Risperidone Pellets, Pycnogenol®, and Glucomannan Gummy Formulation for Managing Weight Gain and ADHD in Autistic Children.

Gummy formulations are defined as gradually or slowly released solid oral dosage forms. Risperidone is an atypical antipsychotic medication used to treat schizophrenia and autism-related irritability. This study presents the development of visually appealing, patient-tailored medicated gummies that act as a novel pharmaceutical form of Risperidone for pediatrics. In this study, two gummy bases were used, one containing Glucomannan and the other containing Gelatin as a gelling agent, where these gummy bases were loaded with coated Risperidone pellets with a controlled release layer. The final products were evaluated for their pH, viscosity, content uniformity, drug content, and dissolution profile. Both formulas showed proper rheology and met content and weight uniformity standards. The release rates for F1 and F2 in the acidic media were 25% and 11%, respectively, after 2 h. At the same time, a full-release profile for Risperidone was noticed in both formulae at pH 6.8 where the release lasts for 24 h. It can be concluded that the chewable semi-solid dosages (gummies) filled with coated pellets are suitable for pediatric patients since pediatrics have drug-related problems which can be solved using high gastro-resistance coated pellets, which also shows a proper release profile for the drug.

In Vivo Evaluation of Chitosan-Titanium Dioxide Nanopowder as Wound Dressing Material.

BACKGROUND: Films used for wound healing have many advantages, but should be flexible, robust, adherable and prevent maceration. Both Chitosan (CS) and Titanium dioxide nanopowder (TiO2 NP) have good properties to accelerate wound healing and can be used in preparing films. OBJECTIVE: CS and TiO2 NP are combined to formulate films for wound healing. The physical, thermal, chemical, and mechanical characteristics of these films are to be assessed. The antibacterial activity of the films and their performance on wounded rats will be explored. METHODS: Films made of CS and TiO2 NP were characterized by FTIR, TGA, DSC, XRD, and SEM. The films' mechanical characteristics and antimicrobial activity were tested. Films with acceptable mechanical properties were evaluated on rats. RESULTS: Generally, CS-TiO2 films had higher weight and thickness but lowered flexibility compared to films prepared using CS only. The chosen film showed excellent folding endurance with weight and thickness of around 21.98 mg and 0.16 mm. The surface pH for CS-TiO2 films was acidic, and for the selected film, it was 5.18. CS-TiO2 film was active against all studied bacteria and significantly higher than CS films. The antimicrobial activity of Gram-negative bacteria (P. aeruginosa and E. coli) was higher than that of Gram-positive bacteria (S. aureus). Finally, adding TiO2 NP to the films accelerated the healing process of the created wounds in a murine model, compared to control and CS-treated groups. CONCLUSION: Films of TiO2 NP and CS have suitable properties to be used in wound healing and can be further used in the future to load drugs.

HAZ, a novel peptide with broad-spectrum antibacterial activity.

Objective: The growing microbial resistance to antibiotics is a global public concern, which creates serious needs for newer antimicrobial agents. Antimicrobial peptides (AMPs) are increasingly exploited in drug development as therapeutic candidates. Here, we aimed to design and characterize a novel peptide with broad spectrum antimicrobial activity. Methods: Hybridization and sequence modification approaches were used to design the novel peptide, named HAZ, aiming at optimizing the physicochemical parameters involved in antimicrobial activity. Peptide activities were assessed alone or combined with different selected antibiotics against various sensitive and drug-resistant bacterial strains. In addition, the hemolysis and the cytotoxic activities of HAZ peptide were evaluated on human red blood cells and epithelial adenocarcinoma cells (A549), respectively. Results: HAZ peptide was sequentially modified to result in favored physicochemical parameters (helicity 95.24 %, hydrophobic ratio 47 %, and net charge of 8 + ). Functional assessment of HAZ revealed significant antimicrobial activity, with MIC values of 15 - 20 µM against tested bacterial strains. It also exhibited biofilm eradication activity at slightly higher concentrations. HAZ-antibiotics combinations exhibited a synergistic action mode that led to dramatic decrease in the MIC values for both HAZ peptide and the antibiotic. Such efficacy was accompanied with minimal hemolytic toxicity on human erythrocytes. Importantly, HAZ displayed promising anticancer activity against human lung cancer cells. Conclusion: Rationally-designed antimicrobial peptides offer promising alternatives to the current antibiotics for management of infectious diseases. HAZ peptide is a broad-spectrum AMP, and a promising candidate for antimicrobial and anticancer drug development.

Polymeric Nanoparticles for Inhaled Vaccines.

