Hypogammaglobulinemia after heart transplantation: use of intravenous immunoglobulin replacement therapy in relapsing CMV disease

Secondary hypogammaglobulinemia after heart transplantation may follow immunosuppressive therapy with the resultant increased risk of infections, including cytomegalovirus (CMV) disease. There is limited information on the use of intravenous immunoglobulin replacement therapy (IVIG) in heart-transplanted patients with hypogammaglobulinemia and CMV disease. We present data on five consecutive heart-transplanted patients with relapsing CMV disease, four of whom developed gastrointestinal disease. The immunosuppressive regimen included prednisone, cyclosporine A, azathioprine, mycophenolate mofetil, tacrolimus and antithymocyte globulin (ATG). Evaluation revealed CMV antigenemia. All the patients had been treated with intravenous ganciclovir. In addition, hyperimmune CMV immunoglobulin was administered in three patients. Significantly reduced levels of immunoglobulin G (IgG) were observed in the patients as compared with 15 heart-transplanted individuals without CMV disease [mean IgG levels: 323+/-18 and 639+/-63 mg/dl, respectively (p=0.003)]. IVIG [FLEBOGAMMA], 200-400 mg/kg every 21 days with the goal of maintaining normal serum IgG levels, was added for the treatment of CMV disease. Selected batches with the highest anti-CMV titers were set apart for the treatment of the patients. IVIG treatment, in combination with antiviral therapy, proved able to control CMV disease. There was a favorable clinical response and the patients became free of gastrointestinal symptoms. Detection of CMV antigens was negative after treatment. During IVIG therapy no immediate or delayed adverse effects were observed. Even if our survey was limited to five cases, the results suggest that addition of IVIG to antiviral chemotherapy might improve outcome in heart-transplanted patients with hypogammaglobulinemia and CMV disease.     

The pharmacokinetics and pharmacodynamics of hydroxyzine in patients with primary biliary cirrhosis

Hydroxyzine, a potent H1-receptor antagonist often used for relief of pruritus in patients with hepatic dysfunction, was studied in eight patients, mean age 53.4 +/- SD 11.2 years, with primary biliary cirrhosis. The patients ingested a single dose of hydroxyzine, 0.7 mg/kg (mean dose 43.9 +/- 6.6 mg). Before the dose, then hourly for 6 hours, every 2 hours from 6-12 hours, at 24 hours, and every 24 hours for 6 days, serum hydroxyzine and cetirizine were measured and an intradermal injection of 0.01 mL of a 0.1 mg/mL solution of histamine phosphate was performed. Wheals and flares were traced at 10 minutes and the areas were calculated. Mean peak hydroxyzine levels of 116.5 +/- 60.6 ng/mL occurred at 2.3 +/- 0.7 hours and mean peak cetirizine levels of 500.4 +/- 302.0 ng/mL occurred at 4.8 +/- 2.8 hours. The mean serum elimination half-life of hydroxyzine was 36.6 +/- 13.1 hours, and the mean serum elimination half-life of cetirizine was 25.0 +/- 8.2 hours. The mean hydroxyzine clearance rate was 8.65 +/- 7.46 mL/min/kg, and the mean volume of distribution was 22.7 +/- 13.3 L/kg. The mean wheal area was suppressed (P less than 0.01) from 1 to 120 hours, with maximal suppression from 2 to 48 hours. The mean flare area was suppressed from 1 to 144 hours, with maximal suppression from 3 to 24 hours (P less than 0.01). All patients became sleepy from 0.5 to 6 hours. Blurred vision, dizziness and dry mouth each occurred in two patients. Hydroxyzine elimination is impaired in patients with primary biliary cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition and metabolism of carbovir in mice dosed intravenously or orally

