Antihypertensive effects of peroxisome proliferator-activated receptor-ß/δ activation.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors, which is composed of three members encoded by distinct genes: PPARα, PPARß/δ, and PPARγ. The biological actions of PPARα and PPARγ and their potential as a cardiovascular therapeutic target have been extensively reviewed, whereas the biological actions of PPARß/δ and its effectiveness as a therapeutic target in the treatment of hypertension remain less investigated. Preclinical studies suggest that pharmacological PPARß/δ activation induces antihypertensive effects in direct [spontaneously hypertensive rat (SHR), ANG II, and DOCA-salt] and indirect (dyslipemic and gestational) models of hypertension, associated with end-organ damage protection. This review summarizes mechanistic insights into the antihypertensive effects of PPARß/δ activators, including molecular and functional mechanisms. Pharmacological PPARß/δ activation induces genomic actions including the increase of regulators of G protein-coupled signaling (RGS), acute nongenomic vasodilator effects, as well as the ability to improve the endothelial dysfunction, reduce vascular inflammation, vasoconstrictor responses, and sympathetic outflow from central nervous system. Evidence from clinical trials is also examined. These preclinical and clinical outcomes of PPARß/δ ligands may provide a basis for the development of therapies in combating hypertension.

Prospective observational study for perioperative volume replacement with 6% HES 130/0,42, 4% gelatin and 6% HES 200/0,5 in cardiac surgery.

BACKGROUND: the constantly growing amount of different kinds of colloid fluids necessitates comparative investigations with regards to the safety and effectivity in clinical use of these preparations. Hence we compared three colloid fluids in an observational study. The objective was the exploration of the influence of these three colloids on blood coagulation, hemodynamics and renal function of the cardiac surgical patient. METHODS: we included 90 patients undergoing an elective open-heart surgery with the use of the heart-lung machine and observed them consecutively. Group 1 [gelatin 4% (n = 30)], Group 2 [HES 200/0,5 (n = 30)] and Group 3 [HES 130/0,42 (n = 30)]. We measured the perioperative volume replacement, the administration of blood- and coagulation-products, the application of catecholamines, the renal function, blood gas and the platelet aggregation using multiplate electrode analyzer (Multiplate, Dynabyte medical, Munich, Germany). RESULTS: the gelatin-group needed significantly more norepinephrine than the HES 130/0.42 group. The responsible surgeon considered the blood coagulation in the HES 200/0.5 group most frequently as impaired. Furthermore we saw a significant decrease in platelet function in the HES 200/0.5 group when performing the multiplate-analysis (ADP-and COL-test). HES 130/0.4 as well as gelatin 4% showed no significant change in platelet function. The gelatin-group and the HES 200/0.5 needed significantly more aprotinine than the HES 130/0.4 group. We saw no significant difference with regards to administration of blood and coagulation products between the three groups. The urinary excretion during the intervention was significantly higher in the HES 200/0.5 group and in the gelatin group than in the HES 130/0.4 group. CONCLUSIONS: our results confirm the lower stabilizing effect of gelatin on circulation during fluid resuscitation. The blood coagulation was mostly impaired due to HES 200/0.5 confirmed by the multiplate®-analysis as well as by different clinical findings.

Ticrynafen: a novel uricosuric antihypertensive natriuretic agent.

Interest in new diuretics with less side effects has led to the synthesis of ticrynafen, an uricosuric diuretic. This agent was compared with hydrochlorothiazide in a crossover design study involving 12 hypertensive men. Both agents significantly decreased mean arterial pressure from 8% to 18% in eight of the 12 patients. In addition to reducing body weight, these diuretics induced reversible changes in BUN and carbon dioxide content (increased) and plasma concentration of potassium and chloride ions (decreased). The most important change in renal function was a 2.5-fold increase in fractional urate clearance by ticrynafen associated with reduction of serum uric acid by 62%. Thus, ticrynafen is a promising therapeutic agent in hypertension, adding a unique uricosuric effect that should improve patient compliance.

Ticrynafen and probenecid in hyperuricemic, hypertensive men.

