Treatment of neuroblastoma with 131I-metaiodobenzylguanidine

Seven patients with neuroblastoma (six children and one adult) were treated with therapeutic doses of high specific activity 131I-metaiodobenzylguanidine (131I-MIBG). Six patients were in stage IV and unresponsive to conventional treatment. One patient, in stage III, was treated at diagnosis, an approach never previously reported. Single doses of 131I-MIBG varying from 70 to 184 mCi split into two parts were administered by slow i.v. infusion (4 to 8 hours) at 2- to 4-day intervals. The following results were obtained in the six evaluable patients: two patients showed transient stabilization of the disease; three had an objective response, with shrinking of the primary tumor and/or regression of the metastatic lesions. Of these three patients, two suffered relapses at 2 and 7 months, respectively, from the first course of MIBG. The third patient, in whom the residual disease almost completely disappeared following MIBG therapy, is still alive in complete remission after autologous bone marrow transplantation with a follow-up of 14 months. The single patient treated at diagnosis showed a dramatic response to a relatively low dosage of MIBG, with histologically proved disappearance of the tumor mass. Our data indicate that MIBG may be useful in the treatment of neuroblastoma unresponsive to conventional chemotherapy. The complete response observed in the patient treated at diagnosis suggests that the full potentiality of MIBG therapy should be explored in untreated patients.     

QSAR in a series of muscarinic agents. Note VI. Five-membered cyclic ligands

Proceeding in our study on the muscarinic receptor site, a refinement of its topology by means of Quantitative Structure-Activity Relationships has been carried out. Specific key structures have been selected considering not only muscarine and the corresponding desether derivative, but also a set of cyclopentenyltrimethylammoniummethyl salts. These derivatives, considered in a correlation equation extended to all of the five-membered cyclic structures previously examined, significantly improve understanding of contributions of critical ligand substructures to the overall interaction. The results obtained reinforce the reliability of correlation equations in structure-activity studies.     

Thyroid carcinoma mimicking a toxic adenoma

A young woman with a thyroid papillary carcinoma behaving as an autonomously hyperfunctioning nodule is described. Only 17 similar patients have been seen in the past 25 years. It is emphasized that hyperthyroidism does not exclude malignant disease in hot nodules. This possibility suggests that all thyroid nodules, either cold or hot, require careful management. Therefore, in at risk cases, surgery could be the most useful treatment.     

A reanalysis of the structure-activity relationships of sulfonamide derivatives.

A reanalysis of correspondence between electronic distribution of sulfonamides and their antibacterial activity is proposed. Correlation equations show that the rate limiting steps for sulfonamide action on E. coli cell-free system and whole cell system have similar dependence on the negative logarithm of the ionization constant. The existence of a "bilinear relationship" demonstrates that the whole class of compounds has a single mechanism of action and that permeability factors are unimportant in both biological processes.     

Retrospective analysis of drug projection using correlative technics]

The problem of choosing substituents to allow correct correlative analysis according to the "Hausch Approach" is discussed. The problem of colinearity among parameters is considered in a case study on 296 anilides which inhibit the Hill reaction. The difficulty in of determining whether, pi or MR is the important variable in changes in activity is shown. "Cluster analysis" is discussed and proposed as a rational method for the selection of substituents to be introduced into biologically active structure in order to explore the scope of each defined physico-chemical parameter. An example of the use of this method conerning auxin activity of 1- and 2-benzotriazole derivatives is given.     

