Evaluation of Silybin Nanoparticles against Liver Damage in Murine Schistosomiasis mansoni Infection.

Silybin (SIB) is a hepatoprotective drug known for its poor oral bioavailability, attributed to its classification as a class IV drug with significant metabolism during the first-pass effect. This study explored the potential of solid lipid nanoparticles with (SLN-SIB-U) or without (SLN-SIB) ursodeoxycholic acid and polymeric nanoparticles (PN-SIB) as delivery systems for SIB. The efficacy of these nanosystems was assessed through in vitro studies using the GRX and Caco-2 cell lines for permeability and proliferation assays, respectively, as well as in vivo experiments employing a murine model of Schistosomiasis mansoni infection in BALB/c mice. The mean diameter and encapsulation efficiency of the nanosystems were as follows: SLN-SIB (252.8 ± 4.4 nm, 90.28 ± 2.2%), SLN-SIB-U (252.9 ± 14.4 nm, 77.05 ± 2.8%), and PN-SIB (241.8 ± 4.1 nm, 98.0 ± 0.2%). In the proliferation assay with the GRX cell line, SLN-SIB and SLN-SIB-U exhibited inhibitory effects of 43.09 ± 5.74% and 38.78 ± 3.78%, respectively, compared to PN-SIB, which showed no inhibitory effect. Moreover, SLN-SIB-U demonstrated a greater apparent permeability coefficient (25.82 ± 2.2) than PN-SIB (20.76 ± 0.1), which was twice as high as that of SLN-SIB (11.32 ± 4.6) and pure SIB (11.28 ± 0.2). These findings suggest that solid lipid nanosystems hold promise for further in vivo investigations. In the murine model of acute-phase Schistosomiasis mansoni infection, both SLN-SIB and SLN-SIB-U displayed hepatoprotective effects, as evidenced by lower alanine amino transferase values (22.89 ± 1.6 and 23.93 ± 2.4 U/L, respectively) than those in control groups I (29.55 ± 0.7 U/L) and I+SIB (34.29 ± 0.3 U/L). Among the prepared nanosystems, SLN-SIB-U emerges as a promising candidate for enhancing the pharmacokinetic properties of SIB.

N, N'-disubstituted Ureas as Novel Antiplatelet Agents: Synthesis, Pharmacological Evaluation and In Silico Studies.

INTRODUCTION: Thrombotic disorders are among the leading causes of morbidity and mortality worldwide. Drugs used in the prevention and treatment of atherothrombosis have pharmacokinetic limitations and adverse effects such as hemorrhagic conditions, highlighting the importance of developing more effective antiplatelet agents. ethod: In this work, we synthesized N,N'-disubstituted ureas 3a-3j and evaluated their antiplatelet profiles through in vitro, ex vivo, and in silico studies. The synthesized derivatives exhibited a selective inhibitory profile against platelet aggregation induced by arachidonic acid (AA) in vitro, without significantly affecting other aspects of primary hemostasis and blood coagulation. The compounds that showed inhibition greater than 85% were submitted to the analysis of their potency by calculating the concentration required to inhibit 50% of platelet aggregation induced by AA (IC50). Urea derivative 3a was the most potent with IC50 of 1.45 µM. Interestingly, this derivative inhibited more than 90% of platelet aggregation induced by AA ex vivo, with a similar effect to acetylsalicylic acid. In the hemolysis assay, most of the urea derivatives presented values below 10% suggesting good hemocompatibility. Additionally, the compounds tested at 100 µM also showed no cytotoxic effects in HepG2 and Vero cells. RESULT: The in silico results suggested that compound 3a may bind to the key residue of COX-1 similar to AA and known COX-1 inhibitors, and the results are also in agreement with our SAR, which suggests that the inhibition of this enzyme is the most likely mechanism of antiplatelet activity. CONCLUSION: Therefore, these results demonstrated that N,N'-disubstituted ureas are promising candidates for the development of novel antiplatelet agents.