In a double-blind crossover study of ticrynafen (TCN) and probenecid (PBC), 9 hypertensive, hyperuricemic men completed 12-wk courses of each drug. With a TCN dose of 125 mg daily, the fall in serum uric acid was prompt, dramatic, and lasting; it was equal to that after PBC, 500 or 1,000 mg daily. There was a small but significant early weight loss (diuresis) after TCN but no antihypertensive effect. Twelve days after resuming TCN for a proposed additional extension study 1 patient suffered acute, reversible bilateral ureteral obstruction, probably caused by sudden urinary uric acid precipitation.

ICI D7114: a novel selective adrenoceptor agonist of brown fat and thermogenesis.

Increasing energy expenditure by treatment with thermogenic drugs is not new, but available drugs have suffered from the problem of lack of selectivity. In the last decade two key findings have allowed the development of selective thermogenic drugs that have promise in the treatment of obesity. 1) The recognition that brown adipose tissue (BAT) plays a role in compensatory increases in energy expenditure has allowed an approach directed at a target organ. 2) The demonstration showing that increases in the activity of BAT may be modulated by an atypical (beta 3) adrenoceptor has led to the development of a new peripherally acting beta-adrenoceptor agonist ICI D7114, which stimulates thermogenesis at doses that have little effect on beta 1 or beta 2 adrenoceptors. Treatment with the compound activates BAT and thermogenesis even in species and situations where the intrinsic capacity is low. 3) The compound has beneficial effects in animal models of obesity and disturbed glucose and lipid homeostasis.

Increased plasma immunoreactive endothelin-1 concentration in hypercholesterolemic rats.

This study examined the influence of hypercholesterolemia on the concentration of plasma immunoreactive (ir) endothelin-1 in rats. Plasma ir-endothelin-1, total cholesterol, triglycerides, and lipoprotein fraction concentrations were measured in three groups of rats; ie, fed a standard diet, a high cholesterol diet, or a high cholesterol diet supplemented with the antihypercholesterolemic drug clinofibrate for 4 and 8 weeks. In the rats fed cholesterol for 8 weeks, morphological changes in thoracic and abdominal aortas were examined. Plasma total cholesterol, low density lipoprotein (LDL), very low density lipoprotein (VLDL) and ir-endothelin-1 concentrations increased significantly in the cholesterol-fed rats after both 4 and 8 weeks. In the clinofibrate-treated rats, these lipid parameters and plasma ir-endothelin-1 levels after 4 and 8 weeks were significantly lower than in the cholesterol-fed rats. The plasma ir-endothelin-1 concentration was correlated with plasma total cholesterol, LDL, and VLDL concentrations in the three study groups after 4 and 8 weeks. Morphologically, neither foam cells formation nor intimal thickening was observed in rats fed the high cholesterol diet for 8 weeks. These observations indicate that hypercholesterolemia without atherosclerosis elevates the plasma ir-endothelin-1 level in rats. The observed increase in plasma ir-endothelin-1 associated with hypercholesterolemia may play a role in the initiation or development of atherosclerotic vascular lesions.

Effect of clinofibrate, a new hypolipidemic agent, on biliary and serum lipids in patients with hyperlipidemia.

Clinofibrate was given to 15 patients with hyperlipidemia, for 6-8 weeks at the daily dose of 600 mg, and its effect on 3 biliary lipid components (cholesterol, bile acids and phospholipids) and on the lithogenic index was investigated. After clinofibrate treatment, 6 of the patients were given 1.5 g/day clofibrate for 6-8 weeks to compare the effect of clofibrate with that of clinofibrate. The molar percentages of biliary cholesterol and phospholipids to the total mol number of the 3 biliary lipid components decreased, and that of bile acids increased during clinofibrate administration. In this way, the molar ratio of bile acids to cholesterol increased during the treatment. Neither the lithogenic index calculated by the formula of Admirand and Small nor that of Hegardt, Dam and Holzbach was altered significantly by the treatment. There was no apparent relationship between the effect of the drug on the lithogenic index and any of the factors initial lithogenic index, rate of decrease of serum lipids, or type of hyperlipidemia. Although clofibrate had no significant effect on the maximum solubility of cholesterol in the bile, the molar percentage of biliary cholesterol was elevated and the lithogenic index increased as compared with the control and clinofibrate period. No significant influence on bile acid composition in the bile was observed, with either clinofibrate or clofibrate.

