RESUMEN
PURPOSE OF THE STUDY The study retrospectively reviews the outcomes of patella stabilisation surgeries performed at our department in the period 2010-2020. It aimed to provide a more thorough evaluation, to compare the respective types of MPFL reconstruction and to confirm the beneficial effect of tibial tubercle ventromedialization on patella height. MATERIAL AND METHODS In the period 2010-2020, a total of 72 stabilisation surgeries of patellofemoral joint in 60 patients with objective patellar instability (OPI) were performed at our department. The surgical treatment outcomes were evaluated retrospectively using a questionnaire, including the postoperative Kujala score. A comprehensive examination was carried out in 42 patients (70%) who had completed the questionnaire. In case of distal realignment, the TT-TG distance and a change in the InsallSalvati index which serve as an indication for surgery, were assessed. RESULTS Altogether 42 patients (70%) and 46 surgical interventions (64%) were evaluated. The follow-up period was 1-11 years, with the mean follow-up of 6.9 years. In the studied group of patients, only 1 case (2%) of new dislocation was seen, in 2 cases (4%) the patients reported a subluxation episode. The mean score using the school grades was 1.76. Thirty-eight patients (90%) were satisfied with the surgical outcome, 39 patients would undergo a surgery in case of identical problems with the other limb. The mean postoperative Kujala score was 76.8 points, range 28-100 points. The mean TT-TG distance in the studied group with the preoperative CT scan (33x) was 15.4 mm (12-30 mm). The mean TT-TG distance in the cases indicated for tibial tubercle transposition was 22.2 mm (15-30 mm). The mean Insall-Salvati index prior to the performance of tibial tubercle ventromedialization was 1.33 (1-1.74). Postoperatively, the index decreased by 0.11 on average (-0.00 to -0.26) to 1.22 (0.92-1.63). No infectious complications were presented in the studied group. DISCUSSION In patients with recurrent patellar dislocation, the instability is often times caused by pathomorphologic anomalies of the patellofemoral joint. In patients with clinically expressed patellar instability and physiological values of the TT-TG distance, an isolated proximal realignment is performed by medial patellofemoral ligament (MPFL) reconstruction. In the case of pathological values of the TT-TG distance, distal realignment is performed by tibial tubercle ventromedialization to achieve physiological values of the TT-TG distance. In the studied group, tibial tubercle ventromedialization helped decrease the Insall-Salvati index by 0.11 points on average. This has a positive side effect on the patella height, thus on increasing its stability in the femoral groove. In patients with both proximal and distal malalignment, a two-stage surgery is performed. In the isolated cases of severe instability or if symptoms of lateral patellar hyperpressure are present, musculus vastus medialis transfer or arthroscopic lateral release are performed as well. CONCLUSIONS When correctly indicated, proximal, distal realignment or their combination can bring very good functional outcomes with a low risk of recurrent dislocation and postoperative complications. The importance of MPFL reconstruction is confirmed by low incidence of recurrent dislocation in the group investigated in this study, namely when compared with studies referred to in this paper, in which the patients underwent patellar stabilisation using the Elmslie-Trillat procedure. Conversely, leaving the bone malalignment untreated during the isolated MPFL reconstruction increases the risk of its failure. Judging from the obtained results, tibial tubercle ventromedialization also has a positive effect on the patella height through its distalization. Provided the stabilisation procedure is correctly indicated and performed, the patients can get back to their normal activities, often even sports activities. Key words: objective patellar instability, patellar stabilisation, MPFL, tibial tubercle transposition.