Many recent studies focus on the pulmonary delivery of vaccines as it is needle-free, safe, and effective. Inhaled vaccines enhance systemic and mucosal immunization but still faces many limitations that can be resolved using polymeric nanoparticles (PNPs). This review focuses on the use of properties of PNPs, specifically chitosan and PLGA to be used in the delivery of vaccines by inhalation. It also aims to highlight that PNPs have adjuvant properties by themselves that induce cellular and humeral immunogenicity. Further, different factors influence the behavior of PNP in vivo such as size, morphology, and charge are discussed. Finally, some of the primary challenges facing PNPs are reviewed including formulation instability, reproducibility, device-related factors, patient-related factors, and industrial-level scale-up. Herein, the most important variables of PNPs that shall be defined in any PNPs to be used for pulmonary delivery are defined. Further, this study focuses on the most popular polymers used for this purpose.

Preparation and Characterization of Docetaxel-PLGA Nanoparticles Coated with Folic Acid-chitosan Conjugate for Cancer Treatment.

The conjugation of chitosan (CS) and folic acid (FA) was prepared and used to coat PLGA nanoparticles (NPs) that are loaded with Docetaxel (DTX) to target cancer cells that have lower pH and overexpression of folate receptors in comparison to normal cells. Three formulations had been prepared to reach the highest loading capacity (LC%) and encapsulation efficiency (EE%) and to study the effect of the amount of FA-CS on the drug release. The sizes, charges, homogeneity, surface morphology, LC% and EE% of the NPs were determined. The NPs were characterized using FTIR and XRD. In vitro release profiles of DTX from PLGA NPs, at pH 5.5 and 7.4 were determined. Finally, in vitro cytotoxicity assay on three cancer cell lines (RPMI 2650, Calu-3, and A549) was studied. The sizes of the three formulations ranged between 250.3±1.7 and 356.3±17.7. All prepared formulations showed acceptable monodispersity with highly positive charges. The EE% was above 85% and the LC% ranged between 6-35%. The in vitro release of DTX show an inverse relation to the amounts of FA-CS used and the pH of the dissolution medium. Coated PLGA NPs showed a significant difference in RPMI 2650, Calu-3, and A549 cell viability in comparison to free DTX. The NPs components were safe and non-toxic to human cells. In conclusion, coating PLGA NPs with FA-CS may be used as a good carrier for chemotherapeutic agents that selectively target carcinogenic tissues.

The effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite, N-desmethyl imatinib, in rats.

BACKGROUND: Imatinib is mainly metabolized by CYP3A4 and to a lesser extent by other isoenzymes, with N-desmethyl imatinib being its major equipotent metabolite. Being a CYP3A4 substrate, imatinib co-administration with CYP3A4 modulators would change its pharmacokinetic profile. The cancer chemoprevention potential and anticancer efficacy of many herbal products such as grape seed (GS) and green tea (GT) extracts had led to an increase in their concomitant use with anticancer agents. GS and GT extracts were demonstrated to be potent inhibitors of CYP3A4. The aim of this study is to investigate the effect of standardized GS and/or GT extracts at two different doses on the pharmacokinetics of imatinib and its metabolite, N-desmethyl imatinib, in SD-rats. METHODS: Standardized GS and/or GT extracts were administered orally once daily for 21 days, at low (l) and high (h) doses, 50 and 100 mg/kg, respectively, before the administration of a single intragastric dose of imatinib. Plasma samples were collected and analyzed for imatinib and N-desmethyl imatinib concentrations using LC-MS/MS method, then their non-compartmental pharmacokinetic parameters were determined. RESULTS: h-GS dose significantly decreased imatinib's Cmax and the [Formula: see text] by 61.1 and 72.2%, respectively. Similar effects on N-desmethyl imatinib's exposure were observed as well, in addition to a significant increase in its clearance by 3.7-fold. l-GT caused a significant decrease in imatinib's Cmax and [Formula: see text] by 53.6 and 63.5%, respectively, with more significant effects on N-desmethyl imatinib's exposure, which exhibited a significant decrease by 79.2 and 81.1%, respectively. h-GT showed similar effects as those of l-GT on the kinetics of imatinib and its metabolite. However, when these extracts were co-administered at low doses, no significant effects were shown on the pharmacokinetics of imatinib and its metabolite. Nevertheless, increasing the dose caused a significant decrease in Cmax of N-desmethyl imatinib by 71.5%. CONCLUSIONS: These results demonstrated that the pharmacokinetics of imatinib and N-desmethyl imatinib had been significantly affected by GS and/or GT extracts, which could be partially explained by the inhibition of CYP3A-mediated metabolism. However, the involvement of other kinetic pathways such as other isoenzymes, efflux and uptake transporters could be involved and should be characterized.

Piperine Alters the Pharmacokinetics and Anticoagulation of Warfarin in Rats.

