O transplante de hepatócitos é uma modalidade terapêutica atrativa para as doenças hepáticas, assim como uma alternativa para o transplante hepático. O objetivo do presente estudo é investigar a efetividade do transplante de hepatócitos de ratos nos modelos de hepatotoxicidade aguda induzida por paracetamol (1g/kg e 1,5g/kg). Os hepatócitos foram isolados de ratos Wistar machos e transplantados 24 horas após em receptoras fêmeas com hepatotoxicidade de 1g/kg. Os ratos fêmeas receberam 1x107 hepatócitos (grupo 1, n=20) ou PBS (grupo 2, n=24) através da veia porta ou no baço. A análise de sobrevida em 3 dias demonstrou que todos os animais do grupo 1 sobreviveram, enquanto 5 animais do grupo 2 morreram (P=0,03), todas as mortes ocorreram nos ratos que receberam PBS através da veia porta (P=0,001). Os níveis de alanina aminotransferase e fator V que foram medidos no experimento não mostraram diferença entre o grupo 1 e o grupo 2 em nenhum momento. A análise molecular e a histologia mostraram a presença de hepatócitos no fígado de animais transplantados através da veia porta ou pelo baço. O modelo de hepatotoxicidade aguda induzida por paracetamol (1g/kg) demonstrou que o transplante de hepatócitos de ratos aumenta a sobrevida quando o local de injeção é na veia porta. No modelo de hepatotoxicidade aguda induzida por paracetamol (1,5g/kg), os hepatócitos foram isolados de ratos Wistar machos, e transplantados 6 horas após em receptoras fêmeas. Os ratos fêmeas receberam 1x107 hepatócitos (grupo 1, n=33) ou PBS (grupo 2, n=24) no baço. A análise de sobrevida em 3 dias demonstrou que 9 animais do grupo 1, e 9 animais do grupo 2 morreram no dia 2. Não houve diferença estatística significativa na análise de sobrevida entre o grupo 1 e o grupo 2. Nossos dados demonstram que o isolamento de hepatócitos é um procedimento factível. O transplante de hepatócitos é uma técnica que pode ser aplicada em modelos animais de IHA levando ao aumento da sobrevida. Entretanto, o modelo utilizado no presente estudo apresentou um alto grau de variabilidade, tornando necessária a avaliação do transplante de hepatócitos em um modelo mais reprodutível. / Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for liver transplantation. The aim of the current study was to investigate the effectiveness of rat hepatocyte transplantation in the acetaminophen-induced acute hepatotoxicity models (1g/kg and 1,5g/kg). Hepatocytes were isolated from male Wistar rats and transplanted 24 hours later in female recipients with hepatotoxicity of 1g/kg of acetaminophen. Female rats received either 1x107 hepatocytes (group1, n=20) or PBS (group 2, n=24) through the portal vein or into the spleen. Survival analyses in 3 days showed that all animals from group 1 survived, whereas 5 rats from group 2 died (P=0.03), all deaths occurred in rats that received PBS into the portal vein (P=0.001). Alanine aminotransferase and factor V levels measured within the experiment did not differ between groups 1 and 2 at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. Our data in acetaminophen-induced hepatotoxicity model (1g/kg) demonstrate that rat hepatocyte transplantation increases survival when the site of injection is into portal vein in this hepatotoxicity model. In the acetaminophen-induced acute hepatotoxicity model (1,5g/kg), hepatocytes were isolated from male Wistar rats and transplanted 6 hours later in female recipients. Female rats received either 1x107 hepatocytes (group1, n=33) or PBS (group 2, n=24) into the spleen. Survival analyses in 3 days showed that 9 rats from group 1 and 9 rats from group 2 died at day 2. There was no statistical significance in survival between group 1 and group 2. Our data demonstrate that hepatocyte isolation is a feasible procedure. Hepatocyte transplantation can be used in animal models of acute liver failure increasing survival. The model of the present study show a higher variability, therefore it´s necessary to evaluate hepatocyte transplantation in a more reproducible model.