Asunto(s)
Luxaciones Articulares , Inestabilidad de la Articulación , Luxación de la Rótula , Articulación Patelofemoral , Humanos , Articulación Patelofemoral/cirugía , Inestabilidad de la Articulación/cirugía , Luxación de la Rótula/cirugía , Estudios Retrospectivos , Ligamentos Articulares/cirugía , Tibia/cirugía , Resultado del Tratamiento , Rótula/cirugíaAsunto(s)
Educación Médica/métodos , Competencia Clínica/normas , Curriculum/normas , Humanos , Quebec , Enseñanza/métodosRESUMEN
To investigate the progression of cellular injury in a model of hippocampal epileptogenesis, we used two histochemical methods reported to specifically label injured neurons, the Dark Neuron stain and Fluoro-Jade. Pilocarpine was administered systemically (380mg/kg i.p.) to induce status epilepticus. The duration of status epilepticus was controlled to last 1h by stopping it with diazepam (4mg/kg i.p.). The progression of cellular damage was quantified at six specific time points following the initial pilocarpine-induced insult: 3h, 6h, 12h, 24h, one week, and three weeks. To assess, in parallel, neuronal loss in specific hippocampal regions throughout epileptogenesis, the neuronal nuclear protein NeuN was used as a specific marker of neurons. Results revealed a different time-dependent progression of Dark Neuron and Fluoro-Jade labelling following status epilepticus. A significantly greater proportion of silver-impregnated cells labelled by the Dark Neuron stain was quantified in the stratum radiatum and stratum pyramidale of CA1 at the early time point of 3h compared with the proportion of Fluoro-Jade labelling in adjacent sections. In contrast, the maximal staining with Fluoro-Jade appeared at a later stage during epileptogenesis (between 24h and one week), with a significantly greater proportion of neurons labelled compared to the Dark Neuron stain in the stratum radiatum of CA1, stratum pyramidale of CA1, stratum radiatum of CA3 and the polymorphic layer of the dentate gyrus. Neurons from control animals were not significantly labelled by either of the two staining methods. Interestingly, the increase in Fluoro-Jade labelling corresponded in time to neuron loss. The two stains therefore appear to highlight separate processes of neuronal damage. This finding indicates that distinct cellular events take place at different stages of epileptogenesis, which may differ considerably from the permanent changes observed in chronically epileptic tissue.
Asunto(s)
Colorantes Fluorescentes , Hipocampo/patología , Hipocampo/fisiopatología , Agonistas Muscarínicos/farmacología , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , Neuronas/metabolismo , Neuronas/patología , Pilocarpina/farmacología , Estado Epiléptico/patología , Estado Epiléptico/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Mapeo Encefálico , Recuento de Células , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Gliosis/inducido químicamente , Gliosis/patología , Gliosis/fisiopatología , Hipocampo/efectos de los fármacos , Masculino , Degeneración Nerviosa/inducido químicamente , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Estado Epiléptico/inducido químicamente , Factores de TiempoRESUMEN
The antiepileptic drug, gamma-vinyl GABA (GVG, vigabatrin), is an irreversible inhibitor of GABA-transaminase, the enzyme responsible for the breakdown of GABA. In hippocampal slices prepared from rats pretreated with either an anticonvulsant dose of GVG (1500 mg/kg) or saline, electrophysiological recordings were performed in order to examine the effects of GVG pretreatment on GABAergic neurotransmission. Although GVG had no effect on the effectiveness of GABA-mediated inhibition when elicited by a single stimulus, it reversed the activity-dependent depression of inhibition which is typically observed when inhibitory pathways are activated repetitively by a train of stimuli delivered at low frequency. Similarly, GVG pretreatment prevented the progressive decline in the amplitude of monosynaptic inhibitory postsynaptic potentials (IPSPs) during low-frequency stimulation of inhibitory interneurons. Thus, in slices from GVG pretreated rats, the amplitudes of both the fast and slow components of the last of a series of IPSPs evoked by a 5 Hz, 4 s train were maintained at 91.5 +/- 6.6% and 87.7 +/- 6.5%, respectively, compared to 61.1 +/- 3.9% and 57.1 +/- 5.0% in control slices. Finally, in slices from GVG pretreated rats, we observed a reduction in the ability of the GABA(B) receptor agonist, baclofen, to decrease the amplitude of monosynaptic inhibitory postsynaptic currents. These results suggest that GVG may produce its frequency-dependent actions by reducing the function of release regulating presynaptic GABA(B) autoreceptors. The frequency-dependent reinforcement of inhibition by GVG may importantly contribute to the anticonvulsant effectiveness of this compound.