Use of In silico Methodologies to Predict the Bioavailability of Oral Suspensions: A Regulatory Approach.

BACKGROUND: Oral suspensions are heterogeneous disperse systems, and the particle size distribution, crystalline form of the dispersed solid, and composition of the formulation can be listed as parameters that control the drug dissolution rate and its bioavailability. OBJECTIVE: The aim of this work was to develop a discriminative dissolution test, which, in association with in silico methodologies, can make it possible to safely anticipate bioavailability problems. METHODS: Nimesulide and ibuprofen (BCS class II) and cephalexin (BCS class I) oral suspensions were studied. Previously, solid-state structure and particle size in active pharmaceutical ingredients were characterized and the impact of differences on solubility was evaluated for the choice of discriminative medium. Afterwards, particle size distribution (0.1 to 360 µm), dissolution profile, and in vitro permeability in Caco-2 cell of commercial suspensions, were determined. These parameters were used as input for the establishment of the in vitro-in vivo correlation (IVIVC) for the suspensions using the GastroPlus™ with Wagner-Nelson and Loo- Riegelmann deconvolution approach. RESULTS: The predicted/observed pharmacokinetic model showed good correlation coefficients (r) of 0.960, 0.950, and 0.901, respectively. The IVIVC was established for one nimesulide and two ibuprofen suspensions with r between 0.956 and 0.932, and the percent prediction error (%PE) did not exceed 15%. CONCLUSION: In this work, we have performed a complete study combining in vitro/in silico approaches with the aim of anticipating the safety and efficacy of oral pharmaceutical suspensions in order to provide a regulatory tool for this category of products in a faster and more economical way.

In vivo evaluation of time-dependent antithrombotic effect of rivaroxaban-loaded poly(lactic-co-glycolic acid)/sodium lauryl sulfate or didodecyl dimethylammonium bromide nanoparticles in Wistar rats.

Rivaroxaban (RVX), an oral direct factor Xa inhibitor, is being explored as an alternative to traditional anticoagulans. However, RVX still faces pharmacokinetic limitations and adverse effects, highlighting the need for more effective formulations. In this regard, pharmaceutical nanotechnology, particularly the use of polymeric nanoparticles (PNPs), offers a promising approach for optimizing RVX delivery. This study aimed to develop and physicochemically characterize RVX-loaded poly(lactic-co-glycolic acid) (PLGA)/sodium lauryl sulfate (SLS) or didodecyl dimethylammonium bromide (DMAB) nanoparticles, and also evaluate their pharmacological and toxicological profiles as a potential therapeutic strategy. The PNPs exhibited sizes below 300 nm and spherical morphology, with both negative and positive surface charges, according to surfactant used. They demonstrated high encapsulation efficiency and suitable yields, as well as rapid initial liberation followed by sustained release in different pH environments. Importantly, in vivo evaluations revealed a time-dependent antithrombotic effect surpassing the free form of RVX when administered orally in SLS or DMAB PNP. No hemolytic or cytotoxic effects were observed at various concentrations of the PNPs. Interestingly, the PNPs did not induce hemorrhagic events or cause liver enzyme alterations in vivo. These findings suggest that RVX-loaded SLS or DMAB PNPs are promising innovative therapeutic alternatives for the treatment of thromboembolic diseases.

Development of SEDDS formulation containing caffeine for dermal delivery.

OBJECTIVE: The objective of this work was to develop a self-emulsifying drug delivery system (SEDDS) containing caffeine for the treatment of cellulite. METHODS: SEDDS were prepared using the solution method. 0.5% (w/v) caffeine was added to the previously selected excipients. The system was characterized by droplet size, zeta potential, emulsification time and long-term stability. In vitro release and skin permeation were investigated using Franz-type diffusion cells. The cytotoxicity was evaluated on normal human keratinocytes. RESULTS: Caffeine SEDDS were thermodynamically stable, with a zeta potential less than - 22 mV and droplet size around 30 nm, and were long-term stable. The permeation study showed that the formulation promoted caffeine accumulation in the skin layers, suggesting an increase in local circulation. Cytotoxicity studies on HaCaT cells were not conclusive as the surfactant used indicated false-positive results due to its high molar mass. CONCLUSION: It was possible to obtain a stable SEDDS that could cause an increase in blood flow in the applied area, resulting in cellulite reduction.

