Charles E. Halstenson

Whole-bowel irrigation as a treatment for acute lithium overdose

STUDY OBJECTIVE To determine if gastrointestinal decontamination using whole-bowel irrigation (WBI) was an effective treatment for acute ingestion of sustained-release lithium. METHODS In a two-phase, crossover protocol, ten normal volunteers ingested in each phase 0.80 mEq/kg sustained-release lithium carbonate. In the second phase, WBI was begun one hour after lithium ingestion, and 10 L of polyethylene glycol solution were administered over five hours. Serum samples were collected every half hour for six hours, every hour for an additional six hours, and then every 24 hours for as long as 72 hours after ingestion. These samples were analyzed for lithium concentration. The area under the lithium serum concentration-versus-time curve was calculated for each phase. RESULTS The average area under the lithium serum concentration-versus-time curve in the WBI phase was 67% +/- 11% less than that in the control phase (P less than .0005 using a two-tailed Students t test). The mean serum lithium concentration was significantly decreased (P = .03) within one hour of beginning WBI. CONCLUSION WBI is an effective treatment for acute ingestion of sustained-release lithium. We recommend it as the decontaminant procedure of choice in this situation.

Pharmacokinetics of codeine after single- and multiple-oral-dose administration to normal volunteers.

The pharmacokinetics of codeine, codeine glucuronide, morphine, and morphine glucuronide were assessed after single‐(60 mg) and multiple‐dose (60 mg every six hours for nine doses) oral administration of codeine sulfate to six normal volunteers. Multiple blood and urine samples were collected after administration of the single‐ and last multiple‐oral doses. Drug concentrations were analyzed using radioimmunoassay techniques. No significant alterations in codeine pharmacokinetics were noted after multiple‐dose oral administration. However, accumulation of morphine during multiple dosing was significant (AUC24 = 102 ± 33 ng/mL/hr after single dose versus 212 ± 118 ng/mL/hr after the last multiple dose). Peak concentration and AUC24 data for morphine glucuronide indicated that significant accumulation of this compound occurs upon multiple‐dose administration. These data indicate that morphine and morphine glucuronide serum concentrations are significantly increased during chronic oral codeine therapy and suggest that morphine, and perhaps morphine glucuronide, contribute significantly to the analgesic activity of chronic oral codeine therapy.

Disposition of Misoprostol and its Active Metabolite in Patients With Normal and Impaired Renal Function

The disposition of misoprostol acid, the active metabolite of misoprostol, was studied in 48 subjects with various degrees of renal function after administration of a single 400 μg oral dose of misoprostol. Subjects were assigned to one of four treatment groups: group 1, normal renal function with creatinine clearance (CLCR) 80–140 mL/min/1.73 m2; group 2, mild renal impairment with CLCR 50–79 mL/min/1.73 m2; group 3, moderate renal impairment with CLCR 20–49 mL/min/1.73 m2 or group 4, end stage renal disease (ESRD) patients maintained on hemodialysis. The maximum plasma concentration (Cmax) and time to reach Cmax (tmax) for misoprostol acid tended to be larger in group 4 subjects; however, it failed to reach statistical significance. Although not statistically significant, in group 4 subjects the terminal half‐life (t1/2) of misoprostol acid was almost twice as large (1.27 ± 0.77 h) as in groups 1, 2, and 3 (0.70 ± 0.72, 0.72 ± 0.67, and 0.73 ± 0.45 h, respectively). Misoprostol acids total area under the plasma concentration curve (AUC0)∞ was larger in group 4 subjects (1173.5 ± 487.4 pg ∞ h/mL, as compared with groups 1, 2, and 3 (421.4 ± 263.1, 418.9 ± 114.5, and 377.0 ± 145.2 pg ∞ h/mL, respectively; P < .05). The apparent total body clearance (CL) of misoprostol acid was statistically significantly smaller in group 4 subjects (0.094 ± 0.044 L/kg/min) as compared only with group 3 subjects (0.284 ± 0.102 L/kg/min). The dose of misoprostol may need to be reduced in ESRD patients on prolonged hemodialysis to prevent unnecessary high plasma levels of misoprostol acid and to avoid possible dose‐related adverse effects.

