Effect of omeprazole on the pharmacokinetics and toxicities of irinotecan in cancer patients: a prospective cross-over drug-drug interaction study

Background

Omeprazole is one of the most prescribed medications worldwide and within the class of proton pump inhibitors, it is most frequently associated with drug interactions. In vitro studies have shown that omeprazole can alter the function of metabolic enzymes and transporters that are involved in the metabolism of irinotecan, such as uridine diphosphate glucuronosyltransferase subfamily 1A1 (UGT1A1), cytochrome P-450 enzymes subfamily 3A (CYP3A) and ATP-binding cassette drug-transporter G2 (ABCG2). In this open-label cross-over study we investigated the effects of omeprazole on the pharmacokinetics and toxicities of irinotecan.

Methods

Fourteen patients were treated with single agent irinotecan (600 mg i.v., 90 min) followed 3 weeks later by a second cycle with concurrent use of omeprazole 40 mg once daily, which was started 2 weeks prior to the second cycle. Plasma samples were obtained up to 55 h after infusion and analysed for irinotecan and its metabolites 7-ethyl-10-hydroxycampothecin (SN-38), SN-38-glucuronide (SN-38G), 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin (NPC) and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC) by high-performance liquid chromatography (HPLC). Non-compartmental modelling was performed. Toxicities were monitored during both cycles. Paired statistical tests were performed with SPSS.

Results

The exposure to irinotecan and its metabolites was not significantly different between both cycles. Neither were there significant differences in the absolute nadir and percentage decrease of WBC and ANC, nor on the incidence and severity of neutropenia, febrile neutropenia, diarrhoea, nausea and vomiting when irinotecan was combined with omeprazole.

Conclusion

Omeprazole 40 mg did not alter the pharmacokinetics and toxicities of irinotecan. This widely used drug can, therefore, be safely administered during a 3-weekly single agent irinotecan schedule.     

First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: molecular characteristics in relation to response

Only a few studies examined the effect of temozolomide (TMZ) in recurrent low-grade astrocytoma (LGA) after surgery, none of which included a homogeneous and sufficiently sized group of patients with progression after radiotherapy (RT). We evaluated a cohort of 58 patients treated with TMZ for progression after RT of a previous LGA and investigated the relation between outcome and mutations in the IDH1, IDH2, and TP53 genes, O⁶-methylguanine-methyltransferase (MGMT) promoter methylation, trisomy of chromosome 7, and loss of chromosomes 1p and 19q. All patients received first-line TMZ 200 mg/m²/day on days 1–5 every 4 weeks for a progressive LGA with a contrast-enhancing lesion on MRI after RT. Six months progression-free survival (PFS) was 67%, and the median overall survival was 14 months. An objective response was obtained in 54%. TP53 mutations and loss of chromosome 19q showed a borderline association with PFS, but none of the other molecular characteristics were correlated with the outcome to TMZ. Both a methylated MGMT promoter gene and IDH1 mutations were found in 86% of the tumor samples. A correlation was found between IDH1 mutations and MGMT promoter methylation (P < .001). Neither MGMT promoter methylation nor IDH1 mutations correlated with PFS, but the interval between the very first symptom of the LGA and the start of the TMZ was significantly longer in the patients with IDH1 mutations (P = .01) and a methylated MGMT promoter (P = .02). We conclude that MGMT promoter methylation and IDH1 mutations seem to predict survival from the time of diagnosis, but not PFS to TMZ.     

Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST)

Although gastrointestinal stromal tumors (GISTs) harboring activating KIT or platelet-derived growth factor receptor A (PDGFRA) mutations respond to treatment with targeted KIT/PDGFRA inhibitors such as imatinib mesylate, these treatments are rarely curative. Most often, a sizeable tumor cell subpopulation survives and remains quiescent for years, eventually resulting in acquired resistance and treatment failure. Here, we report that imatinib induces autophagy as a survival pathway in quiescent GIST cells. Inhibiting autophagy, using RNAi-mediated silencing of autophagy regulators (ATGs) or antimalarial lysosomotrophic agents, promotes the death of GIST cells both in vitro and in vivo. Thus, combining imatinib with autophagy inhibition represents a potentially valuable strategy to promote GIST cytotoxicity and to diminish both cellular quiescence and acquired resistance in GIST patients.     

