RESUMEN
Canine urothelial carcinoma (UC) initially responds favorably to treatment, but is ultimately lethal in most cases. Research to identify modifiable risk factors to prevent the cancer is essential. The high breed-associated risk for UC, e.g. 20-fold higher in Scottish terriers, can facilitate this research. The objective was to identify environmental and host factors associated with UC in a cohort of Scottish terriers. Information was obtained through dog owner questionnaires for 120 Scottish terriers ≥ 6 years old participating in a bladder cancer screening study, with comparisons made between dogs that did or did not develop UC during the 3 years of screening. Univariable models were constructed, and variables with P < 0.20 were included when building the multivariable model, and then removed using a backward stepwise procedure. P < 0.05 was considered statistically significant. Urine cotinine concentrations were measured by liquid chromatography-mass spectrometry to further investigate potential cigarette smoke exposure. Biopsy-confirmed UC which was found in 32 of 120 dogs, was significantly associated with the dogs living in a household with cigarette smokers (odds ratio [OR], 6.34; 95 % confidence intervals [CI], 1.16-34.69; P = 0.033), living within a mile of a marsh or wetland (OR, 21.23; 95 % CI, 3.64-123.69; P = 0.001), and history of previous bladder infections (OR, 3.87; 95 % CI, 1.0-14.98; P = 0.050). UC was diagnosed in 18 of 51 dogs (35.3 %) with quantifiable cotinine concentrations, and six of 40 dogs (15.0 %) without quantifiable cotinine concentrations in their urine (P = 0.0165). In conclusion, the main modifiable risk factor for UC in this cohort of dogs was exposure to second-hand tobacco smoke.
Asunto(s)
Carcinoma de Células Transicionales , Fumar Cigarrillos , Enfermedades de los Perros , Neoplasias de la Vejiga Urinaria , Perros , Animales , Neoplasias de la Vejiga Urinaria/epidemiología , Neoplasias de la Vejiga Urinaria/etiología , Neoplasias de la Vejiga Urinaria/veterinaria , Carcinoma de Células Transicionales/epidemiología , Carcinoma de Células Transicionales/etiología , Carcinoma de Células Transicionales/veterinaria , Estudios de Cohortes , Cotinina , Escocia/epidemiología , Enfermedades de los Perros/epidemiología , Enfermedades de los Perros/etiologíaRESUMEN
We present results of a randomized, controlled, efficacy trial of a handbook intervention for parents of first-year college students. The aim of the interactive intervention was to decrease risk behaviors by increasing family protective factors. The handbook, based in self-determination theory and the social development model, provided evidence-based and developmentally targeted suggestions for parents to engage with their students in activities designed to support successful adjustment to college. We recruited 919 parent-student dyads from incoming students enrolled at a university in the U.S. Pacific Northwest and randomly assigned them to control and intervention conditions. We sent handbooks to intervention parents in June before students' August matriculation. Research assistants trained in motivational interviewing contacted parents to encourage use of the handbook. Control parents and students received treatment as usual. Participants completed baseline surveys during their final semester in high school (time 1) and their first semester at college (time 2). Self-reported frequency of alcohol, cannabis, and simultaneous use increased across both handbook and control students. In intent-to-treat analyses, odds of increased use were consistently lower and of similar magnitude for students in the intervention condition than in the control condition, and odds of first-time use were also lower in the intervention condition. Contact from research assistants predicted parents' engagement, and parent and student report of active engagement with handbook predicted lower substance use among intervention than control students across the transition to college. We developed a low-cost, theory-based handbook to help parents support their young adult children as they transition to independent college life. Students whose parents used the handbook were less likely to initiate or increase substance use than students in the control condition during their first semester in college.ClinicalTrials.gov Identifier: NCT03227809.
