Circulation activation

Solovey A, Lin Y, Browne P, Choong S, Wayner E, Hebbel RP. Circulating activated endothelial cells in sickle cell anemia. N Engl J Med 1997 337 1584-1590. 

Type III reactions are the result of antigen-antibody (IgG or IgM) complexes that accumulate in tissues or the circulation, activate macrophages and the complement system, and trigger the influx of granulocytes and lymphocytes (inflammation). Examples include an Arthrus reaction when soluble antigen is injected into the skin of a sensitized individual and serum sickness, which occurs 7 to 10 days following the administration... 

Circulating active metabolites 0-desmethyl None None... 

Healthy male volunteers (n = 14) were given fluconazole 200 mg/day or matching placebo for 11 days rosuvastatin 80 mg was co-administered on day 8. Plasma concentrations of rosuvastatin, A-desmethylrosuvastatin, and active and total HMG-CoA reductase inhibitors were measured up to 96 hours after the dose. Fluconazole increased the AUC and Cmax of rosuvastatin by 14% and 9% respectively. Limited data available for the N-desmethylated metabolite showed that the feU by about 25%. Fluconazole did not affect the proportion of circulating active or total HMG-CoA reductase inhibitors accounted for by circulating rosuvastatin. Thus, fluconazole produced only small changes in rosuvastatin kinetics, which were not considered to be of clinical relevance. 

It has been suggested that the pharmacokinetics of fluvastatin, including extensive biliary excretion and absence of circulating active metabolites, might be associated with a low incidence of systemic adverse effects compared with other statins. In over 1800 patients treated for an average of 61 weeks, fluvastatin was safe and tolerable (SEDA-19, 408). Pooled data from clinical trials have shown that gastrointestinal symptoms occurred in 14% of fluvastatin recipients compared with 9% taking placebo other complaints occurred... 

Carboxylic acids have also been masked as ketones and alcohols, which would require oxidation to convert to the active acid drugs. Nabumetone (61) is a nonaci-dic nonsteroidal anti-inflammatory prodrug (NSAID).39 After absorption, nabumetone undergoes extensive metabolism, the main circulating active form is 6-methoxy-2-naphthylacetic acid (62), a potent COX-2 inhibitor (Scheme 8). Since... 

Vent gas scrubber with continuous caustic circulation Active... 

Fluconazole 200 mg once daily for 11 days increased the AUC and maximum plasma concentration of rosuvastatin (given on day 8) by 14% and 9%, respectively, in 14 healthy subjects. The proportion of circulating active HMG-CoA reductase inhibitors was not ected by fluconazole." In similar studies by the same workers, itraconazole and ketoconazole also had no clinically significant effect on the levels of rosuvastatin. 

The rates and routes of metabolism can vary with age and the lower rates and reduced routes of metabolism usually seen in the yoimg and the old can make them more susceptible to drug action. Differences in hormonal levels, in particular, can lead to differences in metabolism between sexes. Dietary and environmental factors such as the presence of alcohol and cigarette smoke can affect metabolism, as can certain disease conditions, e.g., liver disorders, diabetes. Such conditions can lead to decreased enzyme activity, altered hepatic blood flow, and changes in plasma protein levels which, in turn, can affect circulating active drug levels. 

Activated platelets stimulate MCP-1 and intercellular adhesion molecule (ICAM)-1 of HUVECs (50). Circulating activated platelets bind to leukocytes, preferentially monocytes, to form platelet-monocyte/leuko-cyte aggregates that interact with atherosclerotic lesions leading to the delivery of the platelet-derived chemokines and platelet factor 4 (CXCL4) to the monocyte surface and endothelium of atherosclerotic arteries (51). 

Huo Y, Schober A, Forlow SB, et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2003 9 61-67. 

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