Encecalol angelate, an unstable chromene from Ageratum conyzoides L.: total synthesis and investigation of its antiprotozoal activity

Ethnopharmacological relevance

In agreement with ethnomedicinal reports, the dichloromethane extract of Ageratum conyzoides L. (Asteraceae) was recently shown to be of considerable activity against Trypanosoma brucei rhodesiense, the etiologic agent of East African Human Trypanosomiasis (East African Sleeping Sickness). Isolated compounds, namely, methoxylated flavonoids as well as the chromene derivative encecalol methyl ether, were less active than the crude extract. The activity of the extract was found to decrease considerably while stored in solution. An unstable compound was detected in the fresh extract by HPLC, which was converted rapidly into the encecalol methyl ether while stored in methanolic solution. This compound, deemed to represent a constituent with antitrypanosomal activity, could not be isolated from the extract in intact form.

Aim of the study

To elucidate the structure of this unstable compound and to investigate its potential role in the antitrypanosomal activity of the total extract.

Materials and Methods

UHPLC/ESI-qQTOF MSMS and NMR data of the degraded product indicated its chemical identity as encecalol angelate (1) which was therefore prepared by total synthesis via a linear six steps synthesis, starting from resorcinol and 2-methylbut-3-en-2-ol.

Results

Total synthesis, in an overall yield of 15%, led to pure 1, which was chromatographically and spectroscopically identical with the natural product. The compound degraded in methanol with a half-life of approximately 6 h to yield encecalol methyl ether (2). The antiprotozoal activity of synthetic encecalol angelate against T. brucei rhodesiense as well as T. cruzi, Leishmania donovani and Plasmodium falciparum was investigated and found to be quite low.

Conclusions

The synthetic approach applied here for the first time also provides access to the related bioactive chromenes encecalin (7) and encecalol (8) with improved yields compared with reported methods. Encecalol angelate, however, is most likely not responsible for the high antitrypanosomal activity of the freshly prepared dichloromethane extract of A. conyzoides.     

Safety and Efficacy of Oral Mifepristone in Pre-induction Cervical Ripening and Induction of Labour in Prolonged Pregnancy

Objective(S)

To study the safety and efficacy of oral mifepristone in pre-induction cervical ripening and induction of labour in prolonged pregnancy.

Method(S)

This is a single blind randomized control trial. 100 women with prolonged pregnancy beyond 40 weeks and Bishop score <6 were recruited, and randomly allocated into two groups. Women who received Tab. Mifepristone 200 mg orally were assigned in Study Group (n = 50) and who received placebo orally were assigned in Control Group (n = 50) At the end of 24 h, change in the Bishop’s score was assessed and Tab. Misoprostol 25 μg was administered intravaginally every 4 h, maximum 6 doses for induction/augmentation of labour. Analysis regarding safety and efficacy of the drug was done with regards to maternal and perinatal outcome.

Result(S)

Among 100 subjects, 50 received mifepristone and 50 received placebo. Mean induction to delivery interval was 1,907 ± 368.4 min for Study Group versus 2,079 ± 231.6 min for Control Group. The improvement in mean Bishop score was 5.0408 ± 1.90 for Study Group compared with 3.26 ± 1.15 was for Control Group after 24 h. Mean dose of misoprostol in Study Group was 40 ± 27.2, while the same in Control Group was 52 ± 19.46. Eight (16 %) women in Study Group and two (4 %) women in Control Group delivered vaginally within 24 h without any need of augmentation. There were 6 (12 %) cesareans and 2 (4 %) instrumental deliveries in Study Group and 8 (16 %) cesareans and 5 (10 %) instrumental deliveries in the Control Group. There was no statistically significant difference in perinatal outcomes between two groups.

Conclusion(S)

Mifepristone had a modest effect on cervical ripening when given 24 h prior to labour induction and appearing to reduce need for misoprostol compared with placebo.     

Anterior skull base surgery— our experience

Anterior skull base surgery is now an accepted treatment modality for many lesions involving the anterior skull base including the pituitory region. This paper deals with a fifteen year experience over various approaches to the anterior skull base, and thereby trying to rationalize the appropriate approach for the tumours in different anatomical situations. Relevant literature has also been reviewed.     