Asunto(s)
Estudiantes , Trastornos Relacionados con Sustancias , Adulto Joven , Humanos , Instituciones Académicas , Universidades , Padres , Trastornos Relacionados con Sustancias/prevención & controlRESUMEN
Flunixin meglumine (FM) is a commonly used Nonsteroidal anti-inflammatory drug (NSAID) in horses, but clinical efficacy is often unsatisfactory. Ketorolac tromethamine (KT) demonstrates superior efficacy compared to other NSAIDs in humans, but its anti-inflammatory effects have not been investigated in the horse. Safety of repeated dosing of KT has not been evaluated. The first objective was to conduct a dose determination study to verify that a previously described dosage of KT would inhibit Lipopolysaccharide (LPS)-induced eicosanoid production in vitro, and to compare KT effects of this inhibition to those of FM. Then, a randomized crossover study was performed using nine healthy horses to evaluate plasma concentrations of KT and FM following IV administration. Administered dosages of KT and FM were 0.5 mg/kg and 1.1 mg/kg, respectively. Safety following six repeated doses of KT was assessed. Ketorolac tromethamine and FM suppressed LPS-induced Thromboxane B2 (TXB2 ) and Prostaglandin E2 (PGE2 ) production in vitro for up to 12 hr. Intravenous administration produced plasma concentrations of KT and FM similar to previous reports. No adverse effects were observed. A KT dosage of 0.5 mg/kg IV inhibited LPS-induced eicosanoids in vitro, and repeated dosing for up to 3 days appears safe in healthy horses. Investigation of in vivo anti-inflammatory and analgesic effects of KT is warranted.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Ketorolaco Trometamina/administración & dosificación , Lipopolisacáridos/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacología , Clonixina/administración & dosificación , Clonixina/efectos adversos , Clonixina/análogos & derivados , Clonixina/sangre , Clonixina/farmacología , Femenino , Caballos , Técnicas In Vitro , Infusiones Intravenosas/veterinaria , Ketorolaco Trometamina/efectos adversos , Ketorolaco Trometamina/sangre , Ketorolaco Trometamina/farmacología , MasculinoRESUMEN
Nonsteroidal anti-inflammatory drugs (NSAIDs) are an integral component of equine analgesia, yet currently available NSAIDs are both limited in their analgesic efficacy and have adverse effects. The NSAID ketorolac tromethamine (KT) is widely used in humans as a potent morphine-sparing analgesic drug but has not been fully evaluated in horses. The purpose of this study was to determine the pharmacokinetic profile of KT in horses after intravenous (i.v.), intramuscular (i.m.), and oral (p.o.) administration. Nine healthy adult horses received a single 0.5-mg/kg dose of KT via each route of administration. Plasma was collected up to 48 h postadministration and analyzed for KT concentration using HPLC/MS/MS. Noncompartmental analysis of i.v. dosage indicated a mean plasma clearance of 8.4 (mL/min)/kg and an estimated mean volume of distribution at steady-state of 0.77 L/kg. Noncompartmental analysis of i.v., i.m., and p.o. dosages indicated mean residence times of 2.0, 2.6, and 7.1 h, respectively. The drug was rapidly absorbed after i.m. and p.o. administration, and mean bioavailability was 71% and 57% for i.m. and p.o. administration, respectively. Adverse effects were not observed after i.v., i.m., and p.o. administration. More studies are needed to evaluate the analgesic and anti-inflammatory properties of KT in horses.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Caballos/sangre , Ketorolaco Trometamina/farmacocinética , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Estudios Cruzados , Vías de Administración de Medicamentos , Femenino , Ketorolaco Trometamina/administración & dosificación , MasculinoRESUMEN
BACKGROUND: Local anaesthetic agents are commonly encountered in the Emergency Department (ED). Local anaesthetic toxicity leading to cardiorespiratory arrest is a rare, but potentially fatal, complication of an overdose of these agents. A recent innovation in the treatment of severe local anaesthetic toxicity has been the introduction of intravenous lipid emulsion therapy (Intralipid 20%). The aim of this study was to gauge the current level of knowledge surrounding the administration and complications associated with commonly used local anaesthetic agents. METHODS: Questionnaires were distributed amongst the training grade doctors working in four Emergency Departments. Results were divided into two groups for ease of analysis. Core Trainees (CT) and Foundation Year 2 (F2) doctors were placed in one group. Specialist Registrars (SPR), Speciality Registrars (StR) and Staff Grades (SG) form the other group. RESULTS: The results showed that less than half of the CT/F2 group knew the maximum dose of lignocaine 1%. 80% of these doctors were unable to calculate the maximum dose of lignocaine 1% for an 80 kg man, and nearly one-third would administer a toxic dose. In addition, only one out of 30 in the CT/F2 group were aware of lipid emulsion therapy. CONCLUSIONS: Those using local anaesthetic should also be able to recognise the signs and symptoms of toxicity should this occur and act accordingly. The lack of knowledge amongst the more junior staff, as demonstrated by this project, highlights failings in teaching the basics of safe practices in the ED.
