Lecithin: cholesterol acyl transfer rate and high density lipoproteins in plasma during dietary and cholestyramine treatment of type Ila hyperlipoproteinaemia

Abstract. Changes in the lecithin:cholesterol acyl transfer rate and the concentrations of lipids and high density lipoprotein lipids in plasma were studied during dietary and cholestyramine treatment of type IIa subjects. Samples were obtained from twenty subjects before and 2 months after the start of a cholesterol lowering diet. Sixteen subjects were studied 1 month after the addition of cholestyramine treatment to the dietary regimen.
During 2 months of dietary modification the mean concentrations of cholesterol, phospholipids and low density lipoprotein cholesterol were reduced by 10%. In the high density lipoprotein fraction there was a 10% mean increase of the cholesterol but no change of the mean phospholipid concentration. There were no changes of the mean triglyceride concentration or the mean fractional or molar lecithin:cholesterol acyl transfer rates in plasma.
One month after the addition of cholestyramine to the diet there were further reductions in the mean plasma concentrations of cholesterol by 22.5%, phospholipids by 12% and low density lipoprotein cholesterol by 32%. The mean triglyceride concentration and the mean concentration and composition of the high density lipoprotein fraction were unchanged. The mean fractional Iecithin _:cholesterol acyl transfer rate was increased by 30%. The type IIa subjects with high molar lecithin: cholesterol acyl transfer rates during the diet showed increments of molar lecithin:cholesterol acyl transfer rates during cholestyramine therapy.
Interpretations of these findings in relation to lipoprotein metabolism are discussed.     

Bezafibrate therapy and biliary lipids: effects of short-term and long-term treatment in patients with various forms of hyperlipoproteinaemia

Several hypolipidaemic drugs increase biliary cholesterol saturation and induce the formation of cholesterol gallstones. In order to determine the influence of bezafibrate, a clofibrate analogue with hypolipidaemic properties, on bile lipid composition, we studied twelve patients with various forms of hyperlipoproteinaemia (six type IIA, three type IIB and three type IV hyperlipoproteinaemia; six had a genetic diagnosis of familial hypercholesterolaemia and five familial combined hyperlipidaemia). After 4 weeks of therapy, when serum lipids were significantly reduced, the relative proportion of cholesterol in stimulated fasting duodenal bile was increased by 28% (P less than 0.001). Phospholipids were concomitantly increased and bile acids decreased, resulting in an increase in biliary cholesterol saturation from 89 +/- 4% to 105 +/- 8% (SEM, P less than 0.02). The changes induced were similar in patients with familial hypercholesterolaemia and familial combined hyperlipidaemia. After 1 year of continued treatment, serum lipid responses were unaltered. The changes in biliary lipids were also persistent as the relative cholesterol concentration remained increased by 33% (P less than 0.01) and cholesterol saturation averaged 106 +/- 8% (P less than 0.02). Although the effect on bile cholesterol appeared to be transient in some patients, the results of the present study suggest that the risk of cholesterol gallstone formation may be increased during bezafibrate therapy.     

Biliary lipids in familial combined hyperlipidaemia: effects of acipimox therapy

Biliary lipid composition and plasma lipoprotein levels were determined in nine gallstone-free male patients with familial combined hyperlipidaemia (FCHL). In the basal situation, stimulated fasting duodenal bile from the patients contained a higher relative concentration of cholesterol than bile obtained from age- and sex-matched normal controls (n = 22), 6.5 +/- 0.3 (SEM) vs. 4.7 +/- 0.2 mol % (P less than 0.01). This resulted in a higher cholesterol saturation of bile from FCHL patients, 85 +/- 6 vs. 70 +/- 2% (P less than 0.05). After 6 weeks of treatment with acipimox, 750 mg day-1, total plasma triglycerides were lowered from 7.5 +/- 1.5 to 4.6 +/- 0.7 mmol l-1 (P less than 0.05) and plasma cholesterol decreased from 8.0 +/- 0.1 to 7.1 +/- 0.3 mmol l-1 (P less than 0.05) in the FCHL patients. These changes were mainly due to a decrease in very low density lipoprotein concentrations while low density lipoprotein levels remained unaltered. The relative proportion of cholesterol in stimulated fasting duodenal bile was reduced from 6.5 +/- 0.3 to 4.3 +/- 0.5 mol % (P less than 0.01), resulting in 'normalization' of biliary cholesterol saturation, from 85 +/- 6 to 58 +/- 6% (P less than 0.005). No correlations between the changes in biliary lipid composition and those in plasma lipoprotein levels were observed. The results indicate that treatment with acipimox in patients with FCHL, a disorder commonly associated with supersaturated bile, does not increase biliary cholesterol, and presumably not the risk for gallstone formation.     

