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Biomedical subjects

D R Uges

Publications and source records attributed to D R Uges.

At least 19 recordsLinked to original sources
PubMed2004

Penetration of isoniazid, rifampicin and pyrazinamide in tuberculous pleural effusion and psoas abscess.

SETTING: Tuberculosis Centre, University Medical Centre, Groningen, The Netherlands. OBJECTIVES: To study intralesional concentrations of isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA) in tuberculous pleural effusions and psoas abscesses, and to compare these to reference serum values and minimal inhibitory concentration (MIC). DESIGN: Intralesional concentrations were measured 2 h after drug administration (six pleural effusions, 10 psoas abscesses). RESULTS: A wide range of concentrations was found for pleural effusions and psoas abscesses. Concentrations were below MIC values in none of 15 patients for INH, in two of 13 for RMP, and in eight of nine for PZA. The Cmax:MIC ratio was always >4 for INH, in four of 13 for RMP, and in none of nine for PZA. In 5/8 patients receiving all three drugs, both RMP and PZA had Cmax:MIC ratios <4, indicating sub-therapeutic drug levels. CONCLUSION: Penetration of INH was always sufficient, penetration of RMP mostly below the desired ratio, and for PZA on average 10 times too low. Five of eight patients on all three drugs had Cmax:MIC ratios <4. This indicates intralesional sub-therapeutic drug levels for RMP and PZA, and local monotherapy with INH. This could induce drug resistance. Drainage as additional therapy seems indicated.

Adolescent↗
PubMed2001

Pharmacokinetics of MEN-10755, a novel anthracycline disaccharide analogue, in two phase I studies in adults with advanced solid tumours.

The doxorubicin analogue MEN-10755 has been identified as a compound with promising antitumour activity based on structure-activity studies of a new series of anthracycline disaccharides. The high antitumour activity of MEN-10755 in human tumour xenografts, including doxorubicin-resistant xenografts, and its unique pharmacological and biological properties made this novel disaccharide analogue an interesting candidate for clinical evaluation. Two pharmacokinetic phase I studies with different dosing schedules were performed in adults with solid refractory malignancies. The pharmacokinetics of MEN-10755 were studied after a 15-min i.v. infusion given once every 3 weeks or once every week for 3 weeks followed by 1 week rest. Plasma and urine levels of MEN-10755 were measured by HPLC with fluorescent detection. It was possible to combine the pharmacokinetic results of the two studies because there was no accumulation of MEN-10755 before the next infusion of MEN-10755 in the weekly study with 1 week rest. The administered dose levels on day 1 in this study were all in the lower range from the 3-weekly study. The postinfusion plasma kinetics of MEN-10755 were best described by a triexponential model. The plasma peak levels (Cmax) of MEN-10755 showed a linear relationship with the administered dose. Peak plasma MEN-10755 levels ranged between 474 and 21,587 microg/l. The mean elimination half-life (T(1/2gamma)) was 20.7+/-9.0 h. The AUC(0-infinity) was proportional to the administered dose. The mean plasma clearance of MEN-10755 was 6.0+/-2.2 l/h per m2 with a mean volume of distribution (Vss) of 95.6+/-43.4 l/m2. The mean renal excretion of unchanged drug within 24 h was 4.3+/-1.8%. Compared to epirubicin and doxorubicin, the pharmacokinetics of MEN-10755 were characterized by an approximately twofold shorter terminal half-life, a much lower total plasma clearance and a much smaller volume of distribution.

Adult↗
PubMed2001

What is the definition of a poisoning?

New insights in medicine and acceptable treatments necessitates an adjustment of the existing definition of clinical or forensic poisoning to: 'An individual's medical or social unacceptable condition as a consequence of being under influence of an exogenous substance in a dose too high for the person concerned'. For medical and legal purposes it is important to know how the victim became poisoned. In general, there are three ways of causing medical poisoning: accidental poisoning, including iatrogenic poisoning, experimental and intentional poisoning. Nowadays iatrogenic intoxication, poisoning caused by the Münchhausen's syndrome (by proxy) and experimental poisoning (designer drugs) have a major place in contemporary toxicology. Although some toxicologists use the word 'intoxication' only overdoses with central effects, in this article 'intoxication' and 'poisoning' are considered to be synonymous.