Asunto(s)
Anestesiología/educación , Anestésicos Locales/administración & dosificación , Competencia Clínica , Servicio de Urgencia en Hospital/normas , Lidocaína/administración & dosificación , Anestésicos Locales/efectos adversos , Educación Médica Continua , Paro Cardíaco/inducido químicamente , Paro Cardíaco/terapia , Humanos , Internado y Residencia , Lidocaína/efectos adversos , Cuerpo Médico de Hospitales , Mal Uso de Medicamentos de Venta con Receta , Encuestas y Cuestionarios , Reino UnidoRESUMEN
Military trauma produces predominantly blast and fragmentation injury, commonly resulting in haemorrhagic shock. Injury patterns to limbs are such that the conventional sites for venous cannulation may be unsuitable. The EZ-IO (Vidacare, San Antonio) system is one of a number of novel products designed for intraosseous (IO) access in adults or children. In three months of combat casualty care in Helmand Province, Afghanistan, the UK Defence Medical Services used EZ-IO for emergency vascular access on 26 patients (16 adults; 10 children). 23/26 patients had IO access obtained in the emergency department; 3/26 had pre-hospital IO access within a tactically flying helicopter. A total of 32 needles were inserted, with 97% effective function. IO needles were used to administer fluid (crystalloid, packed red cells and fresh frozen plasma) and drugs (analgesics, cardiac arrest drugs, antibiotics, drugs for both rapid sequence induction and maintenance of anaesthesia). No complication of infection was noted, but pain was observed in responsive patients with the pain of infusion exceeding that of the underlying injuries in 3 cases.
Asunto(s)
Traumatismos por Explosión/terapia , Infusiones Intraóseas/métodos , Medicina Militar , Personal Militar , Resucitación/métodos , Choque Hemorrágico/terapia , Guerra , Heridas y Lesiones/terapia , Escala Resumida de Traumatismos , Adolescente , Adulto , Afganistán , Niño , Preescolar , Servicios Médicos de Urgencia , Femenino , Humanos , Infusiones Intraóseas/instrumentación , Masculino , Estudios Retrospectivos , Reino UnidoRESUMEN
This case is of an 8-year-old child who had a cardiac arrest and an Emergency Department thoracotomy (EDT) following a penetrating fragmentation injury to the chest. The management included damage control resuscitation, recombinant Factor VIIa and a successful emergency department thoracotomy.
Asunto(s)
Reanimación Cardiopulmonar , Medicina Militar , Personal Militar , Traumatismos Torácicos/cirugía , Guerra , Heridas Penetrantes/cirugía , Niño , Protección a la Infancia , Femenino , Humanos , Masculino , Reino UnidoRESUMEN
A series of 6-(alkylamino)-9-alkylpurines was synthesized and evaluated for the property of antagonizing the behavioral effects in animals of the dopamine agonist apomorphine. This model for identifying potential antipsychotic agents is based on the hypothesis that agents that antagonize apomorphine-induced aggressive behavior in rats and apomorphine-induced climbing in mice, but that do not block stereotyped behavior, could have an antipsychotic effect in humans without producing extrapyramidal side effects. The antiaggressive-behavior activity of lead compound 1 (6-(dimethylamino)-9-(3-phenylalaninamidobenzyl)-9H-purine) was improved 48-fold with 6-(cyclopropylamino)-9-(cyclopropylmethyl)-2-(trifluoromethyl)-9H- purine (80) (po ED50 of 2 mg/kg), which was obtained through an iterative sequence of structure--activity relationship studies that encompassed evaluation of the effects of structure variations at the purine 9-, 6-, and 2-positions. Potency was enhanced with a 9-cyclopropyl group, the duration of action was improved with the 6-(cyclopropylamino) substituent, potency was further enhanced with an N-formyl prodrug, and an agent with reduced cardiovascular effect emerged with the 2-trifluoromethyl purine 80. This potential antipsychotic agent was not developed further due to undesirable effects on the stomach.
