Fluorouracil for allergic reactions to capecitabine

OBJECTIVE: To report the safe use of fluorouracil in a patient with breast cancer who had allergic reactions to capecitabine. CASE SUMMARY: A 42-year-old African American woman with metastatic breast cancer developed progressive disease. Capecitabine 1500 mg taken by mouth twice daily was prescribed as the salvage chemotherapy. She developed a generalized rash and itching, sore throat, and dizziness approximately 4 hours after the first dose of capecitabine. These reactions recurred immediately after the second dose. Capecitabine was discontinued and the allergic reactions resolved after the woman took diphenhydramine for 1 week. In view of limited therapeutic options for her progressive disease, a trial of fluorouracil 300 mg/m(2)/d continuous intravenous infusion over 5 days was initiated without any premedications. She did not experience any reactions. The dose of fluorouracil in the second cycle was increased to 400 mg/m(2)/d continuous infusion over 5 days. DISCUSSION: Capecitabine is not intrinsically cytotoxic, but is converted to fluorouracil in tumor tissues via a 3-step enzymatic pathway. Capecitabine reaches peak blood concentrations in about 1.5 hours, with peak fluorouracil concentrations occurring at 2 hours. The elimination half-life of both drugs is 0.5-0.7 hours. The patient tolerated the rechallenge with fluorouracil without complications. Objective causality assessment revealed that the adverse event was probably drug induced. It was postulated that the allergic reaction was most likely caused by capecitabine or the intermediate metabolites based on the immediate reappearance of symptoms from the rechallenge, pharmacokinetic data, and well-tolerance of fluorouracil. CONCLUSIONS: The use of fluorouracil treatment with careful monitoring can be considered in a patient with mild allergic reactions to capecitabine.     

Pharmacokinetics of ofloxacin after parenteral and oral administration.

In 10 volunteers, the pharmacokinetics of ofloxacin [HOE 280, DL 8280; (+/-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H -pyrido-[1,2,3-de] [1,4]benzoxacine-6-carboxylic acid] was determined after administration of 25, 50, 100, and 200 mg intravenously (30-min infusion) as well as 200 and 400 mg orally. Concentrations in serum and urine were measured by high-pressure liquid chromatography. Concentrations in serum following different parenteral ofloxacin dosages demonstrated dose dependency with long biological half-lives of 231 to 267 min. Pharmacokinetic parameters were calculated on the basis of open two- and three-compartment models, which yielded nearly identical results. High volumes of distribution (1.2 to 1.4 liters/kg of body weight) suggested effective diffusion into the extravascular space. High total and renal clearances indicated primarily renal excretion with additional elimination pathways, such as tubular secretion and extrarenal elimination. After oral administration, absorption was excellent, and the absolute bioavailability following 200 mg of ofloxacin could be calculated at greater than 0.95. Maximal concentrations in serum were attained 1.2 to 1.9 h after dosing; areas under the curve increased in proportion to dose between 200 and 400 mg of oral ofloxacin. The amount of known metabolites (demethyl and N-oxide compounds) excreted in urine reached only 4.3% (intravenously) and 4.0% (orally). Transient headaches in some volunteers were the only side effects registered.     

A clinical safety trial of stroma-free hemoglobin

A stroma-free hemoglobin (SFH) solution was prepared which was sterile, pyrogen free, and contained only 1.2% of the stromal lipid present in unpurified hemolysate, 250 ml of which was administered slowly intravenously to 8 healthy men. Two control subjects received 250 ml of serum albumin. The SFH infusions were generally well tolerated by 7 of the 8 men. One subject developed abdominal pain and costovertebral angle tenderness after infusion, which disappeared within 48 hr. Bradycardia and a mild increase in blood pressure was present during ths SFH infusions and for 4 to 5 hr thereafter. A decrease in urine output and endogenous creatinine clearance appeared during the SFH infusions and for 2 to 4 hr after infusion. A mild prolongation of the activated partial thromboplastin time developed immediately after infusion. Gross hemoglobinuria appeared as expected during the SFH infusions and completely disappeared by 6 to 10 hr after infusion. All the cardiovascular, renal, and clotting changes were present for only a few hours after the SFH infusion, during the hemoglobinemia (free Hb in plasma). At 24 hr and 7 days after infusion all measurements were normal, and 6 mo follow-up showed no abnormalities or hepatitis.     

