Search

Levosimendan is a calcium-sensitizing drug with positive inotropic properties. As an inodilator, this molecule also has a vasodilation effect. While its efficacy has been demonstrated in the adult in the context of cardiac surgery, its pediatric use is still not widespread. Many studies have shown its safety of use in children, including in the newborn. Across the world, a growing number of teams use levosimendan to treat both acute and chronic heart failure. Through a review of the literature, we describe its pharmacodynamic effects, its current applications, and its perspectives of use in children., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Levosimendan is the first available drug of a new class of agents called calcium sensitizers. It increases cardiac contractility without increasing myocardial oxygen consumption. This new molecule has no proarrhythmic effects and has anti-ischemic properties. Levosimendan is infused over a 24-hour period and its hemodynamic effects, similar or superior to those of catecholamines, persist during one week. In a selected group of advanced heart failure patients levosimendan was associated with a mortality reduction at 14 days and at 6 months in comparison with dobutamine. In spite of its cost, this new inotropic agent appears very promising and it is expected that it will be widely used.

The results of several large therapeutic cardiovascular trials were reported in 2002. The LIFE study concluded that losartan is superior compared to atenolol in terms of prevention of cardiovascular morbidity and mortality, the benefit being for CVA without changing the incidence of myocardial infarction. The OPTIMAAL study stated the disappointing results of post-infarct losartan. The IONA study represents a first demonstration with nicorandil of benefit not only in angina crises but equally on cardiac morbidity and mortality. The HPS study confirms the benefit of a statin in secondary prevention but for the first time, no matter what the initial level of LDL-cholesterol. Finally in the LIPS study, it is reported that statins reduce major cardiovascular events after coronary angioplasty. The year 2002 was marked elsewhere by imagination after the publication of the RAVEL study on coated stents delivering anti-proliferative drugs in order to avoid coronary restenosis. Three drugs were the subject of work confirming their potential significance in cardiovascular pathology: a) ezetimibe, representing a new class of cholesterol lowering drugs with which the association with statins seems especially synergic, b) nesiritide recombinant type B natriuretic peptide, whose significance was confirmed in acute cardiac insufficiency. c) levosimendan (calcium sensitisor) which moreover can be a significant treatment in cardiac decompensation as suggested by the LIDO study with a follow up of 180 days. By contrast, omapatrilate did not confirm its potential superiority over ACE inhibitors in the treatment of cardiac insufficiency. Some encouraging data were reported in 2002 in the field of therapeutic angiogenesis as much at the myocardial level as in lower limb arteritis. Finally, 2002 was marked by the publication of the WHI study which intensified suspicions regarding hormonal substitution treatment, confirming the advantage of not only secondary but perhaps primary cardiovascular prevention.

Continuing the investigations concerning synthesis-structure-biological activity in the pyridazine series, the results of the antimicrobial and antifungal tests of some new pyridazinium compounds are presented. The test was performed using the diffusimetric method with rustles steel cylinders based on the diffusion of the tested substances on the gelose surface. The comparative analysis of the obtained data leads to the following conclusions concerning the relation between structure and activity in the pyridazine series: 1. The cis-isomers are always more active comparatively with similar trans- isomers: 2. In the pyrrolopyridazine series we remark that the saturated or partial saturated compounds have always a stronger activity as the related aromatics derivatives. We also noticed that the saturated, partial saturated and aromatic compounds have different selectivity. Thus, the saturated are more active on the Pseudomonas aeruginosa and Candida albicans, the partial saturated are more active on the Staphylococcus aureus and Bacillus subtilis while the aromatic compounds are active on the Bacillus subtilis. 3. The influence of the Y-substitutes of para position of benzoylic radical and the substitutes of pyrrolo ring is not decisive towards activity, these affecting especially the selectivity.

Continuing the investigations in view obtaining new carbon-nitrogen stable dissiniu-ilydes, were obtained new 3-phenyle-pyridaziniu-ylides carbanion disubstituted. The antimicrobial and antifungus action of the products VIa, VIb, VIIa, VIIb and VIIc also studied.

The action of a phosphodiesterase inhibitor, RGW 29 38, was analysed experimentally. A preliminary study with guinea pig isolated heart, using Langhendorf's method, revealed a cardiotonic effect, though less than with isoprenaline and dobutamine, with which it was compared. The inotropic action of the compound was then studied using human isolated atrium. The model is described. It consisted of measurement by a strain gauge of the contractions obtained in a stimulated atrial fragment obtained during a surgical procedure. The following parameters were analysed, expressed as percentage increase in relation to baseline conditions: maximum tension developed, positive dP/dt and negative dP/dt. The effect of RGW (n = 6) was compared with that of isoprenaline (n = 7). RGW caused an increase in maximum tension of 195% +/- 91%, in positive dp/dt of 110% +/- 72% and in negative dp/dt of 168 +/- 54%. This increase was, however, less than that seen in the isoprenaline group. Thus RGW had a definite positive inotropic effect on guinea pig isolated heart and human isolated atrium, though less than that of the catecholamines with which it was compared. Isolated human atrium appears to be a useful study model, in particular for analysis of the inotropic action of drugs.

It has been possible to prepare from 4,6-diaryl pyridazinones a series of derivatives substituted in the 2-position by chains of various lengths bearing a carboxylic acid function. Pig lens aldose reductase inhibitory activity was evaluated for all compounds. N-acetic acid derivative 3c with a chlorine atom on the phenyl nucleus at the 6-position on the pyridazin ring was the most active pyridazinone with an IC50 value of 1.2 x 10(-5) M. Furthermore, it has been shown that lipophilicity and spatial configuration of the synthesized compounds took a prominent part on enzymatic activity.

