Geesteswetenschappen: Beleid en Organisatie

Dit is de tekst van de rede, uitgesproken bij de aanvaarding van het ambt van gewoon hoogleraar in Beleid en Organisatie van de Geesteswetenschappen in Internationaal Vergelijkend Perspectief aan de Faculteit der Historische en Kunstwetenschappen van de Erasmus Universiteit Rotterdam op 12 september 2002. In zijn rede gaat de auteur in op beleidsvraagstukken in de geesteswetenschappen. Na een plaatsbepaling van de geesteswetenschappen of humaniora en een discussie over wetenschappelijke status, gaat Sparreboom onder andere in op de erosie van de traditionele geesteswetenschappelijke disciplines en op vormen van internationale samenwerking.oratie Erasmus Universiteit Rotterda

Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients

The non-linear plasma pharmacokinetics of paclitaxel in patients has been well established, however, the exact underlying mechanism remains to be elucidated. We have previously shown that the non-linear plasma pharmacokinetics of paclitaxel in mice results from Cremophor EL. To investigate whether Cremophor EL also plays a role in the non-linear pharmacokinetics of paclitaxel in patients, we have established its pharmacokinetics in patients receiving paclitaxel by 3-, 24- or 96-h intravenous infusion. The pharmacokinetics of Cremophor EL itself was non-linear as the clearance (Cl) in the 3-h schedules was significantly lower than when using the longer 24- or 96-h infusions (Cl175–3 h = 42.8 ± 24.9 ml h−1 m−2; Cl175–24 h = 79.7 ± 24.3; P = 0.035 and Cl135–3 h = 44.1 ± 21.8 ml h−1 m−1; Cl140–96 h = 211.8 ± 32.0; P < 0.001). Consequently, the maximum plasma levels were much higher (0.62%) in the 3-h infusions than when using longer infusion durations. By using an in vitro equilibrium assay and determination in plasma ultrafiltrate we have established that the fraction of unbound paclitaxel in plasma is inversely related with the Cremophor EL level. Despite its relatively low molecular weight, no Cremophor EL was found in the ultrafiltrate fraction. Our results strongly suggest that entrapment of paclitaxel in plasma by Cremophor EL, probably by inclusion in micelles, is the cause of the apparent nonlinear plasma pharmacokinetics of paclitaxel. This mechanism of a (pseudo-)non-linearity contrasts previous postulations about saturable distribution and elimination kinetics and means that we must re-evaluate previous assumptions on pharmacokinetics–pharmacodynamics relationships. © 1999 Cancer Research Campaig

Effective cross-over to granisetron after failure to ondansetron, a randomized double blind study in patients failing ondansetron plus dexamethasone during the first 24 hours following highly emetogenic chemotherapy

In view of the similarity in chemical structure of the available 5HT3-receptor antagonists it is assumed, whilst these agents all act at the same receptor, that failure to one agent would predict subsequent failure to all 5HT3-receptor antagonists. We conducted a randomized double blind trial of granisetron 3 mg plus dexamethasone 10 mg versus continued treatment with ondansetron 8 mg plus dexamethasone 10 mg in patients with protection failure on ondansetron 8 mg plus dexamethasone 10 mg during the first 24 hours following highly emetogenic chemotherapy. Of 40 eligible patients, 21 received ondansetron + dexamethasone and 19 received granisetron + dexamethasone. We found a significant benefit from crossing-over to granisetron after failure on ondansetron. Of the 19 patients who crossed over to granisetron, 9 patients obtained complete protection, whereas this was observed in 1 of the 21 patients continuing ondansetron, P = 0.005. These results indicate that there is no complete cross-resistance between 5HT3-receptor antagonists, and that patients who have acute protection failure on one 5HT3-receptor antagonist should be offered cross-over to another 5HT3-receptor antagonist. © 2001 Cancer Research Campaign  http://www.bjcancer.co

Dose banding as an alternative to body surface area-based dosing of chemotherapeutic agents