To determine the disposition of carbovir and [3H]carbovir in mice, HPLC and thin-layer chromatographic assays were developed and mice were dosed iv and by gavage. Carbovir had no lethal effect at iv doses up to 500 mg/kg and was stable for 24 hr in mouse plasma at temperatures ranging from 0-37 degrees C. Binding to plasma proteins was minimal. Following an iv dose of 500 mg/kg of carbovir or [3H] carbovir, elimination phases with half-lives of 26-37 min (alpha) and 206-330 min (beta) were observed for plasma. For mice dosed with 27 mg/kg of [3H]carbovir, however, only a single phase with a half-life of 17 min was noted. Of several tissues examined, kidney contained the highest concentration of radioactivity. For the high dose, 19.0 +/- 2.6% was excreted in the urine in 24 hr as unchanged carbovir and 42.2 +/- 2.4% as metabolites; for the low dose, 54.5 +/- 6.1% was excreted as carbovir and 26.5 +/- 5.0% as metabolites. When mice were dosed orally with 500 mg/kg, plasma concentrations of carbovir were low. The initial plasma half-life for carbovir was 69 min; the terminal half-life was 822 min. Urinary excretion of unchanged carbovir was 21.3 +/- 7.1%. These results indicate that clearance of high doses of carbovir is limited and that its absorption is poor after oral dosing.     

Pharmacokinetics of iohexol, a new nonionic radiocontrast agent, in humans

Sixteen healthy men received iohexol intravenously at a concentration of 346 mg of iodine/mL. Doses of 500, 750, 1000, and 1500 mg of iodine/kg of body weight were administered to four volunteers each. Neither clearance nor percent of dose excreted in the urine showed any significant correlation with size of the dose. The overall mean (+/- SD) renal and total body clearances were 120 +/- 18.6 and 131 +/- 18.6 mL/min, respectively. The overall mean apparent volume of distribution was 165 (+/- 30.7) mL/kg. Urine contained 92.3 +/- 4.4% of the dose. Most of the drug (89.9%) was excreted within the first 12 h. An open three-compartment body model gave the best fit to the experimental data. The mean apparent first-order terminal elimination (gamma-phase) half-life was 12.6 h.     

Pharmacokinetics of halofantrine in man: effects of food and dose size.

1. Plasma concentrations of halofantrine (Hf) and its putative principal plasma metabolite desbutyl halofantrine (Hfm) have been measured in two separate studies after oral administration of the hydrochloride salt. 2. Six healthy male volunteers each received single oral doses of 250, 500 and 1000 mg administered after an overnight fast. A washout period of at least 6 weeks was allowed between each dose. A further 250 mg single oral dose was administered to the same six subjects in a fasting state and after a standardised fatty meal in a randomised study, again with a washout period of at least 6 weeks. 3. AUC and maximum plasma concentration (Cmax) for Hf increased in proportion to the dose from 250-500 mg. This increase was non-proportional when the dose was increased from 500 to 1000 mg. For Hfm, in the dose range 250-500 mg, AUC but not Cmax increased in proportion in the increase in dose size. The increase in these parameters was non-proportional when the dose was increased from 500 to 1000 mg. Time to reach peak concentrations for Hf and Hfm and the elimination half-life of Hf remained unchanged across the dosage range. 4. Following a fatty meal, Cmax for Hf was increased from 184 +/- 115 micrograms l-1 (fasting) to 1218 +/- 464 micrograms l-1 (fed). AUC for Hf was increased from 3.9 +/- 2.6 mg l-1 h (fasting) to 11.3 +/- 3.5 mg l-1 h following a fatty meal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mefloquine antimalarial prophylaxis in pregnancy: dose finding and pharmacokinetic study.

