The purpose of this study is to evaluate the in vitro and in vivo performance of gastro-retentive matrix tablets having Metformin HCl as model drug and combination of natural polymers. A total of 16 formulations were prepared by a wet granulation method using xanthan, tamarind seed powder, tamarind kernel powder and salep as the gel-forming agents and sodium bicarbonate as a gas-forming agent. All the formulations were evaluated for compendial and non-compendial tests and in vitro study was carried out on a USP-II dissolution apparatus at a paddle speed of 50 rpm. MOX2 formulation, composed of salep and xanthan in the ratio of 4:1 with 96.9% release, was considered as the optimum formulation with more than 90% release in 12 hours and short floating lag time. In vivo study was carried out using gamma scintigraphy in New Zealand White rabbits, optimized formulation was incorporated with 10 mg of (153)Sm for labeling MOX2 formulation. The radioactive samarium oxide was used as the marker to trace transit of the tablets in the gastrointestinal tract. The in vivo data also supported retention of MOX2 formulation in the gastric region for 12 hours and were different from the control formulation without a gas and gel forming agent. It was concluded that the prepared floating gastro-retentive matrix tablets had a sustained-release effect in vitro and in vivo, gamma scintigraphy played an important role in locating the oral transit and the drug-release pattern.
Background: Tea has been shown to be a potent inhibitor of nonheme iron absorption, but it remains unclear whether the timing of tea consumption relative to a meal influences iron bioavailability.Objective: The aim of the study was to investigate the effect of a 1-h time interval of tea consumption on nonheme iron absorption in an iron-containing meal in a cohort of iron-replete, nonanemic female subjects with the use of a stable isotope (57Fe).Design: Twelve women (mean ± SD age: 24.8 ± 6.9 y) were administered a standardized porridge meal extrinsically labeled with 4 mg 57Fe as FeSO4 on 3 separate occasions, with a 14-d time interval between each test meal (TM). The TM was administered with water (TM-1), with tea administered simultaneously (TM-2), and with tea administered 1 h postmeal (TM-3). Fasted venous blood samples were collected for iron isotopic analysis and measurement of iron status biomarkers. Fractional iron absorption was estimated by the erythrocyte iron incorporation method.Results: Iron absorption was 5.7% ± 8.5% (TM-1), 3.6% ± 4.2% (TM-2), and 5.7% ± 5.4% (TM-3). Mean fractional iron absorption was found to be significantly higher (2.2%) when tea was administered 1 h postmeal (TM-3) than when tea was administered simultaneously with the meal (TM-2) (P = 0.046). An ∼50% reduction in the inhibitory effect of tea (relative to water) was observed, from 37.2% (TM-2) to 18.1% (TM-3).Conclusions: This study shows that tea consumed simultaneously with an iron-containing porridge meal leads to decreased nonheme iron absorption and that a 1-h time interval between a meal and tea consumption attenuates the inhibitory effect, resulting in increased nonheme iron absorption. These findings are not only important in relation to the management of iron deficiency but should also inform dietary advice, especially that given to those at risk of deficiency. This trial was registered at clinicaltrials.gov as NCT02365103.
Matched MeSH terms: Iron/pharmacokinetics*; Iron Isotopes/pharmacokinetics; Iron, Dietary/pharmacokinetics*
We previously developed a new zinc(II) phthalocyanine (ZnPc) derivative (Pc 1) conjugated to poly-L-glutamic acid (PGA) (1-PG) to address the limitations of ZnPc as part of an antitumor photodynamic therapy approach, which include hydrophobicity, phototoxicity, and nonselectivity in biodistribution and tumor targeting. During this study, we discovered that 1-PG possessed high near-infrared (NIR) light absorptivity (λmax = 675 nm), good singlet oxygen generation efficiency in an aqueous environment, and enhanced photocytotoxic efficacy and cancer cell uptake in vitro. In the current study, we discovered that 1-PG accumulated in 4T1 mouse mammary tumors, with a retention time of up to 48 h. Furthermore, as part of an antitumor PDT, low dose 1-PG (2 mg of Pc 1 equivalent/kg) induced a greater tumor volume reduction (-74 ± 5%) when compared to high dose ZnPc (8 mg/kg, -50 ± 12%). At higher treatment doses (8 mg of Pc 1 equivalent/kg), 1-PG reduced tumor volume maximally (-91 ± 6%) and suppressed tumor size to a minimal level for up to 15 days. The kidney, liver, and lungs of the mice treated with 1-PG (both low and high doses) were free from 4T1 tumor metastasis at the end of the study. Telemetry-spectral-echocardiography studies also revealed that PGA (65 mg/kg) produced insignificant changes to the cardiovascular physiology of Wistar-Kyoto rats when administered in vivo. Results indicate that PGA displays an excellent cardiovascular safety profile, underlining its suitability for application as a nanodrug carrier in vivo. These current findings indicate the potential of 1-PG as a useful photosensitizer candidate for clinical PDT.
