Varying systematically the structure of glassy poly(amide imide), poly(ester imide), and polyimide, we have studied the correlation between free volume and transport properties of highly selective polymer membranes. Free volume data were determined by means of positron annihilation lifetime spectroscopy (PALS) while transport properties originate from time-lag measurements of permanent gases. We find a good correlation between PALS average hole size and transport coefficients. The correlation is much better than with free volume data from group contribution methods. It is shown that the permeation properties are controlled not only by free volume fluctuations but also by energy barriers. A modified transport model taking into account the effect of the cohesive energy density on the energy barriers further improves the correlation significantly.

Background and Purpose-Disturbances of cerebrovascular autoregulation are thought to be involved in delayed cerebral ischemia and infarction after aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that the continuous monitoring of brain tissue oxygen (PtiO 2 ) pressure reactivity enables the detection of impaired autoregulation after SAH and that impaired autoregulation is associated with delayed infarction. Methods-In 67 patients after severe SAH, continuous monitoring of cerebral perfusion pressure (CPP) and PtiO 2 was performed for an average of 7.4 days. For assessment of autoregulation, the index of PtiO 2 pressure reactivity (ORx) was calculated as a moving correlation coefficient between values of CPP and PtiO 2 . Higher ORx values indicate disturbed autoregulation, whereas lower ORx values signify intact autoregulation. Results-Twenty patients developed delayed cerebral infarction, and 47 did not. Mean ORx was significantly higher in the infarction group compared with the noninfarction group (0.43Ϯ0.09 vs 0.23Ϯ0.14, respectively; PϽ0.0001). In a day-by-day analysis, ORx did not differ between groups from days 1 to 4 after SAH but was significantly higher from day 5 onward in the infarction group, indicating a deficit of autoregulatory capacity. In a logistic-regression model, ORx values from days 5 and 6 after SAH carried predictive value for the occurrence of delayed infarction but before this event ultimately occurred (Pϭ0.003). Conclusions-ORx

We compare molecular modeling results of two glassy polymer membranes and one rubbery polymer membrane with gas transport parameters and free-volume-related quantities from positronium annihilation. A simple geometric model reveals hole size distributions of asymmetric shape. Among glassy polymers, the distribution parameters show a good correlation with average hole sizes determined by positron annihilation lifetime spectroscopy. Higher permeability is measured in the glassy polymer with the higher mean value of the hole size distribution. The permselectivity of the membranes for permanent gases can be interpreted in terms of the distribution broadness via free-volume-controlled diffusion selectivity. A comparison with the rubbery polymer shows that the permeation behavior is not determined only by the free volume concentration. The thermal fluctuations of the polymer matrix play an important role for gas transport properties.

[Mn(CO)3(tpa-κ(3)N)]Br was prepared as a novel photoactivatable CO-releasing molecule (PhotoCORM) from [MnBr(CO)5] and tris(2-pyridylmethyl)amine (tpa) for the delivery of carbon monoxide to biological systems, with the κ(3)N binding mode of the tetradentate tpa ligand demonstrated by X-ray crystallography. The title compound is a CORM prodrug stable in solution in the dark for up to 16 h. However, photoactivation at 365 nm leads to CO release from the metal coordination sphere and transfer to haem proteins, as demonstrated by the standard myoglobin assay. Different iCORM intermediates could be detected with solution IR spectroscopy and assigned using DFT vibrational calculations. The antibacterial activity of the complex was studied on Escherichia coli. No effects were observed when the cultures were either kept in the dark in the presence of PhotoCORM or illuminated in the absence of metal complex. However, photoactivation of [Mn(CO)3(tpa-κ(3)N)]Br at 365 nm led to the appearance of the spectral signatures of CO-coordinated haems in the terminal oxidases of the bacterial electron transport chain in whole-cell UV/Vis absorption spectra. Significant internalization of the PhotoCORM was demonstrated by ICP-MS measurement of the intracellular manganese concentration. In particular when using medium with succinate as the sole carbon source, a very pronounced and concentration-dependent decrease in the E. coli growth rate could be observed upon illumination in the presence of metal complex, which is attributed to the constrained energy metabolism under these conditions and a strong indicator of terminal oxidase inhibition by carbon monoxide delivered from the PhotoCORM.

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Five manganese(I) tricarbonyl complexes of the general formula [Mn(CO) 3 (bpy R,R )(azole)]PF 6 with R = H, COOCH 3 , and azole = ketoconazole (ktz), miconazole (mcz), and clotrimazole (ctz) were synthesized and fully charaterized, including X-ray structure analysis for the ctz compound. The antibacterial activity on a panel of eight Gram-positive and Gram-negative bacterial strains was determined. While there was no effect on the latter microorganisms, the ctz complex showed submicromolar activity on Staphylococcus aureus and S. epidermidis with MIC values of 0.625 μM. Antiparasitic activity was investigated on Leishmania major and Trypanosoma brucei. Coordination of the organic azole drugs to the Mn(CO) 3 moiety led to complexes with low micromolar IC 50 values, but their potential for antileishmanial therapy is low due to comparable toxicity on mammalian cell lines 293T and J774.1. In contrast, the antitrypanosomal activity is much more promising, and the most potent compound incorparting the ktz ligand has an IC 50 value on T. brucei of 0.7 μM with selectivity on parasitic over mammalian cells as expressed by a selectivity index above 10. These results demonstrate that metal coordination of established drugs can significantly improve their biological activity and expand their range of medicinal applications.

Aims: We set out to investigate the antibacterial activity of a new Mn-based photoactivated carbon monoxide-releasing molecule (PhotoCORM, [Mn(CO)3(tpa-κ3N)]+) against an antibiotic-resistant uropathogenic strain (EC958) of Escherichia coli. Results: Activated PhotoCORM inhibits growth and decreases viability of E. coli EC958, but non-illuminated carbon monoxide-releasing molecule (CORM) is without effect. NADH-supported respiration rates are significantly decreased by activated PhotoCORM, mimicking the effect of dissolved CO gas. CO from the PhotoCORM binds to intracellular targets, namely respiratory oxidases in strain EC958 and a bacterial globin heterologously expressed in strain K-12. However, unlike previously characterized CORMs, the PhotoCORM is not significantly accumulated in cells, as deduced from the cellular manganese content. Activated PhotoCORM reacts avidly with hydrogen peroxide producing hydroxyl radicals; the observed peroxide-enhanced toxicity of the PhotoCORM is ameliorated by thiourea. The PhotoCORM also potentiates the effect of the antibiotic, doxycycline. Innovation: The present work investigates for the first time the antimicrobial activity of a light-activated PhotoCORM against an antibiotic-resistant pathogen. A comprehensive study of the effects of the PhotoCORM and its derivative molecules upon illumination is performed and mechanisms of toxicity of the activated PhotoCORM are investigated. Conclusion: The PhotoCORM allows a site-specific and time-controlled release of CO in bacterial cultures and has the potential to provide much needed information on the generality of CORM activities in biology. Understanding the mechanism(s) of activated PhotoCORM toxicity will be key in exploring the potential of this and similar compounds as antimicrobial agents, perhaps in combinatorial therapies with other agents. Antioxid. Redox Signal. 24, 765–780.

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