O objetivo dessa pesquisa foi avaliar o tempo de latência e duração pulpar anestésica da dose de 1,8ml das seguintes soluções anestésicas locais: cloridrato de articaína 4% associado à epinefrina 1:100.000 (ART 100) e 1:200.000 (ART 200) e cloridrato de lidocaína 2% associado à epinefrina 1:100.000 (LIDO 100) no bloqueio convencional do nervo alveolar inferior. A amostra do experimento consistiu de vinte pacientes normorreativos, submetidos a três consultas para tratamento restaurador de baixa complexidade em três dentes posteriores inferiores. Os períodos de latência e duração da anestesia local na polpa dentária foram monitorados com um estimulador pulpar elétrico (Vitality Scanner Model 2006®-SybronEndo, CA, EUA). Para análise e comparação dos resultados da latência e duração pulpar das três soluções anestésicas locais foi utilizado o teste paramétrico ANOVA e o teste auxiliar de Bonferroni com nível de significância fixado em 5% (p<0,05). Em relação ao período de latência pulpar não houve diferença estatisticamente significante entre nenhuma das três soluções anestésicas locais utilizadas (p > 0,05). Já em relação ao período de duração pulpar houve diferença estatisticamente significante entre ART 100 e LIDO 100 (p=0,000) e entre ART 200 e LIDO 100 (p=0,000). Portanto, a latência das duas soluções de articaína foram similares à solução de lidocaína, mas ambas apresentaram duração de ação anestésica maior do que a solução de lidocaína. / The aim of this study was to evaluate the time of onset and duration of pulp anesthetic dose of 1.8 ml of local anesthetic solutions following: 4% hydrochloride articaine associated with epinephrine 1:100.000 (ART 100) and 1:200.000 (ART 200) and 2% hydrochloride of lidocaine associated with epinephrine 1:100.000 (LIDO 100) in alveolar nerve block lower. The sample of the experiment consisted of twenty healthy patients, underwent three appointments for restorative treatment of low complexity in three subsequent lower teeth. The periods of onset and duration of local anesthetic in dental pulp were monitored with an electric stimulator pulp (Vitality Scanner®, Model 2006 - SybronEndo, CA, USA). To analyze and compare the results of onset and duration of the three pulp solutions local anesthetic was used parametric ANOVA test and the test of Bonferroni help with significance level set at 5% (p < 0.05). For the period of onset there was no statistically significant difference between any of the three approaches used local anesthetic (p> 0.05). Already in relation to the duration of pulp statistically significant difference between ART 100 and LIDO 100 (p = 0000) and between ART 200 and LIDO 100 (p = 0000). Therefore, the onset of the two solutions of articaine were similar to the solution of lidocaine, but both showed duration of anesthetic action superior to the solution of lidocaine.

O presente trabalho teve como objetivo associar modelos indutivos de diabetes e hipertensão, analisar e comparar o efeito de agentes vasoconstritores presentes nas soluções anestésicas locais, injetados por via intravenosa nas doses de 80, 160, 320, 640 e 1280ng (adrenalina) ou 0,125; 0,25; 0,5; 1; 2 e 3 x10-3UI (felipressina), sobre a pressão arterial de ratos normotensos, diabéticos, hipertensos renais um-rim, um clip (1R-1C) e hipertensos1R-1C-diabéticos, além de verificar a glicemia após injeção de doses correspondentes a 20 e 80% da resposta pressora máxima. Ratos Wistar machos pesando 110-160g, foram anestesiados com mistura de quetamina e xilazina (50+10mg/ml/kg de peso), tiveram seu abdômen aberto e receberam um clip de prata com abertura 0,25mm na artéria renal esquerda, removendo-se cirurgicamente o rim direito (ratos 1R-1C). Após 14 dias, receberam injeção subcutânea de estreptozotocina (50 e 60mg/kg de peso) para indução do diabetes mellitus sendo a glicemia testada pela veia caudal previamente aos experimentos (diabéticos). Após 