RESUMEN
State-to-state rotational energy transfer in collisions of ground ro-vibrational state 13CO molecules with N2 molecules has been studied using the crossed molecular beam method under kinematically equivalent conditions used for 13CO + CO rotationally inelastic scattering described in a previously published report (Sun et al., Science, 2020, 369, 307-309). The collisionally excited 13CO molecule products are detected by the same (1 + 1' + 1'') VUV (Vacuum Ultra-Violet) resonance enhanced multiphoton ionization scheme coupled with velocity map ion imaging. We present differential cross sections and scattering angle resolved rotational angular momentum alignment moments extracted from experimentally measured 13CO + N2 scattering images and compare them with theoretical predictions from quasi-classical trajectories (QCT) on a newly calculated 13CO-N2 potential energy surface (PES). Good agreement between experiment and theory is found, which confirms the accuracy of the 13CO-N2 potential energy surface for the 1460 cm-1 collision energy studied by experiment. Experimental results for 13CO + N2 are compared with those for 13CO + CO collisions. The angle-resolved product rotational angular momentum alignment moments for the two scattering systems are very similar, which indicates that the collision induced alignment dynamics observed for both systems are dominated by a hard-shell nature. However, compared to the 13CO + CO measurements, the primary rainbow maximum in the DCSs for 13CO + N2 is peaked consistently at more backward scattering angles and the secondary maximum becomes much less obvious, implying that the 13CO-N2 PES is less anisotropic. In addition, a forward scattering component with high rotational excitation seen for 13CO + CO does not appear for 13CO-N2 in the experiment and is not predicted by QCT theory. Some of these differences in collision dynamics behaviour can be predicted by a comparison between the properties of the PESs for the two systems. More specific behaviour is also predicted from analysis of the dependence on the relative collision geometry of 13CO + N2 trajectories compared to 13CO + CO trajectories, which shows the special 'do-si-do' pathway invoked for 13CO + CO is not effective for 13CO + N2 collisions.
RESUMEN
Photofragment imaging is shown to provide a sensitive method for detection of the O2 A'3Δu Herzberg III state using a one-laser dissociation/O(1D) resonance enhanced multiphoton ionization (REMPI) scheme with a focused nanosecond dye laser beam tuned to 203.8 or 205.2 nm, combined with velocity map imaging of the atomic oxygen photofragment. O2 populated in the Herzberg states is generated by photodesorption at 250 nm of solid O2 ice held at 15 K and by an electric discharge in a pulsed molecular beam of pure O2. Ice photo-desorption results in Herzberg state products with higher translational, vibrational and rotational energy spreads, yielding the same signal as the discharge source but with lower velocity resolution. A clear signal with parallel character (ß â¼ 0.9) assigned to dissociation of O2 A'3Δu(v = 0, 1 Ω = 1) was observed when using a pulsed electric discharge source under specific 'cold' conditions with O(1D) detection, driving one-photon dissociation around 205 nm. No products corresponding to O2 A'3Δu state dissociation were observed for 225.625 or 200.32 nm dissociation with O(3P2) detection, which implies that the O2 A'3Δu state dissociates exclusively to the third (O1D + O1D) dissociation limit. Dissociation is suggested to take place through the 21Πg upper state to the O1D + O1D limit where spin-orbit coupling of the A'3Δu state with the 11Πu state accesses the allowed parallel 1Πu â 1Πg transition. While the absence of a parallel-type photodissociation signal from the c1Σ-u state may be expected, the A3Σ+u should spin-orbit couple through the same pathway as the A'3Δu state. The fact that no clear A3Σ+u signal is observed suggests a faster deactivation process compared to the A'3Δu state in the discharge and ice desorption process.
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The third-generation aromatase inhibitors (AIS) are largely replacing tamoxifen in the adjuvant treatment of early-stage breast cancer in postmenopausal women with hormone receptor-positive tumours. To date, multiple trials have been conducted comparing tamoxifen treatment with an AI, and all have demonstrated improved disease-free survival with AI treatment. Trials have included direct 5-year comparisons between tamoxifen and an AI, switching to an AI within 5 years after initial tamoxifen treatment, or extending treatment with an AI after 5 years of completed tamoxifen treatment. Some of these trials have been completed; others are ongoing; and head-to-head trial comparisons of individual AIS are also in progress. The present article summarizes the data obtained from various clinical trials of hormonal therapy for early breast cancer. It also reviews recent data so as to shed light on the current status of these therapies. The focus is on the efficacy of treatment with an AI. Toxicity is discussed in the second article in this supplement.
