[Strategic plan for reduction of hospital stay in renal transplantation]. / Plan estratégico para la reducción de la estancia hospitalaria en trasplante renal.

Since January 2015 we have carried out a multiple-intervention strategic plan to reduce hospital stay in renal transplant recipients. The main objective of this study is to compare results of renal transplantation before and after putting into effect this plan in terms of graft and patient survival, readmissions and incidence of acute rejection during the first year post transplantation. In this retrospective analysis we included all patients 18 years of age or older who were transplanted at our institution. The strategic plan resulted in a significant reduction of hospital stay of renal recipients from 13.5 days in the pre-plan group (n=97) to 4.6 days in the post-plan group (n=62; p≤0.0001). The incidence of acute rejection during the first year was similar (pre-plan group=14.4% vs. post-plan group=16% [p=0.77]) as it was graft survival (88% vs. 90% [p=0.71]) and patient survival (95% vs. 98% [p=0.37]), respectively. The multiple-intervention strategic plan has significantly reduced the hospital stay of patients after renal transplantation without affecting graft or patient survival, which are comparable to those internationally published, and without jeopardizing patient's safety.

Proteinuria/creatininuria index and its correlation with the 24-hour proteinuria in renal transplanted patients.

BACKGROUND: Proteinuria (P) is a early sign of inflammation and renal damage. It has an important role in the detection, diagnosis, and monitoring of renal disease in transplanted patients. The aim of this study was to examine the correlation between random urinary proteinuria/creatininuria index (P/CI) and 24-hour total protein excretion among stable renal transplant patients. MATERIALS AND METHODS: We obtained 1511 samples of 24-hour protein excretion (24-hr P) with corresponding P/CI were obtained from 197 adult patients beyond 6 months post-transplantation between 2009 and 2011. The population was divided into 2 groups: One to obtain a population of justification (755) and another, of validation (755). A scatter graft yielded was obtained by Pearson's coefficient of correlation. A "receiver operater characteristic curve" analysis was carried out to evaluate the sensitivity and specifity of PCI and 24hr-P, showing a cutoff of 0.15 for PCI. RESULTS: The PCI and 24 hr P Pearson's correlation was significant (r = 0.89; P = .0001). The sensitivities of the P/CI for the justification and the validation samples were 97% and 94%, respectively; the a cutoff was 0.15. Their negative predictive values for P/CI were 92% and 84% respectively (cutoff, 0.15). The specificity was below 50% in both groups. CONCLUSIONS: We observed a significant correlation between P/CI and 24 hr P. The sensitivity was slightly higher than the specificity (50%) but the negative predictive value was >92%. The use of P/CI seemed to be adequate for screening of protein excretion during renal transplant recipient follow-up.

Correction of dyslipoproteinaemia of casein-fed rabbit by FCE 27677, a potent novel ACAT inhibitor.

Rabbits fed a wheat starch casein diet develop hypercholesterolaemia characterized by the plasma elevation of low density lipoprotein (LDL) that is caused by oversecretion of apoB-100 containing lipoproteins by the liver and by the suppression of the EDTA-sensitive hepatic beta- very low density lipoprotein (VLDL)-LDL receptor. In this study, the effect of FCE 27677 ((-)N-[2,6-bis(1-methylethyl)phenyl]-N'-[(4R,5R)-2-(4-dimethylaminoph eny l)-4,5-dimethyl-dioxolan-2-yl]methylurea) a novel potent systemic acylCoA:cholesterol acetyltransferase (ACAT, EC 2.3.1.26) inhibitor, has been evaluated. When New Zealand White rabbits were fed with casein for 4 weeks, LDL cholesterol increased from 14 +/- 3 mg/dl-1 to 77 +/- 6 mg/dl-1. By contrast the animals receiving FCE 27677 (10 mg kg-1 d-1) mixed with the casein diet maintained a normal LDL concentration (22 +/- 3 mg dl-1). This hypolipidaemic effect was also observed when rabbits previously made hypercholesterolaemic by being fed casein for 4 weeks were then treated for a month with FCE 27677. [125I]LDL plasma turnover studies and [125I]LDL binding studies to liver membranes were carried out with the purpose of investigating the mechanism of action of the drug. The LDL apoB-100 production rate in chow-fed, casein-fed, and casein-fed rabbits receiving FCE 27677, was respectively 10.5, 22.4, and 12.5 mg kg-1 d-1. The turnover rate of [125I]LDL in the animals receiving the drug was not, however, different from that in the rabbits fed the casein diet alone (2.381 vs 2.079 pools d-1). Both values were lower than that in chow-fed animals (3.271 pools d-1). FCE 27677 did not normalize the activity of the hepatic beta-VLDL-LDL EDTA-sensitive receptor which is suppressed by casein feeding. Altogether the results are consistent with the idea that FCE 27677 by acting through inhibition of the cholesterol esterification in the liver normalizes the LDL synthetic rate. ACAT inhibitors may be useful drugs for the treatment of human dyslipoproteinaemia secondary to derangement of the apoB-100 synthetic rate.

