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1.
ESMO Open ; 6(5): 100258, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34509803

RESUMEN

INTRODUCTION: Palliative chemotherapy is the principal treatment of patients with advanced soft tissue sarcomas (STS); however prognosis is limited (median overall survival 12-19 months). In this setting, patient values and priorities are central to personalised treatment decisions. PATIENTS AND METHODS: The prospective HOLISTIC study was conducted in the UK and the Netherlands assessing health-related quality of life in STS patients receiving palliative chemotherapy. Participants completed a questionnaire before starting chemotherapy, including attitudes towards quality of life (QoL) versus length of life (LoL), decisional control preferences, and decisional conflict. Chi-square and Fisher's exact tests were used to evaluate associations between patient characteristics and preferences. RESULTS: One hundred and thirty-seven patients with advanced STS participated (UK: n = 72, the Netherlands: n = 65). Median age was 62 (27-79) years. Preference for extended LoL (n = 66, 48%) was slightly more common than preference for QoL (n = 56, 41%); 12 patients (9%) valued LoL and QoL equally (missing: n = 3). Younger patients (age <40 years) prioritised LoL, whereas two-thirds of older patients (aged ≥65 years) felt that QoL was equally or more important than LoL (P = 0.020). Decisional conflict was most common in patients who prioritised QoL (P = 0.024). Most patients preferred an active (n = 45, 33%) or collaborative (n = 59, 44%) role in treatment decisions. Gender, performance status, and country were significantly associated with preferred role. Concordance between preferred and actual role in chemotherapy decision was high (n = 104, 76%). CONCLUSIONS: Heterogeneous priorities and preferences among advanced STS patients support personalised decisions about palliative treatment. Considering individual differences during treatment discussions may enhance communication and optimise patient-centred care.


Asunto(s)
Sarcoma , Neoplasias de los Tejidos Blandos , Adulto , Humanos , Persona de Mediana Edad , Cuidados Paliativos , Estudios Prospectivos , Calidad de Vida , Sarcoma/tratamiento farmacológico
2.
J Clin Pharm Ther ; 40(2): 125-30, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25545040

RESUMEN

WHAT IS KNOWN AND OBJECTIVE: The current pharmacotherapeutic treatment of major depressive disorder (MDD) generally takes weeks to be effective. As the molecular action of these drugs is immediate, the mechanistic basis for this lag is unclear. A drug that has a more rapid onset of action would be a major therapeutic advance and also be a useful comparator to provide valuable mechanistic insight into the disorder and its treatment. COMMENT: Recent evidence suggests that ketamine produces rapid-onset antidepressant action. Important questions are as follows: is it specific or coincidental to other effects; is there a dose-response relationship; and is the mechanism related to that of current antidepressants. NMDA receptor antagonism is unlikely the explanation for ketamine's antidepressant action. WHAT IS NEW AND CONCLUSION: It is not an exaggeration to state that the new findings, if validated, might produce a revolution in understanding and treating depressive disorders.


Asunto(s)
Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Ketamina/uso terapéutico , Animales , Antidepresivos/administración & dosificación , Antidepresivos/química , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Ketamina/administración & dosificación , Ketamina/química , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores
3.
Br J Pharmacol ; 162(2): 521-31, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20955363

RESUMEN

BACKGROUND AND PURPOSE: Surprisingly high contractile activity was reported for 11-deoxy-16,16-dimethyl prostaglandin E2 (DX-DM PGE2) on pig cerebral artery when used as a selective EP3 receptor agonist. This study investigated the selectivity profile of DX-DM PGE2, focusing on the interaction between its EP3 and TP (thromboxane A2-like) agonist activities. EXPERIMENTAL APPROACH: Contraction of guinea-pig trachea (EP1 system) and aorta (EP3 and TP systems) was measured in conventional organ baths. KEY RESULTS: Strong contraction of guinea-pig aorta to sulprostone and 17-phenyl PGE2 (EP3 agonists) was only seen under priming with a second contractile agent such as phenylephrine, histamine or U-46619 (TP agonist). In contrast, DX-DM PGE2 induced strong contraction, which on the basis of treatment with (DG)-3ap (EP3 antagonist) and/or BMS-180291 (TP antagonist) was attributed to self-synergism arising from co-activation of EP3 and TP receptors. EP3/TP self-synergism also accounted for contraction induced by PGF(2α) and its analogues (+)-cloprostenol and latanoprost-FA. DX-DM PGE2 also showed significant EP1 agonism on guinea-pig trachea as defined by the EP1 antagonists SC-51322, (ONO)-5-methyl-1 and AH-6809, although AH-6809 exhibited poor specificity at concentrations ≥3 µM. CONCLUSIONS AND IMPLICATIONS: EP3/TP self-synergism, as seen with PGE/PGF analogues in this study, may confound EP3 agonist potency comparisons and the characterization of prostanoid receptor systems. The competitive profile of a TP antagonist may be distorted by variation in the silent/overt contraction profile of the EP3 system in different studies. The relevance of self-synergism to in vivo actions of natural prostanoid receptor agonists is discussed.


