5'-DMT-dA(Bz)-Suc-CPG; 500 Å

(1) Flumazenil is a highly specific benzodiazepine (BZ) antagonist. It exerts its effect by competitive interaction at the BZ receptor site. (ii) Flumazenil antagonizes all central BZ effects irrespective of its contiguity to the BZ administration. (iii) The pharmacological effect of flumazenil depends upon the number of BZ receptors that can be occupied by flumazenil according to the mass-action law. Receptor occupancy is determined by the affinity of the BZ for the receptor and the free BZ concentration near the receptor. (iv) The minimal effective dose of flumazenil is 0.2 mg. After extreme BZ overdose 1 mg may be needed. (v) The optimal dosing strategy starts with an initial dose of flumazenil 0.2 mg i.v. The administration of further low doses of 0.1 mg at 1-min intervals allows the interruption of the injection of flumazenil exactly at the stage of vigilance that is most convenient for the patient. (vi) The duration of effect depends upon the type and dose of the administered BZ, the dose of flumazenil, and the time interval between flumazenil and the BZ administration. (vii) The therapeutic or safety index is above 3000, which means that a 3000 times overdose is still tolerated.

Ventricular arrhythmias (VA) in patients with myocardial infarction (MI) are thought to be associated with structural and electrophysiological remodeling within the infarct border zone (BZ). Personalized computational models have been used to investigate the potential role of the infarct BZ in arrhythmogenesis, which still remains incompletely understood. Most recent models have relied on experimental data to assign BZ properties. However, experimental measurements vary significantly resulting in different computational representations of this region. Here, we review experimental data available in the literature to determine the most prominent properties of the infarct BZ. Computational models are then used to investigate the effect of different representations of the BZ on activation and repolarization properties, which may be associated with VA. Experimental data obtained from several animal species and patients with infarct show that BZ properties vary significantly depending on disease's stage, with the early disease stage dominated by ionic remodeling and the chronic stage by structural remodeling. In addition, our simulations show that ionic remodeling in the BZ leads to large repolarization gradients in the vicinity of the scar, which may have a significant impact on arrhythmia simulations, while structural remodeling plays a secondary role. We conclude that it is imperative to faithfully represent the properties of regions of infarction within computational models specific to the disease stage under investigation in order to conduct in silico mechanistic investigations.

Heavy reliance on the benzimidazole (BZ) anthelmintics since their introduction in the 1960's for the control of gastrointestinal parasites of livestock has led to widespread BZ resistance in target parasite species. The BZs exert their primary action by binding to tubulin, the major protein component of microtubules. This review discusses the biochemistry of the interaction between the BZs and tubulin from mammalian and BZ-resistant and -susceptible parasite sources, exploring aspects of the selective toxicity of these drugs and examining the mechanism of BZ resistance. Although tubulin is a highly conserved protein present in both the host and the parasite, the BZs demonstrate relatively low mammalian toxicity. The selectivity of these drugs can be explained by the much higher affinity of the BZs for tubulin from the parasite at 37 degrees C compared to their affinity for tubulin from the host. This difference in affinity reflects the considerably slower rate of BZ dissociation from parasite tubulin. BZ-resistance in parasitic nematodes is characterised by a loss of high affinity BZ-parasite tubulin interactions and a corresponding increase in lower affinity interactions, although there are still significant differences between BZ-resistant parasite tubulin and tubulin from the host. These differences suggest the potential for the design of new generation BZs active against 'BZ-resistant' parasites.