Venous thrombosis during olanzapine treatment: a complex association.

Olanzapine, a second generation antipsychotic, has previously been associated with an increased risk of venous thromboembolism (VTE). In this mini-review we describe a case of a thirty-year-old schizophrenic patient who was diagnosed with a deep venous thrombosis (DVT) six months after starting olanzapine therapy, as well as seventeen other VTE cases in patients using olanzapine reported to the Netherlands Pharmacovigilance Centre Lareb. In 14 of these reports, patients had reported additional risk factors for VTE. We found disproportionate Reporting Odds Ratios (RORs) in the global database VigiBase for olanzapine and the reactions deep vein thrombosis (ROR of 1.38 with a 95% CI (Confidence Interval) of 1.22-1.57) and pulmonary embolism (ROR of 1.99 with a 95% CI of 1.81-2.19). The mechanism behind the association of olanzapine with VTE could be explained by two risk factors, substantial weight gain and lethargy, both common side effects of olanzapine. So far, a direct effect of olanzapine on platelet aggregation or coagulation has not been found. Schizophrenic patients are more likely to have diagnostic delay in the diagnosis of VTE, as symptoms such as lethargy and impaired pain perception result in diminished pain perception and pain expression, while they are at increased risk of developing VTE. Currently no validated risk score is available for detection of psychiatric patients who might benefit from pharmacologic VTE prophylaxis. In patients developing a VTE while being treated with olanzapine, discontinuation of olanzapine could be considered based on the individual risk profile, control of psychotic symptoms and antipsychotic treatment options.

Cholesterol embolisms as possible adverse drug reaction of direct oral anticoagulants.

The Netherlands Pharmacovigilance Centre Lareb has received two reports of cholesterol crystal embolisms associated with the use of a direct oral anticoagulant (DOAC). The European pharmacovigilance database contains several other cases concerning this association, and one report was published in the scientific literature. Cholesterol crystal embolisms were described in association with the use of several other antithrombotic drugs, although the role as an independent risk factor is not conclusive. The case series described in this article, indicates the possibility of an adverse drug reaction when a patient develops cholesterol crystal embolisms while using a DOAC.

Nephrotic syndrome under treatment with dasatinib: be aware of a possible adverse drug reaction.

The protein kinase inhibitor dasatinib, targeting BCR-ABL and Src family kinases, is used in chronic myeloid leukaemia and Philadelphia-chromosome positive acute lymphoblastic leukaemia. The Netherlands Pharmacovigilance Centre Lareb has received one report of nephrotic syndrome associated with the use of dasatinib. With some other protein kinase inhibitors, targeting vascular endothelial growth factor, nephrotic syndrome is a well-known adverse drug reaction. The Dutch and European pharmacovigilance databases and scientific literature contain several cases indicating a causal relationship between dasatinib and nephrotic syndrome. Nephrotic syndrome was recently added to the list of adverse drug reactions in the Dutch summary of product characteristics for dasatinib. It is important to recognise the possibility of this adverse drug reaction when a patient develops nephrotic syndrome under treatment with dasatinib.

Reduction in falling after a falls-assessment.

The aim of this single-center retrospective cohort study was to evaluate the effect of a multidisciplinary falls-assessment, consisting of identification and possible modification of risk factors for falls, on the frequency of falls among elderly individuals attending the geriatric outpatient department of the University Medical Center (UMC) Utrecht, the Netherlands. The characteristics of 70 elderly people who visited the outpatient department because of a fall in the period from May 2005 till February 2007 were evaluated. The effectiveness of the falls-assessment was evaluated by telephone interview of those individuals who had attended the falls-assessment. Fifty-three patients (mean age=79.8 years) were interviewed after a mean+/-S.D. of 1.47+/-0.41 years (ranging 0.72-2.34 years) subsequent to the falls-assessment. Falls-assessment led to significantly fewer falls, from 3.78+/-4.66 at the time of the assessment at baseline to 1.10+/-1.86 at the time of the interview (p=0.000041). Fear of falling was also significantly diminished. In conclusion, falls-assessment leads to fewer falls and less fear of falling among elderly individuals.

Recombinant human endostatin administered as a 28-day continuous intravenous infusion, followed by daily subcutaneous injections: a phase I and pharmacokinetic study in patients with advanced cancer.

BACKGROUND: Endostatin is an endogenous collagen XVIII-fragment with anti-angiogenic properties and remarkable antitumor activity in mice. Preclinical data suggest that continuous low dose administration of endostatin is much more potent than intermittent dosing. The feasibility of this approach is tested in a phase I study. PATIENTS AND METHODS: We determined the safety and pharmacokinetic profile of 4-week continuous intravenous infusion of recombinant human (rh)-endostatin, followed after an interval of 1 week by twice daily subcutaneous injections in patients with advanced cancer. Thirty-two patients received rh-endostatin in six dosing cohorts, ranging from 3.75 mg/m(2)/day to 120 mg/m(2)/day. Serum endostatin pharmacokinetics, toxicity and antitumor response were determined. RESULTS: A total of 160 cycles were delivered without significant toxicities. Pharmacokinetic analysis showed a linear increase of steady-state serum endostatin concentrations with dose (i.v. r(2)=0.96; s.c. r(2)=0.99) reaching 300--1,000 ng/ml for the two highest doses, with considerable interpatient variation. The main pharmacokinetic values for both routes of administration were similar. The apparent steady-state concentration and AUC reached at 60--120 mg/m(2)/day were within the range expected to induce anti-angiogenic and antitumor effects based on preclinical tumor models. Although no objective responses were observed, two patients had long-lasting stable disease (defined as a tumor increase<100%). CONCLUSION: rh-endostatin was safely administered both by continuous infusion and by twice daily subcutaneous injections up to 120 mg/m(2)/day. Predictable pK was seen in this dose range and the target endostatin levels were reached from 60 mg/m(2)/day and above.

A patient with a VEGF and endostatin producing gastrointestinal autonomic nerve tumour.

Tumour associated neovascularisation has been characterised as chaotic and insufficient. This report details the results of the analysis of angiogenic factors in tumour cyst fluid, pleural fluid, and blood from a patient with a gastrointestinal autonomic nerve tumour. The tumour produced vascular endothelial growth factor and endostatin in large quantities, which may explain the dysfunctional angiogenesis and tendency to bleeding seen in this tumour type.