Asunto(s)
Aorta/efectos de los fármacos , Dinoprostona/análogos & derivados , Subtipo EP3 de Receptores de Prostaglandina E/metabolismo , Receptores de Tromboxanos/metabolismo , Animales , Aorta/fisiología , Dinoprostona/metabolismo , Dinoprostona/farmacología , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Cobayas , Humanos , Técnicas In Vitro , Masculino , Terapia Molecular Dirigida , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Subtipo EP1 de Receptores de Prostaglandina E/agonistas , Subtipo EP1 de Receptores de Prostaglandina E/metabolismo , Subtipo EP3 de Receptores de Prostaglandina E/agonistas , Subtipo EP3 de Receptores de Prostaglandina E/antagonistas & inhibidores , Receptores de Tromboxanos/antagonistas & inhibidores , Tráquea/efectos de los fármacos , Tráquea/fisiología
4.
N Engl J Med ; 344(19): 1421-6, 2001 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-11346806

RESUMEN

BACKGROUND: Thousands of children, especially poor children living in deteriorated urban housing, are exposed to enough lead to produce cognitive impairment. It is not known whether treatment to reduce blood lead levels prevents or reduces such impairment. METHODS: We enrolled 780 children with blood lead levels of 20 to 44 microg per deciliter (1.0 to 2.1 micromol per liter) in a randomized, placebo-controlled, double-blind trial of up to three 26-day courses of treatment with succimer, a lead chelator that is administered orally. The children lived in deteriorating inner-city housing and were 12 to 33 months of age at enrollment; 77 percent were black, and 5 percent were Hispanic. Follow-up included tests of cognitive, motor, behavioral, and neuropsychological function over a period of 36 months. RESULTS: During the first six months of the trial, the mean blood lead level in the children given succimer was 4.5 microg per deciliter (0.2 micromol per liter) lower than the mean level in the children given placebo (95 percent confidence interval, 3.7 to 5.3 microg per deciliter [0.2 to 0.3 micromol per liter]). At 36 months of follow-up, the mean IQ score of children given succimer was 1 point lower than that of children given placebo, and the behavior of children given succimer was slightly worse as rated by a parent. However, the children given succimer scored slightly better on the Developmental Neuropsychological Assessment, a battery of tests designed to measure neuropsychological deficits thought to interfere with learning. All these differences were small, and none were statistically significant. CONCLUSIONS: Treatment with succimer lowered blood lead levels but did not improve scores on tests of cognition, behavior, or neuropsychological function in children with blood lead levels below 45 microg per deciliter. Since succimer is as effective as any lead chelator currently available, chelation therapy is not indicated for children with these blood lead levels.


Asunto(s)
Quelantes/uso terapéutico , Terapia por Quelación , Conducta Infantil/efectos de los fármacos , Desarrollo Infantil/efectos de los fármacos , Inteligencia/efectos de los fármacos , Intoxicación por Plomo/tratamiento farmacológico , Succímero/uso terapéutico , Preescolar , Cognición/efectos de los fármacos , Método Doble Ciego , Femenino , Humanos , Lactante , Plomo/sangre , Masculino , Pruebas Neuropsicológicas , Áreas de Pobreza , Población Urbana
5.
Pharmacoepidemiol Drug Saf ; 8(5): 343-50, 1999 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15073911

RESUMEN

PURPOSE: The Treatment of Lead-exposed Children (TLC) trial tested whether developmental outcome differed between children treated for lead poisoning with succimer or placebo. On 7 July 1997, TLC was informed that the vitamin and mineral supplements it gave to all children were contaminated with about 35 microg of lead per tablet. METHODS: TLC recalled the contaminated supplements and measured the children's exposure. RESULTS: The families of 96% of the children were contacted with 30 days. Among the 571 children to whom the contaminated supplements were dispensed, the mean increase in blood lead was 0.06+/-0.01 micromol/L (1.2+/-0.2 microg/dL); among 78 children to whom they were not, it was 0.09+/-0.03 micromol/L (1.8+/-0.7 microg/dL). There was no evidence of a dose-response relation between estimated supplement consumption and increase in blood lead concentration. CONCLUSIONS: The children's blood lead concentrations were not detectably affected by the contamination. Since the association of cognitive delay with lead exposure is best described for blood lead, we believe that the trial's inference about the effect of drug therapy on lead induced cognitive delay should be unaffected.

