The Influence of Dirithromycin on the Pharmacokinetics of Cyclosporine in Healthy Subjects and in Renal Transplant Patients

The effect of a standard regimen of the investigational macrolide antibiotic, dirithromycin, on the single-dose kinetics of orally administered cyclosporine (CSA) was investigated in healthy young males and on the steady-state disposition kinetics of cyclosporine in a panel of renal transplant patients. Eight male volunteers participated after giving informed consent. CSA was administered in three single doses (15 mg kg(minus sign1) p.o. each) in each of three phases: (1) prior to a 14-day regimen of dirithromycin; (2) at the end of a 14-day regimen of dirithromycin (500 mg p.o. qAM); and (3) 2 weeks after the last dose of a 14-day regimen of dirithromycin. Pharmacokinetic parameters of CSA were estimated, and the differences among treatments were assessed by analysis of variation. No significant differences among treatment (phase) means were detected (p < 0.05). We conclude that a typical 14-day regimen of dirithromycin failed to alter the disposition kinetics of CSA when taken orally healthy young adult males. The effect of a standard regimen of dirithromycin on the steady-state disposition kinetics of orally administered CSA was investigated in a panel of 15 stable renal transplant patients. Pharmacokinetic parameters for CSA were evaluated prior to, during, and 2 weeks after discontinuing a 14-day (500 mg day(minus sign1)) oral regimen of dirithromycin. Dirithromycin elicited small but significant changes in the following parameters: C(av) was increased by 16% during dirithromycin treatment, and the changes in normalized C(av) were comparable. Likewise, C(SS,min) and normalized C(SS,min) were increased by 19% and 20%, respectively, during dirithromycin treatment. CSA oral clearance, CL/F(SS), decreased by 17% during dirithromycin treatment. C(SS,max) and normalized C(SS,max) were increased by 13% and 17%, respectively, during dirithromycin treatment but were not significantly different from those either before or after dirithromycin. The magnitude of the pharmacokinetic changes for CSA during dirithromycin treatment (<15% in normal subjects and 15--20% in renal transplant patients) when considered in the context of the therapeutic range of cyclosporine concentrations was relatively small, and not likely to warrant special attention to the dosing of CSA in such patients beyond routine whole-blood CSA and serum creatinine monitoring.     

Efficacy of topical gentamicin treatment after 193-nm photorefractive keratectomy in an experimental Pseudomonas keratitis model

Background: The treatment of Pseudomonas keratitis has many limitations, and further investigation to identify more effective approaches is required. We therefore studied the possible contribution of the debridement effect of 193-nm excimer laser on Pseudomonas keratitis in rabbit eyes. Methods: Pseudomonas keratitis was induced in 30 rabbit eyes by inflicting controlled central corneal scratches and applying a drop of Pseudomonas aeruginosa suspension. After 24 h, one cornea of each animal was photo-ablated (excimer laser: fluency 90 mJ/cm², 10 Hz, 213 pulses), yielding 50 m of tissue ablation, while the follow cornea served as control. Five groups of six animals each were formed and received: a subconjunctival injection of gentamicin 20, mg (group 1), topical 14 mg/ml gentamicin hourly (group 2) or every 2.5 h (group 3), or NaCl 0.9% hourly (group 4) for 8 h. In group 5, animals were sacrificed without additional treatment. After 9 h corneas were excised, homogenized, serially diluted, and plated on agar blood plates. The numbers of colony-forming units (CFU) per cornea were statistically evaluated (Mann-Whitney test). Results: In control eyes, a greater decrease of CFU was observed in group 2 than in group 3 (P = 0.03). In laser-ablated eyes, there was no difference in CFU between groups 2 and 3. Comparison of the excimer-treated and control eyes revealed a greater number of bacteria (CFU) in controls only in group 3 (P=0.02). Conclusion: Our study suggests that controlled debridement of cornea with excimer laser may improve the effect of topical antibiotics.Presented at ECORA First Annual Meeting, 5 October 1993, Bonn, Germany     

Food-related illness and death in the United States.