Pharmacokinetics and bactericidal activities of one 800-milligram dose versus two 400-milligram doses of intravenously administered pefloxacin in healthy volunteers.

Pefloxacin pharmacokinetics and serum bactericidal activities (SBA) against Escherichia coli and Staphylococcus aureus were compared after intravenous infusion of either a single 800-mg dose or twice-daily 400-mg doses into 16 healthy volunteers. Plasma pefloxacin concentrations were measured for up to 60 h, and SBAs were determined 1, 12, and 24 h after the start of the infusion. The mean areas under the concentration-versus-time curve for plasma were not different (138 versus 136 h.mg/liter). The mean clearances, volumes of distribution, and half-lives were also comparable. The mean (+/- standard deviation) maximal concentration after the 800-mg infusion was 12.11 +/- 1.35 versus 6.51 +/- 0.73 mg/liter after the first 400-mg infusion and 7.42 +/- 0.76 mg/liter after the second 400-mg infusion. Mean trough concentrations at 24 h were significantly different: 2.77 +/- 0.63 (800 mg) versus 1.93 +/- 0.49 (400 mg twice) mg/liter (P = 0.0007). Mean SBAs against E. coli after 800 mg of pefloxacin were higher than 1/128 (1 h), 1/32 (12 h), and 1/16 (24 h). Mean SBAs against S. aureus under the same conditions were higher than 1/64 (1 h), 1/16 (12 h), and 1/8 (24 h). Mean SBAs at 1 and 12 h were significantly higher after the 800-mg infusion than after the 400-mg infusion but were similar at 24 h for both regimens. Comparison of SBAs according to National Committee for Clinical Laboratory Standards criteria showed a similar adequacy at 24 h for both regimens against both strains. Administration of 800 mg of pefloxacin once a day is bioequivalent to 400 mg twice a day, and bactericidal activity of the 800-mg infusion is not less than that of two 400-mg infusions.     

On the origin of urinary fibrin-fibrinogen-related antigen in glomerulonephritis

A model of antiglomerular basement membrane nephritis in the rat was used to elucidate the origin of urinary fibrin-fibrinogen-related antigen (FRA). The intrarenal distribution and excretion of 125I-rat fibrinogen was examined to determine whether there was increased filtration of bibrinogen or fibrin degradation products (FDP) or lysis of intraglomerular fibrin. 125I-protein appeared in the urine immediately after injection of 125I-fibrinogen and fell in parallel with the fall in plasma 125I-fibrinogen. Renal retention of 125I-fibrin averaged less than 0.2 percent of the administered dose of 125I-fibrinogen. The infusion of epsilon aminocaproic acid (EACA) had no significant effect on either FRA excretion or 125I-protein excretion. Plasma FDP levels and the elution patteren of 125I-protein from the urine were not significantly changed by EACA infusion. These observations support the view that ruinary FRA excretion in glomerulonephritis is derived predominantly from increased filtration of plasma fibrinogen rather than from breakdown of intraglomerular fibrin.     