1. A dose finding pharmacokinetic study was performed in 20 Karen women in the third trimester of pregnancy receiving antimalarial prophylaxis with mefloquine. Ten received 250 mg mefloquine base weekly and ten received identical tablets of 125 mg base/week. 2. Both dose regimens were well tolerated. Malaria was prevented effectively, there were no serious adverse effects, all pregnancies proceeded normally, and there were no abnormalities in the babies followed up to 2 years. 3. The median time from dose administration to peak whole blood mefloquine concentration was 6 (range 3-24) h. Mean (+/- s.d.) peak and trough concentrations in the seventh week were 722 +/- 279 and 488 +/- 155 ng ml-1 with the 250 mg/week dose, and 390 +/- 81 and 185 +/- 53 ng ml-1 with the 125 mg/week dose regimens respectively. These blood concentration values are lower than those reported previously in non-pregnant adults. 4. One and two compartmental models were fitted to the whole blood concentration-time data. Mean (+/- s.d.) clearance (CL/F) was 0.78 +/- 0.27 ml min-1 kg-1, and the apparent terminal elimination half-life (t1/2) was 11.6 +/- 7.9 days. 5. Further studies to determine the oral bioavailability of mefloquine are needed, but these results suggest that clearance may be increased in late pregnancy. These preliminary results of good efficacy without significant toxicity are encouraging, and a more extensive evaluation of mefloquine antimalarial prophylaxis in pregnancy is now warranted.     

Efficacy and pharmacokinetics of oral pirmenol, a new antiarrhythmic drug

Pirmenol is a new orally effective antiarrhythmic agent. Reported are the results of oral administration of pirmenol to six patients (age 48.5 +/- 8.6 years, weight 83 +/- 15 kg) with stable ventricular extrasystoles (PVCs)--average ectopy rate 1040 +/- 630/hr (mean +/- SD). Patients received oral doses of placebo or 200 mg of pirmenol in a double-blind cross-over fashion followed by a single-blind rising-dose administration of 250 mg and 300 mg of pirmenol. The time period between doses was 48 hours. Pirmenol was rapidly absorbed (time to peak plasma levels 1 to 1.5 hours) and the mean maximum plasma concentrations were 1.8, 2.7 and 3.4 micrograms/mL with 200-mg, 250-mg and 300-mg doses, respectively. The elimination half-life was 9.3 +/- 3.0 hours and 31 +/- 14% of the dose was recovered in urine. The response criterion (80% suppression of PVCs of control for 8 hours) was met after the 300-mg dose in three patients. In three patients greater than 80% reduction occurred for up to 8 hours after the 200-mg dose. Pirmenol administration was not associated with any significant changes in blood pressure, heart rate, hepatic and renal function, PR interval or QRS duration. LV ejection fraction determined echocardiographically decreased from 63.0 +/- 6.9% predose to 59.7 +/- 5.0% about 2 hours after the 300-mg dose and QT interval increased by less than 10%. Two patients complained of transient bad taste sensation. Our results suggest that 250 mg to 300 mg of pirmenol, administered twice a day will suppress the PVCs effectively.     

Pharmacokinetics of ranitidine in patients with renal failure

The pharmacokinetics of ranitidine were studied in ten patients with renal failure (creatinine clearance, 6-54 mL/min) after intravenous (IV) (50 mg) and oral doses (150 mg). After oral administration, peak plasma concentrations of 378-808 ng/mL were obtained in two to six hours. Plasma concentrations declined very slowly and concentrations greater than 100 ng/mL were obtained for 16 to 20 hours after the dose. The elimination half-life following oral administration was 8.5 +/- 2.8 hours (standard deviation [SD]), and the bioavailability of ranitidine was 43.3% +/- 10.5%. After IV administration, the elimination half-life, plasma clearance, renal clearance, and volume of distribution were 7.0 +/- 1.0 hours, 170 +/- 38 mL/min, 36.0 +/- 25.0 mL/min, and 1.3 +/- 0.4 L/kg, respectively. About 20% of the IV dose and 9% of the oral dose were recovered unchanged in urine. There was a significant correlation between the renal clearance of ranitidine and creatinine clearance (r = .74, P less than .05) after IV administration. The elimination half-life in patients with renal insufficiency is about three times greater than that reported in the literature for healthy subjects. Similarly, the plasma clearance in these patients is about 20% of that reported in healthy subjects. The results indicate that ranitidine elimination is appreciably reduced in renal failure and that an adjustment of dose in patients with renal failure is warranted. A dose of 75 mg bid may be adequate in maintaining the therapeutic plasma concentrations that are required for adequate H2-blocking activity.     