Design, synthesis, and testing of potential antisickling agents. 4. Structure-activity relationships of benzyloxy and phenoxy acids.

In this paper we further establish the activity of two classes of small molecules, benzyloxy and phenoxy acids, as potent inhibitors of hemoglobin S (HbS) gelation. Structural modifications with a large number of each class confirm our earlier work that the highest activity is observed with compounds that contain dihalogenated aromatic rings with attached polar side chains. We have also found a halogenated aromatic malonic acid derivative to be quite active. Compounds reported in this paper are compared with other antigelling agents studied in our laboratory. Comments are made concerning the antigelling activity and binding sites of four derivatives and their effect on the allosteric mechanism of hemoglobin (Hb) function.

Novel therapeutic strategies for leiomyomas: targeting growth factors and their receptors.

Leiomyomas (fibroids) are benign smooth-muscle cell (SMC) tumors of the uterus and are the most common pelvic tumors in women. These tumors occur primarily during the reproductive years and are the most common indication for hysterectomy in women. Unfortunately the only effective treatments for leiomyomas and the associated abnormal uterine bleeding are surgical, involving either hysterectomy, myomectomy, or hysteroscopic removal of the tumors. The goal of this paper is to discuss recent research findings that support the idea of using therapeutic compounds that block the actions of specific growth factors as therapeutic agents for treatment of leiomyomas and abnormal uterine bleeding. Most of the studies were carried out using cell cultures of leiomyoma or myometrial SMCs. Primary cultures of SMCs provide a system for investigation of the roles of growth factors and their receptors in proliferation of normal myometrial and leiomyoma SMCs. Several growth factors have been shown to be present and to have regulatory roles in the proliferation of uterine SMCs. Bioassay and Western blotting of fast protein liquid chromatography fractions of tissue extracts identified platelet-derived growth factor, heparin-binding epidermal growth factor, hepatoma-derived growth factor, and basic fibroblast growth factor in normal myometrium and fibroid tumors. The presence of heparin-binding growth factors suggests a possible focus for therapeutic agents. RG13577 (a heparinlike compound) and halofuginone (an alkyloid) reversibly inhibited DNA synthesis of normal myometrial and leiomyoma cells without toxic effects. Pirfenidone, a known antifibrotic drug, inhibited DNA synthesis and synthesis of collagen type I mRNA in normal and fibroid cells, and decreased collagen type III mRNA only in normal myometrial cells. Another hopeful therapeutic candidate, interferon-Alpha, significantly inhibited growth factor-stimulated proliferation in both normal and leiomyoma cells. These results suggest that future nonsurgical treatments for leiomyomas may include compounds that block the actions of specific growth factors that regulate proliferation and collagen production by uterine SMCs.

Effects of lipid-lowering drugs on intermediate-density lipoprotein in uremic patients.

BACKGROUND: Patients with chronic renal failure often have alterations in lipoprotein profile including elevated very-low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL), and reduced high density lipoprotein (HDL) levels. Among these changes, raised IDL has been shown as an independent risk factor for atherosclerosis in hemodialysis patients. There are a limited number of studies reporting pharmacological approaches to IDL reduction in a uremic population. METHODS: We therefore summarize the effects of lipid-lowering drugs on IDL levels in patients with chronic renal failure treated by hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). RESULTS: First, a nicotinic acid analog niceritrol was given to hemodialysis patients. The drug increased HDL-cholesterol by 11%, but the reductions in VLDL-, IDL- and LDL-cholesterol were not significant. Second, CAPD patients were treated with a fibric acid derivative clinofibrate, which was excreted mainly into bile unlike other drugs in this class. The fibrate resulted in a remarkable reduction in VLDL-triglycerides, although it did not reduce IDL-cholesterol. Finally, an HMG-CoA reductase inhibitor (statin) pravastatin was used in HD and CAPD patients. Pravastatin reduced IDL- and LDL-cholesterol to the same extent (by 31%). None of these treatments caused serious adverse effects. CONCLUSIONS: We propose that IDL is an important target in the management of uremic dyslipidemia. To date, statins have been shown to be suitable for this purpose, although it remains to be clarified whether such an intervention reduces the risk for atherosclerotic vascular events in the uremic population.