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BACKGROUND: A randomized trial conducted by the Gynecologic Oncology Group (GOG, study #111) in the United States showed a better outcome for patients with advanced ovarian cancer on the paclitaxel-cisplatin regimen than for those on a standard cyclophosphamide-cisplatin regimen. Before considering the paclitaxel-cisplatin regimen as the new "standard," a group of European and Canadian investigators planned a confirmatory phase III trial. METHODS: This intergroup trial recruited 680 patients with broader selection criteria than the GOG #111 study and administered paclitaxel as a 3-hour instead of a 24-hour infusion; progression-free survival was the primary end point. Patient survival was analyzed by use of the Kaplan-Meier technique. Treatment effects on patient survival were estimated by Cox proportional hazards regression models. All statistical tests were two-sided. RESULTS: The overall clinical response rate was 59% in the paclitaxel group and 45% in the cyclophosphamide group; the complete clinical remission rates were 41% and 27%, respectively; both differences were statistically significant (P =.01 for both). At a median follow-up of 38.5 months and despite a high rate of crossover (48%) from the cyclophosphamide arm to the paclitaxel arm at first detection of progression of disease, a longer progression-free survival (log-rank P =.0005; median of 15.5 months versus 11.5 months) and a longer overall survival (log-rank P =. 0016; median of 35.6 months versus 25.8 months) were seen in the paclitaxel regimen compared with the cyclophosphamide regimen. CONCLUSIONS: There is strong and confirmatory evidence from two large randomized phase III trials to support paclitaxel-cisplatin as the new standard regimen for treatment of patients with advanced ovarian cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Alopecia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Terapia Combinada , Estudios Cruzados , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Náusea/inducido químicamente , Estadificación de Neoplasias , Neutropenia/inducido químicamente , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/cirugía , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Análisis de Supervivencia , Trombocitopenia/inducido químicamente , Factores de Tiempo , Resultado del Tratamiento , Vómitos/inducido químicamenteRESUMEN
PURPOSE: To review critically the literature regarding effects of estrogen replacement therapy (ERT)/combined estrogen and progesterone replacement therapy (HRT) on the risk of breast cancer and on other health risks and benefits in postmenopausal women, with a focus on risks and benefits in women with a previous diagnosis of breast cancer. METHOD: A literature search was conducted using Medline, Cancerline, and the bibliographies of reports published as of March 1995. All five published meta-analyses that examined the risk of breast cancer in relation to ERT/HRT in otherwise healthy women were critically reviewed. All known reports of women with a history of breast cancer given ERT/HRT subsequent to diagnosis and additional reports regarding the benefits of ERT/HRT were also reviewed. RESULTS: None of the five meta-analyses demonstrated a significantly increased risk of developing breast cancer in ever users compared with never users of ERT/HRT. Current use may be associated with a small increased risk. This increased risk should be balanced by the expected benefits of ERT/HRT on quality of life, bone metabolism, and cardiovascular function. Preliminary information does not suggest a major detrimental effect of ERT/HRT in women with a previous diagnosis of breast cancer, but these reports include few women with limited follow-up data. There are no randomized trials in women with a previous diagnosis of breast cancer. CONCLUSION: In healthy postmenopausal women, the benefits associated with ERT/HRT outweigh the risks. In women with a previous diagnosis of breast cancer, the balance of risks and benefits should be explored in randomized controlled trials.
