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D R A Uges

Publications and source records attributed to D R A Uges.

15 recordsLinked to original sources
PubMed2006

A phase I study assessing the safety and pharmacokinetics of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with gemcitabine and cisplatin in patients with solid tumors.

BACKGROUND: The aim of the study was to determine the safety profile, pharmacokinetics and potential drug interactions of the angiogenesis inhibitor ABT-510 combined with gemcitabine-cisplatin chemotherapy in patients with solid tumors. PATIENTS AND METHODS: Patients with advanced solid tumors received gemcitabine 1250 mg/m2 intravenously (i.v.) on days 1 and 8 and cisplatin 80 mg/m2 on day 1 of a 3-week cycle in combination with ABT-510. ABT-510 was administered subcutaneously twice daily at doses of 50 mg or 100 mg. Plasma samples for pharmacokinetics were obtained on days 1 (gemcitabine, cisplatin as single agents), 15 (ABT-510 as single agent) and 22 (gemcitabine, cisplatin and ABT-510 as combination). RESULTS: Thirteen patients received ABT-510 as either 50 mg b.i.d. (seven patients) or 100 mg b.i.d. (six patients) in combination with gemcitabine-cisplatin. The most common reported adverse events reflected the known toxicity profile induced by gemcitabine-cisplatin without ABT-510. One episode of hemoptysis occurred in a patient with non-small-cell lung cancer (NSCLC) after 13 days of treatment. No clinically significant pharmacokinetic interactions between ABT-510, gemcitabine and platinum were observed. Three partial responses were observed in 12 evaluable patients (one head and neck cancer, one melanoma and one NSCLC). CONCLUSIONS: Combining ABT-510 at doses of 50 mg and 100 mg with gemcitabine-cisplatin is feasible. Pharmacokinetic interactions were not observed and adding ABT-510 does not appear to increase toxicity.

Adult↗
PubMed2006

Phase I study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with 5-fluorouracil and leucovorin: a safe combination.

We performed a phase I study with the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 combined with 5-fluorouracil and leucovorin (5-FU/LV) to determine safety profile and assess pharmacokinetic interactions. Patients with advanced solid malignancies received LV 20 mg/m(2) followed by 5-FU 425 mg/m(2) both administered intravenously in 15 min daily for 5 days every 4 weeks. ABT-510 was administered subcutaneously twice daily continuously from day 2 onwards. Blood and urine samples for pharmacokinetic analyses were collected at days 1, 5 and 22. Twelve patients received a total of 45 cycles of 5-FU/LV combined with ABT-510. ABT-510 dose levels studied were 50 and 100 mg. The combination was well tolerated, with a toxicity profile comparable to that of 5-FU/LV alone. At the dose levels studied no significant pharmacokinetic interactions were observed. These data indicate that ABT-510 administered twice daily subcutaneously can be safely combined with 5-FU/LV administered daily for 5 days, every 4 weeks.

Aged↗
PubMed2006

Comparison of urine and oral fluid as matrices for screening of thirty-three benzodiazepines and benzodiazepine-like substances using immunoassay and LC-MS(-MS).

Benzodiazepines are the most frequently detected medicinal drugs in drivers. The use of benzodiazepines is associated with an increased road accident risk. In this study, the presence of benzodiazepines detected by liquid chromatography-(tandem) mass spectrometry [LC-MS(-MS)] in oral fluid and urine samples obtained from drivers stopped during a roadside survey was compared. In addition, the sensitivity and selectivity of enzyme multiplied immunoassay technique (EMIT II Plus) relative to LC-MS(-MS) was determined for both matrices. A total number of 1,011 urine samples were collected and screened for benzodiazepines using immunoassay (IA) (EMIT II Plus; cutoff 300 ng/mL). In the IA-positive (n = 25) and a group of randomly selected negative urine samples (n = 79), the presence or absence of benzodiazepines was confirmed by LC-MS-MS after deglucuronidation. The corresponding oral fluid samples (n = 101, 3 samples omitted), were analyzed by LC-MS(-MS) and IA (EMIT II Plus; cutoff 10 ng/mL). The presence of benzodiazepines was demonstrated by LC-MS-(MS) in all IA-positive urine samples, but in only four corresponding oral fluid samples. Concentrations in oral fluid were, one substance excepted, lower than in urine. The sensitivity and specificity of EMIT II Plus were better by using urine as matrix for screening of benzodiazepines than by using oral fluid. The results show that benzodiazepines are detectable in oral fluid. More research has to be done to determine the pharmacokinetic profile of the different benzodiazepines in oral fluid and to study the relationship between dose, concentration (in oral fluid and blood), and impairment.