Editorial↗
PubMed2001

Adsorptive voltametry to determine platinum levels in plasma from testicular cancer patients treated with cisplatin.

Patients cured of metastatic testicular cancer with cisplatin chemotherapy may suffer late adverse effects even after 20 years. The cause of these late adverse effects has not been elucidated yet. One cause might be prolonged tissue retention of platinum in these patients. Therefore, an extremely sensitive method for measuring platinum in plasma was used to investigate whether platinum is still detectable in plasma 10 to 20 years after cisplatin chemotherapy. High-pressure decomposition of plasma is followed by adsorptive voltametric determination of platinum, with a limit of quantification of 6 pg/g plasma. This procedure appeared suitable for the measurement of platinum in 44 former patients with platinum levels ranging from 22 to 140 pg/g plasma. This method is approximately 6000 times more sensitive than the standard flameless atomic absorption spectrophotometry (AAS) method. The platinum levels of these 44 patients were significantly elevated when compared with 20 control patients who were cured of testicular cancer but did not receive cisplatin chemotherapy (p < 0.001). There was a significant correlation between plasma platinum concentrations and follow-up time after cisplatin administration (r = -0.658, p < 0.001). This study shows that patients with testicular cancer who were treated with cisplatin can retain platinum in their body for at least 20 years. More data are needed to investigate whether there is a relation between the prolonged retention of platinum and long-term toxicity.

Adolescent↗
PubMed2001

An automated method for the bioanalysis of vincristine suitable for therapeutic drug monitoring and pharmacokinetic studies in young children.

Pharmacokinetic studies in young children require very sensitive methods using low plasma volumes. Although vincristine has been used as an antineoplastic drug for almost 40 years, data on vincristine pharmacokinetics and pharmacodynamics are scarce, especially in young children. One of the reasons for this is the lack of a specific and sensitive assay suitable for small plasma volumes. Therefore the authors aimed to improve an existing high-performance liquid chromatography (HPLC) assay by changing the solid-phase extraction material and by using a more sensitive and controlled electrochemical detector. An on-line solid-phase extraction was used with a preconcentration column of 10 * 3 mm ID containing octadecyl silane (ODS) reversed-phase material and an analytical microsphere C18 column. The mobile phase was unchanged and consisted of 35% phosphate buffer 0.02 mol (pH 7.00 +/- 0.10), 50% methanol, and 15% acetonitrile. Detection was performed with a new electrochemical detector. This detector comprised a highly stable Faraday-shielded oven compartment that accommodated a column and flowcell. The flowcell had a spacer thickness of 0.25 microm set at 830 mV. It also had an excellent signal-to-noise ratio, which resulted in very sensitive electrochemical analysis. These improvements resulted in a lower required sample volume of only 0.3 mL instead of 1.2 mL plasma with a very low limit of quantitation of 0.483 microg/L according to good laboratory practice (GLP) rules. The intraday coefficients of variation were 6.2% (0.483 microg/L) and 4.2% (18.4 microg/L). The interday coefficients of variation were 10.3% (0.483 microg/L) and 8.5% (18.4 microg/L).

Antineoplastic Agents, Phytogenic↗
PubMed2000

[Acquired medical condition and driving ability].

Under Dutch law a driver's licence requires a written statement of physical and mental health from the applicant. However, after the licence has been issued, no further statements are required, not even when the person involved develops a medical condition that poses a threat to safe driving. If an accident occurs and it is established that the driver suffered from an intercurrently acquired condition, the insurance companies will not pay. Physicians have a moral obligation to advise patients in their care whom this may affect to report to the physician of the licence administration.

Automobile Driving↗
PubMed2000

Surface roughness, porosity and wettability of gentamicin-loaded bone cements and their antibiotic release.

In this study, the release of gentamicin as a function of time was measured for six different gentamicin-loaded bone cements and related with the surface roughness, porosity and wettability of the cements. Initial release rates varied little between the six bone cements (CMW1, CMW3, CMW Endurance, CMW 2000, Palacos, and Palamed) and ranged from 8.6 to 14.1 microg/cm2/h. The total amounts of gentamicin released after 1 week varied between 4.0 and 5.3% of the total amount of antibiotic incorporated for the CMW cements and was 8.4% for Palacos. Palamed released after 1 week significantly more of the gentamicin incorporated (17.0%). The wettability of all cements was similar (water contact angles between 70 and 80 degrees), but the surface roughness and the porosity of the cements varied markedly. Initial release rates increased with surface roughness, although the correlation coefficient was low (0.64), while total amounts released increased linearly (correlation coefficient 0.97) with the bulk porosity of the cements. Consequently, it can be concluded that the release kinetics of gentamicin from bone cements is controlled by a combination of surface roughness and porosity.

