Enrico Strocchi

Thromboxane antagonism and cough induced by angiotensin- converting-enzyme inhibitor

BACKGROUND The increased prostaglandin synthesis that might follow stimulation of the arachidonic acid cascade by angiotensin-converting-enzyme inhibition (ACE-I) has been suggested to underlie the appearance of cough on ACE-I treatment. We investigated whether the prostanoid thromboxane was involved. METHODS Nine patients with essential hypertension who had cough after enalapril 20 mg once a day (coughers) were treated, while continuing the enalapril, in a double-blind crossover study with placebo or picotamide, 600 mg twice daily. Picotamide is a platelet antiaggregant that acts through both inhibition of thromboxane synthase and thromboxane-receptor antagonism. Thirteen hypertensive patients with no history of ACE-I-induced cough were also treated with enalapril and served as controls. Cough frequency was measured by a visual analogue scale and by a daily cough diary. 24 h urinary recovery of 11-dehydro-thromboxane-B2 and 6-keto-PGF1 alpha were measured to assess any changes in endoperoxide metabolism during the study periods. FINDINGS 11-dehydro-thromboxane-B2 (TXB2) recovery was significantly reduced by picotamide, which led to the disappearance of cough in eight patients within 72 h. Picotamide urinary recovery data suggested incomplete absorption in the non-responder. At baseline and after rechallenge with enalapril, 11-dehydro-TXB2 excretion was in the same range in the controls and in the coughers, but the latter showed significantly lower excretion of 6-keto-PGF1 alpha, and their ratio of 11-dehydroTXB2 to 6-keto-PGF1 alpha was twice that of the controls (1.40 [95% CI 0.86-1.95] vs 0.61 [0.37-0.84]). INTERPRETATION A thromboxane antagonist is effective in ACE-I-induced cough. An imbalance between thromboxane and prostacyclin may represent a marker of patients susceptible to ACE-I-induced cough.

Lactotripeptides effect on office and 24-h ambulatory blood pressure, blood pressure stress response, pulse wave velocity and cardiac output in patients with high-normal blood pressure or first-degree hypertension: a randomized double-blind clinical trial

Contrasting data partially support a certain antihypertensive efficacy of lactotripeptides (LTPs) derived from enzymatic treatment of casein hydrolysate. Our aim was to evaluate this effect on a large number of hemodynamic parameters. We conducted a prospective double-blind randomized clinical trial, which included 52 patients affected by high-normal blood pressure (BP) or first-degree hypertension. We investigated the effect of a 6-week treatment with the LTPs isoleucine–proline–proline and valine–proline–proline at 3 mg per day, assumed to be functional food, on office BP, 24-h ambulatory BP monitoring (ABPM) values, stress-induced BP increase and cardiac output-related parameters. In the LTP-treated subjects, we observed a significant reduction in office systolic BP (SBP; −5±8 mm Hg, P=0.013) and a significant improvement in pulse wave velocity (PWV; −0.66±0.81 m s−1, P=0.001; an instrumental biomarker of vascular rigidity). No effect on 24-h ABPM parameters and BP reaction to stress was observed from treatment with the combined LTPs. LTPs, but not placebo, were associated with a mild but significant change in the stroke volume (SV), SV index (markers of cardiac flow), the acceleration index (ACI) and velocity index (VI) (markers of cardiac contractility). No effect was observed on parameters related to fluid dynamics or vascular resistance. LTPs positively influenced the office SBP, PWV, SV, SV index, ACI and VI in patients with high-normal BP or first-degree hypertension.

Minimal effective concentration values of propafenone and 5-hydroxy-propafenone in acute and chronic therapy

