Balance impairment and lower limbs strength in patients with COPD who fell in the previous year.

Fall-related causes in patients with COPD might be associated to functional balance impairments and greater disease severity. We aimed to evaluate the reasons for falls in patients with COPD who had presented any fall during the previous year. This is a cross-sectional study. All COPD's GOLD classifications (mild, moderate, severe, and very severe) patients were recruited. In order to participate, patients ought to be clinically stable and without any exacerbation within 30 days prior to study entry. History of falls was self-reported by patients through an interview. Pre and post bronchodilator (salbutamol 400 µg) spirometry was performed. All patients accomplished postural balance tests such as the Berg Balance Scale, Falls Efficacy Scale-International, Time up and Go, Functional Reach test, Tinetti test and Chalder Scale; furthermore, lower limbs muscle strength (muscle dynamometry) and the COPD Assessment Test (CAT) were assessed. Ninety-six patients with COPD were evaluated and divided into two groups stratified according to any positive history of falls in the previous year. Patients with COPD who had any fall in the previous year presented older age (p=0.01), higher BMI (p=0.04) and worse pulmonary function than those who did not fall. The risk of falls was increased in patients with lower muscle strength in the lower limbs (OR 2.9, CI 95%;1.6 to 3.9), age greater than 65 years (OR 2.7, CI 95%;1.3 to 3.4), BMI greater than 28.8 kg/m2 (OR 3.2, CI 95%;1.1 to 5.6), very severe airway obstruction (OR 3.9, CI 95%;2.2 to 3.9) and fatigue (OR 3.2, CI 95%;1.5 to 5.3). Impaired body balance, reduced lower limb strength, disease severity, presence of fatigue and elevated BMI are important factors for falls in patients with COPD.

Biphosphinic palladacycle complex mediates lysosomal-membrane permeabilization and cell death in K562 leukaemia cells.

The cell death mechanism of cytotoxicity induced by the Biphosphinic Palladacycle Complex (BPC) was studied using a K562 leukaemia cell line. The IC50 values obtained for K562 cells post-72 h of BPC were less than 5.0 microM by using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and trypan blue assays. Using the Acridine Orange vital staining combining fluorescence microscopy it was observed that the complex triggers apoptosis in K562 cells, inducing DNA fragmentation, as analysed through electrophoresis. Lysosomal-membrane permeabilization was also observed in K562 cells post-5 h of BPC, which suggests intralysosomal accumulation by proton-trapping, since its pKa value ranged from 5.1 to 6.5. Caspase-3, and -6 activity induced by BPC in K562 cells was prevented by the cathepsin-B inhibitor [N-(L-3-trans-propylcarbamoyl-oxirane-2-carbonyl)-L-isoleucyl-L-proline] (CA074). These events occurred in the presence of endogenous bcl-2 and bax expression. Acute toxicological studies demonstrated that BPC produces no lesions for liver and kidney fourteen-days after drug administration (100 mg/kg--i.p.). White and red blood cells of BPC-treated mice presented normal morphological characteristics. Taken together, these data suggest a novel lysosomal pathway for BPC-induced apoptosis, in which lysosomes are the primary target and cathepsin B acts as death mediator.

Chiral cyclopalladated complexes derived from N,N-dimethyl-1-phenethylamine with bridging bis(diphenylphosphine)ferrocene ligand as inhibitors of the cathepsin B activity and as antitumoral agents.

Chiral cyclopalladated complexes derived from N,N-dimethyl-1-phenethylamine and the coordinating ligand 1,1'-bis(diphenylphosphine)ferrocene were synthesized and studied as Cathepsin B inhibitors and antitumoral agents against solid tumors. Our results revealed that the palladium compound [Pd2(C2,N-S(-)dmpa)2(mu-dppf)Cl2] (2) was able to inhibit Cathepsin B activity in a reversible fashion. This palladacycle compound binds to free cathepsin B (E) as well as to the enzyme-substrate complex (ES) with dissociation constants of KH=12+/-1 microM and alphaKH=2.4+/-0.3 microM, respectively. The application of this complex, in Walker tumor-bearing rats, resulted in 90% inhibition of the tumor growth. Subcutaneous inoculations of 10(6) tumoral cells produced solid tumors with a mass of 4.0+/-1.0 g in 12 days Walker tumor-bearing rats. However, when these animals were treated with one dose of the palladacycle compound (2.0 mg/kg), the tumoral mass was reduced to 0.3+/-0.1 g. On the other hand, the same complex (2) did not afford any protection to mice bearing the non-metastatic Ehrlich Ascites tumor treated with doses of 0.5, 5.0, and 30 mg/kg for a period of four, three and one day, respectively, beginning 72 h after tumor inoculation. Toxicological studies using mice treated with one high dose of the complex (2) (100 mg/kg) did not show any alterations in red and white blood cell morphology 14 days after the drug administration. Similar results were obtained with hepatic, kidney, and spleen tissues. The results presented in this work introduce the title cyclopalladated complexes as promising antitumoral drugs with reduced toxicity in experimental studies.

Cyclopalladated compounds as chemotherapeutic agents: antitumor activity against a murine melanoma cell line.

Palladacycle compounds obtained from N, N-dimethyl-1-phenethylamine (dmpa), phenyl-2-pyridinyl-acetylene and 1-phenyl-3-N, N-dimethylamine-propine, respectively, were complexed to 1, 2 ethanebis (diphenylphosphine) (dppe) ligand to synthesize antitumor cyclopalladated complexes that were tested in vitro and in vivo against syngeneic B16F10-Nex2 murine melanoma cells of low immunogenicity implanted subcutaneously in mice. Complexes were not toxic to mice injected 3 times i.p. with as much as 60 microM/animal/week. Of 3 cyclopalladated complexes that were inhibitory in vitro at low concentrations (<1.25 microM), complex 7a was the most active in vivo, delaying tumor growth and prolonging animal survival. In vitro, binucleate complex 7a caused a collapse of respiratory activity with an abrupt decrease of extracellular acidification on short incubation (up to 100 min), followed by DNA degradation after 24 hr. The apoptosis-like reaction to this Pd-complex was not accompanied by increased levels of caspases 1 and 3. Complex 7a bound to a bacterial plasmid DNA, causing late conformational changes after 24 hr. Two other complexes with different C, N-cycles were also apoptotic and 2 binucleated ones were inactive. These results introduce the palladacycle-dppe complexes as promising antitumor drugs with exquisite structural specificities and for action in vivo and in vitro.