Characterization and evaluation of solid self-microemulsifying drug delivery systems with porous carriers as systems for improved carbamazepine release

The purpose of this study was to investigate solid self-microemulsifying drug delivery system (SSMEDDS), as potential delivery system for poorly water soluble drug carbamazepine (CBZ). Self-microemulsifying drug delivery system (SMEDDS) was formulated using the surfactant polyoxyethylene 20 sorbitan monooleate [Polysorbate 80] (S), the cosurfactant PEG-40 hydrogenated castor oil [Cremophor(?) RH40] (C) and the oil caprylic/capric triglycerides [Mygliol(?) 812] (O). Four different adsorbents with high specific surface area were used: Neusilin(?) UFL2, Neusilin(?) FL2 (magnesium aluminometasilicate), Sylysia(?) 320 and Sylysia(?) 350 (porous silica). Microemulsion area at the surfactant to cosurfactant ratio (K(m)) 1:1 was evaluated and for further investigation SMEDDS with SC/O ratio 8:2 was selected. Solubilization capacity of selected SMEDDS for CBZ was 33.771±0.041mg/ml. Rheological measurements of unloaded and CBZ-loaded SMEDDS at water content varied from 10 to 60% (w/w) were conducted. It has been found that CBZ has great influence on rheological behaviour of investigated system upon water dilution. Photon correlation spectroscopy has shown the ability of CBZ-loaded SMEDDS to produce microemulsion droplet size. SSMEDDS improved release rate of CBZ, but the type of adsorbent significantly affects release rate of CBZ. For SSMEDDS with different magnesium aluminometasilicate adsorbents, release rate of CBZ decreased with increasing specific surface area due to entrapment of liquid SMEDDS inside the pores and its gradual exposure to dissolution medium. With porous silica adsorbents no difference in release rate was found in comparison to physical mixtures. In physical mixtures at 12.5% (w/w) CBZ content, presence of amorphous CBZ led to high dissolution rate.     

Autonomic mechanisms underpinning the stress response in borderline hypertensive rats

This study investigates blood pressure (BP) and heart rate (HR) short-term variability and spontaneous baroreflex functioning in adult borderline hypertensive rats and normotensive control animals kept on normal-salt diet. Arterial pulse pressure was recorded by radio telemetry. Systolic BP, diastolic BP and HR variabilities and baroreflex were assessed by spectral analysis and the sequence method, respectively. In all experimental conditions (baseline and stress), borderline hypertensive rats exhibited higher BP, increased baroreflex sensitivity and resetting, relative to control animals. Acute shaker stress (single exposure to 200 cycles min-1 shaking platform) increased BP in both strains, while chronic shaker stress (3-day exposure to shaking platform) increased systolic BP in borderline hypertensive rats alone. Low- and high-frequency HR variability increased only in control animals in response to acute and chronic shaker (single exposure to restrainer) stress. Acute restraint stress increased BP, HR, low- and high-frequency variability of BP and HR in both strains to a greater extent than acute shaker stress. Only normotensive rats exhibited a reduced ratio of low- to high-frequency HR variability, pointing to domination of vagal cardiac control. In borderline hypertensive rats, but not in control animals, chronic restraint stress (9-day exposure to restrainer) increased low- and high-frequency BP and HR variability and their ratio, indicating a shift towards sympathetic cardiovascular control. It is concluded that maintenance of BP in borderline hypertensive rats in basal conditions and during stress is associated with enhanced baroreflex sensitivity and resetting. Imbalance in sympathovagal control was evident only during exposure of borderline hypertensive rats to stressors.     