28 dias da implantação do clip, todos os grupos foram novamente anestesiados e implantaram-se cânulas de polietileno (PE-50) na artéria carótida esquerda e veia jugular direita, para registro direto da pressão arterial e injeção de drogas, respectivamente. Animais controle sofreram cirurgia sem implantação do clip (normotensos). O cateter arterial foi conectado ao sistema de registro computadorizado (PowerLab®) utilizando software específico (Chart 5Pro®). A pressão arterial registrada durante os primeiros 5 minutos foi considerada como valor basal. Analisaram-se: a integral da resposta, menor resposta hipotensora, maior resposta hipertensora, duração e intervalo de tempo para atingir respostas máxima e mínima, em todos os grupos, para cada dose injetada dos dois vasoconstritores. No dia seguinte, foi medida a glicemia inicial e após a injeção das doses de 160 e 640ng (adrenalina) ou 0,25 e 2 x10-3UI (felipressina). Os dados foram submetidos à análise de variância de medidas repetidas (ANOVA), seguida do teste de Holm-Sidak (distribuição normal) ou de Mann-Whitney (paramétrico), quando apropriado, nível de significância de 5%. A felipressina, ao contrário da adrenalina, não apresentou ação hipotensora além de apresentar menor efeito hipertensor global e maior duração da resposta. Animais diabéticos e hipertensosdiabéticos apresentaram menor resposta hipotensora à adrenalina, maior resposta hipertensora e respostas significativamente mais duradouras, evidenciando maior sensibilidade aos efeitos deste vasoconstritor. Animais hipertensos apresentaram aumento da integral das respostas, especialmente com grandes doses, evidenciando maior sensibilidade aos efeitos da administração exógena de adrenalina. Nos animais hipertensos-diabéticos a resposta pressora à felipressina foi potencializada. Animais diabéticos e hipertensos-diabéticos apresentaram resposta hiperglicêmica após injeção de 640ng de adrenalina, enquanto apenas o grupo de hipertensos-diabéticos apresentou elevação da glicemia após injeções de ambas as doses de felipressina. Os resultados apontam, de modo geral, para um aumento da sensibilidade aos agentes vasoconstritores na presença simultânea de hipertensão e diabetes. Além disso, somente os hipertensos-diabéticos tiveram elevação da glicemia após injeção de doses baixas de felipressina (0,25mUI). Entretanto, a felipressina demonstrou menores picos hipertensivos, apesar de sua longa duração, nos grupos estudados, o que a coloca como um possível vasoconstritor a ser utilizado em portadores de cardiopatias, incluindo diabéticos. / The present study was designed to induce arterial hypertension associated with diabetes mellitus, analyze and compare the effects of vasoconstrictors drugs, presents in anesthetic cartridge, injected by intravenous route (IV), in doses of 80, 160, 320, 640 and 1280ng (epinephrine) or 0,125; 0,25; 0,5; 1; 2 e 3x10-3UI (felypressin) on arterial pressure (AP) of normotensive, diabetic, one-kidney,one-clip (1K-1C) hypertensive and 1K-1C hypertensive-diabetic rats. The blood glucose levels were determined after IV injection of both drugs in doses that produced 20 and 80% of maximal pressure response. Male Wistar rats weighing 110-160g were anesthetized with a ketamine and xylazine mixture (50+10mg/ml/kg de peso). After abdominal incision, a silver clip with 0.25-mm gap was implanted in the main left renal artery and right kidney was removed (1K-1C rats). Fourteen days after, some animals received subcutaneous injection of streptozotocin (50 and 60mg/kg weight) to induce diabetes mellitus. Tail blood glucose was tested before experiments (diabetics rats). Four weeks after clip implantation all rats were anesthetized again and a catheter (PE50) was inserted into the left carotid artery and right jugular vein, respectively to obtain a direct arterial pressure register and to inject drugs. Control groups were submitted to surgery