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J H Beijnen

Publications and source records attributed to J H Beijnen.

At least 19 recordsLinked to original sources
PubMed1999

Degradation study of thiotepa in aqueous solutions.

The degradation of N,N',N"-triethylenethiophosphoramide (thiotepa) in aqueous solutions has been investigated over the pH range 1-14. Samples were analyzed using a high-performance liquid chromatographic system with UV detection. The degradation kinetics were studied as a function of pH, sodium chloride concentration and temperature. The degradation of thiotepa follows pseudo first order kinetics. The pH-log kobs profile shows that thiotepa is most stable in the pH range 7-11. At pH?11 chloride has no influence on the degradation rate. The degradation products were isolated and the structures identified by mass spectrometry. Chloro adducts of thiotepa are generated in the presence of sodium chloride and in acidic medium. In the pH range 7-11 only the mono-chloro adduct of thiotepa could be found. No detectable degradation products were formed at pH?11.

Algorithms↗
PubMed1999

A single 24-hour plasma sample does not predict the carboplatin AUC from carboplatin-paclitaxel combinations or from a high-dose carboplatin-thiotepa-cyclophosphamide regimen.

PURPOSE: It has been observed that the area under the free carboplatin concentration in plasma ultrafiltrate versus time curve (AUC) is related to toxicity and tumour response. For this reason, it can be important to measure the carboplatin AUC and subsequently adjust the dose to achieve a predefined target AUC. The use of limited sampling strategies enables relatively simple measurement and calculation of actual carboplatin AUCs. METHODS: We studied the performance of a limited sampling model, based on a single 24-h sample (the Ghazal-Aswad model). in 52 patients who received carboplatin in two different chemotherapy regimens (a carboplatin-paclitaxel combination and a high-dose carboplatin-thiotepa-cyclophosphamide combination). RESULTS: The measured mean AUC in our population was 4.1 min x mg/ml (median 3.9, range 1.9 6.3, SD 1.0 min x mg/ml). With the limited sampling model, the predicted mean AUC was 4.4 min x mg/ml (median 4.2, range 2.4-8.4, SD 1.2 min x mg/ml). Statistical analysis revealed that the model was slightly biased (MPE%, 6.5%), but imprecise (RMSE%, 20.6%) in our study population. CONCLUSION: Although easy and attractive to use, the Ghazal-Aswad formula is not precise enough to predict the carboplatin AUC, and needs to be evaluated prospectively in other patient populations.

Adolescent↗
PubMed1999

Potentiation of anti-cancer drug activity at low intratumoral pH induced by the mitochondrial inhibitor m-iodobenzylguanidine (MIBG) and its analogue benzylguanidine (BG).

Tumour-selective acidification is of potential interest for enhanced therapeutic gain of pH sensitive drugs. In this study, we investigated the feasibility of a tumour-selective reduction of the extracellular and intracellular pH and their effect on the tumour response of selected anti-cancer drugs. In an in vitro L1210 leukaemic cell model, we confirmed enhanced cytotoxicity of chlorambucil at low extracellular pH conditions. In contrast, the alkylating drugs melphalan and cisplatin, and bioreductive agents mitomycin C and its derivative EO9, required low intracellular pH conditions for enhanced activation. Furthermore, a strong and pH-independent synergism was observed between the pH-equilibrating drug nigericin and melphalan, of which the mechanism is unclear. In radiation-induced fibrosarcoma (RIF-1) tumour-bearing mice, the extracellular pH was reduced by the mitochondrial inhibitor m-iodobenzylguanidine (MIBG) or its analogue benzylguanidine (BG) plus glucose. To simultaneously reduce the intracellular pH, MIBG plus glucose were combined with the ionophore nigericin or the Na+/H+ exchanger inhibitor amiloride and the Na+-dependent HCO3-/Cl- exchanger inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS). Biochemical studies confirmed an effective reduction of the extracellular pH to approximately 6.2, and anti-tumour responses to the interventions indicated a simultaneous reduction of the intracellular pH below 6.6 for at least 3 h. Combined reduction of extra- and intracellular tumour pH with melphalan increased the tumour regrowth time to 200% of the pretreatment volume from 5.7 +/- 0.6 days for melphalan alone to 8.1 +/- 0.7 days with pH manipulation (P < 0.05). Mitomycin C related tumour growth delay was enhanced by the combined interventions from 3.8 +/- 0.5 to 5.2 +/- 0.5 days (P < 0.05), but only in tumours of relatively large sizes. The interventions were non-toxic alone or in combination with the anti-cancer drugs and did not affect melphalan biodistribution. In conclusion, we have developed non-toxic interventions for sustained and selective reduction of extra- and intracellular tumour pH which potentiated the tumour responses to selected anti-cancer drugs.