OBJECTIF: L'objectif de ce travail était de développer un système d'administration de médicaments auto-émulsifiants (SEDDS) contenant de la caféine pour le traitement de la cellulite. MÉTHODES: Les SEDDS ont été préparés par la méthode en solution. 0,5 % (p/v) de caféine a été ajouté aux excipients préalablement sélectionnés. Le système a été caractérisé par la taille des gouttelettes, le potentiel zêta, le temps d'émulsification et la stabilité à long terme. La libération in vitro et la perméation cutanée ont été étudiées dans des cellules de diffusion de type Franz. La cytotoxicité était évaluée sur des kératinocytes humains normaux. RÉSULTATS: Les SEDDS de caféine étaient thermodynamiquement stables, avec un potentiel Zeta inférieur à -22 mV et une taille de gouttelettes d'environ 30 nm, et stables à long terme. L'étude de perméation a montré que les formulations favorisent l'accumulation de caféine dans les couches de la peau, suggérant une augmentation de la circulation locale. Les études de cytotoxicité sur les cellules HaCaT n'ont pas été concluantes car le surfactant utilisé indique des résultats faussement positifs dus à une masse molaire élevée. CONCLUSION: Il a été possible d'obtenir un SEDDS stable qui peut provoquer une augmentation du flux sanguin dans la zone appliquée, entraînant une réduction de la cellulite.

Alternative Methods for Pulmonary-Administered Drugs Metabolism: A Breath of Change.

Prediction of pulmonary metabolites following inhalation of a locally acting pulmonary drug is essential to the successful development of novel inhaled medicines. The lungs present metabolic enzymes, therefore they influence drug disposal and toxicity. The present review provides an overview of alternative methods to evaluate the pulmonary metabolism for the safety and efficacy of pulmonary delivery systems. In vitro approaches for investigating pulmonary drug metabolism were described, including subcellular fractions, cell culture models and lung slices as the main available in vitro methods. In addition, in silico studies are promising alternatives that use specific software to predict pulmonary drug metabolism, determine whether a molecule will react with a metabolic enzyme, the site of metabolism (SoM) and the result of this interaction. They can be used in an integrated approach to delineate the major cytochrome P450 (CYP) isoforms to rationalize the use of in vivo methods. A case study about a combination of experimental and computational approaches was done using fluticasone propionate as an example. The results of three tested software, RSWebPredictor, SMARTCyp and XenoSite, demonstrated greater probability of the fluticasone propionate being metabolized by CYPs 3A4 at the S1 atom of 5-S-fluoromethyl carbothioate group. As the in vitro studies were not able to directly detect pulmonary metabolites, those alternatives in silico methods may reduce animal testing efforts, following the principle of 3Rs (Replacement, Reduction and Refinement), and contribute to the evaluation of pharmacological efficacy and safety profiles of new drugs in development.

Synthesis and Evaluation of Antiproliferative Activity, Topoisomerase IIα Inhibition, DNA Binding and Non-Clinical Toxicity of New Acridine-Thiosemicarbazone Derivatives.

