Enhancing the use of opioids in pain management: antinociceptive potentiation with opioid agonist/antagonist combinations.La Vincente, Sophie January 2005 (has links)
Title page, table of contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library. / While opioids are the most effective and widely used class of drug for the management of moderate to severe pain, their use may be limited by adverse effects that are unpleasant and potentially dangerous. Research is increasingly directed towards strategies to improve the use of opioids in pain management, investigating methods by which the analgesia afforded by an opioid may be enhanced, while minimising adverse effects. One approach that has produced promising findings in animal studies and some clinical reports is the combination of an opioid agonist and "ultra-low" (nanomole) doses of an opioid antagonist. A recent animal study reported that antinociception may be significantly enhanced with the combination of the partial opioid agonist/antagonist buprenorphine and ultra-low doses of the antagonist naloxone. The central aim of the studies described herein was to investigate the effect of this drug combination on response to experimental nociceptive stimuli and the incidence and severity of adverse effects among healthy volunteers. The first study established normative responses to two commonly used nociceptive tests, the cold pressor and electrical stimulation tests, in 100 healthy volunteers. The effect of buprenorphine on nociceptive test performance had not previously been determined, therefore a dose-ranging study of buprenorphine was conducted to establish a doseresponse relationship. The subsequent two studies investigated the effect of a range of buprenorphine:naloxone IV dose ratios (5:1, 10:1, 12.5:1, 15:1, 20:1 and 25:1) on nociception and adverse effects among healthy volunteers. These studies are the first to investigate the combination of buprenorphine and ultra-low dose antagonist in humans, and the first to assess the agonist:antagonist combination in an experimental model of human nociception. Antinociception was significantly enhanced with the combination of buprenorphine and naloxone in the 12.5:1 and 15:1 ratios. Moreover, this enhanced antinociception occurred without a simultaneous increase in adverse effects and indeed with a reduction in the severity of some effects. An agent that produces greater analgesia and reduces adverse effects has the potential to overcome some of the barriers that limit the use of opioids in pain management. The current findings indicate that further investigation of this drug combination is warranted. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1177227 / Thesis (Ph.D.) -- University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 2005
Efeito antinociceptivo, gastrointestinal e na atividade locomotora espontânea da administração intravenosa e metadona em equinosOliveira, Flávia Augusta de [UNESP] 25 February 2011 (has links) (PDF)
Made available in DSpace on 2014-06-11T19:27:25Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-25Bitstream added on 2014-06-13T20:56:28Z : No. of bitstreams: 1 oliveira_fa_me_botfm.pdf: 358176 bytes, checksum: ff09a48eb440e267705b9b106c021332 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Opioids are the most potent substances used for pain relief. However, these drugs are not widely used in horses, due to substantial sympathetic stimulation, excitement of the central nervous system and decreased of the gastrointestinal motility observed when opioids are administered intravenously. The effects of methadone on antinociception, spontaneous locomotor activity and gastrointestinal motility were investigates. Six adult horses were used in a randomized crossover design. Each animal was subjected to three treatments: saline (control), methadone (0.2 mg / kg - MET0.2) and methadone (0.5 mg / kg - MET0.5) intravenously (IV), within 1 week between each treatment. The antinociceptive effect was evaluated by the hoof- withdrawal reflex latency (HWRL) after painful stimulation with a heat lamp and voltage for the withdrawal reflex of the limb (VRRM) after electrical stimulation (phase 1). Spontaneous locomotor activity (SLA ) was investigated in a behavior box by use of infrared photoelectric sensors (phase 2) and gastrointestinal motility by abdominal auscultation (phase 3). Parametric variables were analyzed by ANOVA followed by Dunnett or Tukey test. For SLA and abdominal auscultation was fitted the generalized linear models with Poisson error and log link function for repeated data. Differences were considered significant when P <0.05.No electrical noxious stimulation test was performed with the dose of 0.5 mg/kg methadone IV. The HWRL did not increase in animals treated with MET0,2. However, after administration of 0.5 mg/kg of methadone IV, HWRL increased significantly at 15 and 30 minutes compared to baseline and control groups and MET0,2, rising from 3,21 seconds (average) to 8.61 and 9.11 seconds respectively (P <0.05). VRRM increased significantly from baseline at all... (Complete abstract click electronic access below)