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Neoplasias de la Mama/inducido químicamente , Terapia de Reemplazo de Estrógeno/efectos adversos , Estrógenos/efectos adversos , Recurrencia Local de Neoplasia/inducido químicamente , Posmenopausia , Progesterona/efectos adversos , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Estudios Cruzados , Estrógenos/administración & dosificación , Femenino , Humanos , Metaanálisis como Asunto , Osteoporosis Posmenopáusica/etiología , Osteoporosis Posmenopáusica/prevención & control , Posmenopausia/efectos de los fármacos , Posmenopausia/fisiología , Posmenopausia/psicología , Progesterona/administración & dosificación , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , RiesgoRESUMEN
The activity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in advanced breast cancer patients who have failed doxorubicin treatment is well established, but the optimal sequence between these two important agents remains to be determined. The European Organization for Research and Treatment of Cancer therefore designed a prospective randomized clinical trial in which patients not exposed to anthracyclines in the adjuvant setting received either first-line paclitaxel, given as a 3-hour infusion at a dose of 200 mg/m2 followed at the time of disease progression by second-line doxorubicin, given as a bolus injection at a dose of 75 mg/m2 or the reverse sequence. The target accrual is 330 patients. Interim results on 207 evaluable patients of 289 randomized are presented.
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Adenocarcinoma/tratamiento farmacológico , Antibióticos Antineoplásicos/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/uso terapéutico , Paclitaxel/uso terapéutico , Adulto , Anciano , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/efectos adversos , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Estudios Cruzados , Progresión de la Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Europa (Continente) , Femenino , Insuficiencia Cardíaca/inducido químicamente , Humanos , Infusiones Intravenosas , Inyecciones Intravenosas , Persona de Mediana Edad , Neutropenia/inducido químicamente , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Estudios Prospectivos , Inducción de RemisiónRESUMEN
Nicotine stimulates the secretion of catecholamines from sympathetic nerve endings and adrenal medulla by acting on peripheral nicotinic cholinergic receptors. Nicotine is also a potent stimulant in the central nervous system but the significance of nicotinic receptors in brain in mediating cardiovascular and sympathoadrenal responses to nicotine is unclear. The responses of resting plasma catecholamines, blood pressure and heart rate were compared in rats receiving nicotine, administered either systemically or intracerebroventricularly (i.c.v.). Sympathoadrenal stress responses were also studied in rats rendered tolerant to nicotine from repeated systemic or intraventricular injections. Nicotine, given either intraventricularly or systemically, produced dose-related increases in the concentration of epinephrine in plasma. Little effect on norepinephrine in plasma was observed with nicotine given intraventricularly, indicating predominant stimulation of adrenomedullary pathways. In contrast, nicotine, given systemically, produced comparable increases in both epinephrine and norepinephrine. Blood pressure increased and heart rate fell in response to either intraventricular or systemic administration of nicotine. Rats exhibited tolerance to nicotine 24 hr after a single intraventricular injection; however, tolerance was not detected with systemically injected nicotine unless the injections were given at least every 30 min. Whereas rats rendered tolerant to systemic administration of nicotine were cross-tolerant to stress, with respect to sympathoadrenal stimulation, cross-tolerance with stress was not detected in rats treated with nicotine repeatedly by the intraventricular route. These results indicate that nicotinic receptors in brain modulate the central sympathetic outflow and adapt readily to nicotine stimulation with prolonged tolerance, but are probably not involved in sympathoadrenal stress responses. Peripheral nicotinic receptors, regulating sympathoadrenal secretion of catecholamines, displayed much shorter-lasting tolerance.
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Médula Suprarrenal/inervación , Sistema Nervioso Central/fisiopatología , Nicotina/farmacología , Nervios Periféricos/fisiopatología , Estrés Psicológico/fisiopatología , Sistema Nervioso Simpático/efectos de los fármacos , Médula Suprarrenal/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Inyecciones Intraarteriales , Inyecciones Intraventriculares , Masculino , Nicotina/administración & dosificación , Ratas , Ratas Endogámicas , Estimulación QuímicaRESUMEN
Although the management of breast cancer has improved over the past few decades, it remains an important challenge for the clinician. Cytotoxic chemotherapy and hormonotherapy, when given in the adjuvant setting, have a definitive though modest impact on the outcome of early-stage breast cancer. In metastatic disease, these therapies help to provide substantial palliation of symptoms but have a limited impact on survival. The discovery of vinorelbine and the taxanes, paclitaxel and docetaxel, certainly represented the most encouraging clinical development of the 1980s in breast cancer therapy. Several other new cytotoxic agents have been recognised for their potential in the treatment of this disorder. Many of them are only in a very early phase of their clinical development and it remains to be proven that they will have a major role in daily practice in the near future.