Asunto(s)
Hipocampo/fisiología , Interneuronas/fisiología , Células Piramidales/fisiología , Vigabatrin/farmacología , Ácido gamma-Aminobutírico/fisiología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Animales , Anticonvulsivantes/farmacología , Estimulación Eléctrica , Potenciales Evocados/efectos de los fármacos , Potenciales Evocados/fisiología , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Masculino , Piperazinas/farmacología , Células Piramidales/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sinapsis/efectos de los fármacos , Sinapsis/fisiología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiologíaRESUMEN
The effects of the 7-aminobutyric acid (GABA) uptake blocker tiagabine on isolated inhibitory postsynaptic potentials (IPSPs) were examined in CA1 pyramidal cells of the rat hippocampal slice preparation. The IPSPs were elicited by either single stimuli or by high frequency (100 Hz, 200 ms) stimulation (HFS) of inhibitory interneurons. Bath applied tiagabine (20 microM) produced little or no increase in the amplitude of IPSPs evoked by low (30-50 microA) or high (200-400 microA) intensity single stimuli. Only the duration of IPSPs evoked by high intensity stimuli was substantially prolonged by tiagabine, the time integral of the hyperpolarizing response being increased 3.2-fold. HFS elicited much larger fast and slow IPSPs than a single stimulus. In addition, with increments in the intensity (80-550 microA) of HFS, a GABA(A) receptor-mediated depolarizing response of progressively larger amplitude appeared between, and overlapped with, the fast and slow hyperpolarizing components of the IPSP. Tiagabine application markedly increased the GABA-mediated responses evoked by both low and high intensity HFS. Increasing the intensity of HFS enhanced the drug effect. Thus, measurements of the time integral of evoked responses showed that with weak (60 microA) HFS, tiagabine caused a 3.6-fold increase in the area of hyperpolarization while, in contrast, with strong (530 microA) HFS, tiagabine produced a 13.5-fold increase in the depolarizing actions of GABA. Our results suggest that tiagabine, a therapeutically effective anticonvulsant, may paradoxically increase, through a GABA(A) receptor-mediated mechanism, neuronal depolarization during the high frequency discharge of neurons involved in epileptiform activity.
Asunto(s)
Anticonvulsivantes/farmacología , Antagonistas del GABA/farmacología , Ácidos Nipecóticos/farmacología , Sinapsis/fisiología , Ácido gamma-Aminobutírico/fisiología , Animales , Estimulación Eléctrica/métodos , Electrofisiología , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/fisiología , Técnicas In Vitro , Interneuronas/fisiología , Masculino , Inhibición Neural/fisiología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Transmisión Sináptica , Tiagabina , Ácido gamma-Aminobutírico/farmacocinéticaRESUMEN
Tiagabine is a potent GABA uptake inhibitor with demonstrated anticonvulsant activity. GABA uptake inhibitors are believed to produce their anticonvulsant effects by prolonging the postsynaptic actions of GABA, released during episodes of neuronal hyperexcitability. However, tiagabine has recently been reported to facilitate the depolarizing actions of GABA in the CNS of adult rats following the stimulation of inhibitory pathways at a frequency (100 Hz) intended to mimic interneuronal activation during epileptiform activity. In the present study, we performed extracellular and whole cell recordings from CA1 pyramidal neurons in rat hippocampal slices to examine the functional consequences of tiagabine-augmented GABA-mediated depolarizing responses. Orthodromic population spikes (PSs), elicited from the stratum radiatum, were inhibited following the activation of recurrent inhibitory pathways by antidromic conditioning stimulation of the alveus, which consisted of either a single stimulus or a train of stimuli delivered at high-frequency (100 Hz, 200 ms). The inhibition of orthodromic PSs produced by high-frequency conditioning stimulation (HFS), which was always of much greater strength and duration than that produced by a single conditioning stimulus, was greatly enhanced following the bath application of tiagabine (2-100 microM). Thus, in the presence of tiagabine (20 microM), orthodromic PSs, evoked 200 and 800 ms following HFS, were inhibited to 7.8 +/- 2.6% (mean +/- SE) and 34.4 +/- 18.5% of their unconditioned amplitudes