William H. Porter

Urolithiasis associated with the protease inhibitor indinavir

OBJECTIVES To report the association between the protease inhibitor indinavir and the development of urolithiasis. METHODS Case reports of three adult patients infected with the human immunodeficiency virus who developed surgical renal stones while being treated with indinavir are presented. RESULTS Of the 3 patients requiring surgical intervention, stone analyses were available in 2. One stone revealed an inner core of an unidentifiable crystal surrounded by calcium oxalate, and another was found to have indinavir components as determined by thin-layer chromatography and gas chromatography-mass spectrometry. Metabolic evaluation of all 3 patients identified significant hypocitraturia as an isolated finding. CONCLUSIONS The widely used protease inhibitor indinavir is associated with the development of urolithiasis and may act as a nidus for heterogeneous nucleation leading to the development of mixed urinary stones. Surgical intervention may be necessary in some cases. Underlying metabolic abnormalities may contribute to the increased incidence of stone formation. Urologists and other health care providers should be aware of this association, as combined medical and surgical intervention may be necessary.

Ethylene Glycol Toxicity: The Role of Serum Glycolic Acid In Hemodialysis

Objective: To correlate serum glycolic acid levels with clinical severity and outcome in ethylene glycol poisoning and to determine if glycolic acid levels are predictive of renal failure and the need for hemodialysis. Methods: We measured serum ethylene glycol and glycolic acid levels by gas chromatography/mass spectrometry for 41 admissions (39 patients) for ethylene glycol ingestion and performed retrospective chart reviews. Results: Eight patients died, all of whom developed acute renal failure. Of the survivors, 15 also developed acute renal failure, whereas 18 did not. Of those with normal renal function, 8 had glycolic acid levels below detection limits (<0.13 mmol/L) despite ethylene glycol levels as high as 710 mg/dL; 7 of these patients coingested ethanol. Pertinent initial laboratory data for each group are as follows (mean; range): Deceased: pH 6.99 (6.82–7.22); bicarbonate, 4.8 mmol/L (2–9); anion gap, 28.6 mmol/L (24–40); glycolic acid, 23.5 mmol/L (13.8–38.0); ethylene glycol, 136.5 mg/dL (6–272). Survived/acute renal failure: pH 7.07 (6.75–7.32); bicarbonate, 5.6 mmol/L (1–12); anion gap, 28.7 mmol/L (18–41); glycolic acid, 20.2 mmol/L (10.0–30.0); ethylene glycol, 238.8 mg/dL (12–810). No acute renal failure with glycolic acid >1.0 mmol/L: pH 7.29 (7.12–7.46); bicarbonate, 14.7 mmol/L (4–23); anion gap, 16.5 mmol/L (10–26); glycolic acid, 6.8 mmol/L (2.6–17.0); ethylene glycol, 269.1 mg/dL (6–675). No acute renal failure with glycolic acid <1.0 mmol/L: pH 7.41 (7.38–7.47); bicarbonate, 23.4 mmol/L (17–25); anion gap, 11.8 mmol/L (8–18); glycolic acid, 0.1 mmol/L (0–0.66); ethylene glycol, 211 mg/dL (8–710). The mean time postingestion to admission generally correlated with severity as follows: deceased, ≥10.4 h; survived/acute renal failure, ≥9.9 h; no acute renal failure with glycolic acid >1.0 mmol/L, ≥6.2 h; no acute renal failure with glycolic acid <1.0 mmol/L, ≥3.7 h. Hematuria was more prevalent than oxaluria (86% and 41%, respectively), but neither was individually predictive of acute renal failure. Good correlations were found between glycolic acid levels and anion gap (r2 = 0.7724), pH (r2 = 0.7921), and bicarbonate (r2 = 0.6579); poor correlations (r2 <0.0023) occurred between ethylene glycol levels and glycolic acid, pH, anion gap, and bicarbonate. Measured ethylene glycol values were highly correlated with ethylene glycol values calculated from the osmolal gap (r2 = 0.9339), but the latter overestimates the true value by about 7%, on average. An initial glycolic acid level ≥10 mmol/L predicts acute renal failure with a sensitivity of 100%, a specificity of 94.4%, and an efficiency of 97.6%. Ethylene glycol levels are not predictive of acute renal failure or central nervous system manifestations of toxicity. If only ethylene glycol values are available (measured or calculated), an initial anion gap >20 mmol/L is 95.6% sensitive and 94.4% specific for acute renal failure when ethylene glycol is present. Likewise, initial pH <7.30 is 100% sensitive and 88.5% specific for acute renal failure. Conclusion: We propose glycolic acid <8 mmol/L as a criterion for the initiation of hemodialysis in ethylene glycol ingestion. Patients with glycolic acid <8 mmol/L probably do not need dialysis, regardless of the ethylene glycol concentration, when metabolism of ethylene glycol is therapeutically inhibited. In the absence of glycolic acid values, an anion gap >20 mmol/L or pH <7.30 predicts acute renal failure.