O transplante de hepatócitos é uma modalidade terapêutica atrativa para as doenças hepáticas, assim como uma alternativa para o transplante hepático. O objetivo do presente estudo é investigar a efetividade do transplante de hepatócitos de ratos nos modelos de hepatotoxicidade aguda induzida por paracetamol (1g/kg e 1,5g/kg). Os hepatócitos foram isolados de ratos Wistar machos e transplantados 24 horas após em receptoras fêmeas com hepatotoxicidade de 1g/kg. Os ratos fêmeas receberam 1x107 hepatócitos (grupo 1, n=20) ou PBS (grupo 2, n=24) através da veia porta ou no baço. A análise de sobrevida em 3 dias demonstrou que todos os animais do grupo 1 sobreviveram, enquanto 5 animais do grupo 2 morreram (P=0,03), todas as mortes ocorreram nos ratos que receberam PBS através da veia porta (P=0,001). Os níveis de alanina aminotransferase e fator V que foram medidos no experimento não mostraram diferença entre o grupo 1 e o grupo 2 em nenhum momento. A análise molecular e a histologia mostraram a presença de hepatócitos no fígado de animais transplantados através da veia porta ou pelo baço. O modelo de hepatotoxicidade aguda induzida por paracetamol (1g/kg) demonstrou que o transplante de hepatócitos de ratos aumenta a sobrevida quando o local de injeção é na veia porta. No modelo de hepatotoxicidade aguda induzida por paracetamol (1,5g/kg), os hepatócitos foram isolados de ratos Wistar machos, e transplantados 6 horas após em receptoras fêmeas. Os ratos fêmeas receberam 1x107 hepatócitos (grupo 1, n=33) ou PBS (grupo 2, n=24) no baço. A análise de sobrevida em 3 dias demonstrou que 9 animais do grupo 1, e 9 animais do grupo 2 morreram no dia 2. Não houve diferença estatística significativa na análise de sobrevida entre o grupo 1 e o grupo 2. Nossos dados demonstram que o isolamento de hepatócitos é um procedimento factível. O transplante de hepatócitos é uma técnica que pode ser aplicada em modelos animais de IHA levando ao aumento da sobrevida. Entretanto, o modelo utilizado no presente estudo apresentou um alto grau de variabilidade, tornando necessária a avaliação do transplante de hepatócitos em um modelo mais reprodutível. / Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for liver transplantation. The aim of the current study was to investigate the effectiveness of rat hepatocyte transplantation in the acetaminophen-induced acute hepatotoxicity models (1g/kg and 1,5g/kg). Hepatocytes were isolated from male Wistar rats and transplanted 24 hours later in female recipients with hepatotoxicity of 1g/kg of acetaminophen. Female rats received either 1x107 hepatocytes (group1, n=20) or PBS (group 2, n=24) through the portal vein or into the spleen. Survival analyses in 3 days showed that all animals from group 1 survived, whereas 5 rats from group 2 died (P=0.03), all deaths occurred in rats that received PBS into the portal vein (P=0.001). Alanine aminotransferase and factor V levels measured within the experiment did not differ between groups 1 and 2 at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. Our data in acetaminophen-induced hepatotoxicity model (1g/kg) demonstrate that rat hepatocyte transplantation increases survival when the site of injection is into portal vein in this hepatotoxicity model. In the acetaminophen-induced acute hepatotoxicity model (1,5g/kg), hepatocytes were isolated from male Wistar rats and transplanted 6 hours later in female recipients. Female rats received either 1x107 hepatocytes (group1, n=33) or PBS (group 2, n=24) into the spleen. Survival analyses in 3 days showed that 9 rats from group 1 and 9 rats from group 2 died at day 2. There was no statistical significance in survival between group 1 and group 2. Our data demonstrate that hepatocyte isolation is a feasible procedure. Hepatocyte transplantation can be used in animal models of acute liver failure increasing survival. The model of the present study show a higher variability, therefore it´s necessary to evaluate hepatocyte transplantation in a more reproducible model.

