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PubMed2002

Therapeutic drug monitoring of anticonvulsant drugs by micellar HPLC with direct injection of serum samples.

BACKGROUND: We developed a micellar liquid chromatographic (MLC) procedure for the determination of three extensively monitored antiepileptics in serum samples: carbamazepine, phenobarbital, and phenytoin. METHODS: We determined the composition of the mobile phase after modeling the elution behavior of the antiepileptics in hybrid micellar mobile phases of sodium dodecyl sulfate (SDS) with different organic modifiers (propanol, butanol, or pentanol) in an experimental design that used five mobile phases, a C(18) column, and ultraviolet detection. In the micellar chromatographic system, the serum samples can be injected directly. RESULTS: The optimum mobile phase was 70 mL/L butanol in 0.05 mol/L SDS, pH 7, in which the three antiepileptics were resolved in <10 min. Intra- and interday precision was evaluated at four different drug concentrations within the therapeutic range (n =10); CVs were <2.1%. The method was applied to the analysis of 120 serum samples, and results were similar to those obtained by the TDx method. CONCLUSIONS: The MLC method allows chromatographic determination of three antiepileptics, using an interpretative strategy of optimization, without pretreatment of the serum samples and with direct injection in a hybrid micellar mobile phase of SDS-butanol. The method provides complete resolution and quantification of mixtures of two and three antiepileptics.

Anticonvulsants↗
PubMed1993

[Incidence of drug side effects by symptoms and syndromes. From the experiences of the Comprehensive Hospital Drug Monitoring and the Swiss Drug Side Effect Center. As an example: allergic and pseudo-allergic reactions with mild analgesics and NSAID].

From 1974 to 1989, 37,392 patients were admitted to the divisions of general internal medicine of the CHDM hospitals. 19,082 of them were treated with a minor analgesic or an NSAID. In 95 of the exposed patients, an allergic or a pseudoallergic reaction to one or two of these drugs was observed. From 1981 to 1990, general practitioners, hospitals and the pharmaceutical industry reported to SANZ 158 individual cases with comparable reactions to 175 exposures of the same kind. Of the 15 different syndromes and symptoms registered in both institutions, most were reactions of the skin, mainly the usual maculopapular exanthemas (rash), urticaria and angioedema. In the CHDM, allergic or pseudoallergic reactions were observed in 0.23% of patients exposed to minor analgesics (including ASA preparations on a daily dose up to 1.0 g and pyrazolones, mainly metamizole, propyphenazone) and in 0.81% of patients exposed to NSAIDs (including the pyrazolone oxyphenbutazone). In the experience of the Comprehensive Hospital Drug Monitoring in Berne and St. Gallen (CHDM) and the Spontaneous Adverse Drug Reactions Center of Switzerland (SANZ).

Adverse Drug Reaction Reporting Systems↗
PubMed2002

Clinical utility of free drug monitoring.

Most drugs are bound to serum proteins to a various degree. Only unbound or free drug is pharmacologically active. Usually total drug is measured for therapeutic monitoring because there is equilibrium between bound and free drugs, and concentration of free drug can be predicted from total drug concentration. However, under certain conditions this equilibrium is disturbed and the measured free drug concentration can be significantly higher than expected from total drug concentrations, especially for strongly protein-bound drugs. In such case a patient may experience drug toxicity even if the total drug concentration is within the therapeutic range. Conditions like uremia, liver disease and hypoalbuminemia can lead to significant increases in free drug concentration. Therefore, monitoring free phenytoin and free valproic acid is recommended in these patients. Drug-drug interactions can also lead to a disproportionate increase in free drug concentration. One strongly protein-bound drug can significantly displace another strongly protein-bound drug if both drugs share the same binding site. Several over-the-counter pain medications such as salicylate, naproxen, and ibuprofen can cause significant displacement of both phenytoin and valproic acid from albumin binding site. Interestingly, such interactions are absent in uremic patients. Elderly patients may have increased free phenytoin or valproic acid due to hypoalbuminemia. Elevated free phenytoin concentrations have also been reported in patients with AIDS. Although digoxin is 25% bound to protein, monitoring free digoxin is useful in patients with elevated endogenous digoxin-like immunoreactive substances or in patients overdosed with digoxin and being treated with digibind. Monitoring free digoxin can also eliminate interference of Chinese medicines Chan Su and Danshen in serum digoxin measurement by certain immunoassays. However, free drug monitoring is not a routine procedure in clinical laboratories due to technical difficulties and lack of established reference ranges for free drugs.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Effect of plantain on therapeutic drug monitoring of digoxin and thirteen other common drugs.