Resolution of chiral drugs

Many drugs are administered as racemates, yet the enantiomers may have important pharmacodynamic and/or pharmacokinetic differences. Chiral analytical techniques are necessary to properly assess and understand such differences. Novel techniques to separate drug enantiomers present in serum and/or urine have recently emerged. This review describes commonly used approaches to chiral drug analysis in: diastereomeric derivatization, chiral mobile-phase additives, chiral stationary phases, and enantioselective immunoassays. Each of these techniques has advantages and disadvantages and no single approach has emerged as the method of choice.

Pentobarbital pharmacokinetics in patients with severe head injury

Intravenous administration of high-dose pentobarbital has been proposed as a treatment for elevated intracranial pressure refractory to other measures in brain-injured patients. The purpose of this clinical study was to examine the pharmacokinetics of high-dose continuous intravenous infusion of pentobarbital in this critical care setting. Six patients received a 25–34 mg/kg intravenous loading dose followed by a 1–3 mg/kg/h continuous infusion for 61–190 hours. Dosing rates were adjusted based on the patients clinical status. The mean clearance was 0.72 ml/min/kg, with a volume of distribution (Vd) of 1.03 L/kg and a terminal half-life of 19.1 h. Considerable variation in individual patient parameters was observed. In addition, a change in clearance was suggested in patients requiring a longer infusion duration.

Severe Phenytoin Intoxication as a Result of Altered Protein Binding in Aids

Alterations in plasma protein binding may alter patient response to pharmaceutical agents because only free drug is considered to be pharmacologically active. Such alterations appear to be more significant with highly bound agents such as phenytoin. Traditionally, most drug assays monitor total drug concentrations and do not quantitate free drug. When binding alterations are present, total drug concentrations may mislead clinicians in evaluating patient response. We describe a case in which profound hypoalbuminemia (0.2 g/dL), associated with focal segmental glomerulosclerosis, produced toxic free phenytoin concentrations (4.9 μg/mL) in an HIV-positive 25-year-old black woman. At such a high serum concentration of free phenytoin, the patient exhibited seizure-like effects. Renal abnormalities and hypoalbuminemia associated with acquired immunodeficiency syndrome (AIDS) may place patients at risk for elevated free fractions of phenytoin and subsequent toxicity.

Measurement of serum isopropanol and the acetone metabolite by proton nuclear magnetic resonance: application to pharmacokinetic evaluation in a simulated overdose model.

The purpose of this investigation was to 1) compare the performance of proton nuclear magnetic resonance spectroscopy to gas chromatography head-space analysis in the measurement of serum isopropanol and its metabolite, acetone, obtained during a simulated overdose, and 2) compare pharmacokinetic parameters obtained using the two analytical techniques. Three healthy volunteers ingested 0.6 mL/kg of 70% isopropanol and blood samples were obtained at baseline, 0.16, 0.33, 0.66, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours post-ingestion. Resulting sera were analyzed by gas chromatography head-space analysis and proton nuclear magnetic resonance spectroscopy for determination of isopropanol and acetone concentrations. A correlation between concentrations quantitated by gas chromatography head-space analysis versus proton nuclear magnetic resonance spectroscopy was determined using linear regression. Pharmacokinetic disposition parameters were determined from serum concentration-time data and compared using analysis of variance. For isopropanol, the linear regression equation which describes the relationship between gas chromatography head-space analysis and proton nuclear magnetic resonance spectroscopy was y = 1.041x - 2.180 (r2 = 0.995, p < 0.0001); for acetone, y = 1.022x - 0.946 (r2 = 0.984, p < 0.0001). Pharmacokinetic disposition parameters derived from the two analytical methods were comparable. Proton nuclear magnetic resonance spectroscopy can be used to rapidly quantitate serum isopropanol and acetone concentrations in the same sample when gas chromatography head-space analysis is unavailable. Also, proton nuclear magnetic resonance spectroscopy can be used to follow serial serum concentrations during an ingestion for the purpose of pharmacokinetic analysis.

