Pharmacokinetic study of extradural and intrathecal sufentanil anaesthesia for major surgery.

We have studied the plasma concentrations (Cp) and pharmacokinetics of sufentanil injected i.v. (IVS), intradurally (IS) or extradurally (ES) under general anaesthesia in 31 patients undergoing major abdominal surgery. Sufentanil appeared in plasma very rapidly and Cpmax was also attained rapidly after both extradural and intrathecal injection. Apart from the first 2 min after injection, Cp after ES and IVS were comparable until the end of the study. Cp after ES was greater than after IS up to 0.25 h. Cp after IS was significantly greater than that after ES at 1 h and 2.5 h, and was also greater than that after IVS at 3 h. At tracheal extubation there was no difference in Cp between groups. Peak Cp values were significantly different between ES and IS, but the times taken to reach Cpmax were comparable. Plasma pharmacokinetics after ES and IS were similar. The plasma mean residence time and volume of distribution of sufentanil at steady state after ES and IS were significantly different in comparison with those after IVS.

Epidural morphine anesthesia for abdominal aortic surgery--pharmacokinetics.

Plasma and CSF pharmacokinetics of morphine given epidurally in combination with general anesthesia for abdominal aortic surgery were recorded. The initial plasma and CSF concentrations of morphine appeared at two minutes. The peak plasma concentrations of morphine were recorded at 8.0 +/- 2.6 minutes after epidural injection. Plasma mean residence time was 84 +/- 25.7 minutes, Vdss 121 +/- 30 L, and C1 1.5 +/- 0.32 L/min. Free morphine was not detected in plasma 360 minutes after epidural administration. The fraction of the epidural morphine that crossed the dura was 3.15% +/- 2.4 The peak CSF morphine concentrations were recorded at 56 +/- 31 minute. MRT (200 +/- 28 minute), Vdss (65 +/- 33.8 ml), and CL (0.32 +/- 0.15 ml/min) showed that variable fractions of morphine remained many hours in the CSF. Factors that could produce the interindividual variability of plasma and CSF concentrations and pharmacokinetics of epidural morphine were discussed. Abdominal aortic surgery appears to influence both plasma and CSF pharmacokinetics.

Pharmacokinetics of morphine in cerebrospinal fluid and plasma after epidural administration in man.

The morphine concentration in serum as well as in cerebrospinal fluid (CSF) after epidural administration of 0.1 mg/kg morphine to 10 patients undergoing aortic abdominal surgery, was determined. Model independent pharmacokinetic parameters in serum and CSF i.e. mean residence time (MRT), clearance (Cl) and apparent volume of distribution were calculated from the concentration time curves using a non-linear square regression fitting programme. Peak concentration of morphine in serum (86 ng/ml) and in CSF (2610 ng/ml) was reached after 10 min respectively 40 min of epidural injection.

The pharmacokinetics of intradural morphine in major abdominal surgery.

The pharmacokinetics of intradural morphine used for major abdominal surgery were evaluated. Lumbar spinal fluid and plasma concentrations were measured at intervals after morphine 0.05 mg/kg had been injected intradurally in 21 patients scheduled for elective abdominal aortic surgery. The CSF morphine concentrations were fitted by a biexponential function. A non-compartmental model based on statistical moment theory was used for calculating the intradural morphine disposition. Mean residence time was 137 +/- 54.9 minutes, mean initial volume of distribution 15 +/- 5.49 ml, mean volume of distribution at steady-state 42 +/- 18.25 ml and mean clearance 0.34 +/- 0.18 ml/min (0.02 +/- 0.01 L/h). The moments of the morphine concentration-time curves and the pharmacokinetic parameters varied between the patients. They were not significantly different with regard to morphine dosage, or patient sex or age. Free morphine could not be detected in plasma. Morphine-3-glucuronide appeared in plasma at 5 minutes, increased to a maximum at 240 minutes and fell below the detection limit at about 16 hours after morphine administration. Possible clinical causes of interindividual variations in the CSF morphine concentrations and the pharmacokinetics of intradural morphine are discussed.

