Comparison of the effects of food on the pharmacokinetics of cefprozil and cefaclor.

The objective of this study was to assess the effects of food on the pharmacokinetics of cefprozil and cefaclor. A group of 12 healthy male volunteers received a single 250-mg dose of cefprozil or cefaclor under fasting conditions as well as after the intake of food. There was a 1-week washout period between each treatment. Serial blood samples were collected and assayed for cefprozil or cefaclor by specific high-pressure liquid chromatographic methods. The mean +/- standard deviation peak concentration (Cmax) of cefprozil in plasma was 6.13 +/- 1.22 micrograms/ml under the fasting condition and 5.27 +/- 1.06 micrograms/ml after breakfast, and these values were not significantly different from each other. The corresponding median time to reach Cmax was prolonged after food intake, but this difference was not significant. The mean Cmax values of cefaclor decreased significantly from 8.70 +/- 2.72 micrograms/ml under the fasting condition to 4.29 +/- 1.52 micrograms/ml after breakfast, and the corresponding median times to reach Cmax were significantly prolonged. The mean half-lives of cefprozil and cefaclor were nearly identical for the two treatments, suggesting that the elimination kinetics of these cephalosporins remained unaltered when the drugs were administered with food. The area under the plasma-concentration-versus-time curves for fasted and fed conditions were not significantly different for both drugs. The results of this study indicate that the extent of absorption and rate of elimination of both cephalosporins remain unaltered in the presence of food. However, the absorption rate of cefaclor is significantly reduced in the presence of food, while that of cefprozil remains unaltered. As a result, the Cmax of cefaclor is significantly reduced in the presence of food, whereas that of cefprozil is not significantly affected. Cefprozil can be administered with a meal without markedly affecting levels in blood.     

Interaction between oral hydralazine and propranolol. I. Changes in absorption, presystemic clearance and splanchnic blood flow

A study was undertaken of propranolol pharmacokinetics in dogs before and after oral coadministration of hydralazine to determine whether interactions described in humans could be reproduced in an animal model. Additionally, physiological parameters considered to be relevant to the pharmacokinetic handling (absorption rate and splanchnic hemodynamics) were studied. Coadministration of oral hydralazine and propranolol in conscious dogs caused an increase in peak plasma concentration ( Cpmax ) and area under the oral plasma concentration-time curve (AUC) of propranolol ( Cpmax = 19.2 +/- 5.8 ng/ml, control; Cpmax = 91.5 +/- 12.8 ng/ml, posthydralazine : AUC = 65.7 +/- 14.6 ng X hr/ml, control; AUC = 152.4 +/- 23.9 ng X hr/ml, posthydralazine : mean +/- S.E.M., n = 5; P less than .01 and P less than .01), without change either in the peak plasma level, time to peak or plasma AUC of [14C] propranolol and metabolites (P greater than .70, P greater than .90 and P greater than .60, respectively) or in urinary recovery (urinary recovery = 39.7 +/- 4.3% dose, control; urinary recovery = 41.8 +/- 6.2% dose, posthydralazine ). When propranolol was administered i.v., hydralazine caused a small (42.3 +/- 18%), but significant (P less than .025), increase in systemic clearance. Oral bioavailability increased from 7.3 +/- 2.1 to 23.6 +/- 5.1% (mean +/- S.E.M., n = 5, P less than .025), hepatic extraction showed correspondingly inverse changes and estimated hepatic blood flow increased from 34.9 +/- 3.8 to 63.3 +/- 10.8 ml/min/kg (P less than .025).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of food and sucralfate on a single oral dose of 500 milligrams of levofloxacin in healthy subjects.