INTRODUCTION: Plantain, a herbal remedy, has been reported to interfere with therapeutic drug monitoring of digoxin. We evaluated three commercially available plantain products for potential interference with therapeutic drug monitoring of digoxin and 13 other common drugs. METHOD: Dry content of plantain capsule or plantain leaf was extracted with either methanol or ethanol:water (60:40 by volume), added to drug-free serum and apparent digoxin was measured by both fluorescence polarization immunoassay and microparticle enzyme immunoassay. Using immunoassays, we also measured apparent concentrations of 13 other drugs (tobramycin, procainamide, tricyclic antidepressants, quinidine, carbamazepine, phenytoin, theophylline, valproic acid, amikacin, gentamycin, phenobarbital, salicylate and acetaminophen [paracetamol]) due to the presence of plantain. In separate experiments, a serum pool prepared from patients receiving digoxin was further supplemented with plantain and observed digoxin values were compared with original digoxin concentration. The presence of any cardiac glycoside in plantain was also investigated using thin layer chromatography (TLC). RESULTS: We observed no apparent digoxin in the presence of plantain in serum. Moreover, when aliquots of digoxin serum pool were supplemented with various amounts of plantain, the observed digoxin concentrations in the presence of plantain compared well with original digoxin concentration. TLC analysis did not show the presence of either digoxin or digitoxin in plantain products studied. Moreover, plantain did not affect immunoassay results of the 13 other drugs studied. CONCLUSIONS: The plantain products studied did not interfere with therapeutic drug monitoring of digoxin as well as 13 other commonly monitored drugs.

Cardiac Glycosides↗
PubMed2005

National differences in reporting 'pneumonia' and 'pneumonia interstitial': an analysis of the WHO International Drug Monitoring Database on 15 drugs in nine countries for seven pulmonary conditions.

PURPOSE: Increased post-marketing reports of 'interstitial pneumonia' as an adverse drug reaction (ADR) from the use of gefitinib, irinotecan, or leflunomide among patients in Japan have not been noted in other countries. The WHO International Drug Monitoring Database was analyzed to examine Japan's pattern of reporting the term 'pneumonia interstitial' for 15 selected drugs with a mixed history of association with pulmonary ADRs. METHODS: ADR counts from the WHO Database for 1992-2001 were obtained for 15 disparate drugs (three androgen blockers, eight cytotoxics, one proton pump inhibitor, one monoclonal antibody, and two anti-epileptics) from nine countries (Australia, France, Germany, Italy, Japan, Spain, Thailand, U.K., and U.S.A.) for seven pulmonary ADR terms (alveolitis fibrosing, pneumonia, pulmonary fibrosis, lung fibrosis interstitial, pulmonary infiltration, interstitial lung disease, and pneumonia interstitial). Statistical analyses included estimating Poisson-distributed expected rates, observed/expected (O/E) ratios, and 95% confidence intervals (CI). The overlapping nature and changes in definition over time of these terms in medical texts and in the WHO-ART, COSTART, J-ART, and MedDRA coding systems is also noted. RESULTS: Compared to other countries, both Japan and France did not have higher O/E reporting ratios for all seven pulmonary ADRs combined, but did have higher O/E ratios for 'pneumonia interstitial' and lower O/E ratios for 'pneumonia' for the same drugs. CONCLUSIONS: Japan and France were found to preferentially use the term 'pneumonia interstitial' for ADR where other countries used 'pneumonia.' This cultural pattern coincides with the fact that 'pneumonia interstitial' in older versions of COSTART, J-ART, and MedDRA were subsumed under infectious pulmonary diseases.

Adverse Drug Reaction Reporting Systems↗
PubMed1994

Bayesian and threshold probabilities in therapeutic drug monitoring: when can serum drug concentrations alter clinical decisions?

