Showing papers by "Gideon Koren published in 1985"

Prevention of Myocardial Damage in Acute Myocardial Ischemia by Early Treatment with Intravenous Streptokinase

Abstract: 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<0.05) and infarct-related regional ejection fraction (51±19 vs. 34±20 per cent; P<0.01) and a lower QRS score (5.6±4.9 vs. 8.6±5.5; P<0.01) than patients receiving treatment between 1.5 and 4 ho...

Fentanyl pharmacokinetics and hemodynamic effects in preterm infants during ligation of patent ductus arteriosus.

Abstract: A bolus of 30 micrograms X kg-1 fentanyl was given to nine preterm infants (gestational age 31.8 +/- 4.7 weeks, weight 1100 +/- 309 g) for induction of anesthesia for ligation of a patent ductus arteriosus. Thirty minutes after the injection, fentanyl plasma concentrations were between 7.7 and 13.6 ng X ml-1. Elimination half-life was 6-32 hr (mean +/- SD, 17.7 +/- 9.3). Systolic blood pressure remained stable throughout surgery. There was a gradual increase in heart rate from 159 +/- 12 min-1 at the time of skin incision to 173 +/- 15 min-1 at the time of skin closure (P less than 0.05). Fentanyl plasma concentrations remained virtually unchanged between 30 min (10.6 +/- 1.9 ng X ml-1) and 120 min (9.6 +/- 1.6 ng X ml-1); whereas at the end of surgery most infants moved and breathed spontaneously. This phenomenon can be explained by redistribution of fentanyl from brain into pharmacodynamically inert tissues.

Probable Efficacy of High-Dose Salicylates in Reducing Coronary Involvement in Kawasaki Disease

Abstract: 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 (≥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. (JAMA1985;254:767-769)

A simple method for the estimation of glomerular filtration rate by gentamicin pharmacokinetics during routine drug monitoring in the newborn.

Abstract: Assessment of the glomerular filtration rate (GFR) in the newborn is often imprecise because of difficulties in urine collection and because the plasma creatinine level, the traditional marker of renal function, is influenced by many factors in this age group. Gentamicin is given to most preterm infants for suspected or proved sepsis. This drug is eliminated almost entirely by the kidney and its rate of elimination parallels the GFR. We calculated gentamicin pharmacokinetic parameters (t1/2, volume of distribution, and clearance) from three consecutive concentration-time points (trough, peak, and next trough levels) in 38 newborn infants. Creatinine clearance was measured by the conventional method. Both t1/2 (r = 0.74; P less than 0.001) and gentamicin clearance (r = 0.77; P less than 0.001) correlated well with measured creatinine clearance. There was no correlation between these variables and urine output. Gentamicin elimination t1/2 and clearance are useful indices of GFR in the newborn infant and can be easily calculated during routine therapeutic drug monitoring.

Influence of hypothermia on the pharmacokinetics of gentamicin and theophylline in piglets.

Abstract: The influence of hypothermia on gentamicin and theophylline pharmacokinetics was studied in anesthetized pigs given an iv bolus of gentamicin and theophylline during normothermia (37 degrees C) and again 1 wk later after the induction of controlled hypothermia (29 degrees C). During hypothermia, the elimination half-time for gentamicin was significantly prolonged (135 +/- 19 min at 37 degrees C vs. 187 +/- 7 min at 29 degrees C), and there were significant decreases in the volume of the central compartment (Vc) of gentamicin, the gentamicin volume of distribution (Vd), and the gentamicin total body clearance (TBC). Hypothermia was associated with a small but significant decrease in theophylline Vd and Vc, but no change in TBC. In separate experiments, cardiac output decreased during the induction of hypothermia in a temperature-dependent fashion. The changes in gentamicin Vd and TBC may be explained by the decrease in cardiac output and the associated decrease in glomerular filtration rate. This study suggests that the elimination of theophylline, which has a relatively low hepatic extraction ratio, is not influenced by the hypothermia-induced decrease in liver blood flow.