Effects of chronic amantadine hydrochloride ingestion on its and acetaminophen pharmacokinetics in young adults.

The authors studied the effect of chronic amantadine ingestion on its own disposition and that of acetaminophen in five healthy young adults. The half-life of amantadine after 42 days ingestion was 15.1 +/- 2.3 hours and was not different from 14.8 +/- 4.4 hours after an acute ingestion (mean +/- SD). However, chronic amantadine ingestion was associated with an increased apparent volume of distribution for acetaminophen, 1.1 +/- 0.1 L/kg compared with 0.9 +/- 0.1 L/kg, when the two drugs were concurrently ingested after a 2-week washout period. This difference in kinetic distribution was not reflected in terminal acetaminophen half-life, 149 +/- 54 versus 151 +/- 55 minutes for chronic and acute amantadine ingestion, respectively. Plasma acetaminophen clearance with chronic amantadine ingestion (5.8 +/- 2.6 mL/min/kg) was not different from that determined after acute coingestion of both drugs (4.3 +/- 1.1 mL/min/kg). Thus, no change in recommended dose is necessary when these two drugs are coingested.     

Enzyme replacement in Fabry disease: pharmacokinetics and pharmacodynamics of agalsidase alpha in children and adolescents

This multicenter, open-label study evaluated pharmacokinetics, pharmacodynamics, and safety of agalsidase alpha in pediatric compared with adult patients with Fabry disease. The pharmacokinetic parameters of pediatric patients (19 boys, 5 girls, 6-18 years old; mean age, 11.8 years) were compared to those of adult male and female patients who participated in other clinical studies. All patients received agalsidase alpha at a dose of 0.2 mg/kg infused over 40 minutes every other week. Agalsidase alpha exhibited a biphasic serum elimination profile with a maximum serum concentration at the end of the 40-minute infusion; <1% of the maximum concentration was detected 8 hours after dosing. In children, serum clearance was 2.0 to 9.4 mL/min/kg and tended to decrease with increasing age. The average clearance in children, 3.7 +/- 1.5 mL/min/kg (mean +/- SD), was significantly greater than that measured in 33 adults (2.3 +/- 0.7 mL/min/kg, P < .0001). Mean terminal elimination half-life of agalsidase alpha was prolonged in week 25 compared with baseline (150 vs 66 minutes) in 8 of 19 male children. The magnitude of the reduction of plasma globotriaosylceremide was similar in all age groups and was independent of area under the curve and other pharmacokinetic parameters. Except for clearance in younger patients, agalsidase alpha appears to have comparable pharmacokinetic and pharmacodynamic profiles in pediatric and adult Fabry patients of both genders.     

Pharmacokinetics and in-situ absorption studies of a new anti-allergic compound 73/602 in rats