The use of Bayesian and threshold probabilities is examined with respect to the range of probabilities of toxicity for which obtaining a patient's serum drug concentration leads to information that is potentially useful in altering a clinical decision. For the situation of potential drug-induced toxicity, three threshold probabilities are needed to characterize the decision process: the decision threshold for deciding between continuing and discontinuing the drug regimen, the testing threshold that separates the decision to continue the regimen without testing the serum drug concentration from the decision to test before deciding, and the companion testing threshold that separates the decision to discontinue the regimen without testing from the decision to test before deciding. For digoxin, theophylline, aminoglycosides, vancomycin, and phenytoin, three prototypical decision threshold probabilities, 0.33, 0.2, and 0.1, are used, along with published true-positive and false-positive rates, to calculate serum concentration testing thresholds for each drug. Practitioners can be more effective in their use of serum drug concentration data when a Bayesian approach to probability assessment is used in conjunction with testing thresholds.

Bayes Theorem↗
PubMed2004

Therapeutic drug monitoring of non-anticancer drugs in cancer patients.

Therapeutic drug monitoring (TDM) or the measurement of drug concentrations in plasma, serum or blood, aims to improve clinical activity, avoid toxicity, and reduce the costs of drug treatment. Specific conditions for TDM to be reasonably applied include the availability of a validated assay, a considerable interindividual pharmacokinetic variability, a high correlation between drug concentration and toxicity, and a narrow therapeutic index. Cancer patients are especially prone to drug-drug interactions due to significant comedication, impaired liver and kidney function and hypoalbuminemia with altered drug binding. This article discusses TDM for various broadly used non-anticancer drugs in cancer patients and gives specific recommendations. Selected drugs covered in this article include those regularly used in febrile neutropenic patients such as the glycopeptide antibiotics, aminoglycosides, the antifungal agents, including flucytosine and azole compounds, the anticonvulsants phenytoin, carbamazepine and valproate, the tricyclic antidepressants, selective-serotonin-reuptake inhibitors, lithium, morphine, digitalis glycosides and the immunosupressants cyclosporin A, tacrolimus, sirolimus and mycophenolate mofetil, crucial compounds in the setting of bone marrow transplantation. In all cases, treating physicians have to consider the variability in patient age, disease stage, comedication, organ function and protein level to weigh the pros and cons of TDM in the individual cancer patient.

Aminoglycosides↗
PubMed2003

A high-performance liquid chromatography method with photodiode-array UV detection for therapeutic drug monitoring of the nontricyclic antidepressant drugs.

A new rapid and sensitive high-performance liquid chromatography method has been developed for the screening and determination in human plasma of the 11 most commonly prescribed nontricyclic antidepressants and two metabolites: fluoxetine, norfluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, moclobemide, mirtazapine, milnacipram, toloxatone, venlafaxine, desmethyl venlafaxine, and viloxazine. It involves liquid-liquid extraction procedures followed by liquid chromatography coupled to photodiode-array UV detection with three fixed wavelengths (220, 240, and 290 nm). Compounds were separated on a 5-microm Hypurity C18 (ThermoHypersil) analytic column (250 x 4.6 mm i.d.) using a gradient of acetonitrile-phosphate buffer pH 3.8 at a flow rate of 1.0 mL/min. The total analysis time was only 18 min per sample. Extraction recoveries were in the 74-109% range for 11 compounds but were of only 59% for moclobemide and less than 10% for toloxatone. Calibration curves were linear in the 25 to 1000 ng/mL range for all compounds, all of them with coefficients of determination (r2 values) > or = 0.999. Limits of detection (LODs) ranged from 2.5 to 5 ng/mL except for toloxatone (10 ng/mL). Intraassay and interassay precision and accuracy were studied at two concentration levels (50 and 500 ng/mL). The intraassay coefficients of variation (CVs) for all compounds were < or = 7.6%, and all interassay CVs were below 11.5% except for milnacipram (14.8%). The intraassay and interassay accuracies for all compounds were found to be within 88.4% and 105.9% at 50 ng/mL and within 87.2% and 100.5% at 500 ng/mL. The performance of the method allows the therapeutic drug monitoring of the most prescribed nontricyclic antidepressant drugs as well as its use in toxicologic screening.

Antidepressive Agents↗
PubMed2005

Therapeutic drug monitoring and the inhibitory quotient of antiretroviral drugs: can they be applied to the current situation?