3-Iodobenzylguanidine↗
PubMed1999

Bioavailability and toxicity after oral administration of m-iodobenzylguanidine (MIBG).

meta-iodobenzylguanidine (MIBG) radiolabelled with iodine-131 is used for diagnosis and treatment of neuroadrenergic neoplasms such as phaeochromocytoma and neuroblastoma. In addition, non-radiolabelled MIBG, administered i.v., is used in several clinical studies. These include palliation of the carcinoid syndrome, in which MIBG proved to be effective in 60% of the patients. Oral MIBG administration might be convenient to maintain palliation and possibly improve the percentage of responders. We have, therefore, investigated the feasibility of oral administration of MIBG in an animal model. Orally administered MIBG demonstrated a bioavailability of 59%, with a maximal tolerated dose of 60 mg kg(-1). The first and only toxicity encountered was a decrease in renal function, measured by a reduced clearance of [51Cr]EDTA and accompanied by histological tubular damage. Repeated MIBG administration of 40 mg kg(-1) for 5 sequential days or of 20 mg kg(-1) for two courses of 5 sequential days with a 2-day interval did not affect renal clearance and was not accompanied by histological abnormalities in kidney, stomach, intestines, liver, heart, lungs, thymus, salivary glands and testes. Because of a sufficient bioavailability in absence of gastrointestinal toxicity, MIBG is considered suitable for further clinical investigation of repeated oral administration in patients.

3-Iodobenzylguanidine↗
PubMed1999

Phase II trial of topically applied miltefosine solution in patients with skin-metastasized breast cancer.

Skin deposits from breast cancer can present serious therapeutic problems, especially when resistant to conventional therapy. Topical application of a cytotoxic drug may represent an attractive new treatment modality devoid of major systemic toxicity. Miltefosine was selected because of its efficacy in breast cancer models. A mixture of alkylated glycerols of various chain lengths and water was used as the pharmaceutical vehicle to dissolve and to further facilitate tissue penetration of miltefosine. In our Institute a phase II study was performed to determine the efficacy and tolerability of topically applied miltefosine in patients with cutaneous metastases from breast cancer. Thirty-three patients in total entered the trial. A 6% miltefosine solution was applied once daily in the first week and twice daily in the following weeks. The planned minimum treatment duration was 8 weeks. We found an overall response rate of 43% for 30 evaluable patients, composed of 23% complete response and 20% partial response. The median response duration was 18 weeks, range 8-68. Toxicity consisted mainly of localized skin reactions, which could be controlled by a paraffin-based skin cream and, where appropriate, by dose modification. No systemic toxicities were observed. We conclude that topical miltefosine is an effective treatment modality in patients with skin metastases from breast cancer.

Administration, Topical↗
PubMed1999

Sampling technique from central venous catheters proves critical for pharmacokinetic studies.

Double-lumen central venous access (CVA) catheters are occasionally used in pharmacokinetic studies for drug administration and blood sampling. The samples are often collected by the nursing staff and thus the investigator may not be aware of the specific sampling technique used. We present an example of the dramatic effect that an incorrect sampling technique from double-lumen CVA catheters can have on pharmacokinetic outcomes. Using a double-lumen Hickman catheter (PolyCath Central Venous Catheter; Strato Medical Corporation/Infusaid Inc., Manchester, GA, U.S.A.), sampling during the infusion can be performed when the infusion is connected to the lumen with the end most downstream and blood is collected from the proximal opening. With a normal double-lumen catheter, sampling can only be performed by briefly interrupting the infusion or after the infusion.

Catheterization, Central Venous↗
PubMed1999

Phase I and pharmacologic study of the combination of paclitaxel, cisplatin, and topotecan administered intravenously every 21 days as first-line therapy in patients with advanced ovarian cancer.