compared with only 35.4 +/- 12.7% and 98.8 +/- 12.4% in control. Whole cell recordings revealed that the bath application of tiagabine (20 microM) either caused the appearance or greatly enhanced the amplitude of GABA-mediated depolarizing responses (DR). Excitatory postsynaptic potentials (EPSPs) evoked from stratum radiatum at time points that coincided with the DR were inhibited to below the threshold for action-potential firing. Independently of the stimulus intensity with which they were evoked, the charge transferred to the soma by excitatory postsynaptic currents (EPSCs), elicited in the presence of tiagabine (20 microM) during the large (1,428 +/- 331 pA) inward currents that underlie the DRs, was decreased on the average by 90.8 +/- 1.7%. Such inhibition occurred despite the presence of the GABAB receptor antagonist, CGP 52 432 (10 microM), indicating that GABAB heteroreceptors, located on glutamatergic terminals, do not mediate the observed reduction in the amplitude of excitatory postsynaptic responses. The present results suggest that despite facilitating the induction of GABA-mediated depolarizations, tiagabine application may nevertheless increase the effectiveness of synaptic inhibition during the synchronous high-frequency activation of inhibitory interneurons by enhanced shunting.
Asunto(s)
Anticonvulsivantes/farmacología , Agonistas del GABA/farmacología , Agonistas de Receptores de GABA-A , Ácidos Nipecóticos/farmacología , Animales , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Masculino , Potenciales de la Membrana/fisiología , Inhibición Neural , Células Piramidales/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , TiagabinaRESUMEN
The influence of synaptic activity on the depression of N-methyl-D-aspartate (NMDA) receptor mediated synaptic responses by the noncompetitive blocker dizocilpine and the competitive antagonist CPP (3-((R)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid) was examined in the rat hippocampal slice preparation. In slices superfused by a Mg(2+)-free medium, both drugs, dizocilpine (2 to 100 microM) and CPP (0.2 to 10 microM), applied by perfusion, depressed the NMDA receptor mediated secondary population spikes (PSs) in the CA1 pyramidal cell layer. Repetitive stimulation (0.2 Hz, 5 min) greatly enhanced the depression produced by dizocilpine but was without any effect on the depression produced by CPP. In slices superfused with a normal medium, dizocilpine applied locally by pressure ejection (100 microM, 380 pL. 1 s) coupled with high-frequency stimulation (100 Hz, 1 s) prevented the appearance of multiple PSs in the subsequent 90-min period of perfusion with a Mg(2+)-free medium but was ineffective when applied without concomitant stimulation. These results indicate that the synaptic NMDA receptor mediated responses, similar to responses evoked by exogenous NMDA agonists, are depressed by dizocilpine in a use-dependent manner.
Asunto(s)
Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Hipocampo/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Estimulación Eléctrica , Hipocampo/metabolismo , Masculino , Piperazinas/farmacología , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/efectos de los fármacosRESUMEN
The acute effects of gamma-vinyl-GABA (GVG) on GABAergic inhibition were investigated in the hippocampal slice preparation using the paired-pulse test of inhibition during extracellular recordings. Superfusion of GVG (100-500 microM) for 60 min resulted in a concentration-dependent decrease in GABAergic inhibition. Slices superfused with higher concentrations of GVG (0.5-1 mM) were hyperexcitable as demonstrated by the appearance of multiple spikes. Binding studies showed that GVG (1 mM) had no effect on the binding of [3H]flunitrazepam or [3H]TBOB and displaced no more than 15% of specific [3H]GABA binding, which indicates that GVG-induced disinhibition is not mediated through an action at the GABAA receptor complex. Consistent with this suggestion is the finding that GVG (500 microM) had little effect on the inhibition of the orthodromically evoked CA1 population spike produced by the GABAA receptor agonist muscimol (10 microM), whereas this inhibition was considerably attenuated by the GABAA receptor antagonist, bicuculline methiodide (5 microM). The results of this study suggest that the acute actions of GVG on the GABAergic neurotransmitter system are not involved in its anticonvulsant effect.
