Sex Differences in Low-Level Multisensory Integration in Developmental Dyslexia.

Reading acquisition involves the integration of auditory and visual stimuli. Thus, low-level audiovisual multisensory integration might contribute to disrupted reading in developmental dyslexia. Although dyslexia is more frequently diagnosed in males and emerging evidence indicates that the neural basis of dyslexia might differ between sexes, previous studies examining multisensory integration did not evaluate potential sex differences nor tested its neural correlates. In the current study on 88 adolescents and young adults, we found that only males with dyslexia showed a deficit in multisensory integration of simple nonlinguistic stimuli. At the neural level, both females and males with dyslexia presented smaller differences in response to multisensory compared to those in response to unisensory conditions in the N1 and N2 components (early components of event-related potentials associated with sensory processing) than the control group. Additionally, in a subsample of 80 participants matched for nonverbal IQ, only males with dyslexia exhibited smaller differences in the left hemisphere in response to multisensory compared to those in response to unisensory conditions in the N1 component. Our study indicates that deficits of multisensory integration seem to be more severe in males than females with dyslexia. This provides important insights into sex-modulated cognitive processes that might confer vulnerability to reading difficulties.

How to Modify Drug Release in Paediatric Dosage Forms? Novel Technologies and Modern Approaches with Regard to Children's Population.

In the pharmaceutical technology, paediatric population still presents the greatest challenge in terms of developing flexible and appropriate drug dosage forms. As for many medicines, there is a lack of paediatric dosage forms adequate for a child's age; it is a prevailing practice to use off label formulations. Children need balanced and personalized treatment, patient-friendly preparations, as well as therapy that facilitates dosing and thus eliminates frequent drug administration, which can be ensured by modified release (MR) forms. MR formulations are commonly used in adult therapy, while rarely available for children. The aim of this article is to elucidate how to modify drug release in paediatric oral dosage forms, discuss the already accessible technologies and to introduce novel approaches of manufacturing with regard to paediatric population.

Taste-masking assessment of orally disintegrating tablets and lyophilisates with cetirizine dihydrochloride microparticles.

Orally disintegrating tablets and oral lyophilisates are novel attractive dosage forms that disintegrate or dissolve in the buccal cavity within seconds without necessity of drinking. The major limitation in designing of these dosage forms is unpleasant taste of the drug substance. Cetirizine dihydrochloride is a H1-antihistamine substance indicated for the treatment of allergy. It is characterized by extremely bitter taste, therefore in order to deliver cetirizine dihydrochloride using orodispersible formulations, effective taste-masking is required. The aim of this study was to investigate whether microparticles containing cetirizine dihydrochloride could be successfully used to formulate orally disintegrating tablets by direct compression method and oral lyophilisates by freeze-drying process. Taste masking of cetirizine dihydrochloride was achieved by the spray-drying technique using Eudragit® E PO as the drug agent carrier. Based on the preliminary studies, optimal compositions of microparticles, tablets and lyophilisates were chosen. Obtained dosage forms were characterized for drug content, disintegration time and mechanical properties. In order to determine whether the microparticles subjected to direct compression and freeze-drying process effectively mask the bitter taste of cetirizine dihydrochloride, the in vivo and in vitro evaluation was performed. The results showed that designed formulates with microparticles containing cetirizine dihydrochloride were characterized by appropriate mechanical properties, uniformity of weight and thickness, short disintegration time, and the uniform content of the drug substance. Taste-masking assessment performed by three independent methods (e-tongue evaluation, human test panel and the in vitro drug release) revealed that microparticles with Eudragit® E PO are effective taste - masking carriers of cetirizine dihydrochloride and might be used to formulate orally disintegrating tablets and oral lyophilisates.

The FGF21 analog pegozafermin in severe hypertriglyceridemia: a randomized phase 2 trial.