PURPOSE: To evaluate the feasibility of administering topotecan in combination with paclitaxel and cisplatin without and with granulocyte colony-stimulating factor (G-CSF) support as first-line chemotherapy in women with incompletely resected stage III and stage IV ovarian carcinoma. PATIENTS AND METHODS: Starting doses were paclitaxel 110 mg/m2 administered over 24 hours (day 1), followed by cisplatin 50 mg/m2 over 3 hours (day 2) and topotecan 0.3 mg/m2/d over 30 minutes for 5 consecutive days (days 2 to 6). Treatment was repeated every 3 weeks. After encountering dose-limiting toxicities (DLTs) without G-CSF support, the maximum-tolerated dose was defined as 5 microg/kg of G-CSF subcutaneously starting on day 6. RESULTS: Twenty-one patients received a total of 116 courses at four different dose levels. The DLT was neutropenia. At the first dose level, all six patients experienced grade 4 myelosuppression. G-CSF support permitted further dose escalation of cisplatin and topotecan. Nonhematologic toxicities, primarily fatigue, nausea/vomiting, and neurosensory neuropathy, were observed but were generally mild. Of 15 patients assessable for response, nine had a complete response, four achieved a partial response, and two had stable disease. CONCLUSION: Neutropenia was the DLT of this combination of paclitaxel, cisplatin, and topotecan. The recommended phase II dose is paclitaxel 110 mg/m2 (day 1), followed by cisplatin 75 mg/m2 (day 2) and topotecan 0.3 mg/m2/d (days 2 to 6) with G-CSF support repeated every 3 weeks.

Adult↗
PubMed1999

Comparative pharmacokinetics of vinblastine after a 96-hour continuous infusion in wild-type mice and mice lacking mdr1a P-glycoprotein.

To determine the tissue-specific impact of P-glycoprotein on the accumulation of a substrate drug, we have studied the tissue distribution of vinblastine in mdr1a(-/-) and wild-type mice at approximately similar, relatively low plasma levels. Vinblastine was administered as a 96-h continuous infusion at dose rates of 1 to 10 microgram/h, which were delivered by a s.c.-implanted osmotic pump. Drug concentrations were determined in plasma and tissues by HPLC. In comparison to wild-type mice, 4.4- to 9.6-fold higher drug concentrations were observed in the brains of mdr1a(-/-) mice (p </=. 014), whereas a 2-fold increase was found in the heart (p =.014) and the intestinal tissues (p </=.028). No or only slight differences were observed in all other tissues. These results indicate that, except for the brain and, to a lesser extent, the heart and the intestinal tissues, P-glycoprotein does not protect individual organs against vinblastine. Given its polarized cell-specific and organ-specific distribution and its affinity for a broad range of compounds, it is suggested that P-glycoprotein has mainly evolved to provide a general protection of the complete organism against potentially toxic substrates by inhibiting their uptake and by mediating their transport from the internal to the external environment. For the clinical application of reversal agents, these data indicate that, in general, a blockade of endogenous P-glycoprotein will probably not result in an increased accumulation of the coadministered anticancer drug in complete organs, but, possibly, only in classes of cells making up a fraction of an organ.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1998

Comparison of the plasma pharmacokinetics and renal clearance of didanosine during once and twice daily dosing in HIV-1 infected individuals.

OBJECTIVE: To compare the plasma pharmacokinetics of didanosine during once daily (qd) and twice daily (bid) dosing. DESIGN: Open-label, randomized, cross-over study. METHODS: HIV-1 infected patients who used didanosine were randomized to either a qd or a bid dosing regimen of didanosine. The total daily dose of didanosine was identical in both regimens. Seven days after the start of the study, the pharmacokinetic profile of didanosine in plasma and urine was assessed during an 8-h period. The next day, the patient was switched to the opposite dosing regimen, and after another 7 days, the study was concluded by again assessing the plasma and urine pharmacokinetics of didanosine during 8 h. RESULTS: A total of 19 patients completed the study. The pharmacokinetics of didanosine in plasma (with maximum plasma concentration adjusted for dose) and urine were not significantly different in the qd and bid dosing regimen (P > 0.28 for all parameters). CONCLUSION: We conclude that qd dosing of didanosine leads to a similar exposure in plasma as bid dosing (using the same total daily dose). Since qd dosing may lead to improved compliance of patients to regimens containing didanosine, these results provide a rationale for prescribing didanosine in a qd regimen, and is reassuring when we realize that the drug is being administered in a qd dosing regimen on a large scale in clinical practice.

Adult↗
PubMed1998

Determination of N,N',N"-triethylenethiophosphoramide and its active metabolite N,N',N"-triethylenephosphoramide in plasma and urine using capillary gas chromatography.

