Exploring the efficacy of ethnomedicinal plants of Himalayan region against the malaria parasite.

ETHNOPHARMACOLOGICAL RELEVANCE: Plasmodium falciparum multi-drug resistant (MDR) strains are a great challenge to global health care. This predicament implies the urgent need to discover novel antimalarial drugs candidate from alternative natural sources. The Himalaya constitute a rich repository of medicinal plants which have been used traditionally in the folklore medicine since ages and having no scientific evidence for their activity. Crambe kotschyana Boiss. and Eremurus himalaicus Baker are used for their antipyretic and hepatoprotective properties in Kinnaur district of Himachal Pradesh, India. AIM OF THE STUDY: This study would investigate the antiplasmodial efficacy of C. kotschyana and E. himalaicus extracts, their fractions and active components using in vitro, in vivo and in silico approaches to provide a scientific insight into their activity. METHODS: The methanol extracts of C. kotschyana (CKME) and E. himalaicus (EHME) were prepared by maceration followed by fractionation using ethyl acetate. The isolation of flavonoid glycosides isorhamnetin-3, 7-di-O-glucoside from C. kotschyana and luteolin-6-C-glucoside (isoorientin) from E. himalaicus was carried out by antiplasmodial activity-guided isolation. In vitro antimalarial activity was assessed by WHO method while in vitro cytotoxicity was ascertained employing the MTT assay. Molecular docking and molecular dynamics simulation were performed using the Glide module of Schrödinger Software and Gromacs-2022 software package respectively. In vivo curative activity was assessed by Ryley and Peters method. RESULTS: The methanol extracts of both the plants illustrated the best antiplasmodial activity followed by the ethyl acetate fractions. Iso-orientin (IC50 6.49 µg/ml) and Isorhamnetin-3,7-di-O-glucoside (IC50 9.22 µg/ml) illustrated considerable in vitro activity even against P. falciparum resistant strain. Extracts/fractions as well as the isolated compounds were found to be non-toxic with CC50 > 640 µg/ml. Molecular docking studies were performed with these 2 O-glucosides against four malaria targets to understand the binding pose of these molecules and the results suggested that these molecules have selectivity for lactate dehydrogenase enzyme. CKME and EHME exhibited curative activity in vivo along with increase in Mean Survival Time of mice. CONCLUSION: The research delineated the scientific evidence that both the therapeutic herbs possessed antimalarial activity and notably, bioactive compounds responsible to exhibit the antimalarial activity have been isolated, identified and characterized. Further studies are underway to assess the antiplasmodial efficacy of isolated compounds alone and in combination with standard antimalarials.

Sigma-2 receptor ligand anchored telmisartan loaded nanostructured lipid particles augmented drug delivery, cytotoxicity, apoptosis and cellular uptake in prostate cancer cells.

Recently, the anticancer activity of telmisartan (TEL) has been discovered against prostate cancer. Nevertheless, despite favorable therapeutic profile, poor aqueous solubility and suboptimal oral bioavailability hamper the anticancer efficacy of TEL. Therefore, in this investigation, sigma-2 receptor ligand, 3-(4-cyclohexylpiperazine-1-yl) propyl amine (CPPA) anchored nanostructured lipid particles of telmisartan (CPPA-TEL-NLPs) were engineered using stearic acid for targeting prostate cancer, PC-3 cells. The mean particle size of TEL-NLPs was measured to be 25.4 ± 3.2 nm, significantly (p < 0.05) lower than 32.6 ± 5.3 nm of CPPA-TEL-NLPs. Correspondingly, the zeta-potential of TEL-NLPs was measured to be -15.4 ± 2.3 mV significantly (p < 0.05) higher than -9.6 ± 2.7 mV of CPPA-TEL-NLPs. The encapsulation efficiency of CPPA-TEL-NLPs was estimated to be 72.7 ± 4.3%, significantly (p < 0.05) lower than 77.5 ± 5.4%, displayed by TEL-NLPs. In addition, FT-IR and PXRD confirmed the molecular encapsulation of the drug in amorphous state. In vitro drug release study was conducted to determine the drug delivery potential of tailored nanoparticles. TEL-NLPs released 93.36% of drug significantly (p < 0.05) higher than 85.81%, released by CPPA-TEL-NLPs in 24 h. The IC50 of CPPA-TEL-NLPs was measured to be 20.3 µM significantly (p < 0.05) lower than 36.3 µM presented by TEL-NLPs in PC-3 cells. In contrast, CPPA-TEL-NLPs displayed the IC50 of 41.3 µM, significantly (p > 0.05) not different from 43.4 µM, exhibited by TEL-NLPs in PNT-2 cells. We elucidated that CPPA-TEL-NLPs entered the PC-3 cells via receptor mediated endocytosis pathway and thus exhibited superior cytotoxicity, apoptosis and greater extent of cellular uptake in PC-3 cells. In conclusion, CPPA-TEL-NLPs may be a promising nanomedicine and warrant further in vivo investigations for gaining clinical success.