Long-term release of copper from two multiload IUD models: MLCu250 and MLCu375.

Decrease of mean copper content was assessed for two commercial types of Multiload IUD with different copper loads. Mean daily loss of copper amounted to about 18 mcg and 30 mcg for MLCu250 and MLCu375 devices, respectively. On the basis of these estimates, we conclude that both these IUD models can be considered long-lasting interceptive agents.

Terbutaline sustained-release treatment during one week 5 mg b.i.d. compared to one week placebo: terbutaline plasma levels, c-AMP plasma levels, lung function and tremor measurement.

In a group of ten patients with chronic asthmatic bronchitis, a good improvement of the lung function was achieved by a sustained-release terbutaline preparation (Bricanyl Retard) in a dosage of 5 mg twice daily. Tremor measurements and c-AMP plasma level showed a statistically significant increase. A good patient compliance was achieved with this dosage of terbutaline two times daily. The sustained-release preparation caused a rather constant and low terbutaline plasma level. We think that this relative low terbutaline plasma level is the most important reason for the lack of side effects.

Combination therapy of theophylline and terbutaline as sustained-release preparations in patients with asthmatic bronchitis.

In a group of ten patients with chronic asthmatic bronchitis, the effect of monotherapy with theophylline and terbutaline and the combination of both drugs, as sustained-release tablets, was compared to placebo, in a double-blind cross-over, triple dummy at random study. Lung function parameters, tremor measurements, c-AMP plasma levels, theophylline- and terbutaline-plasma levels were determinated. Monotherapy with theophylline and terbutaline in a relatively low dosage achieved a good lung function improvement without severe side effects, as compared to placebo. The combination of both drugs in the same dosage achieved a statistically significant enhancement of the lung function improvement, as compared to monotherapy, without an increase of side effects. An additional effect of theophylline and terbutaline on bronchodilation is demonstrated.

A comparative study of a monoclonal immunoassay reagent strip test and high pressure liquid chromatography for theophylline.

Our experience with the determination of theophylline in serum using a monoclonal immunoassay reagent strip test is reported. The day-to-day precision of a series of drug assay controls (n = 74) was investigated with a mean theophylline value of 15,3 +/- 1,2 mg/l. Interference and/or cross reactivity of structurally related compounds and metabolites of theophylline was tested. Serum samples from 148 asthmatic patients who were treated with theophylline were analyzed by the SERALYZER ARIS*) reagent strip test and by high pressure liquid chromatography. A correlation coefficient of 0.99 was found between these techniques using a linear regression analysis.

Lung function improvement, tremor measurements and c-AMP determinations in a group of ten patients with asthmatic bronchitis after one week sustained release theophylline medication (theophylline plasma level +/- 10 mg/l) compared to one week placebo.

After one week theophylline therapy with a sustained release preparation (TheoDur 200 and 300 mg), a mean theophylline level of 10 mg/l was obtained in a group of ten patients with chronic asthmatic bronchitis with a mean dosage of 760 mg theophylline/24 h. A good improvement of the lung function was achieved, although only statistically significant for the mid maximal expiratory flow rate (MMEF) and the end expiratory specific airway conductance (sGaw) compared to placebo therapy. Tremor measurements and cyclic-AMP determinations showed a slight increase after theophylline therapy compared to placebo, although not statistically significant.

Pharmacodynamics (lung function tests, tremor measurements and cAMP determinations) of a single dose of 0.5 mg terbutaline subcutaneously during sustained-release theophylline medication in patients with asthmatic bronchitis.

