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61.
62.
James Cassidy Martin A. Graham Wim Ten Bokkel Huinink Cathy McDaniel Albert Setanoians Elaine M. Rankin David J. Kerr Stanley B. Kaye 《Cancer chemotherapy and pharmacology》1993,31(5):395-400
Summary LL-D491941 is a new cytotoxic antibiotic selected for clinical phase I study because of its impressive pre-clinical anti-tumour activity and its low toxicity profile in experimental animals. A total of 15 patients were treated in centres in Glasgow and Amsterdam at doses ranging from 0.25 to 4 mg/m2. One minor response was noted in a patient with colonic carcinoma. The study was suspended following the discovery of unexpected cardiotoxicity. As this toxicity was not consistent with the standard (EORTC) European Organisation for Research and Treatment of Cancer toxicology profile, we chose to investigate the pharmacokinetics of LL-D491941 in mice and humans in more detail to try to explain this phenomenon. A major difference in plasma protein binding was discovered between mice and patients, with a suggestion of non-linear kinetics being noted at higher doses in humans. It is likely that these differences in drug handling account for the unexpected and serious toxicity encountered in this trial. 相似文献
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Rationale: Defining the mechanism of tolerance development to hallucinogenic drugs will help to explain their mechanism of action. Objectives: The present study was conducted to determine first, if tolerance develops to the discriminative stimulus (DS) properties
of the hallucinogen, 2,5 dimethoxy-4-iodo-amphetamine (DOI) and second, the mechanism mediating tolerance. Methods: Rats were trained to discriminate 0.75 mg/kg DOI from saline on a concurrent VI-30-min schedule of reinforcement with a
15-min time-out for incorrect responses. To evaluate tolerance development, rats were assigned to one of four groups and treated
with either chronic saline or chronic DOI. Prior to chronic treatment, two groups were tested for choice behavior following
vehicle administration while the remaining two groups were tested following the administration of 0.375 mg/kg DOI. One group
from each pre-test condition was injected with either saline or DOI (1 mg/kg) for 8 days. Twenty-four hours after the last
chronic injection the pre-test treatments were replicated. Using receptor autoradiography, the density of 5-HT2A and 5-HT2C receptors was measured in independent groups of rats that had received identical treatment conditions. Results: Animals receiving chronic DOI showed a 60% decrease in DOI lever responding (from 100% to 40%) when tested on 0.375 mg/kg
DOI, while animals receiving chronic saline showed no change in percent choice (100%) on the DOI lever. Significant changes
in binding were observed in 5-HT2A receptors but not 5-HT2C receptors. The results of tests with antagonists were consistent with the changes in binding. Conclusions: These results suggest that behavioral tolerance to DOI reflects neuroadaptive changes in 5-HT2A receptors.
Received: 17 July 1998 / Final version: 19 January 1999 相似文献
66.
David K. Ornstein Ganesh S. Rao Brooke Johnson Elaine T. Charlton Gerald L. Andriole 《Urology》1996,48(6):901-905
Objectives
To evaluate the efficacy of combined finasteride and flutamide therapy in men with advanced prostate cancer by determining (1 ) the short-term tolerability of finasteride monotherapy and its effect on serum prostate-specific antigen (PSA) and hormone (testosterone, dihydrotestosterone) levels, and (2) the effects of the addition of flutamide on tolerability and on serum PSA and hormone levels.Methods
Thirteen hormone-naive men with advanced prostate cancer (4 with Stage D2, 1 with Stage D1, 1 with Stage DO, 7 with rising PSA levels after radical prostatectomy [n = 2]or definitive radiation therapy [n = 5]) were initially treated with 5 mg finasteride daily. Flutamide (250 mg three times a day) was added after serum PSA levels stabilized.Results
Finasteride alone (median 5 weeks) had no significant effect on serum PSA levels (P>0.05). Combined finasteride and flutamide resulted in a mean 91% reduction in serum PSA levels, with 85% of men achieving a nadir serum PSA level of less than 4.0 ng/mL and 46% achieving undetectable levels (0.2 ng/mL or less). Finasteride alone had no significant effect on serum testosterone levels (P>0.05) but did result in a mean 74% reduction in serum dihydrotestosterone levels. Combined finasteride and flutamide resulted in a mean 56% increase in serum testosterone levels but had no additional effect on serum dihydrotestosterone levels (P>0.05). Side effects occurred in 85% (gynecomastia or breast tenderness in 62% [8 of 13]and diarrhea in 23% [3 of 13]) of men on combined therapy. Potency was preserved in 66%. Combined finasteride and flutamide therapy was withdrawn from 15% (2 of 13) because of flutamide-induced diarrhea and from 23% (3 of 13) because of disease progression. All remaining patients (8 of 13) have serum PSA levels below 4.0 ng/mL and 4 of these 8 have undetectable levels. These men have received combined finasteride and flutamide for a median 11 months (range 6 to 19).Conclusions
Finasteride monotherapy is inadequate therapy for advanced prostate cancer, but combined finasteride and flutamide may be a reasonable alternative for men with advanced prostate cancer who refuse conventional hormone therapy. 相似文献67.