Asunto(s)
Hipocampo/metabolismo , Ácido gamma-Aminobutírico/análogos & derivados , Ácido gamma-Aminobutírico/metabolismo , Animales , Antagonistas del GABA/farmacología , Masculino , Ratas , Receptores de GABA/metabolismo , Vigabatrin , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
The effects of lidocaine on repetitive firing of the CA1 pyramidal cells were studied in the hippocampal slice preparation using conventional intracellular recording technique. The cells were activated by injecting depolarizing current through the recording microelectrode. Lidocaine (50 microM) diminished the repetitive firing and progressively reduced the maximal rate of rise of the successive action potentials. The firing produced by low currents was little affected but that produced by high currents was substantially depressed. The maximal rate of rise of successive action potentials produced by a train of short depolarizing pulses was also progressively reduced, especially at high frequency (100 Hz) of activation. These findings suggest that, in the hippocampal pyramidal cells, lidocaine causes a use-dependent depression of the Na+ current. This action may be responsible for the anticonvulsant effects of lidocaine since it occurred at a clinically relevant concentration.
Asunto(s)
Anticonvulsivantes/farmacología , Hipocampo/efectos de los fármacos , Lidocaína/farmacología , Células Piramidales/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Electrofisiología , Potenciales Evocados/efectos de los fármacos , Hipocampo/citología , Hipocampo/metabolismo , Técnicas In Vitro , Masculino , Células Piramidales/metabolismo , Ratas , Ratas Sprague-Dawley , Canales de Sodio/efectos de los fármacosRESUMEN
1. A single administration of the ganglion blocker, chlorisondamine (10 mg kg-1, s.c.) is known to produce a quasi-irreversible blockade of the central actions of nicotine in the rat. The mechanism of this persistent action is not known. It is also unclear whether chlorisondamine can block neuronal responses to excitatory amino acids and whether chronic blockade of nicotinic responses also occurs in the periphery. 2. Acute administration of chlorisondamine (10 mg kg-1, s.c.) to rats resulted in a blockade of central nicotinic effects (ataxia and prostration) when tested 1 to 14 days later, but caused no detectable cell death in tissue sections sampled throughout the rostrocaudal extent of the brain which were stained in order to reveal neuronal degeneration. 3. Long-term blockade of central nicotinic effects by chlorisondamine was not associated with significant alterations in the density (Bmax) of high-affinity [3H]-nicotine binding to forebrain cryostat-cut sections. 4. In cultured dissociated mesencephalic cells of the foetal rat, chlorisondamine and mecamylamine inhibited [3H]-dopamine release evoked by N-methyl-D-aspartate (NMDA, 10(-4) M), but only at high concentrations (IC50 approx. 600 and 70 microM, respectively). A high concentration of chlorisondamine (10(-3) M) had no effect on responses to quisqualate (10(-5) M) and only slightly reduced responses to kainate (10(-4) M). Mecamylamine (10(-3) M) was ineffective against both agonists. 5. In adult rat hippocampal slices, chlorisondamine depressed NMDA receptor-mediated synaptically-evoked field potentials, but again only at high concentrations (10(-4)-10(-3) M). Synaptic responses that were mediated by non-NMDA excitatory amino acid receptors were less affected. 6. In rat isolated superior cervical ganglion, electrically-evoked synaptic transmission was reduced 1 h after acute in vivo administration of chlorisondamine (0.1 mg kg-1, s.c.). However, in vivo administration of a higher dose (10 mg kg-1, s.c.) did not significantly affect ganglionic transmission when tested two weeks later, despite the continued presence of central nicotinic blockade.7. These results indicate that the persistent CNS nicotinic blockade by chlorisondamine is not accompanied by changes in nicotinic [3H]-nicotine binding site density or by neuronal degeneration in the brain; that at doses sufficient to produce nicotinic receptor blockade, chlorisondamine acts in a pharmacologically selective manner; and that chronic central blockade is not accompanied by long-term peripheral ganglionic blockade.
