Pharmacokinetics of raltegravir in individuals with UGT1A1 polymorphisms.

Raltegravir is a human immunodeficiency virus-1 (HIV-1) integrase strand transfer inhibitor metabolized by glucuronidation via UDP-glucuronosyltransferase 1A1 (UGT1A1). In this study, 30 subjects with a UGT1A1*28/*28 genotype (associated with decreased activity of UGT1A1) and 27 UGT1A1*1/*1 control subjects (matched by race, age, gender, and body mass index) received a single 400-mg dose of raltegravir after fasting. No serious adverse experiences were reported, and there were no discontinuations due to adverse experiences. The geometric mean ratio (GMR) (UGT1A1*28/*28 to UGT1A1*1/*1) and 90% confidence interval (CI) were 1.41 (0.96, 2.09) for raltegravir area under the concentration-time curve (AUC(0-infinity)), 1.40 (0.86, 2.28) for maximum plasma concentration (C(max)), and 1.91 (1.43, 2.55) for concentration at the 12-h time point (C(12 h)). No clinically important differences in time to maximum concentration (T(max)) or half-life were observed. Plasma concentrations of raltegravir are modestly higher in individuals with the UGT1A1*28/*28 genotype than in those with the UGT1A1*1/*1 genotype. This increase is not clinically significant, and therefore no dose adjustment of raltegravir is required for individuals with the UGT1A1*28/*28 genotype.

Comparative efficacy and tolerability of two long-acting calcium antagonists, mibefradil and amlodipine, in essential hypertension. Mibefradil Hypertension Study Group.

In a previous forced-titration trial, mibefradil 100 mg QD was as effective as amlodipine 10 mg QD in reducing sitting diastolic blood pressure (SDBP), and it produced significantly less leg edema than did amlodipine 10 mg QD. The present multicenter, double-masked, randomized, parallel-design trial was performed to assess the reproducibility of these results using a flexible-titration design. Following a 4-week, single-masked, placebo run-in period, 296 patients with a trough SDBP of between 95 and 114 mm Hg (21 to 27 hours postdose) were randomized to receive once-daily treatment with mibefradil 50 mg (n = 146) or amlodipine 5 mg (n = 150). In patients whose trough SDBP was greater than 90 mm Hg after 4 or 8 weeks of double-masked therapy, the dosage was titrated upward to mibefradil 100 mg or amlodipine 10 mg for the remainder of the 12-week active treatment period. A greater proportion of amlodipine-treated patients (65%) than of mibefradil-treated patients (54%) required titration to the higher dose. Despite this difference, statistically equivalent reductions in trough SDBP were observed after 12 weeks of treatment with 50 to 100 mg of mibefradil QD (-11.7 +/- 6.4 mm Hg) and 5 to 10 mg of amlodipine QD (-11.9 +/- 6.9 mm Hg). SDBP was normalized to < or = 90 mm Hg at week 12 in 66% of patients treated with mibefradil and 65% of those receiving amlodipine. The tolerability profile of mibefradil was superior to that of amlodipine, with significantly fewer patients (P = 0.009) reporting leg edema after mibefradil treatment (7%) than after amlodipine treatment (17%). The results of this study confirm those of the previous trial. Once-daily treatment with mibefradil 50 to 100 mg for 12 weeks was as effective as 12 weeks of once-daily treatment with amlodipine 5 to 10 mg in reducing SDBP and was associated with a significantly lower incidence of leg edema.

Successful use of cuffed central venous hemodialysis catheters inserted percutaneously.

