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A Abraham M G Nair R L Kisliuk Y Gaumont J Galivan 《Journal of medicinal chemistry》1990,33(2):711-717
Representative examples of folate and antifolate poly-gamma-glutamyl metabolites were synthesized via the [(9-fluorenylmethoxy)oxy]carbonyl (Fmoc) chemistry using the KH polyamide resin. Polyglutamate yields were consistently better in all cases compared to the previous Merrifield method, and the crude products were obtained in greater than 85% purity. The symmetrical anhydride (7) derived from alpha-tert-butyl N-Fmoc-L-glutamate (6) was used for the initial coupling of the first glutamate residue to the KH resin and also for subsequent chain elongation. The alpha-tert-butyl protective groups were not labile under the conditions used for the cleavage of the finished peptide from the resin. A series of poly-gamma-glutamyl metabolites of methotrexate (MTX) with a chain length ranging from two to five glutamyl residues were synthesized and coupled with poly(L-lysine) having an average molecular weight of 27,000 and 52,000. Each conjugate was tested for its ability to inhibit the growth of wild type (H35) and MTX transport resistant (H35R) strains of hepatoma cells in culture, the latter having a 100-fold reduced sensitivity to MTX. 4-Amino-4-deoxy-N10-methylpteroylglutamyl-gamma-glutamylpoly (L-lysine) conjugate [MTX(G2)-poly-L-Lys-52000] and MTX(G4)-poly-L-Lys-52000 were among the most active (I50 = 8.0 and 10 nM against H35 cells) MTX-polylysines synthesized to date, and they were somewhat more inhibitory to the transport resistant cells. MTX(G5)-poly-L-Lys-52000 was approximately 1000 times more effective than MTX(G5)-poly-D-Lys-52000 in inhibiting the growth of H35R hepatoma cells in culture, indicating that internal cleavage of the gamma-glutamate chain of the conjugate with subsequent release of MTX or shorter chain polyglutamates of MTX is unlikely to be an important determinant of MTX-polyglutamate polylysine cytotoxicity. The results indicate that MTX-polyglutamate poly(L-lysine) conjugates are taken up by the cells independently of MTX and probably via endocytosis. 相似文献
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Norethisterone enanthate (NET-En), an established intramuscular long-acting contraceptive agent, has previously been shown to be effective in inhibiting fertility in two rodent species even 4 days after oral ingestion. Pharmacokinetics of NET and NET-En were studied after oral and intramuscular doses in two animal species and a few women. The results suggest that the NET-En was absorbed within a day in all the species after oral dose. The estimates of relative bioavailability ranged from 13 to 51% in rabbits, monkeys, and women. The elimination half-life was 5–10 days. The presence of the active component, NET, in the circulation over the experimental period of 15 days suggests that NET-En could be useful as a long-acting oral pill. The suppression of progesterone levels during the luteal phase of menstrual cycle in women also supports this finding. 相似文献
5.
Lymphangiomatosis is a rare disorder of the lymphatic system that is known to cause chylothorax. Chyloptysis may occur but chylous bronchial cast formation is rare. A case is reported of lymphangiomatosis in a 34 year old woman whose initial manifestation was cough productive of bronchial casts. Two years later the patient developed a chylothorax. Ligation of the thoracic duct through a low thoracotomy was curative. 相似文献
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Sublethal stress of toxicants on organisms is generally measured through metabolic changes. The effects of three pesticides (endosulfan, malathion, and methyl parathion) on tissue lipid levels in the estuarine bivalve, Villorita cyprenoids var. cochinensis, have been measured. The reduction in lipid content was expressed as a function of the pesticide concentrations and the duration of the exposure periods (24, 48, 72, and 96 h). The results point to the existence of a direct relationship between the applied stress and the fall in the lipid content. The order of toxicity was endosulfan > malathion > methyl parathion. The depletion in lipid content observed may reflect an adaptive response of the organism to pesticide stress. Thus lipids in bivalves have been shown to be an important reserve material that may be utilized under stressed conditions as an energy source. © by John Wiley & Sons, Inc. 相似文献
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A case of bladder tumour arising as a metastasis of renal carcinoma and presenting as obstruction to urinary outflow is described. The possible mechanism of spread to bladder is also suggested. 相似文献
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The modulation of drug metabolising enzymes by Masheri extract (ME) and Benzo(a)Pyrene [B(a)P] was studied in male Sprague Dawley rats fed different dietary protein levels. Two groups of 21 days old male Sprague Dawley rats were put on a high protein diet (SHP) with 20% Casein, and a low protein diet (SLP) with 3% Casein semisynthetic based diets for 12 weeks. The SLP fed animals showed lower basal levels of the Phase I activating enzymes viz. Cytochrome P450, Benzo(a)Pyrene hydroxylase, Benzphetamine demethylase and Phase II glutathione detoxification system viz. Glutathione (GSH) and Glutathione-S-transferase. ME and B(a)P treatment significantly depleted the glutathione detoxification system in the SLP group whereas an opposite effect was observed in the SHP group. Interstingly, ME and B(a)P treated rats in the SLP group showed a higher percent increase in the hepatic and pulmonary Phase I enzyme activities than those observed in the treated ME/B(a)P treated SHP rats. Furthermore, both ME and B(a)P significantly decreased the hepatic pool of vitamin A while a concomittant increase in that of vitamin C was observed. 相似文献
9.
B C Morton M P Brais D S Beanlands R J Chambers L A Higginson W L Williams K A Allan R C Nair W J Keon 《Canadian journal of surgery》1987,30(4):269-271
Seventy-nine patients with moderate to severe left ventricular dysfunction who underwent aortocoronary bypass grafting between 1971 and 1977 had follow-up heart catheterization at a mean interval of 3 years. Thirty-three patients (42%) had angiographic improvement in left ventricular function at follow-up and 18 (25%) had a decrease in left ventricular end-diastolic pressure. Fifty-eight patients (73%) had improvement in angina of at least one New York Heart Association class at follow-up. There was no correlation between late improvement in left ventricular function and improvement in angina. Improvement in left ventricular function did not correlate with preoperative indices of severity of coronary disease or with indices of completeness of surgical repair. 相似文献
10.
The quality of medical education during internship is a cause for concern. This paper describes a structured educational programme for interns that was based around learning modules, clinical attachments and bedside teaching. The programme was incorporated into the term rotation of interns within an Area Health Service, and evaluated. Learning modules were timetabled by a Programme Coordinator and interns were reminded to attend. Clinical attachments were organized by the interns from a list of willing supervisors. Attendance at timetabled learning modules averaged 67%, which was greater than the 27% attendance at clinical attachments. Both sessions received high ratings for quality and clinical relevance. This structured education programme was based upon adult learning methods and was both feasible and well received by interns. Intern training programmes need to be programmed into the working week to ensure attendance, and modified following evaluation by interns. Such programmes should be considered by all hospitals to which interns are allocated. 相似文献