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Neoplasias de la Mama/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Femenino , Hormonas/uso terapéutico , HumanosRESUMEN
We compared the plasma catecholamine responses to intracisternal beta-endorphin with those to two mu receptor agonists. Morphine was less potent and [D-Ala2, MePhe4, Gly5-ol]enkephalin (DAGO) was more potent in stimulating catecholamine secretion. Since the hypothalamic paraventricular nucleus (PVN) contains a high level of opioid binding sites and is important for sympathoadrenal regulation, we examined the effects on catecholamine secretion of DAGO infusion into the PVN. DAGO infused into the PVN produced dose-related increases in plasma catecholamine concentrations, with an effective dose as low as 10pmol. This DAGO effect was blocked by the prior systemic administration of naloxone, and DAGO was ineffective when infused into frontoparietal cortex. Thus, endogenous opioid peptides appear to increase central sympathetic outflow and catecholamine secretion by stimulating mu receptors in the PVN.
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Catecolaminas/metabolismo , Endorfinas/farmacología , Animales , Encéfalo/efectos de los fármacos , Encefalina Ala(2)-MeFe(4)-Gli(5) , Encefalinas/farmacología , Masculino , Morfina/farmacología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Ratas , Ratas Endogámicas , Receptores Opioides/efectos de los fármacos , betaendorfinaRESUMEN
Synthetic human beta-endorphin, 7.25 nmol intracisternally, in conscious, freely moving, cannulated adult male rats increased plasma concentrations of the 3 catecholamines, epinephrine, norepinephrine and dopamine. Similarly administered equimolar morphine increased only plasma epinephrine concentration significantly. A 10-fold greater intracisternal dose of morphine significantly increased plasma concentrations of all 3 catecholamines. This effect was inhibited by prior intra-arterial naloxone administration. Intracisternal administration of the selective mu receptor agonist [D-Ala2,NMe-Phe4,Gly-ol5]enkephalin (DAGO), 2.9 nmol, also increased plasma concentrations of the 3 catecholamines and, furthermore, these effects were significantly greater than those noted in response to equimolar beta-endorphin. The greater potency of DAGO than beta-endorphin to increase catecholamine secretion suggests that this opioid peptide-induced effect is mediated at mu receptors. Administration of DAGO, 0.1 nmol, directly into either the hypothalamic paraventricular nucleus (PVN) or brainstem nucleus of the solitary tract (NTS) significantly increased plasma concentrations of all 3 catecholamines when compared with either saline-infused controls or animals administered DAGO into other brain areas. These catecholamine-stimulating effects of DAGO administered into either PVN or NTS were prevented by prior intra-arterial naloxone administration. Heart rate, but not mean arterial blood pressure, increased in response to DAGO administration into the NTS while no significant cardiovascular changes were noted among the experimental groups in response to DAGO administered into the PVN. These data support a hypothesis that mu receptors at discrete and anatomically distant brain sites mediate opioid peptide-induced catecholamine secretion through activation of the central sympathetic outflow to the adrenal medulla and sympathetic nerve terminals.
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Tronco Encefálico/fisiología , Catecolaminas/sangre , Corteza Cerebral/fisiología , Núcleo Hipotalámico Paraventricular/fisiología , Receptores Opioides/fisiología , Sistema Nervioso Simpático/fisiología , Animales , Endorfinas/farmacología , Encefalina Ala(2)-MeFe(4)-Gli(5) , Encefalinas/farmacología , Masculino , Naloxona/farmacología , Ratas , Ratas Endogámicas , Receptores Opioides mu , Núcleo Espinal del Trigémino/fisiología , betaendorfinaRESUMEN
Cocaine (25 mg/kg i.p.) produces analgesia in the rat within 5 min and for a duration of 90 min as determined by the formalin test or for 30 min as determined by the hot plate test. Cocaine analgesia is unaffected by doses of naloxone that are sufficient to attenuate morphine analgesia in both tests. Chlorpromazine (3 mg/kg i.p.), SCH 23390 (100 micrograms/kg i.p.; a D1 dopamine receptor antagonist), and eticlopride (75 micrograms/kg i.p.; a D2 dopamine receptor antagonist) each attenuate cocaine analgesia in both tests at doses that alone do not affect performance in either test. Measurements of blood pressure and heart rate indicate that cocaine analgesia is not due to the activation of baroreceptor reflex afferents. We conclude that cocaine is a supraspinally acting, dopamine-mediated, non-opiate analgesic in the rat.
