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991.
992.
α-Methylene-γ-butyrolactones with Molluscicidal Activity The α-methylene-γ-butyrolactones 1-28 were tested in vitro for molluscicidal activity against Biomphalaria glabrata. The racemic compound 25 shows the best activity. The synthesis was carried out by modified Reformatzky reaction of the corresponding carbonyl compounds and bromomethylacrylic acid ethyl ester. 7-10, 17 and 22-27 have been synthesized for the first time. 相似文献
993.
Mental illness and the continuum of residential stability 总被引:1,自引:0,他引:1
994.
C. J. Bowden W. D. Figg N. A. Dawson O. Sartor R. J. Bitton M. S. Weinberger Donna Headlee Eddie Reed C. E. Myers M. R. Cooper 《Cancer chemotherapy and pharmacology》1996,39(1-2):1-8
Introduction: Suramin is a synthetic polysulfonated naphthylurea which has been used for the treatment of African trypanosomiasis and onchocerciasis,
but since the mid-1980s has received attention as a possible antiretroviral and antineoplastic agent. Objective: This clinical trial of suramin was undertaken as a phase I/II study in patients with hormone-refractory prostate cancer,
with the hypothesis that the intensity of therapy with suramin could be increased significantly if measures were undertaken
to maintain the plasma concentrations of the drug under 300 μg/ml. Methods: We report the clinical results of this trial, wherein patients were treated at three different targeted plasma suramin concentrations
(275, 215 and 175 μg/ml) for varying periods of time (2, 4 or 8 weeks), with delivery of the drug by continuous intravenous
infusion. Results: The major toxicity observed in this trial was neurologic, consisting of a motor and sensory peripheral neuropathy that resulted
in both paresis and paralysis of the limbs. Nearly all of this severe (CTEP grade III, IV) neurologic toxicity was observed
in the patients treated at a plasma suramin concentration of 275 μg/ml for 4 or more weeks. A single patient treated at 215 μg/ml
for 8 weeks developed moderate (CTEP grade III) proximal lower extremity weakness, and no patient treated at 175 μg/ml developed
this toxicity. The second most common toxicity observed was infection of the central venous catheter. The overall response
rate for all of the evaluable patients was 17% (13 of 75 patients). In addition, prostate-specific antigen (PSA)-defined responses
were observed in six patients receiving therapy at 175 μg/ml, but these responses were confounded by cessation of therapy
with flutamide during suramin treatment. Conclusions: In summary, although plasma suramin concentrations were maintained below 300 μg/ml, neurologic toxicity nonetheless occurred
with high frequency in patients treated at 275 μg/ml for 4 or more weeks. Therapy at 215 and 175 μg/ml was in general well
tolerated, but central venous catheter-related infection, as well as the inconvenience and expense of continuous infusional
therapy, make this method of drug delivery impractical. Only moderate antitumor activity was observed during this trial, but
it is possible that both continuation of flutamide and flutamide withdrawal during suramin therapy confounded the assessment
of suramin’s activity in hormone-refractory prostate cancer.
Received: 9 June 1995/Accepted: 18 March 1996 相似文献
995.
A F Cacciapuoti D Loebenberg E L Moss F W Menzel J A Rudeen L R Naples C L Cramer R S Hare A K Mallams G H Miller 《The Journal of antibiotics》1990,43(9):1131-1136
A series of tylosins and acyl derivatives of 23-O-demycinosyltylosin (DMT) were initially tested for in vitro antibacterial activity and serum levels in squirrel monkeys (po) and mice (iv). Overall, the DMT compounds were more active in vitro than the tylosins. Two tetraacylated DMTs, Sch 37644 and Sch 38646, were selected from the initial studies for further evaluation and compared to erythromycin and A-56268 (6-O-methyl erythromycin). Sch 37644 and Sch 38646 were 2 to 8-fold less potent in vitro against Gram-positive bacteria than erythromycin and A-56268. In squirrel monkeys, Sch 37644 (AUC, 19.7 micrograms.hour ml) and A-56268 (21.6 micrograms.hour/ml) had similar serum levels following po administration of 20 mg/kg, while Sch 38646 (11.8 micrograms.hour/ml) and erythromycin (1.5 micrograms.hour/ml) had lower levels. In mice administered 200 mg/kg orally, Sch 37644 (AUC, 19.4 micrograms.hour/ml) and Sch 38646 (15.4 micrograms.hour/ml) had higher serum levels than erythromycin (5.7 micrograms.hour/ml). A-56268 was the most active po macrolide in mouse protection studies (PD50S) against Staphylococci and Streptococci, while Sch 37644 and Sch 38646 were similar to erythromycin. 相似文献
996.
The effects of neuropeptide Y and its fragments upon basal and electrically stimulated ion secretion in rat jejunum mucosa. 总被引:3,自引:3,他引:0 下载免费PDF全文
1. The effects of acute or chronic morphine treatment on the changes in blood pressure and pulse rate in response to ganglionic stimulation or blockade and to vagal stimulation, and of isolated atria to field stimulation or noradrenaline, were studied. 2. In pithed rats, intravenously injected hexamethonium significantly depressed the blood pressure responses to sympathetic nerve stimulation. The ganglionic blocking effects of hexamethonium were significantly greater in chronically morphine-treated rats, but were not significantly affected by acute morphine administration in naive animals. 3. Intravenous administration of nicotine dose-dependently increased blood pressure and pulse rate. The magnitudes of these changes were not significantly affected by acute or chronic morphine pretreatment. 4. Studies with rat isolated atrial preparations revealed that the changes in atrial contractile rate and force in response to noradrenaline or field stimulation were not influenced by either acute or chronic morphine treatment. 5. Cervical vagal stimulation produced voltage- or frequency-dependent decreases in pulse rate and blood pressure. The responses were not significantly affected by chronic morphine treatment. 6. These findings suggest that the site of the changes in sympathetic function following prolonged exposure to the opiate appears to be on the preganglionic nerve fibres. 相似文献
997.
