Publications

Nonrenal clearance of drugs can be significantly lower in patients with end-stage renal disease (ESRD) than in those with normal renal function. Using erythromycin (ER) as a probe compound, we investigated whether this decrease in nonrenal clearance is due to reduced hepatic clearance (CL(H)) and/or gut metabolism. We also examined the potential effects of the uremic toxins 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and indoxyl sulfate (Indox) on ER disposition. Route-randomized, two-way crossover pharmacokinetic studies of ER were conducted in 12 ESRD patients and 12 healthy controls after oral (250 mg) and intravenous (125 mg) dosing with ER. In patients with ESRD, CL(H) decreased 31% relative to baseline values (0.35 +/- 0.14 l/h/kg vs. 0.51 +/- 0.13 l/h/kg, P = 0.01), with no change in steady-state volume of distribution. With oral dosing, the bioavailability of ER increased 36% in patients with ESRD, and this increase was not related to changes in gut availability. As expected, plasma levels of CMPF and Indox were significantly higher in the patients than in the healthy controls. However, no correlation was observed between CL(H) of ER and the levels of uremic toxins.

Therapies for hepatitis B virus (HBV) have continued to evolve, and new therapies for hepatitis C virus (HCV) will soon be available in clinical practice. These medications for hepatitis C will mark the first time that direct antivirals that target HCV functions have been used. When such drugs are used as single agents, previously existing mutants with reduced susceptibility to them are rapidly selected. The relationship between these drug-resistant mutants and "wild-type" virus is unclear, but resistant strains likely have the potential to maintain the progression of liver disease despite successful treatment of "wild-type" virus. Resistant HBV and now HCV are already a clinical problem. The same issue was recognized very early in the development of therapy against HIV, with azidothymidine-resistant mutants detected within the first weeks of therapy. Clinical investigation and a progressive understanding of the pathogenesis of the disease overcame this challenge and led to the substantial and durable benefits of antiretroviral therapy that are evident today. To bring experts from the fields of HIV and viral hepatitis virology and therapy together for interactive discussions about how to apply the lessons from HIV to the further development of viral hepatitis therapy, the American Association for the Study of Liver Diseases held a single-topic conference entitled "Viral Hepatitis Therapy: Lessons to be Learned From HIV" on 24-26 July 2008. This article summarizes that conference.

OBJECTIVES

To define the frequency of post-traumatic stress disorder (PTSD)-related symptoms among veterans who are near the end of life and to describe the impact that these symptoms have on patients and their families.

METHODS

Patients had received inpatient or outpatient care from a participating VA facility in the last month of life, and one family member per patient was selected using predefined eligibility criteria. Family members then completed a telephone survey, The Family Assessment of Treatment at End-of-Life, which assessed their perceptions of the quality of the care that the patients and they themselves received during the patients' last month of life.

RESULTS

Seventeen percent of patients (89 of 524) were reported to have had PTSD-related symptoms in the last month of life. PTSD-related symptoms caused discomfort less often than pain did (mean frequency score 1.79 vs. 1.93; Wilcoxon sign rank test, P<0.001) but more often than dyspnea did (mean severity score 1.79 vs. 1.73; Wilcoxon sign rank test, P<0.001). Family members of patients with PTSD-related symptoms reported less satisfaction overall with the care the patient received (mean score 48 vs. 62; rank sum test, P<0.001). Patients who received a palliative care consult (n=49) had lower ratings of discomfort attributed to PTSD-related symptoms (mean 1.55 vs. 2.07; rank sum test, P=0.007).

CONCLUSION

PTSD-related symptoms may be common and severe among veterans near the end of life and may have a negative effect on families' perceptions of the quality of care that the veteran received.

Colonization of the infant gut by microorganisms over the first year of life is crucial for development of a balanced immune response. Early alterations in the gastrointestinal microbiota of neonates has been linked with subsequent development of asthma and atopy in older children. Here we describe high-resolution culture-independent analysis of stool samples from 6-month old infants fed daily supplements of Lactobacillus casei subsp. Rhamnosus (LGG) or placebo in a double-blind, randomized Trial of Infant Probiotic Supplementation (TIPS). Bacterial community composition was examined using a high-density microarray, the 16S rRNA PhyloChip, and the microbial assemblages of infants with either high or low LGG abundance were compared. Communities with high abundance of LGG exhibited promotion of phylogenetically clustered taxa including a number of other known probiotic species, and were significantly more even in their distribution of community members. Ecologically, these aspects are characteristic of communities that are more resistant to perturbation and outgrowth of pathogens. PhyloChip analysis also permitted identification of taxa negatively correlated with LGG abundance that have previously been associated with atopy, as well as those positively correlated that may prove useful alternative targets for investigation as alternative probiotic species. From these findings we hypothesize that a key mechanism for the protective effect of LGG supplementation on subsequent development of allergic disease is through promotion of a stable, even, and functionally redundant infant gastrointestinal community.

BACKGROUND

HIV protease inhibitors have been shown to worsen glucose and lipid metabolism. Recent studies have suggested that protease inhibitors can impair insulin secretion in HIV-infected patients. We studied the effects of the protease inhibitor combination lopinavir and ritonavir on insulin secretion, insulin sensitivity, and lipid metabolism in HIV-negative persons.

METHODS

A combination dose of lopinavir 400 mg and ritonavir 100 mg was given twice daily to eight HIV-seronegative men for 4 weeks. Fasting glucose, insulin, lipid, and lipoprotein profiles; oral glucose tolerance; insulin secretion and insulin-mediated glucose disposal by hyperglycemic clamp; and body composition by dual energy X-ray absorptiometry were determined before and after lopinavir/ritonavir administration.

RESULTS

There was no change in first-phase insulin secretion (2.82 +/- 0.30 versus 2.71 +/- 0.31 nmol/l; P = 0.60), as well as fasting insulin and glucose levels, oral glucose tolerance, or insulin-mediated glucose disposal after 4 weeks administration of lopinavir/ritonavir. However, there were significant increases in fasting triglycerides (1.02 +/- 0.13 versus 2.20 +/- 0.31 mmol/l; P = 0.001), total cholesterol (4.42 +/- 0.30 versus 5.70 +/- 0.60 mmol/l; P = 0.007), and apo B-100 levels (0.86 +/- 0.07 versus 1.07 +/- 0.11 g/l; P = 0.0009). High-density lipoprotein cholesterol decreased (0.99 +/- 0.11 versus 0.82 +/- 0.10 mmol/l; P = 0.005). There were no changes in body composition, weight, or body fat.

CONCLUSION

Although administration of lopinavir/ritonavir to healthy, HIV-seronegative volunteers for 4 weeks resulted in increased triglyceride and decreased high-density lipoprotein cholesterol levels, there was no change in first-phase insulin secretion during the hyperglycemic clamp. The reported effects of protease inhibitor on insulin secretion in HIV-infected individuals may be due to changes in HIV-related factors and not a direct drug effect.