Colite experimental induzida pelo Ãcido trinitrobenzeno sulfÃnico (TNBS) em ratos reduz a resposta hipernociceptiva inflamatÃria- papel das vias endocanabinÃides, opiÃides endÃgenos e NO/GMPC/PKG/K+ATP. / Colitis experimental induced by trinitric benzene sulfonic acid (TNBS) decreased the mechanical inflammatory hypernoception in rats - role of cannabinoids, opioids and NO/cGMP/PKG/KATP pathway.AndrÃ Luiz dos Reis Barbosa 17 June 2011 (has links)
CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O presente teve por objetivo avaliar a diminuiÃÃo da resposta hipernociceptiva inflamatÃria no curso do desenvolvimento da colite experimental induzida pelo Ãcido TNBS em ratos, bem como avaliar o papel da via NO/GMPc/PKG/K+ATP e a participaÃÃo de opioides endÃgenos e endocanabinoides neste evento. Para tanto, as colites foram induzidas por TNBS (20mg) diluÃdo em etanol a 50% ou etanol a 50%. O grupo controle recebeu somente salina via transanal. TrÃs ou quatorze dias apÃs a induÃÃo das colites foram avaliados os seguintes parÃmetros: edema de pata por carragenina (Cg; 500μg/pata direita) ou dextrana (Dxt; 500μg/pata direita.) por pletismometria, atividade da enzima mieloperoxidase (MPO), migraÃÃo de neutrÃfilos para cavidade pleural induzidas por Cg (500μg/pata direita) e a hipernocicepÃÃo mecÃnica induzida por PGE2 (100ng/pata) ou Cg (500μg/pata) aferido por analgesÃmetro digital (InsightÂ). Para verificar a participaÃÃo da via NO/GMPc/PKG/K+ATP na diminuiÃÃo da resposta hipernocicetiva da colite induzida por TNBS foram usados o L-Noarg (antagonista da NOSi; 100ng/pata) , O ODQ (bloqueador da guanilato ciclase soluivel; 8μg/pata), o KT5823 (antagonista da PKG; 1,5 μg/pata) e a glibenclamida (bloqueadora dos canais de K+ATP; 160μg/pata). Depois, para avaliar a participaÃÃo opiÃide e canabinÃide nesse evento, naloxona (antagonista de receptor opioide, 1,0 μg/pata) ou AM251 (antagonista de receptor canabinoide ; 1, 80 μg/pata) ou AM630 (antagonista de receptor canabinoide tipo 2; 25 μg/pata) foram injetados respectivamente. Os animais com colite induzida por TNBS apresentaram uma inibiÃÃo significativa do edema de pata tanto com o Cg (TrÃs ou quatorze dias apÃs a induÃÃo) quanto com Dxt (TrÃs dias apÃs a induÃÃo), quando comparados com os outros grupos em estudo. Em nenhum dos dias estudados, foram observadas diferenÃas na atividade da MPO na pata e nem na avaliaÃÃo da migraÃÃo de neutrÃfilos para a cavidade pleural induzidas por Cg. Ratos com colite induzida por TNBS apresentavam diminuiÃÃo na resposta hipernociceptiva induzida por Cg e PGE2. O tratamento com o ODQ, KT5823 e glibenclamida, naloxona, AM251 e AM630 reverteram esse efeito. O L-Noarg tambÃm reverteu o efeito entinociceptivo da colite induzida por TNBS, mas com a administraÃÃo da L-Arginina esse efeito foi recuperado. Apartir dos nossos resultados podemos concluir que a colite induzida por TNBS diminuiu a hipernocicepÃÃo inflamatÃria induzida tanto por carragenina quanto por PGE2 por dimimuir parÃmetros inflamatÃrios agudos como a resposta edematogÃnica a estÃmulos inflamatÃrios. AlÃm disso, esse efeito antinociceptivo parece ser independente da infiltraÃÃo de neutrÃfilos, mas dependente da ativaÃÃo da via final NO/GMPc/PKG/K+ATP e estimulada pelas aÃÃes dos opiÃides e canabinÃides endÃgenos. / The aim of this study was to investigate a possible involvement of the opioids, endocannabinoids and NO/cGMP/PKG/K+ATP pathway in the antinociception of the CrohnÂs experimental model in hypernociception induced by carragenan ou PGE2. Colitis was induced in the male Wistar rats (200-250) by intracolonic administration of 20 mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in 50% ethanol, ethanol 50% or an equivalent volume of saline. Three or fourteen days after the colitis induction several parameters were evaluated: paw edema induced by carrageenan (Cg; 500μg/hind paw) or dextran (Dxt, 500μg/hind paw), myeloperoxidase activity (MPO), neutrophil migration to pleural cavity. Paw edema was evaluated the right hind paw and measured by