procedures without clip installation (normotensive). The arterial catheter was then connected to the transducer and to the computer register system (PowerLab®) using a Chart 5 Pro® software. The AP registered in the first five minutes was considered as a basal value. The following parameters were registered: integral of complete response, minimal hypotensive response, maximal hypertensive response, response length (duration) and duration of time to attain maximum and minimum responses, in all animals groups, to every injected dose of both vasoconstrictor drugs. In the next day blood glucose levels were determined initially and after venous injection of 160 e 640ng (adrenaline) or 0,25 an 2 x10-3UI (felipressin). Data were analyzed by one and two ways repeated measures ANOVA followed by Holm-Sidak (normal distribution) or Mann-Whitney (parametric) test, when appropriated. The significance level was 5%. Felypressin didnt show hypotensive effects and produced lower hypertensive responses with prolonged time lengths when compared with epinephrine. The hypotensive response to epinephrine was reduced in diabetic and hypertensive-diabetic rats, and the hypertensive responses were higher and prolonged. These results together suggest increased sensibility to the pressure effects of epinephrine. Hypertensive rats showed increased integral of pressures responses, especially in higher doses, also suggesting increased sensibility to epinephrine. Felypressin responses were potentiated in hypertensive-diabetic group. Diabetic and hypertensive-diabetic rats showed increased blood glucose levels after 640ng epinephrine injection, whereas only hypertensive-diabetic rats had increased values of blood glucose after felypressin injections, at both doses. These results together indicate increased sensibility to both drugs in diabetes association with arterial hypertension. Felypressin presented less hypertensive peak and longer length of activity in all studied groups, what suggests that felypressin, in the concentration used in dental anesthetic solutions, may be a secure vasoconstrictor drug in cardiac patients, including diabetics.

by Perpetua E. Tan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references (leaves 149-157). / Abstract --- p.9 / Acknowledgments --- p.12 / List of abbreviations --- p.13 / List of Tables --- p.16 / List of Figures --- p.19 / Chapter CHAPTER 1 --- INTRODUCTION --- p.21 / Chapter CHAPTER 2 --- LITERATURE REVIEWS CATECHOLAMINES: NORADRENALINE AND ADRENALINE --- p.25 / Chapter 2.1 --- History --- p.25 / Chapter 2.2 --- Origin of plasma catecholamines --- p.25 / Chapter 2.3 --- Kinetics of entry and removal --- p.28 / Chapter 2.4 --- Levels present in plasma --- p.30 / Chapter 2.5 --- Some factors affecting plasma CA levels --- p.31 / Chapter 2.5.1 --- Effects of age --- p.31 / Chapter 2.5.2 --- Postural change --- p.32 / Chapter 2.5.3 --- Exercise --- p.32 / Chapter 2.5.4 --- Temperature change --- p.32 / Chapter 2.5.5 --- Stress --- p.33 / Chapter 2.5.6 --- Pregnancy --- p.34 / Chapter 2.5.7 --- Disease --- p.35 / Chapter 2.6 --- Actions in the body --- p.35 / Chapter 2.6.1 --- Plasma endogenous catecholamines --- p.35 / Chapter 2.6.2 --- Plasma exogenous catecholamines and medicine --- p.36 / Chapter 2.6.2.1 --- Clinical uses --- p.36 / Chapter 2.6.2.2 --- Effects --- p.37 / Chapter 2.6.2.3 --- Side effects --- p.38 / Chapter 2.7 --- Binding of catecholamines in plasma --- p.38 / Chapter 2.8 --- Measurement of catecholamines in plasma --- p.38 / Chapter 2.8.1 --- Chemistry --- p.38 / Chapter 2.8.2 --- Extraction and purification --- p.39 / Chapter 2.8.3 --- Biological methods --- p.40 / Chapter 2.8.4 --- Colorimetry --- p.41 / Chapter 2.8.5 --- Radioimmunoassay and radioenzymatic assay --- p.41 / Chapter 2.8.6 --- Enzyme-linked immunoassay --- p.42 / Chapter 2.8.7 --- Gas chromatography --- p.42 / Chapter 2.8.8 --- Liquid chromatography --- p.42 / Chapter 2.8.8.1 --- Fluorometry --- p.43 / Chapter 2.8.8.2 --- Electrochemical detection --- p.43 / Chapter 2.9 --- Plasma protein binding of basic drugs --- p.44 / Chapter 2.9.1 --- Binding to albumin --- p.45 / Chapter 2.9.2 --- Binding to alpha-1-acid-glycoprotein --- p.45 / Chapter 2.9.3 --- Binding to other proteins --- p.45 / Chapter 2.9.4 --- Factors affecting drug binding --- p.46 / Chapter 2.9.4.1 --- Pregnancy --- p.46 / Chapter 2.9.4.2 --- Age --- p.46 / Chapter 2.9.4.3 --- Disease states --- p.46 / Chapter 2.9.5 --- Separation procedures to reveal and follow drug protein binding --- p.47 / Chapter 2.9.5.1 --- Equilibrium dialysis --- p.47 / Chapter 2.9.5.2 --- Ultrafiltration --- p.48 / Chapter 2.9.5.3 --- Ultracentrifugation --- p.48 / Chapter 2.9.5.4 --- Gel Filtration --- p.48 / Chapter CHAPTER 3 --- ANALYTICAL TECHNIQUE : PLASMA CATECHOLAMINE ANALYSIS --- p.49 / Chapter 3.1 --- HPLC determination with coulometric detection of catecholamines --- p.49 / Chapter 3.1.1 --- Introduction --- p.49 / Chapter 3.1.2 --- Basic equipment --- p.49 / Chapter 3.1.3 --- Mobile phase preparation --- p.50 / Chapter 3.1.3.1 --- Reagent A (Citrate-acetate-EDTA buffer) --- p.50 / Chapter 3.1.3.2 --- Reagent B (ion pairing reagent) --- p.50 / Chapter 3.1.3.3 --- Mobile phase mixture --- p.50 / Chapter 3.1.4 --- Detector settings --- p.51 / Chapter 3.1.5 --- Sample collection and storage --- p.51 / Chapter 3.2 --- Reagents and solutions --- p.52 / Chapter 3.2.1 --- Acid-washed alumina --- p.52 / Chapter 3.2.2 --- Tris buffer solution --- p.53 / Chapter 3.2.3 --- Washing solution --- p.53 / Chapter 3.2.4 --- Acetic acid solution --- p.53 / Chapter 3.2.5 --- EDTA-HC1 solution --- p.53 / Chapter 3.2.6 --- Citric acid solution --- p.53 / Chapter 3.2.7 --- Stock solutions --- p.54 / Chapter 3.2.7.1 --- Catecholamine standards --- p.54 / Chapter 3.2.7.2 --- Dihydroxybenzylamine (Internal) standard --- p.54 / Chapter 3.2.8 --- Stripped fresh frozen plasma --- p.54 / Chapter 3.2.9 --- Sorensen's phosphate buffer containing 0.6% NaCl --- p.55 / Chapter 3.2.10 --- Control standards --- p.55 / Chapter 3.3 --- Voltammogram of catecholamines and internal standard used --- p.55 / Chapter 3.4 --- Maintenance of the HPLC-Coulometric detector system --- p.56 / Chapter 3.5 --- Optimization of the extraction method --- p.58 / Chapter 3.5.1 --- Amount of alumina for adsorption of CA --- p.58 / Chapter 3.5.2 --- pH of tris buffer for maximum uptake of CA onto alumina --- p.58 / Chapter 3.5.3 --- Optimum time for maximum uptake of CA onto alumina --- p.59 / Chapter 3.5.4 --- Optimum time for maximum desorption of CA into acid solution --- p.59 / Chapter 3.5.5 --- Optimum volume of acid solution for maximum desorption of CA --- p.60 / Chapter 3.6 --- Validation of the method --- p.60 / Chapter 3.6.1 --- Linearity --- p.60 / Chapter 3.6.2 --- Recovery --- p.61 / Chapter 3.6.3 --- Reproducibility --- p.62 / Chapter 3.6.4 --- Stability --- p.62 / Chapter 3.7 --- Results --- p.63 / Chapter 3.8 --- Discussion --- p.79 / Chapter CHAPTER 4 --- CLINICAL APPLICATIONS OF THE CATECHOLAMINE ASSAY --- p.84 / Chapter 4.1 --- Introduction --- p.84 / Chapter 4.1.1 --- Applications of catecholamines assay in clinical science --- p.84 / Chapter 4.2 --- : PLASMA CATECHOLAMINES AFTER INDUCTION OF ANAESTHESIA AT CAESARIAN SECTION --- p.84 / Chapter 4.2.1 --- Introduction --- p.84 / Chapter 4.2.2 --- Patients and methods --- p.86 / Chapter 4.2.3 --- Blood sampling and storage --- p.87 / Chapter 4.2.4 --- Statistics used --- p.87 / Chapter 4.2.5 --- Results --- p.88 / Chapter 4.2.6 --- Discussion --- p.99 / Chapter 4.3 --- EPINEPHRINE INFILTRATION IN SINUS SURGERY --- p.101 / Chapter 4.3.1 --- Introduction --- p.101 / Chapter 4.3.2 --- Patients and methods --- p.102 / Chapter 4.3.3 --- Blood sampling and storage --- p.103 / Chapter 4.3.4 --- Results --- p.104 / Chapter 4.3.5 --- Discussion --- p.108 / Chapter CHAPTER 5 --- ANALYTICAL TECHNIQUE: PLASMA PROTEIN BINDING OF CATECHOLAMINES --- p.110 / Chapter 5.1 --- Equilibrium dialysis for protein binding of drugs --- p.110 / Chapter 5.1.1 --- Introduction --- p.110 / Chapter 5.1.2 --- Dialyzing apparatus --- p.110 / Chapter 5.1.3 --- Sample collection and storage --- p.111 / Chapter 5.1.4 --- Reagents and solutions --- p.111 / Chapter 5.1.4.1 --- Ascorbic acid --- p.111 / Chapter 5.1.4.2 --- Glutathione --- p.111 / Chapter 5.1.4.3 --- Sodium metabisulfite --- p.111 / Chapter 5.1.4.4 --- Dialysis buffer --- p.111 / Chapter 5.1.5 --- Dialysis membrane --- p.112 / Chapter 5.1.6 --- Equilibrium dialysis --- p.112 / Chapter 5.2 --- Optimization of the binding parameters --- p.113 / Chapter 5.2.1 --- Types of preservatives for stability of catecholamines during dialysis --- p.113 / Chapter 5.2.2 --- Dialysis buffer --- p.114 / Chapter 5.2.3 --- Dialysis time and volume of sample --- p.114 / Chapter 5.2.4 --- Dialysis membrane --- p.115 / Chapter 5.2.5 --- Catecholamines concentration for dialysis --- p.114 / Chapter 5.3 --- Total protein analysis- Lowry Method --- p.115 / Chapter 5.3.1 --- Reagents and solutions --- p.116 / Chapter 5.3.1.1 --- Reagent A (Alkaline copper reagent) --- p.116 / Chapter 5.3.1.2 --- Reagent B (Folin-Ciocalteus phenol reagent with water) --- p.116 / Chapter 5.3.2 --- Stock standard and controls --- p.116 / Chapter 5.3.2.1 --- Human serum albumin standard --- p.116 / Chapter 5.3.2.2 --- Controls --- p.116 / Chapter 5.3.3 --- Procedure --- p.116 / Chapter 5.4 --- Results --- p.117 / Chapter 5.5 --- Discussion --- p.126 / Chapter CHAPTER 6 --- CONCLUSIONS --- p.130 / APPENDIX --- p.134 / CHEMICALS AND REAGENTS --- p.146 / REFERENCES --- p.149

O presente trabalho teve como objetivo analisar e comparar o efeito de agentes vasoconstrictores presentes nas soluções anestésicas locais, injetados por via intravenosa nas doses de 80, 160, 320, 640 e 1280 ng (adrenalina) ou 0.5, 1, 2, 3 e 4 UI (felipressina), sobre a pressão arterial de ratos, hipertensos renais um-rim, um clip (1R-1C) e 1R-1C tratados com atenolol, comparando com animais nomotensos de mesmo peso e lote. Ratos Wistar machos pesando 150g, foram anestesiados com mistura de igual quantidade de quetamina e xilazina (1mL da mistura/kg), tiveram seu abdômen aberto e receberam um clip de prata com abertura 0,25mm na artéria renal esquerda, removendo-se cirurgicamente o rim direito (ratos 1R-1C). Alguns desses animais, depois de 14 dias, tiveram sua pressão sistólica indireta registrada pela pletsmografia de cauda e começaram a receber tratamento com atenolol (90 mg/kg/dia) por gavage (1R-1C tratados). Após 28 dias da implantação do clip, todos os grupos foram novamente anestesiados e implantaram-se cânulas de polietileno (PE-50) na artéria carótida esquerda e veia jugular direita, para registro direto da pressão arterial e injeção de drogas, respectivamente. Animais de mesmo lote e peso serviram como controle (normotensos). O catéter arterial foi então conectadas ao sistema de registro computadorizado (PowerLab®) utilizando software específico (Chart 5Pro ®). A pressão arterial (PA) e frequência cardíaca (FC) registradas durante os primeiros 5 minutos, foram consideradas como valores basais. Analisaram-se: a menor resposta hipotensora, maior resposta hipertensora, freqüência cardíaca média e duração da resposta, nos três grupos de animais, para cada dose injetada dos dois vasoconstrictores. Os dados foram submetidos à análise de variância de medidas repetidas (ANOVA), seguida do teste de Holm-Sidak ou de Mann-Whitney, quando apropriado, a um nível de significância de 5%. A felipressina, ao contrário da adrenalina, não apresentou ação hipotensora; por outro lado, ambas apresentaram respostas hipertensoras de magnitude semelhante nos 3 grupos de animais, notando-se tendência para menores respostas nos animais tratados com