Absorption characteristics of a microemulsion formulation of cyclosporine in de novo pediatric liver transplant recipients.

In pediatric liver transplant recipients, oral cyclosporine (CsA) therapy may be complicated by impaired or delayed absorption during the initial weeks posttransplant. Neoral (NL) is a microemulsion preconcentrate formulation of CsA expected to increase the rate and extent of absorption of CsA and have less pharmacokinetic variability. The absolute bioavailability (F) of CsA from NL was compared with that of the currently marketed Sandimmune (SM) formulation in a double-blind, crossover study conducted in 9 pediatric liver transplant recipients (age 6 months to 11 years) between 8 and 20 days posttransplant. After determination of CsA pharmacokinetics for a steady-state intravenous dose, patients were randomized to receive a single oral dose of NL or SM in period I and the alternative formulation in period II. Clearance (Clt) and volume of distribution (Vss) values (mean +/- s.d.) calculated from the i.v. dose were similar to that previously reported for pediatric patients (Clt = 12.0 +/- 1.3 ml/min/kg; Vss = 2.2 +/- 0.2 L/kg). Mean F (+/- SD) for NL was significantly higher than SM (NL = 37.6 +/- 14.6%; SM = 24.7 +/- 8.0%; P = 0.05). Although not reaching statistical significance, the observed maximum blood concentration (Cmax) was higher, and the time to Cmax (Tmax) was shorter for NL in 8 or 9 patients. There were no significant correlations between age and any pharmacokinetic parameter for the group as a whole--however, there were statistically significant correlations between age and F for NL (r = 0.87; P = 0.02), and for age and Vss (r = 0.91; P = 0.01) for the 6 patients aged 2 years or less. In this pediatric liver transplant population, Neoral demonstrated improved absorption (% increase in F) compared to Sandimmune. In liver transplant recipients aged 2 years or less, absorption of Neoral may be a function of age and/or bowel length.

Efficacy and pharmacokinetics of two formulations of cyclosporine A in patients with psoriasis.

The efficacy and pharmacokinetic profiles of two oral formulations of cyclosporine A (Sandimmune and Neoral; Sandoz Pharmaceuticals, East Hanover, NJ) were evaluated in 37 patients with moderate to severe plaque psoriasis in a randomized, double-blind, modified, crossover study. Cyclosporine A (150 mg twice daily), administered in either formulation, reduced the severity of plaque lesions: 94% of all patients reported at least moderate improvement and 70% reported complete clearing. Approximately 2 weeks of therapy were required for drug exposure to stabilize on either formulation. Cyclosporine A exposure from Neoral was significantly greater relative to that from Sandimmune across all study weeks. At the eighth week (before crossover), AUC and Cmax values for Neoral and Sandimmune were 5618 +/- 1705 versus 3202 +/- 596 ng.h/mL and 1283 +/- 337 versus 623 +/- 173 ng/mL, respectively. In crossover analysis at steady state, the relative oral bioavailability of cyclosporine from the Neoral formulation was 54% greater than that from Sandimmune. Some pharmacokinetic parameters showed less variability both between and within groups of patients taking Neoral versus Sandimmune. Both formulations were well tolerated, in that most adverse events were of mild severity.

Propafenone-induced liver injury.

OBJECTIVE: To describe propafenone-induced liver injury. DESIGN: Retrospective case report. SETTING: Referred care in a large tertiary care center. Laboratory tests were performed at the auxiliary site and the tertiary care center. PATIENT: A 71-year-old woman with atrial fibrillation developed elevations of greater than two times the upper limit of normal in alkaline phosphatase (ALK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyltransferase (GGT) after initiation of propafenone therapy. INTERVENTIONS: Studies included serial measurements of ALK, ALT, AST, and GGT. RESULTS: The patient developed elevations of greater than two times the upper limit of normal in ALK, ALT, and AST, one month after initiating propafenone therapy. The propafenone dose was decreased from 900 to 675 mg/d and, ten days later, the ALK, ALT, and AST were decreased slightly, but still above the upper limit of normal. One month later, serum transaminases had returned to baseline, but propafenone therapy was discontinued because of recurrent atrial fibrillation, persistent elevation in ALK, and elevation in GGT. Two months after discontinuing propafenone, serum aminotransaminase and ALK concentrations had normalized and GGT had decreased and remained only slightly elevated. CONCLUSIONS: The occurrence of liver injury secondary to propafenone therapy is rare. Reported cases appear to be secondary to hepatocellular injury, cholestasis, or a combination of the two. In this case, the pattern demonstrated by elevations in liver enzymes may be classified as acute cholestatic liver injury. Because the reported incidence is 0.1-0.2 percent and there are no known fatalities secondary to propafenone liver injury, routine monitoring of liver function tests in all patients receiving propafenone cannot be recommended at this time. Baseline liver function tests prior to initiating propafenone therapy with follow-up laboratory studies one month later are recommended in patients with known liver dysfunction. If elevations are noted, a reduction in dose may result in lower liver enzyme concentrations, although discontinuation of therapy may be required in some cases.

