RESUMEN
We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.
Asunto(s)
Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/fisiología , Pirazoles/farmacología , Quinolinas/farmacología , Esquizofrenia/tratamiento farmacológico , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Dopamina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Inhibidores de Fosfodiesterasa/sangre , Inhibidores de Fosfodiesterasa/farmacocinética , Hidrolasas Diéster Fosfóricas/genética , Ratas , Ratas Endogámicas F344 , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética , Reflejo de Sobresalto/efectos de los fármacos , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologíaRESUMEN
RATIONALE: The structurally related neuropeptides, substance P, neurokinin A, and neurokinin B, belong to a family of molecules termed tachykinins and are widely distributed in the central and peripheral nervous systems. These peptides mediate their effects through three G protein coupled receptor subtypes, the neurokinin-1, neurokinin-2 and neurokinin-3 receptors, respectively. OBJECTIVE: To study the physiological functions of NK3, a line of NK3 knockout mice were generated and characterized in a broad spectrum of well-established behavioral tests. RESULTS: In several tests, including spontaneous locomotor activity, elevated plus maze, forced swim, and hot plate, wild-type and knockout mice performed similarly. However, in several cognition tests, including passive avoidance, acquisition of conditioned avoidance responding (CAR), and the Morris water maze, NK3 knockout mice displayed deficits compared to wild-type mice. Although NK3 wild-type and knockout mice performed similarly in the training phase of the passive avoidance test, knockout mice had shorter latencies to enter the dark compartment on days 3 and 4, suggesting impaired retention. In the acquisition phase of the conditioned avoidance responding assay, NK3 knockout mice acquired the CAR task at a slower rate than wild-type mice. Once the CAR test was acquired, both NK3 wild-type and knockout mice responded similarly to clozapine and risperidone, drugs which suppress responding in this test. In the Morris water maze, NK3 knockout mice showed increased latencies to find the escape platform on day 3 of training, suggesting a modest, but significant delay in acquisition compared to wild-type mice. CONCLUSION: These studies suggest a role for NK3 in learning and memory in mice.
Asunto(s)
Reacción de Prevención/fisiología , Trastornos del Conocimiento/fisiopatología , Actividad Motora/fisiología , Receptores de Neuroquinina-3/fisiología , Factores de Edad , Animales , Antipsicóticos/farmacología , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Clozapina/farmacología , Condicionamiento Operante/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Expresión Génica , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Receptores de Neuroquinina-3/deficiencia , Receptores de Neuroquinina-3/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Risperidona/farmacología , Natación , Factores de Tiempo , Aumento de Peso/efectos de los fármacosRESUMEN
PDE1B is a calcium-dependent cyclic nucleotide phosphodiesterase that is highly expressed in the striatum. In order to investigate the physiological role of PDE1B in the central nervous system, PDE1B knockout mice (C57BL/6N background) were assessed in behavioral tests and their brains were assayed for monoamine content. In a variety of well-characterized behavioral tasks, including the elevated plus maze (anxiety-like behavior), forced swim test (depression-like behavior), hot plate (nociception) and two cognition models (passive avoidance and acquisition of conditioned avoidance responding), PDE1B knockout mice performed similarly to wild-type mice. PDE1B knockout mice showed increased baseline exploratory activity when compared to wild-type mice. When challenged with amphetamine (AMPH) and methamphetamine (METH), male and female PDE1B knockout mice showed an exaggerated locomotor response. Male PDE1B knockout mice also showed increased locomotor responses to higher doses of phencyclidine (PCP) and MK-801; however, this effect was not consistently observed in female knockout mice. In the striatum, increased dopamine turnover (DOPAC/DA and HVA/DA ratios) was found in both male and female PDE1B knockout mice. Striatal serotonin (5-HT) levels were also decreased in PDE1B knockout mice, although levels of the metabolite, 5HIAA, were unchanged. The present studies demonstrate increased striatal dopamine turnover in PDE1B knockout mice associated with increased baseline motor activity and an exaggerated locomotor response to dopaminergic stimulants such as methamphetamine and amphetamine. These data further support a role for PDE1B in striatal function.