atenolol. A felipressina provocou queda de FC significativa (p<0,01) nos animais normotensos e tratados, causando aumento de FC nos hipertensos apenas com as maiores doses, enquanto que a adrenalina provocou aumento de FC dose-dependente nos normotensos e hipertensos, sem promover alteração da FC nos ratos tratados. A duração da resposta hipertensora provocada pela felipressina foi significativamente maior que a provocada pela adrenalina (p<0,01) em todos os grupos de animais, indicando possível efeito vasoconstrictor prolongado. Os resultados permitem afirmar que a felipressina apresenta ações semelhantes à adrenalina, com resposta hipertensora mais prolongada, nas populações de animais analisadas. Em função das doses e da via empregada nesse estudo, pode-se sugerir que a felipressina é bastante segura para populações hipertensas ou que estejam recebendo atenolol. / The present study was designed to analyze and compare the effects of some vasoconstrictors, injected by intravenous route in the doses of 80, 160, 320, 640 and 1280 ng (epinephrine) or 0.5, 1, 2, 3 and 4 IU (felypressin) upon the arterial pressure of normotensive, 1K-1C hypertensive and 1K-1C rats treated with atenolol. Male Wistar rats weighting 150g were anesthetized with a mixture of equal proportion of ketamine and xylazine by intraperitonial injection (1mL/kg) and 1K1C hypertension was surgically induced by means of partial constriction of the main left renal artery with a silver clip with a 0.25-mm gap. The right kidney was surgically removed. Fourteen days after surgical procedures arterial pressure (AP) was indirectly measured (tail cuff method) to monitor the development of hypertension. Only 1K1C rats with AP more than 150mm Hg were included in the protocol and received by gavage (1mL/d), for the next 14 days, atenolol (90 mg/kg/day). The treatments were carried out always between 8 and 9 AM. Four weeks after the surgical procedure all rats were anesthetized again with the same mixture and a catheter (PE50) was inserted into the left carotid artery and right jugular vein, respectively to obtain a AP register and to inject drugs. The arterial catheter was then connect to the transducer and to computer register system (PowerLab®) using a Chart 5 Pro® software. The AP and heart rate (HR) registered in the first five minutes were considered basal values. The following parameters were registered: minimal hypotensive response, maximal hypertensive response, mean HR and response lenght (duration), in all animals groups, to every injected dose of epinephrine and felypressin. The data were analyzed by two ways repeated measures ANOVA followed by Holm-Sidak or Mann-Whitney test, when appropriated. The significance level was 5%. Epinephrine, but not felypressin, presents some hypotensive action with the lowest doses. However, both of them present hypertensive responses of same magnitudes in all groups, with non-significant reduced responses noted in the 1K-1C atenolol group. The HR was significantly lowered by felypressin in the normotensive and 1K-1C atenolol group; this vasoconstrictor agent produced elevated HR in hypertensive rats only with the greatest doses. Epinephrine caused dose-dependent increases in HR in normotensive and 1K-1C without modifying the HR of 1K-1C atenolol treated rats. The felypressin response length were significantly longer than that produced by epinephrine in all groups (p<0,01), indicating a prolonged vasoconstrictor effect. Our results suggest that felypressin has equipotent pressure responses when compared with epinephrine, showing greater extent of action. Considering the administration route, the doses used in this study and the concentration in local anesthetics cartridges, we suggest that felypressin was safe enough to be one of the vasoconstrictors of choice in hypertensive subjects and in those who received atenolol as a medication to lower their pressure.

