http://www.farm.ucl.ac.be/Full-texts-FARM/Lambert-2000-1.pdf

Rationale and applications of lipids as prodrug carriers.

Ranolazine is an inhibitor of the late sodium current and, via this mechanism, decreases sodium-dependent intracellular calcium overload during ischemia and reperfusion. Ranolazine reduces angina, but there is little information on its effects in acute myocardial infarction. The aim of this study was to test the effects of ranolazine on left ventricular (LV) function and myocardial infarct size after ischemia/reperfusion in rabbits. Ten minutes before coronary artery occlusion (CAO), anesthetized rabbits were assigned to vehicle (n=15) or ranolazine (2 mg/kg i.v. bolus plus 60 microg/kg/min i.v. infusion; n=15). Hearts received 60 min of CAO and 3 h of reperfusion. CAO caused LV dysfunction associated with necrosis. However, at the end of reperfusion, rabbits treated with ranolazine had better global LV ejection fraction (0.42+/-0.02 versus 0.33+/-0.02; p<0.007) and stroke volume (1.05+/-0.08 versus 0.78+/-0.07 ml; p<0.01) compared with vehicle. The fraction of the LV wall that was akinetic or dyskinetic was significantly less in the ranolazine group at 0.23+/-0.03 versus 0.34+/-0.03 in vehicle-treated group; p<0.02. The ischemic risk region was similar in both groups; however, infarct size was significantly smaller in the treated group (44+/-5 versus 57+/-4% vehicle; p<0.04). There were no significant differences among groups in heart rate, arterial pressure, LV end-diastolic pressure, or maximum-positive or -negative first time derivative of LV pressure (dP/dt). In conclusion, the results of this study show that ranolazine provides protection during acute myocardial infarction in this rabbit model of ischemia/reperfusion. Ranolazine treatment led to better ejection fraction, stroke volume and less wall motion abnormality after reperfusion, and less myocardial necrosis.

Improved Left Ventricular Function and Reduced Necrosis after Myocardial Ischemia/Reperfusion in Rabbits Treated with Ranolazine, an Inhibitor of the Late Sodium Channel

In the past, a prodrug design was used as a last option to improve bioavailability through controlling transport, distribution, metabolism, or other mechanisms. Prodrugs are currently used even in early stages of drug development, and a significant percentage of all drugs in the market are prodrugs. The focus of this article is lipidic prodrugs, a strategy whereby a lipid carrier is covalently bound to the drug moiety. The increased lipophilicity of the lipid-drug conjugate can improve the pharmacokinetic profile and provide meaningful advantages: increased absorption across biological barriers, prolonged circulation half-life, selective distribution profile (eg brain penetration), reduced hepatic first-pass metabolism, and overall enhanced bioavailability of the parent drug. Moreover, lipidic prodrugs may join the endogenous lipid trafficking pathways, thereby facilitate drug targeting, either by selective absorption pathway (eg lymphatic transport) or drug release at specific target site(s). The different lipid-drug conjugates (triglyceride-, fatty acids, phospholipid-, and steroid-based prodrugs), the physiological barriers that challenge the absorption of these conjugates, followed by their current utilization and potential clinical benefits are described and analyzed, and future opportunities this approach could provide are discussed. Altogether, lipidic prodrugs represent an exciting approach for improving different aspects of oral drug delivery/therapy and may provide solutions for various unmet needs; the use of this strategy is expected to grow.

Lipidic prodrug approach for improved oral drug delivery and therapy

Comprehensive 2-D GC (GC x GC) coupled with TOF MS or flame ionization detector (FID) was employed to characterize and quantify the chemical composition of volatile oil in the radixes of Panax ginseng C. A. Mey. (ginseng) at different ages. Thirty-six terpenoids were tentatively identified based on the MS library search and retention index in a ginseng sample at the age of 3 years. An obvious group-type separation was obtained in the GC x GC-TOF MS chromatogram. The data collected by GC x GC-FID were processed using a principal component analysis (PCA) method to classify the samples at different ages. The compounds responsible for the significant differentiation among samples were defined. It was found that the relative abundances of alpha-cadinol, alpha-bisabolol, thujopsene, and n-hexadecanoic acid significantly rise with the increase in age.

