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Biomedical subjects

D M Burger

Publications and source records attributed to D M Burger.

At least 73 records · Page 4Linked to original sources
PubMed1996

Pharmacokinetic individualisation of zidovudine therapy. Current state of pharmacokinetic-pharmacodynamic relationships.

Zidovudine is the cornerstone of current antiretroviral treatment of human immunodeficiency virus (HIV) infection. Its use, however, frequently leads to adverse reactions, including myelosuppression. Zidovudine pharmacokinetics show large interindividual variation with indications of pharmacokinetic-pharmacodynamic relationships, but a clear therapeutic window has not yet been defined. Individualisation of zidovudine therapy with monitoring of drug concentrations might be desirable. This review considers (intracellular) monitoring of zidovudine and anabolites for individualisation of zidovudine therapy and the achievements in describing pharmacokinetic-pharmacodynamic relationships so far.

Antiviral Agents↗
PubMed1995

Study on didanosine concentrations in cerebrospinal fluid. Implications for the treatment and prevention of AIDS dementia complex.

It has been hypothesized that didanosine has a low efficacy in the prevention and treatment of patients with the dementia complex of acquired immunodeficiency syndrome (AIDS) because "... the drug has not been detected in the cerebrospinal fluid". We investigated didanosine concentrations in cerebrospinal fluid (CSF) and plasma of four patients with AIDS who were using didanosine chronically. Didanosine levels, 4 h after the last drug administration, averaged 0.16 (+/- 0.03) mumol/l in CSF and 0.70 (+/- 0.27) mumol/l in plasma. When compared with historical data from patients using zidovudine, didanosine concentrations in CSF appeared to be approximately half (on a molar base) those of zidovudine concentrations in the CSF. Whether this difference in CSF levels is the explanation for the presumed lower efficacy of didanosine in the prevention and treatment of AIDS dementia complex remains to be proven. However, it is clear from this study, in contrast with earlier suggestions, that didanosine is able to pass the blood-CSF barrier in human immunodeficiency virus-infected individuals.

AIDS Dementia Complex↗
PubMed1995

Concise overview of the clinical pharmacokinetics of dideoxynucleoside antiretroviral agents.

In this paper aspects of the clinical pharmacokinetics of the antiretroviral agents zidovudine, didanosine and zalcitabine are reviewed. Special attention is paid to possibly altered pharmacokinetics in special circumstances, such as hepatic and renal dysfunction, pregnancy, stage of disease, etc. The dideoxynucleoside antiretroviral agents have some clinical pharmacokinetic properties in common (rapid absorption and elimination), but substantial differences exist in their degree of absorption, metabolism and penetration into the cerebrospinal fluid. All agents display wide interpatient variability in pharmacokinetic parameters. The relevance of therapeutic drug monitoring of antiretroviral agents is also discussed.

Animals↗
PubMed1994

Short-term, combined use of paracetamol and zidovudine does not alter the pharmacokinetics of either drug.

OBJECTIVE: To investigate a possible pharmacokinetic interaction between zidovudine and paracetamol. METHODS: Six patients with AIDS took both zidovudine (AZT; 1000-1200 mg/day) and paracetamol (500 mg every 6 h) for 7 days. Pharmacokinetic monitoring was performed on day 0 (AZT alone) and after 7 days of combined use of paracetamol and AZT. RESULTS: Combined use of paracetamol and AZT did not result in a significant change in any of the calculated pharmacokinetic parameters of AZT or its primary metabolite AZT-glucuronide. In addition, paracetamol pharmacokinetic parameters at day 7 did not differ from those usually reported in the literature. CONCLUSION: Short-term, combined use of paracetamol and AZT does not lead to a change in the pharmacokinetics of either AZT or paracetamol. The effect of long-term use of this combination remains unknown. A recent case report of AZT-induced paracetamol hepatotoxicity [Am J Med 1992;93: 94-96] indicates that clinicians should still be aware of potential drug toxicity when prescribing both AZT and paracetamol.

Acetaminophen↗
PubMed1994

Pharmacokinetic variability of zidovudine in HIV-infected individuals: subgroup analysis and drug interactions.

