Platelet and von Willebrand factor interactions at the vessel wall

The process of platelet thrombus formation contributes to the haemostatic response that prevents excessive blood loss after tissue injury, but may become a life-threatening disease mechanism by causing the acute thrombotic occlusion of atherosclerotic arteries. The participation of platelets in the formation of thrombi is centered on their adhesive properties and the ability to respond to stimuli with rapid activation. Platelet adhesion and activation are multifaceted and modulated by different environmental conditions, suggesting that it should be possible to obtain a selective pharmacological inhibition of the pathways more relevant to athero-thrombosis than to haemostasis. In particular, progress in understanding the structure and function of von Willebrand factor and the mechanisms that underlie its interactions with vascular surfaces and platelets can elucidate important differentiating aspects of normal haemostasis and pathological arterial thrombosis.     

Thrombospondin-platelet interactions. Role of divalent cations, wall shear rate, and platelet membrane glycoproteins.

The role of thrombospondin, a multifunctional matrix glycoprotein, in platelet adhesion is controversial: both adhesive and antiadhesive properties have been attributed to this molecule. Because shear flow has a significant influence on platelet adhesion, we have assessed thrombospondin-platelet interactions both under static and flow conditions. The capacity of thrombospondin to support platelet adhesion depended upon its conformation. In a Ca(2+)-depleted conformation, such as in citrated plasma, thrombospondin was nonadhesive or antiadhesive as it inhibited platelet adhesion to fibrinogen, fibronectin, laminin, and von Willebrand factor by 30-70%. In a Ca(2+)-replete conformation, however, thrombospondin effectively supported platelet adhesion. Shear rate influenced this adhesion; percent surface coverage on thrombospondin increased from 5.4 +/- 0.3 at 0 s-1 to 41.5 +/- 6.7 at 1,600 s-1. In contrast to the extensive platelet spreading observed on fibronectin at all shear rates, platelet spreading on thrombospondin occurred only sporadically and at high shear rates. GPIa-IIa, GPIIb-IIIa, GPIV, and the vitronectin receptor, which are all proposed platelet receptors for thrombospondin, were not solely responsible for platelet adhesion to thrombospondin. These results suggest that thrombospondin may play a dual role in adhesive processes in vivo: (a) it may function in conjunction with other adhesive proteins to maintain optimal platelet adhesion at various shear rates; and (b) it may serve as a modulator of cellular adhesive functions under specific microenvironmental conditions.     

Discordance of endothelial nitric oxide synthase in the arterial wall and its circulating products in baboons: interactions with redox metabolism

BACKGROUND: Although peripheral arteries and circulating factors have been frequently used to assess systemic or central arterial, such as coronary artery, endothelial nitric oxide synthase (eNOS) functions, there is no direct evidence to support that they are related. DESIGN: We explored relationships in eNOS levels among coronary, aortic, carotid and brachial arteries, and interactions with redox metabolisms in 40 necropsied baboons (Papio hamadryas). RESULTS: We found no correlations in eNOS or NOx levels among all four arteries (R: 0.02-0.19, P > 0.05). While eNOS levels were high in both coronary (133.78 +/- 10.9 pg mg-1 protein) and aortic arteries (168.53 +/- 16.32 pg mg-1 protein), they were low in brachial (82.88 +/- 5.5 pg mg-1 protein) and carotid (89.83 +/- 7.15 pg mg-1 protein) arteries. Arterial eNOS were not correlated with plasma NOx either. However, coronary and aortic eNOS were positively correlated with the corresponding arterial total antioxidant status (TAS) (r = 0.638, P= 0.001, and r = 0.615, P= 0.0001). Coronary eNOS was also negatively associated with coronary advanced glycation end products (AGE) (r = -0.454, P= 0.003). Furthermore, there were significant associations in TAS levels between plasma and arterial wall extracts (R: 0.344-0.369, P < 0.05) and among arteries of different anatomic sites (R: 0.637-0.877, P < 0.001). While arterial TAS was negatively correlated with corresponding arterial AGE, TAS in the arterial wall and plasma were positively associated with plasma AGE. CONCLUSIONS: Our study shows that eNOS is differentially expressed in different anatomic sites and is not associated with plasma NOx, suggesting that brachial eNOS may not be used to assess coronary eNOS. The positive or negative associations between eNOS and TAS or AGE, especially in the coronary artery, indicate an important role of eNOS in arterial wall redox balance.     