6.
Undersea Hyperb Med ; 25(3): 153-9, 1998.
Artículo en Inglés | MEDLINE | ID: mdl-9789334

RESUMEN

The purpose of this study was to determine the effects of a 1-h exposure to 2.0 atm abs (202.6 kPa) and 100% oxygen on subsequent maximal O2 consumption (VO2max), ventilation threshold (VT), lactate threshold (LT), and muscle oxygenation (%Mox) during incremental exercise to maximum on a cycle ergometer. Two baseline exercise tests (T1 and T2) were performed on separate occasions without prior exposure to hyperbaric oxygen (HBO2) and a third test (T3-HBO2) was performed after (22.5 +/- 5.6 min) HBO2 Near infared spectroscopy was used to monitor oxygenation of the left vastus lateralis muscle during T2 and T3-HBO2. No significant differences were observed between VO2max VT, or LT among any of the exercise tests. There was no significant difference in %Mox between T2 and T3-HBO2 except at 235 W where there was a significant elevation in %Mox during T3-HBO2 relative to T2. These results suggest that prior exposure to HBO2 (100% O2 at 2 atm abs for 1 h) has no ergogenic effect on subsequent incremental exercise performance.


Asunto(s)
Ejercicio Físico/fisiología , Oxigenoterapia Hiperbárica , Consumo de Oxígeno , Adulto , Prueba de Esfuerzo , Hematócrito , Humanos , Ácido Láctico/sangre
7.
J Nerv Ment Dis ; 182(3): 127-35, 1994 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-7509371

RESUMEN

One hypothesis of traditional psychoanalytic theory holds that a cardinal aspect of the "natural" development of femininity involves the woman's substitution of the wish for a baby in place of her original wish for a penis. The current study modified and extended earlier research examining the validity of Freud's this "penis-baby" theory. College-aged women and men were presented with either subliminal or supraliminal auditory messages concerned with either pregnancy or penetration themes. Subjects' written responses to Holtzman ink-blots, obtained both before and after exposure to an auditory message, were content-coded for phallic imagery and sexual imagery. Consistent with Freud's speculations about the phallic significance of pregnancy for women, female subjects who were exposed to the subliminal pregnancy message produced significantly more phallic imagery responses to ink-blots than did women in any of the other experimental conditions (p < .01). The phallic imagery production of males did not vary significantly as a function of message condition. Implications of these findings are discussed in the context of modern revisions to Freud's psychology of women and the current psychoanalytic conceptualization of penis envy as a highly condensed mental product with many layers of meaning.


Asunto(s)
Pene , Embarazo/psicología , Teoría Psicoanalítica , Adolescente , Adulto , Percepción Auditiva , Coito/psicología , Femenino , Prueba de Manchas de Tinta de Holtzman , Humanos , Imaginación , Masculino , Recuerdo Mental , Modelos Psicológicos , Desarrollo Psicosexual , Factores Sexuales , Conducta Sexual/psicología , Estimulación Subliminal , Simbolismo , Mujeres/psicología
9.
Biochemistry ; 27(3): 915-23, 1988 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-3365371

RESUMEN

Imino proton and 31P NMR studies were conducted on the binding of actinomycin D (ActD) to self-complementary oligodeoxyribonucleotides with adjacent 5'-GC-3' sites. ActD showed very high specificity for binding to GC sites regardless of oligomer length and surrounding sequence. For a first class of duplexes with a central GCGC sequence, a mixture of 1:1 complexes was observed due to the two different orientations of the ActD phenoxazone ring system. Analysis of 1H chemical shifts suggested that the favored 1:1 complex had the benzenoid side of the phenoxazone ring over the G base in the central base pair of the GCGC sequence. This is the first case in which an unsymmetrical intercalator has been shown to bind to DNA in both possible orientations. A unique 2:1 complex, with significantly different 1H and 31P chemical shifts relative to those of the 1:1 complexes, was formed with these same oligomers, again with the benzenoid side of the ActD molecule over the G base of the central GC base pair. There is considerable anticooperativity to binding of the second ActD in a GCGC sequence. In titrations of oligomers with the GCGC sequence, only the two 1:1 complexes are found up to ratios of one ActD per oligomer. Increasing the ActD concentration, however, resulted in stoichiometric formation of the unique 2:1 adduct. Spectrophotometric binding studies indicated that the apparent binding equilibrium constant for a GC site adjacent to a bound site is reduced by approximately a factor of 20 relative to the ActD binding constant to an isolated GC site.