In this study, we report the synthesis of twenty new acridine-thiosemicarbazone derivatives and their antiproliferative activities. Mechanisms of action such as the inhibition of topoisomerase IIα and the interaction with DNA have been studied for some of the most active derivatives by means of both in silico and in vitro methods, and evaluations of the non-clinical toxicities (in vivo) in mice. In general, the compounds showed greater cytotoxicity against B16-F10 cells, with the highest potency for DL-08 (IC50 = 14.79 µM). Derivatives DL-01 (77%), DL-07 (74%) and DL-08 (79%) showed interesting inhibition of topoisomerase IIα when compared to amsacrine, at 100 µM. In silico studies proposed the way of bonding of these compounds and a possible stereoelectronic reason for the absence of enzymatic activity for CL-07 and DL-06. Interactions with DNA presented different spectroscopic effects and indicate that the compound CL-07 has higher affinity for DNA (Kb = 4.75 × 104 M-1; Ksv = 2.6 × 103 M-1). In addition, compounds selected for non-clinical toxicity testing did not show serious signs of toxicity at the dose of 2000 mg/kg in mice; cytotoxic tests performed on leukemic cells (K-562) and its resistant form (K-562 Lucena 1) identified moderate potency for DL-01 and DL-08, with IC50 between 11.45 and 17.32 µM.

Development of rivaroxaban microemulsion-based hydrogel for transdermal treatment and prevention of venous thromboembolism.

We have developed a microemulsion (ME)-based hydrogel, containing propylene glycol, Azone®, Labrasol®, isobutanol and water (20:3:18:3:56), for the transdermal delivery of rivaroxaban (RVX). Formulation ME-1:RVX, which was loaded with 0.3 mg/g of RVX, presented as a clear, homogenous fluid with a droplet size of 82.01 ± 6.32 nm and a PdI of 0.207 ± 0.01. To provide gelation properties, 20 % (w/w) of Pluronic® F-127 was added to ME-1:RVX to generate formulation PME-1a. An added benefit was an increased capacity for RVX to 0.4 mg/g (formulation PME-1b). PME-1b displayed spherical droplets with a nanoscale diameter as observed by Transmission Electron Microscopy. The release of RVX from PME-1b was 20.71 ± 0.76 µg/cm2 with a permeation through pig epidermis of 18.32 ± 8.87 µg/cm2 as measured in a Franz Cell for 24 h. PME-1b presented a pseudoplastic behavior, pH value compatible with the skin and good stability over 60 days at room and elevated temperatures. The prothrombin time was assessed for each concentration of RVX obtained in the permeation assay and each demonstrated a relevant anticoagulant activity. PME-1b also presented no cytotoxicity against HaCaT cells. Utilizing GastroPlus® software, an in silico analysis was performed to simulate the delivery of PME-1b through a transdermal system that suggested a minimum dose of RVX for the treatment and prevention of venous thromboembolism could be achieved with an 8 h administration regimen. These results suggest that PME-1b is a promising transdermal formulation for the effective delivery of RVX that could be a viable alternative for the treatment and prevention of venous thromboembolism.

Clofazimine functionalized polymeric nanoparticles for brain delivery in the tuberculosis treatment.

Central nervous system tuberculosis (CNS-TB) is the most severe form of the disease especially due to the inability of therapeutics to cross the blood-brain barrier (BBB). Clofazimine (CFZ) stands out for presenting high in vitro activity against multi-drug resistant strains of Mycobacterium tuberculosis, however, CFZ physicochemical and pharmacokinetics properties limit drug penetration into the CNS and, consequently, its clinical use. The aim of this work was to develop polymeric nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) loaded with CFZ and functionalized with a transferrin receptor (TfR)-binding peptide, aiming brain drug delivery for CNS-TB treatment by the intravenous route. The poor water solubility and high lipophilicity of CFZ was overcome through its entrapment into PLGA-PEG NPs manufactured by both conventional and microfluidic techniques using the nanoprecipitation principle. In vitro studies in brain endothelial hCMEC/D3 cells demonstrated that CFZ incorporation into the NPs was advantageous to reduce drug cytotoxicity. The TfR-binding peptide-functionalized NPs showed superior cell interaction and higher CFZ permeability across hCMEC/D3 cell monolayers compared to the non-functionalized NP control, thus indicating the efficacy of the functionalization strategy on providing CFZ transport through the BBB in vitro. The functionalized NPs demonstrate suitability for CFZ biological administration, suggested with low plasma protein binding, off-target biodistribution and precise delivery of CFZ towards the brain parenchyma.

