[Revision of the French colposcopic terminology]. / Nouvelle classification française des images colposcopiques.

OBJECTIVES: To revise the 1983 colposcopic terminology form the French Society of Colposcopy and cervicovaginal pathology (SFCPCV). METHODS: All the three following steps of colposcopic examination were considered for the description of various colposcopic features: inspection without coloration, followed by the application of acetic acid and iodine staining. This revised terminology now includes the different possible colposcopic aspects of the normal cervix, including the ectropion and the normal transformation zone. It also includes colposcopic appearance of abnormal glandular cervical epithelium and of vaginal epithelium. The revised nomenclature was reviewed by all the board of the SFCPCV and was finally approved during the 45th annual conference of the SFCPCV. RESULTS: Abnormal transformation zone grade (TAG) 1a and 1b have been brought together under the sole TAG1 designation. TAG2a and TAG2b now correspond to TAG2, whereas TAG2c corresponds to TAG3. Colposcopic report should mention the interpretability of the colposcopic examination, with the precise type of the squamocolumnar junction (1, 2 or 3), the colposcopic impression, the size of any TAG and finally mention whether one or multiple biopsies were taken and their precise location. Colposcopic impression must give priority to the most pejorative colposcopic aspect which takes precedence over others. CONCLUSION: When performing colposcopy, one should keep in mind that this examination only relies on the interpretation of various colposcopic signs and images with this not guaranteeing for diagnosis. Only histological analysis of a possible guided cervical biopsy provides for a precise diagnosis.

Antifungal canthin-6-one series accumulate in lipid droplets and affect fatty acid metabolism in Saccharomyces cerevisiae.

The mechanism of action of antifungal canthin-6-one series was investigated in Saccharomyces cerevisiae. After a rapid uptake, a preferential accumulation of the drug within lipid droplets was observed. The antifungal action of canthin-6-one was found as reversible. Canthin-6-one did not exhibit affinity for sterols, and membrane ergosterol was not necessary for the antifungal activity since the MICs were similar on an ergosterol-deleted and the wild-type S. cerevisiae clones. Relative amount of unsaturated alkyl chain fatty acids was significantly enhanced suggesting a stimulation of desaturase enzyme systems. No synergistic effect was observed between canthin-6-one and amphotericin B, ketoconazole and caspofungine. Canthin-6-one should now be evaluated in vivo against fungal pathogens.

In vitro and in vivo antileishmanial efficacy of a new nitrilquinoline against Leishmania donovani.

The in vitro activity of a new analogue of 2-alkenylquinoline (2-nitrilquinoline or NQ) against Leishmania donovani was compared to oral reference drug miltefosine (HePC). IC(50) of NQ was found at 38.6 microM against promastigotes and 2.4 microM against intramacrophage amastigotes. In vivo evaluation in the L. donovani Balb/c mice model indicated that oral treatments at 12.5 and 25 mg/kg for 10 consecutive days significantly reduced the parasite burden in the liver by 68.9 and 68.5%, respectively. This activity was similar to those of HePC at 7.5 mg/kg for 10 days which reduced the parasite burden in liver by 72.5%. The present study shows the positive contribution of a nitril substitute being added into the alkenyl chain branched at the 2-position of the quinoline ring to the antileishmanial activity. In addition, any apparent toxicological disorder was observed during the experiments.

[Antileishmanial activity of five 2- or 3- quinolines by enyne group]. / Activité anti leishmanienne de cinq quinoléines substitutées en position 2- ou 3- par un groupement, enyne.

