B. lanceolatus venom produced dose- and time-dependent edema in rat paws. This edema was not dependent on low molecular weight substances in the venom, but was partially dependent on a hemorrhagin and also involved the release of arachidonic acid metabolites, bradykinin, histamine and serotonin.
To investigate the carvedilol-mediated P-gp transporter inhibition on the pharmacokinetics (PK) of zamicastat and its metabolites, and to investigate the safety and tolerability of zamicastat, when administered alone and concomitantly with carvedilol.METHODS: Open-label, 2-periods, fixed-sequence study in 41 healthy subjects to assess the PK of single-dose of zamicastat 200 mg, when administered alone and concomitantly with carvedilol under fed conditions. In the first treatment period, subjects received a single oral dose of zamicastat 200 mg., In the second treatment period, after a washout period of at least 10 days, subjects received single oral daily doses of carvedilol for 6 days (12.5 mg on Day 1 and Day 2, 25 mg on Days 3 to 6). On Day 7, zamicastat 200 mg and carvedilol 25 mg were co-administered. Two-sided 90% confidence intervals (90%CIs) for the geometric mean ratio (GMR) of zamicastat C max , AUC 0-t and AUC 0-inf were calculated for the comparison between test treatment (zamicastat with carvedilol) and reference treatment (zamicastat alone). RESULTS:The GMR (90% CI) for C max , AUC 0-t , AUC 0-inf of zamicastat were 110% (100%-121%), 110% (105%-115%), and 110% (105%-115%) respectively. Median t max of zamicastat occurred at 4 hours for both treatment periods. Co-administration of carvedilol with zamicastat lowered the extent of exposure of the minor metabolites BIA 5-453 [AUC 0-t 78% (70%-86%)] and BIA 5-961 [AUC 0-t 64% (56%-73%)]. The rate of exposure of the minor metabolite BIA 5-961 was decreased in the presence of carvedilol [C max 79% (74%-85%)].No serious adverse events or adverse events (AEs) of severe intensity occurred during the study. Two subjects withdrew during treatment period 2, one subject due to AE "blood bilirubin increased" assessed as mild and not related to zamicastat, and the other subject withdrew consent before zamicastat intake.CONCLUSIONS: Co-administration of carvedilol, strong inhibitor of P-gp, had no substantial effect on the rate and extent of exposure of zamicastat and therefore it is expected that such interaction is devoid of therapeutic impact.CLINICAL IMPLICATIONS: P-glycoprotein (P-gp) is a clinically important efflux transporter extensively expressed in various tissues including the gastrointestinal tract, liver, kidney and brain, which has the potential to impact the oral bioavailability, tissue distribution, hepatic and renal elimination of substrates. Zamicastat is a reversible dopamine b-hydroxylase inhibitor, that modulate sympathetic nervous system by reducing norepinephrine biosynthesis in peripheral sympathetic nerves, which was granted Orphan Drug Designation by Food and Drug Administration for the treatment of Pulmonary Arterial Hypertension.
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