Determination of platinum in urine, ultrafiltrate, and whole plasma by isotope dilution gas chromatography-mass spectrometry compared to electrothermal atomic absorption spectrometry.

Isotope dilution gas chromatography-mass spectrometry (GC-MS) and electrothermal atomic absorption spectrometry (EAAS) are compared for platinum (Pt) determination in urine, plasma ultrafiltrate, and plasma samples from a patient undergoing cisplatin therapy. The isotope dilution GC-MS method is based on the use of lithium bis(trifluoroethyl)dithiocarbamate as a chelating agent and enriched 192Pt as an internal standard. Pt isotope ratios were measured using a Finnigan MAT 8230 organic mass spectrometer, and Pt concentrations were calculated from different sets of isotope ratios in the molecular ion of the Pt-chelate. In the EAAS method, Pt concentrations were determined using three different approaches. These were: (i) calibration curve based on aqueous standards containing Pt in 10% HCl, (ii) standard addition, and (iii) matrix digestion followed by standard addition. Good agreement was obtained for Pt concentrations determined by GC-MS and EAAS in urine samples while there were significant differences in Pt concentrations of ultrafiltrate and whole plasma samples by the two methods. Discussion of possible reasons for these differences emphasizes the need for future critical evaluation of these methods.

The reversal of amiodarone-induced perioperative reduction in cardiac systolic reserve in dogs.

There is controversy about the myocardial depressant effects of amiodarone in patients with decreased cardiac function undergoing surgery. Some surgeons believe that these effects complicate the discontinuation of cardiopulmonary bypass. Accordingly, the hemodynamic effects of amiodarone were evaluated in two groups of anesthetized mongrel dogs that had undergone a median sternotomy. A control group of 10 dogs and an amiodarone-treated group (15 mg/kg per day for 3 weeks) of 10 dogs were studied, and serum (0.26 to 1.09 micrograms/ml) and tissue (cardiac 2.97 to 11.60 micrograms/ml) levels of amiodarone were measured by liquid chromatography. Hemodynamic measurements were made at baseline and after administration of routine therapeutic intravenous doses of dobutamine (10 micrograms/kg per min), isoproterenol (0.06 micrograms/kg per min) and epinephrine (2 micrograms/min). The amiodarone-treated dogs had a smaller increase in cardiac output compared with baseline than did control dogs. For each drug when the amiodarone-treated group was compared with the control group, increases in cardiac output (liters/min) were: dobutamine, 1.32 +/- 0.24 versus 1.73 +/- 0.31; isoproterenol, 0.84 +/- 0.26 versus 1.43 +/- 0.28; epinephrine, 0.25 +/- 0.15 versus 0.44 +/- 0.53. Amiodarone-treated dogs were also given higher doses of drugs, dobutamine (50 micrograms/kg per min), isoproterenol (1.2 micrograms/kg per min) and epinephrine (20 micrograms/min). Increases in cardiac output were 1.24 +/- 0.24, 1.62 +/- 0.25 and 2.82 +/- 0.64, respectively. All cardiac outputs were significantly increased from the baseline values (p less than 0.05) except those measured in the amiodarone group receiving the lower dose of epinephrine. Thus, amiodarone-treated dogs have a relative reduction of perioperative cardiac systolic reserve.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation between amiodarone and desethylamiodarone plasma concentrations and electrophysiologic effects, efficacy and toxicity.

Because the value of monitoring amiodarone plasma concentrations remains undefined, this study was performed to evaluate its role during the management of patients receiving amiodarone. The early electrophysiologic effects of amiodarone were assessed in 40 consecutive patients with coronary artery disease and sustained ventricular tachycardia or fibrillation who underwent electrophysiologic studies and measurement of amiodarone plasma concentration before and 29 +/- 15 (mean +/- SD) days after initiation of therapy. Amiodarone and desethylamiodarone plasma levels did not correlate with changes in either sinus cycle length, QTc interval, ventricular effective refractory period, AH and HV intervals or ventricular tachycardia cycle length. Amiodarone and desethylamiodarone plasma concentrations and the effects of the drug on conduction intervals or right ventricular effective refractory periods were not related to suppression of arrhythmia induction by ventricular stimulation after 1 month of therapy. The relation between amiodarone plasma concentrations and both toxicity and efficacy during long-term therapy were prospectively assessed in a larger series of 114 consecutive patients with either symptomatic supraventricular or ventricular arrhythmias who were followed up on long-term amiodarone therapy for 26 +/- 15 months. Sixty-three patients (55%) had one or more adverse effects attributed to amiodarone. By life-table analysis, 40, 69 and 80% of patients had experienced an adverse reaction after 1, 2 and 3 years of therapy, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Carbamazepine toxicity: comparison of measurement of drug levels by HPLC and EMIT and model of carbamazepine kinetics.