Safety and pharmacokinetics of intravenously administered trospectomycin sulfate

Local and systemic tolerance and drug pharmacokinetics were evaluated after a single intravenous infusion of 75 to 1,000 mg of trospectomycin or placebo in 96 healthy volunteers. No clinically significant changes, trends, or abnormalities were observed in the vital signs, electrocardiograms, or laboratory test results; however, there were some statistically significant dose effects or dose-by-time interactions on some of the measures. Mild, transient, local reactions at the infusion site were reported by 20% of the trospectomycin-treated and 22% of the placebo-treated subjects. No irritation of the surrounding tissue was noted when extravasation occurred. Mild, transient, perioral-facial numbness, which was probably drug-related, was the most commonly reported systemic adverse drug experience, occurring in 17 of 64 trospectomycin-treated subjects, but only at doses of 600 mg and above. Pharmacokinetic analyses showed that after a 1,000-mg intravenous dose of trospectomycin, the mean serum half-life was 2.18 hr, the mean area under the curve (AUC) was 157.0 hr x micrograms/ml, the mean maximum concentration (Cmax) was 82.4 micrograms/ml, the mean time to maximum concentration was 25.0 min, and the elimination rate (Ke) was 0.33 hr-1. The Ke and half-life did not vary with dose, and both Cmax and AUC showed a strong linear trend. From 48% to 62% of the dose was excreted in the urine during the first 48 hours after infusion. Under the conditions of this study, intravenous trospectomycin was well tolerated by human subjects at single doses up to and including 1,000 mg.     

Tolerance of ciprofloxacin at injection site, systemic safety and effect on electroencephalogram

The safety of ciprofloxacin, given via 30- and 60-min intravenous infusions at a dose of 300 mg every 12 h for 4 days, was studied in 12 healthy subjects (6 females, 6 males). Local effects of the drug were assessed by frequent examination at the infusion site while systemic safety was determined by haematological and biochemical tests and by careful microscopic examination of the urine for drug crystals and by electroencephalographic studies performed in all subjects before and after dosing. At the site of infusion erythema, itching and a burning sensation developed 10-15 min after onset of infusion in some subjects. These symptoms were slight and did not necessitate termination of the infusions. The rash disappeared in some instances during the infusion and in others within minutes after the end of infusion. The changes usually disappeared, even during the infusion. The incidence of the adverse reactions was not related to the duration of the infusion (30 or 60 min), but was less (frequency and extent) when the anticubital vein was used for infusion rather than when smaller more peripheral veins were employed. Thrombophlebitis occurred after 1 of 96 administrations, and was followed by a return to normal. The electroencephalograms remained normal in all instances. One subject experienced mild nausea of a few hours duration. Only 1 volunteer showed crystalluria; the two such specimens from this subject had the most alkaline pH of all urine samples collected in this study. The probability of crystalluria upon intravenous administration appears not to be higher than after oral administration of ciprofloxacin.     

Methotrexate in blood, urine, and cerebrospinal fluid of children receiving high doses by infusion.

Methotrexate was determined in plasma (31 patients), urine (eight patients), and cerebrospinal fluid (two patients) after high doses (35 to 150 mg/kg) by infusion, with citrovorum factor rescue. Concentrations in plasma were proportional to dose at 6, 24, 72 h after beginning treatment, but this trend was very minimal for samples obtained at 48 h. Clinical toxicity probably will not be serious if the methotrexate concentration in the serum is less than 4.5 X 10(-6) mol/liter at 48 h after the start of a 6-h infusion. In both of the two patients so examined, therapeutic concentrations appeared in cerebrospinal fluid after intravenous infusion of the drug. A kinetic enzymic method, radioassay, and radioimmunoassay all yielded similar results for drug concentrations.     

Pharmacokinetics and tolerance of lomefloxacin after sequentially increasing oral doses.

The pharmacokinetics of five dose levels of lomefloxacin (100, 200, 400, 600, and 800 mg) were examined in a single-dose, double-blind, placebo-controlled study involving 40 subjects. There were eight subjects in each group: five received active drug and three received placebo; each subject was given only one dose. All subjects completed the study, and lomefloxacin was well tolerated at all doses. No drug crystals were noted in the urine at 3 and 6 h after the dose. The mean maximum concentration in serum (Cmax) ranged from 1.11 to 7.46 micrograms/ml for the 100- to 800-mg doses, respectively, and the AUC increased proportionally with the dose. The mean time to Cmax (Tmax) values averaged 64.8 +/- 28.8 min. The elimination half-life and plasma clearance averaged 7.7 +/- 0.52 h and 259 +/- 37 ml/min, respectively. Mean concentrations in urine were highest during the first 4 h after the dose and ranged from 104 to 713 micrograms/ml following the 100- and 800-mg doses, respectively. Concentrations above 20 micrograms/ml in urine were observed in most subjects over 24 h at the three lower doses and averaged over 120 micrograms/ml during the 12- to 24-h interval at the 400-mg dose, thus supporting once-per-day dosing. Excretion rates from urine and the cumulative amount excreted increased in a dose-related fashion. Renal clearance decreased moderately at the higher doses. Thus, lomefloxacin was well tolerated, and dose proportionality was demonstrated by most pharmacokinetic parameters. The 400-mg dose produced concentrations in plasma and urine above the MIC for susceptible pathogens.     