Background: Dose banding is a recently suggested dosing method that uses predefined ranges (bands) of body surface area (BSA) to calculate each patients dose by using a single BSA-value per band. Thus, drugs with sufficient long-term stability can be prepared in advance. The main advantages of dose banding are to reduce patient waiting time and improve pharmacy capacity planning; additional benefits include reduced medication errors, reduced drug wastage, and prospective quality control. This study compares dose banding with individual BSA dosing and fixed dose according to pharmacokinetic criteria.Methods:Three BSA bands were defined: BSA1.7 m2, 1.7 m2 BSA1.9 m 2, BSA1.9 m2 and each patient dose was calculated based on a unique BSA-value per band (1.55, 1.80, and 2.05 m 2, respectively). By using individual clearance values of six drugs (cisplatin, docetaxel, paclitaxel, doxorubicin, irinotecan, and topotecan) from 1012 adult cancer patients in total, the AUCs corresponding to three dosing methods (BSA dosing, dose banding, and fixed dose) were compared with a target AUC for each drug.Results:For all six drugs, the per cent variation in individual dose obtained with dose banding compared with BSA dosing ranged between 14% and 22%, and distribution of AUC values was very similar with both dosing methods. In terms of reaching the target AUC, there was no significant difference in precision between dose banding and BSA dosing, except for paclitaxel (32.0% vs 30.7%, respectively; P=0.05). However, precision was significantly better for BSA dosing compared with fixed dose for four out of six drugs.Conclusion:For the studied drugs, implementation of dose banding should be considered as it entails no significant increase in interindividual plasma exposure

Surgical Outcomes after Full Thickness Chest Wall Resection Followed by Immediate Reconstruction:A 7-Year Observational Study of 42 Cases

Introduction: Reconstruction of full thickness chest wall defects is challenging and is associated with a considerable risk of complications. Therefore, the aim of this study was to investigate the surgical outcomes and their associations with patient and treatment characteristics following full thickness chest wall reconstruction. Patients and methods: A retrospective observational study was performed by including patients who underwent reconstruction of full thickness chest wall defect at the Erasmus MC between January 2014 and December 2020. The type of reconstruction was categorized into skeletal and soft tissue reconstructions. For skeletal reconstruction, only non-rigid prosthetic materials were used. Patient and surgical characteristics were retrieved and analyzed for associations with postoperative complications. Results: Thirty-two women and 10 men with a mean age of 60 years were included. In 26 patients (61.9%), the reconstruction was performed using prosthetic material and a soft tissue flap, in nine cases (21.4%) only a soft tissue flap was used, and in seven other patients (16.7%) only the prosthetic material was used. Pedicled musculocutaneous latissimus dorsi flaps were used most often (n=17), followed by pectoralis major flaps (n=8) and free flaps (n=8). Twenty-two patients (52.4%) developed at least one postoperative complication. Wounds (21.4%) and pulmonary (19.0%) complications occurred most frequently. Five (11.9%) patients required reoperation. There were no associations between patient and treatment characteristics and the occurrence of major complications. There was no mortality. Conclusions: Reconstruction of full thickness chest wall defects using only non-rigid prosthetic material for skeletal reconstruction appears safe with an acceptable reoperation rate and low mortality, questioning the need for rigid fixation techniques.</p

Measurement of fraction unbound paclitaxel in human plasma

The clinical pharmacokinetic behavior of paclitaxel (Taxol) is distinctly nonlinear, with disproportional increases in systemic exposure with an increase in dose. We have recently shown that Cremophor EL, the formulation vehicle used for i.v. administration of paclitaxel, alters drug distribution as a result of micellar entrapment of paclitaxel, and we speculated that the free drug fraction (fu) is dependent on dose and time-varying concentrations of Cremophor EL in the central plasma compartment. To test this hypothesis, a reproducible equilibrium dialysis method has been developed for the measurement of paclitaxel fu in plasma. Equilibrium dialysis was performed at 37 degrees C in a humidified atmosphere of 5% CO(2) using 2.0-ml polypropylene test tubes. Experiments were carried out with 260-microliter aliquots of plasma containing a tracer amount of [G-(3)H]paclitaxel with high-specific activity against an equal volume of 0.01 M phosphate buffer (pH 7.4). Drug concentrations were measured by both reversed-phase HPLC and liquid scintillation counting. Using this method, fu has been measured in three patients receiving three consecutive 3-weekly courses of paclitaxel at dose levels of 135, 175, and 225 mg/m(2) and found to range between 0.036 and 0.079. The method was also used to define concentration-time profiles of unbound drug, estimated from the product of the total plasma concentration and fu