Novel rivaroxaban-loaded poly(lactic-co-glycolic acid)/poloxamer nanoparticles: preparation, physicochemical characterization, in vitro evaluation of time-dependent anticoagulant activity and toxicological profile.

Rivaroxaban (RXB), an oral direct factor Xa inhibitor, presents innovative therapeutic profile. However, RXB has shown adverse effects, mainly due to pharmacokinetic limitations, highlighting the importance of developing more effective formulations. Therefore, this work aims at the preparation, physicochemical characterization and in vitro evaluation of time-dependent anticoagulant activity and toxicology profile of RXB-loaded poly(lactic-co-glycolic acid) (PLGA)/poloxamer nanoparticles (RXBNps). RXBNp were produced by nanoprecipitation method and physicochemical characteristics were evaluated. In vitro analysis of time-dependent anticoagulant activity was performed by prothrombin time test and toxicological profile was assessed by hemolysis and MTT reduction assays. The developed RXBNp present spherical morphology with average diameter of 205.5 ± 16.95 nm (PdI 0.096 ± 0.04), negative zeta potential (-26.28 ± 0.77 mV), entrapment efficiency of 91.35 ± 2.40%, yield of 41.81 ± 1.68% and 3.72 ± 0.07% of drug loading. Drug release was characterized by an initial fast release followed by a sustained release with 28.34 ± 2.82% of RXB available in 72 h. RXBNp showed an expressive time-dependent anticoagulant activity in human and rat blood plasma and non-toxic profile. Based on the results presented, it is possible to consider that RXBNp may be able to assist in the development of promising new therapies for treatment of thrombotic disorders.

Effects of a novel roflumilast and formoterol fumarate dry powder inhaler formulation in experimental allergic asthma.

In this study we aimed to develop a roflumilast (R) and formoterol fumarate (F) dry powder inhaler formulation (DPI) incorporating HPßCD by spray drying and evaluated if it attenuates the inflammatory process and improves lung function in a murine model of ovalbumin induced allergic asthma. The DPI was characterized by powder X-ray diffraction, thermal analysis, scanning electron microscopy, particle size, density, specific surface area and dynamic vapor sorption analyses. In vitro deposition studies were performed using a NGI, while transepithelial permeability and in vivo effects on lung mechanics and inflammation in a model of allergic asthma were also assessed. The R:F formulation was amorphous with high glass transition temperatures, comprised of wrinkled particles, had low bulk and tapped densities, high surface area, suitable particle size for pulmonary delivery and exhibited no recrystallization even at high relative humidities. MMAD were statistically similar of 4.22 ± 0.19 and 4.32 ± 0.13 µm for F and R, respectively. Fine particle fractions (<5 µm) were of more than 50% of the emitted dose. The R:F formulation led to reduced eosinophil infiltration and airway collagen fiber content, yielding decreased airway hyperresponsiveness. In the current asthma model, the R:F formulation combination decreased inflammation and remodeling, thus improving lung mechanics.

Vancomycin-loaded nanoparticles against vancomycin intermediate and methicillin resistant Staphylococcus aureus strains.

Bacterial infections represent one of the leading causes of mortality in the world. Among causative pathogens, S. aureus is prominently known as the underlying cause of many multidrug resistant infections that are often treated with the first-line choice antibiotic vancomycin (VCM). Loading antibiotics into polymeric nanoparticles (Np) displays promise as an alternative method to deliver therapy due to the greater access and accumulation of the antibiotic at the site of the infection as well as reducing toxicity, irritation and degradation. The aim of this work was to prepare, characterize and evaluate VCM-loaded nanoparticles (VNp) for use against S. aureus strains. Moreover, conjugation of Nps with holo-transferrin (h-Tf) was investigated as an approach for improving targeted drug delivery. VNp were prepared by double emulsion solvent evaporation method using PLGA and PVA or DMAB as surfactants. The particles were characterized for size distribution, Zeta Potential, morphology by transmission electron microscopy, encapsulation yield and protein conjugation efficiency. Process yield and drug loading were also investigated along with an in vitro evaluation of VNp antimicrobial effects against S. aureus strains. Results showed that Np were spontaneously formed with a mean diameter lower than 300 nm in a narrow size distribution that presented a spherical shape. The bioconjugation with h-Tf did not appear to increase the antimicrobial effect of VNp. However, non-bioconjugated Np presented a minimal inhibitory concentration lower than free VCM against a MRSA (Methicillin-resistant S. aureus) strain, and slightly higher against a VISA (VCM intermediate S. aureus) strain. VNp without h-Tf showed potential to assist in the development of new therapies against S. aureus infections.