Complications resulting from use of arterial catheters: retrograde flow and rapid elevation in blood pressure.

Abstract: Arterial catheters, routinely used in neonatal intensive care units, have been associated with serious complications. In the present studies, retrograde blood flow occurring during routine flushing of peripheral and umbilical catheters is described. This retrograde flow is associated with a significant elevation of blood pressure at distant sites. These phenomena depend on the volume flushed and on the velocity of the flushing process. These phenomena can be prevented by flushing a small volume of 0.5 mL for a period of five seconds.

Interpretation of excessive serum concentrations of digoxin in children

Abstract: 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)

Interaction Between Digoxin and Commonly Coadministered Drugs in Children

Abstract: Quinidine and digoxin had been coadministered in cardiac patients for several decades before their interaction was reported in 1978. During the last few years, monitoring of increased digoxin serum concentration when several drugs are commonly coadministered with digoxin has led to reports of toxic accumulation of the cardiac glycoside. Because digoxin toxicity is frequently associated with severe morbidity and mortality, close monitoring of clinical and laboratory signs are mandatory whenever the cardiac glycoside is coadministered with quinidine, verapamil, amiodarone, nifedipine, and indomethacin. Because many of the children receiving a combination of digoxin and interacting drugs are outpatients, it is mandatory to take steps to ensure that toxicity will be detected and treated in its early stages.

Decreased Theophylline Clearance Causing Toxicity in Children during Viral Epidemics

Abstract: (1985). Decreased Theophylline Clearance Causing Toxicity in Children during Viral Epidemics. Journal of Asthma: Vol. 22, No. 2, pp. 75-79.

Postmortem redistribution of digoxin in rats.

Abstract: Adult male Wistar rats were treated with either 0.1 or 3 mg/kg body weight X day of digoxin for five days, then killed and stored at 4 degrees C for 12 h in an attempt to mimic the normal preautopsy procedures in our hospital. In rats treated with 0.1 mg/kg body weight X day, the antemortem serum digoxin concentrations (SDC) were 1.1 +/- 0.4 ng/mL while the 12-h postmortem concentration was markedly increased (16.3 +/- 5.9 ng/mL) (P less than 0.01). In rats treated with 3 mg/kg body weight X day, SDC was not changed significantly (11.2 +/- 4.8 ng/mL antemortem and 13.3 +/- 6 ng/mL postmortem). Postmortem redistribution of digoxin was assessed by injection of 125I-labelled digoxin with or without pretreatment with the unlabelled drug. The results indicate that after death passive redistribution of digoxin may take place. When the SDC are within the therapeutic or low toxic range, digoxin may reenter the blood. High antemortem serum concentrations of digoxin may prevent such passive redistribution. Therefore, antemortem digoxin intoxication cannot be reliably inferred on the basis of high postmortem levels of the drug. Digoxin intoxication can be ruled out when postmortem SDC remain within the therapeutic range. The above changes cast doubt on some of the forensic and cardiologic literature, which has in the past been based on incorrect assumptions concerning postmortem behavior of digoxin.

Morphine-induced seizures in newborn infants.

Abstract: Two neonates suffered from generalized seizures during the course of intravenous morphine sulfate for post-operative analgesia. They received morphine in doses of 32 micrograms/kg/hr and 40 micrograms/kg/hr larger than a group of 10 neonates who received 6-24 micrograms/kg/hr and had no seizures. Plasma concentrations of morphine in these neonates was excessive (60 and 90 mg/ml). Other known reasons for seizures were ruled out and the convulsions stopped a few hours after cessation of morphine and did not reoccur in the subsequent 8 months. It is suggested that post-operative intravenous morphine should not exceed 20 micrograms/kg/ml in neonates.

Organization and efficacy of a therapeutic drug monitoring consultation service in a pediatric hospital.