The development and evaluation of a single step multiplex PCR method for simultaneous detection of Brugia malayi and Wuchereria bancrofti

A single step novel multiplex polymerase chain reaction (PCR) has been developed for simultaneous detection of human filarial parasites, Brugia malayi and Wuchereria bancrofti, from blood samples and mosquitoes. The primers used were novel and have been tested with the parasite DNA amplifying 188bp (BM) and 129bp (WB) DNA fragments, specific to B. malayi and W. bancrofti, respectively, in a single reaction. The specificity of the PCR product was confirmed by DNA sequencing and slot blot hybridization assay. The test was found highly sensitive for both B. malayi and W. bancrofti by detecting the parasitaemia up to the level of one microfilaria per reaction. The assay was further evaluated on 98 blood samples and 144 mosquito samples collected from filarial endemic areas. The PCR was found to be more efficient in comparison to microscopy by detecting 8% and 5% more filarial parasites in field-collected blood and mosquito samples, respectively. This novel PCR that offers scope for simultaneous detection of both the parasites may be used as a diagnostic tool for the detection of filariasis in population and can be adopted for rapid surveillance and monitoring of mosquitoes for use in the effective control of filariasis.     

Pharmacologic Hemostatic Agents in Total Joint Arthroplasty—A Cost-Effectiveness Analysis

Background

Total knee and hip arthroplasties can be associated with substantial blood loss, affecting morbidity and even mortality. Two pharmacological antifibrinolytics, ε-aminocaproic acid (EACA) and tranexamic acid (TXA) have been used to minimize perioperative blood loss, but both have associated morbidity. Given the added cost of these medications and the risks associated with then, a cost-effectiveness analysis was undertaken to ascertain the best strategy.

PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis

Several drugs approved for a variety of indications have been shown to exhibit antiangiogenic effects. Our study focuses on the PPARgamma ligand rosiglitazone, a compound widely used in the treatment of type 2 diabetes. We demonstrate, for the first time to our knowledge, that PPARgamma is highly expressed in tumor endothelium and is activated by rosiglitazone in cultured endothelial cells. Furthermore, we show that rosiglitazone suppresses primary tumor growth and metastasis by both direct and indirect antiangiogenic effects. Rosiglitazone inhibits bovine capillary endothelial cell but not tumor cell proliferation at low doses in vitro and decreases VEGF production by tumor cells. In our in vivo studies, rosiglitazone suppresses angiogenesis in the chick chorioallantoic membrane, in the avascular cornea, and in a variety of primary tumors. These results suggest that PPARgamma ligands may be useful in treating angiogenic diseases such as cancer by inhibiting angiogenesis.     

Vitamin E (D-alpha-tocopheryl-co-poly(ethylene glycol) 1000 succinate) micelles-superparamagnetic iron oxide nanoparticles for enhanced thermotherapy and MRI

We synthesized vitamin E TPGS (d-α-Tocopheryl-co-poly(ethylene glycol) 1000 succinate) micelles for superparamagnetic iron oxides formulation for nanothermotherapy and magnetic resonance imaging (MRI), which showed better thermal and magnetic properties, and in vitro cellular uptake and lower cytotoxicity as well as better in vivo therapeutic and imaging effects in comparison with the commercial Resovist and the Pluronic F127 micelles reported in the recent literature. The superparamagnetic iron oxides originally coated with oleic acid and oleylamine were formulated in the core of the TPGS micelles using a simple solvent-exchange method. The IOs-loaded TPGS showed greatest colloidal stability due to the critical micelle concentration (CMC) of vitamin E TPGS. Highly monodisperse and water soluble suspension was obtained which were stable in 0.9% normal saline for a period of 12 days. The micelles were characterized for their size and size distribution. Their morphology was examined through transmission electron microscopy (TEM). The enhanced thermal and superparamagnetic properties of the IOs-loaded TPGS micelles were assessed. Cellular uptake and cytotoxicity were investigated in vitro with MCF-7 cancer cells. Relaxivity study showed that the IOs-loaded TPGS micelles can have better effects for T2-weighted imaging using MRI. T2 mapped images of xenograft grown on SCID mice showed that the TPGS micelle formulation of IOs had ～1.7 times and ～1.05 times T2 decrease at the tumor site compared to Resovist and the F127 micelle formulation, respectively.