RESUMEN
Neoadjuvant treatment of canine mammary carcinomas with the progesterone receptor (PR) antagonist aglepristone has a PR expression-related inhibiting effect on proliferation index (PI). The aim of this study was to evaluate the effect of the treatment in the disease-free period (DFP) and overall survival (OS) of canine mammary carcinomas. Fifty female dogs with mammary carcinomas were treated with aglepristone (n = 34) or oil vehicle (n = 16) before surgery (day 15). PR expression and PI were analysed by immunohistochemistry in samples taken at days 1 and 15. Epidemiological and clinicopathological data were assessed. DFP and OS data were retrieved every 4-6 months for at least 24 months after surgery. Aglepristone treatment increased DFP of animals bearing PR+ tumours with size smaller than 3 cm, complex and mixed tumours, with histologic grades I and II, and with PI ≤ 10%. Although further studies are necessary, current evidence points to treatment with aglepristone as useful for the management of canine mammary tumours.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Estrenos/uso terapéutico , Neoplasias Mamarias Animales/tratamiento farmacológico , Receptores de Progesterona/metabolismo , Animales , Terapia Combinada/veterinaria , Enfermedades de los Perros/patología , Enfermedades de los Perros/terapia , Perros , Femenino , Neoplasias Mamarias Animales/diagnóstico , Neoplasias Mamarias Animales/patología , Neoplasias Mamarias Animales/terapia , Terapia Neoadyuvante , PronósticoRESUMEN
BACKGROUND: Progesterone receptor (PR) antagonist aglepristone (RU534) has been used successfully for pregnancy termination and therapy of pyometra, vaginal tumors, and mammary hyperplasia in bitches and queens. All of these conditions share with canine mammary carcinomas the expression of PR. OBJECTIVES: To study the effect of RU534 on proliferation and apoptosis in canine mammary carcinomas in relation to PR expression. ANIMALS: Twenty-seven nonspayed bitches with mammary carcinomas were treated with either 2 doses of 20 mg/kg RU534 (n = 22, RU534-treated group) or oil placebo (n = 5, control group) on days 1 and 8. METHODS: Tumor samples were collected before (day 1) and after (day 15) treatment for immunohistochemistry. PR expression, proliferation index (PI), and apoptotic index (AI) were determined using antibodies against PR, Ki67, and cleaved lamin A/C antigens, respectively. The effect of treatment on these parameters was analyzed. RESULTS: Differential expression of PR between day 1 (59.1% PR-positive tumors) and day 15 (36.4% PR-positive tumors) was observed in RU534-treated tumors exclusively. After RU534 treatment, mean PI was significantly decreased in PR-positive but unchanged in PR-negative RU534-treated tumors. A reduction of ≥20% in PI was found in 61.5% of RU534-treated tumors with PR expression. Conversely, no effect on AI was observed after RU534 treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Neoadjuvant RU534 treatment had PR expression-related inhibiting effects on proliferation of canine mammary carcinoma cells.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma/veterinaria , Enfermedades de los Perros/tratamiento farmacológico , Estrenos/uso terapéutico , Neoplasias Mamarias Animales/tratamiento farmacológico , Receptores de Progesterona/metabolismo , Animales , Carcinoma/tratamiento farmacológico , Perros , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Receptores de Progesterona/genéticaRESUMEN
On the basis of a mechanistic understanding of the toxicity of the 4-aminoquinoline amodiaquine (1b), three series of amodiaquine analogues have been prepared where the 4-aminophenol "metabolic alert" has been modified by replacement of the 4'-hydroxy group with a hydrogen, fluorine, or chlorine atom. Following antimalarial assessment and studies on mechanism of action, two candidates were selected for detailed ADME studies and in vitro and in vivo toxicological assessment. 4'-Fluoro-N-tert-butylamodiaquine (2k) was subsequently identified as a candidate for further development studies based on potent activity versus chloroquine-sensitive and resistant parasites, moderate to excellent oral bioavailability, low toxicity in in vitro studies, and an acceptable safety profile.