Relationships between the metabolism of high-density and very-low-density lipoproteins in man: studies of apolipoprotein kinetics and adipose tissue lipoprotein lipase activity

Abstract. In order to gain further insight into the relationship between high-density lipoprotein (HDL) metabolism and plasma triglyceride transport, measurements were made of HDL cholesterol concentration, apoprotein (apo) AI and AII metabolism, very-low-density lipoprotein (VLDL) apo B metabolism, and heparin-elutable adipose tissue lipoprotein lipase (LPL) activity in seventeen subjects with a wide range of plasma triglyceride concentrations (0.8–25 mmol/l).
The fractional catabolic rate (FCR) of VLDL apo B was directly related to LPL activity ( r =+ 0.80), providing evidence that the activity of the enzyme in adipose tissue is a determinant of the rate of lipolysis of VLDL in man. HDL cholesterol concentration was a positive function of both VLDL apo B FCR ( r =+ 0.74) and LPL activity, a finding consistent with previous evidence for the origin of a proportion of HDL cholesterol from 'surface remnants' liberated during VLDL catabolism. The FCRs of both apo AI and apo AII were inversely related to VLDL apo B FCR (AI, r = - 0.52; AII, r = - 0.69) and to LPL activity. The synthetic rate of apo AII, but not that of apo AI, was positively correlated with VLDL apo B synthesis ( r =+ 0.71). Thus, the metabolism of the major proteins of HDL in man appears to be closely associated with VLDL metabolism.     

Role of the liver in the degradation of very low density lipoproteins: a study of lipolysis by heparin releasable liver lipase and uptake during isolated rat liver perfusion

Abstract . The role of the liver and of a heparin-releas-able liver lipase in the metabolism of very low density lipoprotein (VLDL) was investigated in vitro and during recycling rat liver perfusion. Rat plasma VLDL and nascent hepatic VLDL were labelled biosyntheti-cally in their lipid moieties. Incubation in vitro of VLDL with the lipase caused hydrolysis of VLDL-tri-glycerides (>80%) and VLDL-phosphatidylcholine (> 30%). Nascent VLDL was a better substrate for the enzyme. The hydrolytic activities were inhibited by 70–90% when rat plasma (10–30 vol%) was added to the incubation mixture.
VLDL-triglycerides and cholesterol esters were taken up by the liver during 180 min recycling perfusion. The rate of disappearance of nascent VLDL was faster than that of plasma VLDL (half-life times of 56.2 ±13.9 and 125.0±24.8 min respectively). Injection of heparin into the perfusion medium caused accelerated uptake of the hydrolysed VLDL-triglycer-ide by the liver. Addition of plasma ( d > 1.006 g/ml) to the perfusion at a concentration of 10 vol% delayed the rate of disappearance of VLDL from the perfusate by about 50–75%.
These studies have established the capacity of the hepatic lipase to hydrolyse VLDL-lipids and the ability of the liver to degrade nascent and plasma VLDL particles. These two activities, however, are depressed by plasma and therefore previous studies of VLDL metabolism may have to be re-examined when based on incubations or perfusions in the absence of plasma.     

The composition of low (LDL) and very low (VLDL) density lipoprotein subfractions in type III hyperlipoproteinaemia: comparison with normal subjects.