W J Thompson P S Anderson S F Britcher T A Lyle J E Thies C A Magill S L Varga J E Schwering P A Lyle M E Christy 《Journal of medicinal chemistry》1990,33(2):789-808
A series of 73 dibenzo[a,d]cycloalkenimines were synthesized and evaluated for their ability to displace (+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]-(+)-10) from its specific binding site on rat cortical membranes. A number of the more active compounds (Ki ranging from 0.006 to 0.21 microM) were evaluated for N-methyl-D-aspartate (NMDA) antagonist activity in the rat cortical slice (Kb ranging from 0.08 to 0.9 microM) and anticonvulsant activity in the mouse against NMDA induced convulsions. The ED50 values ranged from 0.22 to 7.76 mg/kg and correlated reasonably well with the Kb determination. In the dibenzo[a,d]cyclohepten-5,10-imine series, the (+)-5S,10R enantiomer displayed consistently higher levels of biological activity. While substitution at the 3-position of (+)-10 with electronegative atoms generally increased in vitro activity, a loss of potency relative to (+)-10 (MK-801) was observed in vivo for all of the compounds tested. 相似文献
998.
P2-, but not P1-purinoceptors mediate formation of 1, 4, 5-inositol trisphosphate and its metabolites via a pertussis toxin-insensitive pathway in the rat renal cortex. 总被引:3,自引:3,他引:0 下载免费PDF全文
1. The adenosine receptor (P1-purinoceptor) agonists N6-cyclopentyladenosine and N-5'-ethyl-carboxamidoadenosine at concentrations up to 10 mumols 1(-1) affected neither basal, nor noradrenaline- and angiotensin II-stimulated formation of inositol-1-phosphate, inositol-1,4-bisphosphate, and inositol-1,4,5-trisphosphate in slices of rat renal cortex. 2. In contrast, adenine nucleotides (P2-purinoceptor agonists) markedly stimulated inositol phosphate formation. The observed rank order of potency adenosine-5'-O-(2-thiodiphosphate) (EC50 39 mumols 1(-1] greater than adenosine-5'-O-(3-thiotriphosphate) (587) greater than or equal to 5'-adenylylimidodiphosphate (App(NH)p, 899) greater than adenylyl-(beta, gamma-methylene)-diphosphate (4,181) was consistent with the interaction of the compounds with the P2Y-subtype of P2-purinoceptors. AMP and the ADP analogue (alpha, beta-methylene)-adenosine-5'-diphosphate were ineffective. ATP and ADP (less than or equal to 10 mmol 1(-1] did not produce a consistent increase, owing to their hydrolytic degradation in the incubation medium. 3. Whereas the inositol phosphate response to App(NH)p was linear only up to 5 min incubation, the time-dependent stimulation of noradrenaline declined at a slower rate. Following pre-exposure of the renal cortical slices to App(NH)p, renewed addition of App(NH)p caused no further enhancement in the accumulation of inositol phosphates, whilst noradrenaline was still capable of eliciting a response. This suggests that the apparent loss of responsiveness to App(NH)p is not due to substrate depletion or enzymatic inactivation, but most likely attributable to homologous desensitization of the purinoceptor.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
999.
1000.
Thymuses of rats that had been: a) gamma-irradiated [500 cGy whole-body radiation (R)], or b) thermally injured [20% BSA dorsal, scald burn (TI)], or c) combined injured [irradiation followed by burn (CI)] were studied for involution and recovery processes after sublethal treatments. The expression of surface antigens on thymic cells before and after injuries was evaluated using the monoclonal antibodies (mcAB) MRC OX4, MRC OX7, MRC OX8, W3/13 HLK, and W3/25 and flow cytometric analysis. Thymic cellularity decreased to less than 1% of normal (N), age-matched rats by 4 days after R or CI. Recovery reached 60% to 70% of N by 28 days post treatments. TI caused a biphasic thymic recovery pattern with nadirs of 40% of N on days 7 and 21. Recovery at day 28 was similar to that after R and CI. Expression of OX7, OX8, W3/13, and W3/25 antigens all reached nadirs of 40% of N by day 4 after R and CI. Recovery of antigen expression, except for W3/25, was near completion by day 7 after R and CI. Changes in antigen expression after TI were less pronounced for all mcAB tested. Decreases in labeling of thymocytes with the helper T-cell marker, W3/25, observed after TI, could not be correlated with elevated expressions of the suppressor/cytotoxic T-lymphocyte antigen, OX8. Variations in relative labeling of nonlymphoid thymic cells with OX4 (Ia-antigen) reflected the disappearance and recovery of radiosensitive lymphoid thymocytes. The similarity of results after R and CI demonstrate that the model of CI is 'radiation-dominated.' The addition of burn injury to radiation trauma had no synergistically damaging effect on the parameters studied. 相似文献