Cadralazine is a new antihypertensive drug, acting as a peripheral arteriolar vasodilator through its hydrazinopyridazine metabolite. Since this metabolite actively contributes to the activity of the drug, we administered in a double blind randomized study 10 mg/placebo o.d. to 6 healthy fast and 6 slow normotensive acetylators in order to investigate the influence of the acetylator status on hemodynamics and pharmacokinetics. Blood pressure was measured with a DINAMAP apparatus, forearm hemodynamics with a pulsed doppler and central hemodynamics with impedance-cardiography; active renin (RIA), cadralazine and its metabolite (HPLC) were measured during the 11 measurement points. The results were analysed with repeated analysis of variance (ANOVA). Heart rate significantly increased (p less than 0.001), until the 24th hour (p less than 0.05), meanwhile blood pressure and forearm hemodynamics did not change. Cardiac output was increased as a consequence of the elevation in venous return. The rise in active renin paralleled the increase in heart rate with a significant correlation (r' = 0.580, p less than 0.05). The magnitude of the increase was higher in slow than that in fast acetylators, but did no reached the significance. No differences were found for AUC, Cmax and Tmax between the two groups but the active metabolite was eliminated slower than that of cadralazine. The time course of the effects on heart rate and plasma renin was not parallel to the plasma levels of cadralazine and its metabolite. With respect to the power of the study (1-beta = 80 p. 100), no significant differences were found between the two groups.

By addition of methylisocyanate to 5-arylidene 2-aminoalkyl 3-pyridazinones a series of derivatives substituted in the 2-position by an ureidoalkyl moiety was obtained in good yields. Gastric antisecretory and anti-ulcer activities of these new compounds were evaluated. The influence of the substituents attached to the pyridazine ring was discussed.

Minaprine (MIN) is a 3-amino-pyridazine derivative which exhibits a profile of psychotropic activities which resembles that of antidepressant drugs as well as that of several dopaminomimetic drugs. This spectrum of activity differs from those observed in the same conditions for tricyclic (imipramine, clomipramine) and atypical (indalpine, nomifensine, amineptine, mianserin) antidepressant drugs. It must be noted that MIN is devoid of anticholinergic and motor stimulant effects. In addition, MIN induces behavioural effects predictive of a dopaminergic stimulation; the profile of this activity differs from that of apomorphine, as well as from those of amphetamine and nomifensine, but somewhat resembles that of bromocryptine. MIN does not induce neuroleptic, anxiolytic or anticonvulsant activities in rodents. These data suggest that MIN is an atypical antidepressant drug which activates both serotonergic and dopaminergic neurotransmissions, by as yet not clearly identified mechanisms.

Using pulsed Doppler methods, hemodynamics of the common carotid and the brachial arteries were measured in 10 patients with essential hypertension. After vasodilatation due to Cadralazine, a Dihydralazine-like substance, mean arterial pressure significantly decreased and heart rate increased. Change in PRA was significantly and positively correlated with the change in heart rate. In the brachial artery circulation, diameter and vascular resistance decreased while blood flow velocity and volumic blood flow did not increase significantly. In the common carotid artery circulation, diameter, mean blood flow did not change. However, vascular resistance and tangential tension decreased slightly. The increase in heart rate was strongly and negatively correlated (r = 0.82 p less than 0.01) with the change in the carotid artery tangential tension (measured as the product between mean arterial pressure and arterial radius) while no comparable correlation was observed with the change in blood pressure or arterial radius alone. The study suggested that in essential hypertensives, modifications in the carotid artery tangential tension secondary to arteriolar vasodilatation contribute actively to the baroreflex response.

It has been possible to prepare from 4,6-diaryl pyridazinones a series of derivatives substituted in the 2-position and having urea moiety via the addition of free amines into methylisocyanate. Their gastric anti-secretory and anti-ulcer activities were evaluated. The compounds with an N-2 ethyl chain on the pyridazinone ring (IVa, IVd, IVg) were the most active derivatives.

Cyclization reaction of hydrazine with carbazole-2,3-methyl dicarboxylates gave 1,4-dioxo-1,2,3,4-tetrahydropyridazino[4,5-b]carbazoles. Chlorodehydroxylation provided 1,4-dichloropyridazino[4,5-b]carbazoles and nucleophilic substitution gave 1,4-dialkoxy pyridazino[4,5-b]carbazoles. These compounds were tested for cytotoxic activity against L1210 leukemia in mice.

The reaction of 3-chloro pyridazines with various amines led to a series of minaprine analogues. Most of them exhibited significant antidepressant activity. The influence of the substituents attached to the pyridazine ring was discussed.

The clinical and haemodynamic effects of a single oral dose of cadralazine were studied in 22 patients with an average age of 64 years presenting with severe chronic cardiac failure. Haemodynamic monitoring during the first 24 hours after oral administration of 30 mg of cadralazine showed a peak increase at the 8th hour of the cardiac index (+ 64 p. 100, p less than 0.001), the systolic index (+ 45 p. 100, p less than 0.001) and the left ventricular work (+ 52 p. 100, p less than 0.001) whilst the systemic and pulmonary arterial resistances decreased by 40 p. 100 (p less than 0.0001) and 30 p. 100 (p less than 0.01) respectively. There was no significant change in heart rate or diastolic pulmonary arterial pressures. The haemodynamic improvement was maintained at the 24th hour (cardiac index + 35 p. 100, p less than 0.01 and systemic arterial resistances - 20 p. 100). These results were confirmed at one month. There were few side effects, none of which necessitated withdrawal of the drug. This study shows the efficacy of a single 30 mg daily dose of cadralazine, an arterial vasodilator, in patients with severe cardiac failure. The treatment was well tolerated over the one month study period.