INTRODUCTION: Leishmaniasis is an emergent orphan disease because of its co-infection with HIV AIDS. We report herein the in vitro biological evalution of five news quinolines, 2- or 3- substituted by an enyne group against Leishmania donovani (MHOM/ET/L82/LV9). PATIENTS AND METHODS: The quinolines has been synthesized by using a cross-coupling reaction between a chloroenyne and an organometallic coumpound in a presence of iron a "green" catalyst. Biological evalution is realized by a colorimetric method with the use of 3-(4,5-dimethylthiazol-2,5-diphényl)-tétrazolium bromide. RESULTS: Determination of the inhibitory concentrations as well as the minimal inhibitory concentrations has shown that the substitution by an enyne group made it possible to have a more important antileishmanial activity. In addition, we have seen that the -2 or the -3 position of the enyne group had no influence in the antileishmanial activity. CONCLUSION: Thus, we have shown the real interest of these quinolines which could be favourably compared with pentamidine, which is currently the reference product, and to consider the use of these quinolines in the treament of the leishmaniasis.

Screening of some New Caledonian and Vanuatu medicinal plants for antimycobacterial activity.

Twenty plants, belonging to sixteen families, used in traditional New Caledonian and Vanuatu medicine for treatment of symptoms potentially related to tuberculosis (cough, fever or inflammation) were screened for antimycobacterial activity. We also screened an original endemic plant, Amborella trichopoda, only member of the monogeneric family Amborellaceae and considered the most primitive living angiosperm. In total, 55 extracts were evaluated for inhibitory activity against Mycobacterium bovis BCG strain at a concentration of 100 microg/ml. Methanolic and dichloromethane extracts of Amborella trichopoda, Codiaeum peltatum, Myristica fatua, and essential oils Myoporum crassifolium showed an activity at this concentration. Methanolic extract of Amborella trichopoda fruits presented a significant activity with a minimal inhibitory concentration included between 1 and 2.5 microg/ml. In the same conditions, this activity was comparable with those of the reference drugs pyrazynamide and ethambutol, at 20 and 2.5 microg/ml, respectively.

Screening of New Caledonian and Vanuatu medicinal plants for antiprotozoal activity.

Sixty-seven extracts of 30 medicinal plants traditionally used in New Caledonia or Vanuatu by healers to treat inflammation, fever and in cicatrizing remedies were evaluated in vitro for their antiprotozoal activity against Leishmania donovani, Leishmania amazonensis and Trypanosoma cruzi. Among the selected plants, Pagiantha cerifera was the most active against both Leishmania species; four extracts were active against promastigotes of Leishmania donovani at EC(50) values inferior to 5 microg/ml. Garcinia pedicillata extract had an EC(50) value of 12.5 microg/ml against intracellular amastigotes of Leishmania amazonensis. Alone Amborella trichopoda reduced by more of 80% the trypomastigotes of Trypanosoma cruzi in the blood.

[Antileishmanial activity of five 2- or 3- quinolines by enyne group]. / Activité anti leishmanienne de cinq quinoléines substituées en position 2- ou 3- par un groupement ényne.

INTRODUCTION: Leishmaniasis is an emergent orphan disease because of its co-infection with HIV AIDS. We report herein the in vitro biological evalution of five news quinolines, 2- or 3-substituted by an enyne group against Leishmania donovani (MHOM/ET/L82/LV9). PATIENTS AND METHODS: The quinolines has been synthesized by using a cross-coupling reaction between a chloroenyne and an organometallic coumpound in a presence of iron a "green" catalyst. Biological evalution is realized by a colorimetric method with the use of 3-(4,5-diméthylthiazol-2,5-diphényl)-tetrazolium bromide. RESULTS: Determination of the inhibitory concentrations as well as the minimal inhibitory concentrations has shown that the substitution by an enyne group made it possible to have a more important antileishmanial activity. In addition, we have seen that the -2 or the -3 position of the e nyne group h ad no influence in the antileishmanial activity. CONCLUSION: Thus, we have shown the real interest of these quinolines which could be favourably compared with pentamidine, which is currently the reference p roduct, and to consider the use of these quinolines in the treament of the leishmaniasis.

Synthesis, spectroscopy, and cytotoxicity of glycosylated acetogenin derivatives as promising molecules for cancer therapy.

