Therapeutic drug monitoring
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Randomized Controlled Trial Clinical Trial
Spectral analysis of heart rate variability as a quantitative measure of parasympatholytic effect--integrated pharmacokinetics and pharmacodynamics of three anticholinergic drugs.
The time course and concentration-effect relationship of parasympatholytic effects of three anticholinergic drugs were investigated using spectral analysis of heart rate (HR) variability. Single intravenous (i.v.) doses of atropine (10 microg/kg), glycopyrrolate (5 microg/kg), scopolamine (5 microg/kg), and placebo were given to eight healthy volunteers in a double-blind, randomized cross-over study. Electrocardiogram (ECG) was recorded at baseline and 2.5, 5, 10, 20, and 30 minutes, and 1, 1.5, 2, 3, 4, 5, and 6 hours after drug administration, while the subjects breathed at a fixed 0.25 Hz frequency. ⋯ Spectral analysis of HR variability appears to be a powerful tool in monitoring parasympatholytic drug activity. A sigmoidal Emax model with an extremely steep concentration-response relationship was revealed for atropine and glycopyrrolate. The effects of scopolamine were more incongruous.
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Clinical Trial Controlled Clinical Trial
The influence of the route of administration: a comparative study at steady state of oral sustained release morphine and morphine sulfate suppositories.
Steady state pharmacokinetics of morphine (M), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were investigated in 6 patients with intractable cancer pain administered orally with MST (Mundipharma, Limburg, Germany) and, subsequently, rectally with MSR to make a judgment whether orally administered morphine can be replaced by rectally administered morphine. The parent drug and glucuronide metabolites were measured simultaneously using high-performance liquid chromatography (HPLC) and native fluorescence detection. The mean morphine area under the curve (AUC) value (0-8 h) was smaller (434.3 +/- 170.2 nmolL(-1)h) in the oral administration than in the rectal administration (574.8 +/- 285.0 nmolL(-1)h) (p < 0.05). ⋯ Four of the 6 patients had a greater Cmax of M3G and M6G after oral administration than after rectal administration. The same 4 had lower fluctuation rates for morphine, M3G (p < 0.05), and M6G (p < 0.05) after rectal administration. Therefore, during chronic morphine treatment, it still seems difficult to decide whether oral administration can be replaced by rectal administration.
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Neoral, the microemulsion formulation of cyclosporine (CsA), demonstrates more consistent bioavailability than the corn oil formulation Sandimmune. Because of Neoral's rapid peak and metabolism, 8-hour dosing has to be used in many pediatric and some adult patients to maintain adequate CsA peak-to-trough ratios. Although the area under the curve (AUC) is considered the best estimate of total drug exposure, it requires repeated blood sampling. ⋯ Mean prediction error was -0.4% +/- 5.48%, and no values fell outside the clinically acceptable 15% prediction error limit. Prospectively applying the formula to 83 AUCs of 14 adults who underwent renal transplantation and were taking Neoral three times a day demonstrated an excellent fit (r2 = 0.93; p < 0.001), with 94% of predicted values falling inside the +/-15% limit. The authors describe the development of a clinically acceptable, limited sampling strategy to predict 8-hour Neoral AUCs in children and adults who underwent renal transplantation.
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Immunoassays designed to detect use of older benzodiazepines such as oxazepam or diazepam often cannot detect triazolam use because of the low doses of triazolam administered, rapid biotransformation to metabolites with poor cross-reactivities, and the small amount of alpha OH triazolam glucuronide excreted in the urine. Previous studies have demonstrated that certain immunoassays have high cross-reactivity to alpha OH triazolam but are unable to detect therapeutic triazolam use in urine. ⋯ With a 200 ng/ml cut-off, 4/30 of the urine specimens screened positive for benzodiazepines without enzymatic hydrolysis and 6/30 after enzymatic hydrolysis. When using an in-house 100 ng/ml nitrazepam cut-off calibrator, 10/30 urine specimens were positive in the reformulated CEDIA assay without hydrolysis and 22/30 were positive with enzymatic hydrolysis before screening.
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Case Reports
Quick onset of severe abdominal pain after codeine in an ultrarapid metabolizer of debrisoquine.
The authors describe a 33-year-old woman who experienced severe pain in the epigastrium after codeine intake. This side-effect is consistent with that of morphine. Later, the patient was phenotyped and genotyped as an ultrarapid metabolizer with high capacity to metabolize codeine to morphine.