0%) and lidocaine after injection in the periodontal ligament (92,3%). After the failure of the IANB, the pain in the pulp chamber was the most frequent to articaine and lidocaine and bupivacaine for dentin and after the failure of the periodontal ligament injection, the pain was equal to articaine in different regions, chamber, canal and dentin; for bupivacaine was greater in dentin and lidocaine was higher in the channel. However, these differences were not statistically significant. So the three local anesthetic solutions behave similarly and not present any effective pain control in the treatment of irreversible pulpitis in mandibular molars.

O objetivo deste estudo foi comparar a eficácia anestésica da articaína 4%, da lidocaína 2% e da mepivacaína 2%, todas associadas à epinefrina 1:100.000, durante pulpectomia em pacientes com pulpite irreversível em molares mandibulares. Sessenta e seis voluntários do Setor de Urgência da Faculdade de Odontologia da Universidade de São Paulo receberam, aleatoriamente, 3,6ml de um dos anestésicos locais para o bloqueio convencional do nervo alveolar inferior (NAI). No caso de falha do bloqueio, foram administrados 3,6ml da mesma solução como injeção complementar no ligamento periodontal. O sinal subjetivo de anestesia do lábio, a presença de anestesia pulpar e ausência de dor durante a pulpectomia foram avaliados, respectivamente, por indagação ao paciente, por meio do aparelho estimulador pulpar elétrico (pulp tester) e por uma escala analógica verbal. A análise estatística foi realizada por meio dos testes Qui-quadrado, Kruskal Wallis e Razão de Verossimilhancas. Todos os pacientes reportaram anestesia no lábio após o bloqueio do NAI. A mepivacaína apresentou valores superiores (68,2%) para a anestesia pulpar após o bloqueio do NAI e a lidocaína (90%) após a injeção no ligamento periodontal. A mepivacaína apresentou valores superiores para a analgesia (72,7%) após o bloqueio no NAI e a lidocaína (90%) após a injeção no ligamento periodontal. Após a falha do bloqueio do NAI, a dor na câmara pulpar foi a mais frequente e após a falha da injeção no ligamento periodontal, a dor no canal. No entanto, essas diferenças não foram estatisticamente significantes. Portanto as três soluções anestésicas locais se comportam de forma semelhante e não apresentam efetivo controle da dor no tratamento da pulpite irreversível em molares mandibulares. / The aim of this study was to compare the anesthetic efficacy of 4% articaine, lidocaine 2% and 2% mepivacaine, all associated with epinephrine 1:100,000 during pulpectomy in patients with irreversible pulpitis in mandibular molars. Sixty-six volunteers Sector Emergency Faculty of Dentistry, Universidade de São Paulo randomly received 3.6 ml of a local anesthetic to block conventional inferior alveolar nerve. In case of failure of the lock, were administered 3.6 ml of the same solution as in the periodontal ligament injection complement. The signal subjective lip anesthesia, the presence of pulpal anesthesia and no pain during pulpectomy were evaluated respectively by questioning the patient, via the stimulating device electrical pulp (pulp tester) and a verbal analogue scale. Statistical analysis was performed using the chi-square test, Kruskal Wallis and likelihood ratio. All patients reported lip anesthesia after blockade of the inferior alveolar nerve. The mepivacaine showed higher values (68.2%) for pulpal anesthesia after blockade of the inferior alveolar nerve and lidocaine (90%) after injection in the periodontal ligament. The mepivacaine showed higher values for analgesia (72.7%) after blocking the inferior alveolar nerve and lidocaine (90%) after injection in the periodontal ligament. After the failure of the blockade of the inferior alveolar nerve, the pain in the pulp chamber was the most frequent and after the failure of the periodontal ligament injection, pain in the channel. However, these differences were not statistically significant. Therefore, the three local anesthetic solutions behave similarly and did not exhibit effective pain management in treating irreversible pulpitis in mandibular molars.