The lipid and protein composition of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) subfractions (Sf greater than 100, 60--100 and 20--60 VLDL and Sf 10.4--20, 5.7--12 and 3.5--6.5 LDL) in six subjects with type III hyperlipoproteinaemia (HLP) was compared to that of 12 normal subjects. In type III HLP all VLDL subfractions contained increased concentrations of cholesterol and triglycerides and were relatively enriched in cholesterol. VLDL of Sf 20--60 also contained and increased concentration of B-protein. The tetramethylurea (TMU) soluble apolipoproteins of the VLDL subfractions were separated by polyacrylamide disc gel electrophoresis. In the subjects with type III HLP the proportion of arginine rich protein (ARP) was increased in all subfractions. The concentrations of cholesterol and triglycerides were increased in the LDL subfraction of Sf 10.4--20 and cholesterol was decreased in LDL of Sf 5.7--12, but the ratios of cholesterol to triglycerides were not significantly different from those in the LDL subfractions of the normal subjects and the protein composition was also similar. These results provide further evidence that in type III HLP abnormalities are not confined to the stage of conversion of VLDL to LDL, but occur throughout the VLDL spectrum.     

High density lipoprotein and other lipoproteins in normolipidaemic and hypertriglyceridaemic (type IV) men with coronary artery disease

Abstract. The aim was to investigate whether a low concentration of high density lipoprotein (HDL) may be used as a risk indicator in normolipidaemic (n.l.) subjects, and whether a reduced HDL concentration constitutes an additional risk factor in hyperlipopro-teinaemia. Eighty-two men with angiographically documented coronary artery disease (CAD) were studied. The majority of the CAD men was either n.l. ( n = 38) or had type IV hyperlipoproteinaemia ( n = 22). These two groups were compared separately to one group of healthy n.l. subjects ( n = 44), and one group of healthy subjects with type IV hyperlipoproteinaemia ( n = 29).
In about 50% of n.l. CAD men the HDL-cholesterol (HDL-C) was lower than the 15th percentile (0.90 mmol/1) of n.l. controls, and about 65% of n.l. CAD men had ratios of HDL-C/total plasma cholesterol (C) lower than 0.17, the 15th percentile of n.l. controls. Almost all type IV subjects had reduced HDL-C levels and decreased ratios of HDL-C/C, whether they had obvious CAD or not. Thus, in normolipidaemia, but not in type IV hyperlipoproteinaemia, a low HDL-C level may be used as an additional risk factor for CAD development.     

A Comparison Between the Enzyme Patterns (GO-T,GP-T,LD) in Serum and Tissue Extracts in Cardiac and Hepatic Diseases

A method is described by which it is possible to demonstrate an activation of the thromboplastic system during extracorporeal circulation.

The principle is the same as used in the three-stage thromboplastin activation test where the thromboplastic activity in the plasma sample is estimated by its ability to induce thromboplastic activity in normal, platelet-rich plasma in the thromboplastin activation test. Heparin is neutralized by the combined addition of protamine sulphate and toluidine blue.     

Metabolic effects of fluvastatin extended release 80 mg and atorvastatin 20 mg in patients with type 2 diabetes mellitus and low serum high-density lipoprotein cholesterol levels: a 4-month, prospective, open-label, randomized, blinded—end point (probe) trial

Background

Diabetic dyslipidemia is characterized by greater triglyceridation of all lipoproteins and low levels of plasma high-density lipoprotein cholesterol (HDL-C). In this condition, the serum level of low-density lipoprotein cholesterol (LDL-C) is only slightly elevated. The central role of decreased serum HDL-C level in diabetic cardiovascular disease has prompted the establishment of a target of ≥50 mg/dL in patients with diabetes mellitus (DM).

Objective

The aim of the study was to assess the effects of once-daily administration of fluvastatin extended release (XL) 80 mg or atorvastatin 20 mg on serum HDL-C levels in patients with type 2 DM and low levels of serum HDL-C.