A group of 10 patients with chronic asthmatic bronchitis was titrated with slow-release theophylline (Theolin Retard) to a steady state plasma theophylline level of 10 mg/l. After one week of this treatment a single s.c. dose of 0.5 mg terbutaline (Bricanyl) at 10:30 a.m was administered. Lung function at 8:15 a.m. on this day was better than on the reference day without any medication, but the differences were not statistically significant. At 11:00 p.m., 30 min after s.c. administration of terbutaline all lung function parameters (VC, FEV1, MMEF and sGaw) were significantly raised compared to the values of 8:15 p.m. cAMP levels and tremor were significantly higher after the combined medication (30, as well as 150 min after s.c. administration of terbutaline) than on the reference day. This observation implies that we have to be careful with the administration of terbutaline s.c. to patients on theophylline treatment in the daily practice of the lung function laboratory.

Pharmacokinetics of morphine after epidural administration in man.

The concentration of morphine and morphine glucuronide in serum after epidural injection of 9 patients with aortic abdominal surgery was measured using gas chromatography-mass fragmentography. The decline of morphine serum concentration after epidural administration of 0.1 mg/kg was described by a bi- or triexponential decay equation with a mean terminal half-life (t1/2) of 134.7 +/- 107.9 min. Pharmacokinetic parameters were calculated from the fit parameters mean values for clearance and apparent volume of distribution were 1.16 +/- 0.65 l/min, and 156.6 +/- 107.3 l, respectively, for free morphine and 0.19 +/- 0.09 l/min and 37.2 +/- 17.7 l, respectively, for morphine glucuronide. Peak concentration of morphine 79 +/- 19 ng/ml was reached within 10 min after administration. Haemodynamic values, ECG, end-expiratory CO2 concentration, temperature, acid-base status, hemoglobin, Na+, K+, total Ca++, lactate, glucose concentration in the blood and the urine were registered before, during and after the operation.

Pharmacokinetics and pharmacodynamics of three sustained-release theophylline preparations (Theograd, 350 mg Theolair Retard, and 300 mg Theolin Retard) in steady state in six normals and six patients with chronic asthmatic bronchitis--Part II: Lung function.

The lung function profiles of a group of six healthy volunteers and six patients with moderately severe asthmatic bronchitis were compared after one theophylline infusion and after oral administration of Theograd (350 mg), Theolair Retard (350 mg), and Theolin Retard (300 mg) all given twice daily for 1 week. The group of patients showed a good reversibility of bronchoconstriction after intravenous theophylline administration; however, only minor improvement was observed at the levels reached after relatively low oral doses.

Pharmacokinetics and pharmacodynamics of three sustained-release theophylline preparations (350 mg Theograd, 350 mg Theolair Retard and 300 mg Theodur) in steady state in healthy volunteers and asthmatics--Part I: Theophylline plasma levels.

The pharmacokinetic profiles of three oral sustained-release theophylline preparations in steady state (350 mg Theograd, 350 mg Theolair Retard [= Nuelin Retard], and 300 mg Theolin Retard [= Theodur]) were compared in a group of six normal subjects and six patients with moderately severe asthmatic bronchitis. All preparations were given twice daily for 7 days. Before this study, an intravenous infusion of aminophylline had been administered (5.6 mg theophylline per kg body wt.). The plasma theophylline levels after oral administration were rather low from a clinical point of view (below 55 mumol/l = 10 mg/l). The mean plasma theophylline level of the three different oral preparations in steady state did not show a statistically significant difference. The group of six healthy volunteers reached higher mean theophylline levels than the group of six patients, possibly due to differences in mean weight and smoking habits. This difference was only statistically significant (p = 0.001) for Theograd. Between Theograd, Theolair (Nuelin) Retard, and Theolin (Theodur) Retard no statistically significant difference in absolute bioavailability was observed, and virtually no side effects were reported.

Evaluation of the EMIT-st serum ethyl alcohol assay in toxicology.

