Peripheral inflammatory response in Alzheimer's disease and multiinfarct dementia.

Whether peripheral inflammatory molecules can be considered markers of dementia is still an open issue. We have investigated the presence of circulating cytokines and the ability of blood cells to release them in response to an inflammatory stimulus in patients with different types of dementia and in age-matched controls. A significant increase in circulating interleukin-1beta in moderate Alzheimer and in multiinfarct (145 and 224 times control concentration, respectively) dementia and in circulating tumor necrosis factor-alpha concentration in multiinfarct dementia patient group (156%) were found. Tumor necrosis factor-alpha and interleukin-6 released from blood cells after exposure to lipopolysaccharide were significantly reduced in moderate Alzheimer (60%, both cytokines) and multiinfarct patients (71 and 50%, respectively), while interleukin-10 was decreased only in multiinfarct patients (61%). The results show that patients with Alzheimer disease or multiinfarct dementia have an upregulation of circulating cytokines and a downregulation of cytokines released by blood cells.

Inflammatory markers in Alzheimer's disease and multi-infarct dementia.

Inflammation has been involved in the pathogenesis of dementia. The study evaluates the presence and the source of pro- and anti- inflammatory cytokines in the blood of patients with Alzheimer's disease (AD), multi-infarct dementia (MID) or in non-demented elderly people (controls). Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-10, IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptor I (sTNF-RI) plasma concentrations and release from blood cells stimulated with lipopolysaccharide (LPS, 1 microg/ml) were determined. The results show that TNF-alpha released from blood cells is significantly decreased (27%) in all demented patients compared to controls. Circulating TNF-alpha is increased (400%) only in MID patients. In these patients plasma levels of sTNF-RI are increased (53%) and IL-10 from stimulated blood cells decreased (47%) compared to non-demented subjects. The results show that: (1) peripheral production of TNF-alpha is blunted in demented (both AD and MID) patients compared to non-demented age-matched subjects; (2) AD patients have a selective disregulation of the peripheral TNF-alpha system; (3) different cytokines are up- or down- regulated in MID patients showing that in this condition the pro- and anti-inflammatory peripheral cytokine system is more widely affected.

Apolipoprotein E and intronic polymorphism of presenilin 1 and alpha-1-antichymotrypsin in Alzheimer's disease and vascular dementia.

Apolipoprotein E (ApoE) genotypes, presenilin 1 (PS-1) and alpha(1)-antichymotrypsin (ACT) polymorphism and the association of the genotypes were examined in patients with Alzheimer's disease (AD, n = 121) or vascular dementia (VD, n = 68) in comparison with elderly controls (n = 125). The frequency of the ApoE epsilon 4 allele was significantly increased both in late-onset AD (0.35) and in VD (0.17); the frequency of ApoE epsilon 2 was significantly reduced in AD, but it was similar in VD and controls. The presence of the allele 1 of PS-1 intronic polymorphism was not associated with AD or VD and was not influenced by the ApoE genotypes. Also, the frequency of allele A of the intronic polymorphism of ACT was similar in AD, VD and controls and it was not altered by ApoE or PS-1 genotypes. The results confirm the association between ApoE epsilon 4 and AD and indicate an increase in ApoE epsilon 4 in Vd, too. A potential protective role of ApoE epsilon 2 is also suggested for late-onset AD but not for VD. No association was shown between ACT allele A and PS-1 allele 1 in AD or VD.

[Pravastatin in the treatment of primary hypercholesterolemia: a Swiss multicenter study]. / Pravastatin zur Behandlung der primären Hypercholesterinämie: Schweizer Multizenter-Studie.