Methods

This 4-month, prospective, open-label, randomized, blinded—end point (PROBE) trial was conducted at Endocrinology and Diabetology Service, L. Sacco-Polo University Hospital (Milan, Italy). Patients aged 45 to 71 years with type 2 DM receiving standard oral antidiabetic therapy, with serum HDL-C levels <50 mg/dL, and with moderately high serum levels of LDL-C and triglycerides (TG) were enrolled. After 1 month of lifestyle modification and dietary intervention, patients who were still showing a decreased HDL-C level were randomized, using a 1:1 ratio, to receive fluvastatin XL 80-mg tablets or atorvastatin 20-mg tablets, for 3 months. Lipoprotein metabolism was assessed by measuring serum levels of LDL-C, HDL-C, TG, apolipoprotein (apo) A-I (the lipoprotein that carries HDL), and apo B (the lipoprotein that binds very low-density lipoprotein cholesterol, intermediate-density lipoprotein, and LDL on a molar basis). Patients were assessed every 2 weeks for treatment compliance and subjective adverse events. Serum creatine phosphokinase and liver enzymes were assessed before the run-in period, at the start of the trial, and at 1 and 3 months during the study.

Results

One hundred patients were enrolled (50 patients per treatment group; fluvastatin XL group: 33 men, 17 women; mean [SD] age, 58 [12] years; atorvastatin group: 39 men, 11 women; mean [SD] age, 59 [11] years). In the fluvastatin group after 3 months of treatment, mean (SD) LDL-C decreased from 149 (33) to 95 (25) mg/dL (36%; P < 0.01), TG decreased from 437 (287) to 261 (164) mg/dL (40%; P < 0.01), and HDL-C increased from 41 (7) to 46 (10) mg/dL (12%; P < 0.05). In addition, apo A-I increased from 118 (18) to 124 (15) mg/dL (5%; P < 0.05) and apo B decreased from 139 (27) to 97 (19) mg/dL (30%; P < 0.05). In the atorvastatin group, LDL-C decreased from 141 (25) to 84 (23) mg/dL (40%; P < 0.01) and TG decreased from 411 (271) to 221 (87) mg/dL (46%; P < 0.01). Neither HDL-C (41 [7] vs 40 [6] mg/dL; 2%) nor apo A-I (117 [19] vs 114 [19] mg/dL; 3%) changed significantly. However, apo B decreased significantly, from 131 (20) to 92 (17) mg/dL (30%; P < 0.05). Mean changes in HDL-C (+5 [8] vs −1 [2] mg/dL; P < 0.01) and apo A-I (+6 [18] mg/dL vs −3 [21] mg/dL; P < 0.01) were significantly greater in the fluvastatin group than in the atorvastatin group, respectively. However, the decreases in LDL-C (54 [31] vs 57 [32] mg/ dL), TG (177 [219] vs 190 [65] mg/dL), and apo B (42 [26] vs 39 [14] mg/dL) were not significantly different between the fluvastatin and atorvastatin groups, respectively. No severe adverse events were reported.

Conclusions

Fluvastatin XL 80 mg and atorvastatin 20 mg achieved mean serum LDL-C (≤ 100 mg/dL) and apo B target levels (≤ 100 mg/dL) in the majority of this population of patients with type 2 DM, but mean serum HDL-C level was increased significantly only with fluvastatin—16 patients (32%) in the fluvastatin group compared with none in the atorvastatin group achieved HDL-C levels ≥50 mg/dL. The increase in HDL-C in the fluvastatin-treated patients was associated with an increase in apo A-I, suggesting a potential pleiotropic and selective effect in patients with low HDL-C levels.     

The spectrum of electrophoretic mobility of very low density lipoproteins: role of slower migrating species in endogenous hypertriglyceridemia (type IV hyperlipoproteinemia) and broad-beta disease (type III).