<p>This thesis concerns the development and utilisation of techniques for characterisation and transdermal delivery of various systems for pharmaceutical applications.</p><p>The degree of dissociation of drug molecules and the mobilities of the different species formed are essential factors affecting the rate of drug delivery by iontophoresis. Hence, determination of drug mobility parameters and equilibrium constants are important for the development of iontophoretic systems. With capillary zone electrophoresis using a partial filling technique and methyl-β-cyclodextrin as chiral selector, the enantiomers of orciprenaline were separated. The association constants between the enantiomers of the drug and the selector were also evaluated. Precision conductometry studies were performed for the hydrochloride salts of lidocaine and 5-aminolevulinic acid in aqueous propylene glycol and water as media, respectively.</p><p>Iontophoresis is a technique for drug delivery where charged molecules are transported into and through skin by application of a weak direct electrical current. The drugs 5-aminolevulinic acid and its methyl ester were used as model compounds and incorporated in two different drug delivery vehicles, a sponge phase and carbopol gel. The bicontinuous structure of the sponge phase, constituted of monoolein and a mixture of propylene glycol and water, makes it interesting for use in iontophoretic delivery, since ions can move more or less freely in the aqueous as well as in the lipid domains. Furthermore, all three components are known for their penetration enhancing abilities. Hydrogels like carbopol gels are interesting media with respect to iontophoretic studies, since devices for iontophoresis often utilize hydrogels as contact interfaces between the skin and the electrodes. The results indicate that the transport achieved iontophoretically using the gel (1 % active substance) was comparable with the passive delivery of clinically used formulations (16 % - 20 % active substance).</p>

<p>One of the aims of this thesis was to investigate the involvement of efflux proteins, such as the P-glycoprotein (Pgp), in the drug transport in different regions of the rat and the human intestine. The intestinal extrusion of intracellularly formed CYP3A4 metabolites, including whether this extrusion might be mediated by Pgp, was also studied. The model drugs used were local anaesthetics (LA), which have been evaluated for inflammatory bowel disease, such as ropivacaine, lidocaine and bupivacaine. The intestinal permeability to LAs was found to be high throughout all intestinal regions of the rat and human intestine. Results from the Ussing chamber model indicated only minor efflux involvement as the drug permeability was higher in the serosa to mucosa transport direction than in the opposite direction. However, the involvement of efflux in the absorption of LAs could not be verified using in situ single-pass perfusion of rat jejunum. The extrusion of the ropivacaine metabolite, 2´,6´-pipecoloxylidide (PPX), was polarized to the mucosal reservoir of the Ussing chamber for both rat and human intestinal samples, and was probably not caused by any Pgp involvement. The expression levels of CYP3A4 and efflux transporters were consistent with the enzymes’ activity in human intestine. PPX formation was mediated by CYP3A4 in human intestine, and cyp2c and cyp2d in rat intestine. Species differences were observed, as PPX was formed in rat colon, but not human colon. In conclusion, the permeability of ropivacaine, lidocaine and bupivacaine was not subjected to efflux transport of significance for their intestinal uptake. The transport of ropivacaine metabolites to the mucosal compartment was probably not mediated by Pgp. The Ussing chamber model showed consistent results with those from intestinal microsomes as far as intestinal metabolism is concerned, making it a suitable model for investigations of the interplay of efflux and metabolism. </p>

This thesis concerns the development and utilisation of techniques for characterisation and transdermal delivery of various systems for pharmaceutical applications. The degree of dissociation of drug molecules and the mobilities of the different species formed are essential factors affecting the rate of drug delivery by iontophoresis. Hence, determination of drug mobility parameters and equilibrium constants are important for the development of iontophoretic systems. With capillary zone electrophoresis using a partial filling technique and methyl-β-cyclodextrin as chiral selector, the enantiomers of orciprenaline were separated. The association constants between the enantiomers of the drug and the selector were also evaluated. Precision conductometry studies were performed for the hydrochloride salts of lidocaine and 5-aminolevulinic acid in aqueous propylene glycol and water as media, respectively. Iontophoresis is a technique for drug delivery where charged molecules are transported into and through skin by application of a weak direct electrical current. The drugs 5-aminolevulinic acid and its methyl ester were used as model compounds and incorporated in two different drug delivery vehicles, a sponge phase and carbopol gel. The bicontinuous structure of the sponge phase, constituted of monoolein and a mixture of propylene glycol and water, makes it interesting for use in iontophoretic delivery, since ions can move more or less freely in the aqueous as well as in the lipid domains. Furthermore, all three components are known for their penetration enhancing abilities. Hydrogels like carbopol gels are interesting media with respect to iontophoretic studies, since devices for iontophoresis often utilize hydrogels as contact interfaces between the skin and the electrodes. The results indicate that the transport achieved iontophoretically using the gel (1 % active substance) was comparable with the passive delivery of clinically used formulations (16 % - 20 % active substance).