Multiple-dose pharmacokinetics and safety of oral amifloxacin in healthy volunteers.

The multiple-dose pharmacokinetics and safety of amifloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy male volunteers. Amifloxacin was administered orally at 200, 400, or 600 mg every 12 h (q12h) and 400, 600, or 800 mg every 8 h (q8h) for 10 days. An additional dose was administered on day 11. Concentrations of amifloxacin in plasma and urine were measured on days 1, 5, and 11 by high-performance liquid chromatography. Steady-state amifloxacin concentrations were reached by day 5. Mean +/- standard deviation maximum observed amifloxacin concentrations in plasma were 2.52 +/- 1.12, 4.98 +/- 1.44, 5.40 +/- 2.02, 4.59 +/- 2.17, 6.53 +/- 2.44, and 8.01 +/- 3.00 micrograms/ml after the initial dose and 2.30 +/- 0.98, 5.41 +/- 0.74, 8.05 +/- 1.68, 6.87 +/- 2.81, 9.53 +/- 0.50, and 11.9 +/- 1.92 micrograms/ml on day 11 of the study for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. Amifloxacin was rapidly absorbed, as evidenced by the mean time to the maximum observed amifloxacin concentration of 0.98 h. Mean values for the terminal amifloxacin half-life in plasma ranged from 3.58 to 5.78 h. Mean amifloxacin concentrations in urine on day 11 in samples collected 0 to 2 h after dosing were 105, 417, 376, 336, 518, and 464 micrograms/ml for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. The mean amount of the dose excreted in the urine as amifloxacin was 53.9%. Amifloxacin was generally well tolerated, although there was a tendency for the subjects who received amifloxacin to experience more gastrointestinal, central nervous system, and cutaneous complaints than did those who received placebo. Clinically significant adverse reactions, including pruritus and transaminase elevations, occurred only at doses of 1,200 mg/day or above. Clinical and pharmacokinetic data suggest that orally administered amifloxacin may have utility in the treatment of urinary tract infections.     

Development of an optimal furosemide infusion strategy in infants with modeling and simulation

BACKGROUND: The optimal dosing strategy for continuous intravenous furosemide infusion is unknown in pediatric patients. Eighteen patients less than 1 year old were studied after cardiac surgery during routine clinical care. The current strategy starts with a continuous infusion of 0.1 mg/kg x h, which may be adapted. METHODS: A pharmacokinetic-pharmacodynamic model was developed that linked furosemide dose to furosemide serum concentrations, renal function (creatinine clearance), and urine output. Various regimens were simulated that adapt according to urine production. The modified dosing schedule was prospectively tested in a subsequent population of 18 pediatric patients after cardiac surgery. RESULTS: Data from the follow-up study suggest that urine production is more controlled for the proposed regimen. CONCLUSIONS: Both the modeling and simulation results and the follow-up study indicated that a bolus dose of 1 mg/kg followed 6 hours later with a 1- or 2-mg/kg loading dose and a 0.2-mg/kg x. h intravenous infusion provides a rational starting point for furosemide therapy after cardiac surgery in pediatric patients less than 1 year old. Adjustment of this regimen every 12 hours in steps of 0.1 mg/kg x h on the basis of clinical assessment should lead to adequate control over urinary output.     