To better quantify the impact of foodborne diseases on health in the United States, we compiled and analyzed information from multiple surveillance systems and other sources. We estimate that foodborne diseases cause approximately 76 million illnesses, 325,000 hospitalizations, and 5,000 deaths in the United States each year. Known pathogens account for an estimated 14 million illnesses, 60, 000 hospitalizations, and 1,800 deaths. Three pathogens, Salmonella, Listeria, and Toxoplasma, are responsible for 1,500 deaths each year, more than 75% of those caused by known pathogens, while unknown agents account for the remaining 62 million illnesses, 265,000 hospitalizations, and 3,200 deaths. Overall, foodborne diseases appear to cause more illnesses but fewer deaths than previously estimated.     

The Resource Mothers Program for Maternal Phenylketonuria

OBJECTIVES: The purpose of this study was to measure the effectiveness of resource mothers in reducing adverse consequences of maternal phenylketonuria. METHODS: Nineteen pregnancies in the resource mothers group were compared with 64 pregnancies in phenylketonuric women without resource mothers. Weeks to metabolic control and offspring outcome were measured. RESULTS: Mean number of weeks to metabolic control was 8.5 (SE = 2.2) in the resource mothers group, as compared with 16.1 (SE = 1.7) in the comparison group. Infants of women in the resource mothers group had larger birth head circumferences and higher developmental quotients. CONCLUSIONS: The resource mothers program described here improves metabolic control in pregnant women with phenylketonuria.     

Nuclear magnetic resonance chromatography: applications of pulse field gradient diffusion NMR to mixture analysis and ligand-receptor interactions

Pulse field gradient (PFG) diffusion NMR spectroscopy is a non-invasive method for the spectroscopic separation and identification of compounds of interest from a mixture. Because it relies on differences in translational diffusion rates to resolve NMR signals from individual components, pulse field gradient NMR is a unique method for analyzing complex mixtures and for detecting intermolecular interactions. A number of multidimensional pulse field gradient NMR experiments have been developed to alleviate the overlap of NMR signals arising from a complex mixture and facilitate component identification. The applications of pulse field gradient NMR for mixture analysis and for the direct identification of high affinity ligands are reviewed.     

Loving openness as a meta-world hypothesis: expanding our vision of mind and medicine

In 1942, Stephen C. Pepper published a seminal book, World Hypothesis, that sought to explain how people create hypotheses about the world. Pepper proposed that there were four basic world hypotheses: (1) formistic (the hypothesis that nature exists as categories); (2) mechanistic (the hypothesis that nature obeys cause-effect relationships); (3) contextual (the hypothesis that processes in nature are relative and context dependent); and (4) organismic (the hypothesis that processes in nature reflect interactive relationships in systems). Most classical and modern theories of science and medicine implicitly adopt one or more of these foundational hypotheses. In 1997, Schwartz and Russek proposed that there were four additional world hypotheses: (5) implicit process (the hypothesis that nature consists of invisible forces and information, such as energy and consciousness); (6) circular causality (the hypothesis that nature consists of circulating interactions that inherently change over time); (7) creative unfolding (the hypothesis that processes in nature reflect flexible designs or plans that have adaptive function); and (8) integrative diversity (the hypothesis that phenomena in nature reflect complex integrations of diverse processes). Theories in postmodern and integrative science implicitly adopt hypotheses 5 through 8. However, underlying the creation of the eight world hypotheses is an implicit meta-world hypothesis which we term loving openness (the hypothesis that phenomena in nature reflect levels of openness and caring). This paper briefly explains the origin and implications of the loving openness meta-world hypothesis for understanding mind-body healing in medicine, the reordering of values in integrative medicine (with a primary focus on caring with humility), and the fostering of a new vision for twenty-first century frontier science, spirituality, and medicine.     