A sequential algorithm is developed for the non-linear dual-sorption model developed by Chandrasekaran et al. [1,2] which monitors pharmacokinetic profiles in percutaneous drug absorption. In the experimental study of percutaneous absorption, it is often observed that the lag-time decreases with the increase in the donor concentration when two or more donor concentrations of the same compound are used. The dual-sorption model has sometimes been employed to explain such experimental results. In this paper, it is shown that another feature observed after vehicle removal may also characterize the dual-sorption model. Soon after vehicle removal, the plots of the drug flux versus time become straight lines on a semilogarithmic scale as in the linear model, but the half-life is prolonged thereafter when the dual-sorption model prevails. The initial half-life after vehicle removal with a low donor concentration is longer than that with a higher donor concentration. These features, if observed in experiments, may be used as evidence to confirm that the dual-sorption model gives an explanation to the non-linear kinetic behaviour of a permeant.
Hepatocellular carcinoma or hepatoma is a primary malignant neoplasm that responsible for 75-90% of all liver cancer in humans. Nanotechnology introduced the dual drug nanodelivery method as one of the initiatives in nanomedicine for cancer therapy. Graphene oxide (GO) loaded with protocatechuic acid (PCA) and chlorogenic acid (CA) have shown some anticancer activities in both passive and active targeting. The physicochemical characterizations for nanocomposites were conducted. Cell cytotoxicity assay and lactate dehydrogenase were conducted to estimate cell cytotoxicity and the severity of cell damage. Next, nanocomposite intracellular drug uptake was analyzed using a transmission electron microscope. The accumulation and localization of fluorescent-labelled nanocomposite in the human hepatocellular carcinoma (HepG2) cells were analyzed using a fluorescent microscope. Subsequently, Annexin V- fluorescein isothiocyanate (FITC)/propidium iodide analysis showed that nanocomposites induced late apoptosis in HepG2 cells. Cell cycle arrest was ascertained at the G2/M phase. There was the depolarization of mitochondrial membrane potential and an upregulation of reactive oxygen species when HepG2 cells were induced by nanocomposites. In conclusion, HepG2 cells treated with a graphene oxide-polyethylene glycol (GOP)-PCA/CA-FA dual drug nanocomposite exhibited significant anticancer activities with less toxicity compared to pristine protocatechuic acid, chlorogenic acid and GOP-PCA/CA nanocomposite, may be due to the utilization of a folic acid-targeting nanodrug delivery system.
Multidrug resistance, a major impediment to successful cancer chemotherapy, is the result of overexpression of ATP-binding cassette (ABC) transporters extruding internalized drugs. Silencing of ABC transporter gene expression with small interfering RNA (siRNA) could be an attractive approach to overcome multidrug resistance of cancer, although delivery of siRNA remains a major hurdle to fully exploit the potential of siRNA-based therapeutics. Recently, we have developed pH-sensitive carbonate apatite nanoparticles to efficiently carry and transport siRNA across the cell membrane, enabling knockdown of the cyclin B1 gene and consequential induction of apoptosis in synergy with anti-cancer drugs.
Matched MeSH terms: Apatites/pharmacokinetics; Drug Carriers/pharmacokinetics; RNA, Small Interfering/pharmacokinetics
The intercalation of perindopril erbumine into Zn/Al-NO(3)-layered double hydroxide resulted in the formation of a host-guest type of material. By virtue of the ion-exchange properties of layered double hydroxide, perindopril erbumine was released in a sustained manner. Therefore, this intercalated material can be used as a controlled-release formulation.