Forced degradation studies of norepinephrine and epinephrine from dental anesthetics: Development of stability-indicating HPLC method and in silico toxicity evaluation.

Injectable solutions containing epinephrine (EPI) and norepinephrine (NE) are not stable, and their degradation is favored mainly by the oxidation of catechol moiety. As studies of these drugs under forced degradation conditions are scarce, herein, we report the identification of their degradation products (DP) in anesthetic formulations by the development of stability-indicating HPLC method. Finally, the risk assessment of the major degradation products was evaluated using in silico toxicity approach. HPLC method was developed to obtain a higher selectivity allowing adequate elution for both drugs and their DPs. The optimized conditions were developed using a C18 HPLC column, sodium 1-octanesulfonate, and methanol (80:20, v/v) as mobile phase, with a flow rate of 1.5 mL/min, UV detection at 199 nm. The analysis of standard solutions with these modifications resulted in greater retention time for EPI and NE, which allow the separation of these drugs from their respective DPs. Then, five DPs were identified and analyzed by in silico studies. Most of the DPs showed important alerts as hepatotoxicity and mutagenicity. To the best of our acknowledgment, this is the first report of a stability-indicating HPLC method that can be used with formulations containing catecholamines.

Development of USP Apparatus 3 Dissolution Method with IVIVC for Extended Release Tablets of Metformin Hydrochloride and Development of a Generic Formulation.

Metformin is a euglycemic drug for the treatment of type 2 diabetes mellitus. To date, there are 13 dissolution methodologies described in the U.S. Pharmacopoeia (USP) to evaluate the release profile of metformin from extended-release tablets utilizing either a USP apparatus 1 (basket) or 2 (paddle). In the absence of a protocol for a USP apparatus 3 (reciprocating cylinder), the goal of this work was to develop an in vitro dissolution method for metformin extended-release tablets based on an in vivo-in vitro correlation (IVIVC). Following a systematic evaluation, a final dissolution method, M4, was defined. It applied 30 dips per minute (dpm) over a total period of 10 h into a series of solutions that included 2 h in HCl media (pH 1.2), 1 h in an acetate buffer solution (pH 4.5), 1 h in phosphate buffer solution (PBS) (pH 5.8) and 6 h in PBS (pH 6.8). This method showed a significant IVIVC with a calculated R2 > 0.98 (point-to-point correlation, Level A) and it was successfully used as a tool to assist in the development of generic extended release formulations for metformin consisting of a lipophilic matrix system.

Promoting prompt help-seeking for symptoms - assessing the impact of a gynaecological cancer leaflet on presentations to primary care: a record-based randomised control trial.

