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Biomedical subjects

W R Snodgrass

Publications and source records attributed to W R Snodgrass.

At least 19 recordsLinked to original sources
PubMed1994

Population pharmacokinetic models: effect of explicit versus assumed constant serum concentration assay error patterns upon parameter values of gentamicin in infants on and off extracorporeal membrane oxygenation.

Prior authors had hypothesized (but not clearly found) an increased apparent volume of distribution (Vd) for gentamicin in neonates undergoing extracorporeal membrane oxygenation (ECMO). We chose to study the question in our own clinical setting. To develop population pharmacokinetic models of the drug, we used the nonparametric expectation and maximization population modeling method and data from 11 neonates who received gentamicin on ECMO, including 6 infants who received gentamicin both on and off ECMO for severe respiratory failure. We found an increased Vd for gentamicin on ECMO and attributed much of the difference from prior investigations to our use of an explicitly determined laboratory assay error pattern for the measured serum concentrations rather than using constant weighting of the serum level data points. For six infants, while on ECMO their median Vd was 0.748 L/kg compared with a median Vd of 0.471 L/kg after ECMO was discontinued. The median clearance of gentamicin in the six infants while undergoing ECMO was 0.239 L/h compared with 0.350 L/h after ECMO was discontinued. The median half-time (T1/2) was 9.24 h while on ECMO compared with 3.87 h when off ECMO. We conclude that while undergoing ECMO, neonates have a higher volume of distribution for gentamicin, a lower clearance, and a much longer half-life.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗
PubMed1991

Gentamicin population pharmacokinetic models for low birth weight infants using a new nonparametric method.

Availability of personal computer programs for control of drug regimens has stimulated interest in modeling population pharmacokinetics. In this study, we found parameter values for gentamicin in two infant populations with low birth weights. The models were developed by use of a parametric (i.e., standard two-stage algorithm) and with a new nonparametric expected maximum algorithm. Data for the two populations (i.e., infants less than or equal to 31 weeks' and greater than 31 but less than or equal to 34 weeks' gestational age) were obtained from infants admitted to the University of Texas Medical Branch intensive care nursery between August 1, 1988, and July 31, 1989. The new nonparametric method was demonstrated to be not only the equal of the standard two-stage method for population modeling but better, especially in use of sparse data sets (e.g., single serum levels). It also obviates the need for selecting proper starting conditions for the least-squares fitting procedure used in the standard two-stage method.

Computer Simulation↗
PubMed1990

Urine fluorescence using a Wood's lamp to detect the antifreeze additive sodium fluorescein: a qualitative adjunctive test in suspected ethylene glycol ingestions.

Antifreeze ingestions require rapid and accurate differential diagnosis to prevent fatal outcomes. Sodium fluorescein is added to some commercial antifreeze preparations (ethylene glycol) to a final concentration of approximately 20 micrograms/mL as a colorant to aid in detection of automobile cooling-system leaks. For an adult human being, a potentially toxic volume of antifreeze is 30 mL, which contains 0.4 to 0.6 mg sodium fluorescein. Six male volunteers were given a 0.6-mg oral bolus of sodium fluorescein on an empty stomach. Urine was collected at two-hour intervals. Using a Wood's lamp, visually detectable fluorescence was seen with 100% reliability for two hours and 60% reliability for four hours. A second group of male volunteers was given the same dose of sodium fluorescein, and fluorescence was measured with a fluorometer during a six-hour period. Detectable fluorescence was present in all samples except the zero time point, including those with no fluorescence present by visual examination. We conclude that exposing urine to a Wood's lamp may be a useful adjunctive diagnostic test for early evaluation of patients with suspected antifreeze ingestion while awaiting definitive quantitative analysis of serum ethylene glycol concentration. A prospective clinical trial is needed to evaluate the frequency of false-positives and false-negatives.

Adult↗
PubMed1990

Covalent binding of phenytoin to protein and modulation of phenytoin metabolism by thiols in A/J mouse liver microsomes.