Portal blood flow and liver regeneration in auxiliary partial orthotopic liver transplantation in a canine model

Functional competition has been shown to lead to a detrimental outcome in auxiliary liver transplantation. We evaluated the interaction in auxiliary partial orthotopic liver transplantation between the native liver and the graft in terms of portal flow and regeneration. The need for diversion of the portal flow to the graft was also assessed. Reduced-size liver grafts were transplanted orthotopically after partial hepatectomy in beagles. There were two groups: the preserved group, where portal inflow to the native liver was preserved, and the ligated group, where it was interrupted. Portal flow was measured serially and liver regeneration was evaluated on postoperative day 5. Functional competition was not observed in the preserved group. On the other hand, ligation of the native liver portal vein had no obviously detrimental effects on the remnant native liver. This leads to the conclusion that the portal vein to the native liver can be safely ligated to prevent functional competition.     

The incidence of T2-weighted MR imaging signal abnormalities in the brain of cocaine-dependent patients is age-related and region-specific.

BACKGROUND AND PURPOSE: Cocaine and its metabolites can produce vasospasm, and cocaine-dependent patients are at increased risk for stroke. Based on previous case reports, we hypothesized that the incidence of hyperintense brain lesions observed on T2-weighted MR images would also be increased in asymptomatic cocaine-dependent individuals. METHODS: Sixty-two male "crack" (smoked) cocaine-dependent participants ranging in age from 25 to 66 years were compared with 116 normal male control participants ranging in age from 25 to 80 years. Those with histories of neurologic symptoms or illnesses were excluded. The severity of hyperintense lesions was rated on a 0- to 3-point scale, and ratings of 3 were used in the data analysis as an indicator of a probable pathologic process. Three regions were separately rated: the cerebral white matter, insular subcortex white matter, and subcortical gray matter (basal ganglia and thalamus region). RESULTS: Significantly increased risk of severe lesions was observed in the two white matter regions of the cocaine-dependent group (odds ratio of 16.7 and 20.3) but not in the subcortial gray matter region (odds ratio of 1.4). In the insula subcortex white matter, the risk of lesions increased with age in the cocaine-dependant sample, but remained essentially absent among normal controls through the age of 80 years. In the cerebral white matter, the relationship of age and risk of lesion among normal participants was similar in shape to that in cocaine-dependent participants, but equivalent risk was seen 20 years earlier among cocaine-dependent participants. CONCLUSIONS: Cocaine-dependent participants had a significantly increased age-related risk of white matter damage. The possible clinical implications of this damage are discussed.     

Ischemic preconditioning attenuates functional, metabolic, and morphologic injury from ischemic acute renal failure in the rat

Ischemic preconditioning has been shown to ameliorate injury due to subsequent ischemia in several organs. However, relatively little is known about preconditioning and the kidney. To address this, rats were randomized to control (C, N = 14), 2 min of ischemic preconditioning (P2 N = 10), 3 periods of 2 min of ischemia separated by 5 min periods of reflow (P2,3 N = 7), or three 5 min periods of ischemia separated by 5 min of reflow (P5,3 N = 6) prior to 45 min of bilateral renal ischemia followed by 24 hours of reperfusion. We observed a lower serum creatinine after 24 hours of reflow in P2, P2, 3 but not P5, 3 rats compared with C. Histology was examined in the C and P2, 3 groups and demonstrated less severe injury in the P2, 3 group. To gain insight into the mechanism by which preconditioning ameliorated ischemic injury, we performed near IR spectroscopy and 31P NMR spectroscopy. Based on near IR spectroscopy, the P2, 3 group had closer coupling of cytochrome aa3 redox state with that of hemoglobin during reflow. In the 31P NMR studies, the changes in ATP and pHi were similar during ischemia, but the P2, 3 group recovered ATP and pHi faster than C. These data suggest that ischemic preconditioning may ameliorate ischemic renal injury as assessed by functional, metabolic and morphological methods. The mechanism(s) by which this occurs requires additional study.