plethysmometry. Neutrophil migration was induced by Cg injection in the right hind paw or in the peritoneal cavity. After 4h, rats were sacrificed and the skin of the right hind paw was harvested to measure neutrophil infiltration by MPO assay. Neutrophil migration induced by Cg was also evaluated in the pleural cavity, with the total e differential leucocytes counted. The mechanical behavioral tests were performed by measuring the force in grams (g) applied through a digital analgesymeter (InsightÂ). In this test the rats received PGE2 (100ng/paw) or carrageenan (Cg; 500μg/paw) into the plantar surface. In order to investigate the involvement of the NO/cGMP/PKG/K+ATP pathway in this event there were used L-Noarg (antagonist of iNOS; 100ng/paw), ODQ ( guanilate ciclase blocker; 8μg/paw), L-Arg (200mg/kg), KT5823 ( PKG blocker; 1.5 μg/paw) and Glibenclamide ( K+ATP channels blocker; 160μg/paw). To evaluated the involvement of the opioids and cannabinoids in this event naloxone (opioids receptor blocker; 1 μg/paw) or AM251 ( cannabinoid receptor blocker type I; 80 μg/paw) or AM630 (cannabinoid receptor blocker type II; 25 μg/paw) were inject respectively. Our results shows that, in animals with TNBS-induced colitis, there was a significant inhibition in the Cg (3rd or 14th after colitis induction) and Dxt (3rd after colitis induction)-induced paw edema. There were no differences in MPO activity and neither in the pleural neutrophil infiltration induced by Cg in rats inoculated with TNBS -induced colitis (3rd after colitis induction) when compares to normal animals. Rats with colitis induced by TNBS showed an increased nociceptive threshold when induced by CG and PGE2. Treatment with ODQ, KT5823 and glibenclamide, naloxone, AM251 and AM630 decreased the nociceptive threshold when compared with TNBS colitis. L-NOARG decrease the nociceptive threshold in rats with colitis induced by TNBS and L-arginine reversed this effect. Our results suggest that the antinociceptive effect of the experimental model of CrohnÂs disease induced by TNBS seemed to be mediated a decrease of inflammatory response independent of neutrophil migration and activation of the NO⁄cGMP/PKG pathway followed by the opening of K+ ATP channels and activation of opioid and cannabinoid system.
Dhooper, Harpreet Kaur
01 January 2010
The central hypothesis of the dissertation is that “the design and synthesis of a codrug of an opiate and a cannabinoid can be achieved which is stable in the gastrointestinal tract and shows a superior pharmacological and pharmacokinetic profile when compared to a physical mixture of the two parent drugs.” To prove the hypothesis, a series of novel codrugs were prepared by conjugation of the opiate drug codeine with Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol, abn-cannabidiol and an opiate prodrug 3-O-acetylmorphine with Δ9-THC. Codeine-cannabinoid codrugs were evaluated for analgesic activity in the rat after oral administration. The Cod-THC codrug showed greater effectiveness as well as prolonged pain management properties as compared to the parent drugs. The stability of Cod-THC codrug in aqueous solutions from pH 1-9, in simulated gastrointestinal fluids, in brain homogenate and the hydrolysis of the carbonate ester linkage in rat plasma suggested that after oral administration, the codrug would be absorbed intact from the GI tract and then hydrolyze in the plasma to generate both parent drugs. The enzymes present in rat brain homogenate were incapable of cleaving the codrug into the parent drugs. The pharmacokinetic profiles of the Cod-THC codrug and an equimolar physical mixture of the parent drugs were evaluated in rats. The plasma concentrations of codeine and Δ9-THC were much higher after codrug administration compared to the plasma concentrations of these drugs after oral administration of an equimolar physical mixture. The parent drugs were also present in the plasma for longer period of time compared to the physical mixture, probably due to the sustained release of the parent drugs from codrug in the plasma. The concentrations of codeine and Δ9-THC were much higher in rat brain after oral administration of the Cod-THC codrug as compared to brain concentrations of these drugs after oral administration of the physical mixture. Thus, the design and synthesis of an opiate and a cannabinoid codrug was achieved which was stable in the gastrointestinal tract, showed enhanced analgesic effects as compared to the parent drugs, and also showed a superior pharmacokinetic profile when compared to a physical mixture or the two parent drugs.