Orientadores: Hiroshi Aoyama, Marcio Andre Miranda / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-09T01:06:42Z (GMT). No. of bitstreams: 1 Camargo_CamiladeAndrade_M.pdf: 1153945 bytes, checksum: d090e6ed4e436a5029c6e36de7786df1 (MD5) Previous issue date: 2007 / Resumo: Os flavonóides são fitocompostos polifenólicos, caracterizados quimicamente como heterosídeos flavônicos. Apresentam diversas atividades biológicas devido às suas propriedades antioxidantes e habilidades em modular a atividade de diversas enzimas ou receptores celulares, tornando-os responsáveis pelo efeito protetor contra doenças relacionadas ao sistema cardiovascular; certas formas de câncer e doenças de fotossensibilidade e envelhecimento. As fosfatases ácidas, enzimas que hidrolisam ésteres fosfatos em meio ácido, encontram-se amplamente distribuídas no organismo. Estas enzimas são importantes no catabolismo de diversas substâncias, acreditando-se que a alteração da atividade destas enzimas esteja relacionada com modificações induzidas por drogas e por várias doenças. As transaminases são enzimas hepáticas cujo nível aumenta quando há lesão das células hepáticas (hepatócitos) provocada por qualquer tipo de agressão, como vírus, consumo excessivo de álcool ou drogas. O acetaminofeno é uma droga frequentemente usada como analgésico e antipirético. O dano hepático causado pelo uso frequente ou exagerado do acetaminofeno é comum hoje em dia. A manutenção correta dos sistemas metabólicos hepáticos é de grande importância para a manutenção da saúde. Desta forma, o estudo do flavonóide quercetina como possível protetor dos efeitos hepatotóxicos provocados pelo acetaminofeno pode ser muito promissor. O objetivo do presente trabalho foi estudar os efeitos preventivos e terapêuticos, in vivo, do flavonóide quercetina sobre as atividades de fosfatases ácidas (total, tartarato-resistente e de baixa massa molecular relativa) e de transaminases glutâmica oxalacética (TGO) e glutâmica pirúvica (TGP) no fígado de camundongos, tratados ou não com acetaminofeno. Para o desenvolvimento deste trabalho foi realizado um tratamento agudo (24 horas), de camundongos machos da linhagem Swiss, com quercetina e acetaminofeno, utilizando-se óleo de milho ou nujol como veículo para o flavonóide. A dosagem da TGO e da TGP confirmou que o acetaminofeno pode realmente ser considerado hepatotóxico, quando administrado ou ingerido em grandes concentrações no organismo. A quercetina, dissolvida em óleo mineral, reverteu a hepatotoxicidade induzida pelo acetaminofeno, nos tratamento terapêutico e, em conjunto com acetaminofeno. A quercetina dissolvida em óleo de milho, no tratamento preventivo, pode não ser a única responsável pela reversão da hepatotoxicidade causada pela administração do acetaminofeno, uma vez que quando se substituiu o veículo utilizado, óleo de milho pelo óleo mineral, este efeito não foi mais observado. Comparando-se os resultados obtidos entre fosfatases e transaminases pode-se observar que a atividade da FATR, no tratamento com nujol, demosntra uma semelhança muito grande com os resultados observados nos gráficos das atividades das transaminases e provavelmente pode se considerada uma marcadora de dano hepático. O alfa-tocoferol, presente no óleo de milho, pode ter exercido um efeito antioxidante, e mascarado o efeito protetor da quercetina e a hepatotoxicidade do acetaminofeno. Este estudo foi importante para mostrar que a atividade dos flavonóides no organismo vivo pode ser influenciada por diversos fatores, como: a natureza do veículo utilizado na sua administração, ordem de administração e o tempo de permanecia no organismo / Abstract: Flavonoids are polyphenolic phytocompounds chemically characterized as flavonic heterosides. These compounds present several biological activities due to their antioxidant properties and hability to modulate the activities of enzymes or cellular receptors, making them responsible for the protector effect against diseases related to the cardiovascular system, certain forms of cancer, photosensibility diseases and aging. Acid phosphatases, enzymes that hydrolyze phosphate esters at acid medium, are largely distributed in the organisms. These enzymes are important in the catabolism of several compounds and could be related to the modifications induced by drugs and diseases. Transaminases are hepatic enzymes which levels increase in consequence of hepatic cells (hepatocytes) lesions provoked by agressions such as virus and excessive alcohol and drug consumption. Acetaminophen is a drug frequently used as analgesic and antipyretic. It is common the hepatic damage caused by the frequent or exaggerated use of acetaminophen. The correct maintenance of the hepatic metabolic systems is of great importance for the health. In this way, the study of the flavonoid quercetin as a possible protector of the hepatotoxic effects provoked by acetaminophen seems to be promising. The objectif of the present work was to study the in vivo effects of the flavonoid quercetin on the activities of acid phosphatases (total, tartrate-resistant and relative low molecular weight) and of transaminases glutamic oxalacetic (GOT) and glutamic pyruvic (GPT) in mice livers treated with acetaminophen. To develop this work, it was performed an acute treatment (24 hours) of Swiss male mice, with quercetin and acetaminophen, using corn oil or nujol as a vehicle for the flavonoid. The determination of GOT and GPT activities confirmed that acetaminophen can be considered hepatotoxic, when administered or ingested in great amount. In the therapeutic treatments, when applied with acetaminophen, quercetin, solubilized in mineral oil, reverted the acetaminophen-induced hepatotoxicity. In the preventive treatment, quercetin, solubilized in corn oil, might not be the only responsible for the reversibility, since this effect was no more observed when the vegetal oil was replaced by the mineral oil. The results with FATR, in the treatment with nujol, showed great similarity with the results obtained with transaminases, suggesting that this class of phosphatases could be considered as markers of hepatic damage. The alphatocopherol, present in the corn oil, could be exerting an antioxidant effect, masking the protector effect of quercetin and the acetaminophen hepatotoxicity. The importance of the present study was to stress that the in vivo flavonoids activities can be influenced by several factors, such as, the nature of the vehicle used in the administration, the order of administration and the retention time in the organism / Mestrado / Bioquimica / Mestre em Biologia Funcional e Molecular

No description available.