Background: In order to perform cataract surgery, adequate dilatation of the pupil is essential. This is traditionally achieved by preoperative topical mydriatic eye-drops, commonly cyclopentolate and phenylephrine. This routine has several disadvantages. First, the slow penetration through the cornea delays the onset of mydriasis. Second, the limited bioavailability of topically administered substances with significant systemic absorption may increase the risk for systemic side effects. Third, even if good mydriasis is achieved initially with topical mydriatics (TM), the effect tends to wear off during surgery. In relation to cataract surgery a transient postoperative corneal oedema is sometimes noted, indicating effects on the corneal endothelial pump function. These effects have been ascribed to ultrasonic or mechanical trauma from the phacoemulsification procedure. Corneal endothelial cell loss (ECL) is a commonly studied variable, not least because it is associated with the long-term risk for corneal decompensation. But, there has been a debate whether postoperative corneal swelling after phacoemulsification cataract surgery correlates to ECL. Aims: To evaluate an alternative mydriatic regimen for phacoemulsification cataract surgery: intracameral injection of mydriatics mixed with lidocaine (ICM). Additionally, to determine the correlation between early transient postoperative corneal oedema and permanent ECL after phacoemulsification cataract surgery. Methods: Pupil dilatation with ICM (150 µl of lidocaine 1%, phenylephrine 1.5%, and cyclopentolate 0.1%) was compared to TM (phenylephrine 10% and cyclopentolate 1%) prior to cataract surgery. Additionally, two ICM-groups were randomized to receive either 0.6 µg/ml epinephrine added to the irrigating balanced salt solution or no epinephrine in the irrigation solution. Furthermore, two randomized ICM-groups, with or without cyclopentolate, were analyzed. The patients planned for cataract surgery were examined with ultrasonic pachymetry, specular microscope endothelial photography and Orbscan II slit-scan tomography pre- and postoperatively. Results: With ICM, mydriasis reached 95 ± 3% of its final value within 20 seconds. In the ICM-group, the pupils were smaller than in the TM-group (mean 6.7 ± 1.0 mm versus 7.7 ± 1.0 mm, P&lt;.001), but did not contract intraoperatively as the TM pupils did. Conversely, with ICM the pupil sizes generally increased during the cataract procedures. This increase was significantly greater without epinephrine in the irrigating solution (13 ± 19% versus 4 ± 14%; p = 0.02). No significant differences in pupil sizes were observed between the patients who were given ICM with or without cyclopentolate. The central corneal swelling at the first postoperative day was strongly correlated to the central ECL at 3 months, R2 = 0.785, P &lt; 0.001. Conclusions: ICM is a rapid and safe alternative to TM in phacoemulsification cataract surgery. An irrigating solution without epinephrine can safely be used with ICM. Cyclopentolate, administrated intracamerally, has no immediate additive mydriatic effect to intracameral lidocaine combined with phenylephrine. The degree of permanent corneal endothelial damage in cataract surgery is reflected in the degree of early postoperative corneal swelling.

No description available.