Houston, Abigail Jane
No description available.
Puga, Denise Alejandra
2011 May 1900
We utilize a simple instrumental (response-outcome) learning task to measure spinal plasticity in the isolated spinal cord. Peripheral uncontrollable nociceptive input has been shown to disrupt spinal instrumental learning and induce enhance tactile reactivity. In contrast, 1.5mA of continuous shock has been found to induce antinociception and protect spinal plasticity from the detrimental consequences of uncontrollable stimulation. The experiments of this dissertation examined the link between the beneficial effects of continuous stimulation and antinociception. The results replicated previous work examining the protective and antinociceptive effect of 1.5mA of continuous shock (Experiments 1-2). Novel to this research was the inclusion of a lower (0.5mA) intensity continuous stimulation. Results revealed that 0.5mA of continuous shock induced a comparable antinociception to that seen with 1.5mA of continuous shock (Experiment 1). At this lower intensity, however, continuous shock was unable to protect the isolated spinal cord from the detrimental effect of intermittent stimulation (Experiment 2). Further examination revealed that co-administration of intermittent and continuous shock did not affect continuous shockinduced antinociception. This was true at both the higher (1.5mA) and lower (0.5mA) intensities of continuous shock (Experiment 3). When 0.5mA of continuous shock was administered prior to intermittent shock, this intensity of continuous shock was better able to immunize the spinal cord from the induction of the learning deficit than 1.5mA (Experiment 4). Further analysis called into question the link between antinociception and the protective effect of continuous shock, as the beneficial effect of continuous shock outlasted the expression of antinociception (Experiment 5). Moreover, 0.5mA of continuous shock was found to reverse the expression of the learning deficit, when continuous stimulation was given after intermittent shock treatment (Experiment 6). While blocking the induction of antinociception was not sufficient to prevent the immunizing effect of continuous shock, data suggest that the mu opioid receptor is implicated in the beneficial impact of continuous stimulation (Experiments 7 and 8). Endogenous brain derived neurotrophic factor (BDNF) release was also found to play a role (Experiment 9). Moreover, continuous shock was found to down-regulate the expression of early genes implicated in the development of central sensitization, c-fos and c-jun. Finally, we found that while continuous stimulation was detrimental to locomotor recovery after spinal cord injury, the combined treatment of continuous and intermittent shock did not negatively affect recovery (Experiments 11 and 12).