Asunto(s)
Aminoquinolinas/síntesis química , Amodiaquina/análogos & derivados , Amodiaquina/síntesis química , Antimaláricos/síntesis química , Aminoquinolinas/farmacocinética , Aminoquinolinas/farmacología , Amodiaquina/química , Amodiaquina/farmacocinética , Amodiaquina/farmacología , Animales , Antimaláricos/farmacocinética , Antimaláricos/farmacología , Supervivencia Celular , Cloroquina/farmacología , Perros , Resistencia a Medicamentos , Femenino , Haplorrinos , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Humanos , Técnicas In Vitro , Malaria/tratamiento farmacológico , Malaria/parasitología , Masculino , Ratones , Pruebas de Sensibilidad Parasitaria , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Plasmodium yoelii/efectos de los fármacos , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
N-tert-Butyl isoquine (4) (GSK369796) is a 4-aminoquinoline drug candidate selected and developed as part of a public-private partnership between academics at Liverpool, MMV, and GSK pharmaceuticals. This molecule was rationally designed based on chemical, toxicological, pharmacokinetic, and pharmacodynamic considerations and was selected based on excellent activity against Plasmodium falciparum in vitro and rodent malaria parasites in vivo. The optimized chemistry delivered this novel synthetic quinoline in a two-step procedure from cheap and readily available starting materials. The molecule has a full industry standard preclinical development program allowing first into humans to proceed. Employing chloroquine (1) and amodiaquine (2) as comparator molecules in the preclinical plan, the first preclinical dossier of pharmacokinetic, toxicity, and safety pharmacology has also been established for the 4-aminoquinoline antimalarial class. These studies have revealed preclinical liabilities that have never translated into the human experience. This has resulted in the availability of critical information to other drug development teams interested in developing antimalarials within this class.
Asunto(s)
Aminoquinolinas/farmacología , Antimaláricos/farmacología , Bencilaminas/farmacología , Aminoquinolinas/síntesis química , Aminoquinolinas/química , Aminoquinolinas/farmacocinética , Aminoquinolinas/toxicidad , Amodiaquina/análogos & derivados , Animales , Antimaláricos/síntesis química , Antimaláricos/farmacocinética , Antimaláricos/toxicidad , Bencilaminas/síntesis química , Bencilaminas/química , Bencilaminas/toxicidad , Inhibidores Enzimáticos del Citocromo P-450 , Perros , Evaluación Preclínica de Medicamentos , Resistencia a Medicamentos , Femenino , Haplorrinos , Hemo/química , Humanos , Malaria/tratamiento farmacológico , Ratones , Modelos Moleculares , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Plasmodium yoelii , Ratas , Relación Estructura-ActividadRESUMEN
Sertoli-Leydig cell tumours with a retiform pattern similar to the pattern of the rete testis are a subtype of sex cord-stromal tumours recognized in the human WHO histological classification of ovarian tumours but not in the equivalent classification for domestic animals. The morphology of the tumour may be confused with that of the more common ovarian epithelial tumours. The gross, microscopical and immunohistochemical features of a canine retiform Sertoli-Leydig cell tumour and its comparison with the human counterpart are presented in this report. Both ovaries were enlarged and cystic. Microscopically, the tumour was cystic with tubulopapillary growth characterized by narrow, elongated branching tubules. Immunohistochemically, the tumour cells expressed alpha-inhibin, while epithelial membrane antigen was not detected, indicating a sex cord-stromal origin of the tumour. Additionally, the tumour cells expressed cytokeratin and vimentin in addition to oestrogen receptor alpha and progesterone receptor.
Asunto(s)
Enfermedades de los Perros/metabolismo , Enfermedades de los Perros/patología , Inhibinas/biosíntesis , Mucina-1/biosíntesis , Neoplasias Ováricas/veterinaria , Tumor de Células de Sertoli-Leydig/veterinaria , Animales , Diagnóstico Diferencial , Perros , Femenino , Inmunohistoquímica , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Tumor de Células de Sertoli-Leydig/metabolismo , Tumor de Células de Sertoli-Leydig/patologíaRESUMEN
To test the hypothesis that the parathyroid hormone (PTH) response to hypercalcaemia is influenced by circadian rhythms, the Ca2+ -PTH curve was studied in six dogs after infusion of CaCl2 (0.66 mEq/kg/h) at daytime (09:00 h) and at night-time (21:00 h). Plasma Ca2+ and PTH values measured before or after CaCl2 infusion were not different at day and at night. However, in the recovery from hypercalcaemia, PTH concentrations were significantly lower (P < 0.05) at 21:00 h (23 +/- 7.5 pg/ml at Ca2+ = 1.30 mm) than at 09:00 h (38.8 +/- 6.9 pg/ml at Ca2+ = 1.30 mm). In addition, the Ca2+ -PTH curve showed hysteresis at daytime (for the same Ca2+ concentration, PTH values were higher during recovery than during induction of hypercalcaemia) but not at night-time (PTH values were lower during recovery than during induction of hypercalcaemia). In conclusion, a circadian variation in the PTH secretory pattern during recovery from hypercalcaemia has been identified in dogs.
