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Background and Objectives Catheter-related infection, namely exit-site infection (ESI) and peritonitis, is a major infectious complication and remains a main cause of technique failure for patients receiving peritoneal dialysis (PD). Topical application of antibiotic cream might reduce catheter-related infection but emergence of resistant or opportunistic organisms could be a concern. Optimal topical agents and regimens remain to be determined. We did a study to examine the effect of an alternating topical antibiotic regimen in preventing catheter-related infection.Method We performed a single-center, randomized, open-label study to compare daily topical application of gentamicin cream with a gentamicin/mupirocin alternate regimen to the exit site. Patients randomized to alternating regimen were asked to have daily application of gentamicin cream in odd months and mupirocin cream in even months. Primary outcomes were ESI and peritonitis. Secondary outcomes were catheter removal or death caused by catheter-related infection. A total of 146 patients (71, gentamicin group; 75, alternating regimen group) were enrolled with a total follow-up duration of 174 and 181 patient-years for gentamicin and alternating groups, respectively. All patients were followed up until catheter removal, death, transfer to another unit, transplantation or the end of the study on March 31, 2014. There were no significant differences in the age, sex, dialysis vintage, and rate of diabetes, helper-assisted dialysis and methicillin-resistant Staphylococcus aureus(MRSA) carriage state.Results No difference was seen in the time to first ESI or peritonitis. However, the time to first gram-negative peritonitis seemed longer for the gentamicin group (p= 0.055). The 2 groups showed a similar rate of ESI (0.17/yr vs 0.19/yr, p= 0.93) but P. aeruginosaESI was less common in the gentamicin group (0.06/yr vs 0.11/yr, p< 0.001). There was no difference in the incidence of ESI due to non-tuberculous mycobacteria. Peritonitis rate was significantly lower in the gentamicin group (0.22/yr vs 0.32/yr, p< 0.001), with a striking decrease in gram-negative peritonitis (0.08/yr vs 0.14/yr, p< 0.001), and fungal peritonitis (0.006/yr vs 0.03/yr, p< 0.001), which was all antibiotics-related episodes with antecedent use of systemic antibiotics for the treatment of catheter-related infections. There was no significant difference in the catheter loss or death related to catheter-related infection.Conclusion Alternating gentamicin/mupirocin cream application appeared as effective as gentamicin alone in preventing ESI except for P. aeruginosa. However, it was inferior to gentamicin in the prevention of peritonitis episodes, especially for those caused by gram-negative organisms. It was also not useful in reducing catheter-related infection due to opportunistic organisms but instead associated with a higher incidence of antibiotic-related fungal peritonitis.

Background Encapsulating peritoneal sclerosis (EPS) is the most serious complication of peritoneal dialysis, having high morbidity and mortality. To improve outcomes, early diagnosis is needed to direct treatment during the early inflammatory phase. However, in the early inflammatory phase, clinical features are nonspecific, and no reliable diagnostic criteria have been established. Because bacterial peritonitis and termination of dialysis are two important risk factors triggering the progression of EPS, patients with refractory bacterial peritonitis necessitating dialysis catheter removal are at particularly high risk of developing EPS. Many of these patients might indeed experience non-resolving sterile peritonitis (probably the inflammatory phase of EPS) before progression to full-blown disease (that is, the presence of intestinal obstruction). We undertook a retrospective study to compare, in this particular situation, the clinical characteristics of patients with or without sterile peritoneal inflammation, assessing their clinical outcomes in terms of short-term mortality and the chance of developing full-blown EPS.Methods Our retrospective review included 62 patients whose dialysis catheter was removed because of refractory peritonitis between January 2005 and December 2010.Results Of the 62 patients identified, 39 (63%) had persistent sterile peritoneal inflammation (“high-risk” group, n= 39), and 23 (37%) had resolution of inflammation without significant intra-abdominal collection after catheter withdrawal (“control” group, n= 23). Compared with the control group, the high-risk group had a significantly longer PD duration (71.6 ± 43.3 months vs 42.3 ± 29.9 months, p= 0.003), a higher dialysate-to-plasma ratio (D/P) of creatinine (0.768 ± 0.141 vs 0.616 ± 0.091, p= 0.004), and a higher computed tomography score for EPS (7.69 ± 2.98 vs 1.00 ± 1.00, p< 0.001). During the 6-month study period, the high-risk group had a higher chance of developing full-blown EPS (31% vs 0%, p= 0.002) and a higher 6-month all-cause mortality (36% vs 4.3%, p= 0.004)Conclusions Persistent sterile peritoneal inflammation was common after dialysis catheter removal for refractory bacterial peritonitis, and the patients with such inflammation were at high risk of progression to full-blown EPS.