Asunto(s)
Antipsicóticos/síntesis química , Purinas/síntesis química , Agresión/efectos de los fármacos , Alquilación , Animales , Antipsicóticos/farmacología , Apomorfina/farmacología , Carbazoles/síntesis química , Carbazoles/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dimetilaminas/síntesis química , Dimetilaminas/farmacología , Vaciamiento Gástrico/efectos de los fármacos , Dosificación Letal Mediana , Ratones , Modelos Químicos , Purinas/farmacología , Ratas , Espectrofotometría Ultravioleta , Relación Estructura-ActividadRESUMEN
BACKGROUND AND PURPOSE: Lamotrigine (LTG) is an anticonvulsant drug whose mechanism of action may involve the inhibition of glutamate release by blocking voltage-dependent sodium channels. Glutamate neurotoxicity may contribute to cerebral ischemic damage after recovery from cardiac arrest. Thus, LTG may prevent the brain damage associated with global cerebral ischemia by reducing the release of glutamate from presynaptic vesicles during the ischemic insult or the early recovery period. METHODS: LTG was studied in cardiac arrest-induced global cerebral ischemia with reperfusion in rats. In the first set of experiments, LTG (100 mg/kg, p.o.) was administered before induction of ischemia; and in the second experiment, LTG (10 mg/kg, i.v.) was given 15 minutes after ischemia and a second dose (10 mg/kg,i.v.) was given 5 hours later. RESULTS: In both experiments LTG reduced the damage to the hippocampal CA1 cell population by greater than 50%. Neuroprotection was not associated with changes in brain temperature or plasma glucose concentration. Plasma concentrations of LTG ranged between 8 and 13 micrograms/mL. Patients taking LTG as a monotherapy for epilepsy typically have plasma levels of LTG in the 10 to 15 micrograms/mL range. CONCLUSIONS: These data suggest that LTG may be effective in preventing brain damage after recovery from cardiac arrest. Patients on LTG monotherapy for epilepsy have plasma concentrations very similar to those found to be neuroprotective in this study. Although difficult to extrapolate, our data suggest that LTG at neuroprotective doses may be well tolerated by humans.
Asunto(s)
Anticonvulsivantes/farmacología , Isquemia Encefálica/etiología , Isquemia Encefálica/patología , Paro Cardíaco/complicaciones , Hipocampo/efectos de los fármacos , Hipocampo/patología , Fármacos Neuroprotectores/farmacología , Triazinas/farmacología , Animales , Encéfalo/metabolismo , Lamotrigina , Concentración Osmolar , Ratas , Ratas Endogámicas F344 , Triazinas/sangre , Triazinas/metabolismoRESUMEN
11192U90 was submitted to receptor binding and monoamine uptake assays. It bound potently at serotonin 5-HT2, dopaminergic D2, serotonin 5-HT1A, and adrenergic alpha 1 and alpha 2 receptors. It also bound to dopaminergic D1, serotonin 5-HT3, serotonin 5-HT4, and sigma sites, albeit with lower affinity. It was essentially inactive at 22 other sites, including those for cholinergic M1 and M2. It weakly inhibited uptake of 3H-norepinephrine, 3H-serotonin and 3H-dopamine. Acute doses of 1192U90 (5 and 20 mg/kg P.O.) increased whole-brain levels of dopamine metabolites but did not affect levels of norepinephrine, dopamine, and serotonin. Subcutaneous injection of 1192U90 (0.8 mg/kg/day) and clozapine (20 mg/kg/day) for 28 days preferentially decreased the number of spontaneously active dopamine cells in the ventral tegmental area (VTA) but not the substantia nigra (SN) of rats, as measured by population sampling. This outcome is characteristics of atypical antipsychotics like clozapine. Acute injections of 1192U90 reversed the rate-inhibiting effects of microiontophoretically applied dopamine and intravenously injected apomorphine and d-amphetamine on dopamine cell firing. Intravenous injection or iontophoretic application of 1192U90 or the 5-HT1A agonist (+/-)8-OH-DPAT inhibited the firing rates of dorsal raphe nucleus (DRN) neurons in rats, and the effects of both compounds were blocked by iontophoretically applied S(-) propranolol, a 5-HT1A antagonist. The results suggest that 1192U90 is a preferential dopamine D2 antagonist as well as a 5-HT1A agonist that may prove to be an atypical antipsychotic.
