Development and Characterizations of Pullulan and Maltodextrin-Based Oral Fast-Dissolving Films Employing a Box–Behnken Experimental Design

Migraine is a neurological disorder characterized by severe headaches, visual aversions, auditory, and olfactory disorders, accompanied by nausea and vomiting. Zolmitriptan (ZMT^®) is a potent 5HT1B/1D serotonin receptor agonist frequently used for the treatment of migraine. It has erratic absorption from the gastrointestinal tract (GIT), but its oral bioavailability is low (40–45%) due to the hepatic metabolism. This makes it an ideal candidate for oral fast dissolving formulations. Hence, the current study was undertaken to design and develop oral fast-dissolving films (OFDFs) containing ZMT for migraine treatment. The OFDFs were formulated by the solvent casting method (SCM) using Pullulan (PU) and maltodextrin (MDX) as film-forming agents and propylene glycol (PG) as a plasticizer. The strategy was designed using Box–Behnken experimental design considering the proportion of PU:MDX and percentage of PG as independent variables. The effectiveness of the OFDF’s was measured based on the following responses: drug release at five min, disintegration time (D-time), and tensile strength (TS). The influence of formulation factors, including percent elongation (%E), thickness, water content, moisture absorption, and folding endurance on ZMT-OFDFs, were also studied. The results showed a successful fabrication of stable ZMT-OFDFs, with surface uniformity and amorphous shape of ZMT in fabricated films. The optimized formulation showed a remarkable rapid dissolution, over 90% within the first 5 min, a fast D-time of 18 s, and excellent mechanical characteristics. Improved maximum plasma concentration (C max) and area under the curve (AUC 0–t) in animals (rats) treated with ZMT-OFDFs compared to those treated with an intra-gastric (i-g) suspension of ZMT were also observed. Copolymer OFDFs with ZMT is an exciting proposition with great potential for the treatment of migraine headache. This study offers a promising strategy for developing ZMT-OFDFs using SCM. ZMT-OFDFs showed remarkable rapid dissolution and fast D-time, which might endeavor ZMT-OFDFs as an auspicious alternative approach to improve patient compliance and shorten the onset time of ZMT in migraine treatment.     

Novel flavonoid-based biodegradable nanoparticles for effective oral delivery of etoposide by P-glycoprotein modulation: an in vitro,ex vivo and in vivo investigations

Abstract

A receptor level interaction of etoposide with P-glycoprotein (P-gp) and subsequent intestinal efflux has an adverse effect on its oral absorption. The present work is aimed to enhance the bioavailability of etoposide by co-administering it with quercetin (a P-gp inhibitor) in dual-loaded polymeric nanoparticle formulation. Poly-lactic-co-glycolic acid (PLGA) nanoparticles were optimized for various parameters like o/w phase volume ratio, poly-vinyl alcohol concentration, PLGA concentration and sonication time. The cytotoxicity studies (MTT assay) revealed a 9- and 11-fold decrease in the IC 50 values for etoposide-loaded nanoparticles (ENP) and etoposide?+?quercetin dual-loaded nanoparticles (EQNP) when compared to that of free etoposide, respectively, and the results were further supported by florescent-activated cell sorter studies. The confocal imaging of the intestinal sections treated with ENP and EQNP containing fluorescent probe (rhodamine) showed the superiority of the EQNP to permeate deeper. Furthermore, pharmacokinetic studies on rats revealed that EQNP exhibited a 2.4-fold increase in bioavailability of etoposide than ENP with no quercetin. The developed loaded nanoparticles have the high potential to enhance the bioavailability of the etoposide and sensitize the resistant cells.     

Metabolic and pharmacological profiling of Penicillium claviforme by a combination of experimental and bioinformatic approaches