Bone Cements↗
PubMed2000

Antidepressants self-poisoning and ICU admissions in a university hospital in The Netherlands.

OBJECTIVES: Many overdosed patients are admitted to an ICU. Antidepressants are frequently used. We examined clinical end-points of toxicity recorded during admission to our ICU of all antidepressants used in overdose. DESIGN: Single centre; retrospective analysis, 5 consecutive years (1994-1998). SETTING: Intensive and Respiratory Care Unit, Groningen University Hospital. PARTICIPANTS: 86 patients admitted to the ICU because of antidepressant self-poisoning--database of 258 consecutively admitted patients with (auto-)intoxication. RESULTS: Significantly more patients were intoxicated with TCAs (65) compared with SSRIs (20; p < 0.05), despite the fact that the number of prescriptions of antidepressants in the community was greater for SSRIs than for TCAs. Patients intoxicated with TCAs needed significantly more often tracheal intubation (27/65 vs 7/20; p < 0.05), and these individuals had also significantly more often tachycardia (14 vs. 3) and QRS-complex widening (19 vs. 1), compared to those with non-TCA antidepressant intoxication (p < 0.05). CONCLUSIONS: TCA self-poisoning has remained the predominant cause of morbidity among patients with auto-intoxication admitted to our ICU in the previous years. The data from this ICU-population confirm previous evidence that SSRIs are safer in overdose than TCAs. This finding was not explained by more prescriptions in the community of TCAs compared with SSRIs. Physicians should be more reluctant in prescribing TCAs to depressed patients in whom the risk of self-poisoning is difficult to assess.

Adult↗
PubMed2000

A prolonged methoxymorpholino doxorubicin (PNU-152243 or MMRDX) infusion schedule in patients with solid tumours: a phase 1 and pharmacokinetic study.

The aim of this phase I study was to assess feasibility, pharmacokinetics and toxicity of methoxymorpholino doxorubicin (MMRDX or PNU-152243) administered as a 3 h intravenous infusion once every 4 weeks. Fourteen patients with intrinsically anthracycline-resistant tumours received 37 cycles of MMRDX. The first cohort of patients was treated with 1 mg m(-2) of MMRDX. The next cohorts received 1.25 mg m(-2) and 1.5 mg m(-2) respectively. Common toxicity criteria (CTC) grade III/IV nausea and vomiting were observed in 1/18 cycles at 1.25 mg m(-2) and in 2/11 cycles at 1.5 mg m(-2). Transient elevation in transaminases up to CTC grade III was observed in 2/16 cycles at 1.25 mg m(-2) and 4/11 cycles at 1.5 mg m(-2). No cardiotoxicity was observed. At 1.25 mg m(-2) CTC grade IV neutropenia occurred in 1/17 cycles. At 1.5 mg m(-2) CTC grade III neutropenia was seen in 2/7 and grade IV in 3/7 evaluable cycles. Thrombocytopenia grade III was observed in 2/9 and grade IV in 1/9 evaluable cycles. One patient treated at 1.5 mg m(-2) died with neutropenic fever. Therefore, dose-limiting toxicity was reached and 1.25 mg m(-2) was considered the maximum tolerated dose for MMRDX as 3 h infusion. No tumour responses were observed. Pharmacokinetic parameters showed a rapid clearance of MMRDX from the circulation by an extensive tissue distribution. Renal excretion of the drug and its metabolite was negligible. In conclusion, prolongation of MMRDX infusion to 3 h does not improve the toxicity profile as compared with bolus administration.

Adult↗
PubMed2000

A phase I study of a new polyamine biosynthesis inhibitor, SAM486A, in cancer patients with solid tumours.

