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Biomedical subjects

G Koren

Publications and source records attributed to G Koren.

At least 613 records · Page 34Linked to original sources
PubMed1986

Pharmacokinetic determinants of 6-mercaptopurine myelotoxicity and therapeutic failure in children with acute lymphoblastic leukemia.

The pharmacokinetics of oral 6-mercaptopurine (6MP) was assessed in 20 children with acute lymphoblastic leukemia during maintenance therapy. The AUC was between 0 and 6 X 10 ng X min/ml, and AUC normalized to 1 mg/m2 of 6MP was between 0 and 815 ng X min/ml. Good correlation existed between peak concentrations and AUC (r = 0.866; P less than 0.001). In more than half of the cases there was evidence of prolonged elimination t1/2 or rebound of a serum concentration during the elimination phase corresponding to either an additional compartment or enterohepatic circulation of 6MP. One child did not achieve detectable concentrations on 2 different study days and was switched to a different protocol. The two children who had severe myelotoxicity achieved the largest AUC values per milligram per square meter of 6MP. Our results indicate that pharmacokinetic variability may contribute to either severe myelotoxicity or therapeutic failures. This suggests that monitoring of this drug in children with acute lymphoblastic leukemia may be helpful.

Administration, Oral↗
PubMed1986

Unexpected alterations in fentanyl pharmacokinetics in children undergoing cardiac surgery: age related or disease related?

We assessed the pharmacokinetics of fentanyl in 19 infants and children undergoing cardiac surgery for correction of tetralogy of Fallot, A-V-canal and transposition of the great arteries. Distribution T1/2 (10.2 +/- 2.4 min) and total body clearance (13.3 +/- 6.5 ml/kg/min) were similar to adult values. An elimination t1/2 (102 +/- 85 min) shorter than in adults is readily explained by the significantly smaller distribution volume of the drug (1,203 +/- 777 ml/kg). Good correlation was found between distribution volume (Vss) and elimination t1/2 (r = 0.86, p less than 0.01) and between Vss and age of patients with tetralogy of Fallot (r = 0.85, p less than 0.01). However, older children with Fallot's had higher values of PO2 due to a milder condition (r = 0.89, p less than 0.01); consequently PO2 correlated positively with Vss (r = 0.76, p = 0.05). Fentanyl total body clearance (TBC) tends to decrease with age in these patients (r = 0.66, p = 0.05) similar to noncardiac children. Our studies suggest that the alterations in the distribution volume of fentanyl in these children may largely depend upon the severity of the hemodynamic disturbance whereas TBC of the drug may depend on their age.

Adolescent↗
PubMed1986

Intravenous paraldehyde for seizure control in newborn infants.

We studied 14 newborn infants with seizures after birth asphyxia or other causes. Paraldehyde was given as a 200 mg/kg IV bolus followed by an infusion of 16 mg/kg/h (10 cases), or as a 400 mg/kg bolus (4 cases). Serum concentrations of paraldehyde were higher in periods of adequate seizure control than in periods of little or no response. Paraldehyde serum concentrations above 10 mg/dl were associated with anticonvulsant effects and were achieved in most neonates with a 2-hour infusion of 200 mg/kg/h. If there is no effect, serum concentrations are probably below 10 mg/dl and an additional 200 mg/kg can be given safely over 1 hour.

Female↗
PubMed1986

Pharmacokinetics of oral and intravenous bromide in normal volunteers.

The pharmacokinetics of oral and intravenous bromide was studied in 7 adult volunteers, who served as their own controls. They received 1 ml/kg of 3% sodium bromide, equivalent to 30 mg/kg bromide. Oral bioavailability ranged between 75-118% with a mean of 96 +/- 6%. Elimination T1/2 was 11.9 +/- 1.4 days after oral administration and 9.4 +/- 1.5 days after I.V. administration (P greater than 0.10). The employment of this ion for calculation of extracellular fluid and assessment of its potential significance in environmental toxicology necessitates accurate data on its disposition characteristics.

Administration, Oral↗
PubMed1986

Cellular mechanisms of digoxin transport and toxic interactions in the kidney.

Renal tubular secretion of digoxin appears to be one of the main ports of elimination of the glycoside from the body. Because of its narrow therapeutic window and severe toxicity, the mechanisms of tubular handling of digoxin are important. Moreover, several drugs which are commonly administered with digoxin, including quinidine, spironolactone, verapamil and amiodarone have been shown to decrease renal clearance of digoxin without affecting GFR. We studied the handling of digoxin using in vitro and in vivo approaches. The handling of the glycoside by the brush border suggests passive reabsorption which is not enhanced by commonly coadministered drugs. Digoxin binding to the antiluminal (basal) membrane suggests that the secretion of the glycoside may not involve the pharmacologic receptor, the Na+, K+, ATPase. Using the multiple indicator dilution technique, we could directly show the two steps of secretion of digoxin: Its sequestration from the postglomerular circulation, and its appearance in the urine after transtubular transport. Digoxin transport is not inhibited by a cationic or anionic molecule (PAH and tolazoline). It is possible that digoxin is secreted by a yet unidentified transport mechanism.

