Anti-GD2 induced allodynia in rats can be reduced by pretreatment with DFMO.

BackgroundAnti-GD2 therapy with dinutuximab is effective in improving the survival of high-risk neuroblastoma patients in remission and after relapse. However, allodynia is the major dose-limiting side effect, hindering its use for neuroblastoma patients at higher doses and for other GD2-expressing malignancies. As polyamines can enhance neuronal sensitization, including development of allodynia and other forms of pathological pain, we hypothesized that polyamine depletion might prove an effective strategy for relief of anti-GD2 induced allodynia.MethodSprague-Dawley rats were allowed to drink water containing various concentrations of difluoromethylornithine (DFMO) for several days prior to behavioral testing. Anti-GD2 (14G2a) was injected into the tail vein of lightly sedated animals and basal mechanical hindpaw withdrawal threshold assessed by von Frey filaments. Endpoint serum DFMO and polyamines, assessed 24h after 14G2a injection, were measured by HPLC and mass spectrometry.ResultsAn i.v. injection of 14G2a causes increased paw sensitivity to light touch in this model, a response that closely mimics patient allodynia. Animals allowed to drink water containing 1% DFMO exhibited a significant reduction of 14G2a-induced pain sensitivity (allodynia). Increasing the dosage of the immunotherapeutic increased the magnitude (intensity and duration) of the pain behavior. Administration of DFMO attenuated the enhanced sensitivity. Consistent with the known actions of DFMO on ornithine decarboxylase (ODC), serum putrescene and spermidine levels were significantly reduced by DFMO, though the decrease in endpoint polyamine levels did not directly correlate with the behavioral changes.ConclusionsOur results demonstrate that DFMO is an effective agent for reducing anti-GD2 -induced allodynia. Using DFMO in conjunction with dinutuximab may allow for dose escalation in neuroblastoma patients. The reduction in pain may be sufficient to allow new patient populations to utilize this therapy given the more acceptable side effect profile. Thus, DFMO may be an important adjunct to anti-GD2 immunotherapy in addition to a role as a potential anti-cancer therapeutic

Synthesis, Structure and Cytotoxic Activity of New Acetylenic Derivatives of Betulin

molecule

Factors Affecting Health-Related Quality of Life and Physical Activity after Liver Transplantation for Autoimmune and Nonautoimmune Liver Diseases: A Prospective, Single Centre Study

Background/Aim. With the improvement of the outcomes after liver transplantation (LTx), health-related quality of life (HRQoL) and physical activity are becoming significant outcome parameters. We prospectively assessed these parameters in patients with autoimmune and nonautoimmune liver disorders undergoing LTx. Materials and Methods. Patients (n=107) were subdivided into 3 groups depending on the time after LTx: group-A (n=21): 6–12 months; group-B (n=48): 13–36 months; and group-C (n=38): >37 months. SF-36 and IPAQ were applied in HRQoL and physical activity assessment. Results. Females had impaired HRQoL in most SF-36 domains. Younger patients showed higher scores at SF-36 physical functioning domain but IPAQ was not influenced by age. Group-B had higher general health and physical component summary than group-A (P=0.037, P=0.04, resp.) and total IPAQ than group-C (P=0.047). The sitting time domain was longer in group-A than in group-B and group-C (P=0.0157;  P=0.042, resp.). Employed patients had better HRQoL and higher physical activity than those not working. SF-36 and IPAQ were unrelated to the autoimmune etiology of liver disease. Conclusions. These findings show that female and unemployed patients have worse HRQoL, while gender and age at LTx time do not affect IPAQ’s physical activity. The autoimmune etiology of liver disease does not influence HRQoL and physical activity after LTx

Efficient human breast cancer xenograft regression after a single treatment with a novel liposomal formulation of epirubicin prepared using the EDTA ion gradient method.

Liposomes act as efficient drug carriers. Recently, epirubicin (EPI) formulation was developed using a novel EDTA ion gradient method for drug encapsulation. This formulation displayed very good stability and drug retention in vitro in a two-year long-term stability experiment. The cryo-TEM images show drug precipitate structures different than ones formed with ammonium sulfate method, which is usually used to encapsulate anthracyclines. Its pharmacokinetic properties and its efficacy in the human breast MDA-MB-231 cancer xenograft model were also determined. The liposomal EPI formulation is eliminated slowly with an AUC of 7.6487, while the free drug has an AUC of only 0.0097. The formulation also had a much higher overall antitumor efficacy than the free drug

Data from: Oral administration of Polymyxin B modulates the activity of Lipooligosaccharide E. coli B against lung metastases in murine tumor models

Introduction: Polymyxin B (PmB) belongs to the group of cyclic peptide antibiotics, which neutralize the activity of LPS by binding to lipid A. The aim of this study was to analyze the effect of PmB on the biological activity of lipooligosaccharide (LOS E. coli B,rough form of LPS) in vitro and in experimental metastasis models. Results: Cultures of murine macrophage J774A.1 cells and murine bone marrow-derived dendritic cells (BM-DC) stimulated in vitro with LOS and supplemented with PmB demonstrated a decrease in inflammatory cytokine production (IL-6, IL-10, TNF-α) and down-regulation of CD40, CD80, CD86 and MHC class II molecule expression. Additionally, PmB suspended in drinking water was given to the C57BL/6 mice seven or five days prior to the intravenous injection of B16 or LLC cells and intraperitoneal application of LOS. This strategy of PmB administration was continued throughout the duration of the experiments (29 or 21 days). In B16 model, statistically significant decrease in the number of metastases in mice treated with PmB and LOS (p<0.01) was found on the 14th day of the experiments, whereas the most intensive changes in surface-antigen expression and ex vivo production of IL-6, IL-1β and TNF-α by peritoneal cells were observed 7 days earlier. By contrast, antigen expression and ex vivo production of IL-6, IL-10, IFN-γ by splenocytes remained relatively high and stable. Statistically significant decrease in LLC metastases number was observed after the application of LOS (p<0.01) and in the group of mice preconditioned by PmB and subsequently treated with LOS (LOS + PmB, p<0.01). Conclusions: In conclusion, prolonged in vivo application of PmB was not able to neutralize the LOS-induced immune cell activity but its presence in the organism of treated mice was important in modulation of the LOS-mediated response against the development of metastases

<i>N</i>-Arylaminomethylenebisphosphonates Bearing Fluorine Atoms: Synthesis and Antiosteoporotic Activity

<div><p></p><p>A series of N-phenyl and N-pyridyl-aminomethylenebisphosphonates substituted in their aromatic rings with fluorine atoms or trifluoromethyl groups have been synthesized by a three component approach. They were screened for potential antiosteoporetic activity using mouse macrophage-like J774E cells. Most of the compounds appeared to be moderate inhibitors of macrophage cells proliferation compared to known the antiosteoporetic drug, Incandronate. Their potency was compared with their structural analogues, hydroxymethylene-bisphosphonate 2 and ethylidenebisphosphonates 3, which appeared to be equipotent. Although the aminomethylenebisphosphonates 1 show low stability in aqueous solutions, the most stable, i.e., N-(3-trifluoromethylphenyl)-aminomethylenebisphosphonic acid, was chosen for in vivo testing on sheep with induced osteoporosis. This compound had marginal influence on the bone structure recovery.</p></div

Data - Polymyxin B modulates the activity of Lipooligosaccharide E. coli B; Kicielińska and all

Data - Polymyxin B modulates the activity of Lipooligosaccharide E. coli B; Kicielińska and al