Compound 73/602 (AA) is a structural analogue of vasicinone, an alkaloid present in the leaves and roots of Adhatoda vasica (Acanthaceae). It possesses potent antiallergic activity in mice, rats and guinea pigs. The pK(a) of AA was determined to be 2.87+/-0. 19 by UV spectrophotometry. The absorption kinetics of this compound were studied in-situ using a rat gut technique at pH 2.6 and 7.4. The rate of absorption at pH 2.6 (0.0288+/-0.004 min(-1)) was slightly less than at pH 7.4 (0.035+/-0.0008 min(-1)). This characteristic behavior was attributed to the low pK(a) of AA, a weekly basic compound, where nearly 35% of the compound remained in the unionized form at pH 2.6. Also, the return of compound into the mucosal lumen from the blood capillaries over a period of 2 h after administering a 2 mg dose in tail vein was less than 0.3%. Hence it was concluded that entero-enteric circulation of AA did not contribute significantly to the in-situ absorption rates. Pharmacokinetic parameters of AA were determined in male rats after administering a single 10 mg/kg intravenous dose (i.v.) and 50 mg/kg oral bolus dose. Following i.v. administration the initial decline in serum concentration was rapid with half-life of 20.2 min. After a single oral dose the concentration-time data of AA in rats was best described by a one-compartment model with equal first order absorption and apparent elimination rate constants. The half-life of the decline in serum concentration of AA following oral administration was 50.6 min, indicating absorption rate limiting disposition at the high dose given. Comparison of AUC of oral and i. v. data indicates that only about 60% of the oral dose reach the systemic circulation.     

Clinical pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in patients with B-lineage lymphoid malignancies

The authors examined the pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in 17 patients (4 children, 13 adults) with B-lineage lymphoid malignancies, including 12 patients with acute lymphoblastic leukemia (ALL) and 5 patients with non-Hodgkin's lymphoma (NHL). The immunoconjugate was administered intravenously as a 1-hour continuous infusion at a dose level of either 0.1 mg/kg (N = 12) or 0.18 mg/kg (N = 5), and the plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameters. Pharmacokinetic analyses revealed a plasma half-life of 19 +/- 4 hours, mean residence time of 22 +/- 4 hours, and a systemic clearance of 18 +/- 2 mL/h/kg. The average (mean +/- SEM) values for the maximum plasma concentration Cmax, volume of distribution at steady state (Vss), and area under curve (AUC) were 1092 +/- 225 ng/ml, 291 +/- 37 mL/kg, and 9987 +/- 2021 micrograms x h/L, respectively. The AUC values were higher at the 0.18 mg/kg dose level than at the 0.1 mg/kg dose level (16,848 +/- 5118 micrograms x h/L vs. 7128 +/- 1156 micrograms x h/L, p = 0.009). Patients with ALL had a significantly larger volume of distribution at steady state (332 +/- 47 mL/kg vs. 191 +/- 12 mL/kg, p = 0.04), faster clearance (21 +/- 3 mL/h/kg vs. 11 +/- 2 mL/h/kg, p = 0.03), and lower dose-corrected AUC than patients with NHL (6010 +/- 836 micrograms x h/L vs. 12,044 +/- 2707 micrograms x h/L, p = 0.006). There was a trend toward faster clearance rates (23 +/- 4 mL/h/kg vs. 16 +/- 3 mL/h/kg, p = 0.1), shorter elimination half-lives (5.7 +/- 3.6 hours vs. 13 +/- 8.8 hours, p = 0.1), and shorter mean residence times (11 +/- 3 hours vs. 25 +/- 5 hours, p = 0.08) for non-Caucasian patients as compared to Caucasian patients. When compared to adult patients, pediatric patients showed a significantly larger volume of distribution at steady state (418 +/- 82 mL/kg vs. 252 +/- 34 mL/kg, p = 0.02) and a longer elimination half-lives (18.4 +/- 13.6 hours vs. 8.7 +/- 6.7 hours, p = 0.04). The pharmacokinetics of B43-Genistein was not affected by the gender of the patients or by bone marrow transplantation in past medical history. Overall, B43-Genistein showed favorable pharmacokinetics in this heavily pretreated leukemia/lymphoma patient population, which is reminiscent of its recently reported favorable pharmacokinetics in cynomolgus monkeys. To our knowledge, this is the first clinical pharmacokinetics study of a tyrosine kinase inhibitor containing immunoconjugate.     