Abstract: On July 1, 1982, a therapeutic drug monitoring (TDM) consultation service was instituted in the hope of improving the decision-making of clinicians with respect to drug therapy. Thirteen different drugs are monitored daily, with an average load of 1,600 inpatient samples per month. The team consists of clinical pharmacology fellows and staff who are available 7 days a week to monitor all drug levels that are outside the putative therapeutic range. In order to evaluate the efficacy of this service in preventing development of potentially toxic drug concentrations, the TDM data from July 1982 to December 1983 have been reviewed. The percentage of toxic levels from the total sample load was significantly lower in the period of July-December 1983 compared with July-December 1982 at the beginning of the service (2.25% vs. 4.25%, p less than 0.01). Since January 1983, the percentage has been maintained at less than 3%. A TDM consultation service can help to optimize the use of drug monitoring data by physicians and may lead to improved prescribing in a hospital setting.

Pharmacokinetics of fentanyl in children with renal disease.

Abstract: Two cases of fentanyl anesthesia in children with renal diseases are described. In a case of end stage renal failure, the pharmacokinetic parameters during cardiac surgery were similar to 18 children from the same age group with normal renal function. In a case of Wilm's tumor, there was an unusually prolonged elimination half-life of fentanyl and smaller distribution volume as compared to pediatric parameters during fentanyl anesthesia.

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

Abstract: 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)

Theophylline pharmacokinetics in adolescent females following coadministration of oral contraceptives.

Abstract: The influence of 3-9 months of combined low dose oral contraceptives on theophylline pharmacokinetics was studied in 10 adolescent females (age 15-18 years, mean +/- SD 17 +/- 1) and compared to 10 age-matched control subjects (age 13.8-19 years, mean +/- SD 16.5 +/- 1.6). The distribution volume (0.44 +/- 0.06 L/kg in control vs. 0.44 +/- 0.09 L/kg oral contraceptive group), total body clearance (0.78 +/- 0.13 ml/kg/min vs 0.78 +/- 0.18 ml/kg/min) and elimination T 1/2 (402 +/- 78 min vs. 409 +/- 126 min) were identical in the two groups. It appears that during the first 3-9 months of low dose oral contraceptive treatment, these steroids do not alter the pharmacokinetic behaviour of theophylline in adolescent females.

Evaluating a filter device used for intermittent intravenous drug delivery to newborn infants.

Abstract: Injection of aminoglycosides into a filter chamber was compared with retrograde injection into i.v. tubing for delivery of intermittent drug dosages at low infusion rates in neonates. In 50 infants receiving gentamicin sulfate and 21 receiving amikacin sulfate for at least two days by retrograde i.v. infusion, peak and trough concentrations of the drugs were obtained. A subsequent dose was administered using the filter device, and peak and trough concentrations were obtained. For each infant, the difference between trough and peak concentration (delta C) was compared for the two methods. In vitro testing for gentamicin concentration was performed using the same infusion systems (10 trials for each system). For both in vivo and in vitro testing, the infusion flow rate was 10 mL/hr. For infants receiving gentamicin, delta C was greater for the filter device in 32, greater for retrograde infusion in 13, and equal in 5. The mean gentamicin delta C was significantly greater for the filter chamber method than for retrograde infusion. The in vitro studies showed significantly better gentamicin recovery with the filter device than with retrograde infusion. For amikacin, delta C was greater for the filter device in 15 infants, but the mean amikacin delta C was not significantly different for the two methods. At low flow rates commonly used in infants, the infusion system using the filter device was equal to or superior to retrograde infusion for ensuring complete delivery of intermittent drug doses.

Characteristics of the digoxin-quinidine and digoxin-verapamil interactions in the rat kidney.