The effects of food and sucralfate on the pharmacokinetics of levofloxacin following the administration of a single 500-mg oral dose were investigated in a randomized, three-way crossover study with young healthy subjects (12 males and 12 females). Levofloxacin was administered under three conditions: fasting, fed (immediately after a standardized high-fat breakfast), and fasting with sucralfate given 2 h following the administration of levofloxacin. The concentrations of levofloxacin in plasma and urine were determined by high-pressure liquid chromatography. By noncompartmental methods, the maximum concentration of drug in serum (Cmax), the time to Cmax (Tmax), the area under the concentration-time curve (AUC), half-life (t1/2), clearance (CL/F), renal clearance (CLR), and cumulative amount of levofloxacin in urine (Ae) were estimated. The individual profiles of the drug concentration in plasma showed little difference among the three treatments. The only consistent effect of the coadministration of levofloxacin with a high-fat meal for most subjects was that levofloxacin absorption was delayed and Cmax was slightly reduced (Tmax, 1.0 and 2.0 h for fasting and fed conditions, respectively [P = 0.002]; Cmax, 5.9 +/- 1.3 and 5.1 +/- 0.9 microg/ml [90% confidence interval = 0.79 to 0.94] for fasting and fed conditions, respectively). Sucralfate, which was administered 2 h after the administration of levofloxacin, appeared to have no effect on levofloxacin's disposition compared with that under the fasting condition. Mean values of Cmax and AUC from time zero to infinity were 6.7 +/- 3.2 microg/ml and 47.9 +/- 8.4 microg x h/ml, respectively, following the administration of sucralfate compared to values of 5.9 +/- 1.3 microg/ml and 50.5 +/- 8.1 microg x h/ml, respectively, under fasting conditions. The mean t1/2, CL/F, CLR, and Ae values were similar among all three treatment groups. In conclusion, the absorption of levofloxacin was slightly delayed by food, although the overall bioavailability of levofloxacin following a high-fat meal was not altered. Finally, sucralfate did not alter the disposition of levofloxacin when sucralfate was given 2 h after the administration of the antibacterial agent, thus preventing a potential drug-drug interaction.     

The dopaminergic regulation of plasma growth hormone secretion in normal subjects

The role of endogenous dopamine (DA) on plasma GH secretion was studied using domperidone (DA receptor blocker which does not cross blood brain barrier) in 16 normal subjects. After a bolus injection of domperidone (10 mg, i.v.), plasma PRL in 11 cases rose quickly and markedly from the basal level of 9.5 +/- 1.2 ng/ml (Mean +/- S.E.) to a maximum of 76.3 +/- 10.6 ng/ml at 30 min. In contrast, plasma GH in these cases showed a delayed and slight increases to domperidone injection where the values at 90 min and 120 min (3.5 +/- 0.8 ng/ml and 3.7 +/- 1.0 ng/ml) were significantly higher than those in control study (1.2 +/- 0.2 ng/ml and 1.0 +/- 0.1 ng/ml; p less than 0.05; n = 8). Domperidone infusion (0.22 mg/min/3 hr) was performed in the remaining 5 subjects. The plasma PRL responses were similar to those in the bolus injection of domperidone. These PRL responses were not modified when L-dopa was administered 30 min after the start of iv infusion of domperidone. Plasma GH showed slight but significant increases 135 min after the infusion compared to control study (4.3 +/- 1.2 ng/ml vs. 1.0 +/- 0.1 ng/ml; p less than 0.05). By the prior infusion of domperidone plasma GH responses to L-dopa was delayed and blunted, i.e., the occurrence of elevation and peak value of GH delayed by 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of drug polarity on the absorption of opioid drugs into CSF and subsequent cephalad migration following lumbar epidural administration: application to morphine and pethidine