We report 9 cases of exit-site infection and continuous ambulatory peritoneal dialysis peritonitis associated with atypical mycobacteria. All patients had been using topical gentamicin cream as prophylaxis for exit-site infection before the onset of these infections. Gentamicin cream is postulated to be a potential risk factor for atypical mycobacterial infection because of selective pressure on other micro-organisms. The microbiology of atypical mycobacteria and the treatment for atypical mycobacterial infections are discussed.

Background Fungal peritonitis (FP) is associated with significant mortality and high risk of peritoneal failure. The optimum treatment for peritoneal dialysis (PD)-associated FP remains unclear. Since January 2000 we have been treating FP with a combination of intravenous amphotericin B and oral flucytosine, together with deferred catheter replacement. We examined the clinical course and outcome of the FP patients treated with this approach (study group). An outcome comparison was also made to an alternatively treated historic cohort (control group).Methods This was a single-center retrospective study. The clinical course and outcome of 13 consecutive episodes of FP occurring in 13 patients treated between January 2000 and April 2005 with the study approach were examined. The patients were treated with an incremental dose of intravenous amphotericin B to a target dose of 0.75 – 1 mg/kg body weight/day, and oral flucytosine 1 g/day upon a diagnosis of FP at 3.77 ± 0.93 days from presentation. Replacement of the peritoneal catheter was intended after complete clearing of effluent, after which, antifungal chemotherapy was continued for another 1 – 2 weeks. Their outcome was compared with 14 historic controls that were treated between April 1995 and December 1999.Results Mean age of the study group was 58.7 ± 13.2 years; male-to-female ratio was 2:11; 6 (46.1%) were diabetic. All FP were caused by Candidaspecies (C. albicans, 2; C. parapsilosis, 8; C. glabrata, 3). Two (15.4%) patients died before resolution of the peritonitis. The dialysate effluent cleared in 11 patients (84.6%) after 13.2 ± 3.3 days of treatment, but 2 patients died of acute myocardial infarction before catheter replacement. Nine patients had their catheters replaced at day 26.7 ± 7.7 of treatment; all 9 returned to PD after a total of 31 ± 12.2 days of antifungal chemotherapy. Reversible liver dysfunction was common with this regimen. When compared with the 14 cases in the historic control group (Candidaspecies, 13; Trichosporon, 1), who were treated with amphotericin B, fluconazole, or a combination of the two, and the majority (78.6%) of whose catheters were removed before day 10 of presentation, the study group appeared to have a lower technique failure rate (30.8% vs 78.6%, p= 0.013) and similar all-cause mortality (30.7% vs 28.5%, p= NS), FP-related mortality (15.4% vs 28.5%, p= NS), and length of hospitalization (48.5 ± 30.2 vs 57.0 ± 37.7 days, p= NS). However, a significantly earlier commencement of antifungal treatment in the study group (3.8 ± 0.9 vs 5.8 ± 2.4 days, p= 0.012) could be an important confounder of outcome.Conclusions Combination of intravenous amphotericin B and oral flucytosine with deferred catheter replacement appears to be associated with a relatively low incidence of PD technique failure, without affecting mortality in patients suffering from FP due to yeasts in this preliminary study. Nonetheless, drug-induced hepatic dysfunction was common; close monitoring during treatment is of paramount importance. The reasons accounting for the observed distinctive outcome remain unclear and further study is required to confirm the results and to investigate for the underlying mechanism.

