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Biomedical subjects

P Gal

Publications and source records attributed to P Gal.

At least 37 records · Page 2Linked to original sources
PubMed1993

Comparison of intranasal versus intravenous verapamil bioavailability.

Intranasal verapamil administration may limit intrasubject variability encountered due to the metabolism differences of the d and l-isomers. We simultaneously measured verapamil/norverapamil concentrations, PR interval, heart rate (HR), and mean arterial pressure (MAP) in six healthy volunteers receiving verapamil 5 mg intranasally and intravenously on two separate occasions. Two subjects achieved measurable verapamil concentrations after intranasal administration with a mean bioavailability of 16.1%. Intranasal bioavailability was limited secondary to instillation volume. No relationship between HR, MAP and verapamil concentration was noted. A relationship between mean intravenous verapamil concentration and mean PR interval was observed; however, extensive interpatient variability existed: two subjects demonstrated enough counterclockwise hysteresis to skew mean data. Mean data may falsely represent the verapamil concentration-effect relationship. Intranasal verapamil administration is limited by instillation volume. Development of a concentrated dosage form is necessary to assess bioavailability. Concentration-effect relationships are more accurately described using individual, rather than mean data.

Administration, Intranasal↗
PubMed1992

Recombinant human complement subcomponent C1s lacking beta-hydroxyasparagine, sialic acid, and one of its two carbohydrate chains still reassembles with C1q and C1r to form a functional C1 complex.

In contrast to the human serum protein which is approximately one-half erythro-beta-hydroxyasparagine at asparagine 134 [Theilens et al. (1990) Biochemistry 29, 3570-3578], recombinant C1s expressed by insect cells after infection with recombinant baculovirus entirely lacks posttranslational modification at asparagine 134. It is also incompletely glycosylated, lacking, at least, sialic acid. Site-directed mutagenesis of one of the two sites of carbohydrate attachment (Asn 159 to Gln 159) yields a faster migrating recombinant C1s still abundantly secreted. Furthermore, the mutated protein displays good hemolytic activity when reassembled with C1q and either human serum or recombinant C1r, demonstrating that these posttranslational modifications are not critical for any of the multiple interactions between C1s and C1q, C1r, C2, and C4 required for reassembly of the C1 complex, activation, and initiation of the classical complement pathway. The 4.0S recombinant C1s dimerizes to yield 5.6S C1s2 in the presence of Ca2+ and forms the 9.1S C1s-C1r-C1r-C1s tetramer upon the addition of human serum C1r and the 15.6S C1 complex upon the addition of C1q to the tetramer. The recombinant C1s and human serum C1s have identical N-terminal amino acid sequences, indicating proper recognition by the insect signal peptidase. The recombinant C1s is secreted and isolated as the unactivated zymogen, and it may be activated by human serum C1r which cleaves at Arg422-Ile423 to yield the characteristic heavy and light chains. A very tight complex is formed between C1-inhibitor and the light chain of recombinant C1s.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Altered heparin pharmacodynamics in patients with pulmonary embolism.

Heparin clearance and pharmacodynamic response were examined in 12 patients being treated for deep venous thrombosis (DVT, 6 patients) or pulmonary embolism (PE, 6 patients). A loading dose of 70 units/kg was administered to DVT patients and 100 units/kg to PE patients followed by an initial infusion rate of 15 or 25 units/kg/h for DVT or PE patients, respectively. Heparin clearance was determined at 4, 12, and 24 h after initiating heparin therapy. The mean heparin clearance in the DVT group was 2,164 +/- 1,024 ml/h at 4 h, 2,591 +/- 1,239 ml/h at 12 h, and 2,795 +/- 1,863 m/h at 24 h. The PE patients had clearances of 1,775 +/- 494, 2,004 +/- 321, and 2,843 +/- 1,000 ml/h at 4, 12, and 24 h, respectively. The difference between the two groups was not statistically significant (p greater than 0.50). The activated partial thromboplastin time (aPTT) was used as a measure of heparin effect. The maximum effect (EMAX) and concentration required to attain 50% of the maximum effect (EC50) were determined for each group using the Lineweaver-Burke linearization method. The mean EMAX and EC50 for the DVT patients were 130 +/- 40.99 s and 1.01 +/- 0.70 units/ml, respectively. For the PE patients, the mean EMAX was 418 +/- 200 s and the mean EC50 was 4.32 +/- 2.81 units/ml. The difference between both groups for each parameter was statistically significant (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-Response Relationship, Drug↗
PubMed1991

The impact of changing ventilator parameters on availability of nebulized drugs in an in vitro neonatal lung system.