Effect of cilofungin (LY121019), a fungal cell wall synthesis inhibitor, on interactions of Candida albicans with human neutrophils

The effects of cilofungin, a lipopeptide antifungal agent active against several species of Candida, on human neutrophil candidacidal activity were investigated. While no increase or decrease in neutrophil killing of blastospores was observed when cilofungin was simultaneously incubated with neutrophils and yeasts, preincubation of yeasts with serum containing cilofungin resulted in approximately 90% decrease in killing of five of six strains. Attachment/phagocytosis of these strains was unchanged from controls. We conclude that cilofungin interferes with opsonization of most strains of C. albicans, resulting in a marked decrease in neutrophil candidacidal activity, a phenomenon which may be of significance in vivo in certain tissues where access to antibodies and/or complement is limited.     

Drug-nutrient interactions

Drug-nutrient interactions are a commonly overlooked aspect of the prescribing practices of physicians. As more pharmaceutical agents become available, attention should be focused on interactions of drugs with foods and nutrients. Although drug-nutrient interactions are not as common as drug-drug interactions, they can have an impact on therapeutic outcome. Drugs can affect nutritional status by altering nutrient absorption, metabolism, utilization or excretion. Food, beverages and mineral or vitamin supplements can affect the absorption and effectiveness of drugs. Knowledge of drug-nutrient interactions can help reduce the incidence of these effects. Physicians should question patients about their dietary habits so that patients can be informed about possible interactions between a prescribed drug and foods and nutrients.     

Nicotine-mecamylamine interactions

OBJECTIVES: Mecamylamine blocks nicotinic cholinergic receptors and has been proposed, in combination with nicotine, as a novel therapy to aid smoking cessation. The objective of this study was to characterize the pharmacokinetic and pharmacodynamic interactions between transdermal mecamylamine and intravenous nicotine. STUDY DESIGN: Twelve cigarette smokers were studied while receiving transdermal mecamylamine 6 mg/24 h and placebo patches for 7 days each. On the fifth day of patch use, subjects received a combined infusion of deuterium-labeled nicotine and cotinine, with measurement of disposition kinetics of nicotine and cotinine, and cardiovascular and plasma catecholamine responses to nicotine. Half of the subjects were studied under alkaline urine conditions and the other half under acidic urine conditions. RESULTS: Steady-state plasma mecamylamine concentrations were twice as high (mean, 12.2 versus 6.3 ng/mL), consistent with lower renal clearance (2.1 versus 5.8 mL/min/kg) during alkaline compared with acidic urine conditions. Mecamylamine did not significantly affect the clearances of nicotine or cotinine. Mecamylamine significantly reduced the volume of distribution and inhibited the cardioacceleratory and epinephrine-releasing effects of nicotine. CONCLUSIONS: Mecamylamine has little effect on the clearance of nicotine and is not expected to affect steady-state levels during transdermal nicotine dosing. The reduction of the volume of distribution of nicotine by mecamylamine suggests that part of the antagonism of nicotinic central nervous system effects by mecamylamine may be due to a pharmacokinetic interaction-most likely decreased transport of nicotine into the brain or decreased binding to nicotine receptors. Mecamylamine may decrease the potential adverse cardiovascular effects of coadministered nicotine.     

Drug-alcohol interactions

Drug-alcohol interactions can be potentially life-threatening. These fall into three broad categories: the disulfiram reaction, which can lead to vasodilation, flushing, headache and tachycardia; central nervous system depression, which can lead to excessive sedation and respiratory depression, and a miscellaneous category of drug-alcohol interactions.     

Isoniazid interactions

Isoniazid is an antituberculous drug that is usually administered for nine to 12 months. The potential for clinically important interactions exists because this drug is a potent inhibitor of drug metabolism. Studies and case reports have shown that isoniazid inhibits the metabolism of several drugs, including phenytoin, carbamazepine, anticoagulants, benzodiazepines, and vitamin D. Furthermore, isoniazid inhibits both monoamine oxidase and diamine oxidase (histaminase). Additional study is required to document the clinical significance of other isoniazid interactions. Future investigations will identify new isoniazid interactions.