Determination of radix ginseng volatile oils at different ages by comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry.

Purpose: Ranolazine is a novel antianginal medication that acts by ameliorating disturbed sodium and calcium homeostasis. By preventing myocyte sodium and calcium overload, ranolazine also have potential beneficial effects on myocardial function. Experimental models support this concept, as do 2 small studies in human participants receiving ranolazine intravenously. We evaluated changes in parameters of left ventricular function in stable angina patients treated with oral ranolazine. Methods: Twenty-two participants were enrolled with Doppler echocardiography performed at baseline and a mean of 2 months after initiation of treatment. Results: Global left ventricular function, as assessed by the myocardial performance index, was significantly improved on drug therapy (P < .0001). This was due to improvement in both diastolic and systolic parameters. Of 21 patients, 17 reported less angina and 8 patients reported an increase in activity level. Conclusions: We report improved parameters of left ventricular f...

Improvement in Left Ventricular Systolic and Diastolic Performance During Ranolazine Treatment in Patients With Stable Angina

In order to choose a labelled fatty acid (FA) for the external study of myocardial metabolism, FAs that are different in chain length, saturation, nature and position of the radioactive label, are injected i.v. into mice. Myocardial and blood activities are measured at various times p.i . It appears that hexadecanoic and hexadecenoic acids, iodine labelled in omega position, have the highest maximal myocardial activity among all the FAs studied. Furthermore, the myocardial and blood time-activity course is similar for both FAs. As unsaturated FAs have apparently a higher myocardial fixation in man than the saturated ones, 123I 16 iodo-9 hexadecenoic acid has been selected and seems well suited for the study of myocardial metabolism.

Influence on the myocardial and blood activity course of the characteristics of the labelled fatty acid injected i.v. into mice

External counting, intracellular and subcellular distribution of (16123I) iodohexadecenoic acid are studied on isolated rat hearts perfused with or without glucose. The presence of an exogenous substrate reduces the fatty acid oxidation and induces an increase of total cardiac and organic fraction activities. In this fraction, activity is very low for free fatty acids, but high for triglycerides and especially for polar lipids. The presence of an exogenous substrate leads to a more active esterification of fatty acids. Coronary effluents analysis shows, in the hydrophilic phase, a lower activity rebound in the presence of glucose. In the mitochondrial fraction, activity is mostly in the organic phase, as polar lipids especially. In the non-mitochondrial fraction, activity is much higher in the aqueous phase. 90 s p.i. of (I 14C) palmitic acid, over 80% of the myocardial activity is found in the hydrophilic fraction, which indicates—as for the iodo fatty acid (IHA)—an immediate and important oxidation, especially without glucose. These data seem to prove that IHA is taken up by the myocardial cells, enters the mitochondria where it is, without an early deiodination, oxidized with iodide release. IHA metabolic changes can be seen on the external detection myocardial activity curve. Omega iodinated fatty acids do not undergo a nonspecific important deiodination and are therefore well adapted to an external study of myocardial metabolism.

Kinetics of (16 123I) Iodohexadecenoic Acid Metabolism in the Rat Myocardium, Influence of Glucose Concentration in the Perfusate and Comparison with (1 14C) Palmitate

Etude biologique d'acides gras en C 16 marqués par un atome radioactif

Influence de la longueur de la chaîne et du nombre pair ou impair d'atomes de carbone sur le comportement biologique des acides gras iodés

Synthese a partir d'un acide carboxylique et d'halogeno alcanes, la derniere etape de la synthese etant une iodation. Obtention d'acides gras en C 16 et d'acides phenyl-15 pentadecanoiques marques par 123 I

Méthode de synthèse d'acides gras marqués substitués ou non en α et en β

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