SummaryWe evaluated the antiarrhythmic efficacy and the minimal effective concentrations of propafenone and its metabolite 5-hydroxy-propafenone during a) acute intravenous infusion (1.5 mg/kg in bolus followed by 45 minutes infusion), b) an acute oral single-dose test (450 mg), and c) 14-day chronic therapy (300 mg tid) followed by a washout. Oxidative metabolism was assessed by a debrisoquine oral test in every patient. Eleven patients with stable ventricular premature beats (VPBs)≥300/hr and Lown class ≥ 3 completed the study. The main results emphasized a certain discrepancy between the clinical effect of the acute intravenous infusion (efficacy in 5 out of 11 patients) and of the acute oral test and chronic therapy (efficacy in 11/11), with a time lag of the ECG changes during the acute intravenous infusion. The minimal effective concentrations were lower after acute oral administration compared with chronic treatment both for propafenone (200±189 ng/ml vs. 492±530 ng/ml; p<0.05) and for 5-hydroxy-propafenone (82±40 ng/ml vs. 149±80 ng/ml; p<0.02). A linear correlation was demonstrated between drug/metabolite ratios of propafenone and debrisoquine, either after acute oral (r=0.91) or after chronic administration (r=0.84). The pharmacokinetics of propafenone was nonlinear and showed wide interindividual variations. In conclusion, a) the lower efficacy and delayed electrophysiologic effects of propafenone after intravenous administration suggest that longer infusion times are necessary for complete antiarrhythmic efficacy; b) the differences observed in the minimal effective concentrations of acute versus chronic oral therapy suggest the development of partial tolerance to propafenone during chronic treatment.

The incidence of cough during treatment with angiotensin converting enzyme inhibitors.

The incidence of cough during treatment with angiotensin converting enzyme (ACE) inhibitors was studied using retrospective analysis of outpatient records and a questionnaire; for a more precise evaluation, all reported cases of cough were reviewed according to criteria for the operational assessment of side effects, and those found unrelated were excluded. Cough during treatment with ACE inhibitors appears to be more frequent than previously recorded and substantial differences between patients treated with captopril or enalapril seem unlikely.

Cough during Treatment with Angiotensin Converting Enzyme Inhibitors

SummaryThe role of age, gender, smoking habits and concomitant drug treatment, and type and dose of angiotensin converting enzyme (ACE) inhibitor as prognostic factors for the development of cough during ACE inhibition was investigated in a group of 1591 patients. In 117 of these patients cough was identified as drug related. Logistic regression confirmed that females, nonsmokers and patients treated with enalapril are at greater risk of developing cough. On the other hand, our data provided no evidence for a prognostic role of higher doses of the ACE inhibitor or of concomitant drug treatment; in particular, the use of β-adrenoceptor antagonists was not associated with a higher incidence of cough.

Hemodynamic Effects of Lactotripeptides from Casein Hydrolysate in Mediterranean Normotensive Subjects and Patients with High-Normal Blood Pressure: A Randomized, Double-Blind, Crossover Clinical Trial

Contrasting data partially support a certain antihypertensive efficacy of lactotripeptides derived from enzymatic treatment of casein hydrolysate. We carried out a randomized, double-blind, crossover clinical study to investigate the antihypertensive efficacy of a short-term treatment with lactotripeptides in Mediterranean subjects with normal or high-normal blood pressure (BP). We consecutively enrolled 55 untreated subjects (men:women = 30:25), 40.3 ± 9.8 years old, with normal or high-normal BP. After 4 weeks of dietary standardization, they were allocated to treatment with a fruit juice containing 3 mg of added Ile-Pro-Pro/Val-Pro-Pro lactotripeptides or with placebo for 4 weeks. After a 4-week washout period, they were then assigned to the alternative treatment for a further period of 4 weeks. Overall, no significant difference has been observed in office BP comparing baseline data with those posttreatment. Repeating the analysis by basal BP level, a mild but significant reduction in systolic BP (-1.7 ± 2.3 mm Hg; t = 3.5, P = .002) has been observed only in subjects with high-normal BP after treatment with lactotripeptides. With regard to 24-hour BP measurement, after lactotripeptide treatment only, the subjects experienced a significant reduction in diurnal diastolic BP (-1.6 ± 5.4 mm Hg; P = .042), diurnal mean BP (-2.1 ± 5.9 mm Hg; P = .19), and 24-hour (-5.4 ± 14.2 mm Hg; P = .011) and diurnal (-7.1 ± 19.2%; P = .014) diastolic BP value measurements relative to normal values. No modification has been observed in relation to plasma renin activity and aldosteronemia. In conclusion, diurnal diastolic BP is significantly reduced by lactrotripeptide supplementation in untreated Mediterranean subjects with normal or high-normal BP. Office systolic BP is reduced only in subjects with high-normal BP.

