Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis.

Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is approved for treatment of relapsing multiple sclerosis (MS). In the Phase II/III trials, patients received 12 or 24 mg/day of alemtuzumab in two treatment courses (5 days for course 1 and 3 days for course 2), 12 months apart. Serum concentrations of alemtuzumab peaked on the last day of dosing in each course and mostly fell below the limit of quantitation by day 30. Alemtuzumab rapidly depleted circulating T and B lymphocytes, with the lowest observed values occurring within days. Lymphocytes repopulated over time, with B cell recovery usually complete within 6 months. T lymphocytes recovered more slowly and generally did not return to baseline by 12 months post-treatment. Approximately 40 and 80% of patients had total lymphocyte counts, reaching the lower limit of normal by 6 and 12 months after each course, respectively. The clearance of alemtuzumab is dependent on circulating lymphocyte count. A majority of treated patients tested positive for anti-alemtuzumab antibodies, including inhibitory antibodies, during the 2-year studies, and a higher proportion of patients tested positive in course 2 than in course 1. The presence of anti-alemtuzumab antibody appeared to be associated with slower clearance of alemtuzumab from the circulation but had no impact on the pharmacodynamics. No effects of age, race or gender on the pharmacokinetics or pharmacodynamics were observed. Together, the pharmacokinetics, pharmacodynamics and immunogenicity results support the continued development and use of alemtuzumab for the treatment of MS, and probably explain its sustained effects beyond the dosing interval.

Regulation of myosin phosphatase by a specific interaction with cGMP- dependent protein kinase Ialpha.

Contraction and relaxation of smooth muscle are regulated by myosin light-chain kinase and myosin phosphatase through phosphorylation and dephosphorylation of myosin light chains. Cyclic guanosine monophosphate (cGMP)-dependent protein kinase Ialpha (cGKIalpha) mediates physiologic relaxation of vascular smooth muscle in response to nitric oxide and cGMP. It is shown here that cGKIalpha is targeted to the smooth muscle cell contractile apparatus by a leucine zipper interaction with the myosin-binding subunit (MBS) of myosin phosphatase. Uncoupling of the cGKIalpha-MBS interaction prevents cGMP-dependent dephosphorylation of myosin light chain, demonstrating that this interaction is essential to the regulation of vascular smooth muscle cell tone.

Transient myocardial dysfunction associated with angiotensin-converting enzyme inhibitor-induced angioedema: recognition by serial echocardiographic studies.

We report a case of a 58-year-old woman who had angiotensin converting enzyme inhibitor-induced angioedema after she underwent a biopsy of a hypopharyngeal mass. The angioedema was associated with severe transient myocardial dysfunction documented on echocardiography. She did not have anaphylaxis or coronary artery disease. To our knowledge this is the first reported case of transient myocardial dysfunction in the setting of angiotensin converting enzyme inhibitor-induced angioedema without anaphylaxis.

A case of giant cell myocarditis and malignant thymoma: a postmortem diagnosis by needle biopsy.

This paper reports a case of fulminant giant cell myocarditis arising in association with a malignant thymoma causing death in a 46-year-old woman. Although the diagnosis was suspected in life, postmortem examination was required for confirmation of giant cell myocarditis. Consent was obtained only for percutaneous needle biopsy of the heart. In order to respect the family's wishes and harvest sufficient diagnostic myocardium, a simple needle-based biopsy technique was devised. A bone marrow trephine needle was attached to a 20 ml syringe and, with suction, multiple passes were used to fill 15 tissue cassettes. The cores were placed immediately in formalin and B5 fixatives. High-quality tissue preservation was obtained without crush artefact. Immunohistochemical studies of the biopsy tissue confirmed that the giant cells were of macrophage derivation.

Anacetrapib, a novel CETP inhibitor: pursuing a new approach to cardiovascular risk reduction.

Cholesteryl ester transfer protein (CETP) inhibition is a promising experimental strategy to raise high-density lipoprotein cholesterol (HDL-C) and reduce cardiovascular risk. This review focuses on the highly selective and potent CE TP inhibitor anacetrapib and discusses the available preclinical and clinical information pertaining to it. We also describe strategies to target HDL-C, discuss the mechanism underlying CETP inhibition and its effects on lipid biology, and give an overview of other CETP inhibitors that are currently in development.