Efeito antinociceptivo, gastrointestinal e na atividade locomotora espontânea da administração intravenosa e metadona em equinos /Oliveira, Flávia Augusta de. January 2011 (has links)
Orientador: Stelio Pacca Loureiro Luna / Coorientador: Francisco José Teixeira Neto / Banca: Eduardo Raposo Monteiro / Banca: Juliana Tabarelli Brondani / Resumo:As substâncias mais potentes utilizadas para o alívio da dor conhecidas são os opioides. No entanto, estes fármacos não são amplamente utilizados em equinos, devido ao substancial estímulo simpático, excitação do sistema nervoso central e redução da motilidade do trato gastrointestinal observados quando administrados principalmente pela via intravenosa (IV). Objetivou-se avaliar os efeitos da metadona na antinocicepção, na atividade locomotora espontânea e na motilidade gastrointestinal de equinos tratados com metadona IV. Foram utilizados seis equinos adultos em um delineamento em blocos aleatorizados. Cada animal foi submetido a três tratamentos: salina (controle), metadona (0,2 mg/kg - MET0,2) e metadona (0,5 mg/kg - MET0,5) pela via IV, com intervalo mínimo de 1 semana entre cada tratamento. Foi avaliado o efeito antinociceptivo por meio da latência para o reflexo de retirada do membro (LRRM) com uma lâmpada de projeção de calor e voltagem para o reflexo de retirada do membro (VRRM) após estimulo elétrica (fase 1); atividade locomotora espontânea (ALE) em baias comportamentais por meio da interrupção de feixes de raios infravermelho (fase 2) e motilidade intestinal por meio de escores de auscultação (fase 3).As variáveis paramétricas foram analisadas pela ANOVA seguida pelos testes de Dunnett ou Tukey. Para a ALE e auscultação intestinal foi ajustado um modelo linear generalizado para medidas repetidas considerando o erro aleatório assumindo distribuição de Poisson e função de ligação log. As diferenças foram consideradas significantes quando p< 0.05. Para o estímulo nociceptivo elétrico não foram realizados os testes com a dose 0,5 mg/kg IV de metadona. No teste nociceptivo térmico, não houve aumento no tempo de LRRM no grupo MET0,2, no entanto, após a administração de 0,5 mg/kg... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract:Opioids are the most potent substances used for pain relief. However, these drugs are not widely used in horses, due to substantial sympathetic stimulation, excitement of the central nervous system and decreased of the gastrointestinal motility observed when opioids are administered intravenously. The effects of methadone on antinociception, spontaneous locomotor activity and gastrointestinal motility were investigates. Six adult horses were used in a randomized crossover design. Each animal was subjected to three treatments: saline (control), methadone (0.2 mg / kg - MET0.2) and methadone (0.5 mg / kg - MET0.5) intravenously (IV), within 1 week between each treatment. The antinociceptive effect was evaluated by the hoof- withdrawal reflex latency (HWRL) after painful stimulation with a heat lamp and voltage for the withdrawal reflex of the limb (VRRM) after electrical stimulation (phase 1). Spontaneous locomotor activity (SLA ) was investigated in a behavior box by use of infrared photoelectric sensors (phase 2) and gastrointestinal motility by abdominal auscultation (phase 3). Parametric variables were analyzed by ANOVA followed by Dunnett or Tukey test. For SLA and abdominal auscultation was fitted the generalized linear models with Poisson error and log link function for repeated data. Differences were considered significant when P <0.05.No electrical noxious stimulation test was performed with the dose of 0.5 mg/kg methadone IV. The HWRL did not increase in animals treated with MET0,2. However, after administration of 0.5 mg/kg of methadone IV, HWRL increased significantly at 15 and 30 minutes compared to baseline and control groups and MET0,2, rising from 3,21 seconds (average) to 8.61 and 9.11 seconds respectively (P <0.05). VRRM increased significantly from baseline at all... (Complete abstract click electronic access below) / Mestre
Evaluation multi-échelle de toxines de venins comme agents antinociceptifs potentiels / Multiscale evaluation of venom toxins as potential antinociceptive agentsGonçalves, Tânia Cristina 19 December 2018 (has links)
L’objectif de ma thèse était d’identifier, comme agents antinociceptifs potentiels, des toxines de venins originales par leur séquence et/ou leur provenance. Dans cette optique, un criblage à haut débit de deux banques de venins a été réalisé par des méthodes électrophysiologiques de "patch-clamp" automatique, sur des lignées cellulaires exprimant le sous-type neuronal hNaV1.7 de canaux sodium (versus celles exprimant le sous-type cardiaque hNaV1.5), une cible antidouleur validée génétiquement et fortement exprimée au niveau des neurones sensoriels primaires des ganglions de la racine dorsale, premier support de la transmission du message nociceptif.Le criblage de la première banque de venins (appartenant à Smartox Biotechnology) a permis l’identification et la caractérisation, par des approches structurales et fonctionnelles multi-échelles (de la cellule in vitro à l’organisme in vivo), de 2 peptides de venins d’araignées ayant des propriétés