An in vitro model was developed to assess nebulized drug delivery. The model simulated the intubated neonate and examined the effect of changes in a variety of parameters commonly confronted in the clinical setting. Theophylline was nebulized for 15 minutes and captured in an artificial lung system (a 1000-mL intravenous bag). Variables were: peak pressure (20, 24, 28 cm H2O), ventilator rate (40, 60, 80 breaths/min), nebulizer flow rate (5, 7, 10 L/min), endotracheal tube size (2.5, 3.0, 3.5 mm), and ventilator type (Servo 900C, Bourns BP 200, Bear Cub BP 2001). The amount of drug actually captured in the bag ranged from 0.009 to 12.59 percent (mean 2.08). A multivariate analysis showed that only nebulizer flow rate had a statistically significant effect on drug delivery with 10 L/min delivering the most drug. All factors combined only accounted for 11.5 percent of the variability in drug delivery. In light of the wide and unpredictable amounts of drug delivered through ventilators, dosing to pharmacologic effect rather than staying within narrow dosing guidelines may be more rational in patients responding poorly to standard doses.

Humans↗
PubMed1991

Indomethacin pharmacokinetics in neonates: the value of volume of distribution as a marker of permanent patent ductus arteriosus closure.

Indomethacin (INDO) pharmacokinetics were examined in 18 neonates on 19 occasions, before and after patent ductus arteriosus (PDA) closure. Patients received INDO as an initial dose of 0.25 mg/kg intravenously, and INDO serum concentrations were measured 2 and 8 h after the dose. Subsequent doses were individualized based on clinical response, toxicity, and INDO pharmacokinetics. PDA status was confirmed echocardiographically at the start and end of therapy. INDO pharmacokinetic parameters varied from dose-to-dose within the same patient, and wide interpatient variability was also observed. Pre- and post-PDA closure, only INDO volume of distribution differed significantly (p less than 0.001) with mean values of 0.36 (+/- 0.06) L/kg and 0.26 (+/- 0.08) L/kg. The reason for this occurrence remains unclear. However, a new application for pharmacokinetics as a probe of physiology is demonstrated.

Biomarkers↗
PubMed1990

Gentamicin in neonates: the need for loading doses.

One hundred eighty-four neonates had gentamicin serum concentrations measured twice after an initial loading dose of 5 mg/kg infused over 1 hour. Gentamicin concentrations immediately postinfusion were calculated using a one-compartment pharmacokinetic model. The extrapolated peak gentamicin concentrations achieved with the 5 mg/kg loading dose was optimal (between 5 and 12 micrograms/ml) in 94% of cases. Had an initial dose of 2.5 mg/kg been given as suggested in most references, peak concentrations 5 mg/kg or higher would only have been achieved in 5% of neonates less than 28 weeks' gestation, 10% of neonates 28 to 30 weeks' gestation, 11% of neonates 31 to 34 weeks' gestation, and 36% of neonates more than 34 weeks' gestation. Our data support the need for greater loading doses of gentamicin in newborns. Our recommendation of 5 mg/kg achieves gentamicin concentrations known to be safe and effective.

Dose-Response Relationship, Drug↗
PubMed1990

Effect of phenobarbital administration on theophylline clearance in premature neonates.

The effect of phenobarbital administration on theophylline clearance was studied in 24 premature neonates. Aminophylline was administered according to a standard protocol of 6 mg/kg loading dose followed by a maintenance dose of 2.5-5 mg/kg/12 h. Of the 24 neonates studied, 12 received a mean phenobarbital dose of 26.34 mg/kg/d (ranging from 2 mg every 24 h to 25 mg every 12 h) and the mean phenobarbital concentration was 56.12 micrograms/ml (range 22-112 micrograms/ml). The remaining 12 patients did not require phenobarbital therapy but did receive aminophylline alone. The two groups were closely matched for gestational age, 5-min Apgar scores, and sex (p greater than 0.2). Steady-state theophylline clearance was determined at least once a week for four or more separate weeks. The study lasted a minimum of 8 wk and if more than one theophylline clearance was determined in any given week, the mean of these clearances was used. Both groups demonstrated an increase in mean theophylline clearance over time (from 15.75 and 16.67 ml/h/kg to 30.33 and 35.42 ml/h/kg for the aminophylline and aminophylline plus phenobarbital groups, respectively). The mean slope, an indicator of the average change in theophylline clearance, was 2.19 for the aminophylline group and 3.27 for the aminophylline plus phenobarbital group (p greater than 0.2), indicating that the theophylline clearance for neonates receiving phenobarbital was not significantly different from that for neonates receiving aminophylline alone. Based on this information, aminophylline does not need to be adjusted solely based on concomitant phenobarbital administration; however, theophylline concentrations should be monitored since theophylline clearance can change rapidly and unpredictably in neonates.