Pegozafermin, a long-acting glycopegylated analog of human fibroblast growth factor 21, is in development for the treatment of severe hypertriglyceridemia (SHTG) and nonalcoholic steatohepatitis. Here we report the results of a phase 2, double-blind, randomized, five-arm trial testing pegozafermin at four different doses (n = 67; 52 male) versus placebo (n = 18; 12 male) for 8 weeks in patients with SHTG (triglycerides (TGs), ≥500 mg dl-1 and ≤2,000 mg dl-1). Treated patients showed a significant reduction in median TGs for the pooled pegozafermin group versus placebo (57.3% versus 11.9%, difference versus placebo -43.7%, 95% confidence interval (CI): -57.1%, -30.3%; P < 0.001), meeting the primary endpoint of the trial. Reductions in median TGs ranged from 36.4% to 63.4% across all treatment arms and were consistent regardless of background lipid-lowering therapy. Results for secondary endpoints included significant decreases in mean apolipoprotein B and non-high-density lipoprotein cholesterol concentrations (-10.5% and -18.3% for pooled doses compared to 1.1% and -0.6% for placebo (95% CI: -21.5%, -2.0%; P = 0.019 and 95% CI: -30.7%, -5.1%; P = 0.007, respectively), as well as a significant decrease in liver fat fraction for pooled treatment (n = 17) versus placebo (n = 6; -42.2% pooled pegozafermin, -8.3% placebo; 95% CI: -60.9%, -8.7%; P = 0.012), as assessed in a magnetic resonance imaging sub-study. No serious adverse events were observed to be related to the study drug. If these results are confirmed in a phase 3 trial, pegozafermin could be a promising treatment for SHTG (ClinicalTrials.gov registration: NCT0441186).

[Albuminuria in patients with type 2 diabetes mellitus in relation to percentage of HbA1c]. / Albuminuria u chorych na cukrzyce typu 2 w zaleznosci od odsetka HbA1c.

UNLABELLED: Albuminuria is an early marker of the microvascular and macrovascular complications in patients with type 2 diabetes mellitus. Metabolic complication accompanying the disease, especially hyperglicaemia, have significant influence on the range of albumin excretion. The aim of the study was to evaluate urinary albumin excretion and percentage of glycated hemoglobin (HbA1c), in relation to fasting and postprandial glycaemia. MATERIAL AND METHODS: Research was made in two groups of patients with confirmed albuminuria: in the 1st group with good glycemic control with HbA1c > or = 6,1%-< or = 6,5%, and in the 2-nd group with poor glycemic control with HbA1c > 6,5%-< or = 10%. The control group consisted of 21 patients with essential hypertension and coexisted albuminuria, not suffering from diabetes. The average fasting and postprandial glycemic were calculated for each patient on the basis of the last three values of glycaemia from the patient's self-control test. The extent of albuminuria and the percentage of HbA1c were determined by the immunoturbidimetric test. RESULTS: The highest albumin excretion in urine was noticed in the group with poor glycemic control, a slightly lower level of albuminuria was found in the group with good glycemic control, however the lowest level of albumin excretion was noticed in the control group. The differences were not statistically significant. The fasting glycaemia as well as postprandial glycaemia were increased in the group with higher percentage of HbA1c (p < 0,001) with comparison to the group with good glycemic control. The average percentage of HbA1c was 7,54% in the group with poor glycemic control and was significantly connected with larger glycaemia with comparison to the 2nd group with average percentage of HbA1c 6,3%. CONCLUSIONS: The excretion of albumin in urine rises with increased glycaemia and percentage of glycosylated hemoglobin. Fasting glycaemia as well as postprandial glycaemia have influence on the percentage of glycated hemoglobin.

[Assess the impact of concentrations of inflammatory markers IL-6, CRP in the presence of albuminuria in patients with type 2 diabetes]. / Ocena wplywu stezenia markerów stanu zapalnego: IL-6, CRP na wystepowanie albuminurii u chorych na cukrzyce typu 2.

UNLABELLED: Diabetic nephropathy is one of the most common complications of diabetes. Symptom of nephropathy is albuminuria, in which the mechanism of formation may participates CRP and IL-6. The aim of the study was to evaluate the concentrations of CRP and IL-6 depending on the irregularity of metabolic patients with type 2 diabetes and their impact on the occurrence of albuminuria. MATERIAL AND METHODS: The study was conducted among 68 patients with type 2 diabetes with albuminuria. Patients were divided into groups: group I - patients with type 2 diabetes with HbA1c > or = 6.1 - < or = 6.5%, group II - patients with type 2 diabetes with HbA1c > 6.5 - < or = 10.0%, K - control group, 21 patients with essential hypertension with albuminuria. The material was consisted of venal extracted for clot drawn from the basilic vain. IL 6 concentration was assessed using the ELISA method. The percentage of hemoglobin A1c (HbA1c), CRP, the extent of albuminuria was determined by immunoturbidimetric method. RESULTS: The mean urinary albumin excretion was highest in the second study group, lowerin the test group, the lowest in the control group. The average concentration of IL-6 and CRP was highest in group I, lower in group II, the lowest in the control group (p > 0.05). It has been shown a positive correlation between serum CRP and the magnitude of albuminuria in the test group of patients with type 2 diabetes with HbA1c > or = 6.1 - < or = 6.5% (p < 0.037). The relationship between serum CRP and the magnitude of albuminuria in the control group of patients with essential hypertension were at the border of statistical significance (p < 0.057). Not shown a positive correlation between these parameters in the second group of patients with type 2 diabetes with HbA1c >6.5 - < or = 10.0%. CONCLUSIONS: In patients with type 2 diabetes with better metabolic control, protein CRP is a sensitive marker of albuminuria.