Inhibition of acyl-CoA: cholesterol acyltransferase decreases apolipoprotein B-100-containing lipoprotein secretion from HepG2 cells.

There is evidence that the overproduction of apoB-100-containing lipoproteins by the liver is the underlying event in some forms of dyslipoproteinemia. This metabolic status is associated to an increased risk of developing premature coronary artery disease CAD. The conclusions from previous studies suggested that the availability to the hepatocytes of cholesterol that is readily esterified is an important determinant for VLDL and LDL secretion. In the present study, we set out to investigate the effect of the specific stimulation and inhibition of the rate-limiting enzyme of the cholesterol esterification, acyl-CoA:cholesterol acyltransferase (ACAT, E.C. 2.3.1.26), on the lipid and on the apoB-100 secretion rate from a human hepatoma cell line (HepG2). When the specific ACAT inhibitor FCE 27677 (10-5 M) was added to the cultures, a decrease of the cellular cholesteryl ester content and at the same time a significant reduction of the neutral lipids and of the apoB-100 secretion rate were noticed. The stimulation of ACAT by 25-hydroxycholesterol (20 microgram/ml) caused a 4-fold increase of the cellular cholesteryl ester content and a 2-fold increase of the lipoprotein secretion rate. FCE 27677 (10-5 M to 10-7 M) prevented the effects elicited by the oxysterol. On the contrary, lovastatin (10-6 M) and gemfibrozil (10-6 M) had no effect. The analysis of the lipid and of the apolipoprotein composition of the lipoproteins secreted in the medium revealed that ACAT inhibition had the dual effect of both decreasing the number of apoB-100-containing lipoproteins secreted as well as their cholesteryl ester load. Altogether, these data support the idea of a close relationship between ACAT activation, leading to increased cholesteryl ester availability, and apoB-100-containing lipoprotein secretion. It is speculated that ACAT inhibitors may prove useful for the treatment of human dyslipoproteinemias caused by the hepatic overproduction of apoB-100-containing lipoproteins.

FCE 27677: a novel inhibitor of acyl-CoA: cholesterol acyltransferase with potent oral hypolipidemic activity.

FCE 27677 ([(-)N-[2,6-bis(1-methylethyl)phenyl]-N'-[(4R,5R)-2- (4-dimethylaminophenyl)-4,5 dimethyl-dioxolan-2-yl]methylurea) is a new systemically available ACAT inhibitor belonging to the class of ketalic disubstituted ureas. When tested in microsomes from rabbit intestine, aorta and liver, it inhibited the enzyme with IC50 of 9.31, 6.99 and 92.2 nM, respectively. It had no effect on plasma LCAT and intestinal cytosolic cholesterol esterases and, when tested in a tissue culture system, it did not interfere with the synthesis of cholesterol, triglycerides, and phospholipids. Enzyme inhibition kinetics indicated that FCE 27677 is a non-competitive inhibitor of the enzyme with respect to acylCoA and to cholesterol. When administered mixed to a 1.5% cholesterol and 0.5% sodium cholate-enriched diet to rats, it prevented the development of hypercholesterolemia with ED50 of 0.35 mg kg-1 day-1. Given in a single oral dose to hypercholesterolemic rats it significantly reduced both the plasma lipid levels and the hepatic cholesteryl ester content within 6 h from gavage. VLDL and LDL levels and composition were also significantly affected. Similar effects were observed when the drug was given mixed to a regular chow diet for 4 weeks to hypercholesterolemic rabbits. These results are consistent with the idea that systemically available ACAT inhibitors can affect the composition and the metabolism of the atherogenic cholesteryl ester-rich VLDL and LDL. ACAT inhibitors appear promising for the correction of dyslipoproteinemias secondary to lipoprotein overproduction, and in reducing the atherogenic index of apoB-100 containing lipoproteins.

Imidazolylbenzopyrane derivatives: a new class of acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors.

Inhibitors of the enzyme Acyl-CoA: Cholesterol Acyltransferase are regarded as potentially useful agents in the treatment of hypercholesterolemia and atherosclerosis. We report here a novel series of 2, 6-disubstituted-3-imidazolylbenzopyrane derivatives with significant in vitro ACAT inhibitory activity (IC50 range 0.05-0.5 microM). Compounds of this series such as 26 are examples of a new, structurally distinct class of potent ACAT inhibitors with high specificity for the aortic subtype of the enzyme. The structure-activity relationships of the 3-imidazolylbenzopyrane ACAT inhibitors were investigated by systematic manipulation of two regions of the parent compound 1 and the inhibitory activity resulted linked to the substituent in position 6 of the benzopyrane ring and modulated by the size of lipophilic substituents in position 2. Investigation of the mechanism of the inhibitory effect leads to the conclusion that these compounds act in a non-competitive fashion.

Synthesis of some 3-hydroxy-5-aminopentanoic acid derivatives.

The 5-amino analogues of mevalonic acid and mevalonolactone, 5-amino-3-hydroxy-3-methylpentanoic acid (VII a) and 4-hydroxy-4-methyl-2-piperidone (III a), and some related compounds were synthesized as possible inhibitors of cholesterol biosynthesis. None of them was found effective on the synthesis of cholesterol in rat liver slices and on HMG-CoA reductase activity in vitro, but 4-hydroxy-4-(4-chlorophenyl)-2-piperidone (III b) raised high density lipoproteins (HDL) in normolipaemic rats.