The effect of a TXA2 receptor antagonist ON-579 on experimental allergic reactions.

The effect of a thromboxane A2 (TXA2) receptor antagonist, ON-579, on experimental allergic skin and airway reactions was studied in vivo. ON-579 at doses of 1 and 20 mg/kg clearly inhibited U-46619-induced increases in respiratory resistance (Rrs) in guinea pigs. ON-579 at doses of 1, 20 and 50 mg/kg inhibited the aerosolized antigen-induced biphasic increase in Rrs in guinea pigs. Moreover, ON-579 clearly inhibited repeated aeroantigen-induced airway hyperreactivity in guinea pigs. ON-579, however, did not have any significant effects on allergic cutaneous reactions in rats. These results suggest that ON-579 is a relatively selective TXA2 antagonist, especially in the airways, and indicate the efficacy of ON-579 on antigen-induced increase in airway resistance and antigen-induced airway hyperreactivity in guinea pigs.

2-[3-[2-(4,5-diphenyl-2-oxazolyl) ethyl] phenoxy] acetic acid (BMY 42393): 2). Oral activity and efficacy in animal models of arterial thrombosis.

The oral activity and antithrombotic efficacy of BMY 42393 was examined in ex vivo platelet aggregation studies and arterial thrombosis animal models. In a heterologous ex vivo platelet aggregation assay, ADP-induced human platelet aggregation was inhibited when washed human platelets were combined with rat platelet-poor plasma, taken from rats previously orally-dosed with BMY 42393. The IC50 for platelet aggregation inhibition was approximately 10 mg/kg. In a laser-induced thrombosis model, thrombus formation in a revascularized rabbit ear chamber was prevented in a dose-dependent fashion with an ED50 of about 2 mg/kg. A relatively long duration of anti-thrombotic activity was observed in the rabbit ear laser-induced thrombus study and the ex vivo platelet studies. Inhibition of thrombus formation was also demonstrated in a canine model of electrically-induced coronary artery thrombosis. BMY 42393 also prevented cyclic flow reductions in a monkey stenotic renal artery model. These studies indicate that BMY 42393 is orally active and capable of preventing laser and electric current-induced thrombus formation in animal models of arterial thrombosis.

Antitumor activity of homo-aza-steroidal esters of p-N, N-bis(2-chloroethyl)aminophenoxyacetic acid.

The homo-aza-steroidal esters of carboxylic derivatives of N, N-bis (2-chloroethyl) aniline are reviewed. In particular, we discuss the antitumor activity of the esters of homo-aza steroids in which the p-N,N-bis(2-chloroethyl)aminophenoxyacetic acid is linked to the C-3 or C-17 position, while the lactam nucleus is linked to the D or A ring of the modified steroid respectively. The current literature indicates clearly that the potential of these esters is due to the synergistic activity of both the lactam and the p-N,N-bis(2-chloroethyl)aminophenoxyacetic acid.

Effects of clinofibrate on plasma fibrinogen level in high fructose diet-induced hyperlipidemic rats.

Effects of clinofibrate on the coagulative and fibrinolytic activity in an intrinsic hyperlipidemia induced by a cholesterol free-high fructose diet (HFD) for 14 days were studied using male Wistar rats. There were significant and positive correlations between plasma fibrinogen level and serum lipid content, and between fibrinogen level and VLDL-LDL-lipid content. Clinofibrate administration (50 and 100 mg/kg/day, p.o.) significantly inhibited the increase in plasma fibrinogen level as well as serum- and VLDL-LDL-lipids. It is concluded that clinofibrate, in addition to its beneficial effect on the serum lipid profile, can effectively reduce the plasma fibrinogen level.

Clinofibrate therapy raises high-density lipoprotein levels and lowers atherogenic index in diabetes mellitus patients.

