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In phase I studies, angiogenesis inhibitors were given in increasing doses until severe toxicities became evident.For bevacizumab the MTD was determined to be mg per kg. Headache associated with nausea and vomiting was the doselimiting toxicity, although only one patient stopped treatment at this dose level for this reason.Body surface area is the Heptaminol hydrochloride standard method to dose chemotherapeutics in cancer, and body weight is used to determine the dose of antiangiogenic antibodies to be given in patients.Therefore, these agents are prescribed at a fixed dose, independent of body weight or body surface area.Whether the pharmacodynamics of these drugs are independent of these measures remains an open question.Despite this, toxicities with different rates of onset may be caused by similar andor different underlying mechanisms.Shortterm toxicities may cause acute lifethreatening problems such as gastrointestinal perforations, as have been seen with bevacizumab.Longterm treatment, for example, may reduce the left ventricular ejection fraction, which can also ultimately be life threatening. Overall, in up to of patients treated with bevacizumab, grade, have been reported.Reversible posterior Rebeprazole sodium leukoencephalopathy syndrome A rapidly evolving neurological syndrome.The underlying mechanism seems to be related to an increased permeability and reactivity of brain vasculature.Subungual splinter bleeding A small amount of bleeding that occurs under a finger or toe nail.Thrombocytopenia A low platelet count in the circulating blood.The resistance to flow that must be overcome to push blood though a vessel; determined by diameter, stiffness and length of the vessel.Preclinical in vivo studies indicated that tumours may activate alternative pathways to stimulate the angiogenic process in order to escape from VEGFR inhibition.For example, higher quantities of basic fibroblast growth factor were detected when the VEGF pathway was blocked in mice.Classical resistance mechanisms, such as increased drug metabolism or an increased number of drug efflux pumps located on the cell membrane might also have a significant role.A reciprocal increase in expression of the growth factor or its receptor might be induced by treatment, and could also provoke toxicity of these agents.Increased levels of the growth factor or its receptor might lead to more problems once treatment with the agent is halted owing to increased VEGFR activation after removing the receptor inhibitor in the presence of increased VEGF levels.In the following sections, we will discuss the toxicities of angiogenesis inhibitors that have reached phase II or III trials or have been approved and target at least the VEGF pathway. They also activate the vasomotor centre in response to low blood pressure.Common symptoms include progressive loss of memory and cognitive ability, subtle personality changes, inability to concentrate, lethargy and progressive loss of consciousness.Grade is the mildest toxicity, grade is the most severe lifethreatening toxicity and grade is defined as a fatal toxicity.Often grade toxicity is defined as the doselimiting toxicity for a certain agent.However, some grade toxicities are well manageable.Healing of gastrointestinal ulcers also depends on angiogenesis, and a relationship between gastrointestinal perforations and antiangiogenic antibody therapy has been found.In patients with colorectal cancer, giving bevacizumab in combination with chemotherapy resulted in a higher incidence of gastrointestinal perforations compared with chemotherapy alone.

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