BackgroundPenicillium produces a wide range of structurally diverse metabolites with significant pharmacological impacts in medicine and agriculture. For the first time, a complete metabolome of Penicillium claviforme (P. claviforme) (FBP-DNA-1205) was studied alongside pharmacological research in this study.MethodsThe metabolic profile of P. claviforme fermented on Potato Dextrose Broth (PDB) was investigated in this work. The complete metabolomics studies of fungus were performed using GC-MS and LC-MS-QTOF techniques. An in vitro model was utilised to study the cytotoxic and antioxidant activities, while an in vivo model was employed to investigate the antinociceptive and acute toxicity activities. Molecular Operating Environment (MOE) software was used for molecular docking analysis.ResultsGC-MS study showed the presence of alkanes, fatty acids, esters, azo and alcoholic compounds. Maculosin, obtain, phalluside, quinoline, 4,4’-diaminostilbene, funaltrexamine, amobarbital, and fraxetin were among the secondary metabolites identified using the LC-MS-QTOF technique. The n-hexane fraction of P. claviforme displayed significant cytotoxic activity in vitro, with an LD50 value of 92.22 µgml⁻¹. The antinociceptive effects in vivo were dose-dependent significantly (p < .001). Interestingly, during the 72 h of investigation, no acute toxicity was demonstrated. In addition, a docking study of tentatively identified metabolites against the inflammatory enzyme (COX-2) supported the antinociceptive effect in an in silico model.ConclusionMetabolic profile of P. claviforme shows the presence of biologically relevant compounds in ethyl acetate extract. In addition, P. claviforme exhibits substantial antioxidant and cytotoxic activities in an in vitro model as well as antinociceptive activity in an in vivo model. The antinociceptive action is also supported by a molecular docking study. This research has opened up new possibilities in the disciplines of mycology, agriculture, and pharmaceutics.

Key messages

• The first time explored complete metabolome through GC-MS and LC-MS-QTOF.
• Both in vivo & in vitro pharmacological investigation of P. claviforme.
• In silico molecular docking of LC-MS-QTOF metabolites.

     

Pandora's box: ethics of PGD for inherited risk of late-onset disorders

Until recently, the primary use of preimplantation genetic diagnosis (PGD) has been the selection of embryos to avoid lethal or debilitating gene mutations or abnormal chromosome complement. PGD can be used to reduce the risk of transferring to the uterus an embryo with Down syndrome, and parents who are carriers of severe genetic diseases may choose to avoid having children with these debilitating genetic conditions. The use of PGD is now being extended to include gene mutations that increase the risk of late-onset disorders such as breast and ovarian cancer. This paper argues for caution in advocating reproductive methods that are costly, have a limited chance of success, and for which the long-term outcome is unknown. Counselling should allow women a true choice of declining the option of PGD without recrimination, feelings of guilt or social pressure. There is concern that the Human Fertilisation and Embryology Authority has approved extension of PGD to late-onset multifactorial diseases without clear guidelines for its use. Guidelines for embryo selection should be revised to deal with potential conflict between reproductive success and genetic screening for disorders that do not profoundly affect the embryo or the children.     

Efficacy of crude neem seed kernel extracts against natural infestation of Sarcoptes scabiei var. ovis

This study was aimed to evaluate the efficacy of crude aqueous-methanol and aqueous extracts of neem (Azadirachta indica) seed kernel against sarcoptic mange of sheep. Crude aqueous-methanol (AME) and aqueous extracts (AE) of neem seed kernel (NSK) were prepared and formulated as 10% and 20% ointments (w/w), using Vaseline as vehicle. Forty-two lambs of Pak Karakul breed, having natural infection of sarcoptic mange were divided into seven experimental groups. Skin scrapings and clinical examination were carried out at scheduled intervals after treatment. Ivermectin (positive control) completely cleared infesting mites from animals after 10 days and 20% AME after 16 days. While, clinical mange was completely cured after 16 and 20 days with ivermectin and 20% AME, respectively, under field conditions. Only the higher concentration (20% AME) of NSK extracts completely cured the clinical mange, suggesting a dose-dependent response. Our results consolidate the belief that use of folk remedies can provide an effective and economic way of combating sarcoptic mange in sheep.     

An account of the botanical anthelmintics used in traditional veterinary practices in Sahiwal district of Punjab, Pakistan

AIM OF THE STUDY: The present study was aimed at documentation of botanical anthelmintics used in the traditional veterinary practices in Sahiwal district of Punjab, Pakistan. MATERIALS AND METHODS: In rapid rural appraisal, 331 traditional veterinary healers (TVH) were identified as key respondents in the study area followed by participatory rural appraisal for data collection using a well-structured questionnaire. Information was collected through interviews, focused group discussions and field visits over a period of 2 years. RESULTS: A total of 49 traditional recipes, with 41 plant species representing 39 genera and 27 families, were recorded for the treatment of helminthosis in animals. Most frequently used plants (>/=5 times) were Brassica campestris L. and Mallotus philippinensis (Lam.) Muell.-Arg. and most frequently used families (>/=5 times) were Brassicaceae, Euphorbiaceae and Solanaceae. Most frequently used part of the plant was leaves (n=10) followed in order by seeds (n=9), whole fruit (n=5), aerial parts and whole plant (n=4), fruit (n=3), bulb (n=2) and bark, rhizome, stem, stem plus root and twigs (n=1). Five recipes out of 49 (10.2%) contained more than one plant species and rest 44 (89.8%) contained single plant species. CONCLUSIONS: Twenty out of 41 plants (48.78%) are reported for the first time for their traditional use as anthelmintics in Pakistan. Further studies on pharmacokinetics using scientific procedures may prove these plants as promising candidates for their future use as anthelmintics.     