A simple and validated high-performance liquid chromatography (HPLC) method with UV detection has been used to determine the content of andrographolide (AP) and 14-deoxy-11,12-didehydroandrographolide (DIAP) in rat plasma after oral dose of methanol extract (1 g/kg body weight) of Andrographis paniculata leaf. An increase in plasma concentration of AP and DIAP was observed from 30 min to 3 h after oral administration of the extract. The maximum plasma concentrations of AP and DIAP were 1.42+/-0.09 microg/ml and 1.31+/-0.04 microg/ml, respectively. Fourteen days oral treatment of rats with the methanol extract (1 g/kg body weight) followed by CCl(4) administration preserved catalase (CAT), and superoxide dismutase (SOD) activities in erythrocytes, whereas plasma lipid peroxidation, alanine transaminase (ALT) and aspartate transaminase (AST) activities were restored to values comparable with control values. Treatment of rats with CCl(4) did not showed significant alteration (p>0.05) in plasma total antioxidant status (TAS) as compare to values of control group.
CYP2D6 polymorphisms are well described in normal populations but there are few data on its clinical significance. We therefore investigated the influence of CYP2D6 polymorphism on steady-state plasma concentrations and apparent oral clearance of metoprolol in patients with cardiovascular diseases.
Interleukin (IL)-17A may be an underlying factor in the pathophysiology of chronic obstructive pulmonary disease (COPD). Anti-IL-17 monoclonal antibodies have been used successfully in treating several immune-mediated inflammatory diseases. This phase 2, randomized, placebo-controlled, double-blind, parallel-group, proof-of-concept study is the first clinical study evaluating the efficacy and safety of the anti-IL-17A monoclonal antibody CNTO 6785 in patients with symptomatic moderate-to-severe COPD. Patients were treated with CNTO 6785 (n = 93) or placebo (n = 94) intravenously at Weeks 0, 2, and 4 (induction), then Weeks 8 and 12, and followed till Week 24. The primary efficacy endpoint was the change from baseline in pre-bronchodilator percent-predicted forced expiratory volume in 1 second at Week 16. Samples were collected at all visits for pharmacokinetic (PK) evaluation, and standard safety assessments were performed. The mean difference in the primary efficacy endpoint between CNTO 6785 and placebo was not statistically significant (-0.49%; p = 0.599). No other efficacy endpoints demonstrated clinically or statistically significant differences with CNTO 6785 compared with placebo. CNTO 6785 was generally well tolerated; no major safety signals were detected. The most frequently reported treatment-emergent adverse events were infections and infestations; however, no notable differences were observed between CNTO 6785 and placebo in terms of rates of infections. PK results suggested that the steady state of serum CNTO 6785 concentration was reached within 16 weeks. These results suggest that IL-17A is unlikely to be a dominant driver in the pathology of, or a viable therapeutic target for, COPD. ClinicalTrials.gov Identifier: NCT01966549; EudraCT Identifier: 2012-003607-36.
Drug nanosuspensions have gained tremendous attraction as a platform in drug delivery. In the present work, a nanosuspension was prepared by a wet milling approach in order to increase saturation solubility and dissolution of the water insoluble drug, hydrocortisone. Size of the generated particeles was 290 nm ± 9 nm having a zeta potential of -1.9 mV ± 0.6 mV. Nanosized particles were found to have a rod shape with a narrow particle size distribution (PDI =0.17). Results of differential scanning calorimetry and X-ray diffraction analyses revealed minor modifications of crystallinity of hydrocortisone following the milling process. Solubility of hydrocortisone was enhanced by nanonization to 875µg/ml ±2.5, an almost 2.9-fold compared to the raw hydrocortisone. Moreover, the nanosuspension formulation substabtially enhanced the dissolution rate of hydrocortisone where >97% of the hydrocortisone was dissolved within 10 minutes opposed to 22.3% for the raw 50% for the raw hydrocortisone and the commercial tablet, respectively. The bioavailability study resulted in AUC 0-9h for HC nanosuspensions (31.50±2.50), which is significantly (p<0.05) higher compared to the AUC 0-9h (14.85±3.25) resulted for HC solution. The nanosuspension was physically stable at room temperature for 24 months.