Abstract: Recently quinidine and verapamil have been reported to cause toxic accumulation of digoxin due to mainly decrease in the renal secretion of the cardiac glycoside. Because these drugs do not alter GFR, it was assumed that the renal tubular secretion of digoxin is inhibited by them. We studied the characteristics of the renal cortical specific binding for digoxin in the rat kidney, and the antagonistic effects of quinidine and verapamil on digoxin uptake by the kidney slices. Specific binding of digoxin was documented in the renal slices with B max of 42.34 pmol/gr and Kd of 7.6 pmol/gr. The addition of quinidine in therapeutic concentrations (6.7 microM) caused a mean 23% reduction of digoxin uptake by the kidney slice (p less than 0.01). When quinidine concentrations were elevated above the therapeutic range there was additional reduction in digoxin uptake; 84 mM quinidine caused a mean 61% reduction (p less than 0.0001). A similar interaction was documented with verapamil; therapeutic concentrations (550 mM) of the drug caused 15% reduction in digoxin uptake. Further increase in verapamil concentration resulted in additional reduction in digoxin uptake; the maximal concentration used (42 microM) caused 60% decrease in uptake (p less than 0.0001). The inhibition of the renal uptake of digoxin caused by quinidine and verapamil in conjunction with the pharmacokinetic studies, which have shown that both drugs decrease the renal clearance of digoxin without changing GFR, support the suggestion that they inhibit the renal tubular secretion of digoxin.

775 probable efficacy of high dose salicylate in reducing coronary involvement in kawasaki disease

Abstract: Although acetylsalicylic acid (ASA) is the most widely used drug in Kawasaki disease because of its anti-inflammatory and antiplatelet effect, a previous study failed to show efficacy of ASA 30 mg/kg/day in reducing coronary involvement in this disease. We have recently documented erratic and often reduced absorption of ASA in Kawasaki disease such that 30 mg/kg/day could not be assumed to yield therapeutic concentrations. In the present study the efficacy of high dose salicylates in reducing the coronary features of Kawasaki disease was assessed in 36 children who received ASA 80-180 mg/kg/day, and 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 ASA-treated group the dose was adjusted to achieve a concentration ≥ 20 mg/dl. There were significantly more cases of coronary disease in the non-treated group (50%) than in the salicylate-treated group (16.6%) (P=0.014). Due to impaired absorption of ASA during the febrile phase of the disease salicylate serum concentrations achieved per given dose were on average 50% those observed during the non-febrile phase. Despite the difficulty in achieving therapeutic concentrations of salicylate during the febrile phase of Kawasaki disease even with doses as high as 100 mg/kg/day, this dose appears to reduce coronary artery involvement.

Comment: monitoring pediatric iv drugs.

Abstract: TOTHEEDITOR: Oderda and Klein-Schwartz have presented an excellent essay on adult poisoning, especially poisoning in the elderly (DICP 1984;/8:183-5). The data on chemical exposure and poisoning morbidity are most likely accurate as to agent, consequence, and intent. In research published elsewhere, Klein-Schwartz and Oderda report that only 35 of the 237 events (14.8 percent) were with suicidal intent, including three fatalities.' The majority (83 percent) were unintentional exposures. It is the mortality data they present that raise concern. This concern regards intent or motive as coded on death certificates. A major limitation of the National Center for Health Statistics' mortality data, besides a lack of timeliness (1980 data are only now complete), is misclassification. When examining mortality due to poisonings, misclassification can occur at three levels: identification as a poisoning, identification of the agent involved, and determination of the manner or motive. In International Classification of Diseases' (Adapted) classifications, where suicides are felt to be a common manner of death, the third type of misclassification error can be especially high. Therefore, the 46.2 percent of drug-related deaths due to suicide is probably an artificially low percentage. Although quantification of this misclassification is not possible, Table I illustrates that a bias does exist.t' The 1981 data from the National Institute on Drug Abuse's Drug Abuse Warning Network (DAWN) have only 18.8 percent of drug-related deaths attributable to unintentional motivation and 66.8 percent attributable to suicide. Proudfoot and Park have also reported that only 57 percent of suicidal poisoning deaths met the legal criteria for suicide in England (1974)and were coded as such.' Given the social stigma attached to suicide, this misclassification problem is not surprising. The assumption that motives behind exposures leading to morbid outcomes are the same as those leading to fatal outcomes is tenuous and misleading.