To test whether beta-migrating very low-density lipoproteins (VLDL, d less than 1.006) might not be unique to broad-beta disease (with a Type III lipoprotein pattern) but rather a caricature of an intermediate species in the catabolism of triglyceride-rich lipoproteins of normal composition and electrophoretic mobility in nonretarding media, VLDL from subjects with endogenous hypertriglyceridemia (with a Type IV pattern) or broad-beta disease were analyzed under varying dietary and pharmacologic conditions following starch-block electrophoresis. These studies revealed a spectrum in electrophoretic mobility and lipid composition throughout the Sf20 to 400 range: the more buoyant, triglyceride-rich VLDL migrated faster and the denser, triglyceride-poor VLDL more slowly, but the VLDL were broadly and continuously distributed throughout the entire beta to alpha2 regions in both disorders. However, in each subfraction of VLDL (Sf100 to 400, 60 to 100 and 20 to 60) as well as in the whole Sf20 to 400 class, the relative proportion of slower species was greater in the subjects with broad-beta disease than in those with endogenous hypertriglyceridemia. Under conditions of acutely stimulated VLDL production (following an oral fat load), a late increase in the slower species was observed as alimentary lipemia resolved. During chronic VLDL hypersecretion (with high carbohydrate feeding) both faster and slower species increased in a subject with broad-beta disease. In the same subject during clofibrate therapy, the faster species were decreased more than the slower on both normal and high carbohydrate diets. Acute acceleration of VLDL catabolism by heparin administration increased the slower VLDL at the expense of the faster, both in this subject and in a counterpart with endogenous hypertriglyceridemia. These studies are consistent with the hypothesis that slower migrating, triglyceride-poor VLDL are normal intermediate (or remnant) forms in a continuous catabolic process. The concentration of these remnants is dwarfed by that of the faster species in subjects with endogenous hypertriglyceridemia. However, in subjects with broad-beta disease they accumulate as the beta-VLDL characteristic of this disorder, most likely as a result of a relative blockade in their further catabolism.     

Aggressive lipid lowering does not improve endothelial function in type 2 diabetes: the Diabetes Atorvastatin Lipid Intervention (DALI) Study: a randomized,double-blind,placebo-controlled trial

OBJECTIVE: Endothelial dysfunction is considered an important early marker of atherosclerosis and cardiovascular risk and is currently used as a surrogate end point for cardiovascular risk in clinical trials. Type 2 diabetic patients show a characteristic dyslipidemia. Aggressive lipid lowering might be an effective method to improve endothelial function in these patients. RESEARCH DESIGN AND METHODS: A randomized, double-blind, placebo-controlled trial was completed to study the effect of 30 weeks' administration of atorvastatin 10 mg and 80 mg on endothelial function, as assessed by B-mode ultrasound of the brachial artery, in 133 patients with type 2 diabetes without a history of cardiovascular disease. RESULTS: Patients with diabetes and diabetic dyslipidemia had considerable endothelium-dependent and endothelium-independent dysfunction; mean flow-mediated vasodilation (SD) was 3.16% (3.56), and mean response on sublingual nitroglycerin was 6.58% (6.04). Despite substantial lowering of all atherogenic lipid parameters, no improvement of endothelium-dependent vasodilatation was found (P > 0.8). CONCLUSIONS: We observed considerable baseline endothelium-dependent and endothelium-independent dysfunction in patients with diabetes and diabetic dyslipidemia without a history of cardiovascular disease. Aggressive lipid lowering by administration of atorvastatin, resulting in substantial improvement of the lipid profile, did not reverse endothelial dysfunction.     

Circulating secretory type IIA phospholipase A2, lipoprotein (a) and soluble cellular adhesion molecule levels in patients with angina pectoris

Objectives

To examine the plasma levels of secretory type IIA phospholipase A2 (sPLA₂-IIA), lipoprotein (a) [Lp(a)], soluble intercellular adhesion molecule-1 (sICAM-1) and soluble platelet endothelial CAM-1 (sPECAM-1), as well as ICAM-1 (K469E) and PECAM-1 (Leu125Val) gene polymorphisms, in patients with unstable angina pectoris (UAP) and stable AP (SAP).

Design and methods

We enrolled 75 patients with SAP, 72 with UAP and 80 controls without angina. Blood samples were obtained before angiography.

