Biomedical subjects

A Bult

Publications and source records attributed to A Bult.

At least 91 records · Page 5Linked to original sources

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↗

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

Determination of chloroacetaldehyde, a metabolite of oxazaphosphorine cytostatic drugs, in plasma.

A derivatization high-performance liquid chromatographic method with ultraviolet detection to monitor the plasma concentration of chloroacetaldehyde, a neurotoxic metabolite of oxazaphosphorine drugs, is presented. To prevent the rapid degradation of chloroacetaldehyde, the plasma samples are stabilized with formaldehyde. The method is linear in the concentration range 1-250 nmol/ml. Blood samples from a patient who was treated with a ten-day continuous infusion of ifosfamide were assayed. The chloroacetaldehyde concentrations did not exceed 10 nmol/ml.

Acetaldehyde↗

PubMed1993

Plasma pharmacokinetics of vinblastine and the investigational Vinca alkaloid N-(deacetyl-O-4-vinblastoyl-23)-L-ethyl isoleucinate in mice as determined by high-performance liquid chromatography.

The plasma pharmacokinetics of vinblastine and N-(deacetyl-O-4-vinblastoyl-23)-L-ethyl isoleucinate (VileE) in mice have been studied as part of the preclinical investigations of VileE, a new investigational semisynthetic Vinca alkaloid. Groups of animals received the test compounds through i.v. bolus injection at LD10, 0.5 x LD10, and 0.1 x LD10 doses. VileE has also been administered p.o. Drug plasma levels have been analyzed with a sensitive and selective method using liquid-liquid extraction for sample clean-up and high-performance liquid chromatography combined with fluorescence detection for quantification. Following i.v. injection, plasma kinetics of both vinblastine and VileE can be described adequately by a three-compartment open model. VileE demonstrates nonlinear pharmacokinetics with decreasing clearance and increasing terminal half-lives at increasing doses. Comparison of the plasma concentration versus time curves for vinblastine in humans and mice indicates that the toxicity of these compounds may not be directly related to the drug exposure expressed by the area under curve in plasma but by the terminal half-life and the time that a toxic threshold level is attained. Pharmacokinetically guided dose escalation in coming phase I trials of VileE is, therefore, discouraged.

Animals↗

PubMed1993

Tissue disposition, excretion and metabolism of vinblastine in mice as determined by high-performance liquid chromatography.

We have developed and validated a selective analytical procedure, based on ion-exchange normal-phase liquid chromatography with fluorescence detection and liquid-liquid extraction, for the analysis of vinblastine (VBL) in biological matrices. The assay is suitable for the determination of the parent compound and its metabolites in plasma, tissue, faeces and urine specimens. Pharmacokinetics studies were performed in male FVB mice receiving VBL by intravenous (i.v.) bolus injection at a dose of 6 mg/kg. Plasma concentrations were monitored until 48 h after drug administration. Urine and faeces samples were collected in 24-h portions for up to 72 h and tissue samples were obtained at 4, 24, 72 and 168 h after drug administration. To facilitate a comparison between the findings we obtained by high-performance liquid chromatography (HPLC) and the results of previous studies using radiolabeled drug monitoring, some of the animals were also given radiolabeled drug. Large discrepancies were observed between the results obtained by the two methods. Excretion of the radiolabel in faeces and urine was 85% of the dose within 72 h. HPLC revealed that only 18% of the dose was excreted as unchanged drug and 19%, as measurable metabolites [O4-deacetylvinblastine (DVBL) and two unknown compounds]. In most of the tissues taken at 4 h after drug administration, virtually all of the radioactivity represented VBL or DVBL. In all tissues taken at 72 h after drug administration, however, only very little of the radioactivity remained in the form of these compounds. Following the administration, VBL and DVBL were distributed extensively to most tissues. Many tissues appeared to possess effective means of extruding the cytotoxic drug with decreasing plasma levels. However, in some organs, including those from the genital tract and lymphatic tissues, VBL and DVBL were retained for prolonged periods. Our studies confirm previous indications that selective retention may be the basis of the activity of VBL against malignant transformations derived from these tissues.

Animals↗

PubMed1993

Circadian rhythms differ between selected mouse lines: a model to study the role of vasopressin neurons in the suprachiasmatic nuclei.