Therapeutic drug monitoring is attracting growing interest as a means of increasing the effectiveness of antiretroviral therapy and of decreasing its toxicity, although data supporting this strategy are still scarce. Currently, nucleoside analog reverse-transcriptase inhibitors (NARTI) are not candidates because their effect depends on their active intracellular form and not on plasma concentration. Protease inhibitors (PI) and non-nucleoside analogue reverse-transcriptase inhibitors (NNARTI) meet the criteria for therapeutic drug monitoring. The main limitations are that the parameters to be monitored in order to measure exposure to the drug and the effective concentration of the drug have not been well defined. The few studies performed in treatment-naive patients have demonstrated that monitoring improves therapeutic efficacy. This strategy will be particularly useful when the risk of subtherapeutic or toxic concentrations is especially high (pharmacokinetic interactions, intestinal malabsorption, adverse effects, virological failure without obvious cause, pregnancy, children). Although it remains to be standardized, the inhibitory quotient integrates pharmacological and virological parameters and is useful in patients with prior virological failure. Any therapeutic drug monitoring program should be accompanied by measures to monitor and improve treatment adherence. There are good reasons to believe that therapeutic drug monitoring can be useful to improve treatment in specific circumstances. However, before its widespread use as a routine method can be recommended, the parameters to be used should be standardized and studies with appropriate methodology should be performed to define the role of therapeutic drug monitoring in distinct clinical situations.

Algorithms↗
PubMed2003

Therapeutic drug monitoring of 13 antidepressant and five neuroleptic drugs in serum with liquid chromatography-electrospray ionization mass spectrometry.

Therapeutic drug monitoring of antipsychotic drugs has become more and more important in recent years, and a well-organized therapeutic drug monitoring service with fast turn-around times is very important. Therefore, an analytical method coupling high-performance liquid chromatography to mass spectrometry with electrospray ionization in the positive mode was established in our laboratory. Amitriptyline, citalopram, clomipramine (including norclomipramine), desipramine, dibenzepin, doxepin (including nordoxepin), escitalopram, flupentixol, fluphenazine, fluvoxamine, imipramine, nortriptyline, opipramol, pipamperone, reboxetine, thioridazine, trimipramine and zuclopenthixol were separated on a reversed-phase C18 column. The mobile phase consisted of acetonitrile and ammonium acetate buffer pH 4. Because of different organic solvents used for the liquid-liquid extraction and the different volumes of mobile phases in which the residues were dissolved, four analytical systems had to be applied. Within the run-time of maximal 10 minutes the 13 antidepressant and five neuroleptic drugs were baseline separated on the corresponding mass-to-charge track. The calibration range of each drug was linear, all between-day coefficients of variation were below 7% and the recovery rates were between 60 and 103%. Using 1 ml of serum, the lower limits of quantification were between 1.2 and 54 nmol/l for the different drugs and below the therapeutic range for each of the different drugs.

Antidepressive Agents↗
PubMed1994

Assessment of impact of physico-chemical drug properties on monitoring drug levels by micellar electrokinetic capillary chromatography with direct serum injection.

The impact of physico-chemical properties of 25 compounds, including antiepileptic, anti-inflammatory and beta-blocking drugs, on their determination by micellar electrokinetic capillary chromatography (MECC) with direct serum injection (DSI) is discussed. Having a pH 9.2 buffer containing 75 mM sodium dodecyl sulfate (SDS), elution is dependent on hydrophobicity, the order of emergence being basically according to increasing octanol/water partition coefficients (logP values). Peak shape is determined by the dissociation behavior (expressed by pKa) and plasma protein binding (PPB). Sharp peaks are produced by compounds having low PPB and, independently of PPB, by drugs with pKa values which are similar to the buffer pH. Broad or double peaks are established by drugs of low pKa values and significant (> about 40%) PPB. In order to evaluate the effective amount of a protein-bound drug measured by MECC-DSI, serum levels of drugs with different PPB, namely ethosuximide (no PPB), phenobarbital (PPB of about 50%) and naproxen (PPB > 99%) have been determined by both MECC-DSI and MECC with extract injection (MECC-EXI). In each case, with more than 40 sera, there is good agreement between the two sets of data. Thus, employing MECC-DSI, total amounts of drugs are determined, i.e. a complete release of the drugs from the proteins is effected by the impact of dodecyl sulfate on the sampled proteins.

Adrenergic beta-Antagonists↗