The effect of early customized vestibular rehabilitation on balance after acoustic neuroma resection

OBJECTIVE: To compare the effect of early customized vestibular rehabilitation with general instructions in patients after acoustic neuroma surgery. SETTING: Tertiary referral centre. SUBJECTS: Fifty-three patients after surgery. DESIGN: A prospective assessor-blinded, randomized controlled trial. INTERVENTIONS: After stratification for age (<50 years; >or=50 years), patients were randomly allocated into groups receiving general instructions or customized vestibular rehabilitation protocols for 12 weeks. OUTCOME MEASURES: Standing Balance Sum, Timed Up and Go test, Tandem Gait and Dynamic Gait Index. Balance performance was assessed preoperatively, at discharge (one week after surgery), three, six, nine, 12, 26 and 52 weeks after surgery. RESULTS AND DISCUSSION: All subjects clearly improved within the first six weeks after surgery. However, older subjects receiving vestibular rehabilitation performed significantly (P<0.05) better on standing balance, Timed Up and Go test and Tandem Gait, when compared with the older group that received only general instructions. This effect persisted up to 12 weeks and also became apparent on the Dynamic Gait Index. In addition, the older vestibular rehabilitation group had better balance scores at 12 weeks when compared with their original preoperative scores (P<0.05). This pattern remained even up to one year after surgery (P<0.05). CONCLUSION: In patients over 50, early vestibular rehabilitation facilitates recovery of postural control after acoustic neuroma surgery. Customized vestibular rehabilitation should be given in addition to general instructions that stress the need of exposure to movement. Retention of the early beneficial effects even one year after surgery stresses the importance of customized vestibular rehabilitation.     

Convergence of entorhinal and CA3 inputs onto pyramidal neurons and interneurons in hippocampal area CA1--an anatomical study in the rat

The entorhinal cortex (EC) conveys information to hippocampal field CA1 either directly by way of projections from principal neurons in layer III, or indirectly by axons from layer II via the dentate gyrus, CA3, and Schaffer collaterals. These two pathways differentially influence activity in CA1, yet conclusive evidence is lacking whether and to what extent they converge onto single CA1 neurons. Presently we studied such convergence. Different neuroanatomical tracers injected into layer III of EC and into CA3, respectively, tagged simultaneously the direct entorhino-hippocampal fibers and the indirect innervation of CA1 neurons by Schaffer collaterals. In slices of fixed brains we intracellularly filled CA1 pyramidal cells and interneurons in stratum lacunosum-moleculare (LM) and stratum radiatum (SR). Sections of these slices were scanned in a confocal laser scanning microscope. 3D-reconstruction was used to determine whether boutons of the labeled input fibers were in contact with the intracellularly filled neurons. We analyzed 12 pyramidal neurons and 21 interneurons. Perforant path innervation to pyramidal neurons in our material was observed to be denser than that from CA3. All pyramidal neurons and 17 of the interneurons received contacts of both perforant pathway and Schaffer input on their dendrites and cell bodies. Four interneurons, which were completely embedded in LM, received only labeled perforant pathway input. Thus, we found convergence of both projection systems on single CA1 pyramidal and interneurons with dendrites that access the layers where perforant pathway fibers and Schaffer collaterals end.     