Improvement of glycemic control after a 3–5 day insulin infusion in type 2-diabetic patients with insulin resistance can be maintained with glitazone therapy

INTRODUCTION: Insulin resistance is a common problem in obese patients with type 2 diabetes. In a prospective randomized study, we investigated the improvement of metabolic control after a 3-5 day period of intravenous insulin infusion in poorly insulin-treated, overweight type 2-diabetic patients with and without additional glitazone therapy. METHODS: Twenty-eight overweight patients (BMI > 28) with poorly insulin-treated type 2 diabetes (HbA1c > 8%) requiring > 80 IU insulin/day received a continuous insulin infusion for 3-5 days (initially 4-6 IU insulin/hour). Thereafter, 14 of the patients also received pioglitazone (15 mg/day). The two groups were compared for HbA1c, mean blood glucose (MBG), body weight, cholesterol, triglycerides and insulin requirement (IU/day) three months before insulin infusion, during infusion, and at three and six months after the infusion. RESULTS: Glycemic control was immediately improved under insulin infusion in both groups: MBG was reduced from 188 +/- 32 mg/dl at baseline to 142 +/- 28 mg/dl at the end of insulin infusion (p < 0.05). In the group receiving pioglitazone, the mean HbA1c three months after the insulin infusion was 16% lower and after six months 17% lower than baseline values (p < 0.02). Concomitantly, the required insulin dose decreased significantly by 15% after three months and 18% after six months (p < 0.02). Two patients (14%) were non-responders (< 10% reduction of required insulin dose). In the group without pioglitazone the mean HbA1c level three months after insulin infusion was 10% lower (p < 0.05) than at baseline; at six months the HbA1c value was the same as that before the infusion. The required insulin dose was 10% lower after three months and only 3% lower after six months (NS). Four patients (28%) were non-responders. DISCUSSION: Short-term insulin infusion therapy is effective in improving metabolic control and, concomitantly, in reducing insulin requirement in poorly insulin-treated type 2-diabetic patients; however, these effects are mostly limited to three months. With additional glitazone treatment after the insulin infusion, the improvement in metabolic control and the reduced insulin requirement can be maintained for more than six months.     

Regional and systemic prophylaxis with teicoplanin in monolateral and bilateral total knee replacement procedures: study of pharmacokinetics and tissue penetration.

Twenty-four patients undergoing monolateral or bilateral total knee replacement (TKR) procedures were randomized to receive teicoplanin (T) either systemically or regionally. Subjects scheduled for systemic prophylaxis and undergoing monolateral (six patients) or bilateral (five patients) TKR received a single 800-mg dose of T in 100 ml of saline as a 5-min infusion into a forearm vein 2.5 h before surgery. For regional prophylaxis, patients undergoing monolateral surgery (eight subjects) received 400 mg of T in 100 ml of saline as a 5-min infusion into a foot vein of the leg to be operated on immediately after the tourniquet was inflated. For the five patients scheduled for bilateral operation and regional prophylaxis, the administration of T was also repeated for the second knee operation. The tourniquet, as the standard TKR surgical technique, was inflated to 400 mm Hg (c. 50 kPa) in all 24 patients immediately before the beginning of surgery and kept in place for the duration of the operation. Samples of serum, bone, skin, synovia, and subcutaneous tissue were collected at timed intervals during surgery. They were microbiologically assayed for T by using Bacillus subtilis as the test organism. Overall, the mean T concentrations obtained with regional route prophylaxis were found to be 2 to 10 times higher than those achieved following systemic prophylaxis. Moreover, peak levels in different tissues after regional prophylaxis were significantly higher (P < 0.05). None of the patients experienced adverse effects due to regional or systemic T administration; no prosthetic or wound infections were observed in the follow-up period (from 12 to 26 months).     