Vitamin D Treatment Prevents Uremia-Induced Reductions in Aortic microRNA-145 Attenuating Osteogenic Differentiation despite Hyperphosphatemia

In chronic kidney disease, systemic inflammation and high serum phosphate (P) promote the de-differentiation of vascular smooth muscle cells (VSMC) to osteoblast-like cells, increasing the propensity for medial calcification and cardiovascular mortality. Vascular microRNA-145 (miR-145) content is essential to maintain VSMC contractile phenotype. Because vitamin D induces aortic miR-145, uremia and high serum P reduce it and miR-145 directly targets osteogenic osterix in osteoblasts, this study evaluated a potential causal link between vascular miR-145 reductions and osterix-driven osteogenic differentiation and its counter-regulation by vitamin D. Studies in aortic rings from normal rats and in the rat aortic VSMC line A7r5 exposed to calcifying conditions corroborated that miR-145 reductions were associated with decreases in contractile markers and increases in osteogenic differentiation and calcium (Ca) deposition. Furthermore, miR-145 silencing enhanced Ca deposition in A7r5 cells exposed to calcifying conditions, while miR-145 overexpression attenuated it, partly through increasing α-actin levels and reducing osterix-driven osteogenic differentiation. In mice, 14 weeks after the induction of renal mass reduction, both aortic miR-145 and α-actin mRNA decreased by 80% without significant elevations in osterix or Ca deposition. Vitamin D treatment from week 8 to 14 fully prevented the reductions in aortic miR-145 and attenuated by 50% the decreases in α-actin, despite uremia-induced hyperphosphatemia. In conclusion, vitamin D was able to prevent the reductions in aortic miR-145 and α-actin content induced by uremia, reducing the alterations in vascular contractility and osteogenic differentiation despite hyperphosphatemia.     

Preparation,characterization and in vitro activities evaluation of solid lipid nanoparticles based on PEG-40 stearate for antifungal drugs vaginal delivery

The present article reports the preparation, characterization and performance evaluation of solid lipid nanoparticles (SLNs) based on polyoxyethylene-40 stearate (PEG-40 stearate) for the administration of antifungal agents such as ketoconazole and clotrimazole. These nanoparticles could be useful in the treatment of vaginal infections sustained by Candida albicans. In particular, PEG-40 stearate was made to react with acryloyl chloride in order to introduce an easily polymerizable moiety for the creation of a second shell and to ensure a slow drug release. In addition, the differences on the release profiles between PEG-40 stearate-based nanoparticles, PEG-40 stearate acrylate based and polymerized ones, were analyzed under conditions, simulating the typical environment of Candida albicans infection. Then, the antifungal activity of nanoparticles was also evaluated in terms of minimal inhibitory concentration. Moreover, the nanoparticles were submitted to in vitro studies for evaluating the drug permeability at the site of action. Results indicated that the obtained particles are potentially useful for the treatment of vaginal infections sustained by Candida albicans.     

Preventive Activity of Olive Oil Phenolic Compounds on Alkene Epoxides Induced Oxidative DNA Damage on Human Peripheral Blood Mononuclear Cells

The aim of this study was to investigate the ability of epoxides of styrene (styrene-7,8-oxide; SO) and 1,3-butadiene (3,4-epoxy-1-butene; 1,2:3,4:-diepoxybutane) to cause oxidative stress and oxidative DNA damage on human peripheral blood mononuclear cells (PBMCs) and whether a complex mixture of olive oil phenols (OOPE) could prevent these effects. The DNA damage was measured by the single-cell gel electrophoresis (SCGE; comet assay). We found that the DNA damage induced by alkene epoxides could be prevented by N-acetyl-cysteine (10 mM) and catalase (100 U/ml). Alkene epoxides caused a significant (P < 0.05) increase of both peroxide concentration in extra- and intracellular environment and formamidopyrimidine DNA glycosylase (FPG)- and Endonuclease III (ENDO III)-sensitive sites in PBMCs, demonstrating the presence of oxidized bases. OOPE (1 μg of total phenols/ml) was able to prevent the alkene epoxide induced DNA damage both after 2 and 24 h of incubation. In addition, OOPE completely inhibited the SO-induced intracellular peroxide accumulation in PBMCs and prevented the oxidative DNA damage induced by SO, as evidenced by the disappearance of both FPG- and ENDO III-sensitive sites. This is the first study demonstrating the ability of OOPE to prevent the DNA damage induced by alkene epoxides providing additional information about the chemopreventive properties of olive oil.