OBJECTIVE: To investigate determinants of inter- and intraindividual variability of zidovudine (ZDV) pharmacokinetics in HIV-infected patients. DESIGN: A prospective study in a general 525-bed hospital with special funding for treatment and research of HIV-infected patients. METHODS: Serial blood samples were collected from 68 HIV-infected individuals providing a total of 95 pharmacokinetic curves. ZDV was measured with high-performance liquid chromatography and radioimmunoassay. Pharmacokinetic parameters were calculated by non-compartmental analysis. Patient characteristics were investigated by multivariate analysis for an influence on ZDV pharmacokinetics. RESULTS: Apparent ZDV clearance was significantly lower in patients with a lower body weight, in women, and in patients with a more advanced stage of HIV disease. Co-administration of methadone with ZDV resulted in higher plasma concentrations of ZDV, while rifampin and ganciclovir increased apparent ZDV clearance. Age, the duration of ZDV use, CD4+ cell count, creatinine clearance, elevated serum liver enzyme levels, and the use of 11 other co-administered medications were not independently related to apparent ZDV clearance. CONCLUSIONS: The pharmacokinetic profile of ZDV in several subpopulations has been evaluated, as well as the observation of possible drug-drug interactions between ZDV and 14 different drugs or groups of drugs. These data suggest that patient-individualized antiretroviral therapy may be appropriate once pharmacokinetic-pharmacodynamic relationships have been established.

Adult↗
PubMed1994

Therapeutic drug monitoring of phenytoin in patients with the acquired immunodeficiency syndrome.

Serum phenytoin concentrations were investigated in 109 serum samples from 21 patients with the acquired immunodeficiency syndrome (AIDS) and in 1,231 serum samples from 557 control subjects during phenytoin therapy. Total phenytoin concentrations were significantly lower in patients with AIDS than in the reference population (8.8 +/- 0.7 mg/L (mean +/- SE) vs. 10.6 +/- 0.2 mg/L), although phenytoin doses were significantly higher in the AIDS patients. Body weight and the use of folic acid were negatively related to phenytoin concentrations, whereas use of clarithromycin resulted in higher phenytoin levels. Zidovudine did not influence phenytoin levels. Calculation of the Michaelis-Menten parameters showed that Vmax values were similar in seven human immunodeficiency virus (HIV)-infected patients as compared with 12 controls, but a nonsignificant trend of lower Km values in the HIV-positive group was observed. Measurement of free phenytoin concentrations demonstrated that the fraction of unbound drug was increased in patients with AIDS. Hypoalbuminemia was common in this population, which may complicate the interpretation of total phenytoin concentrations.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Application of a radioimmunoassay for determination of levels of zalcitabine (ddC) in human plasma, urine, and cerebrospinal fluid.

A specific and sensitive radioimmunoassay for the determination of levels of zalcitabine in human plasma, urine, and cerebrospinal fluid has been developed. Commercially available radiolabel and antiserum (Sigma Chemicals) were used after dilution in assay buffer. Prior to the immunoassay, standard and patient samples were subjected to solid-phase extraction on silica columns in order to obtain purified samples. The lower limit of quantitation was determined to be 1 ng/ml. Intra- and interassay variations were less than 11% for a number of quality control samples of drug in plasma and urine. Results from parallelism studies with plasma and urine demonstrated that samples outside the standard range (1 to 30 ng/ml) could be diluted by blank plasma or assay buffer, respectively. A large number of related compounds and potentially coadministered drugs were tested for cross-reactivity. Stability tests showed that heat treatment for 30 min at 60 degrees C or storage for 1 month at -30 degrees C did not affect zalcitabine concentrations in plasma or urine. The radioimmunoassay with solid-phase extraction for sample cleanup discussed here has been successfully applied in a pharmacokinetic study of a single patient, demonstrating its applicability for clinical pharmacokinetic research with zalcitabine.

Humans↗
PubMed1994

Pharmacokinetics of zidovudine and acetaminophen in a patient on chronic acetaminophen therapy.

OBJECTIVE: To report a case of a potential interaction between acetaminophen and zidovudine in a patient who had used high daily doses of acetaminophen over many years. CASE SUMMARY: A 43-year-old man presented with HIV-1 infection, recurrent oral candidiasis, and chronic use of acetaminophen, codeine, and diazepam before he started zidovudine therapy. Although literature was available regarding short-term combined use of acetaminophen and zidovudine, information was lacking on zidovudine therapy and kinetics after long-term use of acetaminophen. Acetaminophen and zidovudine pharmacokinetics were determined on several occasions. The results showed extremely rapid absorption of both drugs (tmax the time to reach maximum concentration, 10-15 minutes for acetaminophen and 15-20 minutes for zidovudine) and, consequently, relatively high maximum plasma concentration (Cmax). No influence on other pharmacokinetic parameters of either drug could be detected. Because the effect of high Cmax values of zidovudine is unknown, the patient was treated with a third of the dose of zidovudine used at that time (zidovudine 100 mg q6h). No toxicity or opportunistic infections developed within the next 8 months, after which the patient died of a cause unrelated to HIV infection. DISCUSSION: The observed pharmacokinetic profiles of both drugs are discussed and compared with two studies dealing with zidovudine therapy in combination with short-term use of acetaminophen and with a case report of acetaminophen-induced hepatotoxicity during concomitant use of zidovudine. CONCLUSIONS: Long-term use of acetaminophen may accelerate the absorption of zidovudine. Although other causes cannot be ruled out, there was no influence on other pharmacokinetic parameters of zidovudine. No influence of zidovudine on acetaminophen concentrations was found. Combined use of zidovudine 100 mg q6h and acetaminophen 500 mg q4h appeared to be safe and effective for at least eight months.