Although endogenous fistulae and grafts are preferred for permanent hemodialysis access, central venous catheters are often required for varying intervals when creating permanent access is not feasible. The prospective experience with 118 catheters in over a 3.5-yr period is reported; 93 (79%) were placed by percutaneous techniques, and 25 (21%) were placed by operative techniques. Seventy seven catheters (65%) were placed in the subclavian vein, 36 (31%) were placed in the internal jugular vein (usually right side), and 5 (4%) were placed in the femoral vein. Early postplacement complications were infrequent. Catheter function at last local follow-up ranged from several days to nearly 2 yr, averaging approximately 3 mo, even though many patients returned to their referring centers with a functioning catheter after only a short follow-up. Actuarial survival for percutaneously placed catheters was approximately 60% at 6 mo and 30% at 12 mo. Catheter failure occurred in 36% of cases, equally divided between malfunction (thrombosis refractory to fibrinolysis, extrusion, kinking, or related event) and infection with septicemia requiring removal. Such failure was not more frequent after percutaneous placement than after operative placement. Failure due to mechanical malfunction, but not that due to infection, tended to be less frequent among catheters placed in the internal jugular vein than among catheters placed in the subclavian vein. Finally, infection with septicemia involved 22% of all catheters and occurred at an average cumulated rate of approximately one infection per patient-year. Coagulase-positive staphylococcus was the most common organism isolated.(ABSTRACT TRUNCATED AT 250 WORDS)

Unusual causes of peritonitis in patients undergoing continuous peritoneal dialysis with emphasis on Listeria monocytogenes.

Peritonitis remains a significant cause of morbidity in ESRD patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Staphylococcus species, Streptococcus species, and less commonly, gram-negative rods comprise the majority of isolated organisms. Other organisms, including unusual bacteria, fungi, and mycobacteria, comprise 5% or less of cases. Many of the uncommon causes of CAPD peritonitis have been reviewed, with special emphasis on antimicrobial therapy and whether catheter removal was required. The presumed third case of CAPD-associated peritonitis caused by Listeria monocytogenes is also described. In contrast to two other reported cases, our patient was not overtly immunosuppressed. L. monocytogenes infection should therefore be considered in CAPD patients with gram-positive rod peritonitis, even if immunocompetence is presumed.

Comparison of mortality risk by choice of CAPD versus hemodialysis among elderly patients.

To evaluate patient survival among geriatric patients by dialytic treatment of choice we assigned all patients aged 65 years and older treated in Michigan to either CAPD at home or center hemodialysis (HD) according to the treatment used on day 120 of ESRD therapy. Michigan Kidney Registry files on all 308 CAPD and 1244 HD patients who started ESRD therapy during 1980-1987 were used for this study. The Cox proportional hazards model revealed a significantly increased relative death rate (RR) for patients with diabetes (RR = 1.91, p less than 0.001) and hypertension (RR 1.4, p less than 0.01) as cause of ESRD when adjusting for age, sex, race, treatment and year of incidence. White patients had a 51% higher relative death rate overall when compared to black patients (p less than 0.001) and specifically among hypertensive (RR = 1.65, p less than 0.001) and diabetic patients (RR = 1.59, p less than 0.001). Those differences were still significant when taking higher rates of withdrawal from dialysis among white patients into account. The relative death rates for CAPD patients was essentially the same as for HD patients overall, however, diabetic CAPD patients appeared to have a higher than diabetic HD patients (RR = 1.58, p = 0.1). This statistically not significant difference may be related to selection of patients with cardiovascular risk into CAPD. There was no trend in mortality over time. By modality on day 120, CAPD has similar outcomes as HD in geriatric non diabetic patients.

Increased monocyte chemiluminescence in cystic fibrosis patients and in their parents.

We examined the chemiluminescence response of peripheral blood monocytes from patients with cystic fibrosis (CF) and their asymptomatic parental carriers of the CF gene to three different types of stimulation. We found that monocytes from both patients and carriers have increased luminol-dependent chemiluminescence in the first 25 min after stimulation by adherence to glass. These results are consistent with the hypothesis that monocytes from both CF heterozygotes and homozygotes respond to adhesion with increased oxygen radical formation. The increased adherence-induced monocyte chemiluminescence of the parental carriers did not vary with age or length of exposure of the parents to a child with CF. Also, repeated exposure to medications and respiratory secretions of CF patients was not associated with an increase in adherence-induced monocyte chemiluminescence of their nonbiologically related caretakers. Thus, this observed increase in chemiluminescence is not simply secondary to the medications or respiratory dysfunction seen in the patients with CF. Patients with other types of obstructive lung disease did not show increased adherence-induced monocyte chemiluminescence. We conclude that increased early phase adherence-induced monocyte chemiluminescence occurs in patients with cystic fibrosis and the obligate carriers of the CF gene independent of environmental influences.