Pharmacokinetics of high-dose diluted lidocaine in local anesthesia for facelift procedures

The maximal recommended local anesthetic dose of lidocaine is 7 mg/kg; higher doses are used in tumescent liposuction. The objective of this study was to characterize the pharmacokinetics of high-dose diluted lidocaine administered together with epinephrine for local anesthesia in facelift procedures. This was a prospective study of six female patients undergoing elective facelift surgery. The local anesthetic solution consisted of 0.33% lidocaine, 0.07% sodium bicarbonate, and 1:600,000 epinephrine in normal saline. Plasma lidocaine levels were determined in the course of 24 hours and were subjected to pharmacokinetic analysis. Patients' age was 58.5 +/- 8 years and weight 68.5 +/- 18.7 kg. Mean lidocaine dose was 21.6 +/- 3.6 mg/kg (range, 17.5-26.3 mg/kg) infiltrated subcutaneously over 20 minutes or less. No lidocaine-related adverse effects were recorded. Major bleeding was not observed. Postoperative analgesia was required only at 11.8 +/- 4.6 hours after surgery. Pharmacokinetic analysis was peak concentration 1.41 +/- 0.4 microg/mL, time to reach peak concentration 9.3 +/- 1.6 hours, terminal half-life 6.2 +/- 1.5 hours, area under the curve from time zero to last data point 1379.8 +/- 470 microg/min/mL, and area under the curve from time zero to infinity 1530.6 +/- 471.6 microg/min/mL. Plasma lidocaine concentrations formed almost a plateau between 2 and 12 hours (ie, at approximately 1.2 microg/mL) after infiltration. It is concluded that local anesthesia with diluted lidocaine at a dose 3.1 times higher than the currently recommended dose (7 mg/kg) administered with epinephrine yielded a peak plasma lidocaine level that was 72% below the level considered safe (5 microg/mL).     

Flecainide pharmacokinetics after multiple dosing in patients with impaired renal function

Study objective: To determine the pharmacokinetics of oral flecainide acetate after single and multiple doses in patients with impaired renal function. Design: Paired study of single followed by multiple oral doses. Setting: Patients enrolled in a Veterans Administration Hospital renal subspecialty clinic and dialysis unit. Patients: Twenty men and one woman between the ages of 33 and 74 years with impaired renal function including ten patients with end-stage renal disease receiving maintenance hemodialysis. Interventions: All patients received a single, oral, 200-mg dose of flecainide acetate followed by sequential venous blood sampling. Seven to 14 days after the single-dose study, each patient received 100 mg of flecainide acetate by mouth every 12 hours or every 24 hours for 10 days. Venous blood samples were drawn periodically during multiple dosing and sequentially after the last dose. Measurements and primary results: Peak flecainide acetate concentrations (micrograms/L) were 330 +/- 104 micrograms/L (mean +/- SD) after the single dose and 687 +/- 505 micrograms/L after multiple doses. Time to peak occurred at 3.3 +/- 2.3 hours and 2.7 +/- 1.2 hours after single and multiple doses, respectively. The apparent volume of distribution was 8.2 +/- 2.9 L/kg and 9.2 +/- 5 L/kg after single and multiple dose studies, respectively. Plasma elimination half-life after the single dose (20.4 +/- 9.0 hours) was significantly shorter (P less than .001) than after multiple doses (37.8 +/- 39.7 hours), as was total body clearance: 391 +/- 154 mL/min versus 302 +/- 194 mL/min. There were no statistically significant differences between pharmacokinetic measurements determined for patients on chronic hemodialysis when compared with nondialysis patients during the multiple-dose study.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of neurotoxic organophosphorus compounds in turkeys

To determine the neurotoxic effects of organophosphorus compounds in turkeys, adult birds were given a single oral dose of 125, 250, 500 mg/kg triorthotolyl phosphate (TOTP) or a single subcutaneous dose of 0.4 mg/kg O,O'-diisopropyl phosphorofluoridate (DFP). At 24 h after dosing with TOTP, neurotoxic esterase activity was found to be inhibited in a dose-related manner, as were the activities of blood cholinesterase and liver cholinesterase. Clinical signs of neuropathy appeared within 2 wk in TOTP-treated groups of birds with neurotoxic esterase activities at 59 +/- 3% (125 mg/kg), 47 +/- 7% (250 mg/kg) and 33 +/- 3% (500 mg/kg) of control values (mean +/- SEM, n = 5) at 24 h after dosing. Signs appeared earlier in turkeys given DFP. Histological examination revealed only mild lesions of delayed neurotoxicity in birds given either TOTP or DFP.     