Asunto(s)
Cloruro de Calcio/farmacología , Calcio/sangre , Ritmo Circadiano/fisiología , Perros/fisiología , Hormona Paratiroidea/sangre , Animales , Área Bajo la Curva , Enfermedades de los Perros/metabolismo , Femenino , Hipercalcemia/metabolismo , Hipercalcemia/veterinaria , MasculinoRESUMEN
Existe un interés creciente por la realización de los bloqueos de nervio periférico (BNP) debido a sus potenciales beneficios como los concernientes a las interacciones de los fármacos anticoagulantes y los bloqueos neuroaxiales. Los BNP de la extremidad inferior, y sobre todo, los bloqueos periféricos del nervio ciático son el pariente pobre de las técnicas de anestesia regional y, en general, son poco conocidos y por tanto poco utilizados. En este artículo se realiza una revisión de los bloqueos del plexo lumbosacro, realizando especial énfasis en los bloqueos continuos mediante catéteres para analgesia postoperatoria y para el tratamiento del dolor crónico. La utilización de anestésicos locales de larga duración de acción, asociada a un escaso bloqueo motor, como es el caso de la ropivacaína, nos permite combinar técnicas de punción única para conseguir una adecuada analgesia intraoperatoria, con las técnicas de perfusión continua para analgesia postoperatoria. Es necesario un conocimiento anatómico preciso, así como de los territorios cutáneos de inervación de las ramas del plexo lumbosacro, para la realización de estas técnicas de bloqueo. La introducción de diferentes técnicas de imagen, fundamentalmente la ultrasonografía, para la localización de las estructuras nerviosas, facilita la realización de estos bloqueos y disminuye el riesgo de lesiones de los órganos adyacentes. La realización de los bloqueos continuos de nervio periférico ofrece el beneficio de una analgesia postoperatoria prolongada, con menores efectos adversos, mayor grado de satisfacción del paciente, y una recuperación funcional más rápida después de la cirugía (AU)
Asunto(s)
Humanos , Dolor Postoperatorio/tratamiento farmacológico , Analgésicos/administración & dosificación , Bloqueo Nervioso/métodos , Enfermedad Crónica , Plexo Lumbosacro , Nervio Ciático , Nervio FemoralRESUMEN
No disponible
Asunto(s)
Humanos , Dolor Postoperatorio/tratamiento farmacológico , Analgesia/métodos , EspañaRESUMEN
BACKGROUND: The prevalence of cardiovascular risk factors is increasing in aboriginal populations in Chile. AIM: To study the prevalence of obesity, type 2 diabetes and serum lipids in two aboriginal populations, Mapuche and Aymara, that were transferred from a rural to a urban environment. SUBJECTS AND METHODS: Two groups of subjects over 20 years were analyzed, Mapuche and Aymara. The Mapuche group was formed by 42 men and 105 women, living in four urban communities of Santiago, and an Aymara group formed by 42 men and 118 women, living in Arica, in Northern Chile. Anthropometric measurements, blood pressure, lipid profile, oral glucose tolerance test, fasting insulin and serum leptin were determined. RESULTS: The prevalence of type 2 diabetes was 6.9% in Aymara and 8.2% in Mapuche subjects. The frequency of glucose intolerance was similar in both groups, but greater among men. A total blood cholesterol over 200 mg/dl was observed in 43.1% of Aymara and 27.9% of Mapuche subjects (p <0.008). Serum triglycerides over 150 mg/dl were observed in 16.9 and 23.1% of Aymara and Mapuche individuals, respectively (p= NS). CONCLUSIONS: The prevalence of type 2 diabetes and dyslipidemia in turban aboriginal populations is higher than that of their rural counterparts. A possible explanation for these results are changes in lifestyles that come along with urbanization, characterized by a high consumption of saturated fat and refined sugars and a low level of physical activity.
