1. Intravenous ACE inhibitor therapy appears to have a role in the treatment of acute heart failure and early after myocardial infarction. Practical experience with intravenous administration with activation of renin is limited. We report responses to perindoprilat (Pt, 0.67 mg) or placebo (P) infused over 4 h in normotensive male volunteers (n = 12, 19-28 years, 53-77 kg) with double-blind, placebo controlled salt depletion (SD) or salt repletion (SR) as a model of the activated renin system. 2. Salt depletion caused no significant fall in serum sodium (P, 139.4 +/- 2.4; Pt, 138.3 +/- 1.9) compared with salt replete preparation (P, 139.9 +/- 1.2; Pt, 139.7 +/- 0.9) but elevation of plasma renin activity 2-3-fold. Pretreatment baseline systolic blood pressure following salt depletion (P, 121 +/- 9.3/71 +/- 7.9; Pt, 121.5 +/- 9.6/69 +/- 8.1) was higher than following salt replete preparation (P, 114 +/- 9.5/61 +/- 7.2; Pt, 116.9 +/- 6.9/67 +/- 7.2). 3. Baseline corrected supine SBP fell significantly and to a similar extent following active treatment regardless of activation of the renin system (SD, -14.6 +/- 9.5/-9.4 +/- 6.4; SR, -12 +/- 14/-10.1 +/- 6.6) compared with placebo (SD, -6.1 +/- 6/-3.7 +/- 5.6; SR, -4.7 +/- 10/-1.3 +/- 6.5). Heart rate was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

/pdf/responses-to-low-dose-intravenous-perindoprilat-infusion-in-tjgh6w54gg.pdf

Responses to low dose intravenous perindoprilat infusion in salt deplete/salt replete normotensive volunteers.

The studies described in this thesis investigated the haemodynamic response to initiation of therapy with a number of angiotensin converting enzyme inhibitor agents in patients with heart failure. The studies were designed to: (i) define differences among agents in terms of the haemodynamic response to initiation of therapy (ii) investigate possible mechanisms for observed differences among agents in this regard (iii) investigate the relationship between plasma concentration of ACE inhibitor agent and the blood pressure response, and (iv) investigate the relationship between baseline clinical and physiological variables and the blood pressure response. Differences were observed among ACE inhibitor agents in terms of the blood pressure response to initiation of therapy. While similar blood pressure responses were observed to single oral doses of the ester prodrug ACE inhibitors enalapril and quinapril, the blood pressure response to oral perindopril did not differ from that seen with placebo. Two possible mechanisms, steric hindrance and "slow, tight binding", for the observed differences were explored using assay of both plasma ACE inhibition and relative concentrations of angiotensin I and angiotensin II. No evidence for either mechanism was gained from these studies. Using pharmacodynamic/pharmacokinetic modelling a direct linear relationship between the pharmacodynamic effect and plasma drug concentration was derived. Marked interindividual variability was apparent in the blood pressure response to oral initiation of ACE inhibitor therapy. The blood response was more consistent when interindividual pharmacokinetic differences were minimised by intravenous dosing. No consistent relationship could be identified between any single baseline physiological variable and the blood pressure response. The strongest relationship was with baseline mean arterial blood pressure. Forward stepwise regression analysis was used to identify the best combinations of predictive variables. The best of these, containing the variables, mean arterial pressure, plasma renin activity, 1/creatinine concentration, age and the ACE inhibitor agent, could explain approximately 25% of the variability in blood pressure response. In conclusion, differences in the individual blood pressure responses to initiation of ACE inhibitor therapy in CHF appear to be largely dependent upon interindividual pharmacokinetic differences. Accurate prediction of the blood pressure response to initiation of therapy is not possible using readily available laboratory and clinical criteria.

The haemodynamic and neurohormonal response to initiation of angiotensin converting enzyme inhibitor therapy in heart failure

1. The transpulmonary pharmacokinetics of the intravenous diacid ACE inhibitor perindoprilat were studied in 10 male patients undergoing diagnostic cardiac catheterisation for the management of ischaemic heart disease. 2. Following successful completion of diagnostic cardiac catheterisation and ventriculography, subjects received a low dose (1 mg) constant rate infusion of perindoprilat over 20 min with co-infusion of the intravenous marker dye indocyanine green (0.5 mg kg-1). Simultaneous transpulmonary blood sampling was conducted for 1 h and subsequent peripheral venous blood samples were collected for 20 h. 3. No acute changes in blood pressure or heart rate were noted despite rapid and marked inhibition of central circulation plasma ACE activity persisting in peripheral venous blood for 20 h. A delayed rise in plasma renin activity was noted. 4. Transpulmonary passage during early accumulation of the drug was seen to incorporate an early delay. Concurrent ICG measurements suggested that this was entirely due to circulatory delay and not to binding of the drug. Thus, despite the suggested high concentration of tissue ACE activity in the pulmonary circulation, transpulmonary passage of perindoprilat was not measurably influenced by binding at this site under the conditions studied.

/pdf/transpulmonary-pharmacokinetics-of-an-ace-inhibitor-327xuvohl1.pdf

Transpulmonary pharmacokinetics of an ACE inhibitor (perindoprilat) in man.

1 Thetranspulmonary pharmacokinetics oftheintravenous diacid ACE inhibitor perindoprilat werestudied in10malepatients undergoing diagnostic cardiac catheterisation forthemanagementofischaemic heart disease. 2 Following successful completion ofdiagnostic cardiac catheterisation andventriculography, subjects received alowdose(1mg)constant rateinfusion ofperindoprilat over20minwithco-infusion oftheintravenous markerdyeindocyanine green(0.5 mg kg-1). Simultaneous transpulmonary bloodsampling was conducted for1hand subsequent peripheral venousbloodsamples were collected for20h. 3 Noacutechanges inblood pressureorheart rate werenoteddespite rapid andmarked inhibition ofcentral circulation plasma ACE activity persisting inperipheral venous blood for20h.A delayed rise inplasma renin activity was noted. 4 Transpulmonary passageduring early accumulation ofthedrug was seentoincorporate anearly delay. Concurrent ICGmeasurements suggested thatthis wasentirely dueto circulatory delay andnottobinding ofthedrug. Thus,despite thesuggested high concentration oftissue ACE activity inthepulmonary circulation, transpulmonary passageofperindoprilat was notmeasurably influenced bybinding atthis site under theconditions studied.

Transpulmonary pharmacokinetics ofanACE inhibitor (perindoprilat) inman

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Transpulmonary pharmacokinetics of an ACE inhibitor (perindoprilat) in man.

Transpulmonary pharmacokinetics ofanACE inhibitor (perindoprilat) inman