Exposure of human cartilage tissue to low concentrations of blood for a short period of time leads to prolonged cartilage damage: an in vitro study

OBJECTIVE: Joint bleeding, or hemarthrosis, leads in time to severe joint damage. This study was carried out to test the in vitro thresholds of exposure time and concentration that lead to irreversible joint damage, to add to the discussion on the usefulness of aspiration of the joint after a hemorrhage. METHODS: Explants of healthy human articular cartilage tissue were cultured in the presence or absence of 50% (volume/volume) blood for 1, 2, 3, or 4 days or in the presence of 0%, 5%, 10%, 20%, 30%, or 50% (v/v) blood for 4 days, followed by a 12-day period of recovery after withdrawal of blood. The effect of blood exposure on cartilage was determined by measuring the rate of proteoglycan synthesis as well as the release and content of cartilage matrix proteoglycans and the activity of matrix metalloproteinases. RESULTS: Exposure of cartilage to 50% (v/v) blood led to adverse changes that were largely independent of the exposure time. The adverse effects persisted after an initial exposure of up to or exceeding 2 days. Exposure of cartilage to increasing concentrations of blood for 4 days led to concentration-dependent adverse changes. These effects persisted when the concentration equaled or exceeded 10% (v/v) blood. Moreover, after 2 days of exposure to a blood load of 10% (v/v), the adverse effects on cartilage were not reversible. CONCLUSION: A 2-day exposure of cartilage in vitro to 10% (v/v) blood leads to prolonged impairment of joint cartilage. This suggests that aspiration of blood from the joint within 2 days after hemarthrosis should be considered to prevent blood-induced joint damage in the long term.     

Phase-contrast magnetic resonance angiography measurements of global cerebral blood flow in the neonate

Cerebral blood flow (CBF) alterations are important in pathogenesis of neonatal ischemic/hemorrhagic brain damage. In clinical practice, estimation of neonatal CBF is mostly based on Doppler-measured blood flow velocities in major intracranial arteries. Using phase-contrast magnetic resonance angiography (PC-MRA), global CBF can be estimated, but there is limited neonatal experience. The objective of this study was to gain experience with PC-MRA for the determination of global CBF in neonates. In infants eligible for MRI, PC-MRA global CBF was determined by measuring volume blood flow in both internal carotid arteries (ICAs) and basilar artery (BA). Thirty newborns (GA, 25.7-42.1 wk; weight, 1050-5858 g; postconceptional age, 225-369 d) were investigated. Total PC-MRA CBF ranged from 27 to 186 mL/min. Significant correlations between PC-MRA CBF and postconceptional age and weight were detected. When calculating PC-MRA measured CBF per kilogram body weight, brain perfusion was about stable over the range of postconceptional ages and ranged between 11 and 48 mL/min/kg (median, 25 mL/min/kg). In conclusion, neonatal PC-MRA CBF seems to be a useful technique to estimate noninvasive CBF.     

Predicting respiratory motion signals for image-guided radiotherapy using multi-step linear methods (MULIN)

Objective

Forecasting of respiration motion in image-guided radiotherapy requires algorithms that can accurately and efficiently predict target location. Improved methods for respiratory motion forecasting were developed and tested.

Materials and methods

MULIN, a new family of prediction algorithms based on linear expansions of the prediction error, was developed and tested. Computer-generated data with a prediction horizon of 150 ms was used for testing in simulation experiments. MULIN was compared to Least Mean Squares-based predictors (LMS; normalized LMS, nLMS; wavelet-based multiscale autoregression, wLMS) and a multi-frequency Extended Kalman Filter (EKF) approach. The in vivo performance of the algorithms was tested on data sets of patients who underwent radiotherapy.

Results

The new MULIN methods are highly competitive, outperforming the LMS and the EKF prediction algorithms in real-world settings and performing similarly to optimized nLMS and wLMS prediction algorithms. On simulated, periodic data the MULIN algorithms are outperformed only by the EKF approach due to its inherent advantage in predicting periodic signals. In the presence of noise, the MULIN methods significantly outperform all other algorithms.

Conclusion

The MULIN family of algorithms is a feasible tool for the prediction of respiratory motion, performing as well as or better than conventional algorithms while requiring significantly lower computational complexity. The MULIN algorithms are of special importance wherever high-speed prediction is required.