potentiellement antinociceptives : (1) la cyriotoxine-1a du venin de Cyriopagopus schioedtei, dont les propriétés fonctionnelles sont proches de celles des peptides appartenant à la famille 1 des toxines d’araignées inhibant les canaux sodium, et (2) la poecitoxine-1a du venin de Poecilotheria subfusca, qui présente une meilleure affinité pour le sous-type hCaV1.2 de canaux calcium que pour le sous-type hNaV1.7. Nous avons également mené une étude de "structure-activité" afin d’améliorer le profil de sélectivité de la phlotoxine-1 d’une araignée Phlogiellus, connue pour son activité antinocieptive. Finalement, nous avons mis en évidence une interaction directe entre l’huwentoxine-IV, déjà connue comme agent antinociceptif potentiel, et le sous-type neuronal NaV1.6, responsable d’effets neuromusculaires indésirables. Le criblage de la deuxième banque de venins (appartenant à SANOFI) a permis d’identifier des hits intéressants provenant de venins d’araignées et de scorpions non étudiés jusqu’à présent et ayant une séquence originale présentant peu d’homologie avec les séquences déjà connues. / The aim of my thesis was to identify original venom toxins, by their sequence and/or origin, as potential antinociceptive agents. In this context, a high-throughput screening of two venom libraries was performed, by automated patch-clamp electrophysiology, on cell lines expressing the hNaV1.7 neuronal subtype of sodium channels (versus those expressing the hNaV1.5 cardiac subtype), a genetically-validated and strongly expressed pain target in the primary sensory neurons of dorsal root ganglia, the first support of nociceptive message transmission.The screening of the first venom library (belonging to Smartox Biotechnology) allowed the identification and characterization, by structural and multiscale functional approaches (from the cell in vitro to the organism in vivo), of 2 peptides from spider venoms having potential antinociceptive properties : (1) cyriotoxin-1a from Cyriopagopus schioedtei venom, whose functional properties are close to those of peptides belonging to family 1 of spider toxins inhibiting sodium channels, and (2) poecitoxin-1a from Poecilotheria subfusca venom, which has a better affinity for the hCaV1.2 subtype of calcium channels than for the hNaV1.7 subtype. We also conducted a "structure-activity" study to improve the selectivity profile of phlotoxin-1 from a Phlogiellus spider, known for its antinociceptive activity. Finally, we evidenced a direct interaction between huwentoxin-IV, already known as a potential antinociceptive agent, and the NaV1.6 neuronal subtype which is the main cause of undesirable neuromuscular effects. The screening of the second venom library (belonging to SANOFI) allowed to identify interesting hits from spider and scorpion venoms, not studied until now, having an original sequence with little homology with already known sequences.
01 January 2011
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissus damage or described in terms of such damage. Opioids are effective in treating moderate to severe pain, but opioid alone therapy is associated with several adverse effects, development of tolerance and addiction potential. One way to solve these problems is to administer opioids with adjuvant drugs. In this project several opioid molecules were combined with other adjuvant drugs in a single chemical entity to form a codrug. A series of codrugs were prepared by conjugation of an opioid with S-(-)-nornicotine, ketamine, norketamine and gabapentin. Several of the synthesized codrugs were evaluated for analgesic activity in the rats after oral administration. Codeine-S-(-)- nornicotine, 3-O-acetylmorphine-S-(-)-nornicotine, and N-ethoxycarbonylgabapentincodeine codrugs showed greater effectiveness as well as prolonged pain management properties as compared to the parent drugs. Stabilities of several synthesized codrugs were studied in aqueous solutions from pH 1.3-7.4, in simulated gastrointestinal fluids, in rat plasma and in brain homogenate. Only the ester-linked codrugs showed sign of hydrolysis in different solutions. Carbamate-linked codrugs didn’t cleave under any hydrolytic condition. Pharmacokinetic study was performed on the following three codrugs: 3-O-acetylmorphine-S-(-)-nornicotine, N-acetylgabapentin-codeine, and N-ethoxycarbonylgabapentin- codeine. The carbamate linkage in 3-O-acetylmorphine-S-(-)- nornicotine codrug did not cleave in vivo to produce parent drugs. The ester linkage in N-acetylgabapentin- codeine codrug cleaved in vivo to produce codeine and N-acetylgabapentin, but N-acetylgabapentin did not undergo hydrolysis to produce gabapentin. The ester linkage in N-ethoxycarbonylgabapentin-codeine codrug hydrolyzed slowly in plasma to produce N-ethoxycarbonylgabapentin and codeine and then the carbamate linkage in N-ethoxycarbonylgabapentin hydrolyzed even slowly to produce gabapentin. Produced codeine also metabolized to generate some amount of morphine. Thus, the design and synthesis of an opiate and gabapentin codrug was achieved which was stable enough in the gastrointestinal tract, showed enhanced analgesic effects as compared to the physical mixture of the parent drugs, and also produced the two parent drugs in blood plasma.