A 23-month-old boy accidently ingested 2000 mg (148 mg/kg) of carbamazepine. The delayed onset of convulsions coincided with the peak serum level of total parent drug and an active metabolite (carbamazepine 10,11-epoxide). Comparisons of homogeneous enzyme multiplied immunoassay technique (EMIT) and high pressure liquid chromatography (HPLC) revealed that the EMIT slightly over-estimated plasma carbamazepine levels due to immunochemical cross reactivity with the epoxide metabolite. The peak plasma levels of the parent drug plus the active metabolite were more accurately determined by HPLC. These results emphasize the need to understand both the presence of active metabolites and characteristics of the assay being used in managing clinical intoxication with carbamazepine.

Adaptation of EMIT drug assays to a random-access automated clinical analyzer.

Enzyme multiplied immunoassay technique (EMIT) assays for theophylline, carbamazepine, phenytoin, phenobarbital, valproic acid, acetaminophen, gentamicin and tobramycin, have been adapted to the Technicon RA-1000 random access analyzer. Working reagents are stable for a period of at least one week, and calibration need only be performed when preparing fresh reagents. Between-day precision ranged from 2.2 to 5.5 percent and correlations with similar EMIT assays performed on a centrifugal analyzer were satisfactory. Excellent results were obtained on proficiency testing samples when analyzed for theophylline, phenobarbital, phenytoin and acetaminophen. The procedures have been adapted to emergency testing of these four drugs.

Acute electrophysiologic effects of bethanidine sulfate in patients with ventricular tachycardia or fibrillation.

Ten patients with a history of ventricular tachycardia or ventricular fibrillation underwent electrophysiologic study with programmed stimulation before and 90 minutes after oral administration of bethanidine sulfate, 20 mg/kg. Mean plasma bethanidine concentration was 2.62 +/- 2.2 (+/- SD) micrograms/ml at the start of repeat testing. This dose of bethanidine produced no effect on sinus node function, atrioventricular conduction, or atrial or ventricular refractoriness. Ventricular tachycardia or fibrillation, inducible in all patients during the control study, could still be initiated by ventricular stimulation in 9 of 10 patients after bethanidine. Bethanidine suppressed the ability to initiate an arrhythmia in one patient with ventricular fibrillation during control stimulation. Orthostatic hypotension was seen in all patients despite pretreatment with the tricyclic antidepressant, protriptyline, 15 mg every 8 hours. The results suggest that bethanidine has few electrophysiologic effects and is of limited efficacy during electrophysiologic testing in patients with life-threatening ventricular arrhythmias.

Improved liquid-chromatographic determination of 3-methoxy-4-hydroxyphenylethyleneglycol in urine with electrochemical detection.

In this improved method for quantifying 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) in urine, after a multistep extraction of MHPG and internal standard (iso-MHPG) from 3.0 mL of urine, the compounds are separated on a C18 reversed-phase column and quantified by use of an electro-chemical detector. The isocratic chromatographic separation takes about 16 min. The mobile phase is phosphate buffer/acetonitrile (88/12 by vol), the flow rate 0.7 mL/min. Recycling the mobile phase and automating the sample injection make possible the unattended assay of more than 70 samples per day. The within-run precision of the method is excellent (CV 1.8%) at a mean concentration of 1.1 mg/L.

Determination of bethanidine in plasma by liquid-chromatography with a microbore reversed-phase column.

In this novel method for quantifying bethanidine in plasma, after a multi-step extraction of bethanidine and internal standard from 2.0 mL of plasma, the drugs are separated on a "microbore" C18 reversed-phase column and quantified by their ultraviolet absorbance at 210 nm. The isocratic chromatographic separation takes about 15 min with use of an ion-pairing regent in the mobile phase (acetate buffer/acetonitrile, 9/1 by vol) and a flow rate of 0.25 mL/min. Sensitivity is increased relative to conventional columns, and solvent consumption is reduced by 90%. The standard curve is linear to at least 5 mg/L, and the detection limit is 0.02 mg/L. The within-run precision of the method is excellent (CV 4%) at a midrange concentration of 1.25 mg/L.