The role of thiols (nonprotein and protein) in the metabolic activation of phenytoin was examined. In vitro phenytoin covalent binding and metabolite formation were determined in hepatic microsomes from A/J mice. Covalent binding of a phenytoin-reactive intermediate to microsomal protein was linear with respect to time, protein concentration and phenytoin concentration. Covalent binding was inhibited by inhibitors of cytochrome P-450. Inducers of cytochrome P-450 enhanced phenytoin covalent binding as follows: phenobarbital greater than 3-methylcholanthrene greater than saline-treated controls. Low molecular weight thiols (GSH, cysteine and cysteamine), a thiol generator (methylthiazolidine carboxylate), and thiol modifying agents (N-ethylmaleimide, mercuric chloride and diamide) significantly inhibited covalent binding. Amino acids other than cysteine did not decrease the covalent binding. Formation of the metabolites, para-hydroxyphenytoin and phenytoin dihydrodiol, was greater following preincubation with GSH or cysteine. In summary, protein thiol groups appear to be important sites for in vitro covalent binding of a reactive intermediate of phenytoin. These data suggest glutathione may protect membrane-bound enzymes responsible for phenytoin metabolism from attack by an electrophilic or free radical reactive intermediate of phenytoin and GSH may inactivate a phenytoin-reactive metabolite by formation of a putative glutathione conjugate.

Amino Acids↗
PubMed1989

Lytic/"DPT" cocktail: time for rational and safe alternatives.

These therapeutic approaches to the premedication of children, in our opinion, offer a more rational, probably safer, and at least equally efficacious treatment regimen as the DPT/lytic cocktail. It is understood that controlled, double-blind comparative clinical trials in children are needed of these or other potential premedicant regimens for specific pediatric procedures (e.g., cardiac catheterization, CT scans, bone marrow aspiration, gastrointestinal endoscopy, pleural taps, etc.) to establish the premedication treatment(s) with the greatest benefit-to-risk ratio. Until these data are available, we must maintain prudence in the selection (design) of premedicant regimens and carefully monitor all children receiving these "cocktails."

Child↗
PubMed1989

Hypocalcemia complicating deferoxamine therapy in an infant with parenteral nutrition-associated aluminum overload: evidence for a role of aluminum in the bone disease of infants.

Aluminum (Al) contaminates total parenteral nutrition (TPN) solutions given to infants, and high levels of Al have been demonstrated in their bone, serum, and urine. However, it is uncertain whether Al at current levels of contamination of TPN solutions is harmful to bone. We report an 8-month-old infant who developed osteopenic bone disease while receiving TPN, which did not respond to large amounts of calcium, phosphate, and vitamin D2. Serum and urine Al levels were greatly elevated and fell after a short course of deferoxamine. However, shortly after treatment began, serum calcium levels fell in the absence of hypercalciuria. We postulate that chelation of Al from this patient's bone permitted increased bone calcium uptake. This would suggest that Al at current levels of contamination of TPN solutions may impair bone calcium uptake and thus contribute to the pathogenesis or exacerbation of TPN-related osteopenia.

Adult↗
PubMed1989

Isocratic separation of phenytoin metabolites by high-performance liquid chromatography from human and animal microsomes and urine.

A rapid and simple high-performance liquid chromatography analytical method is described for the quantitative determination of phenytoin and five of its metabolites--phenytoin dihydrodiol, catechol, methoxycatechol, para-hydroxyphenytoin, and meta-hydroxyphenytoin--in biological materials. Following ethyl acetate extraction and incubation with beta-glucuronidase, samples were passed through a C18 Sep-Pak cartridge. The eluate was chromatographed on a reverse-phase 10 cm C18 Radial Nova-Pak (5 micron) column using a mobile phase of isopropanol:water (20:80) at a flow rate of 1.4 ml/min and monitored at 235 nm. Total chromatographic analysis time was 23 min, with complete baseline resolution of all metabolites. Five different columns and 10 different mobile phase conditions were studied to determine the best system. The 10-cm C18 Radial Nova-Pak (5 micron) gave the best resolution, reproducibility, and durability. This method should prove applicable for clinical use as well as for research purposes.

Animals↗
PubMed1988

Accidental hydrocarbon ingestion cases telephoned to a regional poison center.

One hundred eighty-four telephone calls to the Texas State Poison Center concerning accidental hydrocarbon ingestion were reviewed in an attempt to define the risk of developing any subsequent medical problem requiring therapeutic intervention. Special attention was given to changing symptom severity in an attempt to evaluate its usefulness in predicting future complications. One hundred twenty patients (65%) had no initial symptoms and remained asymptomatic throughout an 18-hour follow-up period. Sixty-two (34%) of patients had symptoms initially but quickly became asymptomatic. Two (1%) developed significant complications (one chemical pneumonitis, one death). These data suggest that the risk of significant complications after accidental hydrocarbon ingestion is low (approximately 1% of patients at risk). Patients who are asymptomatic or who quickly become asymptomatic can be watched safely at home, and referral of asymptomatic patients to a hospital may be unwarranted.

