Th.--Méd.--Nancy 1, 1984. N°: 78.

Thesis (M.Sc.)--University of Adelaide, Dept. of Physiology and Pharmacology, 1973.

Thèse--Méd.--Reims, 1974. N°: N° 37. / Bibliogr. ff. I-VI.

Lanalgésie péridurale est la technique de référence en matière danalgésie obstétricale et les anesthésiques locaux constituent la pierre angulaire des mélanges analgésiques utilisés. Cependant, utilisés seuls, ils requièrent lutilisation de concentrations élevées responsables dun bloc moteur préjudiciable sur le plan du mode daccouchement et de la satisfaction maternelle. Lutilisation dun adjuvant permet de réduire les besoins en anesthésiques locaux et le bloc moteur qui y est associé. Parmi les adjuvants ayant fait la preuve de leur efficacité, les opiacés liposolubles (fentanyl et sufentanil) sont les plus couramment utilisés. La clonidine est aussi proposée dans cette indication de même que ladrénaline et plus récemment la néostigmine. Ces adjuvants présentent une efficacité dosedépendante. Il en va de même de leurs effets secondaires. A efficacité analgésique équivalente, le choix dun adjuvant devrait privilégier celui qui est responsable des effets secondaires maternels et/ou néonataux les moins délétères. Lobjectif de notre travail a été de contribuer à déterminer quel adjuvant aux anesthésiques locaux, du sufentanil ou de la clonidine, est le plus approprié, dans le contexte de lanalgésie obstétricale. Dans une première étude, menée de façon prospective et en double aveugle, les effets de ladjonction de 5 μg de sufentanil ou de 75 μg de clonidine sur la MLAC de la ropivacaïne sont évalués chez 78 parturientes en travail présentant une dilatation cervicale ≤ 5 cm. Ces patientes sont réparties de façon randomisée en trois groupes selon la nature du mélange analgésique administré par voie péridurale : ropivacaïne seule, ropivacaïne + 5 μg de sufentanil ou ropivacaïne + 75 μg de clonidine. La MLAC de la ropivacaïne administrée seule est calculée à 0,099% (95% CI : 0,090 0,109). En association avec 5 μg de sufentanil, la MLAC de la ropivacaïne est réduite à 0,036% (95% CI : 0,024 0,049) et avec 75 μg de clonidine, la MLAC de la ropivacaïne est réduite de façon équivalente à 0,036% (95% CI : 0,027 0,046) (p < 0.001). Le rapport de puissance entre la clonidine et le sufentanil sur le plan de lépargne en anesthésique local est de 15.1 (95% CI : 10,3 23,4). Des doses de 5 μg de sufentanil et de 75 μg de clonidine produisent donc la même réduction de la MLAC de la ropivacaïne. Ce résultat doit permettre dévaluer les effets secondaires de ces adjuvants administrés à des doses équipotentes. Cette évaluation est réalisée dans la deuxième partie de notre travail. Dans cette deuxième étude, menée de façon prospective et en double aveugle, les effets secondaires résultant de ladministration péridurale de solutions équianalgésiques composées de ropivacaïne 0,2% combinée soit, à 5 μg de sufentanil, soit à 75 μg de clonidine sont comparés chez 50 parturientes en travail, présentant une dilatation cervicale ≤ 5 cm. Ces patientes sont réparties de façon randomisée en deux groupes selon la nature du mélange analgésique administré pour instaurer lanalgésie péridurale : ropivacaïne 0,2% + sufentanil 5 μg (groupe RS) ou ropivacaïne 0,2% + clonidine 75 μg (groupe RC). Ultérieurement, lanalgésie est entretenue de façon similaire dans les 2 groupes à laide de ropivacaïne 0,2% sans adjuvant administrée selon le mode PCEA. La qualité de lanalgésie, la consommation de ropivacaïne, le mode daccouchement et le bien-être néonatal sont également comparés. Le délai dapparition et la durée de lanalgésie après ladministration péridurale du bolus initial sont similaires dans les deux groupes. La consommation de ropivacaïne, les scores de douleur et le niveau sensitif sont également identiques dans les deux groupes, de même que lincidence de bloc moteur, le mode daccouchement et les scores dApgar. Dans le groupe RC, 17 patientes sur 26 présentent une hypotension < 100 mmHg contre 6 sur 24 dans le groupe RS (P < 0,05). Cinq patientes dans le groupe RC présentent une hypotension < 90 mmHg contre aucune dans le groupe RS (P< 0,05). En conséquence, le nombre de patientes nécessitant ladministration déphédrine est significativement plus élevé dans le groupe RC que dans le groupe RS (11/26 vs 2 /24, P < 0,05). Ladministration intraveineuse de cristalloïdes est également plus élevée dans le groupe RC (1696 ± 583 ml vs 1264 ± 407 ml, P < 0,05). Dans le groupe RS lincidence de prurit modéré et ne nécessitant aucun traitement est significativement plus élevée que dans le groupe RC (6/24 vs 1/26, P < 0,05). Cette étude confirme donc le caractère équipotent de solutions combinant la ropivacaïne 0,2% avec soit 5 μg de sufentanil, soit 75 μg de clonidine. Administrée à dose équipotente, la clonidine ne procure aucun avantage par rapport au sufentanil lorsquon ladministre comme adjuvant à la ropivacaïne pour lanalgésie péridurale obstétricale. En revanche, la clonidine est associée à une incidence accrue dhypotension et de recours à léphédrine. A linverse du sufentanil, la clonidine ne peut donc pas être considérée comme un adjuvant utilisable en première intention et en routine dans le cadre de lanalgésie pour le travail. Sa place comme adjuvant de second choix, utilisable comme analgésique de secours, reste à préciser par des études appropriées.