Asunto(s)
Conducta Animal/fisiología , Química Encefálica/genética , Ratones Noqueados , Hidrolasas Diéster Fosfóricas/deficiencia , Animales , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Conducta Animal/efectos de los fármacos , Monoaminas Biogénicas/metabolismo , Química Encefálica/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Cromatografía Líquida de Alta Presión/métodos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1 , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados/genética , Ratones Noqueados/metabolismo , Ratones Noqueados/fisiología , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Fenciclidina/farmacología , Factores Sexuales , NataciónRESUMEN
Antiresorptive therapy is usually given in a fixed dose, and we hypothesized that some patients receiving standard doses of hormone replacement therapy (HRT) might benefit from a higher dose, particularly if their bone turnover decreases after increasing the dose of HRT. Eighty-eight women who had been receiving standard-dose (0.625 mg/day) conjugated equine estrogens (CEE) for at least one year were randomized to take either standard-dose (0.625 mg/day, n = 36) or high-dose (1.25 mg/day, n = 52) therapy. Subjects with a uterus were allowed to take either 10 mg of medroxyprogesterone cyclically or 5 mg daily, according to personal preference. Bone Mineral Density (BMD) and biochemical markers of bone turnover were followed for 2 years. Mean bone turnover decreased significantly (-4.1% to -19.1%) after 6 months of high-dose CEE. Decreases in serum BSAP (bone-specific alkaline phosphatase) and serum or urine NTX ( N-terminal telopeptide crosslink of type I collagen) on high-dose therapy were not predictive of an improvement in BMD, but a decrease in serum CrossLaps did predict an improvement in BMD. Mean change in BMD in subjects with a significant decrease in serum CrossLaps at the anteroposterior spine was 3.1% +/- 3.9% versus 1.2% +/- 2.9% for subjects with no significant change in CrossLaps, P < 0.02. There was, however, a wide range of changes in BMD in patients with or without a significant change in CTX on high-dose HRT, making it impossible to predict an improvement in BMD based on an individual's changes in turnover. Measuring of bone density and bone turnover with better precision might be more successful in guiding individual dosing of antiresorptive therapy.
Asunto(s)
Densidad Ósea/efectos de los fármacos , Estrógenos Conjugados (USP)/administración & dosificación , Estrógenos/administración & dosificación , Terapia de Reemplazo de Hormonas , Osteoporosis Posmenopáusica/tratamiento farmacológico , Fosfatasa Alcalina/sangre , Biomarcadores , Huesos/efectos de los fármacos , Huesos/metabolismo , Colágeno/sangre , Colágeno Tipo I , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , Péptidos/sangreRESUMEN
OBJECTIVE: A method is described by which residents can perform transvaginal sacrospinous colpopexy simply, quickly, safely, and effectively. STUDY DESIGN: Over 11 years, 134 sacrospinous suspension procedures have been performed, all or in part by residents, under the direct intraoperative supervision of the author. Minimum follow-up is 1 year. An operative technique has been developed with use of standard instruments and lights. The sitting resident, the attending physician, and the medical student are able to see the ligament penetrated by the suture. If necessary, the attending physician is able to perform the difficult steps of the operation without changing places with the resident. RESULTS: Results are known for 112 of the patients. There have been five recurrences of significant prolapse, and incontinence has developed in 8 patients. Ninety-nine patients felt the outcome to be satisfactory or excellent. There were two major complications and one postoperative death. CONCLUSIONS: This teaching method has provided our residents a direct-view, hands-on familiarity with sacrospinous colpopexy while achieving results for the patients consistent with the outcomes of other centers.
Asunto(s)
Cirugía General/educación , Ginecología/educación , Internado y Residencia , Ligamentos/cirugía , Técnicas de Sutura , Prolapso Uterino/cirugía , Femenino , Humanos , Complicaciones Intraoperatorias , Complicaciones Posoperatorias , Recurrencia , Factores de Tiempo , Incontinencia Urinaria/etiologíaRESUMEN
A series of N-benzylpiperidines (2a-d, 10) with novel isoxazole-containing tricycles has been prepared. This series has shown potent in vitro inhibition of the enzyme acetylcholinesterase (AChE), with IC50S = 0.33 - 3.6 nM. Compound 2a was the most potent inhibitor with an IC50 = 0.33 +/- 0.09 nM. Derivatives 2a-d and 10 displayed weak in vitro inhibition of butyrylcholinesterase (BuChE) with IC50S = 600 - 23,000 nM. The most selective compound was 2a with a BuChE/AChE ratio in excess of 4 orders of magnitude (> 10,000). Pyrrolobenzisoxazole 2a also displayed a favorable profile in vivo. In microdialysis experiments, 2a produced a 200% increase in extracellular levels of acetylcholine (ACh) at a dose of 0.4 mg/kg in freely moving, conscious rats. Peripheral side effects (salivation ED50 = 26 +/- 1.5 mg/kg) and acute lethality (LD50[1 h] = 42 mg/kg) were observed at > 60-fold higher doses. These data indicate that 2a is an AChE inhibitor with good central selectivity and a favorable margin of safety. Compound 2a, designated as CP-118,954, is currently in clinical development for the treatment of cognitive disorders.