Adolescent↗
PubMed1988

Role of indomethacin in ductus closure: an update evaluation.

Patent ductus arteriosus (PDA) in premature infants is a current challenge to pediatricians. Pharmacological closure of PDA with indomethacin, a prostaglandin synthetase inhibitor is an effective drug therapy, along with usual medical treatment. Administration of indomethacin may decrease mortality and morbidity (e.g. bronchopulmonary dysplasia) among very small premature infants (less than 1,000 g). Co-administration of furosemide with indomethacin may lessen the transient renal side effects of indomethacin. The therapeutic efficacy of indomethacin in closure of PDA depends largely on understanding and manipulation of the pharmacokinetic characteristics of the drug in preterm infants. Maintaining a therapeutic level of the drug in plasma is essential to achieve an optimal therapeutic response. Compared to surgical ligation, indomethacin is a noninvasive, less expensive and safer therapy for ductus closure.

Ductus Arteriosus, Patent↗
PubMed1988

Phenytoin metabolic activation: role of cytochrome P-450, glutathione, age, and sex in rats and mice.

Data are reported demonstrating a role for glutathione and age in the metabolic activation of phenytoin to a reactive metabolite. The in vitro liver microsomal covalent binding of [14C]-phenytoin (DPH) was examined in mice and rats. After incubation with 25-300 microM DPH, covalent binding was dose dependent and linear with time. Incubation in an atmosphere of carbon monoxide or nitrogen markedly decreased covalent binding. Comparison of covalent binding in male rats and mice pretreated with inducers of drug metabolism (phenobarbital, 3-methylcholanthrene) showed significantly greater enhancement following phenobarbital induction compared to controls. In vitro addition of inhibitors of drug metabolism (piperonyl butoxide, alpha-naphthylisothiocyanate, cobaltous chloride, SKF-525A) all significantly decreased covalent binding. Binding studies with subcellular fractions showed maximal covalent binding in microsomes. Addition of thiols, i.e., glutathione, cysteine and cysteamine, significantly decreased covalent binding to 9-36% of control. Addition of butylated hydroxyanisole and butylated hydroxytoluene decreased covalent binding to 10-22% of control. In vivo pretreatment with diethyl maleate and in vitro preincubation with trichloropropene oxide resulted in a significant increase in covalent binding. Rats of ages 8 weeks, 24 weeks and 72 weeks showed a decrease both in covalent binding and in inducibility of covalent binding with increasing age. There was no significant difference in covalent binding between male and female rats of similar ages. These findings are consistent with a cytochrome P-450 dependent generation of a phenytoin arene oxide electrophilic arylating reactive intermediate.

Aging↗
PubMed1986

Salicylate toxicity.

Understanding of the pharmacologic principles and the pathogenesis of salicylate toxicity provides a basis for the optimization of clinical management. The role of salicylate as a scientifically proven cause of Reye's syndrome remains controversial despite epidemiologic data. The management guidelines discussed illustrate treatment details based on the pathophysiology of salicylate toxicity.

Absorption↗
PubMed1984

Interaction of oxygen-carrying resuscitation fluids with morphine.

The oxygen-carrying resuscitation fluids, Fluosol DA 20% and stroma-free hemoglobin, are currently being evaluated for efficacy and effects in vivo. Because these fluids may be administered to trauma victims, the pharmacokinetics of morphine was studied in rats after transfusion with one of these fluids. During development of high-performance liquid chromatography assay for morphine in plasma, an in vitro interaction between plasma, Fluosol DA, or stroma-free hemoglobin and morphine was observed at pH greater than 10.5. This interaction was dependent on pH and was specific to morphine, compared with codeine. The interaction between stroma-free hemoglobin and morphine appeared to be covalent in nature. The t1/2 of morphine was significantly prolonged from 1.02 +/- 0.50 hours (mean +/- SD) to 2.46 +/- 2.68 hours (p = 0.03) after transfusion with stroma-free hemoglobin, and to 2.05 +/- 0.95 hours (p = 0.006) after transfusion with Fluosol DA. The volume of distribution was increased from 1.35 +/- 0.81 L X kg-1 to 2.99 +/- 1.45 L X kg-1 (p = 0.004) after transfusion with stroma-free hemoglobin; no such difference was observed after transfusion with fluosol DA (p = 0.86). The area under the time-concentration curve was increased from 2.37 +/- 1.78 mg X hr X L-1 to 6.02 +/- 6.61 mg X hr X L-1 (p = 0.02), and total body clearance was decreased from 1.02 +/- 0.53 L X hr-1 X kg-1 to 0.55 +/- 0.36 L X hr-1 X kg-1 (p = 0.01) after transfusion with Fluosol DA. No significant differences were observed in these parameters after transfusion with stroma-free hemoglobin (p = 0.48 and p = 0.81, respectively). These data show that stroma-free hemoglobin prolongs the t1/2 of morphine by altering the volume of distribution. In contrast, Fluosol DA prolongs the t1/2 of morphine by altering the total body clearance. These data may have important therapeutic implications.