BACKGROUND: Information leaflets have been shown to significantly improve awareness of the symptoms of gynaecological cancers and to reduce perceived barriers to seeking medical help. This record-based, parallel, randomised control trial study aimed to assess whether receipt of a leaflet would change the behaviour of women experiencing symptoms indicative of gynaecological cancers by prompting them to visit their general practitioner (GP). METHODS: 15,538 women aged 40 years or over registered with five general practices in Northamptonshire, UK were randomised to two groups using the SystmOne randomise facility. Those in the intervention group received an educational leaflet from their general practice explaining the symptoms of gynaecological cancers and advising symptomatic women to visit their GP. The control group were not contacted. Electronic records were interrogated to extract sociodemographic data and details of GP consultations for symptoms, tests, referrals and diagnoses relating to gynaecological cancers in the 4-month period following the mail-out of the leaflets. RESULTS: 7739 records were extracted from the intervention group and 7799 from the control group. 231 (3.0%) of the women in the intervention group, and 207 (2.7%) of the controls, presented to their GP with a relevant symptom during the 4-month period following leaflet distribution. The slightly higher rate in the intervention group did not reach statistical significance at the 5% level (RR = 1.11; 95% CI 0.92-1.33; z = 1.08; p = 0.28). There was a significantly lower mean time to first presentation in the symptomatic intervention group (57.2 days, sd = 36.5) compared to the control group (65.2 days, sd = 35.0) (t = - 2.415; p = 0.016). Survival analysis did not reveal a difference between the patterns of presentation in the two cohorts (Log Rank (Mantel-Cox) χ2 = 1.42; p = 0.23). CONCLUSION: There was no difference between intervention and control groups in the proportion of women presenting with symptoms identified in the leaflet in the four months following leaflet distribution, although the women who had been sent a leaflet presented earlier than those in the control group. A larger study is needed to test for a modest effect of leaflet distribution. TRIAL REGISTRATION: Listed on the ISRCTN registry with study ID ISRCTN61738692 on 23-8-2017 (retrospectively registered).

Development of a Discriminative In Vitro Release Test for Rivastigmine Transdermal Patches Using Pharmacopeial Apparatuses: USP 5 and USP 6.

The aim of this study was to develop and validate a discriminating in vitro release test to evaluate rivastigmine transdermal patches. The Exelon® Patch was chosen as a model transdermal product. The studies of in vitro release were designed to determine the impact of the official apparatus chosen (USP apparatus 5 and USP apparatus 6), the rotation speed, and the dissolution medium characteristics on the rivastigmine release profile from transdermal patches. Patches with different drug release profiles were tested in order to evaluate the discriminating power of the in vitro release test developed and validated. Variables such as the apparatus type, the dissolution medium, and the rotation speed have a significant influence on the drug release characteristics from a transdermal patch. The in vitro release methodologies using the USP apparatus 5 at 50 rpm and USP apparatus 6 at 25 rpm using the medium phosphate-buffered saline pH 7.4 were considered discriminative and adequate to characterize the rivastigmine (RV) release from a commercial transdermal patch, Exelon® Patch.

Is there a relationship between objectively measured cognitive changes in patients with solid tumours undergoing chemotherapy treatment and their health-related quality of life outcomes? A systematic review.

BACKGROUND: This systematic review examines whether there is a relationship between objective measures of chemotherapy-related cognitive impairment in patients with solid cancer tumours and health-related quality of life (HRQoL). METHODS: Multiple online databases were searched (including Ovid MEDLINE, EMBASE, PsycINFO, PsycARTICLES, CINAHL, PubMed, and Web of Science) to identify articles published between 1980 and 2016 examining the extent of chemotherapy-related cognitive deficit and its relationship with HRQoL in cancer patients. Of 2769 potentially relevant articles, 17 studies met the inclusion criteria for the current review. RESULTS: Evidence for the presence of cognitive impairment in patients treated with chemotherapy was found in 15 of the 17 studies. Of the 15 studies finding some sort of cognitive impairment, 12 were in female breast cancer patients, 2 in bowel cancer, and 1 each in ovarian and lung cancer. Three of the 15 studies found a significant relationship between various objectively measured cognitively impaired domains and specific HRQoL outcomes. There was, however, only limited testing of the relationships between quantifiable cognitive dysfunction and HRQoL domains. CONCLUSIONS: This review suggests that in patients with solid tumours, where there is a relationship between chemotherapy treatment and cognitive impairment, the type and level of cognitive decline does not consistently appear to affect such patients' HRQoL. This could be partly explained by variations in study design, measures used, definitions of cognitive impairment, varying measurement time frames, small sample sizes, and differences in disease severity and type of treatment regimes.

Comparative evaluation of rivastigmine permeation from a transdermal system in the Franz cell using synthetic membranes and pig ear skin with in vivo-in vitro correlation.

