Pharmacodynamics. In a series of in-vitro experiments, inflammatory challenges were performed on pbmCs and hirudinized whole blood from 4 healthy volunteers (who did not participate in the Phase 1 clinical trial). We assessed the effect of Cnm-au8 on in vitro toll-like receptor -9 (tlr9)-mediated cytokine release after stimulation with well-characterized tlr9 agonists. pbmCs and whole blood samples were incubated with a concentration range of Cnm-au8 for 6 to 24 hours. Subsequently, tlr9 ligands CpG (Cytosine phosphodiester and Guanine 58 measuring pharmacodynamics in early clinical drug studies in multiple sclerosis Chapter iv – gold nanopartiCles pharmaCokinetiCs in healthy volunteers 59 triphosphate) or ss-dna/lyovec were added to the culture, for an additional 3 to 24 hours. The response was quantified by measurement of cytokine release in culture supernatant (pan ifnα, il- 6, il-1β, tnfα). This in vitro study was performed to explore whether Cnm- au8 exerts anti-inflammatory effects. In that case, the tlr9 challenge would have been included as pharmacodynamic assay in the mad part of the clinical study. Statistics All pk parameters were calculated using non-compartmental analysis.Whole blood con- centrations below lloq were taken as 0 for the calculation of the descriptive statistics for whole blood gold concentrations at each sampling time. All pharmacokinetic calculations were done and individual subject whole blood concentration-time graphs were prepared using sas® for Windows® Version 9.4. Individual pharmacokinetic parameters for Cnm-au8 were summarized with descrip- tive statistics. Pharmacokinetic parameters such as the maximum observed plasma con- centration (Cmax), time to Cmax (tmax), the area under the plasma concentration versus time from time 0 to time of measurable plasma concentration after 24 hours (auC0-24h) and terminal-phase half-life (t½) were calculated using non-compartmental analyses and pharmacokinetic modelling. results The study was performed between April 2015 and October 2016. Cohort 1 (single dose of 15 mg) was repeated due to a new batch of Cnm-au8 during the study. Demographics A total of 86 subjects participated in the phase 1 study of which 83 completed the study. Due to circumstances for cohort 5 (multiple dose, 15 mg) 10 subjects were enrolled (instead of the planned 12 subjects). Three subjects discontinued the study after dosing: one sub- ject retracted consent during the follow-up phase of the mad study, one subject of a mad cohort...
Pharmacodynamics. Levosimendan produces significant, dose-dependent increases in cardiac output, stroke volume and heart rate, and decreases in pulmonary capillary wedge pressure, mean blood pressure, mean pulmonary artery pressure, mean right atrial pressure and total peripheral resistance.30 The effect of levosimendan on hemodynamic variables was clearly evident already at the end of a 5-min bolus infusion.31 There is no sign of development of tolerance even with a prolonged infusion up to 48 hours.32 Due to the formation of the active metabolite, the hemodynamic effects are maintained several days after stopping levosimendan infusion.33 Compared with dobutamine, levosimendan produces a slightly greater increase in cardiac output and a profoundly greater decrease in pulmonary capillary wedge pressure.34, 35 In contrast to dobutamine, the hemodynamic effects are not attenuated with concomitant beta-blocker use.35 It has also been shown that at 48 hours after the start of infusion, a 24-hour infusion achieves superior hemodynamic effects over a 48-hour dobutamine infusion in patients with severe acute decompensated heart failure on beta-blockers.34 Several studies indicate that levosimendan produces a rapid and sustained decrease in natriuretic peptides. Xxxxxxxxx et al.33 found that a 24-hour levosimendan infusion induced a 40% decrease in plasma N-terminal atrial natriuretic peptide (NT-proANP) and N-terminal pro-BNP (NT-proBNP) levels and the treatment effect was estimated to last up to 16 and 12 days, respectively. The beneficial effects of levosimendan on hemodynamics and neurohormones are not associated with any significant increase in myocardial energy consumption, as evidenced using dynamic positron emission tomography (PET) in hospitalized patients with NYHA III-IV heart failure.36 Similarly, bolus doses of 8 µg/kg or 24 µg/kg did not increase myocardial oxygen consumption in postoperative patients, although cardiac function markedly improved.37 Levosimendan also possesses anti-stunning effects. This was shown in 24 patients with an acute myocardial infarction (AMI) who had undergone percutaneous transluminal coronary angioplasty (PTCA).38 A bolus dose of levosimendan improved the function of stunned myocardium, as evidenced by a substantial reduction in the number of hypokinetic segments in the left ventricular wall compared to placebo.
Pharmacodynamics. Sulglicotide is a sulphated glycopeptide chemically related to glycoproteins present in the gastric juice, accountable for the defense of the gastro-duodenal mucosa. Three hypotesis of mechanism of action: X cytoprotective action at gastro-duodenal level through increased biosynthesis of prostaglandins; X antagonism to gastric hyper-secretion, induced by most common mediators; X anti-peptic action by combination with pepsin and formation of a less active complex.