The dissolution profiles of eight lots of paracetamol tablets representing seven different tablet brands are determined in a USP rotating basket assembly and a stationary basket-rotating paddle apparatus. The in vitro data are expressed in terms of dissolution parameters and inter-tablet differences are assessed statistically using analysis of variance (ANOVA) and the Scheffe test. Highly significant differences are observed between a number of the tablets at the 95% confidence level. Representative tablets from the dissolution rate study and a control dose of paracetamol dissolved in water are subsequently investigated in a 4 x 4 latin square design bioavailability trial. Serum and urine samples are collected and assayed for paracetamol alone (serum) and together with its metabolites (urine) by means of high pressure liquid chromatography. The in vivo data are expressed in terms of bioavailability parameters and differences between the test doses are assessed by means of ANOVA. No significant differences are observed between the dosage forms at the 95% confidence level.

Class of 2014 Abstract / Specific Aims: To determine the cost of treatment of oral and intravenous n-acetylcysteine (IV NAC) in acute acetaminophen (APAP) toxicity using the length of treatment and length of hospital stay. Methods: A retrospective chart review of Arizona Poison and Drug Information Center electronic records from 2009-2012 and January-June 2013 were evaluated. The following information was collected: age, sex, use oral or intravenous NAC, length of treatment, length of hospital stay (intensive care unit (ICU) and non-ICU) and use of antiemetic. The mean length of stay (MLOS) was calculated for each group as well as the cost of IV and oral NAC. These means were then compared using t-test for independent groups to test for significance. The average total cost of IV and oral NAC treatment was calculated by using monetary values from primary literature. A sensitivity analysis was performed to test the possible effects of an increase or decrease of the final costs by 5 to 10%. Main Results: Patients (≥18 yrs) being treated with IV or oral NAC for acute APAP toxicity (≤8 hours prior to ingestion) were included in this study. A total of 47 patients met the inclusion criteria. Length of hospital stay was shorter in patients receiving IV NAC (42.5% 24-24hr; 37.5% 48-72hr) compared to patients receiving oral NAC (28.6% 48-72hr, 71.4% >72hrs; p<0.001). Total cost of ICU/non-ICU stay in patients receiving IV NAC ($8,720/$3010) was less than patients receiving oral NAC ($12,321/$4703); however, cost of IV NAC-extended (37hrs) in ICU/non-ICU ($13,153/$5535) was greater than oral NAC. The sensitivity analysis performed demonstrated that an increase or a decrease by 5 to 10% in change of cost does not affect our final conclusion. Conclusion: The cost of treatment of IV NAC is lower due to shorter LOS of patients treated with IV NAC (p<0.001). However, when an extended course of treatment is medically necessary for patients on IV NAC then the cost of treatment with IV NAC exceeds the cost of treatment with oral NAC.