The pharmacokinetics and tissue penetration of norfloxacin

The pharmacokinetics and cantharides-induced blister fluid levels of norfloxacin were studied after a single 400 mg oral dose. The mean maximum serum level was 1.45 mg/l and occurred 1.5 h after administration. The serum half-life of norfloxacin was found to be 3.5 h. After 24 h 27% of the administered dose was recovered in the urine as microbiologically active compound. High urine levels were found. Rapid blister fluid penetration occurred, the maximum level (occurring between 2-3 h) was about 1 mg/l. Thereafter the blister fluid level exceeded the serum level, both declining in parallel.     

Pharmacokinetics, pharmacodynamics, and tolerability of single increasing doses of the dipeptidyl peptidase-4 inhibitor alogliptin in healthy male subjects.

BACKGROUND: Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes. OBJECTIVE: This study was conducted to characterize the pharmacokinetics, pharmacodynamics, and tolerability of single oral doses of alogliptin in healthy male subjects. METHODS: This was a randomized, double-blind, placebo-controlled study in which healthy, nonobese male subjects between the ages of 18 and 55 years were assigned to 1 of 6 cohorts: alogliptin 25, 50, 100, 200, 400, or 800 mg. One subject in each cohort received placebo. An ascending-dose strategy was used, in which each cohort received its assigned dose only after review of the safety data from the previous cohort. Blood and urine were collected over 72 hours after dosing for pharmacokinetic analysis and determination of plasma DPP-4 inhibition and active glucagon-like peptide -1(GLP-1) concentrations. RESULTS: Thirty-six subjects (66 per cohort) were enrolled and completed the study (29/36 [81% ] white; mean age, 26.6 years; mean weight, 76.0 kg). Alogliptin was rapidly absorbed (median T(max), 1-2 hours) and eliminated slowly (mean t(1/2), 12.4-21.4 hours), primarily via urinary excretion (mean fraction of drug excreted in urine from 0 to 72 hours after dosing, 60%-71%). C(max) and AUC(0-infinity) increased dose proportionally over the range from 25 to 100 mg. The metabolites M-I (N-demethylated) and M-II (N-acetylated) accounted for <2% and <6%, respectively, of alogliptin concentrations in plasma and urine. Across alogliptin doses, mean peak DPP-4 inhibition ranged from 93% to 99%, and mean inhibition at 24 hours after dosing ranged from 74% to 97%. Exposure to active GLP-1 was 2- to 4-fold greater for all alogliptin doses compared with placebo; no dose response was apparent. Hypoglycemia (asymptomatic) was reported in 5 subjects (11 receiving alogliptin 50 mg, 2 receiving alogliptin 200 mg, 1 receiving alogliptin 400 mg, 1 receiving placebo). Other adverse events were reported in 1 subject each: dizziness (alogliptin 100 mg), syncope (alogliptin 200 mg), constipation (alogliptin 200 mg), viral infection (alogliptin 400 mg), hot flush (placebo), and nausea (placebo). CONCLUSION: In these healthy male subjects, alogliptin at single doses up to 800 mg inhibited plasma DPP-4 activity, increased active GLP-1, and was generally well tolerated, with no dose-limiting toxicity.     

Comparison of continuous versus intermittent furosemide administration in postoperative pediatric cardiac patients.

