Nanoparticle-Encapsulated Epirubicin Efficacy in the Inhibition of Growth of Orthotopic Ovarian Patient-Derived Xenograft in Immunocompromised Mice.

Epirubicin hydrochloride (EPI) is an anticancer drug widely used in the treatment of many solid tumors, including ovarian cancer. Because of its anatomical location, ovarian cancer shows symptoms when it is already in an advanced stage and is thus more difficult to treat. Epirubicin hydrochloride kills cancer cells effectively, but its dose escalation is limited by its severe toxicity. By encapsulating epirubicin in dextran-based nanoparticles (POLEPI), we expected to deliver higher and thus clinically more effective doses directly to tumors, where epirubicin would be released and retained longer in the tumor. The antitumor activity of POLEPI compared to EPI was first tested ex vivo in a series of ovarian cancer patient-derived tumor xenografts (PDX). The most promising PDX was then implanted orthotopically into immunocompromised mice, and tumor growth was monitored via magnetic resonance imaging (MRI). Although we succeeded in suppressing the growth of ovarian cancer derived from a patient, in a mouse model by 70% compared to 40% via EPI in 5 days after only one injection, we could not eliminate serious side effects, and the study was terminated prematurely for humane reasons.

Neurotoxicity of poly(propylene imine) glycodendrimers.

Published results of studies on poly(propylene imine) (PPI) dendrimers indicate their potential use in the treatment of brain cancer or neurodegenerative diseases due to their ability to cross the blood-brain barrier. However, depending on dose, neurotoxicity may occur. Here, we discuss the impact of maltotriose modified PPI dendrimers on rat's nervous system. Wistar rats were treated intravenously for 14 consecutive days with densely (dense-shell; DS) and partly (open-shell; OS) modified PPI dendrimers at doses established as safe in the previous experiment following a single DS or OS administration. The examination included an estimation of the motility and the clinical symptoms of the respiratory, nervous, and cardiovascular systems. Both DS and OS glycodendrimers (GDs) induced adverse effects at the doses tested. Multiple administrations of PPI-OS had a detrimental influence on rats' survival. These findings suggest that the dendrimers adversely influence the nervous system and their toxic effects accumulate over time. In PPI-DS treated animals, the harmful effects were less severe but still present. However, with each treatment day, the clinical symptoms in both groups were less severe as if the animals developed tolerance to GDs. We hypothesize that the neurotoxicity of tested dendrimers is related to nanoparticles-induced autophagy.

Maltotriose-modified poly(propylene imine) Glycodendrimers as a potential novel platform in the treatment of chronic lymphocytic Leukemia. A proof-of-concept pilot study in the animal model of CLL.

Cancer nanotherapeutics have shown promise in resolving some of the limitations of conventional drug delivery systems such as nonspecific biodistribution and targeting, lack of water solubility, and low therapeutic indices, Among the various nanoparticles that are available, dendrimers, highly branched macromolecules with a specific size and shape, are one of the most promising ones. In this preliminary study, we tested the anti-tumor activity of maltotriose-modified fourth-generation poly(propylene imine) glycodendrimers (PPI-G4-M3) in vivo in the subcutaneous MEC-1 xenograft model of human chronic lymphocytic leukemia (CLL) in NOD scid gamma mice. Fludarabine was used for model validation and as a positive treatment control. The anti-tumor response was calculated as tumor volume, tumor control ratio, and tumor growth inhibition. The study showed that PPI-G4-M3 inhibited subcutaneous tumor growth more efficiently than fludarabine. The anti-tumor response was dose-dependent. Cationic PPI-G4-M3 showed the highest anti-tumor activity but also higher toxicity than the neutral dendrimers and fludarabine. These first promising results warrant further studies in the optimization of dendrimers charge, dose, route and schedule of administration to combat CLL.

A super-agonist of growth hormone-releasing hormone causes rapid improvement of nutritional status in patients with chronic kidney disease.