Asunto(s)
Dactinomicina , Desoxicitidina , Desoxiguanosina , Oligodesoxirribonucleótidos , Secuencia de Bases , Hidrógeno , Espectroscopía de Resonancia Magnética/métodos , Fósforo
10.
Nucleic Acids Res ; 15(1): 105-18, 1987 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-3822802

RESUMEN

The electrophoretic mobilities and thermal melting properties of self complementary A-T containing dodecamer oligodeoxyribonucleotides have been investigated as a function of solution conditions. The oligomers contained tracts of nonalternating A-T base pairs of 2 (d(A2T2)3), 3 (d(A3T3)2), and 6 (d(A6T6] as well as the fully alternating (d(A-T)6) sequence. The melting temperature increased with the length of the nonalternating sequence and was approximately 12 degrees C higher in the d(A6T6) sequence than in the alternating oligomer. Under denaturing conditions all oligomers had the same electrophoretic mobility on acrylamide gels. Under conditions which favor duplex formation, the oligomers exhibited significant sequence dependent mobility differences. The mobilities of two oligomers, d(A-T)6 and d(A6-T6), were approximately equal and were less than those of the other oligonucleotides. The greatest mobility was observed for d(A2T2)3. These results are best explained by a model which requires bending at a junction of two or more continuous A or T bases with another sequence.


Asunto(s)
Adenina , Composición de Base , Oligodesoxirribonucleótidos , Timina , Secuencia de Bases , Desnaturalización de Ácido Nucleico , Espectrofotometría Ultravioleta , Relación Estructura-Actividad , Termodinámica
12.
Chest ; 86(2): 184-8, 1984 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-6744959

RESUMEN

Pulmonary function and arterial blood gases were measured in 35 patients undergoing routine diagnostic flexible fiberoptic bronchoscopy (FFB) either through an 8-mm endotracheal tube (ETT) or transnasally in order to investigate whether FFB changes lung function in a way which may explain why hypoxemia commonly occurs during this procedure. In these patients with moderate airway obstruction, functional residual capacity (FRC) increased significantly after inserting the ETT, after placing the FFB in the airway through the ETT, and after inserting the flexible bronchoscope transnasally. The mean increase in FRC was 30 percent in the intubated group before FFB insertion and 17 percent in the transnasal group. Removal of the FFB and ETT caused FRC to return toward the control value. Insertion of the ETT-FFB combination or transnasal FFB did not change PaO2 substantially, although following the examination, PaO2 was decreased significantly in the transnasal group but not in the intubated group. The PaO2 decreased significantly in both groups following removal of the ETT and transnasal FFB. These results suggest that placement of an FFB or ETT-FFB combination in the airway in spontaneously breathing subjects elevates FRC.


Asunto(s)
Broncoscopía/efectos adversos , Pulmón/fisiología , Intercambio Gaseoso Pulmonar , Adulto , Anciano , Anestesia Local , Broncoscopios , Femenino , Tecnología de Fibra Óptica/instrumentación , Capacidad Residual Funcional , Humanos , Hipoxia/etiología , Intubación Intratraqueal , Mediciones del Volumen Pulmonar , Masculino , Persona de Mediana Edad
13.
Exp Hematol ; 7(2): 74-80, 1979 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-371974

RESUMEN

A year-long double-blind study of 2,3-dihydroxybenzoic acid (2,3-DHB) given orally at a dose of 25 mg/kg four times per day was undertaken in 15 patients with beta-thalassemia major. 2,3-DHB and placebo (mannitol) were tolerated to an equal degree and there were no signs of drug toxicity at the end of 1 year. Efficacy in terms of retardation of iron accumulation could be documented using serial liver biopsies, serum ferritin determinations, or clinical laboratory assessment. Serum iron values increased, as did the iron binding capacity, in the group receiving 2,3-DHB. The increase in iron binding capacity was due to drug interference with the method of determination. Because of the greater efficacy of slow infusions of desferrioxamine in chelating iron when administered slowly, the clinic has shifted its emphasis toward further evaluation of that compound. Nevertheless, in view of the minimal toxicity of 2,3-DHB, further work appears warranted to define its role in the treatment of iron-overload.


Asunto(s)
Benzoatos/uso terapéutico , Quelantes/uso terapéutico , Talasemia/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Benzoatos/administración & dosificación , Benzoatos/efectos adversos , Quelantes/administración & dosificación , Quelantes/efectos adversos , Niño , Ensayos Clínicos como Asunto , Método Doble Ciego , Evaluación de Medicamentos , Femenino , Ferritinas/sangre , Humanos , Hierro/sangre , Hierro/metabolismo , Hígado/metabolismo , Masculino , Placebos , Talasemia/sangre , Talasemia/metabolismo , Factores de Tiempo
15.
Planta ; 72(2): 155-61, 1966 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24554208

RESUMEN

A bioassay is described which is dependent upon the fact that gibberellin induced α-amylase release from barley half-seeds is proportional to the logarithm of gibberellin concentration applied. This bioassay has been successfully applied to the estimation of gibberellin-like substances in plant extracts. The bioassay has the following advantages: 1) Release of α-amylase is one step closer to the primary site of action of GA; 2) release of α-amylase is not affected by solvent residues and is apparently completely specific for gibberellin; 3) release of α-amylase is not affected by substances other than gibberellins present in crude plant extracts.

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