Because tumour cell proliferation is highly dependent upon up-regulation of de-novo polyamine synthesis, inhibition of the polyamine synthesis pathway represents a potential target for anticancer therapy. SAM486A (CGP 48664) is a new inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (SAMDC), more potent and specific than the first-generation SAMDC inhibitor methylglyoxal (bis) guanylhydrazone (MGBG). Preclinical testing confirmed promising antiproliferative activity. In this phase I study, SAM486A was given 4-weekly as a 120 h infusion. 39 adult cancer patients were enrolled with advanced/refractory disease not amenable to established treatments, PS </= 2, adequate marrow, liver, renal and cardiac function. Doses were escalated in 100% increments without toxicity in 24 pts from 3 mg m(-2)cycle(-1)up to 400 mg m(-2)cycle(-1). At 550 and 700 mg m(-2)cycle(-1)reversible dose-limiting neutropenia occurred. Other toxicities included mild fatigue, nausea and vomiting. No objective remission was seen. Pharmakokinetic analysis showed a terminal half-life of approximately 2 days. AUC and Cmax were related to dose; neutropenia correlated with AUC. The recommended dose for further phase II studies on this schedule is 400 mg m(-2)cycle(-1).

Adenosylmethionine Decarboxylase↗
PubMed2000

Therapeutic drug monitoring of clozapine: an unexpected outcome.

A patient is described who died with the diagnosis of septicemia. After her death the delayed results of a clozapine determination for TDM were sent to the clinician. The clozapine serum level was 4034 microg/L, which was considered to be the primary cause of death. However, a forensic autopsy revealed unexpected metastases of unknown origin with gross liver involvement. Thus the high clozapine levels were judged to be secondary to liver failure. This case is an example of an unexpected outcome of TDM.

Antipsychotic Agents↗
PubMed1999

Vincristine pharmacokinetics after repetitive dosing in children.

PURPOSE: We studied vincristine disposition after 169 weekly i.v. bolus injections in 32 children with acute lymphoblastic leukemia, non-Hodgkin lymphoma, or Wilms' tumor. The aim of the study was to determine intrapatient and interpatient variability in vincristine disposition and demographic, clinical, and biochemical characteristics influencing this variability. METHODS: Vincristine plasma concentrations were measured by a high-performance liquid chromatography assay with electrochemical detection. A limited sampling strategy was used based on a bayesian parameter estimation algorithm that is part of the ADAPT II software package. A two-compartment, first-order model was fitted to the data, and pharmacokinetic parameters were calculated from the model using the ADAPT II software. For statistical analysis, analysis of variance (ANOVA), t test, simple and multiple regression analysis, and non-parametric or robust equivalents were used. RESULTS: Results showed a large intrapatient and interpatient variability in distribution half-life, elimination half-life, total body clearance, apparent volume of distribution at steady state, and area under the concentration-time curve. Intrapatient variability was significantly smaller than interpatient variability for all these parameters except distribution half-life. The diagnosis or treatment protocol turned out to be the most predictive characteristic; leukemia and non-Hodgkin lymphoma patients had a significantly higher total body clearance than Wilms' tumor patients. CONCLUSIONS: We conclude that both intrapatient and interpatient variability in vincristine pharmacokinetics is large in pediatric cancer patients and that variability, although significantly influenced by diagnosis, largely remains unpredictable.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin.

We conducted a phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin. Fostriecin was administered intravenously over 60 min on days 1-5 at 4-week intervals. Dose was escalated from 2 mg m(-2) day(-1) to 20 mg m(-2) day(-1) in 20 patients. Drug pharmacokinetics was analysed with high performance liquid chromatography with UV-detection. Plasma collected during drug administration was tested in vitro for growth inhibition of a teniposide-resistant small-cell lung cancer (SCLC) cell line. The predominant toxicities were elevated liver transaminases (maximum common toxicity criteria (CTC) grade 4) and serum creatinine (maximum CTC grade 2). These showed only a limited increase with increasing doses, often recovered during drug administration and were fully reversible. Duration of elevated alanine-amino transferase (ALT) was dose-limiting in one patient at 20 mg m(-2). Other frequent toxicities were grade 1-2 nausea/vomiting, fever and mild fatigue. Mean fostriecin plasma half-life was 0.36 h (initial; 95% CI, 0-0.76 h) and 1.51 h (terminal; 95% CI, 0.41-2.61 h). A metabolite, most probably dephosphorylated fostriecin, was detected in plasma and urine. No tumour responses were observed, but the plasma concentrations reached in the patients were insufficient to induce significant growth inhibition in vitro. The maximum tolerated dose (MTD) has not been reached, because drug supply was stopped at the 20 mg m(-2) dose level. However, further escalation seems possible and is warranted to achieve potentially effective drug levels. Fostriecin has a short plasma half-life and longer duration of infusion should be considered.