The role of supraspinal, spinal and peripheral alpha-2 adrenoceptors in the regulation of gastrointestinal motility in mice was investigated using anatomically site specific administration of clonidine and adrenoceptor antagonists. Clonidine produced a dose-dependent inhibition of gastrointestinal transit when given by the i.c.v., i.th., or s.c. routes, and was most potent when given i.c.v. Yohimbine, an alpha-2 adrenoceptor antagonist, but not the alpha-1 antagonist prazosin, antagonized the antitransit effects of clonidine. Yohimbine was most potent in antagonizing i.c.v. clonidine; increased doses of the i.c.v. antagonist were required when the agonist was given s.c. After transection of the spinal cord, i.th. clonidine failed to produce an antitransit effect. Additionally, the i.c.v. potency of clonidine decreased approximately 7-fold in spinally-transected mice. The data suggest that the antitransit effects of clonidine occur through actions at alpha-2 adrenoceptors located at both supraspinal and peripheral sites.

Made available in DSpace on 2014-06-11T19:27:25Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-02-22Bitstream added on 2014-06-13T20:56:29Z : No. of bitstreams: 1 sisto_rka_me_botfm.pdf: 745882 bytes, checksum: 572ac4fa4785affeee08e0c89fedec4c (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Os agentes anticolinesterásicos (neostigmina), quando associados com agonistas de receptores alfa-2 adrenérgicos (clonidina) pela via espinhal, resultam sinergismo no que se refere à analgesia promovida em ratos, ovinos e humanos. Na presente pesquisa, formulou-se a hipótese de que a administração peridural de neostigmina potencializaria a redução da concentração alveolar mínima (CAM) do isoflurano proporcionada pela clonidina peridural em cães. Seis cadelas hígidas (14,9 ± 2,9 kg) foram anestesiadas com isoflurano em 3 ocasiões distintas, com intervalo de 7 dias. Durante as anestesias foi empregada a ventilação controlada a pressão para prevenção da hipercapnia (PaCO2 > 45 mmHg) e a temperatura esofágica foi mantida entre 37,5 a 38,5oC por meios de aquecimento artificiais. Em cada anestesia, os animais receberam aleatoriamente 1 de 3 tratamentos pela via peridural: neostigmina (10 μg/kg), clonidina (20 μg/kg), ou a associação clonidina (20 μg/kg) e neostigmina (10 μg/kg). A CAM do isoflurano, mensurada por meio de estimulação nociceptiva do membro pélvico (50 V, 50 Hz, 10 ms), foi registrada após 2 horas da indução da anestesia (CAM basal) e após 2,5 e 5 horas da administração dos tratamentos peridurais. Em um dos animais, tanto a clonidina como a clonidina/neostigmina resultou em elevação paradoxal da CAM (8-9 %). Nos demais animais estudados (n = 5), os valores de CAM basal (média ± desvio padrão) foram de 1,49 ± 0,26, 1,51 ± 0,23 e 1,49 ± 0,26 vol%, nos tratamentos clonidina, neostigmina e clonidina/neostigmina, respectivamente, não havendo diferença entre tratamentos. As reduções da CAM observadas após a administração peridural de neostigmina não foram significativas (p < 0,05) (reduções percentuais de 11 ± 5% e 8 ± 9% após 2,5 e 5 horas, respectivamente). Houve redução significativa da CAM após a administração peridural de... / Spinal administration of anticholinesterase drugs (neostigmine) in combination with alpha-2 adrenergic receptor agonists (clonidine) results in a synergistic analgesic effect in rats, sheep and humans. The hypothesis of the present study was that the epidural administration of neostigmine would enhance the isoflurane minimum alveolar concentration (MAC) reduction induced by the epidural injection of clonidine in dogs. Six healthy bitches (14,9 ± 2,0 kg ) were anesthetized with isoflurane on 3 distinct occasions, with 7 day intervals among experiments. During the anesthetic episodes, animals were maintained under pressure controlled ventilation to prevent hypercapnia (PaCO2 > 45 mmHg) and esophageal temperature was maintained between 37.5 and 38.5 oC by means of artificial heating devices. During each anesthetic, animals were randomly allocated to receive 1 of 3 epidural treatments: neostigmine (10 μg/kg), clonidine (20 μg/kg), or the combination of clonidine (20 μg/kg) and neostigmine (10 μg/kg). Isoflurane MAC, determined by means of electric stimulation of the pelvic limb (50 V, 50 Hz, 10 ms), was recorded 2 hours after induction of anesthesia (baseline MAC) and 2.5 and 5 hours after epidural injections. In 1 of the animals, clonidine and clonidine/neostigmine caused paradoxical increases in MAC (8-9 % increases). For the remaining animals (n = 5), baseline MAC values (mean ± standard deviation) were 1.49 ± 0.26, 1.51 ± 0.23 e 1.49 ± 0.26 vol%, in the clonidine, neostigmine, and clonidine/neostigmine treatments, respectively. Baseline MAC did not differ among treatments. The isoflurane MAC reductions recorded after epidural injection of neostigmine were not significant (p < 0.05) (percent reductions of 11 ± 5% and 8 ± 9% after 2.5 and 5 hours respectively). The MAC reductions observed after epidural injection of clonidine (35 ± 9% and 22 ± 14% after 2.5 and 5 hours, ... (Complete abstract click electronic access below)