Objective Fungal peritonitis (FP) is a serious complication of continuous ambulatory peritoneal dialysis (CAPD), being associated with significant morbidity and mortality. The role of nystatin prophylaxis during antibiotic therapy in the prevention of FP remains controversial, especially in programs with a modest or low baseline FP rate. The aim of the present study was to evaluate the effect of nystatin prophylaxis on the occurrence of FP in programs with a relatively modest baseline FP rate.Patients and Methods Incident and prevalent patients receiving CAPD between April 1995 and April 2005 at our center were included and divided into 2 groups. The control group included 320 patients (total follow-up 8875 patient-months) being treated without nystatin before October 1999; the nystatin group included 481 patients (total follow-up 13725 patient-months) being treated after October 1999. Nystatin tablets (500000 units, 4 times per day) were given orally during whatever use of antibiotics to cover the whole course of antibiotic therapy. Occurrence of FP and antibiotic-related FP (AR-FP) in patients with and without nystatin prophylaxis was compared.Results The two groups were of similar age but the nystatin group had a significantly higher percentage of diabetics. In addition, the nystatin group had a higher proportion of patients using disconnecting twin-bag exchange systems and had a significantly lower peritonitis rate compared with the control. There were 13 and 14 episodes of FP in the nystatin and control groups respectively. The fungal peritonitis rate of the nystatin group was slightly lower than that of the control group (0.011 vs 0.019 per patient-year) but it did not reach statistical significance. There was, however, a significant decrease in the incidence and proportion of AR-FP in the nystatin group compared with the control group, which persisted even after adjustment for the peritonitis rate. Kaplan–Meier analysis further demonstrated significantly better AR-FP-free survival in the nystatin group compared with the control group. No significant side effects were observed for nystatin. Subgroup analyses in patients of the 2 different connecting systems revealed a similar but nonsignificant trend toward reduction of AR-FP in patients given nystatin prophylaxis.Conclusion Oral nystatin prophylaxis might prevent the occurrence of AR-FP in CAPD patients, resulting in a trend toward reduction in the incidence of FP even in programs with a modest baseline FP rate. A large scale, prospective, randomized controlled trial is needed to further examine this issue.

Vibrio vulnificusis a marine bacterium and opportunistic human pathogen. Associated infections have contributed to the majority of seafood-related deaths in the United States. In patients with such predisposed clinical conditions as chronic liver disease, immunocompromised state, and end-stage renal disease, this organism has been associated with the development of life-threatening primary septicemia and severe wound infection. However, continuous ambulatory peritonitis dialysis (CAPD)–related peritonitis caused by V vulnificushas not been reported. We describe a patient receiving CAPD who developed peritonitis caused by V vulnificusafter handling seafood. This case highlights the importance of strict aseptic technique during CAPD exchanges and calls for an effort in educating our dialysis patients on precautions about seafood handling.

The pharmacokinetics and pharmacodynamics of 7 days of treatment with losartan 50 mg/hydrochlorothiazide 12.5 mg were evaluated in 14 patients with normal renal function and in 12 patients with mild to moderate renal impairment. The efficacy of losartan 50 mg/hydrochlorothiazide 12.5 mg titrated to losartan 100 mg/hydrochlorothiazide 25 mg was examined in 32 hypertensive patients with mild to moderate renal impairment who were treated for 12 weeks. Safety was assessed in both studies by the incidence of adverse experiences. After 7 days of treatment, the AUC for losartan, E‐3174, and hydrochlorothiazide was slightly higher in patients with mild to moderate renal impairment, but the reduction in blood pressure (BP) after 7 days was not different between the two groups. The final (week 12) mean reductions in trough sitting diastolic and systolic BP were 15.0 ± 7.1 mmHg (p< 0.01) and 20.8 ± 16.7 mmHg (p< 0.01), respectively. There were no observed increases in drug‐related adverse experiences in either study. Overall, the combination of losartan/hydrochlorothiazide was effective in lowering blood pressure and was well tolerated in patients with mild to moderate renal impairment.

