Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Anesthesia, a state of being absent of sensation and consciousness, has been recognized since antiquity. Even today anesthesia is still best characterized by the lack of consciousness and sensations. Since anesthetic potency is correlated with lipid solubility, the site of action of general anesthetics has been thought to be hydrophobic in nature and to involve excitable membranes critical for interneuronal communications. Thus, general anesthetics may interact directly with functionally-relevant membrane proteins (via hydrophobic pockets) or indirectly, with the lipids surrounding these proteins. To better understand the details of general anesthetic action, I examined how halothane interacts with a functional synaptic protein, the acetylcholine receptor channel embedded in the membranes of cultured Xenopus myocytes. Next, I examined how changing the lipid composition, of these membranes, affected this interaction. Using the extracellular patch-clamp technique, I found that halothane, at clinically-relevant concentrations, shortened the burst duration of single receptor channels without affecting their conductance. Moreover, the halothane-induced reduction of burst durations was significantly attenuated after pretreatment with cholesterol-rich lipsomes which increased significantly the cholesterol content of these cells. These findings provide the first direct support for the role of membrane lipids in the mechanism of GA action. In particular, I demonstrated that increases in membrane cholesterol antagonize the anesthetic action of halothane. Although direct action of cholesterol on synaptic proteins cannot be ruled out, my data strongly suggest that membrane lipids are involved at a critical, but as yet undefined, site with which GAs interact. The exact manner by which increases in membrane cholesterol antagonize GA action remains to be eludicated.

No description available.

No description available.

<p>Olfaction is one of the most primitive of our senses, and the olfactory receptors that mediate this very important chemical sense comprise the largest family of genes in the mammalian genome. It is therefore surprising that we understand so little of how olfactory receptors work. In particular we have a poor idea of what odorous chemicals are detected by most of the olfactory receptors in the genome, and for those receptors which we have paired with ligands, we know relatively little about how the structure of these ligands can either activate or inhibit the activation of these receptors. Furthermore the large repertoire of olfactory receptors, which belong to the G protein coupled receptor (GPCR) superfamily, can serve as a model to contribute to our broader understanding of GPCR- ligand binding, especially since GPCRs are important pharmaceutical targets.</p><p>In this dissertation, I explore the relationship between olfactory receptors and their ligands, both by manipulating the ligands presented to the olfactory receptors, as well as by altering the structure of the receptor itself by mutagenesis. Here we report the probable requirement of a hydrated germinal-diol form of octanal for activation of the rodent OR-I7 receptor by ligand manipulation, and the successful in vitro modeling and manipulation of ketamine binding to MOR136-1. We also report the results of a large-scale screen of 1190 human and mouse olfactory receptors for receptors activated by volatile general anesthetics, which has lead to the identification of 32 olfactory receptor-volatile general anesthetic pairs.</p> / Dissertation

Purpose: The purposes of this study were four-fold: 1) to determine the types and effectiveness of various topical anesthetics being used among dentists currently treating children, 2) to determine the types of procedures for which topical anesthetics are being used among children, 3) to understand the awareness and use of a relatively newer compounded topical gel Oraqix (Dentsply Caulk) among children, 4) to understand the adverse reactions to topical anesthesia that are seen among children. Methods: A cross sectional survey was designed, regarding the type, procedural use, effectiveness, and adverse reactions noted among children to various topical anesthetics. The survey sampled n=4933 actively practicing member dentists from a database of willing survey participants obtained from the American Academy of Pediatric Dentistry. The survey consisted of 14-items in multiple choice/answer format. The survey was pilot tested by a committee of faculty, and attached via e-mail with a cover letter containing a direct survey link for the study participants. Surveys were collected, posted, and managed through www.surveymonkey.com. Results: The study received 1255 responses from practitioners who are actively treating children giving an effective response rate of 25%. Of those that participated 94% are Pediatric dentists, 6% General dentists or “Other” specialists who treat children. The majority of respondents (95%) routinely use topical anesthetic, rating it as effective or very effective clinically. The most commonly used topical was 20%-Benzocaine gel with a reported 96% effective rate. The most common procedures topical anesthetics are being used for are pre-injection of local anesthetic and extraction of exfoliating deciduous teeth. Very few of the responding practitioners have ever heard of or used Oraqix gel prior to this survey. Many though, would consider using Oraqix if proven effective. Only 10% of respondents reported an adverse reaction to topical anesthetics, the most common being contact dermatitis or tissue sloughing from prolonged contact, followed by an allergic or aversive reaction to the dyes or flavoring in the topical anesthetic. Conclusions: The overwhelming majority of dentists treating children routinely use topical anesthetics to reduce pain response among children. 20%-Benzocaine gel is the most widely used topical anesthetic being used for dental procedures on children. Adverse reactions to topical anesthetic noted among practitioners treating children are very low but must still be strongly considered as potential life threatening risks if not used appropriately. Many practitioners treating children are still looking for the “ideal” topical anesthetic with improvements in taste, the ability to stay localized, the method of delivery, and improved effectiveness being key areas for future research.