Several glycosyl derivatives of squamocin (1) have been synthesized by glycosylation under Lewis acid catalysis with two different 1-O-acetyl sugars. Separation of these compounds has been achieved by HPLC and centrifugal partition chromatography (CPC). A detailed NMR, ESIMS, and LSIMS study allowed complete structural elucidations. The cytotoxic activity of the glycosyl derivatives was investigated and compared with that of squamocin and dihydrosquamocin against human epidermoid carcinoma cells (KB), African green monkey (Cercopithecus aethiops) kidney epithelial cells (VERO), and mouse lymphocytic leukemia cells (L1210). The antiproliferative effects of some derivatives were studied on cell cycles in mouse lymphocytic leukemia cells (L1210).

The mitochondrial complex I inhibitor annonacin is toxic to mesencephalic dopaminergic neurons by impairment of energy metabolism.

The death of dopaminergic neurons induced by systemic administration of mitochondrial respiratory chain complex I inhibitors such as 1-methyl-4-phenylpyridinium (MPP(+); given as the prodrug 1-methyl-1,2,3,6-tetrahydropyridine) or the pesticide rotenone have raised the question as to whether this family of compounds are the cause of some forms of Parkinsonism. We have examined the neurotoxic potential of another complex I inhibitor, annonacin, the major acetogenin of Annona muricata (soursop), a tropical plant suspected to be the cause of an atypical form of Parkinson disease in the French West Indies (Guadeloupe). When added to mesencephalic cultures for 24 h, annonacin was much more potent than MPP(+) (effective concentration [EC(50)]=0.018 versus 1.9 microM) and as effective as rotenone (EC(50)=0.034 microM) in killing dopaminergic neurons. The uptake of [(3)H]-dopamine used as an index of dopaminergic cell function was similarly reduced. Toxic effects were seen at lower concentrations when the incubation time was extended by several days whereas withdrawal of the toxin after a short-term exposure (<6 h) arrested cell demise. Unlike MPP(+) but similar to rotenone, the acetogenin also reduced the survival of non-dopaminergic neurons. Neuronal cell death was not excitotoxic and occurred independently of free radical production. Raising the concentrations of either glucose or mannose in the presence of annonacin restored to a large extent intracellular ATP synthesis and prevented neuronal cell demise. Deoxyglucose reversed the effects of both glucose and mannose. Other hexoses such as galactose and fructose were not protective. Attempts to restore oxidative phosphorylation with lactate or pyruvate failed to provide protection to dopaminergic neurons whereas idoacetate, an inhibitor of glycolysis, inhibited the survival promoting effects of glucose and mannose indicating that these two hexoses acted independently of mitochondria by stimulating glycolysis. In conclusion, our study demonstrates that annonacin promotes dopaminergic neuronal death by impairment of energy production. It also underlines the need to address its possible role in the etiology of some atypical forms of Parkinsonism in Guadeloupe.

Bisbenzylisoquinoline alkaloids from Guatteria boliviana (Annonaceae).

Together with known alkaloids, five new bisbenzylisoquinoline derivatives were isolated from the stem bark of Guatteria boliviana (Annonaceae), puertogalines-A 1 and -B 2, (+)-guatteboline 3, philogaline 4 and (-)-antioquine 5. Their structures were elucidated by spectrometric methods and their antiparasitic activity was evaluated in vitro on Leishmania sp., Trypanosoma cruzi and Plasmodium falciparum. Their cytotoxic activity was also measured in KB cell line.

Annosenegalin and annogalene: two cytotoxic mono-tetrahydrofuran acetogenins from Annona senegalensis and Annona cherimolia.

Two new cytotoxic mono-tetrahydrofuran acetongenins, annosenegalin and annogalene, have been isolated from the cytotoxic methanolic extract of Annona senegalensis and A. cherimolia seeds. Their structures were established on the basis of 1D and 2D NMR spectroscopic techniques. Annosenegalin belongs to the rare type of C37 mono-tetrahydrofuran acetogenins, and annogalene is an olefinic acetogenin.

Isolation of Montecristin, a Key Metabolite in Biogenesis of Acetogenins from Annona muricata and Its Structure Elucidation by Using Tandem Mass Spectrometry.