This study examines the influence of drug polarity on the rate and extent of drug absorption into cerebrospinal fluid (CSF) following lumbar epidural administration. Twelve patients with pain secondary to cancer were simultaneously administered both morphine (10 mg) and pethidine (50 mg) in 10 ml of normal saline via an epidural catheter inserted in the lumbar region (usually L2,3) and attached to a subcutaneously implanted portal reservoir. Frequent blood samples were collected to characterise the vascular uptake of both opioids. In addition, a single CSF sample was collected in each patient from the C7-T1 interspace at one of the following times: 10, 30, 60, 120, 180 and 240 min. There was a rapid vascular uptake of morphine from the epidural space with a mean (+/- S.D.) peak concentration of 173 +/- 80 ng/ml (range 52-345 ng/ml) and a time-to-peak concentration of 8 +/- 6 min (range 2-17 min). In contrast, the vascular uptake of pethidine was more variable with a mean (+/- S.D.) concentration of 274 +/- 294 ng/ml (range 80-1113 ng/ml) and the time-to-peak concentration was 21 +/- 26 min (range 2-75 min). There was a rapid absorption of pethidine across the dura mater into the CSF with peak CSF concentrations between 1400 and 1650 ng/ml occurring between 10 and 60 min in samples collected cephalad (C7-T1 interspace) from the administration point in the lumbar region. However, the peak morphine concentration in CSF was delayed relative to the pethidine peak and occurred at 120 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Single-dose pharmacokinetics of a pleconaril (VP63843) oral solution in children and adolescents. Pediatric Pharmacology Research Unit Network

Pleconaril is an orally active, broad-spectrum antipicornaviral agent which demonstrates excellent penetration into the central nervous system, liver, and nasal epithelium. In view of the potential pediatric use of pleconaril, we conducted a single-dose, open-label study to characterize the pharmacokinetics of this antiviral agent in pediatric patients. Following an 8- to 10-h period of fasting, 18 children ranging in age from 2 to 12 years (7.5 +/- 3.1 years) received a single 5-mg/kg of body weight oral dose of pleconaril solution administered with a breakfast of age-appropriate composition. Repeated blood samples (n = 10) were obtained over 24 h postdose, and pleconaril was quantified from plasma by gas chromatography. Plasma drug concentration-time data for each subject were fitted to the curve by using a nonlinear, weighted (weight = 1/Ycalc) least-squares algorithm, and model-dependent pharmacokinetic parameters were determined from the polyexponential parameter estimates. Pleconaril was well tolerated by all subjects. A one-compartment open-model with first-order absorption best described the plasma pleconaril concentration-time profile in 13 of the subjects over a 24-h postdose period. Pleconaril pharmacokinetic parameters (means +/- standard deviations) for these 13 patients were as follows. The maximum concentration of the drug in serum (Cmax) was 1,272.5 +/- 622.1 ng/ml. The time to Cmax was 4.1 +/- 1.5 h, and the lag time was 0.75 +/- 0.56 h. The apparent absorption rate constant was 0.75 +/- 0.48 1/h, and the elimination rate constant was 0.16 +/- 0.07 1/h. The area under the concentration-time curve from 0 to 24 h was 8,131.15 +/- 3,411.82 ng.h/ml. The apparent total plasma clearance was 0.81 +/- 0.86 liters/h/kg, and the apparent steady-state volume of distribution was 4.68 +/- 2.02 liters/kg. The mean elimination half-life of pleconaril was 5.7 h. The mean plasma pleconaril concentrations at both 12 h (250.4 +/- 148.2 ng/ml) and 24 h (137.9 +/- 92.2 ng/ml) after the single 5-mg/kg oral dose in children were higher than that from in vitro studies reported to inhibit > 90% of nonpolio enterovirus serotypes (i.e., 70 ng/ml). Thus, our data support the evaluation of a 5-mg/kg twice-daily oral dose of pleconaril for therapeutic trials in pediatric patients with enteroviral infections.     

Pharmacokinetics of cefetamet (Ro 15-8074) and cefetamet pivoxil (Ro 15-8075) after intravenous and oral doses in humans.