Asunto(s)
Química Encefálica/efectos de los fármacos , Clorisondamina/farmacología , Ganglios Autónomos/efectos de los fármacos , Nicotina/antagonistas & inhibidores , Aminoácidos/farmacología , Animales , Conducta Animal/efectos de los fármacos , Células Cultivadas , Bloqueadores Ganglionares/farmacología , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Masculino , Degeneración Nerviosa , Nicotina/farmacocinética , Antagonistas Nicotínicos , Ratas , Ratas Sprague-Dawley , Ganglio Cervical Superior/efectos de los fármacos , Sinapsis/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacosRESUMEN
The effects of GABA uptake inhibitors, SKF 89976A and SKF 100330A, on recurrent inhibition were studied in the rat hippocampal slice preparation by the antidromic-orthodromic stimulation test. Population spikes evoked orthodromically by stimulation of the stratum radiatum and recorded in the CA1 pyramidal cell body layer were inhibited antidromically by stimulation of the alveus by a single pulse or by a train of pulses, either at low or at high frequency. Low frequency train conditioning produced less inhibition than a single pulse. The uptake blockers had no effect or slightly enhanced the inhibition produced by single stimuli or low frequency trains. High frequency train conditioning produced more and much longer inhibition than a single pulse. This inhibition was further substantially enhanced and prolonged by the drugs. Frequency-dependent enhancement of inhibition may be responsible for suppression of epileptiform discharges by GABA uptake blockers.
Asunto(s)
Anticonvulsivantes/farmacología , Antagonistas del GABA , Hipocampo/fisiología , Ácidos Nicotínicos/farmacología , Ácidos Nipecóticos/farmacología , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Potenciales Evocados/efectos de los fármacos , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Masculino , Tractos Piramidales/efectos de los fármacos , Tractos Piramidales/fisiología , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
To lessen fact overload and to enhance the teaching of pharmacologic principles in an undergraduate course we introduced a tutorial/essay project into our traditional lecture-based course. Under the guidance of a faculty tutor, each student researched an assigned topic, developed a paper incorporating the results of the literature review and his or her own attitudes and formally discussed and answered questions on the topic with the tutor. Students and tutors were enthusiastic about this learning experience especially in that it required independent student-centred activity, provided opportunity for useful student/tutor interaction and helped students to learn to integrate scientific information with their own thoughts and ideas.
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Educación de Pregrado en Medicina , Farmacología/educación , Curriculum , HumanosRESUMEN
The effects of the competitive NMDA (N-methyl-D-aspartate) receptor antagonist, APV (2-amino-5-phosphonopentanoate; AP5), were examined in the hippocampal slice preparation. APV (50-100 microM) attenuated inhibition of the orthodromically evoked population spikes in the CA1 region produced by a conditioning stimulus to the alveus or to the stratum radiatum. This suggests that NMDA receptors contribute to synaptic activation of the inhibitory interneurons by a single afferent volley.
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2-Amino-5-fosfonovalerato/farmacología , Hipocampo/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/fisiología , Potenciales de Acción/efectos de los fármacos , Animales , Hipocampo/fisiología , Técnicas In Vitro , Magnesio/farmacología , Masculino , Ratas , Ratas Endogámicas , Receptores de N-Metil-D-Aspartato/efectos de los fármacosRESUMEN
The effects of phencyclidine and the dioxolane enantiomers, dexoxadrol and levoxadrol, on long-term potentiation in the hippocampus were compared. Field potentials were evoked by stimulation of Schaffer collaterals and recorded from the CA1 region. Long-term potentiation was induced by stimulation with a single train of 25 pulses at 50 Hz. The drugs were delivered by pressure, 1 min before tetanization. Phencyclidine and its receptors ligand, dexoxadrol, abolished the induction of long-term potentiation. Levoxadrol which has very low affinity for the phencyclidine receptor was devoid of this action although it reduced the magnitude of long-term potentiation. These results indicate that phencyclidine blocks long-term potentiation by stereospecific activation of phencyclidine receptors.