Asunto(s)
Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacología , Isoxazoles/síntesis química , Isoxazoles/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Animales , Butirilcolinesterasa , Inhibidores de la Colinesterasa/toxicidad , Isoxazoles/toxicidad , Masculino , Piperidinas/toxicidad , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tacrina/farmacología , Tacrina/toxicidadRESUMEN
Herein is described the synthesis and structure--activity relationship of a novel series of aromatic and heteroaromatic 3-(1-benzyl-4-piperidinyl)propan-1-one derivatives that display potent and selective inhibition of the enzyme acetylcholinesterase (AChE). 1-(2-Methyl-6-benzothiazolyl)-3-(N-benzyl-4-piperidinyl)propan-1-one hydrochloride, 6d, is one of the most active compounds within this series exhibiting an IC50 for the inhibition of the AChE enzyme equal to 6.8 nM. Compound 6d has shown a dose-dependent elevation of total acetylcholine (ACh) levels in the mouse forebrain with an oral ED50 = 9.8 mg/kg. In addition, in vivo microdialysis experiments in the rat demonstrate that 6d increases extracellular ACh (100% over basal) 1-3 h postdose with an oral ED50 = 4.8 mg/kg.
Asunto(s)
Inhibidores de la Colinesterasa/síntesis química , Tiazoles/farmacología , Animales , Benzotiazoles , Butirilcolinesterasa , Cuerpo Estriado/metabolismo , Diseño de Fármacos , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A series of N-benzylpiperidine benzisoxazoles has been developed as potent and selective inhibitors of the enzyme acetylcholinesterase (AChE). The benzisoxazole heterocycle was found to be an appropriate bioisosteric replacement for the benzoyl functionality present in the N-benzylpiperidine class of inhibitors. The title compounds were synthesized by alkylating 3-methyl-1,2-benzisoxazoles with an iodo piperidine derivatives as the key step. Benzisoxazoles 1b-j,o displayed potent inhibition of AChE in vitro with IC50's = 0.8-14 nM. Particularly interesting were N-acetyl and morpholino derivatives 1g (IC50 = 3 nM) and 1j (IC50 = 0.8 nM), respectively, which displayed outstanding selectivity for acetyl-over butyrylcholinesterase, in excess of 3 orders of magnitude. N-Acetyl 1g also displayed a favorable profile in vivo. This analog showed a dose-dependent elevation of total acetylcholine in mouse forebrain after oral administration with an ED50 = 2.4 mg/kg. In addition, 1g was able to reverse amnesia in a mouse passive avoidance model at doses of 3.2 and 5.6 mg/kg with an average reversal of 89.7%. Molecular dynamics simulations were used to study the possible binding modes of N-benzylpiperidine benzisoxazoles to AChE from Torpedo californica. Key structural insights were obtained regarding the potency of this class of inhibitors. Specifically, Asp-72, Trp-84, Trp-279, Phe-288, and Phe-330 are implicated in the binding of these inhibitors. The N-benzylpiperidine benzisoxazoles may be suitable compounds for the palliative treatment of Alzheimer's Disease.
Asunto(s)
Acetilcolina/metabolismo , Reacción de Prevención/efectos de los fármacos , Inhibidores de la Colinesterasa/síntesis química , Isoxazoles/síntesis química , Piperidinas/síntesis química , Prosencéfalo/metabolismo , Acetilcolinesterasa/metabolismo , Animales , Sitios de Unión , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Gráficos por Computador , Isoxazoles/química , Isoxazoles/farmacología , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratones , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Morfolinas/síntesis química , Morfolinas/farmacología , Piperidinas/química , Piperidinas/farmacología , Prosencéfalo/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The synthesis of a series of alkylcarbamates of 1,5-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-7-ol is reported. Many of these compounds are potent acetylcholinesterase (AChE) inhibitors. The in vitro AChE inhibition, cholinergic effects, acute toxicity, and elevation of brain acetylcholine levels in vivo of this series of compounds are described. A representative compound, 1d (5.6 mg/kg, po), was able to reverse hemicolinium-3-induced amnesia in the mouse passive avoidance assay.