Benzodiazepines↗
PubMed2006

Quantification by HPLC-MS/MS of atropine in human serum and clinical presentation of six mild-to-moderate intoxicated atropine-adulterated-cocaine users.

An unexpectedly high number of initially suspected cocaine-intoxicated patients was presented to a general hospital in Lelystad, The Netherlands. Based on the unusual toxidram rate of not fitting cocaine intoxication, the suspicion of co-presence of an anticholinergic agent was raised. A newly developed HPLC-MS/MS analytical method revealed the presence of 10% atropine in a cocaine sample retrieved and subsequently in the sera of 6 intoxicated patients.

Adult↗
PubMed2006

Pitfalls in TDM of antibiotic drugs: analytical and modelling issues.

The quality assurance program of the Dutch KKGT [Association for Quality Assessment in therapeutic drug monitoring (TDM) and Clinical Toxicology] has been running for more than 25 years. One of these programs concerns TDM of the antibiotic drugs gentamicin, tobramycin, amikacin, and vancomycin. We present two issues encountered in a recent survey. In a case of gentamicin monitoring and dose-adjustment, a systematic analytical error in some centers led to a dosing recommendation that differed from that of the organizers. Correction of the analytical results on the basis of a standard control sample resulted in concentration differences of more than 20% and different dosing recommendations in these centers. In a case of vancomycin TDM, the choice of the population model proved to be critical for dose adjustment. We illustrate this example by presenting the plasma profiles derived from the different population models used by the participants.

Adult↗
PubMed2005

New practical algorithm for modelling retention times in gradient reversed-phase high-performance liquid chromatography.

Computer models have been widely used to predict the chromatographic behaviour of liquid chromatography systems. With the introduction of mass spectrometric detection and the use of lower mobile phase flow rates with conventional LC equipment, the influence of the dwell volume on the shape of the gradient curve becomes an issue in predicting the retention times. A new straight forward algorithm is proposed for the modelling of retention times in reversed-phase LC, taking the effect of the dwell volume on the gradient shape into account. The results show that the dwell volume has a large effect at lower flow rates and on the retention times of the analytes eluting at the end of fast gradient curves. The proposed model is able to make reliable predictions and can be helpful in LC-MS method development.

Algorithms↗
PubMed2005

Drug use and the severity of a traffic accident.

Several studies have showed that driving under the influence of alcohol and/or certain illicit or medicinal drugs increases the risk of a (severe) crash. Data with respect to the question whether this also leads to a more severe accident are sparse. This study examines the relationship between the use of alcohol, illicit drugs and/or medicinal drugs and the severity of an accident within a group of drivers that were involved in a crash in The Netherlands. Blood samples of 993 drivers, collected in the period from October 1998 through September 1999, were linked to accident characteristics as available from the National Transport Research Centre. The outcome measure was the severity of the accident. An accident was considered severe when the accident had resulted in hospital admission or death. All the blood samples obtained after the accident were screened for the presence of alcohol, illicit drugs (opiates, amphetamines and amphetamine-like substances, cocaine and metabolites, methadone, cannabinoids) and medicinal drugs (benzodiazepines, barbiturates and tricyclic antidepressants). The strength of the associations between exposure to the different classes of alcohol/drugs/medicines and the severity of the accident was evaluated using logistic regression analysis and were expressed as odds ratios (OR), adjusted for age, gender, time of the day, day of the week and urban area. The most frequently detected drugs were cannabinoids, benzodiazepines and cocaine. Our results showed no clear association between the use of alcohol, illicit drug and/or medicinal drug use and the severity of the accident. Given the process of obtaining blood samples from drivers involved in accidents and the retrospective nature of the study, we cannot rule out the occurrence of selection bias. Therefore, our findings need further confirmation.