OBJECTIVE: To compare the effects of furosemide administered by intermittent iv infusion vs. continuous iv infusion on urine output, hemodynamic variables, and serum electrolyte concentrations. DESIGN: Prospective, randomized trial. SETTING: Pediatric ICU. PATIENTS: Postoperative pediatric cardiac patients. INTERVENTIONS: Patients were assigned to either the continuous iv infusion or the intermittent infusion groups. The intermittent group received 1 mg/kg iv of furosemide every 4 hrs to be increased by 0.25 mg/kg iv every 4 hrs to a maximum of 1.5 mg/kg iv if the urine output was less than 1 mL/kg.hr. The continuous infusion group received an initial furosemide dose of 0.1 mg/kg iv (minimum 1 mg) followed by an iv infusion rate of 0.1 mg/kg.hr of furosemide to be doubled every 2 hrs to a maximum of 0.4 mg/kg.hr if the urine output was less than 1 mL/kg.hr. MEASUREMENTS AND MAIN RESULTS: Demographic variables, fluids, electrolyte and inotropic requirements were the same in both groups. A significantly (p = .045) lower daily dose of furosemide (4.90 +/- 1.78 vs. 6.23 +/- 0.62 mg/kg.day) in the continuous iv infusion group produced the same 24-hr urine volume as that of the intermittent group. There was more variability in urine output in the intermittent group as well as more urinary losses of sodium (0.29 +/- 0.15 vs. 0.20 +/- 0.06 mmol/kg.day, p = .0007) and chloride (0.40 +/- 0.20 vs. 0.30 +/- 0.12 mmol/kg.day, p = .045). CONCLUSION: Furosemide administered by continuous iv infusion is advantageous in the post-operative pediatric patient because of a more controlled and predictable urine output with less drug requirement and less urinary loss in sodium and chloride.     

Sucralfate reduces the gastrointestinal absorption of norfloxacin.

The effect of sucralfate on the bioavailability of norfloxacin after single 400-mg doses of norfloxacin was evaluated in eight healthy males. Subjects received each of the following treatments in random sequence: (i), norfloxacin, 400 mg alone; (ii) sucralfate, 1 g, concurrently with norfloxacin, 400 mg; and (iii) sucralfate, 1 g, followed by norfloxacin, 400 mg, 2 h later. One day before administration of treatments 2 and 3, 1 g of sucralfate was given at 7 a.m., 11 a.m., 5 p.m., and 10 p.m. Blood samples were collected immediately before the norfloxacin dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 h postdose. Urine was collected in divided intervals: from 0 to 12, from 12 to 24, and from 24 to 48 h. Norfloxacin concentrations in plasma and urine were determined by high-performance liquid chromatography. Mean area under the plasma concentration-versus-time curve extrapolated to infinity decreased significantly (P less than 0.001) after norfloxacin was given with and 2 h after sucralfate. The relative bioavailabilities were 1.8% when norfloxacin was taken with sucralfate and 56.6% when it was taken 2 h after sucralfate. After norfloxacin was given alone, the mean norfloxacin concentrations in urine collected during intervals of 0 to 12, 12 to 24, and 24 to 28 h were 118.9 +/- 72.3, 18.8 +/- 12.5, and 2.4 +/- 2.2 micrograms/ml, respectively. After norfloxacin was given with sucralfate, however, the mean norfloxacin concentrations in urine collected during the same time intervals were 6.8 +/- 4.7, 1.8 +/- 1.4, and 0 +/- 0 microgram/ml, respectively. Because of low pH and relatively high magnesium concentration in urine, susceptibilities of bacteria in urine are 8- to 32-fold lower than in broth. This fact, in combination with the reduced bioavailability of norfloxacin in the presence of sucralfate or antacids, is likely to result in treatment failure. The effect of sucralfate given after norfloxacin was not examined, nor was the effect of sucralfate given more than 2 h before norfloxacin. Administration or norfloxacin with sucralfate should therefore by avoided.     