Asunto(s)
Benzazepinas/síntesis química , Carbamatos/síntesis química , Inhibidores de la Colinesterasa/síntesis química , Administración Oral , Amnesia/tratamiento farmacológico , Animales , Reacción de Prevención/efectos de los fármacos , Benzazepinas/farmacología , Carbamatos/farmacología , Carbamatos/uso terapéutico , Inhibidores de la Colinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Colinesterasas/metabolismo , Relación Dosis-Respuesta a Droga , Inyecciones Intraperitoneales , Espectroscopía de Resonancia Magnética , Masculino , RatonesAsunto(s)
Histerectomía , Laparoscopía , Transexualidad/cirugía , Adulto , Femenino , Humanos , Histerectomía/métodos , VaginaRESUMEN
Sertraline was found to inhibit weight gain and decrease food intake without affecting locomotion in rats and genetically obese (ob/ob) mice. Doses of 10, 17.8, and 32 mg/kg, administered intraperitoneally, (bid) significantly reduced the time rats spent in contact with their feeders and body weight in a dose-related manner. During a 5-d bid treatment regimen, vehicle-treated rats gained 37 +/- 3 g (mean +/- SEM), whereas animals treated with 32 mg sertraline/kg lost 34 +/- 4 g. The effects of sertraline on feeding and body weight in rats appeared to be specific because locomotor activity was not altered. In ob/ob mice, sertraline (44 mg/kg, ip, bid) lowered body weight relative to vehicle-treated controls for the duration of a 12-d study. There was no evidence for tolerance to the hypophagic and weight-loss effects of sertraline during either of the chronic dosing studies. These results suggest a potential role for sertraline in the treatment of human obesity.
Asunto(s)
1-Naftilamina/análogos & derivados , Depresores del Apetito/farmacología , Obesidad/tratamiento farmacológico , Antagonistas de la Serotonina/farmacología , Pérdida de Peso/efectos de los fármacos , 1-Naftilamina/farmacología , 1-Naftilamina/uso terapéutico , Animales , Ingestión de Alimentos/efectos de los fármacos , Masculino , Ratones , Ratones Obesos , Actividad Motora/efectos de los fármacos , Ratas , Antagonistas de la Serotonina/uso terapéutico , SertralinaRESUMEN
A series of quinazolinediones and azaquinazolinediones is described which possess potent inhibitory activity toward the calcium-independent phosphodiesterase enzyme (CaIPDE). In vivo testing showed that this in vitro activity translates to animal models predictive of chronic diseases such as depression and inflammation. These results support the hypothesis that inhibition of CaIPDE may lead to useful activity in such chronic diseases.
Asunto(s)
Inhibidores de Fosfodiesterasa/síntesis química , Quinazolinas/síntesis química , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Fenómenos Químicos , Química , Masculino , Ratones , Inhibidores de Fosfodiesterasa/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Pirrolidinonas/metabolismo , Pirrolidinonas/farmacología , Quinazolinas/metabolismo , Quinazolinas/farmacología , Ratas , Rolipram , Relación Estructura-ActividadRESUMEN
The synthesis and biological properties of a novel series of selective calcium-independent phosphodiesterase inhibitors are described. These compounds also inhibit the specific binding of [3H]rolipram to rat brain membranes and exhibit efficacy in preclinical models of antidepressant activity in mice, such as reducing immobility in the forced-swim test and reversing reserpine-induced hypothermia. Imidazolidinones 4 and 16 were found to be the most potent compounds studied.