Mice selected for differences in nest-building behavior differ in the number of arginine-vasopressin (AVP)-immunoreactive neurons in the suprachiasmatic nuclei (SCN). Although previous efforts to link AVP-immunoreactive neurons in the SCN to clock function have failed, we show that differences in several circadian parameters are associated with differences in the number of AVP-immunoreactive neurons between the selected lines. Although an alternative interpretation is discussed, we hypothesize that these neurons may relay timing information from the circadian pacemaker in the SCN for wheel-running activity. In addition, phase-response curves (PRCs) to 15-min light pulses in constant darkness also differ between the selected lines. However, these differences are not associated with the number of the AVP-immunoreactive neurons in the SCN, but are associated with the level of nest-building behavior. Compared to the Brattleboro rat, in which homozygous rats are deficient for AVP in the entire brain, our system, exhibiting a wide range of variability, has more specific utility for studying the role of the output pathways of the SCN in circadian rhythm control.

Analysis of Variance↗

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↗

PubMed1992

Gas chromatographic determination of 2- and 3-dechloroethylifosfamide in plasma and urine.

The metabolic oxidation of one of the chloroethyl groups of the antitumour drug ifosfamide leads to the formation of the inactive metabolites 2- and 3-dechloroethylifosfamide together with the neurotoxic metabolite chloroacetaldehyde. A very sensitive capillary gas chromatographic method, requiring only 50 microliters of plasma or urine, has been developed to measure the amounts of the drug and the two inactive metabolites in a single run. Calibration curves were linear (r > 0.999) in the concentration ranges from 50 ng/ml to 100 micrograms/ml in plasma and from 100 ng/ml to 1 mg/ml in urine.

Chromatography, Gas↗

PubMed1992

Differences in the number of arginine-vasopressin-immunoreactive neurons exist in the suprachiasmatic nuclei of house mice selected for differences in nest-building behavior.

Arginine-vasopressin (AVP) is a homeostatic modulator of body temperature during fever and may also be involved in normal body temperature control. In the present study the hypothalamus of mice bi-directionally selected for thermoregulatory nest-building behavior was immunocytochemically labeled for AVP. The low-selected mice had a 1.5-fold higher number of AVP-immunoreactive neurons in the suprachiasmatic nuclei (SCN) compared to the unselected control and the high-selected mice. No differences between the selected lines could be detected in the number of AVP-immunoreactive neurons in the paraventricular nuclei (PVN). The neuroanatomical data suggest a possible role of AVP in the SCN and control of thermoregulatory nest-building behavior. Our selected mice may prove to be a model system to study the role of AVP in the SCN.

Animals↗

PubMed1992

On-line phase-transfer catalysed dansylation of phenolic compounds followed by normal-phase liquid chromatography with fluorescence detection.

A study of the on-line phase-transfer catalysed dansylation of phenolic compounds is presented. The extraction-dansylation is performed in the extraction coil of a home-made flow-injection extraction unit. After phase separation, the organic phase is fed to a normal-phase liquid chromatographic system with fluorescence detection. Ethynyloestradiol, oestradiol and paracetamol are used as test compounds. The influence of temperature on the reaction is examined. Calibration graphs showed good linearity (r greater than 0.996) and limits of detection are satisfactory (8 x 10(-7) M for ethynyloestradiol, 2 x 10(-6) M for oestradiol and 5 x 10(-7) M for paracetamol). The method is not applicable for the assay of oxychinoline, phenylephrine and morphine.

Acetaminophen↗

PubMed1991

Gas chromatographic determination of ifosfamide in microvolumes of urine and plasma.

In oncology, particularly in pediatric malignancies, high doses (5-10 g/m2) of the oxazaphosphorine ifosfamide play an important role in the treatment of sarcomas. Pharmacokinetic data of ifosfamide and its metabolites in these cases are scanty. Considering the special demands of the determination of ifosfamide in plasma of young children, a very sensitive capillary gas chromatographic method, requiring only 50 microliters of plasma, has been developed. This bioanalysis of ifosfamide shows good linearity and accuracy in the concentration range 10 ng to 100 micrograms per ml of plasma and 25 ng to 1 mg per ml of urine. The absolute limits of detection in plasma and urine are 2 ng/ml and 5 ng/ml, respectively. The stability of various solutions of ifosfamide and trofosfamide was tested and proved to be satisfactory, except for ifosfamide in plasma and urine kept in the refrigerator. The validity of the method for pharmacokinetic purposes is shown in the case of one patient.