Conductive Layers on a Shrinkable PET Film by Flexographic Printing.

In this study, the extremely important and difficult topic of flexographic printing on a heat-shrinkable substrate was taken up. Six commercially available, electrically conductive inks based on silver, copper and graphite nanoparticles were selected and tested upon their applicability for printing on the temperature-sensitive PET material. As a printing substrate, the one-direction heat-shrinkable PET film, with a maximum shrinkage of 78%, was selected. All of the examined inks were subjected to the printing process throughout three different anilox line screens. The tested inks, along with the electric paths printed with them, were subjected to various tests. The main parameters were evaluated, such as printability combined with the rheology tests and ink adhesion to the examined PET substrate together with the electrical conductivity before and after the shrinkage.

IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen.

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2+) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients' outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2+ patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2+ patients (HR = 0.6 [0.37-0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2+ NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.

Utilization of Ethylcellulose Microparticles with Rupatadine Fumarate in Designing Orodispersible Minitablets with Taste Masking Effect.

Minitablets in orodispersible form constitute a flexible drug delivery tool for paediatric and geriatric population as they eliminate the risk of chocking and do not require drinking water in the application. Due to their direct contact with taste buds, taste sensation is an important factor. Preparing microparticles with taste masking polymers utilizing spray drying is an efficient technique for reducing the bitterness of drugs. Ethylcellulose is a hydrophobic polymer widely used as a taste masking material. Rupatadine fumarate, one of the newest antihistamines, features an intensive bitter taste, hence in designing orodispersible formulations, achieving an acceptable taste is a crucial issue. The main objective of this work was to formulate orodispersible minitablets containing taste masked ethylcellulose-based microparticles with rupatadine fumarate and evaluation of their quality, especially in terms of taste masking efficacy. The accessed data indicated that all obtained minitablets were characterized by beneficial pharmaceutical properties. Three independent methods: in vivo with healthy volunteers, in vitro drug dissolution, and "electronic tongue" confirmed that all designed formulations provided satisfactory taste masking rate and that formulation F15 (prepared with Pearlitol® Flash and Surelease® microparticles with rupatadine fumarate) was characterized by the lowest bitterness score.

Porcine skin as a model system for studies of adverse effects of narrow-band UVB pulses on human skin.

Ultraviolet (UV) radiation has been widely used in medicine, and in recent years there has been a growing interest in narrow-band UVB therapies, especially those employing pulses of the 308-nm line of XeCl excimer lasers. Comparative studies in several skin pathologies showed that narrow-band UVB was more effective than classical broad-band UVB radiation. Simultaneously, UVB is carcinogenic and there is a need for data to establish the risk associated with phototherapies involving irradiations of human skin with different doses of narrow- and broad-band UVA and/or UVB radiation. Relevant data are sparse predominantly due to a lack of suitable model systems for study of this phenomenon. Our comparative study of human and porcine skin responses to pulses of narrow-band UVB radiation demonstrated that for doses ranging from 5 to 10,000 mJ/cm(2) both skin types have similar susceptibility to UVB-induced breaking of nuclear DNA, indicating that pig skin might serve as good model for studies of sensitivity of human skin to UVB radiation.

Ethylcellulose-A Pharmaceutical Excipient with Multidirectional Application in Drug Dosage Forms Development.

Polymers constitute the most important group of excipients utilized in modern pharmaceutical technology, playing an essential role in the development of drug dosage forms. Synthetic, semisynthetic, and natural polymeric materials offer opportunities to overcome different formulative challenges and to design novel dosage forms for controlled release or for site-specific drug delivery. They are extensively used to design therapeutic systems, modify drug release, or mask unpleasant drug taste. Cellulose derivatives are characterized by different physicochemical properties, such as swellability, viscosity, biodegradability, pH dependency, or mucoadhesion, which determine their use in industry. One cellulose derivative with widespread application is ethylcellulose. Ethylcellulose is used in pharmaceutical technology as a coating agent, flavoring fixative, binder, filler, film-former, drug carrier, or stabilizer. The aim of this article is to provide a broad overview of ethylcellulose utilization for pharmaceutical purposes, with particular emphasis on its multidirectional role in the development of oral and topical drug dosage forms.

