Efficacy of a new medical device based on colloidal silver and carbossimetyl beta glucan in treatment of upper airways disease in children.

AIM: Nasal congestion is the main symptom in common upper respiratory diseases in childhood. Intranasal administration of sympatheticomimetics decongestants is commonly adopted for this symptom. The Italian Drug Agency stated a warning against the use of these drugs in children under 12 years of age. The aim of this study is to evaluate the efficacy on nasal symptoms and the safety of a new medical device based on colloidal silver and carbossimetyl beta glucan compared with saline solution treatment in a group of children (0-12 years) affected by viral rhinitis. METHODS: Hundred consecutive outpatient children (0-12 year old), affected by common cold syndrome with evident nasal obstruction were randomly assigned to two type of intervention: group 1. receiving colloidal silver and carbossimetyl beta glucan; group 2. receiving saline solution. Each subject underwent clinical history and objective examination of rhinosinusal district at enrollment. Upper respiratory pathologie-related symptoms were specifically evaluated by using the Canadian Acute Respiratory Illness and Flu Scale (CARIFS). RESULTS: A significant improvement of CARIFS score was observed into the two groups. The score improvement of these two treatment was confirmed in all the age sub-group. We observed a statistically significant difference in mean post-treatment CARIFS score and CARIFS globas VAS (Visual Analogic Scale) in children of group 1 compared with children in group 2 (2.28 ± 1.58 vs. 5.08 ± 3.39; P<0.001 and VAS: 1.87 ± 1.38 vs. VAS: 3.34 ± 2.19; P=0.012, respectively). At the end of treatment, 90% of subjects in group 1 resulted completely recovered, whereas 10% experienced some degree of complications (otitis, tracheitis, bronchitis). In group 2 a complete recovering was achieved in 66 % of subjects, the remaining 34 % developed complications. Tolerability profiles were similar in the two groups with no statistical differences in side effects in all age subgroups. CONCLUSION: Despite both treatments reached significative improvements in CARIFS global score and VAS and in physical examination of nasal mucosa and secretion at the end of the therapy, colloidal silver and carbossimetyl beta glucan showed a better performance with a significant difference in mean post-treatment CARIFS global score and CARIFS VAS compared to treatment with saline solution.

BBR 3464: a novel triplatinum complex, exhibiting a preclinical profile of antitumor efficacy different from cisplatin.

Multinuclear platinum complexes represent a new class of anticancer agents, distinct in terms of DNA binding features and the profile of antitumor activity from their mononuclear counterparts, in particular cisplatin. Among complexes of this class, BBR 3464, a trinuclear platinum compound has been selected for preclinical development. In the present study, we describe the preclinical evaluation of BBR 3464 in a series of human tumor cell lines and tumor xenografts, with special emphasis on tumor types known to be resistant to cisplatin. In a panel of seven human tumor cell lines naturally resistant to cisplatin (three ovarian and four melanomas), BBR 3464 was extremely potent with IC50 values at least 20-fold lower than cisplatin. Against eight human tumor xenografts including four tumors refractory to cisplatin, BBR 3464 was confirmed to be very active with a tumor weight inhibition >80% in seven of them. The efficacy of BBR 3464 against cisplatin-resistant tumors was consistent with the ability of the drug to completely overcome resistance in three cell systems characterized by acquired resistance to cisplatin. Moreover, BBR 3464 caused a more prolonged effect than cisplatin, which was reflected by higher specific growth delay values. This prolonged effect is likely to be related to a more persistent perturbation of the cell cycle induced by BBR 3464 than by cisplatin, as shown in one ovarian tumor cell line. Finally, the profile of sensitivity to BBR 3464 within the 60-cell-lines screening panel of the National Cancer Institute, NIH (Bethesda, MD) differed from those of established drugs, thus supporting the hypothesis of a distinct mechanism of cytotoxic activity of BBR 3464. The novel trinuclear platinum complex, in light of its innovative antitumor activity profile, has the potential to become a useful clinical agent for the treatment of unresponsive tumors.

