Pharmacological activities of benzophenanthridine and phenanthrene alkaloids.
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Biomedical subjects
Publications and source records attributed to A Villar.
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Since prostaglandins are increasingly shown to play an important role on insulin secretion, an evaluation of the PGE1 action on insulin release by isolated islets of Langerhans has been undertaken. Pancreatic islets were prepared after a modification of the Lacy and Kostianovsky technique and incubated in Hanks solution containing glucose 1.63 or 16.3 mM and/or PGE1 10(-5) M. The insulin released was measured after 15, 30 or 60 min of incubation. The results obtained show that PGE1 does not modify insulin release induced by glucose 1.63 mM (non stimulant concentration) but that this PG significantly diminishes the insulin release induced by glucose 16.3 mM (stimulant concentration) after 15 and 30 min of incubation.
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The contraction of the rat uterus incubated in Ca-free EDTA-containing solution in response to PGE1, oxytocin and vanadate has been investigated in order to examine the mechanism of the release of Ca from intracellular stores. The results obtained show that PGE1 evoked a sustained contraction the magnitude of which diminishes slightly after successive additions of PGE1 but not after long exposure to Ca-free medium. Oxytocin induced two different contractions: one of them was transient and observed only after incubating for 5 min in Ca-free solution; the other remained constant during prolonged incubation in Ca-free medium. Vanadate, an inhibitor of Ca-ATPase, induced sustained contraction after prolonged exposure to Ca-free medium, and isoprenaline, which stimulates Ca re-uptake by intracellular organelles, counteracted the sustained contractile response induced by the three agonists.
Eighty-one plants from the Spanish Mediterranean area employed as antimicrobial agents in folk medicine have been identified. The in vitro antimicrobial activity of chloroform and methanol extracts of the plants were studied using the agar dilution method against six selected microorganisms. Thirty extracts had activity against some of the microorganisms tested. Bioautography showed that the antimicrobial activity is probably due to flavonoids, terpenoids and phenolic acids.
Seventy patients with stage IV head and neck cancer were treated by two courses of induction chemotherapy followed by surgery plus postoperative irradiation (7) or radical radiotherapy (62). One patient renounced to further treatment after chemotherapy. Each chemotherapy course consisted of methotrexate (40 mg/m2 days 1 and 14), bleomycin (10 mg/m2 days 1, 7 and 14), and cisplatin (50 mg/m2 day 4). Three patients did not complete the two courses of chemotherapy planned due to bad tolerance whereas the rest of the patients tolerated chemotherapy well. 2 CR (3%) and 35 PR (50%) were achieved for an overall response rate to chemotherapy of 53%. 35 (50%) CR were achieved with the whole treatment schedule. The 5-year disease-free survival is 26% for the whole group of patients. The prior response to chemotherapy neither influenced the complete responses to treatment nor the relapse-free survival. The addition of this chemotherapy to conventional treatment was of no value.
Fifty-seven patients with T1 transitional cell carcinoma of the bladder, 57 patients with T2-3 and 10 patients with T4 were treated by radical irradiation +/- salvage cystectomy. Thirty-five patients with T1 were treated by transurethral resection (TUR) plus local chemotherapy +/- salvage cystectomy. Eleven patients with T2-3 were treated with 5 X 4 Gy in one week followed by cystectomy while four patients with T2-3 were treated with 40 Gy in 4 weeks also followed by cystectomy. Five patients with T4 were treated with 40 Gy in 4 weeks plus cystectomy. Seven year survival rates are: 69% for T1 treated by radical irradiation, 43% for T1 treated by TUR (p less than 0.02), 36% for T2-3 treated either by radical irradiation or 5 X 4 Gy plus cystectomy, and 18% for T4 treated by radical irradiation. All the survival rates indicated are free of disease and include the cases in which salvage cystectomy was successfully performed. Sixty per cent of the cured patients conserved very good functional bladders. We believe that external beam irradiation plus salvage cystectomy is indicated in the treatment of T1 and T2-3 tumours of the bladder.
Hypolaetin-8-glucoside (H-8-G) has been examined for its mode of action in several models of acute inflammation. Its anti-inflammatory activity in carrageenan-induced inflammation of the rat hind-paw is not affected either by adrenalectomy or by phentolamine given with propranolol. H-8-G and its aglycone, hypolaetin, did not antagonize the actions of histamine, 5-hydroxytryptamine (5-HT), bradykinin or prostaglandin E2 (PGE2) on various smooth muscle preparations in-vitro, but protected erythrocytes from heat-induced lysis. The glycoside was more potent than troxerutin on capillary permeability increased by histamine and exerted inhibitory effects on protein exudation, leucocyte migration and beta-glucuronidase activity in the carrageenan air pouch, thereby showing some difference from indomethacin. These results are discussed in relation to the features of non-steroidal anti-inflammatory drugs (NSAID) and flavonoid anti-inflammatory actions.