How to assess orodispersible film quality? A review of applied methods and their modifications.

In recent years, there has been a tendency toward creating innovative, easy to use and patient-friendly drug delivery systems suitable for every consumer profile, which would ensure safety, stability and acceptability of a drug. One of the relatively novel and promising approaches is the manufacture of orodispersible films (ODFs), which is an upcoming area of interest in drug delivery. They are defined as polymer thin films that disintegrate in the oral cavity within seconds, without drinking water or chewing, and eliminate the risk of choking. Gaining special usefulness in therapies of children and the elderly, ODFs seem to fill the gap in the range of preparations available for these groups of patients. As no detailed monography of ODFs including testing methods and uniform requirements has been presented in any of the pharmacopoeias to date, the aim of this article is to give an overview of the applied testing methods, their modifications and innovative approaches related to ODF quality assessment.

Ethylcellulose in Organic Solution or Aqueous Dispersion Form in Designing Taste-Masked Microparticles by the Spray Drying Technique with a Model Bitter Drug: Rupatadine Fumarate.

The taste of drugs is an important factor affecting pharmacotherapy effectiveness, and obtaining formulations with acceptable organoleptic properties is still an ongoing issue in pharmaceutical technology. One of the innovative methods of taste masking is preparation of microparticles by the spray drying technique, utilizing polymers with different physicochemical properties. Rupatadine fumarate (RUP) is one of the newest antihistamines, with an innovative and multidirectional mechanism of action, and an extremely bitter taste. The aim of this work was to investigate the feasibility of utilizing organic or aqueous forms of ethylcellulose (EC) for the preparation of microparticles with RUP by the spray drying technique. Spray dried samples at different drug:polymer ratios were prepared using organic solution (Ethocel®) or aqueous dispersions of EC (Surelease®, Aquacoat® ECD). Evaluation of the taste masking efficacy was performed in vivo in human taste panel, in vitro based on dissolution test, and by self-constructed electronic tongue. It was shown that microparticles obtained from aqueous dispersions of EC have superior pharmaceutical properties in terms of both morphology and taste masking efficacy in comparison to those obtained from organic solution.

Influence of ALA-mediated photodynamic therapy on secretion of interleukins 6, 8 and 10 by colon cancer cells in vitro.

BACKGROUND: Photodynamic therapy has apart from a direct cytotoxic effect also immunomodulatory properties. The aim of our study was to investigate how photodynamic therapy with 5-aminolevulinic acid (ALA-PDT) in sublethal doses influences the secretion of interleukins 6, 8 and 10 from colon cancer cells in vitro. METHODS: We used two human colon cancer cell lines SW480 and SW620 of different malignancies which were treated with a sublethal PDT protocol. Determination of interleukins was carried out using the Bio- Plex Assay Pro™ kit on the Bio- Plex Suspension Array System. RESULTS: Sublethal ALA-PDT did not affect IL-6 secretion by SW480 cells, but caused a 40% decrease of IL-6 release by the SW620 cell line. It increased IL-8 secretion in both, the SW480 and SW620 cell lines, by 23% and 46%, respectively, and decreased the production of IL-10 (25% in SW480 and 32% in SW620 cells). CONCLUSIONS: ALA-PDT in sublethal doses might influence colon cancer cell's progression and invasion by reducing the secretion of IL-6, IL-10 and increasing the IL-8 concentration with higher values in the more malignant cell line.

Application of standard cell cultures and 3D in vitro tissue models as an effective tool in drug design and development.

Cell culture systems are essential tools used in a wide range of biomedical and clinical studies. Two dimensional cell culture models (2D) provide basic information on cytotoxicity, penetration and accumulation of drugs in cells and they are of outmost importance when selecting new compounds of the desired biopharmaceutical properties as candidates for novel drugs. The improvement over 2D growing cells are three dimensional (3D) tissue models that mimic in vivo conditions and the functions of living tissue more accurately. These models reduce the cost of drug development, enable more efficient drug screening, minimise failure rate in medicine discovery and eliminate animal use during experiments. The article provides an overview of 2D cell cultures and 3D tissue models - their properties, basic procedures, conditions of culturing and applications.