Asunto(s)
Antipsicóticos/metabolismo , Piperazinas/metabolismo , Tiazoles/metabolismo , Anfetamina/farmacología , Animales , Apomorfina/farmacología , Aminas Biogénicas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Clozapina/metabolismo , Clozapina/farmacología , Masculino , Neuronas/efectos de los fármacos , Neuronas/fisiología , Piperazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Tiazoles/farmacologíaRESUMEN
1192U90 was developed on the assumption that antagonism of 5-HT2 receptors efficacy yields more potently than D2 receptors against positive and negative symptoms of schizophrenia with minimal liability for extrapyramidal side effects (EPSs), and that 5-HT1A agonism further reduces EPSs and provides anxiolytic and antidepressant activity. 1192U90 was submitted to four tests that predict antipsychotic efficacy (antagonism of apomorphine-induced climbing in mouse, antagonism of apomorphine-induced circling in rats with unilateral 6-OHDA lesions, antagonism of amphetamine-induced hyperlocomotion in rat, and inhibition of conditioned avoidance in rat), two tests of 5-HT2 function (antagonism of 5-MeODMT-induced head twitches in mouse and antagonism of 5-HTP-induced wet dog shakes in rat), and three tests that predict EPS liability (antagonism of apomorphine-induced stereotypy in mouse and rat and induction of catalepsy in mouse). ED50s (mg/kg PO) were as follows: climbing 10.1, circling 7.9, hyperlocomotion 6.6, and avoidance 5.7; head twitches 5 and wet dog shakes 4.6; stereotypy in mouse 91.1, stereotypy in rat 133.4, and catalepsy 192.4. The ratio of ED50 for stereotypy antagonism to ED50 for climbing antagonism was 9 (compared to 4, 3, and 4 for clozapine, risperidone, and haloperidol). The ratio of ED50 for catalepsy induction to ED50 for climbing antagonism was 19 (compared to 7, 2, and 17 for clozapine, risperidone, and haloperidol). 1192U90 was also submitted to three tests that predict anxiolysis: It produced only a small increase in punished lever pressing for food in rat (Geller-Seifter conflict test), which is specific for rapid-onset efficacy, but produced large increases in punished key pecking for food in pigeon and cork gnawing in rat, which identify the delayed onset 5-HT1A agonists such as buspirone. The results suggest that 1192U90 would be effective for positive and negative symptoms of schizophrenia, with minimal liability for EPSs, and may also have anxiolytic properties.
Asunto(s)
Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Piperazinas/farmacología , Esquizofrenia/fisiopatología , Tiazoles/farmacología , Animales , Columbidae , Masculino , Ratones , Ratas , Ratas WistarAsunto(s)
Encéfalo/fisiología , Indoles/farmacología , Piridinas/farmacología , Núcleos del Rafe/fisiología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Serotonina/metabolismo , Triptófano Oxigenasa/antagonistas & inhibidores , Triptófano/metabolismo , Animales , Encéfalo/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Fluoxetina/farmacología , Cinética , Pargilina/farmacología , Núcleos del Rafe/efectos de los fármacos , Ratas , Triptófano/farmacologíaRESUMEN
Extracts of Ginkgo biloba leaves produce reversible inhibition of rat brain monoamine (MAO). Both MAO-A and -B types were inhibited to a similar extent. The MAO inhibitory compound(s) were present in dried or fresh Ginkgo biloba leaves as well as in commercially available capsules of Ginkgo biloba and appear to be heat stable with relatively low molecular weight. MAO inhibition by Ginkgo biloba may be a mechanism underlying reported anti-stress and anxiolytic activities of this natural product.
Asunto(s)
Isoenzimas/antagonistas & inhibidores , Inhibidores de la Monoaminooxidasa/farmacología , Extractos Vegetales/farmacología , Plantas Medicinales/química , Animales , Encéfalo/enzimología , Hojas de la Planta/química , RatasRESUMEN
Eleven substituted 8-amino-3-benzyl-1,2,4-triazolo[4,3-a] pyrazines were synthesized and tested for anticonvulsant activity against maximal electroshock-induced seizures (MES) in rats. The compounds were prepared in four stages from the phenylacetonitriles. I. The intermediate (2,2,2-triethoxyethyl)benzenes III were condensed with 2-chloro-3-hydrazinopyrazine (IV) to provide the 3-benzyl-8-chloro-1,2,4-triazolo[4,3-a]pyrazines V. The latter were converted to the 8-amine targets VI with methylamine or ammonia. Several compounds exhibited potent activity against MES; the 3-(2-fluorobenzyl)-8-(methylamino) and 3-(2,6-difluorobenzyl)-8-(methylamino)congeners (4 and 12) exhibited the best anticonvulsant activity with oral ED50S of 3 mg/kg. The 1,2,4-triazolo[4,3-a]pyrazine ring system serves as a bioisostere of the purine ring for anticonvulsant activity; however, these agents exhibit less propensity to cause emesis.