Tocotrienols are forms of vitamin E that are present in several important food crops. Compared to tocopherols, less research has been conducted on these compounds because of their low bioavailability and distribution in plant tissues. Both tocotrienols and tocopherols are known for their antioxidant and anticancer activities, which are beneficial for both humans and animals. Moreover, tocotrienols possess certain properties which are not found in tocopherols, such as neuroprotective and cholesterol-lowering activities. The contents of tocotrienols in plants vary. Tocotrienols constitute more than 70% and tocopherols less than 30% of the total vitamin E content in palm oil, which is the best source of vitamin E. Accumulation of tocotrienols also occurs in non-photosynthetic tissues, such as the seeds, fruits and latex of some monocotyledonous and dicotyledonous plant species. The use of biotechnological techniques to increase the tocotrienol content in plants, their biological functions, and benefits to human health are discussed in this review.
In this study, we developed positively charged liquid crystalline nanoparticles (LCN) coated with chitosan (CHI) to enhance the skin permeation and distribution of 5α-reductase inhibitors for the treatment of androgenetic alopecia. LCN and surface-modified LCN (CHI-LCN) were prepared by ultrasonication method, and their physicochemical properties were characterized. In vitro and in vivo skin permeation and retention were studied using porcine abdominal skin and mice skin using the Franz diffusion cell. Skin distribution and cellular uptake of LCN and CHI-LCN were also investigated. The particle size and surface charge were 244.9 ± 2.1 nm and -19.2 ± 1.1 mV, respectively, for LCNs and 300.0 ± 7.6 nm and 24.7 ± 2.4 mV, respectively, for CHI-LCN. The permeation of 5α-reductase inhibitors was significantly greater with CHI-LCN compared with LCN, whereas there was no significant difference observed in the skin distribution. In fluorescence studies, fluorescence intensity was higher for CHI-LCNs throughout the skin, whereas more intense fluorescence was seen only in the epidermis layer for LCN. CHI-LCN showed greater cellular uptake than LCN, resulting in internalization of 98.5 ± 1.9% of nanoparticles into human keratinocyte cells. In conclusion, surface modification of LCN with CHI is a promising strategy for increasing skin permeation of 5α-reductase inhibitors for topical delivery.
Mitragyna speciosa is reported to be beneficial for the management of chronic pain and opioid withdrawal in the evolving opioid epidemic. Data on the blood-brain barrier (BBB) transport of mitragynine and 7-hydroxymitragynine, the active compounds of the plant, are still lacking and inconclusive. Here, we present for the first time the rate and the extent of mitragynine and 7-hydroxymitragynine transport across the BBB, with an investigation of their post-BBB intra-brain distribution. We utilized an in vitro BBB model to study the rate of BBB permeation of the compounds and their interaction with efflux transporter P-glycoprotein (P-gp). Mitragynine showed higher apical-to-basolateral (A-B, i.e. blood-to-brain side) permeability than 7-hydroxymitragynine. 7-Hydroxymitragynine showed a tendency to efflux, with efflux ratio (B-A/A-B) of 1.39. Both were found to inhibit the P-gp and are also subject to efflux by the P-gp. Assessment of the extent of BBB transport in vivo in rats from unbound brain to plasma concentration ratios (Kp,uu,brain ) revealed extensive efflux of both compounds, with less than 10 percent of unbound mitragynine and 7-hydroxymitragynine in plasma crossing the BBB. By contrast, the extent of intra-brain distribution was significantly different, with mitragynine having 18-fold higher brain tissue uptake in brain slice assay compared with 7-hydroxymitragynine. Mitragynine showed a moderate capacity to accumulate inside brain parenchymal cells, while 7-hydroxymitragynine showed restricted cellular barrier transport. The presented findings from this systematic investigation of brain pharmacokinetics of mitragynine and 7-hydroxymitragynine are essential for design and interpretation of in vivo experiments aiming to establish exposure-response relationship.
