Thorir D. Bjornsson

Interpatient variability in bioavailability is related to the extent of absorption: Implications for bioavailability and bioequivalence studies

Clinical Pharmacology & Therapeutics (1996) 60, 601–607; doi:

Immunohistochemical demonstration of tissue transglutaminase in amyloid plaques

Abstract The brain of Alzheimer’s disease patients contains deposits of the 39–42-amino acid (∼ 4 kDa) amyloid β-peptide, which is derived from the β-amyloid precursor protein. These pathological deposits have been shown to consist in part of insoluble 8- and 16-kDa aggregates of the amyloid β-peptide. This report confirms that the amyloid β-peptide is a substrate for tissue transglutaminase (TGase) and demonstrates that human brain preparations from Alzheimer’s disease patients and control patients form cross-linked dimers from added iodinated amyloid β-peptide. Immunohistochemical staining for TGase revealed its presence in tissue sections and isolated amyloid plaque cores obtained from brains of patients diagnosed as having Alzheimer’s disease. These results provide evidence that the previously described insoluble amyloid deposits in Alzheimer’s disease may involve TGase-mediated cross-linked amyloid β-peptide polymers, and suggest a potential role for TGase in the pathogenesis of this disease.

Inhibition of intimal hyperplasia after arterial injury by heparins and heparinoid

The efficacies of standard heparin (SH), low molecular weight heparin (LMWH), and a mixture of sulfated glycosaminoglycans (Org 10172) were investigated with respect to their inhibitory effects on intimal thickening after endothelial injury in the common carotid artery of the rat. The injury was induced by air infusion into an isolated segment of the artery; the pharmacologic agents were administered by continuous intravenous infusion. After 2 weeks the animals were killed and the arteries examined. The control animals developed a marked intimal thickening. A dose-dependent decreases in the intima to media area (I-M) ratio was seen after SH, with approximately 50% and 90% inhibition of intimal thickening at doses of 5 and 50 USP U/kg/hr, respectively. At these effective doses, the effect of SH was associated with reendothelialization of the injured area. The effects of LMWH and Org 10172 were similar to that of SH at doses of 50 anti-Xa U/kg/hr, but these agents had only about 40% inhibition at doses of 15 anti-Xa U/kg/hr. The activated partial thromboplastin times were slightly prolonged in the animals treated with 50 USP/anti-Xa U/kg/hr of SH, LMWH, and Org 10172, whereas significant anti-Xa levels were observed at doses higher than 15 USP/anti-Xa U/kg/hr. It is concluded that SH, LMWH, and Org 10172 have significant inhibitory effects of intimal thickening after injury even at nonanticoagulant levels, with SH being the most potent.

The regulation of plasminogen activators and plasminogen activator inhibitor type 1 in endothelial cells by sex hormones

OBJECTIVE The purpose of this study was to assess the effect of 17 beta-estradiol, progesterone, and testosterone on secretion of plasminogen activators and plasminogen activator inhibitor type 1 by cultured endothelial cells. STUDY DESIGN Bovine aortic endothelial cells were cultured in medium that contained 17 beta-estradiol, progesterone, or testosterone at various concentrations (10(-13) to 10(-6) mol/L). Plasminogen activator activity in culture medium in the presence of cells was assayed after a 36-hour incubation using chromogenic substrate and iodine 125-labeled fibrin plate assays. Plasminogen activator inhibitor type 1 antigen was detected in conditioned media of bovine aortic endothelial cells by Western blotting analysis. RESULTS All three steroid hormones exhibited biphasic dose-response effects, characterized by stimulation of plasminogen activator secretion at lower concentrations and inhibition of plasminogen activator secretion at higher concentrations. A significant stimulatory effect on plasminogen activator secretion (74% over control) was observed at a 17 beta-estradiol concentration of 10(-12) mol/L (p < 0.03). At higher concentrations of 17 beta-estradiol, progesterone, and testosterone, inhibition of plasminogen activator secretion was observed (p < 0.05). Decreased levels of plasminogen activator inhibitor type 1 antigen were detected in supernatants treated with either 17 beta-estradiol or progesterone at a concentration of 10(-12) mol/L and were maximal at 10(-7) mol/L 17 beta-estradiol, progesterone, and testosterone. CONCLUSION The secretion of plasminogen activators and plasminogen activator inhibitor type 1 is regulated in a biphasic dose-dependent manner by sex hormones in bovine aortic endothelial cells.

Losartan does not affect the pharmacokinetics and pharmacodynamics of warfarin

Losartan, an orally active, nonpeptide angiotensin II receptor antagonist is being developed as a therapeutic agent for the treatment of hypertension and heart failure. Many patients requiring anticoagulant therapy with warfarin also may have hypertension or heart failure, and thus, are potential candidates for losartan therapy. This study was designed to investigate whether losartan at likely dosage levels would alter the anticoagulant response to warfarin. In a two‐period, placebo‐controlled, randomized, crossover study, ten healthy male subjects received a single oral dose of 30 mg warfarin sodium on the seventh day of a 13‐day treatment with losartan, 100 mg daily by mouth, or placebo. Multiple plasma samples were collected over a 6‐day period after both warfarin doses for the measurements of R‐ and S‐warfarin concentrations and prothrombin times. The pharmacokinetics of R‐ and S‐warfarin were comparable in the absence and presence of losartan (no significant effects of losartan on area under the curve, Cmax, or tmax). Losartan also had no significant effect on the anticoagulant effect of warfarin, as assessed by the area under the prothrombin time versus time curve and the maximum response for prothrombin time. The lack of pharmacokinetic or pharmacodynamic interaction between warfarin and losartan observed in this investigation suggests that a clinically important interaction between these drugs is unlikely to occur in patients requiring concomitant administration of both drugs.