Protease inhibitor therapy and fetal growth potential in HIV-positive women

Our objective was to test if protease inhibitors (PIs) increase the incidence of fetal growth restriction (FGR). Human immunodeficiency (HIV)-seropositive women were studied. At birth the neonatal weight percentile was assigned by predicted growth potential (GP), accounting for race, parity, weight, height, gestational age, birthweight, and gender (Gardosi, 1992). FGR was defined as GP < 10% percentile. Maternal age, CD4 count, viral load, weight gain, prenatal care, tobacco, alcohol, substance abuse, and PI use were related to FGR using chi-square and multiple regression analysis. Ninety-three of 191 women received PI. In these, FGR occurred in 27 (29%) compared with 15 (15.3%) in the non-PI group ( P = 0.02). Maternal CD4 count ( P < 0.0001) was the primary determinant, and smoking ( P = 0.037) was an independent cofactor for FGR (Nagelkerke r2 = 0.24). Twenty-six of 82 (31.7%) smokers had FGR, versus 16 of 109 (14.7%) of nonsmokers (odds ratio, 2.69; 95% confidence interval, 1.33 to 5.46; P = 0.005). After exclusion of the CD4 count, PI became a cofactor for FGR ( P = 0.021 and Nagelkerke r2 = 0.104). We concluded that maternal HIV status and smoking determine the risk for FGR. Although PIs increase the risk for FGR, this effect appears to depend on maternal disease severity.     

Maternal mortality and maternity care from 1990 to 2005: uneven but important gains

Maternal mortality continues to be the major cause of death among women of reproductive age in many countries. Data from published studies and Demographic and Health Surveys show that gains in reducing maternal mortality between 1990 and 2005 have been modest overall. In 2005, there were about 536,000 maternal deaths, and the maternal mortality ratio was estimated at 400 per 100,000 live births, compared to 430 in 1990. Noteworthy declines took place in east Asia (4% per year) and north Africa (3% per year). Maternal deaths and mortality ratios were highest in sub-Saharan Africa and southeast Asia and low in east Asia and Latin America/Caribbean. In 11 of 53 countries with data, fewer than 25% of women had had at least four antenatal visits. About 63% of births were attended by a skilled attendant: from 47% in Africa to 88% in Latin America/Caribbean. In 16 of 23 countries with data, less than 50% of the recommended levels of emergency obstetric care had been fulfilled. Only 61% of women who delivered in a health facility in 30 developing countries received post-partum care, and far fewer who gave birth at home. Countries with maternal mortality ratios of 750+ per 100,000 live births shared problems of high fertility and unplanned pregnancies, poor health infrastructure with limited resources and low availability of health personnel. The task ahead is enormous.     

槟榔子中抗血小板聚集及抑制乙酰胆碱酯酶活性的有效成分（英文）

目的：研究槟榔子（Areca catechu）粗提取物中所含的抗血小板聚集及抑制乙酰胆碱酯酶活性的有效成分及其作用机制。方法：使用70%甲醇水溶液对槟榔子进行粗提取。使用生物发光血小板凝集仪在富血小板血浆中测定槟榔子粗提取物的抗血小板聚集作用,使用分光光度计在试管内测定槟榔子粗提取物对乙酰胆碱酯酶活性的抑制作用。检测槟榔子中的多种化合物以测定槟榔子中抗血小板聚集及抑制乙酰胆碱酯酶活性的有效成分。结果：槟榔子粗提取物能够抑制花生四烯酸、二磷酸腺苷、血小板活化因子、肾上腺素及钙离子载体引起的血小板聚集,尤其对二磷酸腺苷及钙离子载体引起的血小板聚集的抑制最为明显;槟榔子粗提取物能够显著抑制乙酰胆碱酯酶的活性。在所检测的槟榔子所含化合物中,只有儿茶素对肾上腺素引起的血小板聚集有显著的抑制作用,而这种抑制作用显著弱于槟榔子粗提取物,提示槟榔子中的其他成分参与了这种抑制作用;鞣酸、没食子酸、薯蓣皂苷元和异去甲槟榔次碱能够抑制乙酰胆碱酯酶的活性,其中鞣酸的抑制作用强于槟榔子粗提取物。结论：槟榔子中含有抗血小板聚集及抑制乙酰胆碱酯酶活性的有效成分,而发挥这些功效的确切成分有待进一步的研究证实。