Accidents, Traffic↗
PubMed2005

Genetic factors influencing pyrimidine-antagonist chemotherapy.

Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumour-specific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5'-nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.

Antineoplastic Agents↗
PubMed2004

Quantitative analysis of 33 benzodiazepines, metabolites and benzodiazepine-like substances in whole blood by liquid chromatography-(tandem) mass spectrometry.

A quantitative method using high-performance liquid chromatography-mass spectrometry (LC-MS, ion trap) after matrix supported liquid-liquid extraction is described for the simultaneous determination in whole blood of 33 benzodiazepines including metabolites and benzodiazepine-like substances. The limits of detection (LOD) range from 0.0001 to 0.0126 mg/l. Linearity is satisfactory for all compounds. The extraction recoveries for the benzodiazepines in whole blood are between 60 and 91%, desmethyldiazepam, OH-bromazepam and brotizolam excepted. Selectivity, accuracy and precision are satisfactory for clinical and forensic purposes.

Benzodiazepines↗
PubMed2004

Development of an optimal sampling strategy for clinical pharmacokinetic studies of the novel anthracycline disaccharide analogue MEN-10755.

AIM: MEN-10755 is a novel anthracycline analogue that has shown an improved therapeutic efficacy over doxorubicin in animal models, especially in gynaecological and lung cancers and is currently under clinical development for the treatment of solid tumours. The aim of the project was to develop an optimal sampling strategy for MEN-10755 to provide an efficient basis for future pharmacokinetic/pharmacodynamic investigations. METHODS: Data from 24 patients who participated in a phase I clinical pharmacokinetic study of MEN-10755 administered as a short i.v. infusion were included. Individual pharmacokinetic values were calculated by fitting the plasma concentration data to a two-compartment model using nonlinear least-squared regression (KINFIT, Ed 3.5). Population pharmacokinetic analysis was carried out using (a) the traditional standard two-stage method (STS) based on all data (KINFIT-ALL), (b) the iterative two-stage Bayesian (IT(2)B) population modelling algorithm (KINPOP), and (c) the STS method using KINFIT and using four optimally timed plasma concentrations (KINFIT-OSS4). Determinant (D) optimal sampling strategy (OSS) was used to evaluate the four most information-rich sampling times. The pharmacokinetic parameters V(c) (l), k(el) (h(-1)), k(12) (h(-1)) and k(21) (h(-1)) calculated using KINPOP served as a model for calculation of four D-optimal sampling times. D-optimal sampling data sets were analysed using KINFIT-OSS4 and compared with the population model obtained by the traditional standard two-stage approach for all data sets (KINFIT-ALL). RESULTS: The optimal sampling times were: the end of the infusion, and 1.5 h, 3.8 h and 24 h after the start of the infusion. The four-point D-optimal sampling design determined in this study gave individual parameter estimates close to the basic standard estimates using the full data set. CONCLUSION: Because accurate estimates of pharmacokinetic parameters were achieved, the four-point D-optimal sampling design may be very useful in future studies with MEN-10755.

Algorithms↗
PubMed2003

Vincristine in childhood leukaemia: no pharmacokinetic rationale for dose reduction in adolescents.

AIM: To investigate whether there is any pharmacokinetic rationale for the common practice of administering vincristine to adolescents at relatively lower doses than those to younger children. METHODS: A total of 98 children, aged 1.3-17.3 y, with acute lymphoblastic leukaemia (ALL) were studied on day 1 of induction therapy. Plasma samples were drawn before and 10, 30, 360 and 1380 min after injection of vincristine 2.0 mg/m2 (maximum dose 2.0 mg) and analysed by high-performance liquid chromatography. RESULTS: The median value (and range) for distribution half-life was 6.4 min (0.8-11.8), elimination half-life 1014 min (258-2570), volume of distribution 445 L/m2 (137-1241) and total body clearance 362 ml/min/m2 (134-2553). No correlation was found between age and any of these pharmacokinetic parameters. The area under the concentration time curve (AUC) was significantly correlated to age (p = 0.002; p - 0.31), as expected from the dosage of vincristine. The lower AUC in children with a body surface area > 1 m2, which is reached at 8-9 y of age, indicates that they received a less intense treatment because of the capping of the vincristine dose at 2.0 mg. CONCLUSIONS: Vincristine pharmacokinetics were not age dependent in this paediatric population. Thus, we found no pharmacokinetic rationale for dose reduction in adolescents. The common practice of limiting the vincristine dose to 2.0 mg should be carefully reconsidered.