The potent analgesic property of acetylsalicylic acid and acetaminophen makes these the most commonly used analgesics in the world. Easy accessibility and cost effectiveness of these agents are attractive to patients seeking pain relief. However, the abuse of nonnarcotic analgesics such as acetaminophen and acetylsalicylic acid by alcoholics and patients seeking to relieve dysphoric moods is well documented. These agents therefore impact on the brain neurotransmitter levels and therefore all processes involved in the synthesis and metabolism of neurotransmitters may be affected. The use of non-narcotic analgesics has been reported to reduce the incidence of neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The mode of action by which acetylsalicylic acid and acetaminophen elicit neuroprotection is however unclear as many mechanisms of action have been inconclusively postulated. The first part of this study aims to elucidate the various mechanisms by which acetylsalicylic acid and acetaminophen affect the enzymes responsible for the catabolism of tryptophan, which is a precursor for the mood elevating neurotransmitter serotonin, as well as to investigate whether these agents alter the interplay between serotonin and pineal indole metabolism. The second part of this study focuses on the neuroprotective properties of acetylsalicylic acid and acetaminophen utilizing the neurotoxic metabolite of the kynurenine pathway, quinolinic acid and the potent Parkinsonian neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). The ability of acetylsalicylic acid and acetaminophen to alter TRP metabolism was determined by investigating the effects of these agents on the primary enzymes of the kynurenine pathway i.e. tryptophan 2, 3-dioxygenase and indoleamine 2,3-dioxygenase as well as to investigate whether these agents would have any effects on 3-hydroxyanthranilic acid oxygenase. 3-Hydroxyanthranilic acid oxygenase is the enzyme responsible for the synthesis of quinolinic acid. Acetylsalicylic acid and acetaminophen alter tryptophan metabolism by inhibiting tryptophan 2, 3-dioxygenase and indoleamine 2,3-dioxygenase thus increasing the availability of tryptophan for the production of serotonin. Acetylsalicylic acid and acetaminophen also inhibit 3-hydroxyanthranilic acid oxygenase thus implying that these agents could reduce quinolinic acid production. Acetaminophen administration in rats induces a rise in serotonin and norepinephrine in the forebrain. Acetylsalicylic acid curtails the acetaminophen-induced rise in brain norepinephrine levels as well as enhances serotonin metabolism, indicating that analgesic preparations containing both agents would be advantageous, as this would prevent acetaminophen-induced mood elevation. The results from the pineal indole metabolism study show that acetylsalicylic acid enhances pineal metabolism of serotonin whereas acetaminophen induces an increase in melatonin levels in the pineal gland. Neuronal damage due to oxidative stress has been implicated in several neurodegenerative disorders such as AD and PD. The second part of the study aims to elucidate and characterize the mechanism by which acetylsalicylic acid and acetaminophen afford neuroprotection. The hippocampus is an important region of the brain responsible for memory. Agents such as quinolinic acid that are known to induce stress in this area have detrimental effects and could lead to various types of dementia. The striatum is also a vulnerable region to oxidative stress and hence (MPP+), which is toxic for this particular region of the brain, was also used as a neurotoxin. The results show that ASA and acetaminophen alone and in combination, are potent superoxide anion scavengers. In addition, the results imply that these agents offer protection against oxidative stress and lipid peroxidation induced by several neurotoxins in rat brain particularly, the hippocampus and striatum. Histological studies, using Nissl staining and Acid fuchsin, show that acetylsalicylic acid and acetaminophen are able to protect hippocampal neurons against quinolinic acidinduced necrotic cell death. Immunohistochemical investigations show that QA induces apoptotic cell death in the hippocampus, which is inhibited by ASA and acetaminophen. In addition, ASA and acetaminophen inhibited MPP+ induced apoptotic cell death in the rat striatum. The study also sought to elucidate possible mechanisms by which ASA and acetaminophen exert neuroprotective effects in the presence of MPP+ as these agents are shown to prevent the MPP+-induced reduction in dopamine levels. The results show that acetylsalicylic acid and acetaminophen inhibit the action of this neurotoxin on the mitochondrial electron transport chain, a common source of free radicals in the cell. In addition, these agents were shown to block the neurotoxic effects of MPP+ on the enzymatic defence system of the brain i.e. superoxide dismutase, glutathione peroxidase and catalase. The reduction in glutathione levels induced by MPP+ is significantly inhibited by acetylsalicylic acid and acetaminophen. The results imply that these agents are capable of not only scavenging free radicals but also enhance the cell defence mechanism against toxicity in the presence of MPP+. These agents also block the MPP+-induced inhibition of dopamine uptake into the cell. This would therefore reduce auto-oxidation of dopamine thus implying another mechanism by which these agents exert a neuroprotective role in MPP+-induced neurotoxicity. The discovery of neuroprotective properties of acetylsalicylic acid and acetaminophen is important considering the high usage of these agents and the increased incidence in neurological disorders. The findings of this thesis point to the need for clinical studies to be conducted as the results show acetylsalicylic acid and acetaminophen to have a definite role to play as antioxidants. This study therefore provides novel information regarding the neuroprotective effects of these agents and favours the use of these agents in the treatment of neurodegenerative disorders, such as AD and PD, in which oxidative stress is implicated.