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Analgesia , Encéfalo/fisiología , Cocaína/farmacología , Receptores Dopaminérgicos/fisiología , Animales , Benzazepinas/farmacología , Presión Sanguínea/efectos de los fármacos , Encéfalo/efectos de los fármacos , Clorpromazina/farmacología , Cocaína/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Naloxona/farmacología , Dolor/metabolismo , Ratas , Ratas Endogámicas , Receptores Dopaminérgicos/efectos de los fármacos , Salicilamidas/farmacologíaRESUMEN
These studies examined the effects of cocaine on thalamic neurons that respond maximally either to noxious or to innocuous somatic stimulation. Cocaine attenuated high intensity electrically-evoked nociceptive responses of all 25 units studied in the parafascicular and central lateral nuclei of the medial thalamus. A dose of 1 mg/kg intravenously (i.v.) suppressed medial thalamic unit discharge evoked by both noxious somatic stimulation (49.4 +/- 8.7% of control response) and spinal cord stimulation (76.2 +/- 6.6% of control response). The effect of cocaine on unit responses to noxious somatic stimulation was dose-related in the range of 0.3-3.5 mg/kg i.v. and was attenuated by eticlopride, a D-2 selective dopamine receptor antagonist. Morphine also suppressed noxious somatic evoked responses of medial thalamic units in a dose-dependent manner. Units in the lateral (ventrobasal) thalamus (n = 4) that responded only to innocuous stimuli were not affected by cocaine at doses up to 3.5 mg/kg i.v. Ibotenic acid lesions in the parafascicular nucleus of the medial thalamus attenuated the analgesic effect of cocaine in the formalin test. These results suggest that both cocaine and the parafascicular nucleus interact with dopaminergic mechanisms that attenuate nociceptive spinal projections to the medial thalamus.
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Analgésicos , Conducta Animal/efectos de los fármacos , Cocaína/farmacología , Dopamina/fisiología , Neuronas/fisiología , Tálamo/fisiología , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Endogámicas , Tálamo/citologíaRESUMEN
The role of dopaminergic descending supraspinal processes in mediating the antinociceptive action of cocaine was studied in the rat using a combination of extracellular neuronal recording and behavioral techniques. Neurons in the superficial laminae (I-II) of the spinal dorsal horn with receptive fields on the tail were recorded in anesthetized rats using insulated metal microelectrodes. Stimulation of the receptive field with either high intensity transcutaneous electrical pulses or with an infrared CO2 laser beam produced a biphasic increase in dorsal horn unit discharge. Conduction velocity estimates indicated that the early discharge corresponded to activity in A delta whereas the late response corresponded to activity in C afferent fibers. Cumulative doses of cocaine (0.1-3.1 mg/kg i.v.) inhibited the late response to either electrical or laser stimulation in a dose-related manner. The early response to laser, but not electrical, stimulation was also suppressed by cocaine. Neurons in the spinal dorsal horn with receptive fields on the ipsilateral hindpaw were activated by natural noxious (pinch) or innocuous (tap) somatic stimulation. Cocaine selectively suppressed nociceptively evoked dorsal horn unit discharge. This antinociceptive effect was dose-related (0.3-3.1 mg/kg, i.v.) and antagonized by eticlopride (0.05-0.1 mg/kg, i.v.), a selective D2 dopamine receptor blocker. The same doses of cocaine failed to inhibit the responses of dorsal horn neurons to low threshold innocuous stimulation. Complete thoracic spinal cord transection eliminated the antinociceptive effect of cocaine on dorsal horn neurons and also eliminated the cocaine-induced attenuation of the tail-flick reflex.(ABSTRACT TRUNCATED AT 250 WORDS)
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Cocaína/farmacología , Dopamina/fisiología , Nociceptores/fisiología , Médula Espinal/fisiología , Animales , Estimulación Eléctrica , Electrofisiología , Rayos Infrarrojos , Rayos Láser , Masculino , Neuronas/efectos de los fármacos , Neuronas/fisiología , Dolor/fisiopatología , Dimensión del Dolor , Estimulación Luminosa , Ratas , Tiempo de Reacción , Médula Espinal/citologíaRESUMEN