Adolescent↗
PubMed2002

[Non-fatal rupture of a cocaine packet in a man with the 'bodypacker' syndrome].

A 24-year-old patient was admitted to the intensive care unit because he had swallowed about 20 cocaine packets 48 hours before admission; he also complained of abdominal cramps, perspiration and dizziness. The patient reported that he had not defecated since swallowing the packets. Abdominal X-ray revealed only coprotasis. On conservative therapy with bowel irrigation, two packets were eliminated, after which a second abdominal X-ray revealed several cocaine packets in the colon. Four days afterwards, the cocaine packets in the colon had not progressed despite adequate bowel irrigation. The patient now showed signs of mild cocaine intoxication (hallucinations and tachycardia). It was therefore decided to perform a laparotomy. Via a sigmoidotomy, 7 intact packets were removed; another 3 had already ruptured and were empty. The rupture of 3 cocaine packets in this patient was probably not fatal because of the sedation with midazolam and because the patient had diarrhoea as a result of the extensive irrigation, so that a large proportion of the cocaine was probably not absorbed. This case also shows that the presence of foreign bodies cannot be established adequately by an abdominal X-ray if there is coprostasis.

Adult↗
PubMed2002

Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene.

5-fluorouracil pharmacokinetics, dihydropyrimidine dehydrogenase-activity and DNA sequence analysis were compared between a patient with extreme 5-fluorouracil induced toxicity and six control patients with normal 5-fluorouracil related symptoms. Patients were treated for colorectal cancer and received chemotherapy consisting of leucovorin 20 mg m(-2) plus 5-fluorouracil 425 mg m(-2). Blood sampling was carried out on day 1 of the first cycle. The 5-fluorouracil area under the curve(0-->3h) in the index patient was 24.1 mg h l(-1) compared to 9.8+/-3.6 (range 5.4-15.3) mg h l(-1) in control patients. The 5-fluorouracil clearance was 520 ml min(-1) vs 1293+/-302 (range 980-1780) ml min(-1) in controls. The activity of dihydropyrimidine dehydrogenase in mononuclear cells was lower in the index patient (5.5 nmol mg h(-1)) compared to the six controls (10.3+/-1.6, range 8.0-11.7 nmol mg h(-1)). Sequence analysis of the dihydropyrimidine dehydrogenase gene revealed that the index patient was heterozygous for a IVS14+1G>A point mutation. Our results indicate that the inactivation of one dihydropyrimidine dehydrogenase allele can result in a strong reduction in 5-fluorouracil clearance, causing severe 5-fluorouracil induced toxicity.

Aged↗
PubMedDate not supplied

Outcome of local application of amifostine (WR-1065) on epirubicin-induced oral mucositis. A phase II study.

BACKGROUND: Intravenous administration of amifostine reduces chemotherapy-induced toxicity. Preclinical experiments showed a reduction in radiation-induced mucositis after local application of the active metabolite of amifostine (WR-1065). This study evaluated the effect of local application of WR-1065 on chemotherapy-induced oral mucositis. PATIENTS AND METHODS: Non-small cell lung cancer patients treated with gemcitabine and epirubicin every 3 weeks for a maximum of five cycles were included. WR-1065 was administered during the second and third cycle as an oral rinse. Oral mucositis evaluation included WHO toxicity grading, a validated oral mucositis assessment scale (OMAS) and a questionnaire. RESULTS: Twenty-four patients were evaluated for at least one control and one rinse cycle. Mucositis scores, pain and feeding difficulties increased from day 1 to day 15, and were not significantly different between the control and rinse cycles. Local application of WR-1065 leads to detectable quantities of WR-1065 in epithelial mucosa cells. A negative correlation between the WR-1065 concentration and OMAS score was found. CONCLUSION: No clinical detectable influence of WR-1065 on oral mucositis was found.

Aged↗