Chronic kidney disease is frequently associated with protein-energy wasting related to chronic inflammation and a resistance to anabolic hormones such as insulin and growth hormone (GH). In this study, we determined whether a new GH-releasing hormone super-agonist (AKL-0707) improved the anabolism and nutritional status of nondialyzed patients with stage 4-5 chronic kidney disease randomized to twice daily injections of the super-agonist or placebo. After 28 days, this treatment significantly increased 24-h GH secretion by almost 400%, without altering the frequency or rhythmicity of secretory bursts or fractional pulsatile GH release, and doubled the serum insulin-like growth factor-1 level. There was a significant change in the Subjective Global Assessment from 'mildly to moderately malnourished' to 'well-nourished' in 6 of 9 patients receiving AKL-0707 but in none of 10 placebo-treated patients. By dual-energy X-ray absorptiometry, both the mean fat-free mass and the body mineral content increased, but fat mass decreased, all significantly. In the AKL-0707-treated group, both serum urea and normalized protein equivalent of nitrogen appearance significantly decreased with no change in dietary protein intake, indicating a protein anabolic effect of treatment. Thus, our study shows that stimulation of endogenous GH secretion by AKL-0707 overcomes uremic catabolism of patients with advanced chronic kidney disease.

[Physiological functions of L-ornithine and L-aspartate in the body and the efficacy of administration of L-ornithine-L-aspartate in conditions of relative deficiency]. / Fizjologiczne funkcje L-ornityny i L-asparaginianu oraz celowosc podawania asparaginianu ornityny w stanach wzglednego niedoboru.

L-ornithine-L-aspartate (LOLA) is a stable salt of two natural nonessential L-amino acids: ornithine and aspartic acid. It is formulated and marketed in low and high doses. Low doses are used as a food supplement and high doses (above 5 g) as a medicinal product to lower blood ammonia concentration and to eliminate symptoms of hepatic encephalopathy associated with liver cirrhosis. The aim of this review is to present physiological roles of L-ornithine and L-aspartate in the human body, to assess conditions under which these amino acids could be deficient, to analyze consequences of these deficiencies, and to review the current state of knowledge on the effects of LOLA administration. The data used in this publication result from searches of different electronic databases such as Cochrane Trials Register, MEDLINE, PubMed, Medscape, or Google Scholar, with a cut-off date of November 29, 2009, using terms: L-ornithine-L-aspartate, ornithine aspartate, ornithine, Hepa-Merz, ornithine deficiency, hyperammonemia, hepatic encephalopathy, and liver cirrhosis. Both amino acids play key roles in ammonia detoxification and in proline and polyamine biosyntheses. Polyamines are considered critical for DNA synthesis and cell replication and have been shown to stimulate hepatic regeneration. Supplementation with ornithine in animal models demonstrated enhanced wound breaking strength and collagen deposition. It has been shown in vitro, in vivo and in perfused organs that urea synthesis from ammonia is limited by endogenous ornithine and that ornithine can pharmacologically promote urea formation to a greater degree than any ammonia supply. Administration of LOLA in high doses reduced high blood ammonia induced either by ammonium chloride or protein ingestion or existing as a clinical complication of cirrhosis. In health and with proper diet, L-ornithine and L-aspartate are synthesized de novo in sufficient quantities, but in the states of disease, tissue damage, organ insufficiency, excessive metabolic demand, growth, pregnancy, or urea cycle enzyme deficiencies, these amino acids need to be supplemented with the food. The review of available data indicate that there is direct and indirect (resulting from physiology) scientific rationale for dietary use of LOLA, depending on an individual's physiological, metabolic or pathological conditions. In conditional ornithine deficiency, daily supplementation with LOLA at doses about 1 g/day is safe and, as demonstrated in vitro, should be sufficient to saturate tissue ornithine concentration to prevent postprandial hyperammonemia and to stimulate tissue regeneration.

Anti-Tumour Activity of Glycodendrimer Nanoparticles in a Subcutaneous MEC-1 Xenograft Model of Human Chronic Lymphocytic Leukemia.