A sensitive assay for the determination of N,N',N"-triethylenethiophosphoramide (thioTEPA) and its metabolite N,N',N"-triethylenephosphoramide (TEPA) in micro-volumes human plasma and urine has been developed. ThioTEPA and TEPA were analysed using gas chromatography with selective nitrogen-phosphorus detection or mass spectrometry after extraction with a mixture of 1-propanol-chloroform from the biological matrix. Diphenylamine was used as internal standard. The limit of detection was 1.5 ng/ml for thioTEPA and 2.5 ng/ml for TEPA, using 100 microl of biological sample; recoveries ranged between 70 and 90% and both accuracy and precision were less than 10%. Linearity was accomplished in the range of 10-1000 ng/ml for plasma and 100-10000 ng/ml for urine using thermionic nitrogen-phosphorus detection. With mass spectrometry a linear range of 100-25000 ng/ml TEPA in plasma or urine was obtained. For thioTEPA a second-order polynomial function describes the relationship between the analyte concentration in the range of 500-25000 ng/ml and detection response. TEPA proved to be stable in plasma and urine for at least 10 weeks at -80 degrees C. ThioTEPA and TEPA plasma concentrations of two patients treated with thioTEPA are presented demonstrating the applicability of the assay for clinical samples.

Chromatography, Gas↗
PubMed1998

High-performance liquid chromatographic bio-analysis of PSC 833 in human and murine plasma.

We have developed a rapid, sensitive and selective method for the determination of the cyclosporin analog PSC 833 in human and mouse plasma using cyclosporin A as internal standard. The assay uses liquid-liquid extraction with diethyl ether for sample clean-up followed by reversed-phase high-performance liquid chromatography with UV detection at 210 nm. Good peak shapes were obtained using a NovaPak Phenyl column operating at 72 degrees C. Good selectivity from endogenous compounds was achieved using a mobile phase composed of methanol-acetonitrile-water (34:34:32). The retention times of cyclosporin A and PSC 833 were approximately 7.8 and 11.7 min, respectively, with two major endogenous peaks at 9.2 and 16.7 min. Selective decreasing of the retention times of cyclosporin A and PSC 833 relative to these interferences occurring upon aging of the column was balanced by increasing the percentage of methanol relative to acetonitrile. No other late eluting peaks were present, resulting in a total analysis time of 20 min per sample. The assay performance in human plasma was good. The absolute recovery of PSC 833 after the sample clean-up step was 48+/-6%. The lower limit of quantitation was 0.05 microM using 500 microl of sample. Within the linear dynamic range of the assay (0.10-5.0 microM) the accuracy was close to 100% and within-day and between-day variation less than 7%. Because of the limited availability of blank mouse plasma, the concentration in samples from mice were determined using calibration curves constructed in human plasma. The lower limit of quantitation in mouse was 0.25 microM using 200 microl of sample. Overall, the performance of the assay in mouse plasma was somewhat less than in human plasma but accuracy and precision were within the ranges that are considered acceptable for bio-analytical assays.

Animals↗
PubMed1998

Simultaneous quantitative determination of the HIV protease inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir in human plasma by ion-pair high-performance liquid chromatography with ultraviolet detection.

A reversed-phase high-performance liquid chromatographic assay for the simultaneous quantitative determination of five HIV protease inhibitors (i.e. amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir) in human plasma is described. Sample pretreatment consisted of solid-phase extraction prior to ion-pair, reversed-phase high-performance liquid chromatography with ultraviolet detection at 210 nm (amprenavir, indinavir and nelfinavir) and 239 nm (saquinavir and ritonavir). For amprenavir, indinavir and saquinavir the method has been validated over the range of 25 ng/ml to 25 microg/ml using a 0.6 ml sample volume. For nelfinavir and ritonavir the method has been validated over the range of 50 ng/ml to 25 microg/ml. The method proved to be accurate, with an average accuracy at four concentrations ranging from 90.6 to 109.2%, and precise, with the within-day and between-day precision ranging from 1.8 to 6.7%, and 0.7 to 7.6%, respectively. The protease inhibitors which can be quantified by using this assay proved to be stable under various conditions. This assay can readily be used in a hospital laboratory for the routine monitoring of plasma concentrations of these protease inhibitors.

Anti-HIV Agents↗
PubMed1998

High-performance liquid chromatographic determination of stabilized 4-hydroxyifosfamide in human plasma and erythrocytes.