During the course of our continuing search for acetogenins from Annonaceae, a new metabolite, montecristin, possibly involved in the biogenesis of acetogenins, was isolated from the roots of Annona muricata. Its structure was elucidated on the basis of UV, IR, (1)H and (13)C NMR, and mass spectrometry. The identification of the main stuctural features of montecristin (1) was obtained from the NMR spectra whereas their locations on the alkyl chain were evidenced by using mass spectrometry. The attribution of each carbon and location of substituents on the alkyl chain of this fatty acid gamma-lactone was evidenced by using tandem mass spectrometry (MS/MS) and high-energy collisional activation of [M + Li](+) lithium complexes. Finally, the structure determination of montecristin was strengthened by epoxidation and transformation leading to a known adjacent bis-tetrahydrofuran acetogenin.

Antitumoral effects of squamocin on parental and multidrug resistant MCF7 (human breast adenocarcinoma) cell lines.

The antiproliferative effects of squamocin, one of the easiest annonaceous acetogenins to obtain, were studied in the parental (MCF7-S) and the multidrug resistant (MCF7-R) human breast adenocarcinoma cell lines. Squamocin inhibited proliferation of both cell lines identically, by blocking the cell cycle in the G1-phase. This inhibition was reversible in the long term. Squamocin decreased the ATP pool in both MCF7 cell lines, but did not seem to induce apoptosis. Cytotoxic activity of adriamycin was not restored in MCF7-R Pgp expressing cells by squamocin addition.

In vitro antileishmanial activity of acetogenins from Annonaceae.

Twelve acetogenins from Annonaceae were evaluated in vitro for their antileishmanial activities in order to search for new lead-compounds having antileishmanial properties. The compounds were comparatively evaluated by the 50% inhibitory concentrations (IC50) determination on promastigote forms of wild-type and four drug-resistant lines of Leishmania donovani. In addition, after testing the toxicity on mouse peritoneal macrophages, the compounds were evaluated on amastigote infected macrophages and a therapeutic index was calculated. The IC50 of the acetogenins against promastigote forms of L. donovani was in a range 4.7-47.3 microM. The most active compound was Rolliniastatin 1 (IC50 at 4.7 microM). On the intramacrophage amastigote in vitro model, only seven compounds exhibited measurable antileishmanial activity with IC50 values in a range 2.5-29.7 microM. Rollinistatin 1 was the most interesting compound with IC50 of 2.5 microM and it appears as the most promising one on the basis of therapeutic index (18.08). Isoannonacin, which is active against intramacrophagic amastigotes (IC50 of 6.2 microM) with a therapeutic index of 2.05, exhibited a strong action on drug-resistant strains (IC50 from 5.1 to 9.8 microM). Acetogenins are a new chemical series with interesting in vitro antileishmanial activity and further studies will be focused on the understanding of this selectivity in regard to the membrane and mitochondrial action using specific probes.

cis-monotetrahydrofuran acetogenins from the roots of annona muricata1

Phytochemical investigation of roots of Annona muricata led to the identification of seven mono-tetrahydrofuran (mono-THF) acetogenins. Six new acetogenins having the unusual cis-configuration of the THF ring, cis-solamin (1), cis-panatellin (2), cis-uvariamicin IV (3), cis-uvariamicin I (4), cis-reticulatacin (5), and cis-reticulatacin-10-one (6) were identified, in addition to a known compound, solamin.

Antiplasmodial activity of acetogenins and inhibitory effect on Plasmodium falciparum adenylate translocase.

Three Annonaceous acetogenins exhibited in vitro antimalarial activities on a chloroquine-resistant Plasmodium falciparum strain, with IC50s ranging from 5 to 10 microM. Structure-activity relationships showed that maximal antimalarial activity occurred in the presence of at least one tetrahydrofuran moiety and a synergistic action with chloroquine was observed. These acetogenins partially inhibited the P. falciparum adenylate translocase.

Biological and chemical studies of Pera benensis, a Bolivian plant used in folk medicine as a treatment of cutaneous leishmaniasis.