Critical Care↗
PubMed1990

The effect of hemodialysis and hemoperfusion on serum valproic acid concentration.

We report a patient with dialysis-induced encephalopathy who was taking divalproex sodium for a seizure disorder. Her serum valproic acid concentration appeared to be in the low therapeutic range at 54 mg/l yet she continued to have seizure activity. The elimination half-life and apparent clearance of valproic acid were the same for both a dialysis and nondialysis day, indicating that hemodialysis/hemoperfusion has little effect on the overall removal of valproic acid from the body.

Female↗
PubMed1990

Pharmacokinetics and pharmacodynamics of heparin during hemodialysis: interpatient and intrapatient variability.

Heparin pharmacokinetics and pharmacodynamics were studied in 17 patients undergoing hemodialysis, once a week for 4 weeks in order to evaluate intrapatient variability over time. A single bolus injection of heparin was administered directly into the circulation immediately prior to the start of hemodialysis in doses ranging from 3000 to 12,000 U. Blood samples were obtained to determine activated coagulation times (ACT) and heparin concentrations (HC). Combined zero- and first-order elimination was seen in each of the 4 weeks. The half-life of heparin decreased from beginning to end of hemodialysis during each week, with the percentage of decrease from the start of dialysis ranging from 70-74%, indicating concentration-dependent elimination. Since the zero-order component did not appear to be clinically significant, first-order elimination was assumed. A linear decline in ACT over the time of the dialysis period was also seen during each week. A profile of ACT versus HC was generated for each patient as well as for the mean data to assess the relationship of HC to response. An excellent correlation was found for both individual patient data and mean data. In the third week the patients were randomized to receive standard treatment or an individualized dose. They were then crossed over to the opposite group in the fourth week to see if this relationship between ACT and HC would be useful in predicting heparin dose. These profiles were used to individualize the dose during either the third or fourth week of the study. No significant differences were noted between actual and predicted ACT. A significant degree of interpatient variability was demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Indomethacin for patent ductus arteriosus closure. Application of serum concentrations and pharmacodynamics to improve response.

Indomethacin dosing for patent ductus arteriosus closure has been standardized despite wide interpatient variability in indomethacin pharmacokinetics. We compared a novel indomethacin dosing approach using individual pharmacokinetic and pharmacodynamic information (group A) with a control group from our institution (group B) and a level 3 university-based intensive care nursery (group C) who were dosed using current dosing guidelines. Permanent patent ductus arteriosus closure was achieved in 27 of 28 (96.4%) group A patients, 10 of 16 (62.5%) group B patients, and 7 of 13 (52.8%) group C patients. Success rates were significantly higher in group A than Groups B and C (P less than .02). Renal toxicity was the only toxicity reported in any group. The major manifestations of renal toxicity, ie, urine output below 1 mL/kg/h or increased serum creatinine by greater than or equal to 0.5 mg/dL, occurred in none of the group A patients but in seven (43.8%) group B and eight (61.5%) group C patients. Renal toxicity was significantly greater in groups B and C than group A (P less than .02). A pharmacodynamic concentration versus response curve was developed and proved predictive of patent ductus arteriosus closure rates in previous studies where indomethacin concentration versus response data were available. Serum concentration monitoring is a valuable adjunct to indomethacin therapy for patent ductus arteriosus closure, especially when a pharmacodynamic approach is used.

Algorithms↗
PubMed1989

Heparin pharmacokinetics during hemodialysis.

The disposition of heparin was studied in 21 chronic hemodialysis patients. Heparin was administered as a bolus injection in doses of 3,000-12,000 U. Combined zero and first-order elimination was demonstrated, with heparin half-life declining by 74% over 3.5 h during dialysis. Assumption of a first-order pharmacokinetic model of elimination resulted in a mean difference of 0.001 U/ml between actual and predicted heparin concentrations. Mean first-order pharmacokinetic parameters were: half-life, 117 min; heparin volume of distribution (V), 68 ml/kg; clearance, 28 ml/min. A high degree of interpatient variability was also observed. A comparison of V and plasma volume (PV) revealed V to be significantly greater than PV (p less than 0.001), indicating distribution outside the plasma compartment. When compared to blood volume, there was no significant difference (p greater than 0.1), indicating that blood volume may be used to approximate V. The nonlinear component of the elimination process is not clinically significant within the range of therapeutic plasma concentrations used during hemodialysis, but the high degree of interpatient variability indicates that dosage individualization may be useful.

Adult↗