Enterohepatic circulation of lorazepam and acetaminophen conjugates in ponies

Adult female ponies (130-225 kg) with chronically implanted external biliary fistulas (T-tubes) participated in three-way cross-over studies using either i.v. lorazepam (10 mg) or acetaminophen (2 g), two model drugs biotransformed mainly by hepatic conjugative reactions. The objectives were to determine the systemic pharmacokinetics, urinary and biliary excretion and degree of enterohepatic circulation (EHC) of these compounds. Trial conditions were: A: EHC intact, with blood and urine, but not bile, collected after i.v. drug administration; B: EHC interrupted, with blood, urine and bile collected after i.v. drug administration; and C: bile infused, EHC open, without i.v. drug administration, with bile collected from trial B (containing biliary excreted drug) infused into the duodenum via the T-tube, followed by collection of blood, urine and bile. At least 2 weeks elapsed between trials. Interruption of the EHC caused lorazepam plasma half-life to shorten (3.4 vs. 2.3 hr with the EHC intact, P less than .1), clearance to increase (9.2 vs. 12.3 ml/min/kg, P less than .1) and total area under the plasma concentration curve for lorazepam glucuronide to decrease (210 vs. 310 ng/ml X hr, P less than .06). Recovery of lorazepam as its glucuronide in bile was 24.5% of the i.v. injected dose. Urinary elimination of lorazepam glucuronide was reduced from 41 to 36% of the dose due to bile collection. Subsequent duodenal infusion of collected bile, containing an average of 2.45 mg of lorazepam as glucuronide, was followed by urinary excretion of 0.48 mg of lorazepam as glucuronide in urine and 0.36 mg re-excreted into bile.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of an acute oral lithium intake on urinary Aquaporin-2 in healthy humans with and without simultaneous stimulation with hypertonic saline infusion

OBJECTIVE: Animal experiments have shown that lithium interferes with the formation of Aquaporin-2 in the distal renal tubuli. The effect of lithium on formation of renal water channels has not been studied in healthy humans. The aim of this study was to test the hypotheses that a single oral dose of lithium will reduce the formation of water channels both with and without stimulation with hypertonic saline infusion, and that this effect can be detected by measurement of urinary excretion of Aquaporin-2 (u-AQP2). METHODS: In healthy subjects, Study 1 (n = 11) and Study 2 (n = 12), urine was collected in 6 and 7 periods between 08.00 and 14.00, respectively, and blood samples were drawn at 30- to 60-min intervals. The study medication was given at 09.00; u-AQP2 was determined by radioimmunoassay. RESULTS: In Study 1 neither u-AQP2 nor urinary output were significantly changed by lithium. In Study 2, u-AQP2 was increased by hypertonic saline infusion in parallel with an increase in arginine vasopressin. At the end of the study, u-AQP2 was increased by 30% with placebo but only by 13% with the 600 mg lithium dose, and urinary output was significantly higher after 600 mg lithium than after placebo and 300 mg lithium. CONCLUSIONS: U-AQP2 was not significantly changed after a single oral dose of lithium. The antidiuretic response to hypertonic saline infusion was reduced when lithium was given. It is suggested that lithium increases urinary output by inhibiting trafficking of renal water channels in healthy humans.     

Pharmacokinetics and tissue penetration of fleroxacin after single and multiple 400- and 800-mg-dosage regimens.

The pharmacokinetics and suction-induced blister fluid penetration of fleroxacin following single and multiple (every 24 h for 5 days) oral administration of 400- and 800-mg-dosage regimens were studied in 12 young male volunteers. Plasma and urine samples up to 72 h were assayed by high-pressure liquid chromatography. The peak levels of fleroxacin in plasma were significantly higher after multiple dosing of 800 mg (14.3 versus 8.2 micrograms/ml; P less than 0.01) but not after the last 400-mg dose (6.7 versus 5.0 micrograms/ml). Increased elimination half-life occurred after multiple dosing of 800 mg, from 13.45 +/- 2.94 to 15.60 +/- 3.16 h (P less than 0.05). Mean peak concentrations in blister fluid were significantly different when the first (3.7 +/- 0.8 and 7.7 +/- 1.8 micrograms/ml for 400 and 800 mg, respectively) and last (5.7 +/- 0.9 and 12.3 +/- 2.1 micrograms/ml for 400 and 800 mg, respectively) doses were compared (P less than 0.01). The percentage of blister fluid (BF) penetration (AUCBF/AUCplasma, where AUC is area under the concentration-time curve) yielded values greater than 100% (range, 113.7 to 132.6%). After multiple administration of 800 mg, fleroxacin was cleared from the body more slowly: from 98.80 ml/min after a single dose to 77.72 ml/min following 800 mg every 24 h (P less than 0.01). Saturation of apparent nonrenal clearance is suggested to explain this difference. Fleroxacin was well tolerated by the volunteers.