The effects of clinofibrate on serum lipoprotein concentrations, lecithin cholesterol acyl transferase activity and atherogenic index were studied in 10 diabetes mellitus patients. The patients comprised five with well-controlled non-insulin-dependent diabetes, and five with poorly controlled insulin-dependent diabetes; six non-insulin-dependent diabetics acted as placebo controls. No adverse side-effects were reported and there were no significant changes in total cholesterol, triglyceride or high-density lipoprotein 3-cholesterol concentrations following 600 mg/kg clinofibrate treatment for 4 weeks in either insulin-dependent or non-insulin-dependent diabetics. High-density lipoprotein-cholesterol concentrations and lecithin cholesterol acyl transferase activity were significantly (P less than 0.05) increased by clinofibrate treatment in insulin-dependent and non-insulin-dependent diabetics and high-density lipoprotein 2-cholesterol concentrations were significantly (P less than 0.05) increased by clinofibrate in insulin-dependent diabetics. The atherogenic index was significantly (P less than 0.01) reduced in non-insulin-dependent diabetics. It is suggested that the enhanced plasma lecithin cholesterol acyl transferase activity following clinofibrate therapy is the result of increased high-density lipoprotein-cholesterol and high-density lipoprotein 2-cholesterol concentrations and may play a central role in the efficacy of clinofibrate.

[Therapy of hyperlipidemia. Clinical experience with clinofibrate]. / Terapia delle iperlipidemie. Esperienza clinica con clinofibrato.

The results are reported of a double-blind crossover trial intended to evaluate the effectiveness and safety of a new aryloxy derivative compared to placebo. Twenty patients with hyperlipidemia not responding to dietary treatment received either one capsule of the active substance or of placebo (200 mg) three times daily for 16 weeks. Total cholesterol, HDL and triglycerides showed the following changes at the of the treatment period: -11%, +6% and -48% with clinofibrate and -1%, -4% and -1% during control periods. The substance was well tolerated; only in one patient clinofibrate was withdrawn as a precaution in view of the onset of medium severe diarrhea and abdominal pain.

Ticrynafen and hydrochlorothiazide. A double-blind study of antihypertensive properties with an open crossover.

Twenty-eight patients completed a double-blind study of the antihypertensive effects of ticrynafen compared with those of hydrochlorothiazide. The results of blood pressure reduction were comparable in the two groups. After six months, 12 patients were crossed over to ticrynafen therapy from hydrochlorothiazide. They maintained their blood pressure reduction. The most striking difference between the two groups was in the uric acid response. The uric acid level in the patients receiving hydrochlorothiazide therapy rose from a baseline of 5.9 to 7.5 mg/dL (normal range, 3.0 to 8.0 mg/dL). The uric acid level of those patients receiving ticrynafen therapy decreased from a baseline of 6.4 mg/dL to a low of 3.3 mg/dL. In view of ticrynafen's appreciable antihypertensive and uric-acid-lowering effects, it appears to be a useful new antihypertensive drug.

[Experiences with a new hypouricemic diuretic (tienilic acid): comparison with hydrochlorothiazide]. / Erfahrungen mit einem neuen harnsäuresenkenden Diuretikum (Thienylsäure): Vergleich mit Hydrochlorothiazid.

A new hypouricemic diuretic (tienilic acid) was compared with hydrochlorothiazide in a double-blind study in 8 patients with mild essential hypertension. After a two-week placebo period the patients received either 250 mg tienilic acid or 50 mg hydrochlorothiazide in a single daily dose for 3 weeks. After a second placebo period of 2 weeks the patients received, in a crossover design, either tienilic acid or hydrochlorothiazide for a further 3 weeks. The reduction of blood pressure and of body weight was similar for both drugs. When treatment was started diuresis and natriuresis increased with tienilic acid and with hydrochlorothiazide. Whereas serum sodium levels showed only minor variations, serum potassium levels fell with both diuretics and urinary potassium excretion increased. Urinary calcium excretion decreased and serum calcium levels slightly increased under both treatments. Both diuretics induced similar increases of plasma renin activity, plasma aldosterone concentration and aldosterone-18-glucuronide excretion. Blood urea nitrogen and, to a lesser extent, serum creatinine levels were raised slightly under both drug regimens. Whereas the serum uric acid level rose and remained elevated for the duration of hydrochlorothiazide treatment, it fell significantly and remained lowered during treatment with tienilic acid. Uric acid clearance was about twice as high with tienilic acid as with hydrochlorothiazide. Tienilic acid therefore appears to be a therapeutic alternative to thiazides and other hyperuricemic diuretics in hypertensive patients in whom hyperuricemia should be avoided or corrected.