BACKGROUND: Chronic Lymphocytic Leukaemia (CLL) is an indolent disorder, which mainly affects older adults. Since the advent of chemoimmunotherapy, great progress has been made in its treatment. However, some patients develop a more aggressive form of the disease and are included in the group of high-risk CLL patients with a dismal prognosis and a need for new therapies. OBJECTIVE: Maltotriose-modified poly(propylene imine) dendrimers were presented as potential agents in targeted therapy for CLL in the murine xenograft model. METHODS: Tumour, brain and internal organs resected from NOD scid gamma mice were subjected to gross and histopathological evaluation. RESULTS: The results of ex vivo tissue examination indicated that open-shell glycodendrimers prevented/inhibited the spread of CLL into the brain and internal organs and its transformation into a more aggressive form. CONCLUSION: The results of the study have a potentially important impact on the design of future personalized therapies as well as clinical trials.

Role of probiotics in the prevention and treatment of meticillin-resistant Staphylococcus aureus infections.

Meticillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant micro-organism and is the principal nosocomial pathogen worldwide. Following initial in vitro experiments demonstrating that Lactobacillus acidophilus CL1285(®) and Lactobacillus casei LBC80R(®) commercial strains exhibit antibacterial activity against clinical MRSA isolates, we conducted a literature search to find any evidence of probiotic efficacy in decolonisation or treatment of S. aureus infection. As summarised below, many strains of lactobacilli and bifidobacteria isolated from a variety of sources inhibited the growth of S. aureus and clinical isolates of MRSA in vitro. The most active strains were Lactobacillus reuteri, Lactobacillus rhamnosus GG, Propionibacterium freudenreichii, Propionibacterium acnes, Lactobacillus paracasei, L. acidophilus, L. casei, Lactobacillus plantarum, Lactobacillus bulgaricus, Lactobacillus fermentum and Lactococcus lactis. Their effects were mediated both by direct cell competitive exclusion as well as production of acids or bacteriocin-like inhibitors. L. acidophilus also inhibited S. aureus biofilm formation and lipase production. In vitro antimicrobial activity did not necessarily assure efficacy in vivo in animal infectious models, e.g. S. aureus 8325-4 was most sensitive in vitro to L. acidophilus, whilst in vivo Bifidobacterium bifidum best inhibited experimental intravaginal staphylococcosis in mice. On the other hand, L. plantarum, which showed the highest inhibition activity against S. aureus in vitro, was also very effective topically in preventing skin wound infection with S. aureus in mice. Very few clinical data were found on the interactions between probiotics and MRSA, but the few identified clinical cases pointed to the feasibility of elimination or reduction of MRSA colonisation with probiotic use.

The role of counselling and other factors in compliance of postmenopausal osteoporotic patients to alendronate 70 therapy.

INTRODUCTION: The aim of the study was to assess the role of patient counselling, nurse assistance and effects of biochemical examinations in adherence of women with postmenopausal osteoporosis to alendronate 70 administration over 12 months of therapy. MATERIAL AND METHODS: Compliance and persistence to alendronate 70 therapy were assessed in a prospective study of 123 postmenopausal women, followed up for one year. The patients were divided into 4 groups (controls, counselled group, biochemical group and nurse assisted group) with monitoring every 6 months; in the nurse assisted group, additional phone contacts were made after 3 and 9 months of treatment. After 12 months, compliance and persistence were analysed. The medication possession ratio (MPR) was regarded as optimal when its value exceeded 80%. RESULTS: The compliance to alendronate 70 therapy was 54.03% in the control group and the mean persistence with medication was 197 days. The MPR above 80% was observed in 37.5%, and, after 1 year, 43.75% of patients were found persistent with the therapy. In the remaining groups, both compliance and persistence were higher but not statistically significantly, compared to the control group. Neither patient's age, education, diet, nor physical activity influenced the compliance with prescribed therapy. The most common reason to discontinue therapy was either its side effects or smoking. CONCLUSIONS: The obtained results suggest that better adherence with medical recommendations is observed in patients who receive additional attention, e.g. counselling, biochemical tests or nursing care. The critical elements for therapy discontinuation were side effects and smoking.