Forty children with hypertension between the age of 2 months and 15 years received 0.07 to 0.14 mg/kg of enalapril as a single daily dose. Enalapril was administered orally as a novel extemporaneous suspension in children younger than 6 years of age and as tablets in older children. First‐dose and steady‐state pharmacokinetics were estimated in children ages 1 to 24 months, 25 months to < 6 years, 6 to < 12 years, and 12 to < 16 years. Maximum serum concentrations for enalapril occurred approximately 1 hour after administration. Serum concentrations of enalaprilat, the active metabolite of enalapril, peaked between 4 and 6 hours after the first dose and 3 and 4 hours after multiple doses. The area under the concentration versus time curve (AUC), adjusted for body surface area, did not differ between age groups. Based on comparison of first‐dose and steady‐state AUCs, the accumulation of enalaprilat in children ranged from 1.13‐ to 1.45‐ fold. For children ages 2 to 15 years, mean urinary recovery of total enalaprilat ranged from 58.3% in children ages 6 to < 12 years to 71.4% in children ages 12 to < 16 years. Urinary recovery for children ages 2 to < 6 years was 66.8%. The mean percentage conversion of enalapril to enalaprilat ranged from 64.7% for children ages 1 to 24 months to 74.6% for children ages 6 to < 12 years. The median effective half‐life for accumulation ranged from 14.6 hours in children ages 12 to < 16 years to 16.3 hours in children ages 6 to < 12 years. There were two serious adverse events, neither of which was attributed to enalapril or resulted in discontinuation of the study drug. The extemporaneous suspension used in this study was tolerated well. The pharmacokinetics of enalapril and enalaprilat in hypertensive children ages 2 months to 15 years with normal renal function appears to be similar to that previously observed in healthy adults.

The angiotensin‐converting enzyme (ACE) inhibitor enalapril is commonly used to treat pediatric hypertension.Because some children are unable to swallow tablets or require doses less than the lowest available enalapril tablet, an enalapril suspension was developed. This study examined the relative bioavailability of enalapril suspension (10 mg) (S) compared with 10‐mg marketed VASOTEC™ tablets (T) in 16 healthy adult subjects. The geometric mean ratio (S/T) estimate of urinary recovery of free enalaprilat, the active moiety, was 0.92 (90% confidence interval (CI): 0.80, 1.07). Urinary recovery data indicate that approximately 50% of the dose was absorbed (50% recovered in urine as enalapril plus enalaprilat) with about 30% of the dose recovered as free enalaprilat for both S and T. The geometric mean ratios (S/T) of serum AUC and Cmaxwere 1.01 (90% CI: 0.90, 1.13) and 0.98 (90% CI: 0.83, 1.16), respectively. Suspension Tmaxwas slightly shorter (0.5 h) than that for tablet, but this difference is not clinically significant. Both formulations were well tolerated and there were no clinically significant adverse experiences. We conclude that the bioavailability of enalapril oral suspension 10‐mg is similar to that of VASOTEC™ 10‐mg tablet. Instructions for compounding enalapril are provided. Copyright © 2000 John Wiley & Sons, Ltd.

The angiotensin-converting enzyme (ACE) inhibitor enalapril is commonly used to treat pediatric hypertension. Because some children are unable to swallow tablets or require doses less than the lowest available enalapril tablet, an enalapril suspension was developed. This study examined the relative bioavailability of enalapril suspension (10 mg) (S) compared with 10-mg marketed VASOTEC™ tablets (T) in 16 healthy adult subjects. The geometric mean ratio (S/T) estimate of urinary recovery of free enalaprilat, the active moiety, was 0.92 (90% confidence interval (CI): 0.80, 1.07). Urinary recovery data indicate that approximately 50% of the dose was absorbed (50% recovered in urine as enalapril plus enalaprilat) with about 30% of the dose recovered as free enalaprilat for both S and T. The geometric mean ratios (S/T) of serum AUC and Cmax were 1.01 (90% CI: 0.90, 1.13) and 0.98 (90% CI: 0.83, 1.16), respectively. Suspension Tmax was slightly shorter (0.5 h) than that for tablet, but this difference is not clinically significant. Both formulations were well tolerated and there were no clinically significant adverse experiences. We conclude that the bioavailability of enalapril oral suspension 10-mg is similar to that of VASOTEC™ 10-mg tablet. Instructions for compounding enalapril are provided. Copyright © 2000 John Wiley & Sons, Ltd.