The stem barks of Pera benensis are employed by the Chimane Indians in the Bolivian Amazonia as treatment of cutaneous leishmaniasis caused by the protozoan Leishmania braziliensis. The chloroform extracts containing quinones were found active against the promastigote forms of Leishmania and the epimastigote forms of Trypanosoma cruzi at 10 micrograms ml-1. The activity guided fractionation of the extract by chromatography afforded active compounds. Their structures were elucidated, by spectral and chemical studies, as known naphthoquinones, plumbagin, 3,3'-biplumbagin, 8-8'-biplumbagin, and triterpene, lupeol. The activity in vitro of each compound was evaluated against 5 strains of Leishmania (promastigote), 6 strains of Trypanosoma cruzi (epimastigote) and the intracellular form (amastigote) of Leishmania amazonensis. The baseline drugs used were Glucantime and pentamidine (Leishmania spp.), nifurtimox and benznidazole (T. cruzi). Plumbagin was the most active compound in vitro. This study has demonstrated that Pera benensis, a medicinal plant used in folk medicine, is an efficient treatment of cutaneous leishmaniasis.

[ Active trypanocidal alkaloids, bisbenzylisoquinoles ii. active in vitro against trypanosoma cruzi the agent responsible for trypanosomiasis, south america]. / Activité antiparasitaire d'alcaloïdes bisbenzylisoquinoléiques. II. Activité in vitro sur des epimastigotes de trois souches typifiees de Trypanosoma cruzi.

Chagas disease caused by the protozoan Trypanosoma cruzi is an endemic parasitic disease in Central and South America. The chemotherapeutic agents against Trypanosoma cruzi (imidazol compounds, lampit and benznidazol) are not very convenient products. Since it is known that protozoan Trypanosoma are close to Leishmania we studied the action of 14 bisbenzylisoquinoline alkaloids, in vitro, on three strains of T. cruzi (Tulahuen, C8C11, and 1979 CL1). As in the case of Leishmania, gyrocarpine, daphnandrine and obaberine showed an interesting activity and we judge them to be worthy of in vivo assays.

[Active antihelminitic alkaloids: active in vitro against Leishmanic Tropica the protozoa involved in leishmaniasis]. / Activité antiparasitaire d'alcaloïdes bisbenzylisoquinoleiques. I: Activité in vitro sur des promastigotes de trois souches de Leishmania.

Leishmaniasis caused by protozoan Leishmania ssp., is an endemic parasitic disease in Central and South America. The chemotherapeutic agents against Leishmania ssp. (pentavalent antimony compounds, pentamidine and amphothericine B) are toxic and expensive products. Basing on the Bolivian folk medicine, we tried to find new active principles. Fourteen isoquinoline alkaloids, especially bisbenzylisoquinoline alkaloids extracted from Annonaceae, Berberidaceae, Hernandiaceae and Menispermaceae, demonstrate highly effective activity against this protozoan. Among them gyrocarpine, daphnandrine and obaberine seem to be of particular interest. The therapeutic effect was studied by biological assays on culture forms in vitro three strains of Leishmania, L. donovani, L. braziliensis (cutaneous and mucocutaneous leishmaniasis), L. mexicana amazonensis (cutaneous) and L. donovani (visceral leishmaniasis).

Antiparasitic activities of medicinal plants used in Ivory Coast.

During an ethnopharmacological survey of antiparasitic medicinal plants used in Ivory Coast, 17 plants were identified and collected. Polar, non-polar and alkaloidic extracts of various parts of these species were evaluated in vitro in an antiparasitic drug screening. Antimalarial, leishmanicidal, trypanocidal, antihelminthiasis and antiscabies activities were determined. Among the selected plants, Anogeissus leiocarpus and Terminalia glaucescens were strongly active against Plasmodium falciparum. Lawsonia inermis, selectively prescribed against trypanosomiasis shows interesting trypanocidal activities as did other 15 plants. Anthelmintic activities were found for 10 active species and 2 species (Uvaria afzelli and Monodora myristica) were actives against mites.