A method using reversed-phase high-performance liquid chromatography (RP-HPLC) is described for the measurement of the stabilized activated metabolite of ifosfamide, 4-hydroxyifosfamide (4-OHIF), in human plasma and erythrocytes. Immediately after sample collection and plasma-erythrocyte separation at 4 degrees C, 4-OHIF was stabilized by derivatization with semicarbazide (SCZ). The sample pretreatment involved liquid-liquid extraction with ethyl acetate. RP-HPLC was executed with a C8 column and acetonitrile-0.025 M potassium dihydrogenphosphate buffer (pH 7.40)-triethylamine (13.5:86:0.5, v/v) as mobile phase. The analyte was determined with UV detection at 230 nm. Complete validation, optimisation and stability studies were performed and the method proved to be specific, sensitive and with a stable analyte in the range of clinically relevant concentrations (0.1-10 microg/ml) after conventional dosing. The lower limit of quantitation was 100 ng/ml using 1.00 ml of sample. Accuracy was between 94.1 and 107.0%. Within-day and between-day precisions were less than 6.2% and 7.2%, respectively. 4-OHIF-SCZ was found to be stable in the biological matrix at -20 degrees C for at least 1 month. A pharmacokinetic study conducted in a patient receiving 9 g/m2 over 3 days by means of a continuous infusion, demonstrated the applicability of this method.

Acetonitriles↗
PubMed1998

Simultaneous determination of N,N',N"-triethylenethiophosphoramide, cyclophosphamide and some of their metabolites in plasma using capillary gas chromatography.

A sensitive assay for the simultaneous determination of N,N',N"-triethylenethiophosphoramide (thioTEPA), its metabolite N,N',N"-triethylenephosphoramide (TEPA), cyclophosphamide (CP) and its metabolite 2-dechloroethylcyclophosphamide (2-DCE-CP) in plasma has been developed and validated. The analytes were determined using gas chromatography with nitrogen/phosphorus selective detection after liquid-liquid extraction with chloroform using 100 microl of plasma. Diphenylamine (for TEPA, thioTEPA and 2-DCE-CP) and imipramine (for CP) were used as internal standards. The limits of quantitation for thioTEPA, TEPA, CP and 2-DCE-CP were 5, 5, 50 and 250 ng/ml, respectively. Linear calibration curves were observed over two decades of concentration. Accuracy, within-day and between-day precision were less than 13% for all analytes. Stability of the analytes proved to be satisfactory for at least 1 month, stored at -70 degrees C. Analysis of samples obtained from patients receiving cyclophosphamide, thioTEPA and carboplatin in a high-dose regimen demonstrated the applicability of the assay.

Antineoplastic Agents, Alkylating↗
PubMed1998

Multidrug resistance protein 1 protects the oropharyngeal mucosal layer and the testicular tubules against drug-induced damage.

The multidrug resistance protein 1 (MRP1) gene encodes a transporter protein that helps to protect cells against xenobiotics. Elevated levels of MRP1 in tumor cells can result in active extrusion of a wide range of (anticancer) drugs with different cellular targets, a phenomenon called multidrug resistance (MDR). To explore the protective function of the mouse mrp1 protein during drug treatment, we investigated the toxicity caused by the anticancer drug etoposide-phosphate (ETOPOPHOS) in mice lacking the mrp1 gene (mrp1(-/-) mice). We show here that the lack of mrp1 protein results in increased etoposide-induced damage to the mucosa of the oropharyngeal cavity and to the seminiferous tubules of the testis. The high concentrations of mrp1 that we find in the basal layers of the oropharyngeal mucosa and in the basal membrane of the Sertoli cells in the testis apparently protect wild-type mice against this tissue damage. We also find drug-induced polyuria in mrp1(-/-) mice, which correlates with the presence of mrp1 protein in the urinary collecting tubules, the major site of kidney water reabsorption. Our results indicate that specific inhibitors of MRP1 used to reverse MDR, in combination with carcinostatic drugs transported by MRP1, might lead to drug-induced mucositis, (temporary) infertility, and diabetes insipidus.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Analytical techniques used to study the degradation of proteins and peptides: chemical instability.

Instability of peptides and proteins can be divided into two forms: chemical and physical instability. Chemical instability is due to modification/alteration of amino acid residues. There are several types of degradation reactions responsible for this instability. Most frequently described reactions are oxidation, reduction, deamidation, hydrolysis, arginine conversion, beta-elimination and racemisation. However, any study of the degradation of a chemical substance lacks reliability when the analytical methodology, that is used is not properly validated. Especially in the investigation, where degradation processes lead to their parent compounds, validation of the analysis is pivotal for the correct interpretation of the results. It is therefore appropriate and useful to assemble an overview of degradation processes in relation to the analytical methods to monitor them. An overview like this can help investigators to make the right choices in their analytical approach of stability problems. The degradation reactions involved in peptide/protein degradation as well as the methods to monitor them are summarized and discussed.

Arginine↗