INTRODUCTION: Piperine, the bioactive compound of black pepper, and warfarin are metabolized by cytochrome P450 enzymes and are both highly plasma protein-bound compounds. In this study, we evaluated the effect of co-administered piperine on the pharmacokinetics and anticoagulation of warfarin in rats. METHODS: We studied four Sprague-Dawley rat groups: a negative control group receiving only oral warfarin, a test group receiving warfarin plus piperine, a positive control group receiving warfarin plus sulfaphenazole (CYP2C inhibitor), and another positive control group receiving warfarin plus ketoconazole (CYP3A inhibitor). We also analyzed plasma concentrations of warfarin and its major metabolite, 7-hydoxywarfarin. Blood clotting time, calculated as international normalized ratio (INR), was also measured. RESULTS: Our results showed that although co-administration of piperine produced a non-significant decrease in warfarin concentrations, it resulted in significantly lower 7-hydroxywarfarin metabolite concentrations. Piperine significantly decreased, by sixfold, AUC0-∞, by eightfold, Cmax, but significantly increased, by fivefold, CL/F and, by sixfold, Vd/F of 7-hydroxywarfarin. The INR values were consistent with the decrease in warfarin concentration in the presence of piperine and showed a significant decrease at 24 h after warfarin dose. CONCLUSION: We conclude that piperine could be a potent inhibitor of cytochrome P450 metabolism of warfarin in vivo and, contrary to the expectation, may reduce the plasma concentration and anticoagulation of warfarin. This interaction could have a clinical significance and should be investigated in patients.

The effect of cannabidiol on the pharmacokinetics of carbamazepine in rats.

Carbamazepine (CBZ) is mainly metabolized by CYP3A4 into carbamazepine-10,11-epoxide (CBZE). Cannabidiol (CBD) is a potent inhibitor of the CYP3A family. The aim of this study is to determine the effect of acute and chronic administration of CBD on the pharmacokinetics of CBZ and CBZE. Male SD rats were assigned into four acute and four chronic groups: control (CBZ only), positive control (ketoconazole), low-dose cannabidiol (l-CBD), and high-dose cannabidiol (h-CBD). Acute CBD groups were administered a single dose of CBD, while chronic CBD groups were given multiple doses of CBD for 14 days (q.d.) before CBZ administration. Plasma samples had been collected and analyzed for CBZ and CBZE, then their noncompartmental pharmacokinetic parameters before and after CBD administration were determined. The co-administration of a single l-CBD has significantly increased CBZ's [Formula: see text] by 53.1%. Furthermore, CBZE kinetics showed a significant decrease in Cmax by 31.8%. Acute h-CBD caused similar effects on CBZ's [Formula: see text] with 40.4% significant decrease in CBZE's Cmax, when compared to the control. Chronic h-CBD caused a significant decrease in CBZ's Cmax and [Formula: see text] by 75.3% and 65.7%, respectively. Besides, [Formula: see text] and Cmax of CBZE significantly decreased by 75.3% and 78.3%, respectively. These results demonstrated that the pharmacokinetics of CBZ and CBZE had been significantly affected by CBD. When CBD has been administered as a single dose, the effect is believed to be mainly caused by the inhibition of CBZ metabolism through CYP3A. The effect of chronic administration of CBD probably includes kinetic pathways other than the inhibition of CYP3A-dependent pathways. Graphical abstract.

Simultaneous determination of warfarin and 7-hydroxywarfarin in rat plasma by HPLC-FLD.

In this study, high-performance liquid chromatography with fluorescence detection (HPLC-FLD) has been used for the first time, for direct determination of warfarin and its major metabolite, 7-hydroxywarfarin, in rat plasma. The simple and sensitive method was developed using Fortis® reversed-phase diphenyl column (150 × 4.6 mm, 3 µm) and a mobile phase composed of phosphate buffer (25 mmol L-1)/methanol/acetonitrile (70:20:10, V/V/V), adjusted to pH 7.4, at a flow rate of 0.8 mL min-1. The diphenyl chemistry of the stationary phase provided a unique selectivity for separating the structurally related aromatic analytes, warfarin and 7-hydroxywarfarin, allowing their successful quantification in the complex plasma matrix. The method was linear over the range 0.01-25 µg mL-1, for warfarin and 7-hydroxywarfarin, and was found to be accurate, precise and selective in accordance with US FDA guidance for bioanalytical method validation. The method was sensitive enough to quantify 0.01 µg mL-1 of warfarin and 7-hydroxywarfarin (LLOQ) using only 100 µL of plasma. The applicability of this method was demonstrated by analyzing samples obtained from rats after oral administration of a single warfarin dose, and studying warfarin and 7-hydroxywarfarin pharmacokinetics.

Gold nanoparticles and angiogenesis: molecular mechanisms and biomedical applications.