Pharmacokinetics of felodipine in chronic hemodialysis patients

Five chronic hemodialysis patients (1 woman and 4 men, aged, 46-68 yr) were given an oral dose of 10 mg felodipine followed by 0.057 mg [3H] felodipine IV. After 5 hours, a hemodialysis treatment lasting 4 hours was performed. Blood and dialysate flows were 200 mL/min and 500 mL/min, respectively. Capillary dialyzers with 1.3 m2 cellulose acetate membrane were used. The pharmacokinetic characteristics and reduction in diastolic BP were similar to those in hypertensive patients with normal renal function and in uremic patients who were not treated with dialysis. There was no measurable removal of felodipine by hemodialysis. Dialyzer clearance of radioactive metabolites was about 10 mL/min, and only 8.9% of the dose was eliminated by the treatment. The half-life of radioactive metabolites was 10 days (6-14 days) in three patients dialyzed thrice weekly. Since the metabolites are biologically inactive, no adjustment of dose is required in hemodialysis patients.     

Pharmacokinetics of nafimidone in patients with chronic intractable epilepsy

Nafimidone is a new antiepileptic drug which may be effective in partial onset seizures. We studied the pharmacokinetics of nafimidone and its metabolite, nafimidone alcohol, in 12 patients already taking phenytoin and/or carbamazepine. The half-life of nafimidone was 1.34 +/- 0.48 hours after a 100mg single dose and 1.69 +/- 0.91 hours after a 300mg single dose. However, the half-life of nafimidone alcohol increased from 2.84 +/- 0.72 hours after a 100mg single dose to 4.22 +/- 1.09 hours after a 300mg single dose (p less than 0.02). The clearance of nafimidone was 43.56 +/- 22.11 L/h/kg after a 100mg single dose and 35.51 +/- 28.93 L/h/kg after the 300mg single dose. The respective apparent volumes of distribution of nafimidone after single 100 and 300mg doses were 80.78 +/- 46.11 L/kg and 71.01 +/- 36.86 L/kg. After short term (9 to 10 weeks) and long term (127 to 152 weeks) maintenance therapy on nafimidone 600mg per day the half-life of nafimidone alcohol was 2.23 +/- 0.36 hours and 2.16 +/- 0.60 hours, respectively. No nafimidone could be detected in urine but from 4 to 7% of the daily nafimidone dose was recovered as nafimidone alcohol. Thus, it appears that over 90% of the administered dose of nafimidone is metabolised by pathways other than glucuronidation of nafimidone alcohol and urinary excretion.     