Asunto(s)
Diabetes Mellitus Tipo 2/epidemiología , Indígenas Sudamericanos , Lípidos/sangre , Obesidad/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Chile/epidemiología , Chile/etnología , Diabetes Mellitus Tipo 2/etnología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/etnología , Prevalencia , Población UrbanaRESUMEN
Aspartimide formation is one of the most common secondary reactions on solid phase peptide synthesis. In the present work, we describe the optimization of the synthesis of two thrombospondin fragments containing an Asp-Gly sequence that show a strong tendency to form cyclic aspartimide derivatives in an unusual high percentage. Several different strategies were applied changing type of resin, Fmoc-deprotection reagents, coupling additives, resin cleavage cocktails and the use of Hmb-Gly derivative to minimize the extension of this byproduct. Best results were obtained with cross-linked ethoxylate acrylate (CLEAR-cross-linked ethoxylate Acrylate Resin)-type resin and pip/dimethylformamide deprotection. Besides, as in biological assays the aspartimide containing sequence resulted to be more active than the linear one, the optimization of its synthesis was also carried out.
Asunto(s)
Ácido Aspártico/análogos & derivados , Ácido Aspártico/química , Péptidos/química , Péptidos/síntesis química , Trombospondinas/química , Secuencia de Aminoácidos , Línea Celular Tumoral , Humanos , Datos de Secuencia MolecularRESUMEN
We have determined if thoracic extradural block before surgical incision for thoracotomy produces pre-emptive analgesia. Using a double-blind, placebo-controlled, crossover design, 45 patients (ASA II-III) undergoing posterolateral thoracotomy for lung resection were randomized to one of three groups: group 1 received 0.5% bupivacaine and adrenaline 1/200,000 (B+E) 8 ml through a thoracic extradural catheter (tip T3-T5) 30 min before skin incision and saline 8 ml 15 min after skin incision; group 2 received saline 8 ml extradurally before incision and B+E 8 ml after incision; group 3 received saline 8 ml extradurally before and after incision. General anaesthesia was induced and maintained with propofol, alfentanil and atracurium. The alfentanil infusion was stopped before chest closure and fentanyl 50 micrograms in saline 10 ml was given extradurally. Patient-controlled extradural analgesia (PCEA) was commenced with 0.125% bupivacaine, adrenaline 1/400,000 and fentanyl 6 micrograms ml-1 (continuous rate of 2 ml h-1 and supplementary doses of 0.5 ml per 6 min). Visual analogue scale (VAS) scores (recorded at rest, on mobilization and after cough), verbal rating scale (VRS) (recorded at rest), number of successful PCEA demands and complications were measured during the first 48 h after operation. There was no significant difference between groups, either in PCEA requirements (P > 0.21) or in VAS scores (either at rest, during mobilization of the ipsilateral arm of surgery or after cough). No significant differences between groups were found in the VRS. Thoracic extradural block with bupivacaine did not produce an early preemptive effect after thoracotomy.
Asunto(s)
Analgesia Epidural , Anestésicos Locales , Bupivacaína , Pulmón/cirugía , Dolor Postoperatorio/prevención & control , Adulto , Anciano , Analgesia Controlada por el Paciente , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND AND OBJECTIVES: Continuous brachial plexus anesthesia with local anesthesia has been used since 1946 for prolonged surgical procedures, in postoperative pain relief, and in sympathetic nerve block. The benefit or effectiveness of this technique in the relief of sympathetically maintained pain has yet to be established. METHODS: The following case report describes the placement of an axillary catheter connected to a port for the self-administration of local anesthesia to provide brachial plexus anesthesia in a 43-year-old woman suffering from sympathetically maintained pain. RESULTS: The administration of local anesthesia through this injection system resulted in complete pain relief without motor impairment of the arm. The device functioned for 118 days, making physical therapy easier. An infection occurred at the entry site, requiring the removal of the port. CONCLUSIONS: Controlled studies need to be done to establish the safety and efficacy of this form of therapy.
Asunto(s)
Plexo Braquial , Bombas de Infusión Implantables , Bloqueo Nervioso/métodos , Adulto , Brazo/inervación , Catéteres de Permanencia , Femenino , Humanos , Dolor/fisiopatología , Dolor/prevención & control , Sistema Nervioso Simpático/fisiopatología , Factores de TiempoRESUMEN
The absolute radiometer on Spacelab 1 was used to obtain solar irradiance observations from space. A number of effects must be taken into account in the data reduction. A provisional value was obtained for the mean solar constant during the observation period (6 to 8 December 1983).