Elaine Walster Ph.D. Jane Traupmann G. William Walster Ph.D. 《Archives of sexual behavior》1978,7(2):127-141
Equity theory has recently been found to be a useful framework for under-standing the effects of imbalances in intimate contractual relationships such as marriage. Equitable couples seem to be happier, more satisfied with their relationship, and more confident that it will last than are their more mismatched, i.e., inequitable, counterparts. Furthermore, inequitable couples predictably act to set things right in their marriage. They either restore actual equity to the relationship or psychologically set their relationship in balance. If neither works, they may leave the field. Extramarital sex may be viewed as an equity restoration mechanism in that (1) it may be used by the deprived partner to achieve actual equity, (2) it may indicate a partner's readiness to leave the relationship because he feels he can do better, or (3) it may represent a desire to achieve equity in an alternative relationship(s) when inequity pervades the primary one. The hypothesis that the inequitable/underbenefited group should be more likely than the equitable group or the inequitable/overbenefited group to have engaged in extramarital sex was tested using data from a large-scale Psychology Todayquestionnaire. The results indicated that men and women in inequitable/under-benefited relationships had more extramarital affairs and began their extramarital activities earlier than did men and women in equitable and inequitable/over-benefited relationships. Alternative explanations of this finding, sex-role demands and length of the relationship, are explored and discarded as untenable.
Research supported in part by National Institute of Mental Health Grant MH 26681. 相似文献
68.
Francisco José H. N. Braga Elaine B. Araújo Edwaldo E. Camargo Leontina C. M. Tedesco-Marchesi Maria Cecilia M. Rivitti Hateme Bouladour Pierre Galle 《European journal of nuclear medicine and molecular imaging》1991,18(11):866-869
Gallium 67 imaging was used in 12 patients with documented Hansen's disease undergoing treatment or not, in an attempt to determine the pattern of the disease. Diagnosis was confirmed by histopathology in all patients. The Mitsuda reaction was seen in all patients. Specific nuclear studies were performed when needed to evaluate particular organs better. Gallium 67 images show homogeneous, diffuse and moderate accumulation over the entire skin surface (except for the face) of untreated patients with multibacillary disease. The facial skin in these cases presented homogeneous, diffuse but very marked uptake of gallium. Internal organ involvement was variable. There was a very good correlation among clinical, scintigraphic, immunological and histopathological data. The pattern of the body skin (skin outlining) and facial skin (beard distribution) may be distinct for untreated patients with multibacillary leprosy. 相似文献
69.
Rats were trained to discriminate the stimulus properties of l-5-hydroxytryptophan (l-5-HTP) (30 mg/kg SC), the immediate precursor of serotonin (5-HT). The peripheral decarboxylase inhibitor R04-4602, administered prior to l-5-HTP, greatly attenuated the disruptive effects observed on responding when l-5-HTP alone was injected. Following acquisition, the discrimination was dosedependent and generalized to fenfluramine, a 5-HT-releasing drug, but not to amphetamine, a catecholamine-releasing agent. Further evidence for the involvement of 5-HT receptor stimulation in mediating the discrimination was that pretreatment with fluoxetine, a highly specific 5-HT uptake inhibitor, markedly potentiated the cue. Nevertheless, the classical 5-HT antagonists methysergide, cyproheptadine, metergoline, and methiothepin did not block the l-5-HTP-related discriminative stimulus. This finding suggested that the cue properties of l-5-HTP might be mediated by a population of 5-HT receptors previously identified electrophysiologically in limbic structures. As in the present experiment, the putative 5-HT antagonists did not block the synaptic effects of 5-HT in these structures. 相似文献
70.
PURPOSE: Monoclonal antibody-mediated targeting of liposomal anticancer drugs to surface antigens expressed on malignant B cells can be an effective strategy for treating B-cell malignancies. In a murine model of human B-cell lymphoma, we have made in vitro and in vivo comparisons of long-circulating sterically stabilized (Stealth) immunoliposome (SIL) formulations of two anticancer drugs, vincristine (VCR) and doxorubicin (DXR), with different mechanisms of action and drug release rates. EXPERIMENTAL DESIGN: SIL formulations of VCR or DXR were conjugated to the monoclonal antibody anti-CD19 (SIL[alphaCD19]) or its Fab' fragments (SIL[Fab']). Specific binding of SILs to Namalwa cells was studied using radiolabeled liposomes, and cytotoxicities of DXR- or VCR-loaded SILs were quantitated by a tetrazolium assay. Pharmacokinetic and drug leakage experiments were performed in mice using dual-labeled liposomes, and the therapeutic responses of SILs were evaluated in a Namalwa (human B lymphoma) cell xenograft model. RESULTS: SIL[alphaCD19] or SIL[Fab'] had higher association with and cytotoxicity against Namalwa cells than nontargeted liposomes. SIL[Fab'] had longer circulation times than SIL[alphaCD19], and VCR had faster release rates from the liposomes than DXR. SIL formulations of either VCR or DXR had significantly better therapeutic outcomes than nontargeted liposomes or free drugs. SILs loaded with VCR were superior to those loaded with DXR. SIL[Fab'] had better therapeutic outcomes than SIL[alphaCD19] for the drug DXR but were equally efficacious for the drug VCR. CONCLUSIONS: Treatment of a B lymphoma model with single injections of anti-CD19-targeted liposomal formulations of VCR resulted in high levels of response and long-term survivors. Responses to anti-CD19-targeted liposomal DXR were more modest, although the longer circulation times of SIL[Fab'] versus SIL[alphaCD19] led to superior therapeutics for DXR-loaded immunoliposomes. 相似文献