The Influence of Food on the Bioavailability of a Twice-Daily Controlled Release Carbamazepine Formulation

Carbatrol®, a new dosage form of carbamazepine (CBZ), was developed consisting of three different types of pellets (immediate release, controlled release, and enteric release). The objective of this study was to explore the influence of food on absorption of CBZ. This was a randomized, open‐label, single‐dose crossover study conducted in 12 healthy volunteers. Treatments were 2 × 200 mg Carbatrol with a high‐fat meal, fasted, or sprinkled over applesauce (but otherwise fasted). Each subject received one dose of each treatment separated by a washout period of at least 2 weeks. CBZ bioequivalence was established based on the equivalence of AUC (extent of absorption) in all three conditions. Carbatrol may be taken with or without food or the capsule opened and sprinkled on food.

Hemodialysis elimination rates and clearance of gentamicin and tobramycin.

The apparent hemodialyzer elimination rate constant and clearance for gentamicin and tobramycin were determined during 100 routine hemodialysis treatments in 49 patients. Three different dialyzers (CDAK 3500, CF 1211, and CF 1511), which vary in membrane composition, surface area, and thickness, were evaluated. The elimination rate constant in each patient was calculated from the slope of the log serum concentration-time curves. Two different elimination rate constants for each patient were derived, one during hemodialysis (KT) and one off hemodialysis (K). The hemodialyzer elimination rate constant (KD) for each dialyzer was calculated as the difference between these two values. The hemodialyzer clearance (Cd) was calculated by multiplying the hemodialyzer elimination rate constant by the volume of distribution of the patient. The KDS of gentamicin and tobramycin by the three dialyzers were significantly different. The gentamicin KD of the CDAK 3500 was lower than the values of the CF 1211 and CF 1511 (0.086 versus 0.123 versus 0.131 h-1, respectively). The Cd of the CDAK 3500 for gentamicin was also significantly lower than that of the CF 1511. Although the CdS of tobramycin for the CF 1211 and CF 1511 were 24 and 43% greater than that for the CDAK 3500, these differences were not statistically significant. The KD and Cd of tobramycin were greater than those of gentamicin for all three dialyzers. These data demonstrate that commonly used hemodialyzers vary markedly with respect to their elimination and clearance characteristics of gentamicin and tobramycin. Clinically, these observations may be helpful in designing the correct dose of gentamicin and tobramycin to achieve maximum drug safety and efficacy in hemodialysis patients.

Effect of concomitant administration of piperacillin on the dispositions of isepamicin and gentamicin in patients with end-stage renal disease.

Piperacillin inactivation of the aminoglycosides isepamicin and gentamicin in 12 chronic hemodialysis patients was assessed. Six subjects each received isepamicin (7.5 mg/kg of body weight) or gentamicin (2 mg/kg) alone and in combination with piperacillin (4 g every 12 h for four doses). Isepamicin and gentamicin concentrations in plasma and urine were monitored over 48 h after each dose and analyzed by high-performance liquid chromatography and fluorescence polarization immunoassay, respectively. The pharmacokinetics of isepamicin were not significantly altered during combination treatment with piperacillin. The total body clearance (3.79 +/- 0.71 versus 3.94 +/- 1.05 ml/min), the steady-state volume of distribution (0.19 +/- 0.04 versus 0.18 +/- 0.03 liter/kg), and the terminal elimination half-life (47.91 +/- 7.20 versus 45.08 +/- 10.34 h) were not significantly altered in the presence of piperacillin. In contrast, the terminal elimination half-life (47.68 +/- 20.58 versus 35.67 +/- 11.18 h) of gentamicin was significantly reduced when gentamicin was given with piperacillin. The total body clearance (4.26 +/- 3.07 versus 4.89 +/- 1.94 ml/min) and the steady-state volume of distribution (0.19 +/- 0.04 versus 0.20 +/- 0.04 liter/kg) of gentamicin were not significantly altered during combination therapy; however, the nonrenal clearance of gentamicin administered in combination with piperacillin (3.56 +/- 0.38 ml/min) increased significantly compared with that of gentamicin (2.03 +/- 0.50 ml/min) given alone. The results of this study suggest that no additional dosage adjustment of isepamicin during concomitant therapy with piperacillin in hemodialysis patients is necessary. However, this does not preclude the need for appropriately ex vivo-handled specimens for monitoring isepamicin concentrations in plasma to ensure therapeutic efficacy and prevent toxicity. Furthermore, additional dosage adjustments may be necessary when gentamicin is used concomitantly with piperacillin, on the basis of the significant in vivo inactivation that takes place in end-stage renal disease patients.