Antineoplastic Agents↗

PubMed1991

Effect of cyclodextrins on the chemical stability of mitomycins in alkaline solution.

The effects of cyclodextrins on the chemical stability of several mitomycin antibiotics in an alkaline medium have been investigated. A stability-indicating high-performance liquid chromatographic method was used to determine the overall degradation rate constants. The influence of various parameters such as structural variations of the cyclodextrins and mitomycins, temperature and pH was studied. It appears that complexation is most favourable with gamma-cyclodextrin. All mitomycin-gamma-cyclodextrin complexes degrade at lower rates than those of the free drugs. Moreover, it was shown that gamma-cyclodextrin influences the equilibrium between mitomycin C and its zwitterion mesomer.

Alkalies↗

PubMed1991

A systematic study on the chemical stability of ifosfamide.

The degradation kinetics of ifosfamide in aqueous solution have been investigated over the pH region 1-13 at 70 degrees C. A stability indicating high-performance liquid chromatographic assay with UV detection was used to separate degradation products from the parent compound. The degradation kinetics were studied as related to pH, buffer composition, ionic strength, temperature and drug concentration. A pH-rate profile at 70 degrees C, obtained from (pseudo) first-order kinetic plots, was constructed after corrections for buffer effects were made. The degradation reactions of ifosfamide were found to be largely independent of pH, although proton or hydroxyl catalysis occurs at extreme pH values. Ifosfamide shows maximum stability in the pH region 4-9, corresponding to a half-life of 20 h.

Buffers↗

PubMed1990

Determination of penicillin in pharmaceutical formulations by flow injection analysis using an optimised immobilised penicillinase reactor and iodometric detection.

An automated assay for the determination of penicillin in formulations suitable for use in pharmaceutical quality control is presented. The method is based on the classical iodometric penicillin assay which is incorporated in a flow injection analysis (FIA) system. The required hydrolysis is performed on-line by using an immobilised penicillinase reactor. Packed-bed and single-bead-string enzyme reactors are compared. It turns out that a packed-bed penicillinase reactor (10 cm x 1.5 mm i.d.) provides complete hydrolysis within short residence time, while only little back-pressure is generated. This enzyme reactor is stable for at least 9 months. Enzymatic hydrolysis of the beta-lactam ring results in the formation of the corresponding penicilloic acid, which consumes iodine. The iodine consumption is determined colorimetrically by measuring the decrease of the absorbance of the blue coloured iodine/starch complex. The optimum reactor length and flow rate for the colourimetrical detection reaction are determined. The optimised method is applied to the assay of penicillin in formulations and the results are compared with the "true" results obtained with a reference method: a mercurimetric titration. The reliability of the flow injection method is evaluated quantitatively by determining the maximum total error (MTE). The reliability is shown to be highest when measuring at a 0.3-mM level. Eight formulations including capsules, tablets and injectables containing penicillin G, amoxicillin or flucloxacillin are assayed. The MTE does not exceed the 6% level and the most probable MTE is between 1.5 and 3.5%.

Enzymes, Immobilized↗

PubMed1990

Rapid determination of benzalkonium chloride in pharmaceutical preparations with flow injection liquid-liquid extraction.

Benzalkonium chloride was assayed by on-line extraction of the benzalkonium ion with picrate to chloroform. The absorbance of picrate was measured. The extractions were performed with a home-made flow injection extraction unit. Calibration curves (1.5-180 x 10(-4)% w/v) were straight lines (r = 0.9993) and the relative standard deviation of a series of injections was less than or equal to 2%. Pharmaceutical benzalkonium preparations, containing xylometazoline, timolol, phenylephrine or carbachol could also be assayed. The method was compared with a modified HPLC assay.

Benzalkonium Compounds↗

PubMed1990

Inclusion complexation of doxorubicin and daunorubicin with cyclodextrins.

The interaction of alpha-, beta- and gamma-cyclodextrins with the anthracycline antibiotics doxorubicin and daunorubicin was investigated by LC, circular dichroism (CD) and absorption spectroscopy. All studies were performed in aqueous media at different temperatures and pH values. The anthracyclines complex only with gamma-cyclodextrin. Lineweaver-Burk and Scott's plots were used to calculate the stability constants of the anthracycline-gamma-cyclodextrin inclusion complexes.

Chromatography, High Pressure Liquid↗