Asunto(s)
Antidepresivos/síntesis química , Encéfalo/metabolismo , Corteza Cerebral/enzimología , Inhibidores de Fosfodiesterasa/síntesis química , Animales , Temperatura Corporal/efectos de los fármacos , Calcio/farmacología , Femenino , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Ratones , Conformación Molecular , Estructura Molecular , Actividad Motora/efectos de los fármacos , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Pirrolidinonas/farmacología , Ratas , Ratas Endogámicas , Reserpina/farmacología , Rolipram , Relación Estructura-ActividadRESUMEN
The effects of tryptophan administration on neurochemical estimates of synthesis [5-hydroxytryptophan (5-HTP) accumulation following administration of a decarboxylase inhibitor], storage [5-hydroxytryptamine (5-HT) concentrations], and metabolism [5-hydroxyindoleacetic acid (5-HIAA) concentrations] of 5-HT in selected regions of the hypothalamus were determined using HPLC coupled to an electrochemical detector. Tryptophan methyl ester HCl (30-300 mg/kg i.p.) produced a dose-dependent increase in the rate of 5-HTP accumulation throughout the hypothalamus but had no effect on the rate of accumulation of 3,4-dihydroxyphenylalanine. Peak 5-HTP levels were attained by 30 min following administration of tryptophan (100 mg/kg i.p.) and were maintained for an additional 60 min. Tryptophan also produced concomitant dose-dependent increases in 5-HT and 5-HIAA concentrations in these same regions without changes in the 5-HIAA/5-HT ratio. These results indicate that exogenous tryptophan administration selectively increases the synthesis, storage, and metabolism of 5-HT in the hypothalamus without altering the synthesis of catecholamines. Inhibition of 5-HT uptake with chlorimipramine or fluoxetine produced modest (10-40%) reductions in 5-HIAA concentrations throughout the hypothalamus, revealing that only a minor portion of 5-HIAA is derived from released and recaptured 5-HT, whereas the major portion of this metabolite reflects intraneuronal metabolism of unreleased 5-HT. In both chlorimipramine- and fluoxetine-treated rats, 5-HIAA concentrations were significantly increased by tryptophan administration, indicating that the increase in synthesis of 5-HT following precursor loading is accompanied by an increase in the intraneuronal metabolism of 5-HT.
Asunto(s)
Hipotálamo/metabolismo , Neuronas/metabolismo , Serotonina/metabolismo , Triptófano/farmacología , Animales , Dihidroxifenilalanina/metabolismo , Relación Dosis-Respuesta a Droga , Ácido Hidroxiindolacético/metabolismo , Hipotálamo/citología , Masculino , Concentración Osmolar , Ratas , Ratas EndogámicasRESUMEN
The intracerebroventricular (i.c.v.) administration of 6-hydroxydopamine (6-OHDA; 50 micrograms X 3) and the systemic administration of DSP4 (50 mg/kg X 2; i.p.), alone and in combination, were compared for their abilities to alter the concentrations of norepinephrine (NE), dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and 5-hydroxytryptamine (5-HT) in selected hypothalamic and extra-hypothalamic (striatum, frontal cortex, hippocampus) regions of the male rat brain. DSP4 markedly lowered NE concentrations in extrahypothalamic regions, and within the hypothalamus produced a mild and variable reduction of NE without altering concentrations of DA, DOPAC or 5-HT. 6-OHDA markedly lowered NE concentrations in all brain regions, but was without effect on DA, DOPAC and 5-HT concentrations in any region analyzed. Combined treatment with DSP4 and 6-OHDA did not produce additional effects on levels of NE, DA and DOPAC over either drug alone, but did cause a mild reduction of 5-HT in several brain regions. These results indicate that systemic treatments with DSP4 per se are not as effective as i.c.v. 6-OHDA in depleting NE in the hypothalamus, and that when the two neurotoxins are administered there appears to be some destruction of 5-HT neurons.
Asunto(s)
Aminas/farmacología , Bencilaminas/farmacología , Hidroxidopaminas/farmacología , Hipotálamo/análisis , Neurotransmisores/análisis , Ácido 3,4-Dihidroxifenilacético/análisis , Animales , Química Encefálica/efectos de los fármacos , Dopamina/análisis , Masculino , Norepinefrina/análisis , Oxidopamina , Ratas , Serotonina/análisisRESUMEN
Hyperandrogenic states in women are often accompanied by disruption of gonadotropin secretion. However, the role of androgens per se in the pathogenesis of this abnormality is poorly understood. We report a woman with a virilizing ovarian tumor in whom the effects of continuous androgen secretion on the hypothalamic-pituitary axis were investigated in detail. A 29-yr-old woman with previously normal reproductive function, including prior fertility, was evaluated for amenorrhea and hirsutism. She had elevated peripheral serum levels of testosterone (T; 337-500 ng/dl) and androstenedione (A; 258-353 ng/dl). Her serum LH level was above the normal follicular phase range and was hyperresponsive to LHRH, whereas the FSH level was below normal early follicular phase levels and increased minimally in response to LHRH. A luteinized thecoma of the left ovary, shown by catherization of the ovarian venous blood to be secreting both T and A, was removed. Postoperatively, serum T and A levels returned to normal, and the patient had a normal ovulatory menstrual cycle in the 30 days after the operation, documented by daily determinations of plasma estradiol, progesterone, and gonadotropin levels. A repeat LHRH test in the follicular phase of the second postoperative menstrual cycle was completely normal. This case indicates that the characteristic abnormalities of gonadotropin secretion observed in hyperandrogenic states such as polycystic ovarian disease can result from chronic androgen secretion by an ovarian tumor and that normal folliculogenesis and gonadotropin secretion can be promptly restored by the elimination of the androgen excess.