Pharmacokinetics and Blood Pressure Response of Losartan in End-Stage Renal Disease

BackgroundLosartan is a selective angiotensin AT1 receptor antagonist currently employed in the management of essential hypertension. This compound is in common use in populations with renal failure and end-stage renal disease (ESRD).ObjectiveTo investigate the pharmacokinetics and pharmacodynamics of losartan in patients with ESRD in order to establish administration guidelines.MethodsPatients were administered losartan 100 mg/day for 7 days, and after the seventh and final dose pharmacokinetic parameters were determined for both losartan and its active metabolite E-3174. During the study, the haemodialytic clearances of losartan and E-3174 were measured during a standard 4-hour dialysis session. Neurohumoral and biochemical changes were assessed during losartan administration.ResultsThe pharmacokinetics of losartan and E-3174 in haemodialysis patients did not alter to a clinically significant level. Losartan administration was accompanied by a decline in plasma aldosterone level as well as by an increase in plasma renin activity. Losartan administration resulted in a decline in plasma uric acid level, despite the fact that the study participants had no residual renal function. Losartan and E-3174 were not dialysable.ConclusionsThe pharmacokinetics of losartan and E-3174 are minimally altered in ESRD; thus, dosage adjustment is not required in the presence of advanced dialysis-dependent renal failure. In addition, postdialysis supplementation is not required for losartan because of the negligible dialysability of losartan and E-3174.

Effect of haemodialysis on the pharmacokinetics of cetirizine

SummaryThe pharmacokinetics of Cetirizine, a histamine H1-receptor antagonist, were investigated in five renal failure patients undergoing chronic haemodialysis therapy. The patients received one 10 mg cetirizine dihydrochloride capsule 3 h before haemodialysis.Concentrations of cetirizine in serum and dialysate were determined by HPLC. The maximum serum cetirizine concentration and the time to reach that maximum were 285 μg·1−1 and 2.0 h, respectively. The terminal disposition half-life of cetirizine in these patients was 19.3 h.The haemodialysis clearance of cetirizine was 14.0 ml · min−1. Although this is approximately 33% of the apparent total body clearance of cetirizine in subjects with normal renal function, the fraction of the dose removed by dialysis was only 9.4%. Thus, since haemodialysis does not produce a clinically significantly alteration in cetirizine elimination, no supplemental dose should be necessary after dialysis.

Cefotaxime and desacetyl cefotaxime kinetics in renal impairment

Cefotaxime and desacetyl cefotaxime kinetics after a single, 1 gm intravenous dose were evaluated in five groups of subjects: group I, normal creatinine clearance (CLCR >90 ml/min); group II, mild renal insufficiency (CLCR 30 to 89 ml/min); group III, moderate renal insufficiency (CLCR 16 to 29 ml/min); group IV, severe renal insufficiency (CLCR 4 to 15 ml/min); and group V, end‐stage renal disease requiring maintenance hemodialysis (CLCR <6 ml/min). The steady‐state volume of distribution (Vss) ranged from 10% to 55% of body weight but was not related to CLCR. The terminal t½ values of cefotaxime and desacetyl cefotaxime were 0.79 and 0.70, 1.09 and 3.95, 1.55 and 5.65, 2.54 and 14.23, and 1.63 and 23.15 hours in groups I to V, respectively. There were no significant changes in Vss or t½ after multiple dosing, but there were significant correlations between CLCR and cefotaxime total body clearance, cefotaxime and desacetyl cefotaxime renal clearance, and cefotaxime nonrenal clearance. Dosage regimens for the use of cefotaxime in patients with renal impairment are proposed.

Pharmacokinetics of Zileuton and Its Metabolites in Patients with Renal Impairment

The pharmacokinetics of zileuton and its conjugated metabolites were evaluated in patients with chronic renal impairment. Five healthy volunteers (creatinine clearance >90 mL/min), five patients with renal failure requiring hemodialysis, six with mild (creatinine clearance, 60–90 mL/min), eight with moderate (creatinine clearance, 30–59 mL/min), and six with severe (creatinine clearance <30 mL/min) renal impairment participated in the study. Zileuton was well tolerated by all participants including those with severe renal impairment and those receiving hemodialysis. The pharmacokinetics of zileuton were similar in healthy volunteers; in patients with mild, moderate and severe renal impairment; and in patients with renal failure requiring hemodialysis. The mean metabolite/parent‐area ratios for the pharmacologically inactive zileuton glucuronides progressively increased with the decline in renal function. A very small percentage of the administered zileuton dose (<0.5%) was removed by hemodialysis. Therefore, adjustment in the dose regimen of zileuton does not appear to be necessary for patients with various degrees of renal impairment and patients with renal failure requiring hemodialysis.