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Biomedical subjects

P Gal

Publications and source records attributed to P Gal.

At least 19 recordsLinked to original sources
PubMed1997

Gentamicin pharmacokinetics in neonates with patent ductus arteriosus.

OBJECTIVES: To determine the effect of patent ductus arteriosus on the pharmacokinetics of gentamicin in neonates and to examine whether any particular pharmacokinetic parameter is of value as a marker of patent ductus arteriosus. DESIGN: Cohort study of neonates treated with gentamicin, according to a standard dosing protocol. SETTING: A 24-bed, Level III, neonatal intensive care unit. PATIENTS: Neonates treated with gentamicin at the time of admission to the neonatal intensive care unit, using a standard protocol, and who were < 36 wks of gestational age. INTERVENTIONS: All patients received a gentamicin loading dose, and had gentamicin concentrations measured at 2 and 12 hrs after this dose, in order to determine pharmacokinetic parameters and calculate the optimum maintenance dose. Those neonates subsequently diagnosed to have patent ductus arteriosus, based on clinical suspicion and echocardiographic confirmation, were compared with those neonates without clinically suspected patent ductus arteriosus. Gentamicin pharmacokinetic parameters were calculated using a one-compartment model. MEASUREMENTS AND MAIN RESULTS: A total of 322 courses of gentamicin were administered (patent ductus arteriosus, n = 106; control, n = 216). Gentamicin clearance was decreased in the patent ductus arteriosus group vs. the control group (40.02 vs. 44.73 mL/kg/hr; p < .0108). Volume of distribution was greater for patent ductus arteriosus patients (0.61 L/kg) than for controls (0.54 L/kg) (p < .0002). Also, volume of distribution was a useful marker for presence of patent ductus arteriosus, with a 92% specificity for patent ductus arteriosus. CONCLUSIONS: Gentamicin dosing should be altered in neonates with patent ductus arteriosus to reflect the impact of higher volume of distribution and lower clearance. When the gentamicin volume of distribution exceeds 0.7 L/kg, it may be of predictive value for the presence of patent ductus arteriosus.

Anti-Bacterial Agents↗
PubMed1995

Recent advances in pediatrics.

The challenging issues in pediatric pharmacotherapy are both profound and exciting. Microtechnologies for evaluating the impact of genetics in disease (e.g., using polymerase chain reactions) and the possibilities of therapeutic interventions create major clinical and ethical dilemmas that remain to be resolved. Inclusion of pediatric patients in drug development and marketing trials also remains a point of contention. Finally, well-established therapies should not be overlooked in favor of new but unestablished treatment approaches. Future columns will continue to use the current format, in which a few selected topics of high therapeutic importance are discussed. The research technologies, discussion of new drug therapy interventions, and preventive strategies most likely to benefit the health care of infants, children, and adolescents will remain the scope of this column.

Adolescent↗
PubMed1994

Ticarcillin-clavulanic acid pharmacokinetics in preterm neonates with presumed sepsis.

The objective of the reported study was to characterize the pharmacokinetics of ticarcillin and clavulanic acid in premature low-birth-weight (less than 2,200 g) neonates with presumed sepsis. Eleven infants received 12 courses of ticarcillin-clavulanic acid at 75 mg/kg of body weight intravenously every 12 h. Blood samples were collected at 0.5, 1.5, 4, and 8 h following the infusion of the initial dose. The concentrations of ticarcillin and clavulanic acid were determined by a microbiologic assay. Median (interpatient coefficients of variation) values for the volume of the central compartment, total steady-state volume, distributional clearance, total clearance, and terminal elimination half-life for ticarcillin were 0.030 liter/kg (21%), 0.26 liter/kg (48%), 0.41 liter/h/kg (47%), 0.047 liter/h/kg (47%), and 4.2 h (45%), respectively. For clavulanic acid the parameters were 0.28 liter/kg (32%), 0.36 liter/kg (34%), 11 liters/h/kg (36%), 0.12 liters/h/kg (72%), and 1.95 h (40%), respectively. Our results suggest that the current dosing recommendations of 75 mg/kg every 12 h risk subtherapeutic clavulanic acid concentrations and that 50 mg/kg every 6 h is a more rational dosing strategy.

Anti-Bacterial Agents↗
PubMed1994

The role of inhaled steroids in the treatment of bronchopulmonary dysplasia.