An evaluation of the EMIT-st serum alcohol assay is reported. Although the assay was developed as a qualitative procedure, the day-to-day precision of the test with respect to the differences in absorbance (delta A) was evaluated, in order to establish its applicability for quantitative analyses. The mean values +/- SD (n = 10) for the delta A of the positive control and the cutoff calibrator were 146 +/- 14 (CV = 9.6%) and 57 +/- 5 (CV = 8.8%) respectively. The detection limit of the assay was 0.3 mg/ml ethanol. A series of spiked serum samples with ethanol concentrations in the range of 0.1 to 4.0 mg/ml was analyzed in triplicate by EMIT-st and by gas chromatography. Qualitatively, the correlation between these two methods was nearly 100 percent. For the EMIT-st assay, the response was only linear between 0.3 and 2.0 mg/ml ethanol. Concentrations higher than 2.0 mg/ml showed no pronounced difference in absorbance measurements. Serum samples (n = 54) of people involved in automobile driver alcohol blood checks were analyzed by EMIT-st and the results were compared to the corresponding gas chromatographic data. In the range up to 2.0 mg/ml ethanol, a linear regression curve was calculated with a slope of 76.7, a y-intercept of 36.4, and a correlation coefficient of 0.79. Spiked serum samples at concentrations of the calibrator and the positive control as provided by Syva appeared to be identical in delta A response.(ABSTRACT TRUNCATED AT 250 WORDS)

Copper release from the MLCu375 intrauterine contraceptive device.

PIP: The longterm copper release from the MLCu 375 IUD was calculated, and the effect of increased copper load and surface area on the average rate of release was assessed by comparing these findings with data on the MLCu 250 model. The latter model has a thicker copper filament, resulting in a 50% increase in the exposed metal surface area and an 86% increase in the mass of pure copper affixed to the vertical stem of the device. Copper wires from MLCu 375 devices were recovered from 106 women after periods of use ranging from 1-66 months. 10 devices that had never been inserted were used for comparison purposes. The copper concentration was determined by flameless atomic absorption spectrophotometry. The regression line of the mean values of each time point indicated that approximately 8% of the original amount of copper had been released after 3 years and 18% after 5 years in utero. The mean copper release over a 5.5-year period was 37 mcg/day. Corresponding data for the MLCu 250 showed the mean copper release to be about 64 mcg/day measured over a 3-year period. No explanation can be proposed for the great difference in copper release rates between the 2 models. In contrast to previous studies, a significant enhanced dissolution rate during the 1st year of use was not observed with either device. Assuming that corrosion and calcareous deposit formation are uniform, the copper filament does not fracture, and bleeding problems do no occur, the effective intrauterine lifespan of the MLCu375 should exceed 25 years. This estimation is considered to be unrealistic, however, because these specifications are not satisfied under clinical conditions and the minimum amount of copper required for maintenance of the optimal infertility effect is unknown.^ieng

EMIT-st drug detection system for screening of barbiturates and benzodiazepines in serum.

The determination of barbiturates and benzodiazepines in serum using the EMIT-st drug detection system is reported. The within-day and the day-to-day precision of this assay was investigated by replicate analysis (n = 20) of the serum negative (no drug) and serum positive control of secobarbital (8.0 micrograms/mL) and diazepam (1.0 microgram/mL), respectively. In all cases the coefficients of variation for intra- and interday analysis for both drugs were between 9 and 15%. No temperature influence on the benzodiazepine assay could be observed by running the tests at temperatures ranging from 20 to 25 degrees C as well as at a temperature of 23 degrees C. The specificity and sensitivity of the EMIT-st assay was investigated by measuring various serum concentrations of 14 different barbiturates and 15 different benzodiazepines. A definitive positive response was obtained at a level of 10 micrograms/mL for 5 out of the 14 barbiturates. A positive result at a concentration of 1 microgram/mL was obtained for 10 of the 15 benzodiazepines. A good correlation in response was found for the barbiturates and benzodiazepines compared to the HPLC and GC procedures at concentrations above the detection limit of the assay. In our opinion the EMIT-st tests are useful to clinical toxicological practice. However, the applicability of the screenings test for barbiturates is limited since only a number of these compounds can be detected.