This report summarizes the results of three pharmacokinetic studies of cefetamet and cefetamet pivoxil conducted in normal adult male volunteers. In the first study the pharmacokinetics of cefetamet were evaluated after intravenous infusion of doses ranging from 133 to 2,650 mg. Over this dose range, the pharmacokinetics were linear. A dose-proportional increase in the area under the curve from zero to infinity was observed, whereas total clearance (140.3 +/- 23.6 ml/min), renal clearance (130.3 +/- 18.2 ml/min), volume of distribution at steady state (0.288 +/- 0.023 liter/kg), fraction excreted unchanged in the urine (94 +/- 11%), and elimination half-life (2.07 +/- 0.18 h) were independent of dose. In a second study the absolute bioavailability of single 1,500-mg doses of a tablet formulation of the pivaloyloxymethylester of cefetamet was evaluated under conditions of fasting and after a standard breakfast. Administration with food increased the extent of absorption (from 31 +/- 7 to 44 +/- 4%) while decreasing the rate of absorption (time to maximum concentration of drug in plasma increased from 3.0 +/- 0.6 to 4.8 +/- 0.4 h). The third study consisted of multiple oral administration of 1,000 mg of a similar oral tablet formulation twice daily for 10 days. This regimen was preceded and followed by intravenous administration of a 500-mg bolus dose of cefetamet. Oral doses were administered with breakfast and dinner. The absolute bioavailability of the tablet formulation was assessed after the first dose and after both the morning and the evening doses on day 10 of oral therapy. The compound was consistently absorbed to the extent of approximately 50% with no significant differences observed between the morning and evening doses on day 10.     

Clinical pharmacology and pharmacokinetics of clonidine.

A 300-mug oral dose of clonidine was administered to 5 normal volunteers and measurements of plasma concentration and effects upon blood pressure, heart rate, circulatory reflexes, sedation, and dry mouth were made for the following 8 hr. The plasma concentration rose to a peak of 1.02 +/- 0.52 ng/ml (SD) at 90 min and fell with a mean half-life of 12.7 hr. Blood pressure of the group fell from 111.0/77.0 to 87.2/60.4 after 3 hr and was 95.2/62.2 mm Hg at 8 hr. Heart rate in recumbency was slowed. Marked sedation and a fall in salivary flow followed the same time-course as the plasma concentration. The cold pressor response was reduced but the Valsalva overshoot was little affected.     

Concentrations of aerosolized pentamidine in bronchoalveolar lavage, systemic absorption, and excretion.

Pentamidine pulmonary pharmacokinetics were studied in 13 patients receiving once-daily inhaled therapy and 4 patients receiving low-dose intravenous treatment for Pneumocystis carinii pneumonia. Twenty-four hours after inhaled or intravenous therapy, the mean (+/- standard deviation) concentrations of pentamidine in serial bronchoalveolar specimen fluid ranged from 28.6 +/- 10 to 177.5 +/- 28 ng/ml and 6.05 +/- 2.29 to 21.4 +/- 15.7 ng/ml, respectively. Pentamidine concentrations in brochoalveolar fluid were generally higher after 2 weeks than after day 1 of therapy; however, the differences were not statistically different (P greater than 0.05). The pulmonary half-life after inhaled therapy is long; pentamidine was detectable in bronchoalveolar fluid at 33 (one patient), 69 (one patient), and 115 (one patient) days following the completion of 2 weeks of therapy. Systemic absorption of pentamidine was minimal; the mean (+/- standard deviation) plasma concentration at the completion of inhalation was 13.84 +/- 11.8 ng/ml, or 5% of the mean peak plasma concentration achieved after intravenous administration. Accumulation in the plasma did not occur with repeated inhalation as has been described with multiple intravenous dosing. Cumulative urinary excretion 24 h after the first dose was 5% of that observed with intravenous administration. These data may have importance in designing dosage regimens for the further investigation of inhaled pentamidine for treatment or prophylaxis of P. carinii pneumonia.     