Dramatic increase in naive T cell turnover is linked to loss of naive T cells from old primates

The loss of naïve T cells is a hallmark of immune aging. Although thymic involution is a primary driver of this naïve T cell loss, less is known about the contribution of other mechanisms to the depletion of naïve T cells in aging primates. We examined the role of homeostatic cycling and proliferative expansion in different T cell subsets of aging rhesus macaques (RM). BrdU incorporation and the expression of the G₁-M marker Ki-67 were elevated in peripheral naïve CD4 and even more markedly in the naïve CD8 T cells of old, but not young adult, RM. Proliferating naïve cells did not accumulate in old animals. Rather, the relative size of the naïve CD8 T cell compartment correlated inversely to its proliferation rate. Likewise, T cell receptor diversity decreased in individuals with elevated naïve CD8 T cell proliferation. This apparent contradiction was explained by a significant increase in turnover concomitant with the naïve pool loss. The turnover increased exponentially when the naïve CD8 T cell pool decreased below 4% of total blood CD8 cells. These results link the shrinking naïve T cell pool with a dramatic increase in homeostatic turnover, which has the potential to exacerbate the progressive exhaustion of the naïve pool and constrict the T cell repertoire. Thus, homeostatic T cell proliferation exhibits temporal antagonistic pleiotropy, being beneficial to T cell maintenance in adulthood but detrimental to the long-term T cell maintenance in aging individuals.     

Signaling status of IgG B cell receptor (IgG BCR) is indicative for an activated state of circulating B cells in multiple myeloma

Circulating post-switch B cells have been proposed as proliferative and disseminating progenitors in multiple myeloma. It is unclear whether the class-switched antigen receptor expressed at the surface of these cells plays a role in their expansion. In this work, the signaling status of IgG B cell receptor (BCR) isolated from the lysates of peripheral blood lymphocytes of 32 patients with IgG multiple myeloma, at the time of diagnosis, was investigated by examining whether phosphorylation of BCR Igalpha and Igbeta signal transducer factors (co-receptors) or other signaling molecules was abnormal in these cells when compared with healthy controls. In IgG BCR of normal controls, weak phosphorylation of 56 and 61 kDa Src kinase-related proteins and unphosphorylated co-receptors were found. In myeloma, p56 and p61 kDa proteins, co-receptors, and other IgG BCR-associated proteins from the signal cascade were phosphorylated. Myeloma patients can be classified into subgroups by IgG BCR phosphorylation profiles which characteristically coordinated with the level of IgG paraprotein in serum and the stage of disease. There was a correlative trend between the extent of phosphorylation reduction and advanced stage of disease. Reduced phosphorylation was more pronounced with advanced stages of multiple myeloma.     

Effect of tadalafil on erectile dysfunction in male patients with diabetes mellitus

BACKGROUND/AIM: [corrected] During the first 10 years over 50% of diabetes patients develop erectile dysfunction (ED). It is more severe and resistant to therapy than in male patients with normal glucoregulation. The purpose of this pilot study was to estimate the tadalafil (Cialis) efficacy and safety in male patients with diabetes mellitus (DM), together with moderate to severe ED. METHODS: The study included 30 male patients with diagnozed type 1 or type 2 DM together with ED. ED was estimated through the International Index of Erectile Function (IIEF-6), Sexual Encounter Profile (SEP) questionnaire and prostaglandin test, at the beginning of the research and three months after the 20 mg tadalafil therapy initiation, once a week (on Fridays). Glycosylated haemoglobin in blood (HbAlc) values were also monitored. According to the ED severity (IIEF values at the beginning of the therapy) the patients were divided into 2 groups. The previous experience with sildenafil citrate (Viagra) and prostaglandin E1 intracavernous therapy was recorded. RESULTS: Tadalafil significantly improved ED (p < 0.001) for 7.40 points of the IIEF score, i.e. for 58% and 60% towards SEP2 and SEP3 questionnaire, respectively. Compared to the previous ED therapy subjectively better tadalafil experience was recorded. Each group experienced a significant improvement in IIEF score (p < 0.001), more significantly in the group 2 (8.26+/-1.49 points) compared with the medium improvement in the group 1 (6.27+/-1.35 points). After three months HbA1c values decreased for 2.26+/-1.62 (p < 0.001). CONCLUSION: Tadalafil is an effective tool for treating ED in diabetes patients. In some situations tadalafil application could replace prostaglandin test. The sexual sphere motivation leads to the improvement of glucoregulation in DM patients.     