Conventional lipid-lowering agents displayed only limited efficacy in lowering total and LDL cholesterol and a high incidence of side effects. Pravastatin is a new potent cholesterol-lowering agent, which selectively inhibits hepatic HMG-CoA-reductase. In a double-blind, placebo-controlled Swiss multicenter study with determination of lipids and lipoprotein in a central laboratory, the efficacy and safety of 6 months' therapy with pravastatin was evaluated in 50 patients with mild hypercholesterolemia and additional coronary risk factors. Compared to baseline and after 26 weeks' therapy, pravastatin significantly reduced total cholesterol (pravastatin vs placebo, -17% vs +7%, p < 0.0001) and LDL cholesterol (-26 vs +2%, p < 0.0001). The total/HDL cholesterol ratio ( = "atherogenic index") was comparable in the two groups at baseline (5.9 +/- 1.1 vs 6.3 +/- 0.9), and was distinctly lowered by pravastatin but not placebo (-20 vs 0%, p < 0.0001). In 11 patients in whom the reduction of serum total cholesterol after 13 weeks' treatment with 20 mg pravastatin was still below target (on average -9.1%), doubling of the dose produced a further decrease of 4.3%. Serum HDL cholesterol and serum triglyceride levels did not change significantly during pravastatin treatment as compared to baseline and placebo. Pravastatin was well tolerated during the 26 weeks without relevant subjective side-effects. There were 5 dropouts during the study, 2 patients in the pravastatin group and 3 in the placebo group. These findings document that pravastatin, administered in a single daily dose of 20 to 40 mg, effectively lowers serum cholesterol and total-/HDL-cholesterol improving action and is well tolerated.

Aortic and coronary atheromatosis in a woman with severe hypercholesterolaemia without LDL receptor alterations.

Familial hypercholesterolaemia (FH) is a monogenic disorder, with a strong family history, characterized by a deficiency in functional receptors for low density lipoproteins (LDL). The case of a patient with all the clinical traits of FH, including elevated cholesterol, xanthomas and early coronary and peripheral arterial lesions, but with a normal LDL receptor function, is described. In the patient the molecular weight and immunological properties of apolipoprotein (apo) B were normal; furthermore, autoantibodies to either LDL or to their receptor were also absent. The increased apo B/cholesterol ratio in LDL was compatible with the diagnosis of hyperapobetalipoproteinaemia. With the help of a turnover study using 131I homologous and 125I autologous LDL, it could be established that the patient had an almost three-fold increase in LDL-apo B biosynthesis, with, however, a fractional catabolic rate within normal limits. These findings pointed to the possibility of a genomic alteration in the region responsible for the control of apo B biosynthesis. However, extensive studies both at the cDNA level and in the 5' region of the apo B gene, failed to detect any significant alteration vs published nucleotide sequences. Although the exact mechanism for this unusual clinical presentation of an FH-like syndrome could not be uncovered, this case provides an extreme example of hypercholesterolaemia, with early and severe arterial disease, solely explained by an increased LDL biosynthesis.

Therapeutic efficacy of the HMG-CoA-reductase inhibitor pravastatin in hyperlipoproteinaemia type II.

The efficacy and safety of the HMG-CoA-reductase inhibitor pravastatin was assessed in a double-blind, placebo controlled study. Thirty patients (51 y) with hyperlipoproteinaemia Type IIa (N = 22) or IIb (N = 8) received for 16 weeks either pravastatin 5 mg b.d. for 8 weeks followed by 10 mg b.d. for 8 weeks (Group I), or 10 mg b.d. for 8 weeks followed by 20 mg b.d. to 16 weeks (Group II), or placebo (Group III). In Groups I and II, mean serum total cholesterol was reduced by -26% and -22%, respectively; low-density lipoprotein (LDL)-cholesterol decreased by -28% and -27%, apolipoprotein B by -25% and -23%, and apolipoprotein E by -9% (NS) and -16%, respectively. Serum high-density lipoprotein (HDL)-cholesterol was increased by 11% in Group II, and so the total/HDL-cholesterol ratio fell by 33%. Apoprotein A1 and A2 were not significantly changed. No serious clinical and laboratory abnormalities were observed. The data suggest considerable therapeutic efficacy of pravastatin in the treatment of Type II hyperlipoproteinaemia.