Asunto(s)
Andrógenos/metabolismo , Sistema Hipotálamo-Hipofisario/fisiología , Neoplasias Ováricas/metabolismo , Neoplasia Tecoma/metabolismo , Hormona Adrenocorticotrópica , Adulto , Andrógenos/sangre , Androstenodiona/sangre , Dexametasona/administración & dosificación , Femenino , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina , Humanos , Hormona Luteinizante/sangre , Neoplasias Ováricas/cirugía , Testosterona/sangre , Neoplasia Tecoma/cirugíaRESUMEN
The in vivo effects of four psychomotor stimulants (d-amphetamine, beta-phenylethylamine, cocaine and methylphenidate) were determined on: 1) the rate of dopamine (DA) synthesis, as measured by the accumulation of dihydroxyphenylalanine (DOPA) after aromatic L-amino acid decarboxylase inhibition, in the striatum (terminals of nigrostriatal neurons) and in the nucleus accumbens and olfactory tubercle (terminals of mesolimbic neurons) and 2) the efflux of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) into cerebroventricular perfusates of conscious, freely-moving rats. d-Amphetamine and beta-phenylethylamine produced biphasic responses with lower doses of each drug increasing both the efflux of DOPAC and the rate of DA synthesis in the striatum. Higher doses of each drug either had no effect or actually decreased the efflux of DOPAC and also decreased the rate of DA synthesis in the striatum. On the other hand, cocaine and methylphenidate only decreased the efflux of DOPAC and the rate of DA synthesis in the striatum. The effects of the drugs on the rate of DA synthesis in the nucleus accumbens and olfactory tubercle were similar to, but less pronounced than those seen in the striatum. These results are consistent with the following suggestions: 1) low doses of d-amphetamine and beta-phenylethylamine facilitate the neuronal release of DA while higher doses of both drugs facilitate release and inhibit neuronal reuptake of the amine, and 2) cocaine and methylphenidate preferentially block the neuronal reuptake of DA.
Asunto(s)
Encéfalo/metabolismo , Fármacos del Sistema Nervioso Central/farmacología , Dopamina/metabolismo , Neuronas/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Ventrículos Cerebrales/metabolismo , Cocaína/farmacología , Cuerpo Estriado/metabolismo , Dextroanfetamina/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Metilfenidato/farmacología , Núcleo Accumbens/metabolismo , Bulbo Olfatorio/metabolismo , Fenetilaminas/farmacología , Ratas , Ratas EndogámicasRESUMEN
Members of an interdisciplinary design group, funded to conduct ongoing research in state psychiatric facilities, developed a process by which a seven-year-old facility for geriatric patients could be better adapted to meet users' and program needs. The facility, considered good by many standards, had been planned on a "motel model"more suitable for transient occupancy than for providing opportunities for interaction, communication, stimulation, and challenging roles. Randomly selected residents and staff were involved in making decisions about design changes, which focused on rearranging and remodeling day-rooms to increase interaction. The controlled research design, involving baseline and follow-up evaluations, indicated that measurable, positive changes in residents' behavior occurred, especially among residents who took part in decision-making about the environmental changes.
Asunto(s)
Anciano/psicología , Arquitectura y Construcción de Instituciones de Salud , Hospitales Psiquiátricos/organización & administración , Diseño Interior y Mobiliario , Medio Social , Actitud , Femenino , Humanos , Relaciones Interpersonales , Masculino , Conducta SocialRESUMEN
Cell-mediated and humoral immune responses against antigens associated with primate C-type oncoviruses were evaluated in humans by microcytotoxicity and radioimmunoprecipitation assays. Five of six women tested sequentially during pregnancy developed selective cell-mediated reactivity against baboon endogenous virus (BEV)--infected human fibroblasts. Responsiveness peaked during the second and third trimesters and corresponded temporally with elevated antibody levels to BEV antigens. Similar cell-mediated reactivity was not observed in nonpregnant individuals. Selective cell-mediated reactivity directed against cells infected with the simian sarcoma virus-simian sarcoma associated virus complex (SSV--SSAV) was observed in four of 20 healthy adults (three of 14 nonpregnant, one of six pregnant). These observations suggest that cell-mediated reactivity against primate C-type oncoviruses is occasionally detected in healthy nonpregnant adults, but that during pregnancy both cell-mediated and humoral reactivity against BEV may become selectively expressed.