Excessive cigarette smoking acts synergistically with atheromatous coronary artery disease to greatly enhance the risk of acute myocardial infarction. To explore a possible mechanism of this relation, the present study tested the hypotheses that diet-induced atherosclerosis in rabbits is associated with an increase in myocardial (-)-norepinephrine content and that the increased (-)-norepinephrine can be released by nicotine. Adult male rabbits were rendered atherosclerotic by feeding them a standard laboratory diet enriched with 2% cholesterol. After 12-13 weeks on the diet, hearts were excised and retroperfused according to the Langendorff technique. There were no differences between control and atherosclerotic animals in terms of baseline (-)-norepinephrine concentration in the coronary effluent. However, increases in effluent (-)-norepinephrine concentration provoked by 10 micrograms and 30 micrograms nicotine were significantly greater in atherosclerotic hearts than in controls. Similarly, myocardial tissue from atherosclerotic animals contained significantly more (-)-norepinephrine than controls. These observations suggest that diet-induced atherosclerosis in rabbits is associated with an increase in myocardial (-)-norepinephrine content and that the augmented (-)-norepinephrine pool can be mobilized by nicotine.
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Arteriosclerosis/metabolismo , Corazón/efectos de los fármacos , Miocardio/metabolismo , Nicotina/farmacología , Norepinefrina/metabolismo , Animales , Arteriosclerosis/etiología , Arteriosclerosis/patología , Colesterol en la Dieta/efectos adversos , Vasos Coronarios/patología , Epinefrina/análisis , Epinefrina/metabolismo , Masculino , Contracción Miocárdica/efectos de los fármacos , Infarto del Miocardio/etiología , Norepinefrina/análisis , ConejosRESUMEN
D-ala2-met-sulfoxide5-enkephalinamide, DALA(0), was synthesized by oxidizing the 5-methionine residue of D-ala2-met5-enkephalinamide (DALA). Antinociception was assessed on the hot-plate and catalepsy estimated using an immobility test in rats administered DALA, DALA(0) and morphine intraventricularly. By comparing areas under time-effect curves, DALA(0) was 30 times more antinociceptive and up to 40 times more cataleptogenic than DALA. For comparison, morphine induced one-tenth the antinociception and one-fortieth the immobility caused by DALA(0). These results demonstrate that the opiate activity of DALA is clearly enhanced by oxidation of its terminal methionine.
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Analgésicos Opioides/farmacología , Encefalina Metionina/análogos & derivados , Metionina , Analgésicos Opioides/síntesis química , Animales , Encefalina Metionina/síntesis química , Encefalina Metionina/farmacología , Masculino , Microinyecciones , Morfina/farmacología , Oxidación-Reducción , Ratas , Ratas Endogámicas , Relación Estructura-ActividadRESUMEN
To examine the role of dopamine receptor subtypes mediating analgesic and motor responses to opioids, rats were pretreated with either saline or a selective D-1 or D-2 dopamine receptor antagonist 10 min prior to morphine (12 mg/kg IP). Analgesic response latency was determined using the hot plate test (52.5 degrees C and 55 degrees C), and catalepsy was assessed using the abnormal posture test. Morphine increased analgesic response latency to 44.5 +/- 7.9% of the maximum possible response, but had no cataleptic effect in the abnormal posture test. Pretreatment with either the D-1 antagonist, SCH 23390 (50-100 micrograms/kg), or the D-2 antagonist, eticlopride (20-150 micrograms/kg), potently enhanced morphine analgesia as measured on the 52.5 degrees C hot plate. Peak analgesic responses to morphine increased to 100 +/- 0% and 91.9 +/- 7.5% of maximum with the highest doses of SCH 23390 and eticlopride, respectively. These treatments also produced catalepsy. Increasing the hot plate temperature to 55 degrees C reduced response latency in groups treated with either dopamine receptor antagonist plus morphine. This indicates that the animals were capable of responding at a shorter latency and demonstrates that motor impairment cannot account for potentiation of morphine analgesia by D-1 and D-2 antagonists at 52.5 degrees C. These results show that the relationship between dopamine and opioids with respect to analgesic and motor systems involves both dopamine receptor subtypes.