Comparative absorption kinetics of imidazole and salicylic acid in volunteers after administration of ITF 182 tablets and suppositories.

Comparative absorption kinetics in volunteers of a new antiinflammatory drug (Selezen), in the form of 750 mg tablets and suppositories, were studied. The two components of the drug, imidazole and salicylic acid were found in plasma. Pharmacokinetic parameters were calculated according to a first order absorption. Salicylic acid showed a maximum concentration 59.2 +/- 5 min and 75.4 +/- 7.6 min after the administration of the tablet and suppository respectively; and imidazole after 86.3 +/- 10.8 min and 75.2 +/- 5.4 min, respectively.

Apolipoprotein A-IMilano. Correlation between high density lipoprotein subclass distribution and triglyceridemia.

Carriers of the apolipoprotein A-IMilano (apo A-IM) variant represent a selected group of subjects showing low levels of high density lipoprotein (HDL), variable hypertriglyceridemia, and low prevalence of atherosclerotic vascular disease. The distribution of HDL subfractions and the correlation with abnormalities in triglyceride transport were determined in these subjects. Sera from 24 apo A-IM carriers (A-IM+ and from age- and sex-matched normolipidemic controls (A-IM-) were analyzed by rate zonal ultracentrifugation. The A-IM+ subjects showed a marked decrease of HDL3 mass with reduced flotation rates and major compositional alterations; the HDL2 were nearly absent. The HDL subclasses from 10 A-IM+ subjects were resolved according to particle size by gradient gel electrophoresis (GGE). The HDL patterns detected in the carriers were unique in exhibiting a distinct peak in the (HDL3b)gge interval, undetectable in the controls. Three patterns reflecting the relative contributions of smaller (HDL3b)gge and larger (HDL3a)gge particles could be distinguished in the carriers, and these were clearly related to different triglyceride and HDL cholesterol levels in plasma. These findings in a highly selected group of subjects with generally low HDL levels and quite variable triglyceridemia confirmed the existence of relationships between alterations in triglyceride transport and abnormalities in the HDL subclass distribution, possibly reflecting the variable atherosclerotic risk in hypertriglyceridemic subjects.

Hypercholesterolaemia treated by soybean protein diet.

After a period of stabilisation on a controlled low lipid low cholesterol diet with animal proteins a group of 16 children with familial hypercholesterolaemia were given a textured soybean protein based diet, with a similar fat composition. All the children had a highly significant reduction in total cholesterol, averaging -21.8% against the baseline after eight weeks. Compliance became less strict afterwards, but more than half of the patients have regularly continued the diet and results have been maintained for one year. Minimal changes were noted in triglyceridaemia and in high density lipoprotein cholesterol concentrations, which showed a slight rise only at the end of treatment. The children's growth during the trial was normal. In view of the psychological difficulties of prescribing treatment with drugs to children with severe hypercholesterolaemia before puberty and of the relative ineffectiveness of standard low lipid diets in this condition the soybean protein diet may offer a satisfactory alternative.

Pharmacokinetics of defibrotide in healthy volunteers.

A pharmacokinetic study of defibrotide, an antithrombotic polydeoxyribonucleotide extract, was performed in 5 healthy volunteers after rapid intravenous injection at three different doses: 0.5, 4 and 16 mg/kg. Defibrotide was given to 2 additional healthy volunteers by slow perfusion of 600 mg over 6 h, after a 200-mg intravenous bolus injection. The blood levels of defibrotide were determined by a method supplied by Crinos (detection of 6-desoxyribose). A one-compartment model was used to describe the kinetics of the drug in plasma. All the most important pharmacokinetic parameters (i.e. elimination constant, half-life, AUC and volume of distribution) were dose dependent. The half-lives were 9.8 min at 0.5 mg/kg, 14.2 min at 4 mg/kg and 21.1 min at 16 mg/kg. The dose-response curves for elimination indicated saturation. During slow infusion following the bolus injection a steady state was reached at 90-120 min, with a blood level of 10-15 micrograms/ml.