The Food and Drug Administration (FDA) issued a second‐draft guidance in August 1999 on the subject of in vivo bioequivalence, which is based on the concepts of individual and population bioequivalence (IBE and PBE, respectively). The intention of this guidance is to replace the 1992 guidance that requires that in vivo bioequivalence be demonstrated by average bioequivalence (ABE). Although the concepts of population and individual bioequivalence are intuitively reasonable, a detailed review of the literature has not uncovered clinical evidence to justify the additional burden to the innovator and generic companies as well as the consumer that the new guidelines would impose. The criteria for bioequivalence described in the draft guidance employ aggregate statistics that combine information about differences in bioavailability between formulation means and differences in bioavailability variation of formulations between and within subjects. The purely technical aspects of the statistical approach are reasonably sound. However, PhRMA believes that important operational issues remain that need to be resolved before any changes to current practice are implemented. PhRMA believes that the ideals of prescribability and switchability are intuitively reasonable, but it is uncertain of the extent to which the proposed guidance can achieve these goals. It is not clear whether the attainment of such goals is necessary in the evaluation of bioequivalence given the role this plays in drug development, and the lack of clinical evidence argues against a pressing need to change current practice. PhRMA is concerned that the trade‐off offered by the aggregate criteria may ultimately represent more harm than good to the public interest. PhRMA recommends more rigorous evaluation of methods based on two‐way crossover designs before moving to methods that require more complex designs. One such method is identified herein and contains procedures for estimating prescribability and switchability. The possibility of a phase‐in or trial period to collect replicate crossover data to further evaluate IBE and PBE and possibly allow market access based on these criteria as they are being evaluated has been proposed. PhRMA believes this is unprecedented and will offer little additional information beyond that which can be obtained by simulation or has already been collected by the FDA. Simulation studies have the advantage of allowing evaluation of the sensitivity of various procedures to represent the data patterns as created within the simulation. Operating characteristics by which proposed criteria can be adequately judged have not yet been defined. The limitations of ABE for highly variable drugs and narrow therapeutic drugs are well appreciated and may be addressed by means other than a wholesale change in the current criteria.

The pharmacokinetics of a selective AT1‐subtype, nonpeptide, orally active, angiotensin II receptor antagonist, losartan, were characterized in 11 patients with heart failure (New York Heart Association class II, n = 6; class III, n = 4; class IV, n = 1) after oral and intravenous administration. In these patients, average plasma clearance of losartan was 566 mL/min, volume of distribution at steady‐state was 34 L, and terminal plasma half‐life was 1.5 hours. Average bioavailability was 36%. No clinically significant accumulation of losartan or its active metabolite, EXP3174, occurred after multiple‐dose oral administration for 7 to 8 days. Terminal plasma half‐life of EXP3174 after oral administration of losartan was 7.6 hours. The pharmacokinetics of losartan in patients in this study appear to be similar to those in healthy subjects studied previously.

To support the use of a combination of losartan, a highly specific and selective AT1angiotensin II receptor antagonist, and hydrochlorothiazide for treatment of hypertension, a pharmacokinetic drug interaction study was conducted. In this open‐label, randomized, three‐period, crossover study, patients with mild to moderate hypertension received a 12.5‐mg tablet of hydrochlorothiazide, a 50‐mg losartan tablet, or a combination tablet of 12.5 mg of hydrochlorothiazide and 50 mg of losartan for 7 days. Twelve patients (age range, 35–55 years; mean age, 44 years) were allocated to treatment. Drug interactions were evaluated by comparing the 24‐hour area under the concentration‐time curve (AUC24) for losartan and its active metabolite, E‐3174, when losartan (50 mg) was given alone or in combination with 12.5 mg hydrochlorothiazide. The urinary recovery over the 24‐hour period of hydrochlorothiazide was compared for hydrochlorothiazide (12.5 mg) given alone or in combination with 50 mg losartan. A clinically significant interaction was defined as a treatment difference of more than 35%. There was no evidence of a clinically significant effect of hydrochlorothiazide on the pharmacokinetics of losartan or E‐3174, as the geometric mean AUC24ratio (90% confidence interval [CI]) was 1.02 (0.95, 1.09) for losartan and 1.02 (0.96, 1.09) for E‐3174. Based on urinary recovery over a 24‐hour period of hydrochlorothiazide, losartan did not affect the pharmacokinetics of hydrochlorothiazide, as the geometric mean ratio of urinary hydrochlorothiazide recovery (90% CI) was 0.898 (0.79, 1.20). There was a minor (17%) decrease in the AUC24of hydrochlorothiazide after administration of the combination tablet. Coadministration of hydrochlorothiazide and losartan was well tolerated.