Plasma insulin and C-peptide levels during continuous subcutaneous insulin infusion

A study was performed to estimate the absorption kinetics of insulin infused subcutaneously. Four insulin-dependent diabetic subjects had their insulin pumped through a subcutaneously implanted fine polyethylene catheter at a constant rate of 5.0 +/- 0.3 ml/h but at two different insulin concentrations: 218 mU/ml between meals, and 2400 mU/ml at the start of breakfast, lunch, and dinner (lasting 20, 30, and 30 min, respectively). The amount (40 U/day) and distribution of insulin delivered was identical in the four patients in order to facilitate comparison between the subjects. No attempt was made to normalize their blood glucose during the study period. A study of the kinetics of insulin absorption was made by assaying plasma insulin levels; lack of plasma anti-insulin antibodies was verified; plasma C-peptide levels were measured and were far below values observed in the fed state in nondiabetic patients. The mean maximum insulin level reached after switching from low to high concentration insulin was observed 87 +/- 2 min after breakfast, 117 +/- 22 min after lunch, and 125 +/- 20 min after dinner. Differences observed are not significant. These values are similar to those observed after subcutaneous injection of 40 U/ml Regular insulin as a single bolus. After switching from high to low concentration, plasma insulin levels did not return to their basal values before the third or fourth hour. Subcutaneous insulin infusion could be a safe and easy way of insulin administration in an open-loop system; however, this method does not seem to be suitable for a closed-loop system.     

Effect of nifedipine on serum digoxin concentration and renal digoxin clearance

Nifedipine has been reported either to decrease or not to affect digoxin elimination. We studied the effect of oral nifedipine on steady-state digoxin concentrations and renal clearance in 20 healthy male subjects. After 2 wk of digitalization, all received digoxin, 0.375 mg a day, with placebo for 2 wk, then digoxin and nifedipine, 18.5 +/- 4 mg every 8 hr, for 2 wk, and then digoxin with placebo for 2 wk. Mean (+/- SD) digoxin concentrations of 0.74 +/- 0.20 and 0.75 +/- 0.25 ng/ml on placebo were not altered by nifedipine (0.77 +/- 0.23 ng/ml). Digoxin clearance was 2.2 +/- 0.6 and 2.7 +/- 0.8 ml/kg/min on placebo and 2.5 +/- 0.6 ml/kg/min on nifedipine. No change in pharmacologic effect of digoxin by nifedipine was observed, but mean blood pressure was lower and heart rates were accelerated. These data indicate that oral nifedipine does not alter digoxin concentrations or decrease renal clearance in healthy subjects.     

Digoxin intoxication: the relationship of clinical presentation to serum digoxin concentration

A radioimmunoassay for serum digoxin concentration has been used to study the interrelationships of circulating levels of the drug and various factors in the clinical setting in 48 hospitalized patients with cardiac rhythm disturbances due to digoxin intoxication. 131 patients on maintenance doses of digoxin without toxicity and 48 patients with equivocal evidence of digoxin excess were also studied and compared with the toxic group.Patients with cardiac rhythm disturbances due to digoxin intoxication tended to be older and to have diminished renal function compared with the nontoxic group; body weight, serum potassium concentration, underlying cardiac rhythm, and nature of cardiac disease were not significantly different for the groups as a whole. Despite comparable mean daily digoxin dosages, digoxin intoxicated patients had a mean serum digoxin concentration of 3.7 +/-1.0 (SD) ng/ml, while nontoxic patients had a mean level of 1.4 +/-0.7 ng/ml (P < 0.001), 90% of patients without evidence of toxicity had serum digoxin concentrations of 2.0 ng/ml or less, while 87% of the toxic group had levels above 2.0; the range of overlap between the two groups extended from 1.6 to 3.0 ng/ml. Patients with atrioventricular block as their principal toxic manifestation had a significantly lower mean serum digoxin concentration than those in whom ectopic impulse formation was the chief rhythm disturbance.Patients with equivocal evidence of digoxin excess had received comparable daily maintenance doses of digoxin but had a mean serum concentration of 1.9 +/-0.8 ng/ml, intermediate between those of the nontoxic (P < 0.005) and toxic (P < 0.001) groups. Renal function as judged by mean blood urea nitrogen concentration was also intermediate.The data indicate that knowledge of the serum digoxin concentration, weighed in the clinical context, is useful in the management of patients receiving this drug.     