Acetaminophen↗
PubMed1993

Determination of 3'-amino-3'-deoxythymidine, a cytotoxic metabolite of 3'-azido-3'-deoxythymidine, in human plasma by ion-pair high-performance liquid chromatography.

A sensitive high-performance liquid chromatographic assay has been developed to determine the levels of 3'-amino-3'-deoxythymidine (AMT), a cytotoxic metabolite of 3'-azido-3'-deoxy-thymidine (AZT, zidovudine), in human plasma. The sample pretreatment involved solid-phase extraction using cation-exchange extraction columns. Chromatography was carried out on a C8 column, using a mobile phase of methanol-0.01 M ammonium acetate (pH 5)-0.25 M sodium dioctylsulfosuccinate (60:40:4, v/v/v) and ultraviolet detection at 265 nm. The method has been validated, and stability tests under various conditions have been performed. The lower limit of quantitation is 5 ng/ml (using 500-microliters human plasma samples). The bioanalytical assay has been used for the determination of AMT in patients with AIDS who used AZT.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Ocular complications of the acquired immunodeficiency syndrome. Focus on the treatment of cytomegalovirus retinitis with ganciclovir and foscarnet.

The most common ocular complication in patients with the acquired immunodeficiency syndrome (AIDS) is cytomegalovirus retinitis. Incidence figures vary from 20 to 76%. Patients with cytomegalovirus may suffer from mild visual impairment of one or both eyes, but as the disease progresses the retinitis will almost certainly lead to blindness. Although cytomegalovirus retinitis is not a life-threatening infection, it can largely diminish the patient's quality of life. Clinical trials for the treatment of cytomegalovirus retinitis with a number of antiviral drugs have resulted in two drugs of choice, ganciclovir and foscarnet. Both drugs have an initial efficacy with induction therapy of 80-90%, but maintenance therapy is always needed to prevent a relapse. To exclude systemic side-effects of ganciclovir, intravitreal administration has been investigated with good results. Combination therapy of foscarnet and ganciclovir may be worthwhile in resistant cytomegalovirus retinitis.

Acquired Immunodeficiency Syndrome↗
PubMed1993

2',3'-dideoxyinosine (ddI): its chemical stability and cyclodextrin complexation in aqueous media.

The chemical stability of 2',3'-dideoxyinosine has been studied over a wide pH range (0-12). A stability-indicating HPLC method was used to separate the degradation product from the parent drug. The effects of temperature, ionic strength and buffer components on the degradation kinetics were investigated. Furthermore, the influence of some cyclodextrins (alpha-, beta-, HP-beta-, DM-beta- and gamma-cyclodextrin) on the drug stability have been studied.

Buffers↗
PubMed1993

Penetration of zidovudine into the cerebrospinal fluid of patients infected with HIV.

OBJECTIVE: To investigate penetration of zidovudine (ZDV) into the cerebrospinal fluid (CSF) of HIV-infected patients for whom a lumbar puncture was indicated. DESIGN: A prospective study. SETTING: General 525-bed hospital with special funding for treatment and research of HIV-infected patients. PATIENTS, PARTICIPANTS: Thirty-nine patients with a medical indication for lumbar puncture who used ZDV chronically were included in this study (50 samples in total). MAIN OUTCOME MEASURE: Determination of ZDV and proteins in CSF and plasma samples. RESULTS: CSF concentrations of ZDV showed little fluctuation 1-8 h after the last ingestion of ZDV. In contrast, plasma levels displayed large variability in this period and decreased exponentially over time. As a result, the CSF/plasma ratio increased linearly over time. No significant relation between the ZDV dose, neither the medical indication for lumbar puncture nor the protein ratio (as a measure for the integrity of the blood-brain barrier), and CSF levels of ZDV was found. The CSF/plasma ratio of ZDV did not give essential information on drug distribution into CSF. CONCLUSIONS: Penetration of ZDV into the CSF appears to be independent of the dose (range, 200-1250 mg daily), which may be an explanation for the efficacy of low doses of ZDV in the prevention and treatment of HIV-related neurological diseases. ZDV levels were at steady-state during the first 6 h after ingestion. The CSF/plasma ratio of ZDV concentrations is not an appropriate marker for drug penetration into CSF.

Adult↗
PubMed1993

Pharmacokinetic interaction between rifampin and zidovudine.