Simplified high performance liquid chromatographic method for the determination of clonazepam and other benzodiazepines in serum.

A convenient and sensitive high performance liquid chromatographic method was developed for determination of clonazepam in serum using a C-18 reverse-phase column, and mobile phase consisting of a 50:35:15 mixture by volume of pH 6.0 phosphate buffer:methanol:acetonitrile. Quantitation was performed at 313 nm with flunitrazepam as the internal standard. Using 1 ml of serum for extraction, the assay is linear for clonazepam concentrations between 10 and 250 ng/ml. The relative recovery averaged 100.3%, and the coefficient of variation for between-day and within-day assays was less than 7%. A simple modification permits analysis of 200 microliter of serum, with little loss of precision and with a detection limit of 20 ng/ml. Only three drugs tested (nitrazepam, methaqualone, and norchlordiazepoxide) interfered with the assay, and none are likely to be used therapeutically with clonazepam. Importantly, carbamazepine and carbamazepine-10,11-epoxide do not interfere under the conditions of the assay. The method is equally suitable for the determination of nitrazepam. By adjusting the mobile phase so that volume ratios of phosphate buffer, methanol, and acetonitrile are 45:35:20, and using nitrazepam as the internal standard, seven other benzodiazepines (demoxepam, oxazepam, chlordiazepoxide, norchlordiazepoxide, temazepam, diazepam, and nordiazepam) can be resolved at 254 nm.

Improved GC-MS Procedure for Simultaneous Measurement of Ethylene Glycol and Glycolic Acid

To the Editor: Our laboratory developed procedures for the simultaneous measurement of ethylene glycol and glycolic acid by gas chromatography–flame ionization detection (GC-FID)1 (1) and by GC-MS (2). The selection of a suitable structurally similar internal standard for glycolic acid proved problematic because of either coeluting interference during GC-FID or ion overlap of deuterated and nondeuterated di- tert -butyldimethylsilyl derivatives during GC-MS analysis. As a compromise, 1,3-propanediol (1,3-PD), an acceptable internal standard for ethylene glycol, was also selected as the internal standard for glycolic acid in the GC-MS procedure. Considerable experience with the procedure has revealed a limitation of this structurally dissimilar internal standard for measuring glycolic acid. In the procedure, serum proteins are precipitated with acetonitrile containing 1,3-PD, the supernatant is dehydrated with a water scavenger, and the volume is reduced to <100 μL in a N , N -dimethylformamide …

Hemodialysis clearance of pentobarbital during continuous infusion

The hemodialysis clearance of pentobarbital during continuous infusion was determined in a 34-year-old man in acute renal failure. Pentobarbital specimens were obtained simultaneously from arterial blood entering and leaving the dialysis machine at five 1-h intervals. The mean hemodialysis clearance of pentobarbital was 22.3 ml/min. Pentobarbital concentration was relatively unaffected throughout the dialysis period, because of the high dose and continuous infusion of a drug with low hepatic intrinsic clearance and a short dialysis period. A large contribution to total body clearance was not evident, and dosage adjustment would have been unwarranted.

Evaluation of Precision and Accuracy of a Fluorescence Polarization Immunoassay System After Dilution of Serum Samples Containing Fluorescein Dye

The accuracy and precision of a fluorescence polarization immunoassay for diluted gentamicin serum samples in the presence of fluorescein dye is described.