Cancer chemopreventive agents. New depsidones from Garcinia plants.

In a search for cancer chemopreventive agents from natural sources, chemical constituents of two kinds of Garcinia plants, Garcinia neglecta and Garcinia puat, collected in New Caledonia, were examined. Five new depsidones, garcinisidone-B (2), -C (3), -D (4), -E (5), and -F (6), were isolated, and their structures were determined by spectrometric analyses. Inhibitory effects of these depsidones on EBV-EA activation induced by TPA in Raji cells were also demonstrated.

Xanthone and dihydroisocoumarin from Montrouziera sphaeroidea.

A xanthone, montrouxanthone and a dihydroisocoumarin, montroumarin were isolated from the stem bark of Montrouziera sphaeroidea Pancher Ex Planchon et Triana [Guttiferae], along with two known compounds. Their structures were elucidated on the basis of spectroscopic analyses. This is the first report of the analysis of chemical constituents of Montrouziera species.

Carbamazepine-nefazodone interaction in healthy subjects.

The pharmacokinetic interaction between nefazodone and carbamazepine was investigated in 12 healthy male volunteers. Subjects received nefazodone 200 mg twice daily for 5 days, and blood sample collection was performed on day 5 for 0- to 48-hour pharmacokinetic analysis. A 4-day wash-out phase then followed from days 6 to 9. Carbamazepine 200 mg was administered once daily from days 10 to 12, and then 200 mg was given twice daily from days 13 to 44. A 0- to 48-hour pharmacokinetic analysis was performed on day 38. Nefazodone 200 mg twice daily was added to the dosing regimen from days 40 to 44, and a subsequent 0- to 48-hour pharmacokinetic analysis was performed on day 44. Coadministration of nefazodone increased steady-state plasma area under the concentration-time curve (AUC) of carbamazepine from 60.77 (+/-8.44) to 74.98 (+/-12.88) microg x hr/mL (p < 0.001) and decreased the active carbamazepine-10,11-epoxide metabolite AUC concentration from 7.10 (+/-1.16) to 5.71 (+/-0.52) microg x hr/mL (p < 0.005). During the combination, the steady-state AUC of nefazodone decreased from 7,326 (+/-3,768) to 542 (+/-191) ng x hr/mL, and the AUCs of its metabolites (hydroxynefazodone, meta-chlorophenylpiperazine, and triazoledione) decreased significantly as well (p < 0.001). Coadministration of nefazodone 200 mg twice daily and carbamazepine 200 mg twice daily was found to be safe and well tolerated; however, the increased plasma exposure to carbamazepine may warrant monitoring of plasma carbamazepine concentrations with the combination. However, higher doses (>400 mg/day) of carbamazepine could yield more extensive induction, affecting tolerability of the combination. No change in the initial nefazodone dose is necessary, and subsequent dose adjustments should be made on the basis of clinical effects; however, the repercussion of carbamazepine induction of nefazodone metabolism on the antidepressant efficacy has yet to be studied.

Pharmacokinetic evaluation of co-administration of nefazodone and lithium in healthy subjects.

OBJECTIVES: To evaluate the possible pharmacokinetic interaction between nefazodone and lithium. METHODS: Twelve healthy volunteers received nefazodone 200 mg b.i.d. for 5 days. A 4-day washout phase followed from day 6 to day 9. From day 10 to day 20, escalating doses of lithium 250 mg b.i.d. to 500 mg b.i.d. were given; the daily dose of 1000 mg was obtained on day 13. From day 16 to day 20, nefazodone 200 mg b.i.d. was added to the lithium dosing regimen. Venous blood sampling was performed on days 5, 15 and 20 for 0- to 48-h-pharmacokinetic analysis. Nefazodone and its metabolites, hydroxynefazodone, mCPP and triazoledione were assayed by high-performance liquid chromatography (HPLC). Lithium was assayed by flame photometry. RESULTS: Co-administration of nefazodone did not modify pharmacokinetic parameters of lithium at steady-state. Comparison of the area under the plasma or serum concentration-versus-time curve calculated from 0-12 h (AUC0-12) of nefazodone and hydroxynefazodone revealed no significant differences when nefazodone was administered alone or with lithium. The mean maximum peak plasma concentration Cmax and AUC0-12 of meta-chlorophenyl-piperazine (mCPP) were significantly reduced by 27% (P < 0.001) and 16% (P < 0.001) with the co-administration. The mean Cmax and AUC0-12 of triazoledione were reduced by 23% (P < 0.005) and 16% (P < 0.01) by the co-administration. CONCLUSION: Since there were no clinically significant changes in the pharmacokinetics of the parent compounds or metabolites, and the combination was well tolerated, no dosage adjustments of nefazodone or lithium are necessary when they are co-administered.