Asunto(s)
Hipocampo/efectos de los fármacos , Fenciclidina/farmacología , Receptores de Neurotransmisores/efectos de los fármacos , Analgésicos/farmacología , Animales , Dioxolanos/farmacología , Potenciales Evocados/efectos de los fármacos , Masculino , Piperidinas/farmacología , Ratas , Ratas Endogámicas , Receptores de FenciclidinaRESUMEN
In a period of five years in the diabetes intervention study (DIS), 1,139 diabetics aged 30-55 years, who in a 6-week screening phase had been classified as dietetically manageable, were treated in a controlled randomized study with intensified non-medicamentous basic therapy and--in a double blind trial--with 1,6 g clofibric acid. The essential components of the basic therapy were a fat-modified diet (so-called prudent diet) and recommendations for endurance training. Thus in comparison to the control group we succeeded in performing a ca. 40% decrease of the application of oral antidiabetic drugs. The fasting blood values were, nevertheless, with 155 mg% significantly lower than in the control group (169 mg%). Clofibric acid had no influence neither on the necessity to use insulin or oral antidiabetic drugs nor to the control of glycaemia.
Asunto(s)
Clofibrato/análogos & derivados , Ácido Clofíbrico/administración & dosificación , Diabetes Mellitus Tipo 2/rehabilitación , Modalidades de Fisioterapia/métodos , Ensayos Clínicos como Asunto , Terapia Combinada , Dieta para Diabéticos , Grasas de la Dieta/administración & dosificación , Fibras de la Dieta/administración & dosificación , Método Doble Ciego , Ejercicio Físico , Humanos , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Distribución AleatoriaRESUMEN
The effects of phencyclidine (PCP) and two dioxolane stereoisomers, dexoxadrol and levoxadrol, on hippocampal inhibition were compared. Field potentials were recorded in the CA1 pyramidal cell layer in the rat hippocampal slices in vitro. Recurrent inhibition of the population spikes evoked orthodromically by stimulation of the Schaffer collaterals was induced by antidromic conditioning stimulation at appropriate time intervals before the orthodromic stimulation. The drugs were applied by micropressure ejection in concentrations which did not affect the unconditioned population spike. After PCP or dexoxadrol administration, the orthodromically evoked population spike was much less reduced by the antidromic conditioning stimulation than before, suggesting that the recurrent inhibition was diminished. Levoxadrol had only negligible effect. Since dexoxadrol has many PCP-like pharmacological properties but levoxadrol does not, we concluded that PCP attenuates hippocampal recurrent inhibition by activating the PCP receptors. It is suggested that this action results in depression of excitatory synaptic transmission from axon collaterals to the inhibitory interneuron with possible involvement of the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor.
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Hipocampo/efectos de los fármacos , Fenciclidina/farmacología , Receptores de Neurotransmisores/metabolismo , Analgésicos/farmacología , Animales , Dioxolanos/farmacología , Técnicas In Vitro , Masculino , Piperidinas/farmacología , Presión , Ratas , Ratas Endogámicas , Receptores de FenciclidinaRESUMEN
In the hippocampal slice preparation, perfusion with benzyl penicillin evokes multiple population spikes and spontaneous discharges. Doses of 0.25 to 2 mM of the drug produced this effect within 20-40 min. Cleavage products and analogues of benzyl penicillin, penicilloic acid, 6-aminopenicillanic acid, cephalexin, thioproline and penicillamine, were devoid of such action. It is concluded that the structural requirements for epileptogenic action of penicillin include not only the beta-lactam ring and side chain substitution on C-6, but also the thiazolidine ring.
