Analysis of gabapentin in serum and plasma by solid-phase extraction and gas chromatography-mass spectrometry for therapeutic drug monitoring. (1/1600)

A simple method for the determination of gabapentin (Neurontin) is described. The method uses solid-phase extraction by disk column and derivatization followed by gas chromatographic-mass spectrometric analysis. The single-step derivatization with MTBSTFA produces a t-BDMS derivative of both the carboxylic and amine moieties of the molecule. Each step of the procedure was optimized to assure reliable performance of the method. The assay limit of detection was 0.1 microg/mL with a linear range from 1.0 to 35 microg/mL. Within-run (n = 3) and between-run (n = 40) coefficients of variation were less than 8.2 and 15.9%, respectively. The method has proven reliable in routine production for more than a year, producing clean chromatography with unique ion fragments, consistent ion mass ratios, and no interferences. Statistical analysis of the gabapentin concentrations measured in 1020 random specimens over a 2-month period showed a mean concentration of 6.07 microg/mL with a standard deviation of 5.28.  (+info)

The therapeutic monitoring of antimicrobial agents. (2/1600)

AIMS: To review the basis and optimal use of therapeutic drug monitoring of antimicrobial agents. METHODS: Antimicrobial agents for which a reasonable case exists for therapeutic drug monitoring were reviewed under the following headings: pharmacokinetics, why monitor, therapeutic range, individualisation of therapy, sampling times, methods of analysis, interpretative problems and cost-effectiveness of monitoring. RESULTS: There is a strong historical case for monitoring aminoglycosides. The recent move to once-daily dosing means that criteria for therapeutic drug monitoring need to be redefined. Vancomycin has been monitored routinely but many questions remain about the most appropriate approach to this. A case can be made for monitoring teicoplanin, flucytosine and itraconazole in certain circumstances. CONCLUSIONS: The approach to monitoring aminoglycosides needs to be redefined in the light of once-daily dosing. It is premature to suggest that less stringent monitoring is necessary as toxicity remains a problem with these drugs. The ideal method of monitoring vancomycin remains to be defined although a reasonable case exists for measuring trough concentrations, mainly to ensure efficacy. Teicoplanin is monitored occasionally to ensure efficacy while flucytosine is monitored occasionally to avoid high concentrations associated with toxicity. Itraconazole has various pharmacokinetic problems and monitoring has been suggested to ensure that adequate concentrations are achieved.  (+info)

Record-linkage for pharmacovigilance in Scotland. (3/1600)

Record-linkage is the linkage of patient-specific information that is stored separately. Recent advances in computerization have meant that record-linkage techniques in medical research are increasingly being used and refined. In particular, they have made a significant contribution to pharmacovigilance, which involves linking drug exposure to outcomes data. In this article, the contribution of record-linkage in Scotland to medical research is described. The two organizations that utilize record-linkage techniques are the Medicines Monitoring Unit (MEMO) of the University of Dundee and the Information and Statistics Division (ISD) of the NHS in Scotland. Pharmacovigilance is MEMO's main concern (using data from the Tayside region of Scotland), while ISD link health care datasets for Scotland for general health care research. The experience of the two groups is now being combined to carry out drug safety studies in the entire population of Scotland.  (+info)

Cough and angiotensin II receptor antagonists: cause or confounding? (4/1600)

AIMS: Cough is one of the most frequent side effects associated with angiotensin converting enzyme inhibitors (ACEIs) but is not thought to be associated with losartan, an angiotensin II receptor antagonist (ARA). This study compares reports of cough with losartan and three ACEIs used in general practice. METHODS: Studies have been conducted for losartan, and three ACEIs enalapril, lisinopril and perindopril, using the technique of Prescription-Event Monitoring. Patients were identified using dispensed prescription data. Questionnaires were sent to patients' general practitioners 6 months after the date of first prescription. Cases of cough within the first 60 days of treatment with losartan resulting in withdrawal of the drug were followed up with additional questionnaires. Incidence rates for reports of cough were calculated. In order to reduce the impact of carry-over effects, rate ratios were calculated for first reports of cough between days 8 and 60 using losartan as the index drug. RESULTS: The cohort for each drug exceeded 9000 patients. Age and sex distributions and indications for prescribing the four drugs were similar. Cough was the most frequent reason for discontinuation of losartan and the most frequently reported event in the first month of treatment with this drug. When reports of cough between days 1-7 were excluded, rates of cough were significantly higher for the three ACEIs when compared with losartan (rate ratios 1.5, 4.8 and 5.7, all P<0.03). 101 patients had discontinued losartan due to cough. 91% of these had previously been prescribed an ACEI and 86% had previously experienced ACEI cough. CONCLUSIONS: Carry-over accounted for the observed excess of reports of cough with losartan. Rates of cough between days 8 and 60 were significantly higher for the three ACEIs compared with losartan. Confounding factors associated with comparative observational cohort studies are discussed.  (+info)

When do HIV-infected persons start with antiretroviral therapy? A retrospective analysis of patients' monitoring and treatment status in general practice, as compared with the 1991 Dutch HIV treatment guidelines. (5/1600)