Five new flavone 5-O-glycosides from Lethedon tannaensis: lethedosides and lethediosides.

Five new 7-methoxy-flavone 5-O-glycosides were isolated from a cytotoxic MeOH extract of Lethedon tannaensis, and the structures were elucidated by 2D NMR spectral analysis and by chemical methods. Lethedosides A (1), B (2), and C (3) were 5-O-glucosides of 7,3', 4'-tri-O-methylluteolin, 7,3',4',5'-tetra-O-methyltricetin, and 7,3', 4'-tri-O-methytricetin, respectively; lethediosides A (4) and B (5) and a known compound 6 were 5-O-xylosylglucosides of 7,3', 4'-tri-O-methylluteolin, 7,3',4',5'-tetra-O-methyltricetin, and 7, 4'-di-O-methylapigenin, respectively. These flavonoids were either inactive or weakly active against KB tumor cells, in contrast to previously isolated flavones from the same plant.

Hyperaccumulation, complexation and distribution of nickel in Sebertia acuminata.

The nickel content in different parts of the hyperaccumulating tree Sebertia acuminata was analysed by atomic absorption spectroscopy. Nickel was found to be mainly located in laticifers. The total nickel content of a single mature tree was estimated to be 37 kg. By gel filtration and NMR spectroscopy, citric acid was unequivocally identified as counter ion for about 40% of this metal present. Nitrate was assumed to be a further partner for a complete ionic balance. Phytochelatins were not found to be involved in nickel detoxification in Sebertia. The localization of nickel complexes inside the laticifers was demonstrated by light microscopy as well as by scanning electron microscopy in combination with an EDX system for the analysis of elements. A repellent effect of the plant sap was observed on the fruit fly Drosophila melanogaster indicating that in hyperaccumulating plants nickel functions as an agent to prevent predation.

DNA topoisomerase I inhibitors: cytotoxic flavones from Lethedon tannaensis.

From ethyl acetate and methanolic extracts of Lethedon tannaensis leaves, which were cytotoxic against murine leukemia (P-388) and human nasopharynx carcinoma (KB) cells, one new and six known 5-hydroxy-7-methoxyflavones variously substituted on the B ring were isolated and their structures determined by spectral analysis. Compounds active against KB cells were velutin (4) (IC50 4.8 microM), 7,3',5'-tri-O-methyltricetin (2) (IC50 22.2 microM), genkwanin (6) (IC50 30.6 microM), and the novel compound, 7,3',4'-tri-O-methyltricetin, named lethedocin (1) (IC50 47.6 microM). These flavones required the presence of hydroxyl groups at C-5 and C-4' and methoxyl groups at C-7 and C-3' for inhibition of calf thymus DNA topoisomerase I activity.

Antimitotic and cytotoxic flavonols from Zieridium pseudobtusifolium and Acronychia porteri.

Bioassay-guided fractionation of the extracts of Zieridium pseudobtusifolium and Acronychia porteri led to the isolation of 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone [1], which showed activity against (KB) human nasopharyngeal carcinoma cells (IC50 0.04 micrograms/ml) and inhibited tubulin assembly into microtubules (IC50 12 microM). Two other known flavonols, digicitrin [2] and 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone [5], were also isolated together with three new ones, 3-O-demethyldigicitrin [3], 3,5,3'-trihydroxy-6,7,8,4'-tetramethoxyflavone [4], and 3,5-dihydroxy-6,7,8,3',4'-pentamethoxyflavone [6]. All of these flavonols showed cytotoxic activity against KB cells.

[The course of color vision in early diabetic retinopathy treated with Ginkgo biloba extract. A preliminary double-blind versus placebo study]. / Evolution de la vision des couleurs dans la rétinopathie diabétique débutante traitée par extrait de Ginkgo biloba. Etude préliminaire à double insu contre placebo.

The therapeutic efficiency of the Ginkgo biloba extract was estimated in a double-blind trial, during a 6 months period, in 29 diabetic subjects with an early diabetic retinopathy evidenced by angiography, and associated with a blue-yellow dyschromatopsia. The functional criterion was the color vision evolution, studied by the Desaturated Panel D-15 and the 100-Hue Farnsworth test at the beginning of the trial and 6 months later. An improvement tendency was evidenced in subjects treated by Ginkgo biloba extract, and an aggravation in subjects with placebo, this improvement being statistically significative with the Desaturated Panel D-15 among subjects without retinal ischemia. These clinical results on visual function corroborate the pharmacological actions of Ginkgo biloba extract on diabetic retina.

[Epidermoid carcinoma of the bladder. Apropos of 46 cases]. / Carcinome épidermoïde de vessie. A propos de quarante-six observations.