Surgical Outcomes after Full Thickness Chest Wall Resection Followed by Immediate Reconstruction:A 7-Year Observational Study of 42 Cases

Introduction: Reconstruction of full thickness chest wall defects is challenging and is associated with a considerable risk of complications. Therefore, the aim of this study was to investigate the surgical outcomes and their associations with patient and treatment characteristics following full thickness chest wall reconstruction. Patients and methods: A retrospective observational study was performed by including patients who underwent reconstruction of full thickness chest wall defect at the Erasmus MC between January 2014 and December 2020. The type of reconstruction was categorized into skeletal and soft tissue reconstructions. For skeletal reconstruction, only non-rigid prosthetic materials were used. Patient and surgical characteristics were retrieved and analyzed for associations with postoperative complications. Results: Thirty-two women and 10 men with a mean age of 60 years were included. In 26 patients (61.9%), the reconstruction was performed using prosthetic material and a soft tissue flap, in nine cases (21.4%) only a soft tissue flap was used, and in seven other patients (16.7%) only the prosthetic material was used. Pedicled musculocutaneous latissimus dorsi flaps were used most often (n=17), followed by pectoralis major flaps (n=8) and free flaps (n=8). Twenty-two patients (52.4%) developed at least one postoperative complication. Wounds (21.4%) and pulmonary (19.0%) complications occurred most frequently. Five (11.9%) patients required reoperation. There were no associations between patient and treatment characteristics and the occurrence of major complications. There was no mortality. Conclusions: Reconstruction of full thickness chest wall defects using only non-rigid prosthetic material for skeletal reconstruction appears safe with an acceptable reoperation rate and low mortality, questioning the need for rigid fixation techniques.</p

Paclitaxel in self-micro emulsifying formulations: oral bioavailability study in mice

The anticancer drug paclitaxel is formulated for i.v. administration in a mixture of Cremophor EL and ethanol. Its oral bioavailability is very low due to the action of P-glycoprotein in the gut wall and CYP450 in gut wall and liver. However, proof-of-concept studies using the i.v. formulation diluted in drinking water have demonstrated the feasibility of the oral route as an alternative when given in combination with inhibitors of P-glycoprotein and CYP450. Because of the unacceptable pharmaceutical properties of the drinking solution, a better formulation for oral application is needed. We have evaluated the suitability of various self-micro emulsifying oily formulations (SMEOF’s) of paclitaxel for oral application using wild-type and P-glycoprotein knockout mice and cyclosporin A (CsA) as P-glycoprotein and CYP450 inhibitor. The oral bioavailability of paclitaxel in all SMEOF’s without concomitant CsA was low in wild-type mice, showing that this vehicle does not enhance intestinal uptake by itself. Paclitaxel (10 mg/kg) in SMEOF#3 given with CsA resulted in plasma levels that were comparable to the Cremophor EL-ethanol containing drinking solution plus CsA. Whereas the AUC increased linearly with the oral paclitaxel dose in P-glycoprotein knockout mice, it increased less than proportional in wild-type mice given with CsA. In both strains more unchanged paclitaxel was recovered in the feces at higher doses. This observation most likely reflects more profound precipitation of paclitaxel within the gastro-intestinal tract at higher doses. The resulting absolute reduction in absorption of paclitaxel from the gut was possibly concealed by partial saturation of first-pass metabolism when P-glycoprotein was absent. In conclusion, SMEOF’s maybe a useful vehicle for oral delivery of paclitaxel in combination with CsA, although the physical stability within the gastro-intestinal tract remains a critical issue, especially when applied at higher dose levels