Angiogenesis is the formation of new blood vessels from pre-existing vessels. It is a highly regulated process as determined by the interplay between pro-angiogenic and anti-angiogenic factors. Under certain conditions the balance between angiogenesis stimulators and inhibitors is altered, which results in a shift from physiological to pathological angiogenesis. Therefore, the goal of therapeutic targeting of angiogenic process is to normalize vasculature in target tissues by enhancing angiogenesis in disease conditions of reduced vascularity and blood flow, such as tissue ischemia, or alternatively to inhibit excessive and abnormal angiogenesis in disorders like cancer. Gold nanoparticles (AuNPs) are special particles that are generated by nanotechnology and composed of an inorganic core containing gold which is encircled by an organic monolayer. The ability of AuNPs to alter vasculature has captured recent attention in medical literature as potential therapeutic agents for the management of pathologic angiogenesis. This review provides an overview of the effects of AuNPs on angiogenesis and the molecular mechanisms and biomedical applications associated with their effects. In addition, the main synthesis methods, physical properties, uptake mechanisms, and toxicity of AuNPs are briefly summarized.

Pramlintide, an antidiabetic, is antineoplastic in colorectal cancer and synergizes with conventional chemotherapy.

BACKGROUND: Approximately 90% of patients with metastatic colorectal cancer fail therapy mainly due to resistance. Taking advantage of currently approved agents for treatment of disease conditions other than cancer for the identification of new adjuvant anticancer therapies is highly encouraged. Pramlintide is a parenteral antidiabetic agent that is currently approved for treatment of types 1 and 2 diabetes mellitus. OBJECTIVES: To address the antineoplastic potential of pramlintide in colorectal cancer and to evaluate the ability of pramlintide to enhance the cytotoxicity of 5-fluorouracil, oxaliplatin, and irinotecan against colorectal cancer cell lines expressing wild-type and mutant p53. MATERIALS AND METHODS: The antiproliferative effect of pramlintide alone or in combination with 5-fluorouracil, oxaliplatin, or irinotecan in HCT-116 and HT-29 colorectal cancer cell lines was investigated using MTT cell proliferation assay. IC50 values were calculated using Compusyn software 1.0. Synergy values (R) were calculated using the ratio of IC50 of each primary drug alone divided by combination IC50s. For each two pairs of experiments, Student's t-test was used for analysis. For combination studies, one-way analysis of variance and Tukey post hoc testing was performed using R 3.3.2 software. A p-value of <0.05 was considered significant. RESULTS: Pramlintide inhibited the growth of HCT-116 and HT-29 in a dose-dependent manner, with higher efficacy against the latter (IC50s; 48.67 and 9.10 µg/mL, respectively; p-value =0.013). Moreover, the addition of 5, 10, and 20 µg/mL of pramlintide to HCT-116 and HT-29 with 5-fluorouracil, oxaliplatin, or irinotecan induced the antiproliferative effect synergistically (R>1.6, p-value <0.05). CONCLUSION: Pramlintide enhances the cytotoxicity of conventional chemotherapy against colorectal cancer cell lines harboring wild-type or mutant p53. Thus, pramlintide is a promising potential adjuvant chemotherapy in colorectal cancer.

In vitro lung epithelial cell transport and anti-interleukin-8 releasing activity of liposomal ciprofloxacin.

As a promising long-acting inhaled formulation, liposomal ciprofloxacin (Lipo-CPFX) was characterized in the in vitro human lung epithelial Calu-3 cell monolayer system, compared to ciprofloxacin in solution (CPFX). Its modulated absorptive transport and uptake, and sustained inhibitory activity against induced pro-inflammatory interleukin-8 (IL-8) release were examined. The absorptive transport and uptake kinetics for Lipo-CPFX and CPFX were determined at 0.1-50 mg/ml in the Transwell system. The Lipo-CPFX transport was then challenged for mechanistic exploration via cell energy depletion, a reduced temperature, endocytosis and/or lipid fusion inhibition, and addition of excess non-loaded liposomes. The inhibitory activities of Lipo-CPFX and CPFX against lipopolysaccharide (LPS)-induced IL-8 release were assessed in a co-incubation or pre-incubation mode. In the tight Calu-3 cell monolayers, Lipo-CPFX yielded 15-times slower ciprofloxacin flux of absorptive transport and 5-times lower cellular drug uptake than CPFX. Its transport appeared to be transcellular; kinetically linear, proportional to encapsulated ciprofloxacin concentration; and consistent with the cell energy-independent lipid bilayer fusion mechanism. Lipo-CPFX was equipotent to CPFX in the anti-IL-8 releasing activity upon 24 h co-incubation with LPS. Additionally, Lipo-CPFX, but not CPFX, retained the anti-IL-8 releasing activity even 24 h after pre-incubation. In conclusion, Lipo-CPFX enabled slower absorptive lung epithelial cell transport and uptake of ciprofloxacin, apparently via the lipid bilayer fusion mechanism, and the sustained inhibitory activity against LPS-induced IL-8 release, compared to CPFX.