[Modification of serum lipids, lipoproteins and apoproteins AI and B in patients with hyperlipidemia Type IIa and IIb using polyenylphosphatidylcholine]. / Beeinflussung der Serumlipide, -lipoproteine und -apoproteine AI und B bei Patienten mit Hyperlipidämie Typ IIa und IIb durch Polyenylphosphatidylcholin.

In a double blind study 27 patients with type II hyperlipidemia (8 IIa and 19 IIb) were treated as follows: 13 received placebo and 14 sn-polyenylphosphatidylcholin (PPC) (P 0206/1/01, Nattermann GmbH, Cologne) in a dose of three times 450 mg b.i.d. In all patients, and also in the two subclasses of patients with type IIa and type IIb hyperlipidemia, total cholesterol and LDL cholesterol were lowered significantly by PPC. The other parameters showed only minor variation. There was a downward trend in apoprotein B, triglycerides and VLDL cholesterol, and an upward trend in apoprotein AI, with virtually unchanged HDL cholesterol. None of these variations was significant compared with placebo. The fall in LDL cholesterol with unchanged HDL cholesterol caused a statistically significant decrease in the LDL cholesterol/HDL cholesterol ratio, thus supporting the hypothesis of an antiatherogenic property of PPC, as demonstrated experimentally in various animals.

[Effective long-term treatment of primary hyperlipoproteinemias with bezafibrate]. / Wirksame Langzeitbehandlung primärer Hyperlipoproteinämien mit Bezafibrat.

Bezafibrate, a new hypolipidemic agent, was evaluated in a single blind, placebo-controlled study lasting 14 months to 3 years in 40 patients with primary hyperlipoproteinemia of various types (23 patients with type II, 15 with type IV and 2 with type V). Bezafibrate in a dose of 200 mg 3 times daily reduced total serum cholesterol by an average of 17% (p less than 0.001) in hyperlipoproteinemia type II and by 24% (p less than 0.001) in type IV or V, lowered serum triglycerides by 31% (p less than 0.001) in hyperlipoproteinemia type II and by 58% (p less than 0.001) in type IV or V, while high-density-lipoprotein-cholesterol was increased by 17% (p less than 0.001) in type II and by 36% (p less than 0.001) in type IV or V. The few side effects encountered were only mild and transient. These findings show that bezafibrate affords safe and effective long-term treatment of patients with hyperlipoproteinemia.

Controlled evaluation of pantethine, a natural hypolipidemic compound, in patients with different forms of hyperlipoproteinemia.

Pantethine (P), the stable disulphate form of pantetheine, major component and precursor of coenzyme A, was evaluated within a double-blind protocol (8 weeks for P or for a corresponding placebo) in 29 patients, 11 with type IIB hyperlipoproteinemia, 15 with type IV, and 3 with an isolated reduction of high density lipoprotein cholesterol (HDL-C) levels. In type IIB patients, P (300 mg t.i.d.) determined a highly significant lowering of plasma total and low density lipoprotein (LDL) associated cholesterol (-13.5% for both parameters). In the same patients, HDL-C levels increased about 10% at the end of treatment. Switching from P to placebo was associated with a rapid return to the baseline cholesterolemia. Both in type IIB and type IV patients, plasma triglyceride levels were reduced around 30%, when P was given as the first treatment; when it was preceded by placebo, reductions were less striking (respectively, -17.8% for type IIB and -13.0% for type IV, at the end of P treatment). HDL-C levels were not increased by P, either in type IV, and in the patients with low HDL cholesterolemia. In type IV, LDL cholesterol levels showed a variable response to P: they tended to increase when below 132 mg/dl, prior to treatment, and to be reduced when above this level. This study provides evidence for a significant hypocholesterolemic effect of P, a natural compound free of overt side effects. It also indicates that P may raise HDL-C levels in type IIB patients, while moderately reducing triglyceridemia.