Asunto(s)
Anticonvulsivantes/farmacología , Pirazinas/farmacología , Animales , Anticonvulsivantes/química , Estimulación Eléctrica , Masculino , Pirazinas/química , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine (1) containing isosteric replacements of the imidazole ring atoms were synthesized and tested for anticonvulsant activity. The pyrrolo[2,3-d]-, pyrazolo[3,4-d]-, and triazolo[4,5-d]pyrimidines were less active than 1 against maximal electroshock-induced seizures (MES) in rats when given po. The differences in anti-MES activity for these analogues was not explained by differences in pKa or lipophilicity. However, the four classes of heterocycles have distinctly different calculated electrostatic isopotential maps, which may be related to optimum anticonvulsant activity.
Asunto(s)
Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacología , Purinas/síntesis química , Purinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Anticonvulsivantes/química , Masculino , Purinas/química , Pirimidinas/química , Ratas , Ratas Wistar , Convulsiones/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
A series of (fluorobenzyl)triazolo[4,5-c]pyridines was synthesized and tested for activity against maximal electroshock-induced seizures in rodents. The most promising compound, 14 (BW 534U87), which is a carbon-nitrogen isoster of a purine anticonvulsant, has a profile in rodents that suggests 14 will be free of emesis and useful in the treatment of seizure disorders for which phenytoin is presently indicated.
Asunto(s)
Anticonvulsivantes/síntesis química , Triazoles/síntesis química , Animales , Anticonvulsivantes/farmacología , Perros , Masculino , Ratas , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: Elevated glutamate levels are thought to be a primary cause of neuronal death after global cerebral ischemia. The purpose of this study was to investigate the potential neuroprotective effects of lamotrigine, a novel antiepileptic drug that inhibits the release of glutamate in vitro, with both behavioral and histological measures of global ischemia in gerbils. METHODS: The common carotid arteries of gerbils were occluded for either 5, 10, or 15 minutes. Twenty-one days after reperfusion, gerbils were tested for impairments in a spatial memory task (Morris water maze). After water maze testing the animals were killed, and damage to hippocampal pyramidal cells was assessed. The effect of lamotrigine on the behavioral and histological outcome of either 5 or 15 minutes of global ischemia was evaluated. RESULTS: Bilateral occlusion of the common carotid arteries for 5 minutes resulted in severe degeneration of hippocampal CA1 and CA2 pyramidal cells. Lamotrigine significantly prevented loss of hippocampal CA1 neurons when administered acutely (100 mg/kg PO) immediately after reperfusion or when administered in two equal doses of 30 or 50 mg/kg 2 hours before and immediately after reperfusion. Gerbils subjected to 5 minutes of ischemic insult were not impaired in their ability to solve a spatial memory task 21 days after cerebral ischemia. However, gerbils subjected to 10 and 15 minutes of carotid artery occlusion showed significant impairment in their ability to solve a water maze task. Lamotrigine significantly protected against the cognitive deficits associated with 15 minutes of cerebral ischemia. Histologically, increased durations of cerebral ischemia resulted in a progressive loss of CA1, CA2, and CA3 pyramidal cells. Lamotrigine completely protected gerbils exposed to 15 minutes of cerebral ischemia against CA3 cell loss and greatly reduced damage to the CA1 and CA2 cell tracts of the hippocampus. Lamotrigine also reduced the mortality associated with 15 minutes of ischemia. CONCLUSIONS: Lamotrigine had neuroprotective effects in a gerbil model of global cerebral ischemia. Lamotrigine protected gerbils against behavioral deficits resulting from 15 minutes of carotid occlusion and also prevented histological damage resulting from 5 and 15 minutes of global cerebral ischemia.