Pharmacokinetics and pharmacodynamics of tepoxalin after single oral dose administration to healthy volunteers

This study was conducted to examine the pharmacokinetics and pharmacodynamics of tepoxalin in healthy volunteers, an antiinflammatory compound that inhibits cyclooxygenase and lipoxygenase. Tepoxalin was absorbed after oral administration of single doses from 35 to 300 mg, after which it was rapidly converted to an acidic metabolite, RWJ 20142, which inhibits cyclooxygenase but not lipoxygenase. The areas under the concentration‐time curve (AUC) of tepoxalin and RWJ 20142 in plasma increased in a dose‐dependent fashion. Administration of the lowest dose of tepoxalin completely inhibited whole blood cyclooxygenase for the entire period of observation. This inhibition correlated closely with that of secretion and aggregation induced by collagen of platelets obtained from these subjects. Similarly, administration of tepoxalin was associated with significant inhibition of lipoxygenase in whole blood. Lipoxygenase was inhibited a maximum of 60% in a time‐dependent fashion, and the duration of inhibition was dose‐dependent. These studies demonstrate that tepoxalin inhibits whole blood cyclooxygenase, lipoxygenase, and platelet function after oral administration in humans.

Pharmacologic inhibition of transglutaminase-induced cross-linking of Alzheimer's amyloid β-peptide

The brain of Alzheimers disease (AD) patients contains deposits of amyloid beta-peptide (A beta). Recent studies have shown that A beta is a substrate for tissue transglutaminase (TGase), which induces the formation of cross-linked dimers and polymers, and that tacrine, indomethacin and deferoxamine, which have widely different chemical structures, attenuate the progression of symptoms of AD. This report evaluated the potential of a total of ten different pharmacological agents to inhibit TGase-induced cross-linking of A beta, including known TGase inhibitors (dansylcadaverine, spermine), non-steroidal anti-inflammatory drugs (indomethacin, meclofenamic acid, diflunisal, salicylic acid), monoamine oxidase inhibitors (tranylcypromine, phenelzine), an acetylcholinesterase inhibitor (tacrine), and an iron chelating agent (deferoxamine). All but one (salicylic acid) of these ten agents had an inhibitory effect on TGase-induced A beta cross-linking. These results suggest that inhibition of TGase-induced cross-linking of A beta is a potential pharmacologic target for the treatment of AD. A method is also presented for the determination of percent inhibition of TGase-induced A beta cross-linking based on the separated monomer, dimer and polymer bands on SDS-PAGE gels.

Fibrinolytic activity after vessel wall injury

The goal of this study was to assess fibrinolytic activity after vessel wall injury and to correlate changes in fibrinolytic activity with angiographic and histologic findings. Accordingly, in 18 atherosclerotic rabbits, vessel wall injury was produced by means of iliac artery balloon angioplasty (the injury group), whereas 8 atherosclerotic rabbits served as a control group. In all rabbits from the injury group, deep vessel wall injury was documented by either angiography or histologic study. Plasminogen activator inhibitor-1 activity in plasma increased significantly, from 21.79 +/- 1.29 arbitrary units/ml (AU/ml) at baseline study to 32.05 +/- 1.47 AU/ml at 6 h after vessel wall injury (p less than 0.01), whereas activity remained unchanged throughout the 24-h period in the control group. Plasma levels of tissue plasminogen activator activity were similar in both groups. Intravascular thrombus was found in five of six additional rabbits 6 h after vessel wall injury, that is, at the time of impaired fibrinolytic activity, whereas no thrombus was found in the control group (p less than 0.05). It is concluded that deep vessel wall injury is associated with reduced fibrinolytic activity. In addition to other procoagulant factors, elevated plasminogen activator inhibitor-1 activity may lead to intravascular thrombosis and impaired resolution of thrombus.

A Classification of Drug Action Based on Therapeutic Effects

A systematic classification system has been developed for the categorization of therapeutic effects of individual drugs based on their relationships to the underlying disease processes being treated or prevented, rather than on the pharmacologic or biochemical effects of the individual drugs. This system involves a total of six categories of different therapeutic specificities, involving four categories based on disease process‐oriented mechanisms of drug action (Categories I through IV), and two additional ones (Categories 0 and V) to complete the classification system. Category 0 includes drugs or drug uses that prevent the development of a disease when none exists; Category I, those that affect etiologic factors of a disease; Category II, those that affect specific disease processes; Category III, those that affect specific disease manifestations; Category IV, those that affect non‐specific disease manifestations or symptoms; and Category V includes drug uses or drugs used to diagnose or facilitate treatment of a disease. Examples are provided for each category as well as for applications of the classification system.

Estimation of pharmacokinetic parameters for simulations of time courses of drug concentrations after oral administration

Simulations of time courses of drug concentrations after oral administration are frequently hampered by the lack of pharmacokinetic parameters after oral dosing. This article presents methods by which to estimate such parameters from pharmacokinetic parameters after intravenous dosing and knowledge of time of peak concentration and bioavailability after oral dosing. The application of these approaches enables the generation of meaningful graphic simulations of time courses of drug concentrations after oral administration that can have educational and illustrative uses.