Animals↗
PubMed1986

Pharmacokinetics of intravenous clindamycin in newborn infants.

We studied 12 newborn infants (gestational ages 26-39 wk [mean +/- SD, 30.6 +/- 4.7]; birth weight 640-2700 g, [mean, 1,322 +/- 688]; postnatal age 1-24 days [mean, 9.6 +/- 8.5]) who received clindamycin phosphate for suspected or proven necrotizing enterocolitis (ten patients) or suspected anaerobic septicemia (two patients) in doses of 3.2-11 mg/kg every six hours. Range of mean serum concentration of clindamycin at steady state was between 12.7 and 40 micrograms/ml (therapeutic range = 2-10 micrograms/ml). High concentrations could be attributed to elimination T1/2 (6.3 +/- 2.1 hr) 100% longer than in older children or adults. Clindamycin clearance (61.6 +/- 31.6 hr ml/kg/hr) was lower than in older children or adults. Because of the observed prolongation in T1/2 and correspondingly lower clearance, the IV dose of clindamycin in newborn infants should be reduced to 15-20 mg/kg/day given in four daily doses.

Clindamycin↗
PubMed1986

Pharmacokinetic studies of nifedipine and digoxin co-administration.

We have studied the possible interactions between nifedipine and digoxin in 8 healthy subjects in two ways: A. The effect of digoxin (0.25 mg, tablet q.d. for 8 days) on the pharmacokinetics of nifedipine following single-dose (10 mg capsule) administration. Mean values for peak concentration, area under the serum concentration time curve (AUC), total serum clearance and the half-life of elimination of nifedipine did not differ before and concomitantly with digoxin administration. B. The effect of nifedipine (30 mg t.i.d.p.o. for 6 days) on the pharmacokinetics of digoxin following single dose (0.5 mg i.v.) administration. No significant differences were found between the mean values of the half-life of the alpha and beta phases, the AUC and the apparent volume of distribution of digoxin before and concomitantly with nifedipine administration. However, during the later period, the mean cumulative 96 h urinary excretion of digoxin increased by 18% (p less than 0.05) and the renal clearance of digoxin by 26% (p less than 0.05). No change was found, however, in the total plasma clearance of digoxin.

Adult↗
PubMed1985

Prevention of myocardial damage in acute myocardial ischemia by early treatment with intravenous streptokinase.

We evaluated the effectiveness of early intravenous administration of 750,000 units of streptokinase in 53 patients with acute myocardial ischemia treated by a mobile-care unit at home (9 patients) or in the hospital (44 patients). Treatment was begun an average (+/- S.D.) of 1.7 +/- 0.8 hours from the onset of pain. Non-Q-wave infarctions developed subsequently in eight patients, whereas all the others had typical Q-wave infarct patterns. In 81 per cent of the patients the infarct-related artery was patent at angiography performed four to nine days after admission. Vessel patency was independent of the time of treatment, but residual left ventricular function was time dependent. Patients treated less than 1.5 hours after the onset of pain had a significantly higher ejection fraction (56 +/- 15 vs. 47 +/- 14 per cent; P less than 0.05) and infarct-related regional ejection fraction (51 +/- 19 vs. 34 +/- 20 per cent; P less than 0.01) and a lower QRS score (5.6 +/- 4.9 vs. 8.6 +/- 5.5; P less than 0.01) than patients receiving treatment between 1.5 and 4 hours after the onset of pain. Patients treated earlier by the mobile-care unit also had better-preserved left ventricular function than patients treated in the hospital. We conclude that thrombolytic therapy with streptokinase is most effective if given within the first 1.5 hours after the onset of symptoms of acute myocardial infarction.

Adult↗
PubMed1985

Probable efficacy of high-dose salicylates in reducing coronary involvement in Kawasaki disease.

The efficacy of high-dose salicylates in reducing the coronary artery involvement of Kawasaki disease was compared in 36 children who received acetylsalicylic acid, 80 to 180 mg/kg/day, and in 18 who did not receive high-dose salicylates during the febrile phase of the disease and whose fever was controlled mainly with acetaminophen. The two groups were comparable with respect to age and body weight. In the acetylsalicylic acid-treated group, the dose was adjusted to meet the therapeutic serum concentration range (greater than or equal to 20 mg/dL). There were significantly more cases of coronary involvement in the nontreated group (50%) than in the salicylate-treated group (16.6%) and of coronary aneurysms (39% vs 3%). During the febrile phase of the disease, salicylate serum concentrations achieved with a given dose were on the average twofold lower than during the nonfebrile phase, owing to impaired absorption of acetylsalicylic acid. It is suggested that despite the difficulty in achieving therapeutic serum concentrations of salicylate during the febrile phase of Kawasaki disease with a dose as high as 100 mg/kg/day, this dose is potentially capable of preventing the associated coronary disease.