[Separation of high density lipoproteins (HDL) using zonal ultracentrifugation in patients with apolipoprotein AI Milano variant]. / Trennung der Lipoproteine hoher Dichte (HDL) mittels zonaler Ultrazentrifugierung bei Patienten mit der Apolipoprotein-AIMilano-Variante.

Investigations of HDL with zonal ultracentrifugation were carried out in three patients with apolipoprotein AIMilano. HDL in patients with AIMilano apolipoprotein are characterized by the practically total absence of HDL2. The HDL3 peak is broader than normal. In spite of the marked reduction or practically total absence of HDL2, which is believed to be a protective factor against atherosclerosis, our patients show no signs of clinical atherosclerosis.

[Acipimox treatment of hyperlipidemia type II]. / Behandlung der Hyperlipidämie Typ II mit Acipimox.

The hypolipidemic effect of acipimox, a new inhibitor of lipolysis, was investigated in a double blind crossover trial versus placebo. The trial showed an appreciable and significant reduction in total cholesterol (-14%) and of LDL cholesterol (-20%), a slight but significant increase in HDL cholesterol (+6%), and only a slight diminution of triglycerides and VLDL cholesterol.

Reduced apoprotein B and increased lipoprotein turnover in cholesterol-fed rabbits after partial ileal bypass.

Plasma lipid and lipoprotein levels and composition of the very low-, low-, and high-density lipoproteins (VLDL, LDL, HDL) were studied in white New Zealand rabbits in the control state, 8 weeks after initiation of a 2% cholesterol-enriched diet, and sequentially for 16 weeks following a partial ileal bypass (PIB) procedure. Turnover and aortic uptake of 125I-labeled VLDL, obtained from the rabbits before and 16 weeks after PIB, were also analyzed. A significant reduction of plasma cholesterol from the postdiet levels to well below the prediet mean, despite continuation of the high cholesterol diet, followed PIB. A very early reduction of the apoprotein B percentage content in both VLDL and LDL was observed after the procedure, even when a relative cholesterol ester enrichment of these lipoproteins was still present. HDL cholesterol levels were somewhat lowered by the experimental diet and further reduced after PIB. 125I-labeled VLDL after PIB showed a reduced arterial uptake, as compared to the same lipoproteins from animals before PIB. These findings may provide an interpretation for the decreased atherogenesis after PIB.

[The therapeutic efficacy of bezafibrate in hyperlipoproteinemias of various types]. / Therapeutische Wirksamkeit von Bezafibrat bei Hyperlipoproteinämien verschiedenen Typs.

17 patients with hyperlipoproteinemia of type 11 (9 type IIa and 8 type IIb), 4 with hyperlipoproteinemia of type IV and 1 with hyperlipoproteinemia of type V were treated for 4.6 +/- 0.7 months with the new lipid lowering agent bezafibrate in a dose of 200 mg three times daily. Bezafibrate markedly lowered total serum cholesterol and triglycerides and increased HDL-cholesterol in each of these types of hyperlipoproteinemia. These data suggest that bezafibrate may be effective in reducing the possibly atherogenic LDL- and VLDL-fractions while increasing the antiatherogenic HDL-fraction.

Multicentre study of soybean protein diet for outpatient hyper-cholesterolaemic patients.

The animal proteins in a low-lipid, low-cholesterol diet were substituted with a textured soybean preparation for 127 outpatients with stable type II hyperlipoproteinaemia selected from eight Italian and one Swiss lipid clinics. Eight weeks of the modified diet reduced plasma cholesterol by 23.1% in the 67 participating male patients and by 25.3% in the 60 females. No significant changes in plasma triglycerides, high-density lipoprotein cholesterol, and body weight were recorded. Better reductions in plasma cholesterol occurred in non-familial cases and in very young male patients. The acceptable taste of the soybean preparation used in this study, and its easy handling, indicate that this type of dietary treatment may be suitable for outpatients.