Ethyl 2-([5,6-dihydro-7-(1H-imidazol-1-yl)-2-naphthalenyl]oxy)- 2-methylpropanoate as a new potent oxyisobutyrate hypolipidaemic with unusual features.

Some compounds containing the N-imidazolyl and the ethyl oxy-isobutyrate groups linked to a naphthalene ring structure and some related analogues were synthesized and tested for hypolipidaemic activity. Ethyl 2-([5,6- dihydro-7-(1H-imidazol-1-yl)-2-naphthalenyl]oxy)- 2-methylpropanoate (V) proved to be a strong hypolipidaemic agent, several times more potent than clofibrate. Structural requirements for activity and differences from clofibrate analogues are discussed.

N-imidazolylchroman-4-ones, N-imidazolyl-1-tetralones, and their alcohols as hypolipemic agents raising high-density lipoproteins.

A series of 3-(1-imidazolyl)chroman-4-ones and 2-(1-imidazolyl)-1-tetralones II, some of their alcohols, and some related compounds were synthesized and tested for hypolipidemic activity. Compounds II, bearing appropriate lipophilic substituents on the phenyl ring, strongly reduced total serum cholesterol while raising high-density lipoprotein cholesterol in diet-induced hypercholesterolemic rats. 3-(1-Imidazolyl)chroman-4-ols and 2-(1-imidazolyl)-1-tetralols corresponding to II retained the hypolipidemic activity while removal of the carbonyl or hydroxy group adjacent to imidazole gave inactive compounds. Although many of the active compounds significantly increased liver weight, the one studied as a model, 6-chloro-3-(1-imidazolyl)-2,3-dihydro-4H-1-benzopyran-4-one (5), caused no peroxisome proliferation. Compound 5 and the corresponding alcohol 40, as representatives of the ketone and alcohol series, showed significant hypolipidemic activity in normolipemic rats. Some of the compounds assayed in cholesterol biosynthesis inhibited acetate incorporation but none inhibited HMG-CoA reductase. 5-Bromo-6-hydroxy-2-(1-imidazolyl)-3,4-dihydro-1(2H)-naphthalenone (38), which showed strong activity but caused little hepatomegaly in the rat, was chosen for further pharmacological evaluation.

Effect of the antilipolytic compound acipimox on peroxisome marker enzymes, lipid pattern and biotransformation related functions in rat liver.

The antilipolytic drug acipimox (5-methylpyrazine-2-carboxylic acid 4-oxide) was given to male rats for 1 week at 500, 1000 and 2000 mg/kg/day and for 2, 6 and 7 months at 20, 100 and 500 mg/kg/day. The peroxisome proliferative effect was evaluated determining the activity of catalase and carnitine acetyltransferase, the rate of cyanide-insensitive palmitoyl CoA oxidation and the electrophoretic profile of liver polypeptides. Hepatic lipid content and distribution were evaluated after 2 and 6 months' treatment. The effect on liver detoxificating function was evaluated by assaying glutathione, cytochrome P-450, glutathione-S-transferase and glutathione-reductase activities after 7 months' treatment. Sub-acute and chronic treatment with a wide range of acipimox doses did not cause hepatomegaly, liver peroxisome proliferation or liver steatosis and did not change some important biochemical variables related to detoxification and biotransformation mechanisms. Acipimox given to rats does not have the negative side-effects of other compounds and seems a safe blood lipid lowering drug.

Hypolipidemic activity of some derivatives of 6H-dibenzo[b,d]pyran.

This paper describes the synthesis of 6-carboxy derivatives of 6H-dibenzo[b,d]pyran. These compounds are among the most rigid structures related to clofibrate ever synthesized, which means they have very few possible conformations of relative stability compared with the many for clofibrate. Compound 6H-2-chloro-6-methyl-dibenzo[b,d]pyran-6-carboxylic acid 3g showed very high hypolipidemic activity being 12 times more potent than clofibrate in reducing plasma cholesterol concentration in the hypercholesterolemic rat and 11 times more potent in reducing plasma triglyceride concentration in the normolipemic rat.

Inhibition of lipolysis by nicotinic acid and by acipimox.

Acipimox (5-methylpyrazinecarboxylic acid 4-oxide) is a new lipolysis inhibitor that has a distant chemical relationship with nicotinic acid (NA). The tritiated compound (100 mg) is rapidly absorbed, peak plasma radioactivity being reached after 2 hr, with an almost total elimination unchanged in urine. A comparison of th antilipolytic activity of three doses of acipimox and three doses of NA showed acipimox to be 20 times as potent as NA. There was a correlation between intensity and duration of effect for acipimox, but not for NA. Plasma acipimox levels correlated with inhibition of lipolysis. In consideration of the very good subjective tolerability of acipimox at all doses tested, this drug may be suitable for control of lipolysis in hyperlipidemias.