Nanovesicular carrier-based formulation for skin cancer targeting: evaluation of cytotoxicity, intracellular uptake, and preclinical anticancer activity.

CONTEXT: Skin cancer has turned into global epidemic leading to higher incidences among cancer stricken population. OBJECTIVE: The aim of the present investigation is to evaluate the anticancer potential and intracellular uptake of a novel nanovesicular formulation of 5-FU. MATERIALS AND METHODS: Detailed intracellular uptake study in conjunction with estimation of intracellular reactive oxygen species was done using skin melanoma cell lines (A375) along with cytotoxicity studies. To further obtain the mechanistic insights into inhibition of tumor cell proliferation, cell-cycle arrest studies were conducted. The preclinical anticancer activity was carried out employing in vivo DMBA-croton oil-induced skin cancer model in mice. RESULTS AND DISCUSSION: Significant reduction in the number of papillomas was observed in skin cancer-bearing mice on treatment with nanovesicular formulation (51.4 ± 3.2%) in comparison with marketed formulation (21.3 ± 2.1%) of 5-FU. Tumor volume was found to be reduced to 46.3 ± 3.5% with prepared formulation, whereas the marketed formulation-treated group showed the reduction of 18.6 ± 1.8% in comparison with the control (untreated) group. CONCLUSION: The results of present study demonstrated that nanovesicular formulation of 5-FU possessed the enhanced anticancer activity which could be attributed to better intracellular uptake, cellular retention, and sustained release of drug.

Development, characterization and in vivo localization study of topical 5-fluorouracil gels: a comparative study with conventional formulation.

5-Fluorouracil (5-FU) is one of the most effective antineoplastic agents used for the treatment of skin cancers and actinic keratosis (AK). Currently commercial formulation for topical 5-FU administration is available in the form of solution or cream. Commercial topical formulations are associated with the limitation of very short retention time at the administration site resulting in very poor skin permeation and deposition of drug. In the present study attempt was made for the preparation, optimization and characterization of bioadhesive gel formulations for localized delivery of 5-FU. Four bioadhesive gel formers, Carbopol 934, Carbopol 980, Methylcellulose (MC) and Poloxamer 188 were selected for the preparation of 5-FU bioadhesive gel formulations. The formulations were characterized for characteristic parameters including bioadhesive strength, skin deposition and interaction study. Carbopol 934 based bioadhesive gel formulation at the concentration of 1.5% w/w showed the best physicochemical properties such as viscosity (2670±12.2 cP), which was similar to the value obtained with the marketed cream (2870±14.4 cP), highest skin deposition (1290±56.4µg) and bioadhesive strength (18.62 gf). Cutaneous irritation of optimized bioadhesive gel formulations was also tested using the Draize test and only very slight erythema and no oedema was observed. In comparison, marketed formulation showed well defined erythema along with oedema formation. The result of the present study demonstrated that formulation of Carbopol 934 based 5-FU bioadhesive gel is a better alternative to the traditional cream base for enhanced topical delivery of 5-FU. The developed formulation will have the ease of application, better skin deposition and sustained release characteristic with reduced skin toxicity.

Ethogel topical formulation for increasing the local bioavailability of 5-fluorouracil: a mechanistic study.

5-Fluorouracil (5-FU) is an anticancer drug and is considered a gold standard for the treatment of skin cancer. At present, topical chemotherapy with 5-FU is associated with the limitations of poor skin permeation, retention at target site, and skin irritation potential. In the present study, an attempt has been made to develop an ethosome-based topical gel formulation (ethogel) for skin targeting of 5-FU. The ethosomal formulation was prepared using the classical dispersion method, and loading of 5% w/w of the drug was optimized to the commercial strength of marketed 5-FU cream. Carbopol 934P was used as a gel former in 0.5, 0.75, 1.0, and 1.5% w/w concentration for preparation of ethosome-based ethogel formulation. The ethogel formulation was characterized for viscosity, spreadability, extrudability, and pH. Viscosity of the developed ethogel and that of the marketed formulation was found to be 3070±14.7 and 2870±14.4 cP, respectively. An in-vitro skin permeation and deposition study was carried out across rat skin using the marketed cream and 5-FU drug solution as controls. The amount of drug deposition was found to increase 5.9- and 9.4-fold on treatment with ethogel in comparison with the marketed cream and drug solution, respectively. The result of antitumor activity evaluated using a Cytoselect 96-well cell transformation assay revealed a large reduction in tumor density with treatment with the 5-FU ethogel formulation in comparison with the marketed formulation. A significant reduction in the skin irritation potential of 5-FU ethogel formulation was also found in comparison with that of the marketed formulation as measured by the Draize test. The results of the present study demonstrated ethogel as a better alternative for increasing the local bioavailability of 5-FU in comparison to the marketed formulation.