This randomized, double-blind, placebo-controlled study was conducted to compare the effectiveness of intravenous acetaminophen vs. oral acetaminophen or placebo as an adjunct to opioids on lowering post-operative pain scores, discharge time, need for opioids, and opioid-related side effects, as well as assessing for any effects pain treatment has on embryological and pregnancy outcomes. Secondary analysis included identifying risk factors in patients that cause them to have worsening pain or minor relief from traditional pain management. This study was conducted at a single academic fertility center at Massachusetts General Hospital in Boston with a patient population of 159 English-speaking women between 18-43 years old, undergoing oocyte retrieval as a part of In Vitro Fertilization procedure. Participants were randomly placed in one of three treatment groups to receive either 1000mg IV acetaminophen and PO placebo (Group A), IV placebo, and 1000mg PO acetaminophen (Group B), or IV and PO placebo (Group C) as pain control before oocyte retrieval procedure. The primary outcomes measured were patient-reported post-operative visual analogue scale pain scores in the recovery room at 10 minutes, 30 minutes, and discharge time. Using these values to measure the effectiveness of each treatment at improving post-operative pain. To assess the relationship, if any, between demographical or clinical factors and pain, we analyzed what factors were common in those experiencing high or low pain. We used the Visual Analog Scale (VAS) which has patients rank pain from 1-10. For this analysis, low pain is defined as those whose 10-minute post-operative pain score was less than 5 (VAS score <5/10) and high pain as those whose 10-minute postoperative pain score is 5 or greater (VAS score 5+/10). Results showed that mean post-operative pain scores were similar between the study groups at 10 minutes (A:2.3, B: 2.6, C:2.8, p=0.51). Timing of discharge was also similar (A:60.1 mins, B: 58.8 mins, C:57.6mins; p=0.76). Although not statistically significant, the mean post-operative opioid dose for patients in group A was less than half of that in Group B and C (0.24mg vs. 0.59mg vs. 0.58mg; p=0.34) and fewer required rescue pain medication in the recovery room (4% vs. 19% vs. 15% respectively; p=0.24). There was a trend towards decreased side effects of constipation in Group A compared to Groups B and C (15% vs. 31% vs. 33%, respectively; p=0.07). There were no differences in embryological or early pregnancy outcomes between study groups. An analysis of predictors of pain, patients with BMI >/=30kg/m2 (obese) were more likely to report high post-operative pain (p=0.009). Prior abdominal surgeries, including pelvic laparoscopy and laparotomy, were associated with low post-operative pain (p=0.069 and p=0.025, respectively). Those who reported having pre-operative pain greater than zero were more likely to report lower postoperative pain (p=0.002). There was no significant relationship between race/ethnicity, infertility diagnosis, and procedure length and pain. This study's findings showed no significant difference between post-operative pain scores or discharge times in women undergoing oocyte retrieval when given IV acetaminophen, PO acetaminophen, or a placebo. There were severe findings that suggested that IV acetaminophen may reduce the need for post-operative narcotics and lead to fewer opioid-related side effects, however these findings while large were statistically insignificant. The predictors of higher post-operative pain we found, including high BMI, no prior history of abdominal procedures, and lack of pre-operative pain, indicate that further investigation into these predictors could be beneficial. This information may allow physicians and anesthesiologists to optimize their pain control.