Results

The concentrations of sPLA₂-IIA, sICAM-1 and sPECAM-1 were higher for UAP patients than for SAP patients and controls, and the level of Lp(a) was higher for UAP patients than for controls. Lp(a) and sPLA₂-IIA levels were significantly correlated, and high plasma Lp(a) level (≥ 300 mg/L) was an independent risk factor for angina.

Conclusion

Lp(a) may play an important role in the development of angina. Further research should investigate the role of sPLA₂-IIA, sICAM-1 and sPECAM-1 in UAP.     

13C-labeled mixed triglyceride breath test (13C MTG-BT) in healthy children and children with cystic fibrosis (CF) under pancreatic enzyme replacement therapy (PERT): a pilot study

The MTG-BT estimates the hydrolysis of triacyl-glycerols by pancreatic lipase, and appears attractive for monitoring exogenous lipase requirements in patients with exocrine pancreatic insufficiency. To assess the test's discrimination capacity and repeatability, 9 CF patients with PERT and 10 healthy children underwent the ¹³C-MTG-BT twice, at a 2- to 4-week interval. The test distinguished well between patients with severe exocrine pancreatic insufficiency (SEPI) and healthy subjects. However, within-subject variability for postprandial ‰¹³C-enrichment and postprandial % dose recovery (PDR) was high in both groups. Therefore, the ¹³C-MTG-BT seems useful to distinguish between SEPI and normal exocrine pancreatic function, but requires further development to improve its repeatability.     

Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus: role of lipolytic enzymes, lecithin:cholesterol acyltransferase and lipid transfer proteins

Insulin resistance and type 2 diabetes mellitus are generally accompanied by low HDL cholesterol and high plasma triglycerides, which are major cardiovascular risk factors. This review describes abnormalities in HDL metabolism and reverse cholesterol transport, i.e. the transport of cholesterol from peripheral cells back to the liver for metabolism and biliary excretion, in insulin resistance and type 2 diabetes mellitus. Several enzymes including lipoprotein lipase (LPL), hepatic lipase (HL) and lecithin: cholesterol acyltransferase (LCAT), as well as cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), participate in HDL metabolism and remodelling. Lipoprotein lipase hydrolyses lipoprotein triglycerides, thus providing lipids for HDL formation. Hepatic lipase reduces HDL particle size by hydrolysing its triglycerides and phospholipids. A decreased postheparin plasma LPL/HL ratio is a determinant of low HDL2 cholesterol in insulin resistance. The esterification of free cholesterol by LCAT increases HDL particle size. Plasma cholesterol esterification is unaltered or increased in type 2 diabetes mellitus, probably depending on the extent of triglyceride elevation. Subsequent CETP action results in transfer of cholesteryl esters from HDL towards triglyceride-rich lipoproteins, and is involved in decreasing HDL size. An increased plasma cholesteryl ester transfer is frequently observed in insulin-resistant conditions, and is considered to be a determinant of low HDL cholesterol. Phospholipid transfer protein generates small pre beta-HDL particles that are initial acceptors of cell-derived cholesterol. Its activity in plasma is elevated in insulin resistance and type 2 diabetes mellitus in association with high plasma triglycerides and obesity. In insulin resistance, the ability of plasma to promote cellular cholesterol efflux may be maintained consequent to increases in PLTP activity and pre beta-HDL. However, cellular cholesterol efflux to diabetic plasma is probably impaired. Besides, cellular abnormalities that are in part related to impaired actions of ATP binding cassette transporter 1 and scavenger receptor class B type I are likely to result in diminished cellular cholesterol efflux in the diabetic state. Whether hepatic metabolism of HDL-derived cholesterol and subsequent hepatobiliary transport is altered in insulin resistance and type 2 diabetes mellitus is unknown. Specific CETP inhibitors have been developed that exert major HDL cholesterol-raising effects in humans and retard atherosclerosis in animals. As an increased CETP-mediated cholesteryl ester transfer represents a plausible metabolic intermediate between high triglycerides and low HDL cholesterol, studies are warranted to evaluate the effects of these agents in insulin resistance- and diabetes-associated dyslipidaemia.     