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Analgésicos , Morfina/farmacología , Actividad Motora/efectos de los fármacos , Receptores Dopaminérgicos/fisiología , Animales , Benzazepinas/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Actividad Motora/fisiología , Ratas , Ratas Endogámicas , Tiempo de Reacción/efectos de los fármacos , Receptores Dopaminérgicos/efectos de los fármacos , Salicilamidas/farmacologíaRESUMEN
The value of adjuvant systemic therapy in breast cancer patients is well established but remains essentially modest. Operable breast cancer patients with positive or negative axillary lymph nodes, will have a 20% decrease in their annual odds of death at 10 years with appropriate systemic therapy. Several questions are still open in the field of systemic adjuvant therapy. For patients with node negative disease, treatment recommendations were recently issued by a group of experts with the aim to percent over- and under-treatment. The optimal duration of tamoxifen adjuvant therapy is still debatable, as is its role in a prevention setting. In patients with 10 or more positive axillary nodes, the search for more effective therapies prompted investigators to compare standard dose chemotherapy to high dose chemotherapy. Also, the value of adding a taxoid in the adjuvant chemotherapy regimen, is tested by several research groups. Hopefully, some of these hypothesis will be translated into a greater benefit for each individual breast cancer patient.
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Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Terapia Combinada , Femenino , Humanos , Metástasis de la Neoplasia , Ovariectomía , Tamoxifeno/uso terapéuticoRESUMEN
Adjuvant therapy for breast cancer is an effective mean to reduce the likelihood of recurrence and to increase overall survival, as shown by the Early Breast Cancer Trialists' Group Overview. Although these benefits are clearly significant, they represent a modest improvement in the care of breast cancer. The role of pre-operative chemotherapy remains to be defined in early stage breast cancer. Otherwise, pre-operative chemotherapy has become 'standard of care' in locally advanced and inflammatory breast cancer. There are still several questions to be answered in the field of adjuvant and pre-operative chemotherapy. Prospective randomized clinical studies are the only way to obtain further therapeutic progress for this highly lethal disease.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante , Tamoxifeno/uso terapéutico , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Femenino , Humanos , Metástasis de la Neoplasia , Cuidados Posoperatorios , Cuidados PreoperatoriosRESUMEN
B cell chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is a clonal expansion of CD5(+)CD19(+) B lymphocytes. Two types of CLLs are being distinguished as carrying either unmutated or somatically mutated immunoglobulins (Igs), which are associated with unfavorable and favorable prognoses, respectively. More than 30% of CLLs can be grouped based on their expression of stereotypic B cell receptors (BCRs), strongly suggesting that distinctive antigens are involved in the development of CLL. Unmutated CLLs, carrying Ig heavy chain variable (IGHV) genes in germline configuration, express low-affinity, poly-, and self-reactive BCRs. However, the antigenic specificity of CLLs with mutated IGHV-genes (M-CLL) remained elusive. In this study, we describe a new subset of M-CLL, expressing stereotypic BCRs highly specific for ß-(1,6)-glucan, a major antigenic determinant of yeasts and filamentous fungi. ß-(1,6)-glucan binding depended on both the stereotypic Ig heavy and light chains, as well as on a distinct amino acid in the IGHV-CDR3. Reversion of IGHV mutations to germline configuration reduced the affinity for ß-(1,6)-glucan, indicating that these BCRs are indeed affinity-selected for their cognate antigen. Moreover, CLL cells expressing these stereotypic receptors proliferate in response to ß-(1,6)-glucan. This study establishes a class of common pathogens as functional ligands for a subset of somatically mutated human B cell lymphomas.