Isosorbide 5-mononitrate kinetics

The kinetics of isosorbide 5-mononitrate (5-ISMN) were studied in 12 healthy subjects after intravenous infusion and oral doses of 20 mg. Kinetic parameters calculated by model-independent methods or by assumption of a one-compartment open model were in good agreement. Mean (+/- SD) systemic clearance of 5-ISMN was 127 +/- 21 ml/min, volume of distribution was 48.5 +/- 6.1 l, t 1/2 was 4.4 +/- 0.5 hr, and mean residence time was 6.2 +/- 0.7 hr. At the end of intravenous infusion of 5-ISMN at a rate of 8 mg/hr for 2.5 hr, mean plasma drug concentrations reached 356 +/- 39 ng/ml. Oral doses of 5-ISMN were essentially completely absorbed (93% +/- 13% systemic availability), and mean peak plasma drug concentrations of 388 +/- 70 ng/ml occurred at 0.83 +/- 0.46 hr. Mean absorption t 1/2 was 19 +/- 12 min. Unlike other vasodilator organic nitrates in clinical use, 5-ISMN is notable for its relatively long t 1/2, essentially complete oral absorption, lack of active metabolites, and low intersubject variability in kinetics.     

Cerebrospinal fluid kinetics of epidural clonidine in man.

Ten patients with deafferentation pain after spinal cord injury were given 150 micrograms clonidine epidurally. CSF and plasma samples were collected over the following 24 h, and drug concentrations were measured by radio-immunoassay. The results of only 6 patients are included in the pharmacokinetic analysis because the catheters were not in the epidural space in the remaining 4 patients. These analyses revealed a mean maximum CSF concentration of 228 ng/ml whereas the mean plasma concentration at all time points was less than 0.7 ng/ml. The elimination half-life of epidural clonidine was 66 +/- 2 min, while the absorption half-life was 31 +/- 7 min, Tmax was 60 +/- 7 min and Cmax was 228 +/- 56 ng/ml. The ratio of the area under the curve (AUC) for CSF and plasma was 52. One patient's catheter was intrathecal and 3 were not in the epidural space. The measured plasma concentrations were similar after all injections. As 4 of 6 patients with epidural catheters obtained pain relief and all 3 patients with spasms obtained relief from epidural clonidine, these data suggest that clonidine has a place in the treatment of patients with spinal cord injury.     

The effects of digoxin and β-methyldigoxin on the heart rate of decompensated patients with atrial fibrillation

Eighteen patients with atrial fibrillation were given digoxin 0.13 mg twice daily for 3 weeks and beta-methyldigoxin 0.10 mg twice daily for another 3 weeks. At the end of each 3 week period an exercise test was performed and the effects on the heart rate of the two drugs were compared. No difference in heart rate was obtained at rest, whereas the heart rate after 6 min of exercise was higher during treatment with digoxin (131 beats/min) than when the patients were taking beta-methyldigoxin (124 beats/min). There were no significant differences between digoxin and beta-methyldigoxin in their effects on the ECG (R-R intervals, T-wave, Q-T duration). The plasma concentrations of the two glycosides were determined by radioimmunoassay and by 86Rb-uptake inhibition assay. Comparable plasma concentration values (1.0 ng/ml for digoxin, 1.1 ng/ml for beta-methyldigoxin, mean values) were obtained by radioimmunoassay, but the 86Rb-technique gave significantly higher values (mean 1.5 ng/ml) for beta-methyldigoxin. It is concluded that beta-methyldigoxin is equal to digoxin for producing slowing of the heart rate in patients with atrial fibrillation.     