Adult↗
PubMed1999

Valproic acid toxicokinetics: serial hemodialysis and hemoperfusion.

The toxicity and pharmacokinetic properties of a drug determine whether hemodialysis and/or hemoperfusion are indicated in acute intoxications. Valproic acid is considered unremovable by hemodialysis because of the high protein binding of 90%-95%. A 27-year-old male with a history of seizures was admitted to the emergency room because of coma, hypernatriemia, and respiratory failure caused by an intoxication with a large dose of valproic acid. At admission, the plasma valproic acid level was 1414 mg/L (9.9 mmol/L) (therapeutic range: 50-100 mg/L (350-700 micromol/ L). The anion gap was 26 mmol/L (normal <12-14 mmol/L) and corresponded fairly well with this valproic acid level. Because of the potential toxicity of this high valproic acid level serial hemodialysis and hemoperfusion was performed. The first session was done with a charcoal column and the second session with a resin column. The patient recovered during the course of treatment. The valproic acid plasma clearances during treatment were: 80 mL/min (hemodialysis); 40 mL/min (hemoperfusion by charcoal) and 80 mL/min (hemoperfusion by resin, only in the first hour). The protein binding of valproic acid in plasma was only 32% at the start and was 54% at the end of the two sessions. In this specific case of a severe valproic acid intoxication, saturated protein binding resulted in an increased fraction of unbound valproic acid. This made hemodialysis an effective treatment, while hemoperfusion was relatively less effective because of saturation of the column. In conclusion, the toxicokinetics of valproate are quite different from the pharmacokinetics at therapeutic levels. The anion gap and protein binding are important parameters in toxicokinetics.

Adult↗
PubMed1999

Pharmacokinetics of high-dose oral and intravenous dexamethasone.

Pharmacokinetics of intravenous and oral pulsed high-dose dexamethasone were studied in four patients with pemphigus vulgaris. Doses for dexamethasone were varied from 100 to 300 mg. Serum concentrations were measured by high-performance liquid chromatographic procedure with diode assay detection. Bioavailability was assessed by comparing the areas under the serum concentration-time curves following oral administration with those of intravenous administration. Mean bioavailability of high-dose oral dexamethasone was 63.4%. Side effects were minor and were limited to temporary facial flushing both after oral and intravenous administration. Oral administration of dexamethasone in pemphigus patients showed to be more convenient and cost effective than administration by the intravenous route.

Administration, Oral↗
PubMed1999

Phase II study of oral platinum drug JM216 as first-line treatment in patients with small-cell lung cancer.

PURPOSE: This multicenter phase II trial was performed to determine tumor efficacy and tolerance of the oral platinum drug JM216 in patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients with SCLC limited disease unfit for intensive chemotherapy or those with extensive disease received JM216 120 mg/m(2)/d for 5 consecutive days every 3 weeks. Individual dose escalation to 140 mg/m(2)/d was allowed if toxicity was </= grade 2 according to the National Cancer Institute Common Toxicity Criteria. Tumor response was evaluated according to World Health Organization criteria. RESULTS: Twenty-seven patients were assessable for toxicity and 26 for tumor response. Eighty-eight cycles were administered. Common Toxicity Criteria grade 3 and 4 hematologic toxicities were neutropenia in 15.9% and 3.7%, lymphocytopenia in 47.6% and 17.1%, and thrombocytopenia in 19.5% and 10.3% of cycles, respectively. One patient suffered from neutropenic fever. Nausea, vomiting, and diarrhea were the most common nonhematologic toxicities. Except for grade 4 diarrhea in one patient, no grade 4 nonhematologic toxicity was observed. No severe neurotoxicity or nephrotoxicity was observed. Tumor response rate was 10 of 26 (38%; 95% confidence interval, 19% to 58%), excluding five unconfirmed partial responses. No complete responses were observed. Median overall time to progression was 110 days (range, 5 to 624 days). Median overall survival time was 210 days (range, 5 to 624 days). CONCLUSION: Oral JM216 is active in previously untreated patients with SCLC and shows mild toxicities.

Aged↗