Silva Júnior, José Ribamar da [UNESP]
18 December 2009
(has links) (PDF)
Made available in DSpace on 2014-06-11T19:31:11Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-12-18Bitstream added on 2014-06-13T19:20:15Z : No. of bitstreams: 1 silvajunior_jr_dr_jabo.pdf: 913369 bytes, checksum: 3bdbada76534ca341602e017a918fbd1 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Os efeitos antinociceptivos, comportamentais (atividade locomotora espontânea - ALE, altura de cabeça - AC) e sobre as variáveis fisiológicas de seis equinos tratados com tramadol, como agente analgésico preventivo, nas doses intravenosas de 2 (TT2), 3 (TT3) e 5 mg/kg (TT5), assim como da associação tramadol (3 mg/kg) e xilazina (0,5 mg/kg) (TTX) ou ainda da xilazina (0,5 mg/kg) isolada (TX) foram avaliados. Para ALE, diferenças (P<0,05) foram observadas entre os grupos TT2, TT3 e TT5, porém estas não foram significativas (P>0,05) entre esses e os grupos TTX e TX. Para a AC os grupos TTX e TX foram semelhantes sendo esses diferentes dos grupos tratados com tramadol isolado (P<0,05). Diferenças não foram observadas (P>0,05) quanto à ação antinociceptiva. No grupo TTX as variações nas frequências cardíaca e respiratória, pressão arterial sistólica e motilidade intestinal foram significativas (P<0,05). Pode-se concluir pelo exposto que, embora o tramadol isoladamente não promova alteração significativa no estado comportamental de equinos, não constitui um fármaco analgésico somático ao menos para o estímulo usado, e que a associação tramadol/xilazina, não constitui uma opção como associação, visando à sedação e à analgesia, principalmente quando for desejado incrementar, nas técnicas de anestesia, a antinocicepção somática preventiva. / Antinociceptive and behavioral effects (spontaneous locomotor activity [SLA] and head height [HH]) and effects on physiological parameters in six horses treated with tramadol as a preventive analgesic agent were assessed. Tramadol was administered at intravenous doses of 2 (TT2), 3 (TT3) and 5 mg/kg (TT5), as well as a combination of tramadol (3 mg/kg) and xylazine (0.5 mg/kg) (TTX) or xylazine alone (0.5 mg/kg) (TX). Differences in SLA (P<0.05) were seen in TT2, TT3, and TT5 groups but they were not statistically significant (P>0.05) between these groups and TTX and TX groups. TTX and TX groups showed similar HHs but there were differences of HH between TTX and TX and those groups treated with tramadol alone (P<0.05). However, no differences (P>0.05) were found regarding antinociceptive action. Significant changes (P<0.05) of heart and respiratory rates, systolic blood pressure, and intestinal motility were seen in TTX group. Although tramadol alone does not have a significant effect on horse behavior, it failed to produce analgesia and it has no somatic analgesic action to the stimulus studied. In conclusion, the combination of tramadol plus xylazine should be carefully prescribed to patients with prior cardiovascular and gastrointestinal conditions but it is not an adequate drug combination for sedation and analgesia, especially when anesthesia is intended to increase preventive somatic antinociception.
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