A potential pharmacokinetic interaction between rifampin (Rimactan, Rifadin) and zidovudine (AZT, Retrovir) was investigated in the population of human immunodeficiency virus-infected patients at our hospital. The results from four patients who were on long-term (> or = 6 months) combination therapy with zidovudine and rifampin are presented. In all cases of combined use of zidovudine and rifampin, a lower area under the plasma concentration-time curve (AUC) and, consequently, a higher apparent clearance of zidovudine were found, compared with a reference population of zidovudine users. Patients had a low to normal maximum concentration of zidovudine in plasma. Elimination half-lives were normal in all but one patient. Zidovudine glucuronide concentrations were determined in three patients and three control subjects. The patients all had relatively higher peak plasma concentrations and higher AUCs of zidovudine glucuronide than the control subjects. In one patient, zidovudine and zidovudine glucuronide were also measured 2.5 months after discontinuation of rifampin. The AUC of zidovudine increased by a factor of 2. These data are in agreement with an enzyme-inducing effect of rifampin on the glucuronidation of zidovudine. They indicate that long-term combination therapy of rifampin and zidovudine leads to increased clearance of zidovudine, which may have therapeutic consequences.

Adult↗
PubMed1992

Determination of stavudine, a new antiretroviral agent, in human plasma by reversed-phase high-performance liquid chromatography with ultraviolet detection.

A sensitive high-performance liquid chromatographic assay has been developed to determine the levels of a new antiretroviral agent, stavudine (2',3'-didehydro-3'-deoxythymidine, d4T), in human plasma. Didanosine (2',3'-dideoxyinosine, ddI) was used as the internal standard. The very selective sample pretreatment involved solid-phase extraction using silica gel columns. Chromatography was carried out on a mu Bondapak phenyl column, using a mobile phase of 0.005 M phosphate buffer (pH 6.8)-methanol (90:10, v/v) and ultraviolet detection at 265 nm. The method has been validated, and stability tests under various conditions have been performed. The detection limit is 10 ng/ml (using 500-microliters human plasma samples). The bioanalytical assay has been used in a single pharmacokinetic experiment in a rat to investigate the applicability of the method in vivo.

Animals↗
PubMed1991

Omeprazole. A pharmaco-epidemiological study of its use in a university hospital.

A pharmaco-epidemiologic study in hospitalized patients was carried out in order to establish the place and use of omeprazole (Losec), a new and promising drug in the treatment of acid-related diseases. A comparison is made with cimetidine and ranitidine use. It appeared that prescribed omeprazole doses were high in relation to the established defined daily doses and that substitution of H2 receptor antagonists by omeprazole led to tremendously increased drug costs. From the clinical indication data it could be established that the drug was prescribed appropriately.

Adult↗
PubMed1991

Pharmacological profile of various kappa-agonists at kappa-, mu- and delta-opioid receptors mediating presynaptic inhibition of neurotransmitter release in the rat brain.

1. The potency, relative efficacy and selectivity of a series of kappa-opioid receptor agonists at the mu-, delta- and kappa-opioid receptors mediating inhibition of electrically-induced (radiolabelled) neurotransmitter release from superfused rat brain slices was determined. 2. With regard to their potencies at kappa-receptors mediating inhibition of striatal [3H]-dopamine release, the highest pD2 value (8.7) was found for bremazocine and the lowest (7.1) for U50488; the pD2 values for ethylketocyclazocine (EKC), tifluadom, U69593 and PD117302 were between 8.0 and 8.3. There were no marked differences between the relative efficacies of the kappa-agonists (maximum inhibition being 60-70%). In contrast to the other kappa-agonists, at a concentration of 1 microM, PD117302 caused a significant (25-40%) increase of the spontaneous efflux of tritium. 3. None of the kappa-agonists significantly affected striatal [14C]-acetylcholine (ACh) release, with the exception of a slight inhibitory effect of EKC. The delta-receptor-mediated inhibitory effect of [D-Ala2, D-Leu5]enkephalin (DADLE) on [14C]-ACh release was antagonized in a concentration-dependent manner by bremazocine (0.1 and 1.0 microM) and also partially by EKC (1 microM), but not by the other kappa-agonists. The pA2 value for bremazocine as an antagonist at the delta-receptors involved was 8.0, compared to 7.6 for naloxone. 4. None of the kappa-agonists significantly affected cortical [3H]-noradrenaline (NA) release, with the notable exception of tifluadom, which strongly inhibited release by activating mu-receptors. The mu-receptor-mediated inhibitory effect of Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAMGO) on [3H]-NA release was antagonized in a concentration-dependent manner by bremazocine and EKC, but not by the other K-agonists. The pA2 value for bremazocine as an antagonist at the mu-receptors involved was 8.2, compared to 8.6 for naloxone. 5. Thus, whereas U69593 and PD1 17302 display high potency and selectivity towards K-opioid receptors, the potent benzomorphan K-agonists bremazocine and EKC also appear to be strong mu-opioid receptor antagonists.

Acetylcholine↗