Orientador: Francisco José Teixeira Neto / Banca: Eduardo Raposo Monteiro / Banca: Silvia Renata Gaido Cortopassi / Resumo: Os agentes anticolinesterásicos (neostigmina), quando associados com agonistas de receptores alfa-2 adrenérgicos (clonidina) pela via espinhal, resultam sinergismo no que se refere à analgesia promovida em ratos, ovinos e humanos. Na presente pesquisa, formulou-se a hipótese de que a administração peridural de neostigmina potencializaria a redução da concentração alveolar mínima (CAM) do isoflurano proporcionada pela clonidina peridural em cães. Seis cadelas hígidas (14,9 ± 2,9 kg) foram anestesiadas com isoflurano em 3 ocasiões distintas, com intervalo de 7 dias. Durante as anestesias foi empregada a ventilação controlada a pressão para prevenção da hipercapnia (PaCO2 > 45 mmHg) e a temperatura esofágica foi mantida entre 37,5 a 38,5oC por meios de aquecimento artificiais. Em cada anestesia, os animais receberam aleatoriamente 1 de 3 tratamentos pela via peridural: neostigmina (10 μg/kg), clonidina (20 μg/kg), ou a associação clonidina (20 μg/kg) e neostigmina (10 μg/kg). A CAM do isoflurano, mensurada por meio de estimulação nociceptiva do membro pélvico (50 V, 50 Hz, 10 ms), foi registrada após 2 horas da indução da anestesia (CAM basal) e após 2,5 e 5 horas da administração dos tratamentos peridurais. Em um dos animais, tanto a clonidina como a clonidina/neostigmina resultou em elevação paradoxal da CAM (8-9 %). Nos demais animais estudados (n = 5), os valores de CAM basal (média ± desvio padrão) foram de 1,49 ± 0,26, 1,51 ± 0,23 e 1,49 ± 0,26 vol%, nos tratamentos clonidina, neostigmina e clonidina/neostigmina, respectivamente, não havendo diferença entre tratamentos. As reduções da CAM observadas após a administração peridural de neostigmina não foram significativas (p < 0,05) (reduções percentuais de 11 ± 5% e 8 ± 9% após 2,5 e 5 horas, respectivamente). Houve redução significativa da CAM após a administração peridural de ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Spinal administration of anticholinesterase drugs (neostigmine) in combination with alpha-2 adrenergic receptor agonists (clonidine) results in a synergistic analgesic effect in rats, sheep and humans. The hypothesis of the present study was that the epidural administration of neostigmine would enhance the isoflurane minimum alveolar concentration (MAC) reduction induced by the epidural injection of clonidine in dogs. Six healthy bitches (14,9 ± 2,0 kg ) were anesthetized with isoflurane on 3 distinct occasions, with 7 day intervals among experiments. During the anesthetic episodes, animals were maintained under pressure controlled ventilation to prevent hypercapnia (PaCO2 > 45 mmHg) and esophageal temperature was maintained between 37.5 and 38.5 oC by means of artificial heating devices. During each anesthetic, animals were randomly allocated to receive 1 of 3 epidural treatments: neostigmine (10 μg/kg), clonidine (20 μg/kg), or the combination of clonidine (20 μg/kg) and neostigmine (10 μg/kg). Isoflurane MAC, determined by means of electric stimulation of the pelvic limb (50 V, 50 Hz, 10 ms), was recorded 2 hours after induction of anesthesia (baseline MAC) and 2.5 and 5 hours after epidural injections. In 1 of the animals, clonidine and clonidine/neostigmine caused paradoxical increases in MAC (8-9 % increases). For the remaining animals (n = 5), baseline MAC values (mean ± standard deviation) were 1.49 ± 0.26, 1.51 ± 0.23 e 1.49 ± 0.26 vol%, in the clonidine, neostigmine, and clonidine/neostigmine treatments, respectively. Baseline MAC did not differ among treatments. The isoflurane MAC reductions recorded after epidural injection of neostigmine were not significant (p < 0.05) (percent reductions of 11 ± 5% and 8 ± 9% after 2.5 and 5 hours respectively). The MAC reductions observed after epidural injection of clonidine (35 ± 9% and 22 ± 14% after 2.5 and 5 hours, ... (Complete abstract click electronic access below) / Mestre

