No abstract

Statins are one of the most commonly prescribed drugs in clinical practice. They are usually well tolerated and effectively prevent cardiovascular events. Most adverse effects associated with statin therapy are muscle-related. The recent statement of the European Atherosclerosis Society (EAS) has focused on statin associated muscle symptoms (SAMS), and avoided the use of the term ‘statin intolerance’. Although muscle syndromes are the most common adverse effects observed after statin therapy, excluding other side effects might underestimate the number of patients with statin intolerance, which might be observed in 10–15% of patients. In clinical practice, statin intolerance limits effective treatment of patients at risk of, or with, cardiovascular disease. Knowledge of the most common adverse effects of statin therapy that might cause statin intolerance and the clear definition of this phenomenon is crucial to effectively treat patients with lipid disorders. Therefore, the aim of this position paper was to suggest a unified definition of statin intolerance, and to complement the recent EAS statement on SAMS, where the pathophysiology, diagnosis and the management were comprehensively presented.

New N-substituted hydrazine linkers were synthesized and their hydrazone derivatives of adriamycin were prepared. These functionalized adriamycin derivatives were conjugated with a monoclonal antibody, 5E9. The release rate of adriamycin from the hydrazones and from some of the conjugates was studied, and their relationship to the IC50's of the conjugate against 5E9-positive Daudi cells was investigated.

No abstract

Adriamycin hydrazone (ADM-Hzn) immunoconjugates have previously been shown to exhibit antibody-directed antitumor activity in vitro and in vivo. In this report, the biological and biochemical properties of the mAb and linker were investigated. Conjugates prepared with two antibodies 5E9 [anti-(transferrin receptor)] and G28.1 (anti-CD37), (which internalize from the surface of target cells following binding) were more cytotoxic in vitro and had greater antitumor activity against Daudi B lymphoma tumor xenografts than a non-internalizing immunoconjugate prepared with mAb 2H7 (anti-CD20). In addition, the 13-acylhydrazone bond linking the drug to the mAb was labile at pH 5 and released unmodified ADM at a rapid rate (t1/2 = 2.5 h). Immunoconjugates prepared with an oxime linkage at the C-13 position were stable to acid and were not cytotoxic. These findings suggest that internalization of ADM-Hzn immunoconjugates and release of free ADM from the mAb in acidic intracellular compartments were important steps in the mechanism of action of ADM-Hzn immunoconjugates.