Asunto(s)
Epilepsia/inducido químicamente , Penicilinas/farmacología , Animales , Estimulación Eléctrica , Potenciales Evocados/efectos de los fármacos , Hipocampo/efectos de los fármacos , Masculino , Penicilina G/análogos & derivados , Penicilina G/farmacología , Ratas , Ratas Endogámicas , Relación Estructura-ActividadRESUMEN
Clonazepam (0.5 mg/kg, i.v.) changed the characteristic pattern of the exponential decline of the monosynaptic responses, the early tetanic rundown, evoked by trains of 10 stimuli (2, 5 or 10 Hz) applied to either the biceps-semitendinosus or triceps surae nerve, and recorded from the ventral root in spinal cats. In the case of the biceps-semitendinosus, clonazepam did not affect the first monosynaptic response or the last five monosynaptic responses forming the plateau, while the second monosynaptic response was markedly depressed, especially at the higher frequencies tested. The triceps surae reacted differently to the administration of clonazepam, in that the first response was increased and the amount of depression of the second response was lessened, with no change of the plateau. All the effects of clonazepam were reversed by the benzodiazepine antagonist, ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate (Ro15-1788; 5 mg/kg, i.v.), which alone had no effect of its own on any parameters, suggesting that the effects of clonazepam were mediated by central benzodiazepine receptors. Diazepam (1.0 mg/kg, i.v.), caused the same changes in the homosynaptic depression of the biceps-semitendinosus pathway as did clonazepam, but increased the plateau instead of the second response in that of the triceps surae pathway.
Asunto(s)
Benzodiazepinonas/farmacología , Clonazepam/farmacología , Diazepam/farmacología , Receptores de GABA-A/efectos de los fármacos , Reflejo de Estiramiento/efectos de los fármacos , Raíces Nerviosas Espinales/efectos de los fármacos , Animales , Gatos , Femenino , Flumazenil , Masculino , Reflejo Monosináptico/efectos de los fármacos , Raíces Nerviosas Espinales/fisiología , Sinapsis/efectos de los fármacosRESUMEN
Spinal monosynaptic responses, evoked by repetitive stimulation, undergo homosynaptic depression the pattern of which is altered by 0.5 mg/kg of clonazepam. The dependence of this effect of clonazepam on the GABAergic system was examined in spinal unanaesthetized cats. Topical application of bicuculline to the spinal cord did not change any feature of the homosynaptic depression in the biceps-semitendinosus (BST) or triceps surae (TS) monosynaptic pathway but antagonized the action of clonazepam. Semicarbazide (200 mg/kg, i.v.) also prevented the effect of the benzodiazepine but alone had actions of its own. Evidence is presented that clonazepam influenced homosynaptic depression of the biceps-semitendinosus pathway by lengthening the primary afferent depolarization (PAD). This prolongation of the primary afferent depolarization did not last for the entire duration of the train as primary afferent depolarization also underwent depression. Therefore later responses in the train were unaffected by clonazepam. Homosynaptic depression of the triceps surae pathway was not similarly affected because activation of triceps surae afferents does not cause significant depolarization of its own afferents. It is suggested that the enhancement of GABAergic transmission at least partially underlies the effect of clonazepam on homosynaptic depression.
Asunto(s)
Médula Espinal/fisiología , Ácido gamma-Aminobutírico/fisiología , Animales , Bicuculina/farmacología , Gatos , Clonazepam/farmacología , Reflejo Monosináptico/efectos de los fármacos , Semicarbacidas/farmacología , Transmisión Sináptica/efectos de los fármacosRESUMEN
Effects of ammonia on excitatory synaptic transmission were studied in the rat hippocampal slice preparation. Population spikes, elicited by orthodromic or antidromic stimulation, were recorded in the cell body layer of the CA1, CA3 and dentate regions. Perfusion with 5 mM ammonium chloride induced a profound and reversible depression of orthodromically evoked population spikes in all three regions. Antidromic population spikes were not depressed in any of the regions, indicating that neither axonal conduction nor electrical excitability were affected by ammonia. The paired-pulse test revealed a transient disinhibition during the early phase of perfusion. Iontophoretic application of glutamate evoked unit firing even when the synaptically evoked responses were reduced by ammonia, indicating that the postsynaptic sensitivity to the putative transmitter was not depressed. Depression of release of the excitatory transmitter, probably because of depletion following the block of transmitter synthesis, is the likely explanation of these findings. It is suggested that ammonia-induced depression of excitatory transmission may account for coma and other symptoms of central nervous system depression encountered in hyperammonemic states.