Effects of fosinopril on blood pressure, lipid profile, and lipoprotein(a) levels in normotensive patients with type 2 diabetes and microalbuminuria: An open-label, uncontrolled study

Background: Patients with type 2 diabetes mellitus often have other cardiovascular risk factors, and alterations in lipid profile play an important role. The angiotensin-converting enzyme inhibitors are often used in these patients, particularly those with type 2 diabetes and proteinuria.Objective: This study evaluated the effects of fosinopril therapy on fasting plasma glucose (FPG), lipid profile, and lipoprotein(a), or Lp(a), levels in normotensive patients with type 2 diabetes mellitus and microalbuminuria.Methods: Normotensive (systolic blood pressure [SBP] <130 mm Hg and diastolic blood pressure [DBP] <85 mm Hg) patients with type 2 diabetes and microalbuminuria and a normal lipid profile were enrolled. Patients had their diabetes controlled by diet alone or diet plus oral hypoglycemic agents. Fosinopril 10 mg/d was administered for 6 months and then interrupted for 1 month. FPG, glycosylated hemoglobin, SBP, DBP, lipid profile (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides), Lp(a), albumin excretion rate (AER), and creatinine levels were evaluated at baseline; 1, 3, and 6 months after initiation of treatment; and 1 month after interruption of treatment.Results: A total of 120 patients were enrolled (63 men, 57 women; mean age ± SD, 54 ± 10 years; duration of diabetes, 7 ± 2 years). Significant decreases versus baseline were observed in the following parameters at month 6: SBP (122 ± 7 vs 117 ± 9.1 mm Hg, P < 0.01), DBP (80 ± 4.8 vs 74 ± 4.5 mm Hg, P < 0.05), TC (186 ± 11 vs 176 ± 10 mg/dL, P < 0.05), LDL-C (124 ± 10 vs 114 ± 11 mg/dL, P < 0.05), Lp(a) (24 ± 10 vs 19 ± 7.5 mg/dL, P < 0.05), and AER (103 ± 45 vs 48 ± 21 mg/24 hours, P < 0.01). When fosinopril therapy was interrupted for 1 month, the values for all these parameters tended to return to baseline values; SBP, TC, and Lp(a) values were significantly different from month 6 values, whereas DBP, LDL-C, and AER did not change significantly during the washout period.Conclusions: Fosinopril therapy for 6 months resulted in a reduction of microalbuminuria and an improvement in lipid profile and Lp(a) levels in patients with type 2 diabetes. This suggests that fosinopril may improve lipid profile and reduce Lp(a) levels by lowering proteinuria or by other more direct actions on lipid and Lp(a) metabolism. Additional controlled studies are needed to confirm these results.     

New azole compounds: vibunazole (Bay n7133) and Bay L9139, compared with ketoconazole in the therapy of systemic candidosis and in pharmacokinetic studies, in mice

Ketoconazole, a new imidazole: Bay L9139, and a new triazole: vibunazole (Bay n7133) were compared in therapy of systemic candidosis. CD-1 male mice were challenged with Candida albicans intravenously (greater than LD80), and treated twice a day, orally, for one month. The isolate of Can. albicans used, and isolates obtained after treatment with the antifungals, were susceptible to all three drugs (MICs less than or equal to 0.5 mg/l). No drug was lethal to uninfected mice in doses of 200 mg/kg/day for one month. With therapy started on the day after infection, all three drugs at 50 or 100 mg/kg/day prolonged survival, compared with controls (P less than 0.05), with ketoconazole slightly superior to the other two drugs, but none did so at 25 mg/kg/day. At 200 mg/kg/day ketoconazole and vibunazole were protective, but L9139 was not, and this suggested synergistic toxicity of L9139 with Can. albicans infection, at this dose. With treatment begun on day 4, ketoconazole prolonged survival (P less than 0.005) at 200 or 100 mg/kg/day compared with controls, but ketoconazole at 10-50 mg/kg/day, and vibunazole and L9139 at 10-200 mg/kg/day were ineffective. Survivors had renal lesions and culture-proven residual infection. Pharmacokinetic studies indicated lower peak vibunazole and 9139 serum concentrations, and reduced area-under-curve (AUC), after 26 days of treatment, as against single dose administration. The relative inefficacy of vibunazole and L9139 appears to be related to unfavourable pharmacokinetic properties with continued administration.     

Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 1 diabetes: results of a 6-month, randomized, comparative trial

OBJECTIVE: The aim of this study was to determine whether premeal pulmonary delivery of rapid-acting, dry-powder insulin (Exubera) plus Ultralente could provide glycemic control comparable to a conventional insulin regimen in type 1 diabetes. RESEARCH DESIGN AND METHODS: Three hundred thirty-five subjects were randomly assigned to receive either premeal inhaled insulin plus bedtime Ultralente or two to three injections of regular and NPH insulin for 24 weeks. The primary end point was a change in HbA(1c). RESULTS: Mean decreases in HbA(1c) values were comparable for inhaled (8.1-7.9%) and conventional groups (8.1-7.7%) (adjusted treatment group difference 0.16% [95% CI -0.01 to 0.32]). There were greater reductions for inhaled versus conventional regimen in fasting and postprandial plasma glucose (adjusted mean change differences -25.17 and -30.28 mg/dl, respectively [95% CI -43.39 to -6.95 and -54.58 to -5.97, respectively]). Hypoglycemia (events/subject month) was lower for the inhaled (8.6) versus the conventional (9.0) group (risk ratio, 0.96 [95% CI 0.93-0.99]). In subjects receiving inhaled insulin, increased insulin antibody levels were observed, but there were no associated clinical or laboratory changes. Adverse events were comparable between groups. Mild to moderate cough was more frequent in the inhaled insulin group (27 vs. 5%) but decreased during the treatment. Pulmonary function tests were not different between the groups except for a greater decrease in carbon monoxide diffusing capacity in the inhaled insulin group. Treatment satisfaction was greater in the inhaled than in the conventional group. CONCLUSIONS: Inhaled insulin is effective, well tolerated, and well accepted in patients with type 1 diabetes and provides glycemic control comparable to that with a conventional insulin regimen.     

Efficacy and safety of inhaled insulin (exubera) compared with subcutaneous insulin therapy in patients with type 2 diabetes: results of a 6-month, randomized, comparative trial

OBJECTIVE: Glycemic control using inhaled, dry-powder insulin plus a single injection of long-acting insulin was compared with a conventional regimen in patients with type 2 diabetes, which was previously managed with at least two daily insulin injections. RESEARCH DESIGN AND METHODS: Patients were randomized to 6 months' treatment with either premeal inhaled insulin plus a bedtime dose of Ultralente (n = 149) or at least two daily injections of subcutaneous insulin (mixed regular/NPH insulin; n = 150). The primary efficacy end point was the change in HbA1c from baseline to the end of study. RESULTS: HbA1c decreased similarly in the inhaled (-0.7%) and subcutaneous (-0.6%) insulin groups (adjusted treatment group difference: -0.07%, 95% CI -0.32 to 0.17). HbA1c < 7.0% was achieved in more patients receiving inhaled (46.9%) than subcutaneous (31.7%) insulin (odds ratio 2.27, 95% CI 1.24-4.14). Overall hypoglycemia (events per subject-month) was slightly lower in the inhaled (1.4 events) than in the subcutaneous (1.6 events) insulin group (risk ratio 0.89, 95% CI 0.82-0.97), with no difference in severe events. Other adverse events, with the exception of increased cough in the inhaled insulin group, were similar. No difference in pulmonary function testing was seen. Further studies are underway to assess tolerability in the longer term. Insulin antibody binding increased more in the inhaled insulin group. Treatment satisfaction was greater in the inhaled insulin group. CONCLUSIONS: Inhaled insulin appears to be effective, well tolerated, and well accepted in patients with type 2 diabetes and provides glycemic control comparable to a conventional subcutaneous regimen.