A associação do anestésico local (AL) com hialuronidase é muito utilizada em oftalmologia melhorando a eficácia anestésica. Foi demonstrado que uma fração muito pequena das moléculas de AL injetadas atingem o feixe nervoso e o restante se difunde para os tecidos ao redor. O objetivo deste estudo foi verificar se a hialuronidase 75 UTR é capaz de prolongar a duração de ação anestésica quando injetada antes da regressão do efeito AL. Foram realizadas 40 cirurgias de terceiros molares inferiores bilaterais e simétricos, pelo mesmo operador, utilizando-se mepivacaína 2% com epinefrina para bloqueio pterigomandibular, em 20 pacientes saudáveis. Para cada cirurgia foi injetada aos 40 minutos, hialuronidase ou placebo, de modo duplo-cego. Utilizou-se estímulo elétrico na polpa para a avaliação da anestesia pulpar e estímulo mecânico (picada) na gengiva. Os testes foram feitos no pré-molar inferior, colateral à cirurgia. Em ambos tecidos avaliados, a duração da anestesia com hialuronidase foi maior (p<0,01) do que com o placebo. Indiretamente, estes resultados são um indício de que a hialuronidase redireciona as moléculas de AL para a fibra nervosa, prolongando o tempo de bloqueio nervoso. Nestas condições experimentais, pode-se concluir que, a hialuronidase prolonga a duração de ação anestésica local. / The association of local anaesthetic (LA) with hyaluronidase is widely used in ophthalmic anaesthesia improving its efficacy. It was demonstrated that a fraction of molecules of the LA applied reached the nerve and the others spreads out to the tissues around. Our purpose was to verify if hyaluronidase (75 TRU) is able to prolong the duration of anaesthesic action when it was injected immediately before the end of pulpal anesthesia. It was realized 40 bilateral and symmetrical third inferior molar surgeries by the same operator, with 2% mepivacaine with epinephrine to block inferior alveolar nerve , in 20 healthy patients. In each surgeries was injected at 40 minutes hyaluronidase or placebo, in a double blinded manner. It was used electrical stimulus to evaluate pulpal anesthesia, and was done mechanical stimulus (pick) to evaluated gingival anaesthesia. The tests were done in the inferior premolar, collateral side to the surgery. In both tissues, the duration of action with hyaluronidase was longer (p<0.01) than placebo. Indirectly, these outcomes indicate that hyaluronidase redirects the molecules of LA to the nervous fiber. Regarding these experimental conditions, it is possible to conclude that hyaluronidase induce long-term local anesthesia.