Hemoperfusion removal of digoxin from dogs

Removal of digoxin by XAD-4 hemoperfusion columns was tested after four dogs were given 0.06 mg/kg of digoxin i.v. Dogs were perfused for 4 to 5 hr at a flow of 105 ml/min through a 100 gm XAD-4 column 16 hr after the dose. Pharmacokinetic analysis of digoxin levels was performed with a three-compartment model. The apparent postdistribution t1/2 was 16.0 +/- 2.9 (S.D.) hr and decreased to 7.1 +/- 2.1 hr during perfusion. Digoxin perfusion clearance was 46 ml/min. An average of 51 microgram of digoxin was recovered from used columns. CP of digoxin calculated from the total R was 127.5 +/- 13 ml/min or 2.3 times greater than plasma flow. With the use of 3H-digoxin, canine blood was found to contain 2.5 times as much digoxin as did plasma. After perfusion there was an increase in serum digoxin levels in all dogs. Computer analysis showed that the increase in plasma digoxin levels immediately after hemoperfusion occurred because the central compartment, which was depleted of digoxin during hemoperfusion, was refilled from peripheral compartments. This study demonstrated that (1) XAD-4 hemoperfusion doubles the rate of removal of digoxin from dogs, (2) dog whole blood contains more than twice as much digoxin than does plasma, so that hemoperfusion clearance exceeds plasma flow, and (3) a multicompartmental pharmacokinetic model explains the increase in serum digoxin concentrations observed at the completion of hemoperfusion.     

Coupling of mitoxantrone to poly(I).poly(C) reduces absorption after intraperitoneal administration

Coupling of mitoxantrone (M), an intercalating cytostatic, to macromolecular polynucleotides may reduce side effects after direct intraperitoneal chemotherapy by interfering with systemic absorption of M. We have administered free M (30 mg/m2) or M mixed with poly(I).poly(C) (90 mg/m2) intraperitoneally to 5 patients with peritoneal carcinosis (cross-over study): peak plasma levels (HPLC assay) were 62 +/- 12 versus 28 +/- 4 ng/ml (p less than 0.0025), AUC0-24h were 583 +/- 126 versus 481 +/- 57 ng X h/ml (p less than 0.025). Coupling of M to poly(I).poly(C) seems to reduce M absorption after intraperitoneal administration.     

Effect of furosemide on plasma concentration and beta-blockade by propranolol.

Although propranolol and furosemide are used together for hypertension, the effects of furosemide on plasma levels and beta-blocking action of propranolol are not known. Ten healthy subjects received propranolol 40 mg orally; the mean plasma propranolol levels in 60, 90, 180, and 300 min were 85 +/- 16, 90 +/- 7, 82 +/- 8, and 58 +/- 8 ng/ml. Propranolol was then given together with furosemide (25 mg orally) and the propranolol blood level was measured. Mean propranolol plasma levels were 106 +/- 11 ng/ml at 60 min, 120 +/- 12 ng/ml at 90 min (p less than 0.01), 102 +/- 8 ng/ml at 180 min (p less than 0.05), and 78 +/- 8 ng/ml at 300 min (p less than 0.01). Six additional subjects were given an infusion of 1 microgram/min isoproterenol increased by 0.5 microgram/min every 2 min until the heart rate rose by 25% after oral administration of furosemide 25 mg. This procedure was repeated after propranolol (40 mg orally) and propranolol with furosemide (25 mg orally). The amount of isoproterenol which raised the heart rate by 25% was 2.6 +/- 0.3 micrograms after furosemide alone and 17.7 +/- 2 micrograms after propranolol (p less than 0.01). After propranolol with furosemide the dose of isoproterenol required to elevate heart rate by 25% was 109 +/- 15 micrograms (p less than 0.001).     

Enhanced GFR response to oral versus intravenous arginine administration in normal adults.