In the present study, in vitro permeation experiments in a Franz diffusion cell were performed using different synthetic polymeric membranes and pig ear skin to evaluate a rivastigmine (RV) transdermal drug delivery system. In vitro-in vivo correlations (IVIVC) were examined to determine the best model membrane. In vitro permeation studies across different synthetic membranes and skin were performed for the Exelon(®) Patch (which contains RV), and the results were compared. Deconvolution of bioavailability data using the Wagner-Nelson method enabled the fraction of RV absorbed to be determined and a point-to-point IVIVC to be established. The synthetic membrane, Strat-M™, showed a RV permeation profile similar to that obtained with pig ear skin (R(2)=0.920). Studies with Strat-M™ resulted in a good and linear IVIVC (R(2)=0.991) when compared with other synthetic membranes that showed R(2) values less than 0.90. The R(2) for pig ear skin was 0.982. Strat-M™ membrane was the only synthetic membrane that adequately simulated skin barrier performance and therefore it can be considered to be a suitable alternative to human or animal skin in evaluating transdermal drug transport, potentially reducing the number of studies requiring human or animal samples.

Quantitative evaluation of an information leaflet to increase prompt help-seeking for gynaecological cancer symptoms.

BACKGROUND: Provision of written information may improve awareness of cancer symptoms and encourage timely presentation in primary care. This study assessed changes in symptom knowledge, perceived barriers to help-seeking, anxiety and intention to seek help, following exposure to a leaflet to raise awareness of gynaecological cancer symptoms. METHODS: Women (N = 484) completed questionnaires before and after reading the leaflet. The primary outcome was change in anticipated time to help-seeking for 12 symptoms. Changes in symptom knowledge, barriers and anxiety, and their association with prompt help-seeking were evaluated using Wilcoxon signed rank tests and logistic regression analyses. RESULTS: After reading the leaflet, symptom knowledge increased (p < 0.001), and perceived barriers (p < 0.001) and anxiety (p = 0.008) decreased. The number of symptoms for which women anticipated seeking help promptly increased (p < 0.001). Changes in knowledge (OR 4.21, 95 % CI 1.95-9.13) and perceived barriers (OR 4.60, 95 % CI 1.91-11.04) were independently associated with increased help-seeking. CONCLUSION: Increased symptom knowledge and lowered perceived barriers were related to increased prompt anticipated help-seeking. This occurred without an increase in anxiety. This intervention is effective in altering knowledge, beliefs and help-seeking intentions for gynaecological cancer symptoms, at least in the short-term, and should be trialled in primary care.

Development of a novel dry powder inhalation formulation for the delivery of rivastigmine hydrogen tartrate.

The purpose of this study was to prepare engineered particles of rivastigmine hydrogen tartrate (RHT) and to characterize the physicochemical and aerodynamic properties, in comparison to a lactose carrier formulation (LCF). Microparticles were prepared from ethanol/water solutions containing RHT with and without the incorporation of L-leucine (Leu), using a spray dryer. Dry powder inhaler formulations prepared were characterized by scanning electron microscopy, powder X-ray diffraction, laser diffraction particle sizing, ATR-FTIR, differential scanning calorimetry, bulk and tapped density, dynamic vapour sorption and in vitro aerosol deposition behaviour using a next generation impactor. The smooth-surfaced spherical morphology of the spray dried microparticles was altered by adding Leu, resulting in particles becoming increasingly wrinkled with increasing Leu. Powders presented low densities. The glass transition temperature was sufficiently high (>90 °C) to suggest good stability at room temperature. As Leu content increased, spray dried powders presented lower residual solvent content, lower particle size, higher fine particle fraction (FPF<5 µm), and lower mass median aerodynamic diameter (MMAD). The LCF showed a lower FPF and higher MMAD, relative to the spray dried formulations containing more than 10% Leu. Spray dried RHT powders presented better aerodynamic properties, constituting a potential drug delivery system for oral inhalation.