Invasive Lobular Breast Cancer Presenting an Unusual Metastatic Pattern in the Form of Peritoneal and Rectal Metastases: A Case Report

Gastrointestinal metastases from invasive lobular breast cancer are uncommon with the stomach and small intestines being the most common metastatic sites. Peritoneal and rectal metastases are very rare and only rarely occur as the first manifestation of disease. We herein report the case of a 47-year-old woman who presented with abdominal carcinomatosis as a first sign of invasive lobular breast carcinoma (ILC). Identifying the most important immunohistochemical markers for ILC: gross cystic disease fluid protein 15, estrogen and progesterone receptors enabled a correct diagnosis. After a six year disease-free period, relapse occurred with severe obstruction due to rectal metastasis from lobular breast carcinoma. Since there was no widespread metastatic disease, surgery with concomitant hormonal therapy was performed.     

Epidemiological and mechanistic data suggest that 1, 3-butadiene will not be carcinogenic to humans at exposures likely to be encountered in the environment or workplace

1, 3-Butadiene (BD) is a carcinogen in both rats and mice withmice being substantially more sensitive than rats. It is notknown if BD poses a carcinogenic risk for humans. Findings fromexposure assessment studies indicate that potential industrialexposure to BD in monomer, polymer, and end-user industriesis typically <2 p.p.m. Epidemiologic studies of persons occupationallyexposed to BD are inconclusive. In vitro metabolism of BD inrats, mice and human tissues indicate that there are significantquantitative species differences in the metabolic activationof BD to butadiene monoepoxide (BMO) and butadiene diepoxide(BDE) and the detoxication of BMO. Activation/detoxica-tionratios calculated using in vitro kinetic constants reveal thatratios in mice were 12-fold greater than rats and humans. Inrats and mice exposed to BD, concentrations of BMO in bloodand tissues of mice were up to 14-fold higher than in rats andBDE was only detected in mice thereby providing a strong argumentfor why mice are highly sensitive to BD carcinogenicity. Thefact that human tissues do not appear to metabolize BMO to BDEto any significant extent suggest that humans may not be sensitiveto BD carcinogenicity. In mice, BDE is a more potent carcinogenthan BMO. BDE is mutagenic in vitro at the hprt locus in humanTK6 lymphoblasts at concentrations that were 100-fold less thanthe concentration of BMO required to yield a similar mutationfrequency. Importantly, the concentrations of BDE that weregenotoxic in vitro are nearly identical to the concentrationsof BDE measured in blood and tissues of mice exposed to BD byinhalation. BD is genotoxic in mice, but not rats, followinginhalation exposure and this is paralleled by species differencesin observed tumor susceptibility. BD is not genotoxic in occupationally-exposedworkers. The genetic basis for BD carcinogenicity appears tobe primarily through induction of point mutations and deletionevents mediated via the potent genotoxic metabolite, BDE. Thegenotoxic endpoints induced by BDE (e.g., deletion and pointmutations) rather than BMO (e.g., point mutations) likely representthe underlying mechanism responsible for the striking speciesdifferences observed in the genotoxicity and carcinogenicityof BD in mice versus rats. In summary, the preponderance ofevidence which includes both epidemiological and mechanisticdata in mice, rats, and humans strongly suggests that BD willnot be carcinogenic to humans at occupational or environmentalexposures. Any cancer risk assessment for BD should use in vitrohuman tissue metabolic data and in vitro and in vivo rat datafor estimation of human cancer risks.     

Evaluation of the immunomodulatory activities of royal jelly components in vitro

In this work the effect of different components isolated from royal jelly (RJ) was studied using an in vitro rat T-cell proliferation assay. We found that lower concentrations of MEL 174 (final water extract of RJ) and MEL 147 (3-10-dihydroxydecanoic acid) stimulated T-cell proliferation, triggered by concanavalin A (Con-A) and the process was followed by an increase in the production of interleukin-2 (IL-2). Higher concentrations of MEL 174, MEL 247 (dry powder of RJ) and MEL 138 (trans-10-hydroxydec-2-enoic acid) inhibited T-cell proliferation. The inhibition of T-cell proliferation in the presence of MEL 174 was followed by a decrease in IL-2 production, which was partly abrogated by exogenous IL-2, a decrease in nitric oxide (NO) production and increased apoptosis. In conclusion, our results showed the complexity of biological activity of RJ and suggest that its water extract possesses the most potent immunomodulatory activity in vitro.