The pharmacokinetics of intravenous and oral nalbuphine were studied in 24 healthy male volunteers ranging in age from 21 to 30 years. On separate test days over a five‐week period, subjects received single doses of each of four different formulations of nalbuphine, with a one‐week washout period between treatments: 10 mg intravenously administered over two minutes, 45 mg orally given as a solution, and 45 mg orally administered in two tablet formulations (formulation A and formulation B). Blood samples were collected over 48 hours postadministration, and plasma nalbuphine concentrations were determined by reversed‐phase high‐performance liquid chromatography (HPLC) with electrochemical detection. The mean nalbuphine plasma concentration five minutes after 10 mg intravenously was 53 ng/mL, and the half‐life of nalbuphine with this route of administration was 2.3 hours, In contrast, mean maximum nalbuphine concentrations (Cmax) after the three orally administered preparations ranged from 14.4 to 15.5 ng/mL, and occurred 0.9 to 1.2 hours after dose administration. Mean elimination half‐lives after administration of the three nalbuphine oral formulations were essentially identical, ranging from 6.9 to 7.7 hours. Nalbuphine plasma concentration curves decayed biexponentially regardless of route of administration or type of formulation. Absolute bioavailability of the orally administered forms of nalbuphine ranged from 16.4 to 17.4% and Cmaxand AUC data further established the bioequivalence of the three oral formulations. The low absolute bioavailability and prolonged elimination half‐life of nalbuphine associated with oral administration are likely due to extensive first‐pass metabolism and enterohepatic circulation, respectively.

The pharmacokinetics of the angiotensin II receptor antagonist losartan potassium and its active carboxylic acid metabolite EXP3174 were characterized in 18 healthy male subjects after administration of intravenous losartan, intravenous EXP3174, and oral losartan. In these subjects, the average plasma clearance of losartan was 610 ml/min, and the volume of distribution was 34 L. Renal clearance (70 ml/min) accounted for 12% of plasma clearance. Terminal half-life was 2.1 hours. In contrast, the average plasma clearance of EXP3174 was 47 ml/min, and its volume of distribution was 10 L. Renal clearance was 26 ml/min, which accounted for 55% of plasma clearance; terminal half-life was 6.3 hours. After oral administration of losartan, peak concentrations of losartan were reached in 1 hour. Peak concentrations of EXP3174 were reached in 312 hours. The area under the plasma concentration-time curve of EXP3174 was about four times that of losartan. The oral bioavailability of losartan tablets was 33%. The low bioavailability was mainly attributable to first-pass metabolism. After intravenous or oral administration of losartan the conversion of losartan to the metabolite EXP3174 was 14%.

We investigated the tolerability and angiotensin II antagonist activity of oral DuP 532 in healthy male subjects. DuP 532 (1 to 200 mg) was well tolerated, with no effect on blood pressure or heart rate. Compared with losartan (100 mg), DuP 532 (200 mg) was a weak antagonist of pressor responses to intravenous angiotensin II. Maximum inhibition of diastolic pressor response was 86% (95% confidence interval [CI], 84%, 88%) approximately 4.6 hours after losartan and 48% (95% CI, 38%, 56%) 8.7 hours after DuP 532. Twenty-four hours after dosing, inhibition by losartan and DuP 532 was similar (40% to 45%). DUP 532 is extensively bound in human plasma, with an in vitro free fraction of 0.06. Although DuP 532 and EXP3174 (losartan's active metabolite) have similar AT1-receptor potency, and plasma concentrations of DuP 532 were much greater than losartan/EXP3174, the level of antagonism was much less for DuP 532. These results indicate that multiple factors determine the in vivo potency of angiotensin II antagonists, including affinity for and distribution to the receptor as modulated by plasma binding.