Poly propyl ether imine (PETIM) dendrimer: a novel non-toxic dendrimer for sustained drug delivery.

In the present study, an attempt was made to study the acute and sub-acute toxicity profile of G3-COOH Poly (propyl ether imine) [PETIM] dendrimer and its use as a carrier for sustained delivery of model drug ketoprofen. Drug-dendrimer complex was prepared and characterized by FTIR, solubility and in vitro drug release study. PETIM dendrimer was found to have significantly less toxicity in A541 cells compared to Poly amido amine (PAMAM) dendrimer. Further, acute and 28 days sub-acute toxicity measurement in mice showed no mortality, hematological, biochemical or histopathological changes up to 80 mg/kg dose of PETIM dendrimer. The results of study demonstrated that G3-COOH PETIM dendrimer can be used as a safe and efficient vehicle for sustained drug delivery.

Drug-cyclodextrin-vesicles dual carrier approach for skin targeting of anti-acne agent.

In the present study attempt was made for preparation of isotretinoin-hydroxypropyl beta cyclodextrin (HP-beta-CD) inclusion complex and encapsulate this complex in elastic liposomes to study the effect of dual carrier approach on skin targeting of isotretinoin. The isotretinoin HP-beta-CD complex was prepared by freeze-drying method and characterized by IR spectroscopy. The drug and drug-CD complex loaded elastic liposomal formulation were prepared and characterized in vitro, ex-vivo and in vivo for shape, size, entrapment efficiency, no. of vesicles per cubic mm, in vitro skin permeation and deposition study, photodegradation and skin toxicity assay. The transdermal flux for different vesicular formulations was observed between 10.5 +/- 0.5 to 13.9 +/- 1.6 microg/cm(2)/h. This is about 15-21 folds higher than that obtained from drug solution (0.7 +/- 0.1 microg/cm(2)/h) and 4-5 folds higher than obtained with drug-CD complex solution (2.7 +/- 0.1 microg/cm(2)/h). The amount of drug deposit was found to increase significantly (p < 0.05) by cyclodextrin complexation (30.1 +/- 0.1 microg). The encapsulation of this complex in elastic liposomal formulation further increases its skin deposition (262.2 +/- 21 microg). The results of skin irritation study using Draize test also showed the significant reduction in skin irritation potential of isotretinoin elastic liposomal formulation in comparison to free drug. The results of the present study demonstrated that isotretinoin elastic liposomal formulation possesses great potential for skin targeting, prolonging drug release, reduction of photodegradation, reducing skin irritation and improving topical delivery of isotretinoin.

Coronary artery bypass graft surgery patient education: a systematic review.

Patient education post-coronary artery bypass graft (CABG) surgery is an essential component of nursing care aimed at assisting patients in caring for themselves at home, following discharge from hospital. While there has been a recent interest in conducting meta-analysis and systematic reviews on the effectiveness of patient education during the preoperative period, no review was found on the topic of postoperative CABG patient education. This systematic review addressed the clinically-relevant questions: what approach, mode, and dose is most effective in producing changes in CABG patient education? Studies were included in the systematic review if they met the following selection criteria: (1) the sample represented adult (> or =18 years) patients who underwent CABG surgery; (2) the educational intervention involved the provision of self-care information following surgery but before discharge from hospital; (3) the outcome assessed related to self-care behavior; and (4) the study report was published in English between 1986 and 2008. A descriptive synthesis was used to code and extract data on publication information, study design, sample size, and quality of study, as well as postoperative CABG teaching, self-care behavior performance, and demographic characteristics of the patients who participated in the studies. A quantitative synthesis consisted of a statistical approach, which was used to calculate the magnitude of the treatment effects on self-care behavior. Results indicated larger effect sizes for CABG patient education in which the content was individualized, and given in a combination of media on an individual basis, and in more than one session.