Animals↗
PubMed1984

Effect of oxygen-carrying resuscitation fluids on the pharmacokinetics of antipyrine, diazepam, penicillin, and sulfamethazine in rats.

The effects of exchange transfusion with an oxygen-carrying resuscitation fluid, Fluosol DA 20% or stroma-free hemoglobin, on the pharmacokinetics of antipyrine, diazepam, penicillin, and sulfamethazine were studied in rats. After transfusion with Fluosol DA 20% or stroma-free hemoglobin the pharmacokinetics of antipyrine, diazepam, and penicillin were unchanged when compared to control animals. After transfusion with Fluosol DA 20%, the t 1/2 of sulfamethazine was increased from 3.15 +/- 0.56 to 7.65 +/- 2.41 hr (p less than 0.05) and the Vd was increased from 60.7 +/- 17.5 to 152 +/- 16 ml (p less than 0.05). In contrast, after transfusion with stroma-free hemoglobin, the AUC of sulfamethazine was decreased from 129 +/- 28 to 80.5 +/- 27.7 micrograms X h X ml-1 (p less than 0.05) and there was an increase in Cl from 12.2 +/- 3.4 to 20.2 +/- 6.0 ml X h-1 (p less than 0.05) and Vd from 60.1 +/- 11.8 to 132 +/- 49 ml (p less than 0.05). The reason for these alterations is not clear. Fluosol DA 20% and stroma-free hemoglobin may alter the acetylation of sulfamethazine.

Animals↗
PubMed1980

Isoniazid hepatoxicity: the relationship between covalent binding and metabolism in vivo.

The relationship between the hepatotoxicity and metabolism of isoniazid and its metabolites, acetylisoniazid and acetylhydrazine, has been investigated. Toxic doses of acetylisoniazid and acetylhydrazine, radiolabeled in the acetyl group, were found to bind covalently to liver protein in vivo. This binding was mediated by the microsomal enzyme system as indicated by the effects of pretreatments altering the activity of these enzymes. Metabolic studies revealed that the pretreatments increased the metabolism of the acetylhydrazine moiety of acetyl-labeled acetylisoniazid and of acetylhydrazine itself by the microsomal enzyme system. Pretreatment with the acyl amidase inhibitor, bis-p-nitrophenyl phosphate, inhibited the hydrolysis of acetylisoniazid to isonicotinic acid plus acetylhydrazine and concomitantly decreased the covalent binding of acetyl-labeled acetylisoniazid. The changes in the metabolism of isoniazid, acetylisoniazid and acetylhydrazine effected by various pretreatments paralleled changes in the severity of the hepatic necrosis caused by the compounds. These results strongly suggest that acetylhydrazine is the metabolite responsible for the hepatic necrosis caused by isoniazid and that mirosomal metabolism of acetylhydrazine in vivo leads to the production of a reactive acylating species capable of reacting covalently with tissue macromolecules.

Acetylation↗
PubMed1979

Iproniazid-induced biochemical changes in mice.

Single doses of iproniazid to Swiss-Webster mice caused a prolonged hypoglycemic reaction and transient biphasic changes in liver triglycerides. In contrast, the same dose of iproniazid in mice on a pyridoxine deficient diet elevated plasma glucose and FFA and liver FFA and TGL. Administration of the same dose of ipioniazid for 30 days elevated liver TGL in Swiss-Webster, C57/B1, DBA, and AKR mice; this effect was reversed in all but the AKR mice when the animals were maintained on a pyrodoxine-deficient diet.

Animals↗