These data show benefits of using an alkalinized lidocaine-filled ETT cuff in combination with water-soluble gel lubrication in preventing post-intubation sore throat.

In clinical trials, a significant interaction between the endothelin receptor antagonist bosentan and the immunosuppressant cyclosporin A was observed, which could not be rationalized in terms of inhibition of drug-metabolizing enzymes. We present here a study performed in rats investigating the mechanisms underlying this interaction, including the inhibition of active drug transport processes as part of the gastrointestinal absorption and disposition into the liver. In vitro, the majority of bosentan uptake into liver cells was shown to depend on active transport and to be efficiently inhibited by cyclosporin A. All known members of the organic anion transporting polypeptide (oatp) transport protein family expressed in rat liver, i.e., oatp1, oatp2, and oatp4, were shown to be involved in the uptake of bosentan. Results from both series of experiments point to inhibition of active bosentan uptake into the liver by cyclosporin A as the major underlying mechanism for this pharmacokinetic interaction that is in line with reports on other oatp-transported drugs. Significant contributions of other mechanisms such as inhibition of mdr1-mediated drug efflux during gastrointestinal absorption, inhibition of bosentan metabolism, or inhibition of hepatobiliary excretion seemed to be unlikely. The interaction between bosentan and cyclosporin A is a rare example of a pharmacokinetic interaction, which can mostly be attributed to the inhibition of transport processes in the liver. It also demonstrates that inhibition of uptake into the liver might become rate-limiting in the overall elimination process even for compounds whose clearance is dependent on metabolism. The relevance of these findings in the rat for clinical use remains to be explored. It is, however, clear that inhibition of CYP3A4-mediated metabolism by cyclosporin A alone is insufficient to explain the increased bosentan concentrations and that inhibition of hepatocellular uptake offers an attractive mechanistic alternative also in human.Bosentan (Tracleer) is a dual endothelin receptor antagonist (Clozel et al., 1994;Neidhart et al., 1996) approved as the first oral treatment for pulmonary arterial hypertension (Rubin et al., 2002). During the clinical development of bosentan, the potential interaction between bosentan (500 mg b.i.d.) with the immunosuppressant cyclosporin A (300 mg b.i.d.) has been investigated in healthy male volunteers. After the 1st day of concomitant dosing, a 30-fold increase of bosentan trough plasma concentrations was observed compared with volunteers receiving bosentan alone. In humans, bosentan is extensively metabolized by the cytochrome P450 isoforms 2C9 and 3A4 before excretion into bile, the latter process accounting for more than 90% of total drug elimination. Cyclosporin A is a known inhibitor of CYP3A4 (Wacher et al., 1998) and the observed pharmacokinetic interaction was initially assigned to the inhibition of CYP3A4-mediated clearance in the liver. However, in another interaction study with the potent CYP3A4 inhibit...

The endothelin (ET) system has emerged as a novel target for hypertension treatment where a medical need persists despite availability of several pharmacological classes, including renin angiotensin system (RAS) blockers. ET receptor antagonism has demonstrated efficacy in preclinical models of hypertension, especially under low-renin conditions and in hypertensive patients. We investigated the pharmacology of aprocitentan (N-[5-(4bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4pyrimidinyl]-sulfamide), a potent dual ET A /ET B receptor antagonist, on blood pressure (BP) in two models of experimental hypertension: deoxycorticosterone acetate (DOCA)-salt rats (lowrenin model) and spontaneously hypertensive rats [(SHR), normal renin model]. We also compared the effect of its combination with RAS blockers (valsartan and enalapril) with that of the combination of the mineraloreceptor antagonist spironolactone with the same RAS blockers on BP and renal function in hypertensive rats. Aprocitentan was more potent and efficacious in lowering BP in conscious DOCA-salt rats than in SHRs. In DOCA-salt rats, single oral doses of aprocitentan induced a dose-dependent and long-lasting BP decrease and 4-week administration of aprocitentan dose dependently decreased BP (statistically significant) and renal vascular resistance, and reduced left ventricle hypertrophy (nonsignificant). Aprocitentan was synergistic with valsartan and enalapril in decreasing BP in DOCA-salt rats and SHRs while spironolactone demonstrated additive effects with these RAS blockers. In hypertensive rats under sodium restriction and enalapril, addition of aprocitentan further decreased BP without causing renal impairment, in contrast to spironolactone. In conclusion, ET A /ET B receptor antagonism represents a promising therapeutic approach to hypertension, especially with low-renin characteristics, and could be used in combination with RAS blockers, without increasing the risk of renal impairment.

Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.

Treatment of pulmonary arterial hypertension with the endothelin receptor antagonist bosentan has been associated with transient increases in liver transaminases. Mechanistically, bosentan inhibits the bile salt export pump (BSEP) leading to an intrahepatic accumulation of cytotoxic bile salts, which eventually results in hepatocellular damage. BSEP inhibition by bosentan is amplified by its accumulation in the liver as bosentan is a substrate of organic anion-transporting polypeptide (OATP) transport proteins. The novel endothelin receptor antagonist macitentan shows a superior liver safety profile. Introduction of the less acidic sulfamide moiety and increased lipophilicity yield a hepatic disposition profile different from other endothelin receptor antagonists. Passive diffusion rather than OATP-mediated uptake is the driving force for macitentan uptake into the liver. Interaction with the sodium taurocholate cotransporting polypeptide and BSEP transport proteins involved in hepatic bile salt homeostasis is therefore limited due to the low intrahepatic drug concentrations. Evidence for this conclusion is provided by in vitro experiments in drug transporter-expressing cell lines, acute and long-term studies in rats and dogs, absence of plasma bile salt changes in healthy human volunteers after multiple dosing, and finally the liver safety profile of macitentan in the completed phase III morbidity/mortality SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) trial.

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The increasing spread of drug-resistant malaria strains underscores the need for new antimalarial agents with novel modes of action (MOAs). Here, we describe a compound representative of a new class of antimalarials. This molecule, ACT-213615, potently inhibits in vitro erythrocytic growth of all tested Plasmodium falciparum strains, irrespective of their drug resistance properties, with half-maximal inhibitory concentration (IC(50)) values in the low single-digit nanomolar range. Like the clinically used artemisinins, the compound equally and very rapidly affects all 3 asexual erythrocytic parasite stages. In contrast, microarray studies suggest that the MOA of ACT-213615 is different from that of the artemisinins and other known antimalarials. ACT-213615 is orally bioavailable in mice, exhibits activity in the murine Plasmodium berghei model and efficacy comparable to that of the reference drug chloroquine in the recently established P. falciparum SCID mouse model. ACT-213615 represents a new class of potent antimalarials that merits further investigation for its clinical potential.

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