Asunto(s)
Isquemia Encefálica/prevención & control , Fármacos Neuroprotectores/uso terapéutico , Triazinas/uso terapéutico , Animales , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Anticonvulsivantes/uso terapéutico , Arteriopatías Oclusivas/fisiopatología , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Química Encefálica , Isquemia Encefálica/patología , Isquemia Encefálica/fisiopatología , Enfermedades de las Arterias Carótidas/fisiopatología , Muerte Celular/efectos de los fármacos , Cognición/efectos de los fármacos , Cognición/fisiología , Modelos Animales de Enfermedad , Gerbillinae , Ácido Glutámico/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/patología , Lamotrigina , Masculino , Memoria/efectos de los fármacos , Memoria/fisiología , Degeneración Nerviosa/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/patología , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/sangre , Células Piramidales/efectos de los fármacos , Células Piramidales/patología , Daño por Reperfusión/patología , Daño por Reperfusión/prevención & control , Triazinas/administración & dosificación , Triazinas/sangreRESUMEN
The effects of a novel inhibitor 680C91 ((E)-6-fluoro-3-[2-(3-pyridyl)vinyl]-1H-indole) of the key enzyme of tryptophan catabolism tryptophan 2,3-dioxygenase (TDO), and a novel inhibitor 709W92 ((E)-6-fluoro-3-[2-(4-pyridyl)vinyl]-1H-indole), of both TDO and 5-hydroxytryptamine (5-HT) reuptake, were examined on tryptophan catabolism, cerebrospinal fluid (CSF) concentrations of tryptophan and 5-HT and serotonergic-mediated physiology and behaviour in the rat. The catabolism of L-[ring-2-14C]tryptophan in vivo was completely inhibited by prior administration of 709W92. 709W92, but not 680C91, potentiated head-twitch produced by 5-hydroxytryptophan, prevented head-twitch and whole brain 5-HT depletion produced by p-chloroamphetamine and rapidly decreased dorsal raphe firing. Both 709W92 and 680C91 elevated CSF tryptophan by up to 260% of basal concentration. A maximally effective dose of 680C91 elevated a global measure of brain extracellular 5-HT (CSF 5-HT) to concentrations similar to those seen maximally after exogenous tryptophan administration (approx 170% of basal). Maximally effective doses of 709W92 increased CSF 5-HT to concentrations comparable to those seen after tryptophan and 5-HT reuptake inhibitor coadministration (approx 900% of basal) and to concentrations greater than those achieved maximally with serotonergically active antidepressant monotherapy (approx 500% of basal). 709W92 did not elevate CSF 5-HT to concentrations associated with the serotonin syndrome (approx 3000% of basal). The combined TDO inhibitor/5-HT reuptake inhibitor, 709W92, showed anxiolytic activity in the rat-pup vocalization model of anxiety. These results show that 709W92 (a novel inhibitor of both TDO and 5-HT reuptake), can produce an elevation of CSF 5-HT similar to that achieved with a serotonin reuptake inhibitor/tryptophan combination therapy but with a more sustained timecourse; such compounds may therefore have superior antidepressant efficacy in the clinic.
Asunto(s)
Indoles/farmacología , Serotonina/metabolismo , Triptófano/farmacología , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Fluoxetina/farmacología , Masculino , Pargilina/farmacología , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Bupropion (BW 323U66) has been considered a dopaminergic antidepressant based on its ability to inhibit the uptake of dopamine (DA) somewhat more selectively than it inhibits uptake of norepinephrine (NE) or serotonin (5-HT). This report describes new evidence that bupropion selectively inhibits firing rates of NE cells in the locus coeruleus (LC) at doses significantly lower than those that inhibit activity of midbrain DA cells or dorsal raphe 5-HT cells. The IC50 dose (13 mg/kg i.p.) for inhibition of LC firing produced plasma concentrations that were not significantly different from those generated by the ED50 in the Porsolt test (10 mg/kg i.p.). The fourfold higher dose needed to inhibit DA cell firing (IC50 = 42 mg/kg i.p.) was similar to the dose associated with locomotor stimulation in freely moving rats. Bupropion did not change the firing rates of 5-HT cells in the dorsal raphe nucleus at any dose. In both in vitro and in vivo tests, the metabolite 306U73 (hydroxybupropion), a weak inhibitor of NE uptake, was approximately equipotent to bupropion with regard to inhibition of LC cells. Another metabolite, 494U73, had no effect on LC firing rates over a wide range of doses. Because of species variation in metabolism, 306U73 was not detected in plasma of rats after i.v. doses of bupropion that inhibited LC firing. Only trace amounts of 306U73 were detected after bupropion dosing for the Porsolt test. Pretreatment with reserpine markedly depleted catecholamines and reduced (by 30-fold) the potency of bupropion to inhibit LC firing.(ABSTRACT TRUNCATED AT 250 WORDS)