Bronchopulmonary dysplasia has been well described in premature infants requiring mechanical ventilation. Systemic steroids are one of many treatment modalities used in the management of these infants, but these agents have been associated with a number of adverse effects. Aerosolized therapy has been proposed as an alternative in order to minimize the systemic complications that occur with the parenteral route. The initial reports of inhaled steroids, although limited, have shown promising results with minimal side effects. This article addresses the mechanism of action, the role in therapy, and potential complications associated with the use of inhaled steroids in the treatment of bronchopulmonary dysplasia.

Administration, Inhalation↗
PubMed1993

Drug disposition in neonates with patent ductus arteriosus.

OBJECTIVE: To review the literature on the physiologic changes created by neonatal patent ductus arteriosus (PDA) and the potential impact on drug disposition in these infants. DATA SOURCES: An Index Medicus and bibliographic search of the English-language literature pertaining to neonatal PDA and drug usage in newborns. DATA SYNTHESIS: PDA in premature infants is associated with a variety of physiologic changes that could alter drug disposition. Perfusion of drug-elimination organs (i.e., liver and kidney) may be diminished, resulting in decreased drug elimination. Further, the general fluid overload state associated with PDA may result in larger volumes of distribution (Vd), and dilutional effects for many drugs. Drug absorption, Vd, tissue penetration, and clearance may be affected by the physiologic changes incurred by a PDA. Although the pharmacokinetics of several categories of therapeutic agents may be affected by a PDA, disposition changes with the aminoglycosides and indomethacin have been the best documented. The most reliable pharmacokinetic change appears to be related to drug Vd. The interpretation of many of these studies is confounded by a potential drug interaction with the concurrent administration of indomethacin for PDA closure. CONCLUSIONS: Close therapeutic drug monitoring is indicated in newborns with PDAs as abrupt changes in drug disposition can occur with PDA closure. PDA-induced changes in specific pharmacokinetic parameters of agents such as the aminoglycosides, indomethacin, and perhaps vancomycin may prove to be a valuable diagnostic adjunct for the identification of babies with undiagnosed PDA. More research into this pharmacophysiologic aspect of pharmacokinetics is warranted.

Absorption↗
PubMed1993

Rapid determination of maintenance heparin infusion rates with the use of non-steady-state heparin concentrations.

OBJECTIVE: To compare heparin dosage adjustment using only activated partial thromboplastin time (APTT) with a method using non-steady-state heparin concentrations (HCs) to rapidly achieve and maintain an APTT ratio greater than or equal to 1.5 times baseline throughout the first 24 hours of therapy. DESIGN: Randomized, blind, parallel comparison of an empiric dosing method based only on APTT with a dosing method based on the calculation of heparin clearance using non-steady-state HCs. SETTING: A private community teaching hospital. The patient, physician, nurses, and investigators were blinded to the dosing method. Only the clinical staff pharmacist, who received the consult and made all dosage adjustments, was not blinded. PATIENTS: All patients requiring heparin for the treatment of thromboembolic disease were evaluated for potential inclusion in the study. Patients were enrolled in the study if they had a clinical diagnosis of deep venous thrombosis confirmed by objective means such as venography or ultrasonography. Patients were excluded if they had active bleeding, platelet dysfunction, thrombocytopenia, severe hepatic disease (total bilirubin > 25.7 mumol/L), renal disease, or evidence of stroke. Patients were also excluded if they were receiving heparin prior to enrollment. MAIN OUTCOME MEASURE: Maintenance of an APTT ratio greater than or equal to 1.5 times baseline throughout the first 24 hours of heparin therapy. RESULTS: Thirty-four patients were enrolled in the study; 17 in each group. The groups were not significantly different with regard to gender, age, baseline APTT, or mean loading dose (p > 0.5). Mean initial infusion rates for the control and HC groups were 1042 +/- 194 and 1071 +/- 143 units/h, respectively (p > 0.5). After the first rate adjustment at 4 hours, the difference achieved significance at 1032 +/- 232 and 1367 +/- 317 units/h for the control and HC groups, respectively (p < 0.01). At 12 hours, 18.8 percent of the patients in the control group were subtherapeutic; by 24 hours, 33.3 percent were subtherapeutic. No patients became subtherapeutic in the HCs group during the first 24 hours. CONCLUSIONS: This study demonstrates that, in contrast to standard heparin dosing methods, the use of non-steady-state HCs allows patients with deep venous thrombosis to rapidly achieve and maintain therapeutic APTT ratios throughout the critical first 24 hours of therapy.

Female↗
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↗