Aneurysm↗
PubMed1985

Interpretation of excessive serum concentrations of digoxin in children.

Between January 1981 and April 1984, excessive serum concentrations of digoxin (5 ng/ml or higher) were recorded in 47 children, aged 2 days to 16 years. In 10 patients, the high concentrations were measured 9.25 to 48 hours after death and were significantly higher than antemortem levels in all cases (8.3 +/- 2.4 (+/- standard deviation) postmortem vs 3.3 +/- 1.5 antemortem, less than 0.0001). In 15 patients (40.5% of the living patients) serum concentrations of 5 ng/ml or higher reflected sampling errors; drug levels were monitored too closely to the administration of a dose. None of these children had toxic manifestations of digoxin. In 10 patients, the excessive concentrations were associated with renal failure and a prolonged elimination half-life (T1/2) of digoxin; in 3 of these patients, there were signs of digoxin toxicity. Six cases were caused by digoxin overdose (accidental ingestions, pharmacy error and a suicide attempt). In 6 additional cases, the existence of an endogenous digoxin-like substance (EDLS) was shown to contribute to the excessive levels of the drug. One case could be attributed to digoxin-amiodarone interaction. In 10 of 37 living patients, digoxin toxicity was diagnosed. After excluding the 15 sampling errors and 6 cases with EDLS, this represents 63% of the cases. There was a good correlation between digoxin elimination T1/2 and serum creatine concentrations (r = 0.71, p less than 0.01). The above observations suggest that excessive serum concentrations of digoxin may not necessarily reflect potentially toxic levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1985

Altered PABA pharmacokinetics in cystic fibrosis. Implications for bentiromide test.

The bentiromide test has been proposed as a useful noninvasive method for assessing exocrine pancreatic function in cystic fibrosis (CF) patients. Following oral administration, this peptide is selectively cleaved by pancreatic chymotrypsin liberating PABA which is passively absorbed. Recent studies have suggested that PABA measured in plasma is superior to the more established method of estimating urinary recovery of this marker. However, in using the plasma test in CF patients, one makes the assumption that the PABA marker has similar distribution and elimination patterns in normal and CF subjects. Since many drugs display altered pharmacokinetics in CF patients, we studied the disposition of PABA following ingestion of free PABA in six controls (age 19-28 years) and 18 CF patients (13-18 years; seven steatorrheic and 11 nonsteatorrheic). Elimination of T1/2 of PABA was significantly shorter in CF patients (58 +/- 21 min) compared to controls (93.5 +/- 28) (P less than 0.005). PABA clearance was similar in the control and CF patients (2.99 +/- 1.21 and 3.27 +/- 1.02 ml/min/kg, respectively). PABA distribution volume was smaller, although not significantly so, than in the controls (268 +/- 107 vs 376 +/- 140 ml/kg). Good correlation was found between PABA distribution volume and T1/2 (r = 0.51 P less than 0.02). Our simulation data suggest that altered pharmacokinetics of PABA in CF patients would cause their PABA levels to be 7% lower than controls at 90 min, 18% at 120 min, 29% at 150 min, and 38% at 180 min.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminobenzoic Acid↗
PubMed1985

Postoperative morphine infusion in newborn infants: assessment of disposition characteristics and safety.

Twelve newborn infants were given morphine intravenously for postoperative analgesia. They received a continuous infusion of 6.2 to 40 micrograms/kg/hr for 9 to 105 hours (mean +/- SEM 59.5 +/- 10.2 hours); in four the infusion was preceded by a loading dose of 50 to 100 micrograms/kg. Morphine plasma concentrations correlated with the rate of infusion, but with large variability. There was a tendency for plasma morphine concentrations to decrease in some patients receiving a constant infusion rate, suggesting improvement in morphine clearance rate. Elimination half-life of morphine (13.9 +/- 6.4 hours) was significantly longer than in older children and adults (about 2 hours). Similarly, morphine concentrations in neonates receiving 20 micrograms/kg/hr for 24 hours were three times higher (52 +/- 31 ng/ml) than in older children receiving the same schedule. Two infants who received 32 and 40 micrograms/kg/hr, respectively, developed generalized seizures. Because of the apparently greater sensitivity to morphine and the lower elimination rate in newborn infants, the infused dose should not exceed 15 micrograms/kg/hr.

Half-Life↗