Pharmacokinetics of rhein from Onpi-to,an Oriental herbal medicine,in rats

Onpi-to, an herbal medicine composed of five crude drugs (Rhei Rhizoma, Glycyrrhizae Radix, Ginseng Radix, Zingiberis Rhizoma and Aconiti Tuber), was administered orally to rats. Onpi-to includes 1.240% of total potential rhein derived from sennoside A, sennoside B, rhein 8-O-glucopyranoside and rhein. Plasma, urinary and biliary levels of rhein were determined by an HPLC-UV method. The plasma levels displayed curves characterized by maximum peaks at 8.3+/-5.2 min, 8.3+/-5.2 min and 20.0+/-21.9 min following dosages of 125, 250 and 500 mg/kg with mean concentrations of 1302.5+/-926.4, 2973.6+/-684.3 and 3118.8+/-1701.2 ng/ml, respectively, followed by a subsequent decline. Area under the concentration-time curve (AUC)(0-48 h) at doses of 125, 250 and 500 mg/kg were 752.3+/-321.5, 2443.3+/-554.4 and 4443.2+/-2641.3 ng.h/ml, respectively. In female rats, rhein plasma levels showed curves which had a maximum peak at 45.0+/-16.4 min after a dosage of 250 mg/kg with mean concentration of 3058.0+/-1533.7 ng/ml, followed by a subsequent decline. AUC(0-48 h) was 5537.7+/-1876.0 ng.h/ml. The cumulative urinary excretion of rhein and of conjugated rhein was 3.14+/-1.56% and 38.21+/-18.87% of dose, respectively, 48 h after dosing at 500 mg/kg of Onpi-to in male rats. The cumulative biliary excretion of rhein was 1.34+/-0.44% of dose 48 h after dosing at 500 mg/kg of Onpi-to in male rats.     

Correlation of glutamate plus aspartate dose, plasma amino acid concentration and neuronal necrosis in infant mice

Eight-day-old mice were given by gavage glutamate and aspartate mixtures providing each amino acid at 125, 250 or 500 mg/kg body weight (250, 500 and 1000 mg total dicarboxylic amino acids/kg) and the degree and extent of neuronal necrosis were determined. Similar studies were carried out in mice given monosodium L-glutamate at 250 or 500 mg/kg body weight. Plasma aspartate and glutamate concentrations were determined at each dose level. No animal given either glutamate or the glutamate plus aspartate mixture at 250 mg/kg developed neuronal necrosis. However, neuronal necrosis developed in 30% of animals given glutamate at 500 mg/kg (12+/-2 necrotic neurons/section in the region of maximal damage) and in 17% of animals given 250 mg glutamate/kg plus 250 mg aspartate/kg (11-13 necrotic neurons/section in the region of maximal damage). The threshold mean peak plasma glutamate plus aspartate concentration associated with neuronal necrosis was 128+/-24 mumol/dl. Using these data, and previously published data for aspartate-induced neurotoxicity (Finkelstein et al. Toxicology 1983, 29, 109), the individual threshold plasma glutamate and aspartate concentrations associated with neuronal necrosis were calculated to be 110 mumol/dl for aspartate and 75 mumol/dl for glutamate.     

Pharmacokinetics of ranitidine following oral administration with ascending doses and with multiple-fixed doses

The aim of these studies was to further delineate pharmacokinetic characteristics of ranitidine, a new histamine H2-receptor antagonist. In one study, ranitidine was administered orally to six normal men in increasing doses of 100 mg, 150 mg, 250 mg, and 400 mg weekly over a four-week period. The peak serum concentrations increased with the corresponding increases in dose but the time needed to reach peak serum concentration did not vary significantly with increased doses. The pharmacokinetic parameters were calculated for each subject at each of the four dose levels. The total area under the curve (AUC) at the four different doses was linearly related to the dose for each individual subject; and a plot of AUC versus dose had a correlation coefficient of .886 (P less than .001). The apparent plasma clearance did not vary with the increase in dose; and the average corrected clearance values ranged between 6.7 and 10 mL/(min X kg). Elimination half-life was between 2.6 and 3.0 hours; and the volume of distribution (Vd area) was between 1.6 and 2.4 L/kg. About 35% of the ranitidine dose was excreted in the urine in the unchanged form over a 12-hour excretion interval. In the second study, ranitidine was administered orally to 12 normal subjects in doses of 150 mg and 200 mg twice daily for 28 days. The pharmacokinetic parameters for ranitidine with multiple-dose treatment were similar to those obtained with single-dose administration. Predose ranitidine concentrations (trough levels) did not increase with multiple dose administration.(ABSTRACT TRUNCATED AT 250 WORDS)