The effects of MgCl2 on the oestrogen-dominated rat uterus have been examined. Tissues were preincubated in a Ca2+- and Mg2+-free medium containing 3 mM EDTA. Most experiments were subsequently performed in a similar medium containing either no EDTA or EDTA (1 mM). When MgCl2 was added cumulatively (1-32 mM) no contractile responses were obtained in Ca,Mg-free medium or in Ca,Mg-free high K+ solution. When 2 mM CaCl2 was added, a sustained contraction was obtained. Subsequent addition of cumulative concentrations of MgCl2 caused concentration-dependent relaxation. Oxytocin, 2 microM, produced a small and sustained contraction in a Ca,Mg-free medium. Addition of MgCl2, 2 mM, increased this contraction. In a Ca,Mg-free medium vanadate (8 X 10(-5)M) did not evoke spasm of uterine smooth muscle. After addition of MgCl2 in cumulative amounts (1-32 mM) in the presence of vanadate, a concentration-dependent contraction was obtained. The present work shows that in Ca-free solution, maintained contractions induced by oxytocin and vanadate are augmented by Mg2+.
Forty-six patients with advanced gastric carcinoma (Stage IV) were evaluated in a prospective randomized comparison of two chemotherapy regimens (FAM versus 5-FU plus BCNU) to identify therapeutic activity. Treatment groups were well balanced with respect to known prognostic factors. Thirty-three patients had measurable disease and thirteen had only microscopic residual disease in the resection margins. The overall median survival of the entire group was 13.2 months. Two (6%) patients with measurable disease reached complete response (CR), 1 (3%) partial response (PR), 12 (36%) had stable disease (SD) and 18 (56%) had progressive disease (PD). The responders had not reached the median survival yet, the patients with SD had a median survival of 14.7 months and the PD 9.5 months. In the FAM arm there were 3 (18%) responders (2 CR and 1 PR), 7 (41%) SD and 7 (41%) PD, versus O responders, 5 (31%) SD and 11 (69%) PD in the 5-FU plus BCNU arm. In the FAM arm the median survival was 15.7 months versus 9.9 months in the other therapeutic arm. The statistical analysis indicated that survival associated with FAM regimen was superior to that reached with the 5-FU plus BCNU regimen. Thirteen patients with unmeasurable disease had a median survival of 15.9 months.
1. Previous studies have demonstrated that the administration of prostaglandins (PGs) inhibits insulin secretion in vivo and have suggested that these compounds may be involved in the pathogenesis of diabetes mellitus. The present study was carried out in order to explore the effect of PGE2 on sulfonylurea-induced insulin release. 2. We determined glycemia and insulinemia in rat blood samples, at different times before and after the intraarterial administration of: (a) glibenclamide, (b) tolbutamide, (c) PGE2, (d) glibenclamide and PGE2, (e) tolbutamide and PGE2; in all cases with and without a glucose pulse. (Glibenclamide 0.5 mg/kg, tolbutamide 50 mg/kg, PGE2 100 micrograms/kg and glucose 500 mg/kg). 3. The results of these experiments demonstrate that PGE2 partially inhibits sulfonylurea-induced insulin release. The plasma insulin and glucose levels remain within the range of intermediate values as compared to the control groups (sulfonylurea or PGE2-treated rats) both in presence and absence of glucose.
We have investigated the action of acetylcholine on the release of Ca ions from intracellular stores. The results obtained show that in Ca-free solution acetylcholine induces two different contractions. One of them is a transient contraction that was observed after loading for 5 min in Ca(-) or Ca,Mg(-) solution and its magnitude was not modified by the absence of Mg. Another contraction remains constant after long exposure to Ca(-) medium but decreases in Ca,Mg(-) solution thus indicating that Mg ions are related to it. These results suggest that Mg plays an interesting role in stimulus-contraction coupling mediated by acetylcholine in Ca-free medium. This action can be explained by a release of stored Ca caused by Mg or by a direct effect of the ion on contractile proteins.
The antimicrobial in vitro activity of 14 benzylisoquinoline alkaloids was investigated by agar diffusion and agar dilution methods against several genera of microorganisms that included Streptococcus, Staphylococcus, Bacillus, Lysteria, Escherichia, Salmonella, Klebsiella, Pseudomonas, Enterobacter, Serratia, Shigella, Mycobacterium and Candida. Anolobine was the most active compound against grampositive bacteria with MIC90 between 12 and 50 mg/l; less active were anonaine, lysicamine and liriodenine. All the alkaloids of the noraporphine and oxoaporphine groups, with the exception of isopiline, showed activity against Mycobacterium phlei (MIC 6-25 mg/l). Candida albicans ATCC26555 was inhibited by anonaine, nornantenine and xylopine (MIC 3-12 mg/l). None of the alkaloids tested had a significant activity against gramnegative rods. The action against susceptible microorganisms was bactericidal.
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Intravenous administration of a lyophilized hot water extract and various organic solvent extracts of Rhamnus lycioides to normotensive anesthetized Wistar rats produced a lowering of systemic arterial blood pressure. Acute toxicity of the lyophilized extract was studied in mice by intraperitoneal injection. The phytochemical analyses revealed the presence of steroids-triterpenes, catechin tannins, flavonoids, sugars and resins.
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To clarify the action of sulphonylureas on calcium, the effect of tolbutamide and glibenclamide has been investigated on a Ca-dependent process, the contractile activity of uterine smooth muscle. Both sulphonylureas antagonized the contractions evoked by CaCl2 in a non-competitive manner when the uterus was maintained in depolarizing solution and did not affect the spontaneous contractions of rat uterus. The capacity of tolbutamide and glibenclamide to relax vanadate-induced contraction of rat uterus in Ca-free medium suggests that sulphonylureas may have an intracellular site of action related to cytosolic free Ca levels, or effect a reduction in Ca action.