OBJECTIVE: We aimed to compare, in a sample of Amsterdam general practices, the monitoring and treatment status of HIV-infected patients according to the 1991 Dutch consensus guidelines for antiretroviral treatment of HIV-infection, which advise that therapy be started at a peripheral blood CD4+ cell count of < or = 300 x 10(6)/l in asymptomatic patients, or < or = 400 x 10(6)/l in symptomatic patients. METHOD: In 1994, data were collected from the records of all 511 HIV-infected patients registered in 14 Amsterdam general practices (20 doctors). The main outcome measures were the antiretroviral treatment status of all patients who were eligible for treatment, and the disease stage and CD4+ cell counts at the onset of therapy for patients who started treatment after publication of the 1991 guidelines. RESULTS: For 472 patients, data were available on CD4+ cell measurement status and disease stage. For 15.9% of patients, CD4+ cells had never been measured; most of them were asymptomatic. In 84.1 % of patients, CD4+ cells had been measured. Of the 8.9% of patients whose results were not known to GPs, 93% were treated by a specialist and 76% were symptomatic. Of the remaining 355 (75.2%) patients whose CD4+ count and disease status were known, 201 (56.7%) met the guideline criteria for treatment. Of these, 53.7% received treatment, 27.4% were never treated and 18.9% had discontinued treatment. Of the 67 patients who started treatment after publication of the guidelines, 36.2% of asymptomatic patients and 92.8% of symptomatic patients started later than the guidelines advised. CONCLUSION: In the population studied, we found a discrepancy between the 1991 treatment guidelines and the actual situation. In a substantial proportion of eligible patients, antiretroviral treatment was either not administered at all or was administered at a (very) late disease stage. This can only be attributed to physicians' and/or patients' attitudes towards antiretroviral treatment. Other studies confirm that a number of psychological factors may influence treatment decisions. The new combination treatment of HIV-infection requires an early start and compliance with the guidelines. The degree to which doctors and patients are willing and able to comply with the guidelines is an important factor to be taken into account, both in research and in the development of guidelines.  (+info)

Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. (6/1600)

PURPOSE: The incidence of secondary leukemia after epipodophyllotoxin treatment and the relationship between epipodophyllotoxin cumulative dose and risk are not well characterized. The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) has developed a monitoring plan to obtain reliable estimates of the risk of secondary leukemia after epipodophyllotoxin treatment. METHODS: Twelve NCI-supported cooperative group clinical trials were identified that use epipodophyllotoxins at low (<1.5 g/m2 etoposide), moderate (1.5 to 2.99 g/m2 etoposide), or higher (> or =3.0 g/m2 etoposide) cumulative doses. Cases of secondary leukemia (including treatment-related myelodysplastic syndrome) occurring on these trials have been reported to CTEP, as has duration of follow-up for all patients, thereby allowing calculation of cumulative 6-year incidence rates of secondary leukemia for each etoposide dose group. RESULTS: The calculated cumulative 6-year risks for development of secondary leukemia for the low, moderate, and higher cumulative dose groups were 3.3%, (95% upper confidence bound of 5.9%), 0.7% (95% upper confidence bound of 1.6%), and 2.2%, (95% upper confidence bound of 4.6%), respectively. CONCLUSION: Within the context of the epipodophyllotoxin cumulative dose range and schedules of administration encompassed by the monitoring plan regimens, and within the context of multiagent chemotherapy regimens that include alkylating agents, doxorubicin, and other agents, factors other than epipodophyllotoxin cumulative dose seem to be of primary importance in determining the risk of secondary leukemia. Data obtained by the CTEP secondary leukemia monitoring plan support the relative safety of using epipodophyllotoxins according to the therapeutic plans outlined in the monitored protocols.  (+info)

Therapeutic drug monitoring of antimetabolic cytotoxic drugs. (7/1600)

Therapeutic drug monitoring is not routinely used for cytotoxic agents. There are several reasons, but one major drawback is the lack of established therapeutic concentration ranges. Combination chemotherapy makes the establishment of therapeutic ranges for individual drugs difficult, the concentration-effect relationship for a single drug may not be the same as that when the drug is used in a drug combination. Pharmacokinetic optimization protocols for many classes of cytotoxic compounds exist in specialized centres, and some of these protocols are now part of large multicentre trials. Nonetheless, methotrexate is the only agent which is routinely monitored in most treatment centres. An additional factor, especially in antimetabolite therapy, is the existence of pharmacogenetic enzymes which play a major role in drug metabolism. Monitoring of therapy could include assay of phenotypic enzyme activities or genotype in addition to, or instead of, the more traditional measurement of parent drug or drug metabolites. The cytotoxic activities of mercaptopurine and fluorouracil are regulated by thiopurine methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD), respectively. Lack of TPMT functional activity produces life-threatening mercaptopurine myelotoxicity. Very low DPD activity reduces fluorouracil breakdown producing severe cytotoxicity. These pharmacogenetic enzymes can influence the bioavailability, pharmacokinetics, toxicity and efficacy of their substrate drugs.  (+info)

A pilot study to determine the usefulness of the urinary excretion of methadone and its primary metabolite (EDDP) as potential markers of compliance in methadone detoxification programs. (8/1600)

Fourteen subjects (selected on the basis of compliance with the methadone-maintenance program prescribed by the consultant psychiatrist in charge of their treatment) undergoing opiate detoxification by methadone-replacement therapy were studied to determine if a relationship exists between the dose of methadone prescribed and the urinary excretion of methadone and/or its primary metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). After the derivation of this relationship, it was hoped that the urinary concentrations of methadone and/or EDDP could be used as a noninvasive technique to monitor the methadone compliance of 56 drug abusers. Despite statistically significant correlations (p<0.001) between methadone dose and urine concentrations of methadone and EDDP, the large variation in concentrations measured in the urine of drug abusers negated the possibility of any clear-cut relationship being confirmed. However, it may be possible to use excretion data to monitor individual compliance but only through long-term monitoring of individual subjects to establish their own intraindividual variation in excretion patterns.  (+info)