Aaps J
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Comparative Study
Pharmacokinetics of 1,4-butanediol in rats: bioactivation to gamma-hydroxybutyric acid, interaction with ethanol, and oral bioavailability.
1,4-Butanediol (BD), a substance of abuse, is bioactivated to gamma-hydroxybutyrate (GHB), but its fundamental pharmacokinetics (PK) have not been characterized. Because this bioactivation is partly mediated by alcohol dehydrogenase, we hypothesized that there may also be a metabolic interaction between ethanol (ETOH) and BD. We therefore studied, in rats, the plasma PK of GHB, BD and ETOH each at two intravenous (IV) doses, when each substance was given alone, and when GHB or BD was co-administered with ETOH. ⋯ GHB (192 +/- 28 min vs. 117 +/- 2 min, respectively, p < 0.05). Relative to IV dosing, oral BD produced similar but more variable LRR effects. These results may provide a quantitative PK framework for the understanding of the toxicokinetics and toxicodynamics of both BD and GHB.
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Comparative Study
Microencapsulation of hemoglobin in chitosan-coated alginate microspheres prepared by emulsification/internal gelation.
Chitosan-coated alginate microspheres prepared by emulsification/internal gelation were chosen as carriers for a model protein, hemoglobin (Hb), owing to nontoxicity of the polymers and mild conditions of the method. The influence of process variables related to the emulsification step and microsphere recovering and formulation variables, such as alginate gelation and chitosan coating, on the size distribution and encapsulation efficiency was studied. The effect of microsphere coating as well its drying procedure on the Hb release profile was also evaluated. ⋯ At pH 6.8, uncoated microspheres dissolved in less than 1 hour; however, Hb release from air-dried microspheres was incomplete. Chitosan coating decreased the release rate of Hb, but an incomplete release was obtained. The 2-stage coated microspheres showed no burst effect, whereas the 1-stage coated microspheres permitted a higher protein release.
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Comparative Study
Pharmacokinetic and pharmacodynamic effects of high-dose monoclonal antibody therapy in a rat model of immune thrombocytopenia.
Intravenous administration of pooled, polyvalent human immunoglobulin (IVIG) has been used for over 20 years as a therapy for immune thrombocytopenia (ITP). IVIG is available in limited quantities, and clinical preparations have been associated with the transfer of human pathogens. We have proposed that high-dose monoclonal antibody may be used in lieu of IVIG to achieve beneficial effects in the treatment of ITP. ⋯ AMI pretreatment dramatically affected 7E3-induced thrombocytopenia, significantly altering the time course of thrombocytopenia (P < .05) and significantly decreasing the severity of 7E3-induced thrombocytopenia (ie, following AMI pretreatment, nadir platelet count was greater than 8-fold that of the control group, P < .05). In addition, AMI pretreatment induced a 57% increase in 7E3 clearance (1.13 +/- 0.13 mL h(-1) kg(-1) vs 0.72 +/- 0.08 mL h(-1) kg(-1), P < .05). Consequently, high-dose monoclonal antibody therapy attenuated thrombocytopenia and produced a moderate increase in the clearance of antiplatelet antibodies in a rat model of ITP.
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In this article we review how population pharmacokinetic/pharmacodynamic (PD) modeling has evolved in the specialty of anesthesiology, how anesthesiology benefited from the mixed-effects approach, and which features of modeling need careful attention. Key articles from the anesthesiology literature are selected to discuss the modeling of typical anesthesiological PD end points, such as level of consciousness and analgesia, interactions between hypnotics and analgesics, estimation with poor and sometimes rich data sets from populations of various sizes, covariate detection, covariances between random effects, and Bayesian forecasting.
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Thalidomide and its immunomodulatory (IMiDs) analogs (lenalidomide, Revlimid, CC-5013; CC-4047, ACTIMID) are a novel class of compounds with numerous effects on the body's immune system, some of which are thought to mediate the anticancer and anti-inflammatory results observed in humans. Thalidomide is currently being used experimentally to treat various cancers and inflammatory diseases. It is approved for the treatment of dermal reaction from leprosy and is currently in phase III trials for multiple myeloma. ⋯ This has led to their use in various oncology clinical trials. The second generation IMiD, lenalidomide, has shown potential in treating the bone marrow disorders myelodysplastic syndrome and multiple myeloma. It is currently in phase II and III trials for these diseases respectively with numerous phase II trials in other hematologic and solid tumors.