Both oral protein ingestion and intravenous amino acid infusions have been shown to increase glomerular filtration rate (GFR) and renal plasma flow (RPF) in normal subjects. Although the mechanism of this effect is not known, the renal responses to these loads have been associated with increases in peripheral glucagon concentrations. Conflicting data exist concerning the role of glucagon in the hyperfiltration response after an oral protein meal or administration of an intravenous amino acid mixture. Using a single amino acid as the stimulus for hyperfiltration, we compared the renal responses in six normal subjects to 30 gm oral arginine-HCl, intravenous arginine-HCl, and intravenous glucagon infused at the rate of 10 ng/kg/min. GFR, RPF, and glucagon concentration, as well as levels of plasma amino acids and selected gastrointestinal hormones, were measured for six 30-minute clearance periods after each load. Significant rises in mean peak GFR were noted after both oral arginine (104 +/- 5 ml/min x 1.73 m2 to 145 +/- 9 ml/min x 1.73 m2, p less than 0.02) and intravenous arginine (118 +/- 10 ml/min x 1.73 m2 to 134 +/- 11 ml/min x 1.73 m2, p = 0.02) administration. Mean peak RPF rose significantly after oral arginine (510 +/- 26 ml/min x 1.73 m2 to 710 +/- 32 ml/min x 1.73 m2, p less than 0.01) but not after intravenous arginine (616 +/- 60 ml/min x 1.73 m2 to 687 +/- 64 ml/min x 1.73 m2, p = 0.18). Intravenous glucagon infusion also increased both mean peak GFR (99 +/- 9 ml/min x 1.73 m2 to 149 +/- 10 ml/min x 1.73 m2, p less than 0.01) and RPF (514 +/- 48 ml/min x 1.73 m2 to 771 +/- 38 ml/min x 1.73 m2, p less than 0.01) significantly. We found the mean peak percent rise in GFR (43% +/- 13%) and RPF (42% +/- 12%) after oral arginine to be notably greater than that after intravenous arginine (14% +/- 5% and 13% +/- 9%, respectively). However, the mean peak percent rise in glucagon concentration after oral arginine was significantly lower than that after intravenous arginine (62% +/- 25% versus 479% +/- 176%, respectively, p = 0.04). Infusion of glucagon increased GFR (54% +/- 13%) and RPF (55% +/- 12%) to a degree similar to that seen after oral arginine, but again with a significantly higher mean peak percent rise in peripheral glucagon concentrations when compared with the rise after oral arginine (798% +/- 348% vs 62% +/- 25%, p less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)     

Renal biopsy findings in children receiving long-term treatment with cyclosporine a given as a single daily dose

Long-term treatment of childhood nephrotic syndrome (NS) and rheumatic diseases with cyclosporine A (CsA) given as a single daily dose may yield better results and allow safer use of the drug than the conventional twice-daily dosing. However, the safety of such long-term treatment from the histological standpoint remains to be established. Posttreatment renal biopsy was conducted in a total of eight children (5 with minimal change NS, 2 with focal segmental glomerulosclerosis and 1 with X-linked immune dysregulation, polyendocrinopathy and enteropathy) receiving CsA as a single daily dose, after a mean treatment duration of 20 months (9-36 months). The initial daily dose of CsA (Neoral) was 2.0 mg/kg, given as a single daily dose before breakfast. The dose was subsequently adjusted to achieve a peak (between 1 and 2 hrs post-dosing, C1-C2) blood level of around 800 ng/ml. The mean daily CsA dose, mean C1-C2 blood level, and mean trough blood level in the subjects were 1.9 +/- 0.6 mg/kg, 803.8 +/- 117.2 ng/ml and 36.1 +/- 12.7 ng/ml, respectively. The result revealed no evidence of CsA-related nephrotoxicity, including arteriopathy, striped interstitial fibrosis or tubular atrophy, in any of the study participants. Also, no significant changes were observed in the mean estimated glomerular filtration rate as compared to the pretreatment values (127.6 +/- 14.9 ml/min/1.73 m(2) vs 115.6 +/- 22.8 ml/min/1.73 m(2), and except for mild hypertrichosis, no significant adverse effects of CsA were observed. These findings lend further support to the safety of long-term low-dose CsA treatment (median treatment duration in this study, 20 months), with the drug administered as a single daily dose while maintaining a peak (C1-C2) blood level of around 800 ng/ml.