Objectives: To review, develop, and validate appropriate methods for quality control testing of sublingual (SL) tablets; to formulate and characterize new generations of SL tablets of epinephrine (E) for the potential first-aid treatment of anaphylaxis; and to evaluate the effects of non-medicinal ingredients (NMIs) on the in vitro characteristics and in vivo bioavailability of the formulated tablets. Methods: A custom-made apparatus and a novel method that simulates SL conditions were evaluated for dissolution testing of SL tablets. An electronic tongue (e-Tongue) was used to assess the degree of E bitterness and to demonstrate the masking effects of sweetening and/or flavoring agents. The effect of several NMIs in various properties on the in vitro characteristics of new generations of E SL tablets was evaluated. Formulations with the best in vitro characteristics, containing E 30 mg and 40 mg, were evaluated in vivo using our validated rabbit model and compared with placebo SL tablets (negative control) and E 0.3 mg intramuscular (IM) injection (positive control). Results: The novel in vitro dissolution testing resulted in accurate and reproducible data and was capable of detecting the effect of minor changes in formulations. Using the e-Tongue, E bitartrate had an extremely bitter taste which was masked to various degrees by the addition of aspartame, acesulfame potassium, and citric acid alone or in combination. Citric acid alone masked the bitter taste by >80%. The evaluation of NMIs revealed that the best formulation contained specific proportions of mannitol and coarse and fine grades of microcrystalline cellulose. Appropriate comparative testing resulted in the selection of a taste-masked E SL formulation with optimum in vitro characteristics. This formulation containing E 40 mg resulted in similar bioavailability to E 0.3 mg IM. This formulation containing E 30 mg had higher bioavailability than placebo, but lower bioavailability than E 40 mg tablets. Conclusions: Grades and proportions of NMIs carefully selected using appropriate in vitro testing resulted in successful formulations. The results of these in vitro tests enabled the development of the optimum E SL tablet formulation which was bioequivalent to the EpiPen. These tablets are potentially suitable for Phase 1 studies in humans and might transform the first-aid treatment of anaphylaxis in community settings.

Objectives: To review, develop, and validate appropriate methods for quality control testing of sublingual (SL) tablets; to formulate and characterize new generations of SL tablets of epinephrine (E) for the potential first-aid treatment of anaphylaxis; and to evaluate the effects of non-medicinal ingredients (NMIs) on the in vitro characteristics and in vivo bioavailability of the formulated tablets. Methods: A custom-made apparatus and a novel method that simulates SL conditions were evaluated for dissolution testing of SL tablets. An electronic tongue (e-Tongue) was used to assess the degree of E bitterness and to demonstrate the masking effects of sweetening and/or flavoring agents. The effect of several NMIs in various properties on the in vitro characteristics of new generations of E SL tablets was evaluated. Formulations with the best in vitro characteristics, containing E 30 mg and 40 mg, were evaluated in vivo using our validated rabbit model and compared with placebo SL tablets (negative control) and E 0.3 mg intramuscular (IM) injection (positive control). Results: The novel in vitro dissolution testing resulted in accurate and reproducible data and was capable of detecting the effect of minor changes in formulations. Using the e-Tongue, E bitartrate had an extremely bitter taste which was masked to various degrees by the addition of aspartame, acesulfame potassium, and citric acid alone or in combination. Citric acid alone masked the bitter taste by >80%. The evaluation of NMIs revealed that the best formulation contained specific proportions of mannitol and coarse and fine grades of microcrystalline cellulose. Appropriate comparative testing resulted in the selection of a taste-masked E SL formulation with optimum in vitro characteristics. This formulation containing E 40 mg resulted in similar bioavailability to E 0.3 mg IM. This formulation containing E 30 mg had higher bioavailability than placebo, but lower bioavailability than E 40 mg tablets. Conclusions: Grades and proportions of NMIs carefully selected using appropriate in vitro testing resulted in successful formulations. The results of these in vitro tests enabled the development of the optimum E SL tablet formulation which was bioequivalent to the EpiPen. These tablets are potentially suitable for Phase 1 studies in humans and might transform the first-aid treatment of anaphylaxis in community settings.

Diss. (sammanfattning) Linköping : Univ., 2002. / Härtill 4 uppsatser.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2008. / Härtill 5 uppsatser.