Losartan, a selective angiotensin II (AT1) receptor antagonist for hypertension, is metabolized to an active carboxylic acid metabolite, E-3174, which has a longer half-life. To investigate the effects of induction of cytochrome P450 on the metabolism of losartan, we evaluated the effects of phenobarbital on the plasma profiles of losartan and E-3174 in 15 healthy male subjects. Ten subjects received a single 100 mg oral dose of losartan before and during phenobarbital administration (100 mg/day for 16 days), and five subjects received losartan before and during placebo. Urinary excretion of 6-β-hydroxycortisol (relative to 17-hydroxycorticosteroids) was measured as an endogenous marker of cytochrome P450 induction. The geometric mean area under the plasma concentration-time curve ratios (with/without phenobarbital and 90% confidence intervals) for losartan and its metabolite (E-3174) were 0.795 (0.723, 0.875) and 0.799 (0.778, 0.820), respectively, indicating that phenobarbital treatment significantly but to a clinically minor extent reduced plasma concentrations of losartan and E-3174 (p < 0.01). Half-life values of losartan and E-3174 were unchanged. The ratio of 6-β-hydroxycortisol to 17-hydroxycorticosteroids doubled in the phenobarbital group (p < 0.001) and did not change appreciably in the placebo group.

To determine the effect of renal insufficiency on the pharmacokinetics and pharmacodynamics of losartan (MK-954) and its metabolite E3174

The formation of four major metabolites of propranolol by the liver was examined at steady state in three dogs that had undergone surgical portacaval transposition, following which injection of drug into the hindlimb delivers the total dose to the liver. Propranolol was infused directly into the liver via a hindlimb vein at dose rates ranging from 1.01 to 6.3 mg/min. In all dogs the formation of 4-hydroxypropranolol, a-naphthoxylactic acid, and propranolol glycol was saturable. Vmax and Km values were determined at steady state by relating the rate of excretion of each metabolite into bile and urine to the blood concentration of propranolol. The formation of propranolol glucuronide was a first order process. The use of a dog with a portacaval transposition has permitted development of a method to estimate, in vivo,the kinetic properties of enzymes responsible for hepatic first-pass metabolism of drugs.

Tumoral calcinosis is a rare but debilitating condition that can affect dialysis patients. Optimal management is largely unknown. We report the clinical course, treatment, and outcome of a peritoneal dialysis (PD) patient who developed tumoral calcinosis refractory to conventional treatment but improved with teriparatide therapy. A 26-year-old lady on PD for 2 years presented to us with tumoral calcinosis involving bilateral hands. Response to surgical excision, parathyroidectomy, and conversion to hemodialysis failed to result in sustained remission, and tumoral calcinosis progressed. After total parathyroidectomy, the patient had transient but partial remission in which her calcinosis deposits remained but were asymptomatic without pain or clinical signs of inflammation. However, she later experienced a relapse with involvement of the left elbow, right shoulder, right hip, and right thigh. Tumoral calcinosis remained uncontrolled resulting in debilitation, likely attributable to poor calcium and phosphate control because of adynamic bone disease after parathyroidectomy despite treatment of superimposed tuberculosis and therapy with sodium thiosulphate and pamidronic acid. Clinical improvement was however evident after the use of teriparatide. Asymptomatic hypocalcemia occurred after teriparatide therapy but resolved after 2 months. In conclusion, teriparatide appears to be useful for treating tumoral calcinosis in the presence of adynamic bone disease. Hypocalcemia can occur in the initial months of therapy.

An automated HPLC method is described for the simultaneous determination of propranolol, 4-hydroxypropranolol, and N-desisopropylpropranolol in plasma and urine before and after β-glucuronidase/aryl sulfatase treatment. It involves extraction with ether at pH 10 in the presence of ascorbic acid, added to prevent oxidation of 4-hydroxypropranolol. The compounds are then back extracted into dilute acid and assayed on an HPLC using a fluorescence detector. Three HPLC columns have been used (a phenyl, an octyl, and an octadecyl column). The last column was found to be most reproducible with minimal inter-column variation. The solvent system includes a combination of acetonitrile, methanol, and phosphoric acid. Concentrations as low as 0.2, 1.0, and 0.2 ng/ml of propranolol, 4-hydroxypropranolol, and N-desisopropylpropranolol , respectively, can be measured using 1 ml of plasma.