O uso do adjuvante hialuronidase (H) ao anestésico local (AL) é largamente utilizado em anestesia oftalmológica por melhorar a eficácia anestésica. Quando utilizada em odontologia concomitantemente ao AL na concentração de 150 UTR/ mL, não melhorou o índice de sucesso da anestesia do bloqueio do nervo alveolar inferior e ainda induziu ao trismo. Recentemente foi demonstrado que a H na concentração de 75 UTR/ mL injetada após 40 minutos do início da anestesia pterigomandibular prolongou a duração da anestesia. Ainda não foi avaliada se a H à 75 UTR/mL (metade da concentração) injetada concomitantemente o AL melhora o índice de sucesso sem induzir ao trismo. O objetivo deste estudo foi avaliar a influência da H 75 UTR/ mL injetada concomitantemente ao AL local em relação a latência de ação, duração de ação anestésica, índice de sucesso anestésico, edema pós-operatório e abertura bucal pós-operatória. Em 25 pacientes saudáveis foram realizadas 50 cirurgias (n=25) de terceiros molares inferiores, bilaterais, simétricos, pelo mesmo operador, utilizando para o bloqueio do nervo alveolar inferior 1,8 mL de lidocaína 2% associada à epinefrina 1:100.000 com a hialuronidase ou placebo (veículo) de modo duplo-cego e 1,0 mL para anestesia do nervo bucal. Para a avaliação da latência e duração de ação anestésica na polpa utilizou-se estímulo elétrico e para a gengiva, foi utilizado estímulo mecânico (picada). O edema foi avaliado através de medidas faciais (distância entre pontos) e a abertura bucal pela distância interincisal, ambos utilizando régua milimetrada. Estas medidas foram obtidas nos tempo: préoperatório, segundo e sétimo dia pós-operatório. A latência e duração de ação anestésica não apresentaram diferenças significativas (p>0,05) e não houve aumento do índice de sucesso da anestesia. O edema e a abertura bucal não variaram em relação às soluções utilizadas (p>0,05), porém houve diferença significativa de acordo com o tempo pós-operatório (p<0,05). Embora a H em menor concentração não tenha induzido efeitos adversos (trismo), também não melhorou sua eficácia. Nestas condições experimentais, pode-se concluir que a hialuronidase na concentração 75 UTR/ mL injetada concomitantemente ao AL não apresenta vantagem clínica. / The association of local anaesthetic (LA) with hyaluronidase (H) is widely used in ophthalmic anesthesia in order to improve its effectiveness of anesthesia. In dentistry, H 150 UTR/ mL injected concomitantly to LA solution did not enhance the success rate of anesthesia in inferior alveolar nerve (IAN) block and increased postoperative trismus. Recent studies have proved that when a concentration of 75UTR/ mL was injected 40 minutes after the beginning of the anesthesia in IAN block and lasts the local anesthesia. The purposes of this study were to evaluate the influence of H (75UTR/ mL) in onset time of action (OA), duration of LA action (DA), success rate, trismus and edema after surgical extractions of mandibular thrid molars. In each surgery was injected 1.8ml of 2% lidocaine with epinephrine added to hyaluronidase or placebo (vehicle) in a double blinded method, in 25 healthy patients for bilateral and symmetrical third inferior molar surgeries. The OA and DA were evaluated by electrical stimulus (pulpal anesthesia) in the inferior premolar and by mechanical stimulus (pick) for gingival anaesthesia. Trismus was determined by measuring maximum interincisal opening. Facial swelling was assessed by a tape measuring method (distance between points on the face) at second and seventh postoperative days. There were no significant difference between the H and placebo solutions in OA, DA, success rate, trismus and edema (p>0.01). Trismus and edema were significant diferent in the second day postoperative (p<0.01) for H and placebo. H added to LA did not influence sucess rate of LA, OA and DA, trismus and edema postoperative. The concomitant use of LA to H in the concentration of 75 UTR/ mL does not seem advantageous in IAN block.

Research suggests biological sex differences may affect pain perception, however the difference in analgesic tolerance between male and females not been extensively studied. Therefore, here we studied the response of male and female Sprague-Dawley rats to prolonged duration local anesthetics; including conventional amino-amide anesthetics (bupivacaine), site 1 sodium channel blockers (tetrodotoxin) and a prolonged duration liposomal formulation (Exparel). This study examined the incidence and duration of sensory and motor blockade; systemic side effects, as well as local neurotoxicity and myotoxicity in both male and female rodents in an in vivo model of sciatic nerve blockade. The data collected does not indicate a sexual dimorphism among the agents studied. / 2019-07-03T00:00:00Z