Target-directed catalytic metallodrugs

Most drugs function by binding reversibly to specific biological targets, and therapeutic effects generally require saturation of these targets. One means of decreasing required drug concentrations is incorporation of reactive metal centers that elicit irreversible modification of targets. A common approach has been the design of artificial proteases/nucleases containing metal centers capable of hydrolyzing targeted proteins or nucleic acids. However, these hydrolytic catalysts typically provide relatively low rate constants for target inactivation. Recently, various catalysts were synthesized that use oxidative mechanisms to selectively cleave/inactivate therapeutic targets, including HIV RRE RNA or angiotensin converting enzyme (ACE). These oxidative mechanisms, which typically involve reactive oxygen species (ROS), provide access to comparatively high rate constants for target inactivation. Target-binding affinity, co-reactant selectivity, reduction potential, coordination unsaturation, ROS products (metal-associated vs metal-dissociated; hydroxyl vs superoxide), and multiple-turnover redox chemistry were studied for each catalyst, and these parameters were related to the efficiency, selectivity, and mechanism(s) of inactivation/cleavage of the corresponding target for each catalyst. Important factors for future oxidative catalyst development are 1) positioning of catalyst reduction potential and redox reactivity to match the physiological environment of use, 2) maintenance of catalyst stability by use of chelates with either high denticity or other means of stabilization, such as the square planar geometric stabilization of Ni- and Cu-ATCUN complexes, 3) optimal rate of inactivation of targets relative to the rate of generation of diffusible ROS, 4) targeting and linker domains that afford better control of catalyst orientation, and 5) general bio-availability and drug delivery requirements.

Cord blood gas patterns identifying newborns at increased risk of group B streptococcal sepsis.

The effect of group B streptococcal sepsis acquired in utero on umbilical cord gas values is not known. Hypothesizing that fetal acid-base balance may be affected, we sought to identify a pattern of cord gas values that might detect newborns at increased risk of group B streptococcal sepsis. This review encompassed all newborns from January 1, 1986 to March 31, 1990 who manifested group B streptococcal sepsis as confirmed by a positive blood culture. An increased-risk cord gas profile was identified as an arterial pH less than 7.18 with either an arterial carbon dioxide pressure less than 59 mmHg or bicarbonate level less than 19 mEq/L. This pattern was found in four of 11 newborns with group B streptococcal disease but in only 43 of 4290 controls, yielding a relative risk of 51.7 (95% confidence interval 13.1-224.9). Our results suggest that a mild metabolic acidosis characterized by these indices may serve as an indicator of increased risk of early-onset group B streptococcal disease.

Diagnosis and treatment of intrapericardial teratoma.

Intrapericardial teratoma is a rare mediastinal tumor that originates from aberrant clusters of multipotential cells from three germinal layers. Previous reports have used the combination of cardiac angiography, CT scan, and echocardiogram to establish the diagnosis prior to surgery. We report a case of intrapericardial teratoma diagnosed noninvasively and removed surgically within the first three days of life. Furthermore, we compare the diagnostic accuracy of echocardiography and computerized tomography (CT), and discuss the superiority of noninvasive evaluation in the management of these critically ill infants.