Le paracétamol est l'antalgique le plus consommé au monde et pourtant son mécanisme d'action n'est toujours pas élucidé. Longtemps reconnu comme un produit proche des anti-inflammatoires non stéroïdiens (AINS) son profil est aujourd'hui reconsidéré grâce aux travaux effectués depuis une dizaine d'années. Il est désormais admis que le paracétamol est un antalgique d'action prioritairement cérébrale et l'impact sur les cyclo-oxygénases, cibles traditionnelles des AINS, ne représente plus la base de son mécanisme d'action. Nos travaux de thèse montrent que l'action antalgique du paracétamol est perdue chez des animaux dont le canal Cav3.2 a été invalidé, ceci dans divers contextes expérimentaux. Ainsi ces canaux semblent être indispensables à l'effet antalgique du paracétamol. Nous avons également démontré le site de cette implication. En effet, seuls les canaux Cav3.2 cérébraux sont impliqués dans l'effet du paracétamol, ce qui rejoint les résultats précédents qui présentent le paracétamol comme un antalgique d'action centrale. Au niveau cérébral nous avons aussi démontré que les canaux Cav3.2 agissaient de concert avec deux acteurs primordiaux pour l'effet du paracétamol : l'AM404, son métabolite actif et les récepteurs TRPV1. La finalité de cette relation est l'inhibition des canaux Cav3.2 qui induit l'effet antalgique du paracétamol. Parallèlement, nous avons démontré pour la première fois que l'inhibition des canaux Cav3.2 cérébraux induisait une antalgie. Ceci confirme l'implication tonique de ces canaux supra-spinaux dans la perception douloureuse. Enfin, nous avons également démontré que les canaux Cav3.2 étaient fortement impliqués dans la douleur de type inflammatoire et, de manière plus surprenante et intéressante, dans les processus inflammatoires associés (développement oedémateux et production des médiateurs pro-inflammatoires). En conformité avec ces résultats, nous avons démontré que l'éthosuximide (un bloqueur des canaux Cav3.2) était efficace dans le traitement des douleurs inflammatoires et de l'inflammation ainsi que sur leurs comorbidités associées (anxiété et dépression). En conclusion, la confirmation de l'implication des canaux Cav3.2 dans l'effet du paracétamol et dans la douleur inflammatoire ouvre une voie nouvelle dans la compréhension du mécanisme d'action de cet antalgique et dans la conception et le développement de nouveaux antalgiques, ciblant ces canaux. Cette perspective est renforcée par les démonstrations déjà faites du rôle de ces canaux dans la physiopathologie des douleurs neuropathiques. De plus et de façon intéressante, l'éthosuximide, un antiépileptique utilisé chez l'homme et inhibiteur des canaux Cav3, permet d'envisager la réalisation d'une étude clinique pilote sur l'évaluation de son effet antalgique. Nous proposons le protocole de cette étude, preuve de concept, réalisée dans un premier temps chez des patients atteints de douleurs neuropathiques. / Acetaminophen is the most analgesic consumed worldwide, but its mechanism of action is still not understood. Long recognized as non-steroidal anti-inflammatory drugs (NSAIDs), its profile is now reconsidered thanks to the work done over the last ten years. It is now accepted that acetaminophen is an analgesic with a central action and the impact on cyclooxygenase, traditional targets of NSAIDs, is no longer the basis of its mechanism of action. This work show that the analgesic effect of acetaminophen is lost in animals whose Cav3.2 channel has been invalidated, this in various experimental contexts. Thus, these channels appear to be essential for the analgesic effect of acetaminophen. We also demonstrated the nature of that involvement. Indeed, only the brain Cav3.2 channels are involved in the effect of acetaminophen, which joined the previous results showing that acetaminophen is a centrally acting analgesic. In the brain, we also demonstrated that Cav3.2 channels acting in concert with two crucial actors to the effect of acetaminophen: AM404, its active metabolite, and TRPV1 receptors. The purpose of this relationship is the inhibition of Cav3.2 channels that induces analgesic effect of acetaminophen. In parallel, we have demonstrated for the first time that inhibition of brain Cav3.2 channels induced analgesia. This confirms the tonic involvement of these channels in supraspinal pain perception. Finally, we also demonstrated that Cav3.2 channels were heavily involved in the inflammatory pain and, more surprising and interesting, in inflammatory processes associated (edema development and production of pro-inflammatory mediators). Related to these results, we demonstrated that ethosuximide (a Cav3.2 channel blocker) was effective in the treatment of inflammatory pain and inflammation as well as their associated comorbidities (anxiety and depression). In conclusion, the confirmation of the interaction of Cav3.2 channels in the effect of acetaminophen and pain perception opens a new path in understanding the mechanism of action of acetaminophen and in the design and development of new analgesics targeting Cav3.2 channels. This perspective is reinforced by the demonstrations previously done of the role of these channels in the pathophysiology of neuropathic pain. More and interestingly, ethosuximide, an antiepileptic drug used in humans and Cav3 channels inhibitor, allows to consider the realization of a pilot clinical study on the evaluation its antalgic effect. We propose the protocol of this study, proof of concept, performed in a first time in patients of neuropathic pain.

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