Rapid eye movement sleep decreases between 10 and 30 days postnatally in the rat. The pedunculopontine nucleus is known to modulate waking and rapid eye movement sleep, and pedunculopontine nucleus neurons are thought to be hyperpolarized by noradrenergic input from the locus coeruleus. The goal of the study was to investigate the possibility that a change in α-2 adrenergic inhibition of pedunculopontine nucleus cells during this period could explain at least part of the developmental decrease in rapid eye movement sleep. We, therefore, recorded intracellularly in 12-21 day rat brainstem slices maintained in oxygenated artificial cerebrospinal fluid. Putative cholinergic vs. non-cholinergic pedunculopontine nucleus neurons were identified using nicotinamide adenine dinucleotide phosphate diaphorase histochemistry and intracellular injection of neurobiotin (Texas Red immunocytochemistry). Pedunculopontine nucleus neurons also were identified by intrinsic membrane properties, type I (low threshold spike), type II (A) and type III (A+low threshold spike), as previously described. Clonidine (20 μM) hyperpolarized most cholinergic and non-cholinergic pedunculopontine nucleus cells. This hyperpolarization decreased significantly in amplitude (mean±S.E.) from -6.8±1.0 mV at 12-13 days, to -3.0±0.7 mV at 20-21 days. However, much of these early effects (12-15 days) were indirect such that direct effects (tested following sodium channel blockade with tetrodotoxin (0.3 μM)) resulted in hyperpolarization averaging -3.4±0.5 mV, similar to that evident at 16-21 days. Non-cholinergic cells were less hyperpolarized than cholinergic cells at 12-13 days (-1.6±0.3 mV), but equally hyperpolarized at 20-21 days (-3.3±1.3 mV). In those cells tested, hyperpolarization was blocked by yohimbine, an α-2 adrenergic receptor antagonist (1.5 μM). These results suggest that the α-2 adrenergic receptor on cholinergic pedunculopontine nucleus neurons activated by clonidine may play only a modest role, if any, in the developmental decrease in rapid eye movement sleep. Clonidine blocked or reduced the hyperpolarization-activated inward cation conductance, so that its effects on the firing rate of a specific population of pedunculopontine nucleus neurons could be significant. In conclusion, the α-2 adrenergic input to pedunculopontine nucleus neurons appears to consistently modulate the firing rate of cholinergic and non-cholinergic pedunculopontine nucleus neurons, with important effects on the regulation of sleep-wake states.

Summary: The possible involvement of an adrenergic-endorphin system in the mediation of the pressor response to isometric muscular contraction was studied in cats. Fatiguing contractions of the gastrocnemius and plantaris muscles caused an increase in the mean arterial blood pressure by 35 to 70 mmHg. Intravenous infusion (30 μg·kg-1) as well as intracisternal injection (2.5 μg) of clonidine-HCl eliminated the pressor response to muscular contraction. In both sets of experiments, the mean blood pressure remained at the resting level throughout the duration of the isometric contraction. Injection of naloxone (0.5 μmol·litre-1) into the cisterna magna did not alter the resting blood pressure and did not affect the rise in mean arterial pressure during muscle contractions. Intracisternal injection of naloxone (0.5 μmol·litre-1) prior to an intracisternal injection of clonidine (2.5 μg) did not alter the resting blood pressure but effectively antagonised the anti-pressor effects of clonidine during fatiguing isometric contractions. These data may indicate that activation of muscle "ergoreceptor" afferents (group III and IV fibres) during muscular contraction may cause an increase in the arterial blood pressure by interfering with an inhibitory adrenergic-endorphinergic pathway in the brainstem.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.