Oral delivery of amphotericin B (AmpB) is desirable because it provides a more patient-friendly mode of administration compared to the current delivery approach akin with the marketed AmpB formulations. The goal of the study was to investigate the pharmacokinetics and tissue distribution of orally administered chitosan-coated AmpB-loaded nanostructured lipid carriers (ChiAmpB NLC) administered to Sprague Dawley rats at a dose of 15 mg/kg. Orally administered ChiAmpB NLC resulted in a two-fold increase in the area under the curve (AUC0-∞) compared to the uncoated AmpB NLC and marketed Amphotret®. This enhanced bioavailability of AmpB suggests prolonged transit and retention of ChiAmpB NLC within the small intestine through mucoadhesion and subsequent absorption by the lymphatic pathway. The results show that mean absorption and residence times (MAT & MRT) were significantly higher from ChiAmpB NLC compared to the other two formulations, attesting to the mucoadhesive effect. The ChiAmpB NLC presented a lower nephrotic accumulation with preferential deposition in liver and spleen. Thus, the limitations of current marketed IV formulations of AmpB are potentially addressed with the ChiAmpB NLC in addition to utilizing this approach for targeting internal organs in visceral leishmaniasis.
Vaccine administration via the oral route is preferable to parenteral routes due to ease of administration. To date, most available oral vaccines comprises of live attenuated pathogens as oppose to peptide-based vaccines due to its low bioavailability within the gastrointestinal (GI) tract. Over the years, probiotic-based peptide delivery vehicles comprising of lactic acid bacteria such as Lactococcus lactis has emerged as an interesting alternative due to its generally recognized as safe (GRAS) status, a fully sequenced genome, transient gut colonization time, and is an efficient cellular factory for heterologous protein production. However, its survivability through the GI tract is low, thus better delivery approaches are being explored to improve its bioavailability. In this study, we employ the incorporation of a double coated mucoadhesive film consisting of sodium alginate and Lycoat RS 720 film as the inner coat. The formulated film exhibits good mechanical properties of tensile strength and percent elongation for manipulation and handling with an entrapment yield of 93.14±2.74%. The formulated mucoadhesive film is subsequently loaded into gelatin capsules with an outer enteric Eudragit L100-55 coating capable of a pH-dependent breakdown above pH 5.5 to protect against gastric digestion. The final product and unprotected controls were subjected to in vitro simulated gastrointestinal digestions to assess its survivability. The product demonstrated enhanced protection with an increase of 69.22±0.67% (gastric) and 40.61±8.23% (intestinal) survivability compared to unprotected controls after 6 hours of sequential digestion. This translates to a 3.5 fold increase in overall survivability. Owing to this, the proposed oral delivery system has shown promising potential as a live gastrointestinal vaccine delivery host. Further studies involving in vivo gastrointestinal survivability and mice immunization tests are currently being carried out to assess the efficacy of this novel oral delivery system in comparison to parenteral routes.
The fungal transformations of medroxyrogesterone (1) were investigated for the first time using Cunninghamella elegans, Trichothecium roseum, and Mucor plumbeus. The metabolites obtained are as following: 6β, 20-dihydroxymedroxyprogesterone (2), 12β-hydroxymedroxyprogesterone (3), 6β, 11β-dihydroxymedroxyprogesterone (4), 16β-hydroxymedroxyprogesterone (5), 11α, 17-dihydroxy-6α-methylpregn-4-ene-3, 20-dione (6), 11-oxo-medroxyprogesterone (7), 6α-methyl-17α-hydroxypregn-1,4-diene-3,20-dione (8), and 6β-hydroxymedroxyprogesterone (9), 15β-hydroxymedroxyprogesterone (10), 6α-methyl-17α, 11β-dihydroxy-5α-pregnan-3, 20-dione (11), 11β-hydroxymedroxyprogesterone (12), and 11α, 20-dihydroxymedroxyprogesterone (13). Among all the microbial transformed products, the newly isolated biotransformed product 13 showed the most potent activity against proliferation of SH-SY5Y cells. Compounds 12, 5, 6, 9, 11, and 3 (in descending order of activity) also showed some extent of activity against SH-SY5Y tumour cell line. The never been reported biotransformed product, 2, showed the most potent inhibitory activity against acetylcholinesterase. Molecular modelling studies were carried out to understand the observed experimental activities, and also to obtain more information on the binding mode and the interactions between the biotransformed products, and enzyme.