Drug monitoring in the neonate.

Drug monitoring has recently been extended into the neonatal population largely owing to improvements in analytical techniques. This important area of study represents a wide diversity of patients,-from mature infants to low-birth weight infants owing either to premature birth or intrauterine growth retardation. Neonates provide a highly variable population base which undergoes rapid changes in rate of absorption, metabolism, and elimination of drugs during the first weeks of life. Rational drug administration at this time can be very difficult. Drug monitoring in conjunction with effective therapeutic ranges can be of great assistance to the physician.

Erythrocyte polyamine determinations in patients with head and neck cancer.

Erythrocyte polyamine levels were measured in the blood from 29 untreated patients whose conditions were diagnosed as head and neck cancer. Only nine (31%) of these patients had elevations of erythrocyte spermidine and/or spermine levels above the reference ranges determined for normal persons. However, a positive correlation was observed between the erythrocyte spermidine levels and the clinical tumor stage. Serial erythrocyte polyamine determinations were performed on the blood from 12 of these patients before and after either surgical or radiation therapy. In 11 of the cases, the erythrocyte spermidine levels decreased after tumor therapy regardless of whether there was prior elevation above the reference range. The erythrocyte spermine levels in these patients were more variable in their response to tumor treatment. Therefore, although erythrocyte polyamine levels were only slightly to moderately elevated in response to the small tumors characteristic of the head and neck, the measurement of erythrocyte spermidine, potentially, may offer a simple and effective means of monitoring the course of therapy used in patients with head and neck cancer.

Human xylazine overdose: a comparative review with clonidine, phenothiazines, and tricyclic antidepressants.

We report a case of horse tranquilizer (xylazine) overdose from oral ingestion in man, detail a gas-liquid chromatography/mass spectrometer method for xylazine assay in the blood and urine, and suggest the management of acute poisoning. We present a comparative review of some toxicological properties that xylazine shares with the pharmacologically related clonidine and with the structurally related phenothiazines and the tricyclic antidepressants.

Erythrocyte polyamine levels in rats with H4IIE hepatomas before and after radiation treatment.

The concentration of the polyamines, spermidine and spermine associated with the erythrocytes of rats with H-4-II-E hepatomas increased with tumor growth. Following radiation therapy the erythrocyte spermidine and spermine levels decreased by 63 and 47% respectively. Six days after radiation treatment the erythrocyte polyamines had increased to the pre-treatment elevated levels. These data suggest that erythrocyte polyamine levels may be useful in assessing the response to therapy and in detecting the continued growth of the tumor in patients with malignant disease.

High performance liquid chromatographic separation and fluorescence detection of polyamines in plasma and erythrocytes.

A high performance liquid chromatography has been adapted to the measurement of putrescine, spermidine and spermine in plasma and erythrocytes. Detection was by fluorimetry using o-phthalaldehyde which formed fluorophores with the polyamines. Sensitivity of the method was better than 10 pmol of each polyamine, and recovery averaged 93.9 percent. The precision of the analysis was two percent (R.S.D.). Good correlation was obtained with a reference chemical ionization gas chromatographic-mass spectrometric procedure. Reference intervals for polyamines in both plasma and erythrocytes were estimated on the basis of 25 normal volunteers.

Clearance of [14C] polyamines from plasma and erythrocytes in the rat.

The [14C] polyamines, putrescine, spermidine and spermine were administered intravenously to rats. Arterial blood samples were obtained 2, 4, 6, 12, 20, 30, 60 and 120 min. after injection. Plasma and erythrocyte fractions were separated and assayed for [14C] activity. The clearance of radiolabelled polyamines from both the plasma and erythrocytes was rapid. Within 10 min. of injection, plasma putrescine had decreased by 70%, spermine by 80% and spermidine by 85%. In the same time interval the erythrocyte putrescine level had decreased by 50%, spermine by 70% and spermidine by 80%. This data suggests that exogenously injected radiolabelled polyamines and presumably endogenously produced polyamines are rapidly cleared from the circulation.