Persistence on Treatment and Blood Pressure Control with Different First-Line Antihypertensive Treatments: A Prospective Evaluation

We enrolled 347 hypertensive patients, randomly allocated them to different first-line treatments, and followed-up for 24 months. Persistence on treatment was significantly higher in patients treated with ARBs (68.5%) and ACE inhibitors (64.5%) vs. CCBs (51.6%), β-blockers (44.8%), and diuretics (34.4%). No ARB, ACE inhibitor, β-blocker, or diuretic was associated with a greater persistence in therapy as compared with the other molecules used in each therapeutic class. The rate of persistence was significantly higher in patients treated with lercanidipine vs. other CCBs (59.3% vs. 46.6%). Systolic and diastolic BP decreased more in patients treated with ARBs (-11.2/-5.8 mmHg), ACE inhibitors (-10.5/-5.1 mmHg), and CCBs (-8.5/-4.6 mmHg) when compared to ß-blockers (-4.0/-2.3 mmHg) and diuretics (-2.3/-2.1 mmHg).

Comparison of Two Automatic Devices and the Standard Mercury Sphygmomanometer in Hypertensive Patients

The standard mercury sphygmomanometer (SMS) and two automatic blood pressure recording devices, Dinamap 845 (D) and Sentron (S), were compared by means of a randomized 3-period cross-over experiment. Both devices recorded diastolic BP lower than SMS, on average and for most individual patients. Systolic BP was similar for SMS and S, and slightly lower for D, with variations for individual patients. A second study failed to detect effects of the physicians presence when BP was measured, whereas the difference between D and SMS was substantially confirmed.

Heterogeneity of the erythrocyte Na-K pump status in human obesity

The number of Na-K pump units, the Na-K-ATPase activity, the K transport turnover rate per pump unit and the intracellular Na and K concentrations were measured in the erythrocytes of 56 obese patients and 20 normal subjects. No differences were found between the two groups. In obese patients, we failed to observe any influence of dietary habits, age of onset, or family history of obesity on the Na pump status. On the other hand, we found that the number of pump units was not a close reflection of the membrane cation transport and in some patients with an abnormally high number of pump units, an inappropriately low Na-K-ATPase activity was observed. We also identified two small groups of obese patients with, respectively, abnormally high or low K transport turnover rate per pump unit. Our study seems to support the hypothesis that abnormalities in the erythrocyte Na-K pump system are not usual in the obese population but are probably present only in a limited number of selected patients.

Short- and Long-Term Stroke Risk after Urgent Management of Transient Ischaemic Attack: The Bologna TIA Clinical Pathway

Background: Rapid management can reduce the short stroke risk after transient ischaemic attack (TIA), but the long-term effect is still little known. We evaluated 3-year vascular outcomes in patients with TIA after urgent care. Methods: We prospectively enrolled all consecutive patients with TIA diagnosed by a vascular neurologist and referred to our emergency department (ED). Expedited assessment and best secondary prevention was within 24 h. Endpoints were stroke within 90 days, and stroke, myocardial infarction, and vascular death at 12, 24 and 36 months. Results: Between August 2010 and July 2013, we evaluated 686 patients with suspected TIA; 433 (63%) patients had confirmed TIA. Stroke at 90 days was 2.07% (95% confidence interval (CI), 1.1-3.9) compared with the ABCD2-predicted risk of 9.1%. The long-term stroke risk was 2.6% (95% CI, 1.1-4.2), 3.7% (95% CI, 1.6-5.9) and 4.4% (95% CI, 1.9-6.8) at 12, 24 and 36 months, respectively. The composite outcome of stroke, myocardial infarction, and vascular death was 3.5% (95% CI, 1.7-5.1), 4.9% (95% CI, 2.5-7.4), and 5.6% (95% CI, 2.8-8.3) at 12, 24, and 36 months, respectively. Conclusions: TIA expedited management driven by vascular neurologists was associated with a marked reduction in the expected early stroke risk and low long-term risk of stroke and other vascular events.