Synthesis and antitumor evaluation of 2,5-disubstituted-indazolo[4, 3-gh]isoquinolin-6(2H)-ones (9-aza-anthrapyrazoles).

The synthesis and antitumor evaluation of 2, 5-disubstituted-indazolo[4,3-gh]isoquinolin-6(2H)-ones (9-aza-APs) are described. The key intermediates in the synthesis are benz[g]isoquinoline-5,10-diones which are substituted at positions 6 and 9 with groups of different nucleofugacity for SNAr displacements. The initial displacement of fluoride by a substituted hydrazine leads to the pyrazole analogues. Substitution of the remaining leaving group by an amine or BOC-protected amines leads to the 9-aza-APs 12. These analogues were converted into their maleate or hydrochloride salts 13. In two cases, namely, 13x and 13z, sidearm buildup was also employed in the synthetic pathway. In vitro evaluation of 9-aza-APs against the human colon tumor cell line LoVo uncovered for most of the compounds a cytotoxic potency lower than that of DuP-941 or mitoxantrone and comparable to that of doxorubicin. Only analogues 13c, 13n, and 13ff were as cytotoxic as DuP-941. Interestingly, while DuP-941 was highly cross-resistant in the LoVo cell line resistant to doxorubicin (LoVo/Dx), the 9-aza-APs carrying a distal lipophilic tertiary amine moiety in both chains were capable of overcoming the MDR resistance induced in this cell line. The 9-aza-APs show outstanding in vivo antitumor activity against both systemic P388 murine leukemia and MX-1 human mammary carcinoma transplanted in nude mice. At their optimal dosages, congeners 13a-c, 13f, 13n, 13q, 13x, and 13dd were highly effective against P388 leukemia with T/C% of 200-381, while the T/C% value of DuP-941 was 147. In the MX-1 tumor model, 24 compounds elicited percentages of tumor weight inhibitions (TWI) ranging from 50% to 99%. Congeners 13d, 13k, 13l, 13x, 13z, and 13ee emerged as the most effective ones, with TWI% 96, simliar to that of DuP-941 (TWI% = 95). On the basis of their efficacy profile in additional experimental tumors and lack of cardiotoxicity in preclinical models, two congeners have surfaced as potential clinical candidates.

N-acyl-2-substituted-1,3-thiazolidines, a new class of non-narcotic antitussive agents: studies leading to the discovery of ethyl 2-[(2-methoxyphenoxy)methyl]-beta-oxothiazolidine-3-propanoate.

The synthesis of a novel class of antitussive agents is described. The compounds were examined for antitussive activity in guinea pig after cough induction by electrical or chemical stimulation. Ethyl 2-[(2-methoxyphenoxy)methyl]-beta-oxothiazolidine-3-propanoate (BBR 2173, moguisteine, 7) and other structurally related compounds showed a significant level of activity, comparable to that of codeine and dextromethorphan. The compounds presented in this paper are characterized by the N-acyl-2-substituted-1,3-thiazolidine moiety, which is a novel entry in the field of antitussive agents. The serendipitous discovery of the role played by the thiazolidine moiety in determining the antitussive effect promoted extensive investigations on these structures. This optimization process on N-acyl-2-substituted-1,3-thiazolidines led to the initial identification of 2-[(2-methoxypheoxy)methyl]-3-[2-(acetylthio)acetyl]- 1,3-thiazolidine (18a) as an interesting lead compound. The careful study of the rapid and very complicated metabolism of 18a provided further insights for the design of newer related derivatives. The observation that the metabolic oxidation on the lateral chain's sulfur of 18a to sulfoxide maintained the antitussive properties suggested the introduction of isosteric functional groups with respect to the sulfoxide moiety. Subsequent structural modifications showed that hydrolyzable malonic residues in the 3-position of the thiazolidine ring were able to assure high antitussive activity. This optimization ultimately led to the selection of moguisteine (7) as the most effective and safest representative of the series. Moguisteine is completely devoid of unwanted side effects (such as sedation and addiction), and its activity was demonstrated also in clinical studies.