Beta-adrenergic antagonists for primary prevention of gastrointestinal hemorrhage in patients with cirrhosis and esophageal varices.

The use of beta-adrenergic antagonists for primary prevention of gastrointestinal hemorrhage in patients with cirrhosis and esophageal varices is discussed. In five controlled trials, patients with cirrhosis and endoscopically proven esophageal varices were treated with either propranolol or nadolol in doses to reduce heart rate by 20-25% or in doses to decrease hepatic vein pressure by 25% of basal levels or to a level of less than 12 mm Hg. In two of three studies, investigators found that propranolol significantly reduced frequency of initial bleeding in patients with esophageal varices. In one of two studies, nadolol significantly decreased the risk of variceal bleeding in patients with cirrhosis; in the other study, a significant difference in the frequency of initial bleeding was found only among patients who were compliant with therapy. Only one of the five studies showed a significant difference in survival between the treatment group and the placebo group. Adverse effects of therapy included dizziness, fatigue, cardiac insufficiency, Raynaud's phenomenon, and risk of bleeding associated with propranolol withdrawal. Therapy with a nonselective beta-adrenergic antagonist should be considered for primary prevention of gastrointestinal hemorrhage in patients with cirrhosis and suspected or documented large varices; however, abrupt discontinuation of the medication is associated with risk of bleeding.

Effect of antigravity suit inflation on cardiovascular, PRA, and PVP responses in humans.

Blood pressure, pulse rate (PR), serum osmolality and electrolytes, as well as plasma vasopressin (PVP) and plasma renin activity (PRA), were measured in five men and two women [mean age 38.6 +/- 3.9 (SE) yr] before, during, and after inflation of an antigravity suit that covered the legs and abdomen. After 24 h of fluid deprivation the subjects stood quietly for 3 h: the 1st h without inflation, the 2nd with inflation to 60 Torr, and the 3rd without inflation. A similar control noninflation experiment was conducted 10 mo after the inflation experiment using five of the seven subjects except that the suit was not inflated during the 3-h period. Mean arterial pressure increased by 14 +/- 4 (SE) Torr (P less than 0.05) with inflation and decreased by 15 +/- 5 Torr (P less than 0.05) after deflation. Pulse pressure (PP) increased by 7 +/- 2 Torr (P less than 0.05) with inflation and PR decreased by 11 +/- 5 beats/min (P less than 0.05); PP and PR returned to preinflation levels after deflation. Plasma volume decreased by 6.1 +/- 1.5% and 5.3 +/- 1.6% (P less than 0.05) during hours 1 and 3, respectively, and returned to base line during inflation. Inflation decreased PVP from 6.8 +/- 1.1 to 5.6 +/- 1.4 pg/ml (P less than 0.05) and abolished the significant rise in PRA during hour 1. Both PVP and PRA increased significantly after deflation: delta = 18.0 +/- 5.1 pg/ml and 4.34 +/- 1.71 ng angiotensin I X ml-1 X h-1, respectively. Serum osmolality and Na+ and K+ concentrations were unchanged during the 3 h of standing.(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise thermoregulation in men after 6 hours of immersion.

Rectal (Tre) and mean skin (Tsk) temperature, skin heat conductance (Ksk), heart rate, and total body sweat rate were measured in 6 men (20-35 years) during 70 min of supine leg exercise (Ta = 23.5 degrees C, rh = 40%) at 50% of their peak O2 uptake (VO2 peak); these data were taken after a 6-h control (C) period in air and after immersion to the neck (NI) in water (34.5 degrees C) for 6 h after overnight food and fluid restriction. After NI mean (+/- S.E.) water balance was -1,285 +/- 104 ml for the 6 h and plasma volume (delta Hb and Hct) decreased by 5.2%. End exercise heart rates after C (141 +/- 3 b X min-1) increased to 148 +/- 3 b X min-1 (p less than 0.05) after NI while Vo2 were both 2.2 L X min-1 Tre increased by 0.5 C degrees (p less than 0.05) between the end of NI and the start of exercise. During exercise following C and NI, delta Tre were +1.0 degrees C and +0.9 degrees C (NS), Ksk were 44 +/- 2 and 43 +/- 1 kcal X m-2 X hr-1 X degrees C-1 (NS), while sweat rates increased from 248 +/- 19 to 366 +/- 52 g X h-1 (p less than 0.05), respectively. Both the total integrated Tre and Tsk curves after NI were higher (p less than 0.05) than for C. These results suggest that, compared with control responses, the equilibrium level of core temperature during submaximal exercise is regulated at a higher level after immersion.