In order to define the prognosis of pure squamous carcinomas of the bladder, on the one hand (group I), and the possible aggravating role of the presence of squamous tissue in an invasive renal cell tumour, on the other hand (group II), 46 cases files of patients treated between 1975 and 1984 were analysed retrospectively. Group I consisted of 18 cases of pure squamous carcinoma (11 men with a mean age of 71 years and 7 women with a mean age of 74 years). 66% of cases presented with haematuria, but urinary cytology was of little help. The diagnosis was established by transurethral resection with 18 grade 3 tumours: stage A in 4 cases and stage B in 14 cases. 10 patients had unilateral (8 cases) or bilateral (2 cases) complications of the upper urinary tract. The presence of lymph node and/or haematogenous metastases was investigated by bone scan, hepatic ultrasonography, pulmonary tomography and, most importantly, by bipedal lymphography combined with percutaneous cyto-aspiration of suspicious nodes. 4 patients presented with invasion of the obturator lymph nodes (2 cases) and iliac lymph nodes (2 cases). 9 patients were treated by total cysto-prostatectomy, 6 patients by radiotherapy (60 Grays) and 3 patients did not receive any treatment. The overall survival was 12.5% after 2 years. None of the patients treated by radiotherapy were alive after 2 years. 29% of the patients treated by surgery survived for 2 years, but none of them were alive after 5 years, essentially as a result of local recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)

[66% glucose, a safe sclerosant. Experimental study]. / Le glucose à 66%, sclérosant de sécurité. Etude expérimentale.

Although accidents due to the intra-arterial injection of detergent sclerosant are very rarely observed, they are dramatic in their effects and often result in amputations, a risk accepted with difficulty for a treatment with a functional aim. To avoid these incidents, which may occur even when treatment is applied by the most experienced surgeons, the authors have used 66% glucose solution without accident since 1948. To confirm efficacy of the method, an experimental study compared 66% glucose (66 G) with a very commonly used product, 1% sodium tetradecyl sulfate (STD), in the rabbit. Except when enormous doses of 66 G are employed, the only effect noted was eosinophilic necrosis of the vessel wall without clinical symptoms, whereas doses eight times lower of STD produced an irreversible ischemia from obliterating endarteritis of the branches of the vascular tree injected. The 66% glucose solution appears to be a very safe, gently acting sclerosant, and the product of choice for peri- and post-operative sclerosis, particularly in regions where accidental arterial puncture is anatomically possible.

[Association of trisomy 21 and gonosomal trisomy. Apropos of 2 cases]. / Association de trisomie 21 et de trisomie gonosomique. A propos de deux observations.

The existence of double autosomal trisomy is exceptional in a newborn child: --Down syndrome and trisomy 18. --Down syndrome and trisomy 13. On the other hand, the association of an autosomal trisomy, generally Down syndrome with gonosomal trisomy, is less rare with an extra X (triplo X, Klinefelter) or an extra Y. The association of Down syndrome with Turner XO syndrome (autosomal gonosomal association) doesn't insert in the subject, and has been described only once in the literature.

[Varicose recurrence: opinion of a team]. / La récidive variqueuse : opinion d'une équipe.

Relapse, or the continuation of the development of varicose disorder, seems to us to be common after sclerosis when there is a manifest insufficiency of the saphenous valves. Relapse following surgical operation is rare : 0.4 p. cent in our files. Most often it follows initial surgery which has been too limited, or else faulty. However, one out of every thousand of our patients has relapsed, and there has been no possible valid explanation of the venous redevelopment, whose factors are analysed.

Reinterventions for primary varices.

Out of more than 6,000 patients operated for varices since 1949, in private practice, 281 had already been operated on once before. In 230 of these cases, the first operation performed elsewhere had been incorrect or incomplete: partial stripping, a badly performed excision of the saphenofemoral-junction, neglect of gross perforants, neglect of the saphena parva which was partly or wholly responsible for 96% of the recurrences. Moreover, a partial operation, even if correct, does not check the development of a disorder which is often bilateral (89%) and which often affects the four saphenous veins (59%). 51 had been operated by myself, hoping that they would not have to come back; 29 cases in which 2/3 of the long saphenous vein was stripped and with crossectomy of the short saphenous vein until 1964, and 22 cases of complete stripping after 1965. 49 short saphenae had been causal in the first group but we noted 14 popliteal recurrences in the second. A mistaken anatomical abnormality, sixteen perforants but more particularly 30 regrown internal saphenofemoral junctions were noted in these two groups. It is difficult to give reasons for them. Finally the post-operative phlebological follow-up is often irregular or neglected. Re-operations are difficult but, with the aid of a phlebographical control, they give good results, except for deteriorations of the deep tract necessitating certain static hygiene. The best guarantees of a satisfying and lasting result are a complete and correct initial treatment of the main varices, and regular phlebological check-up.