Soybean protein diet increases low density lipoprotein receptor activity in mononuclear cells from hypercholesterolemic patients.

The effect of two diets containing different protein sources (animal vs. soybean) on the low density lipoprotein (LDL) receptor activity was tested in freshly isolated mononuclear cells from 12 individuals with severe type II hyperlipoproteinemia. The two diets, both taken for 4 wk in a crossover design were of otherwise identical composition. During the soybean protein diet period, total cholesterol was reduced by 15.9% and LDL-cholesterol by 16.4%. The diet containing animal proteins exerted no significant change in plasma lipid levels vs. the baseline findings. The soybean diet regimen dramatically affected the degradation of LDL by mononuclear cells. Degradation was increased 16-fold vs. the basal activity and 8-fold compared with the standard low lipid diet with animal proteins. There was, however, no clear relationship between the reduction of total and LDL-cholesterolemia and the increased LDL degradation. These findings confirm similar data previously obtained in cholesterol-fed rats and suggest that some factor/s, most likely of a protein nature, may regulate the expression of lipoprotein receptors in peripheral cells, particularly when receptor activity is suppressed by experimental diets and/or spontaneous hypercholesterolemia.

Lipid effects of celiprolol, a new cardioselective beta-blocker, versus propranolol.

The metabolic effects of celiprolol, a new beta-adrenoceptor blocking agent with intrinsic sympathomimetic activity and alpha 2-blocking properties, were evaluated in a series of patients with hypertension, both with and without hyperlipidemia. Propranolol was tested as the reference drug in a randomized double-blind trial. Of the 35 patients of both sexes who completed the study, 17 were hyperlipidemic (low-density lipoprotein cholesterol greater than or equal to 170 mg/dl) and 18 were normolipidemic. Both drugs exerted a similar hypotensive effect after gradual dose adjustment; however, propranolol reduced heart rate to a higher extent (-20.5%) than celiprolol (-7.7%). Propranolol determined a significant rise of total and very low-density lipoprotein (VLDL) associated triglyceridemia, whereas high-density lipoprotein cholesterol (HDL cholesterol) levels and the total cholesterol/HDL cholesterol ratios were significantly depressed, particularly in hyperlipidemic patients. Celiprolol, in contrast, slightly decreased triglyceridemia (significantly in the hyperlipidemic group at week 12) and caused a 5% increase of the HDL cholesterol levels. The total cholesterol/HDL cholesterol ratio was reduced by celiprolol at week 16 in both hyperlipidemic and normolipidemic patients. The effects of the two beta-adrenoceptor blockers on HDL cholesterol and triglyceride levels differed significantly after 12 and 16 weeks of treatment, which confirm the divergent metabolic effects of the two agents.

Clinical experience with the soybean protein diet in the treatment of hypercholesterolemia.

The efficacy of the total substitution of animal proteins with a textured soybean protein in hypercholesterolemic individuals was assayed in 42 in-patients and 18 out-patients. The in-patients studied followed one of three different crossover protocols: in protocol A, the soybean diet was compared with a standard low lipid diet; protocol B compared two soybean diets, one with added cholesterol, one without; and protocol C compared a soybean diet containing a high P/S fatty acid ratio to one with a low P/S ratio. In all three protocols, the soybean regimen provided valid and reproducible hypocholesterolemic effects that were not modified by the addition of cholesterol. P/S variations appeared, however, to modify the final effect: soybean definitely had a decreased effectiveness with a low P/S (0.1) regimen. The overall plasma cholesterol changes in the 42 in-patients after 3 weeks on the different soybean diet protocols was -20%. Patients with type IIA and IIB hypercholesterolemia provided almost equivalent results, whereas patients with mixed phenotypes (IIB-III) appeared somewhat more sensitive to the dietary effect. Cholesterol decreased mostly in the low density lipoprotein fraction, but some very low density lipoprotein changes were also noted upon variation of the P/S ratio. The out-patients studied provided less satisfactory results. possibly due to the difficulty of adequately complying with the diet. These studies indicate that treatment with the soybean diet is an effective regimen for inducing a significant cholesterol reduction in type II patients refractory to standard low lipid regimens.

Controlled evaluation of fat intake in the Mediterranean diet: comparative activities of olive oil and corn oil on plasma lipids and platelets in high-risk patients.

Activities of low-fat diets with olive oil or corn oil on lipids and platelets were studied in 23 middle-aged patients with high atherosclerosis risk for 8 wk. The olive oil diet had a polyunsaturated-saturated ratio of 0.33 vs 1.28 for the corn oil diet. Plasma total cholesterol was reduced with corn oil, but high-density lipoprotein cholesterol levels were lower with corn oil and unchanged or raised by olive. Plasma apolipoprotein B levels were equally reduced by both diets; apolipoprotein AI and the apo AI:B ratio rose only with olive oil. Plasma-glucose levels were lowered significantly with olive oil. Changes in platelet function were characterized by a reduced sensitivity to arachidonic acid (particularly with corn oil) and to collagen (particularly with olive). An olive oil diet with a moderate fat intake (about 30% of total calories) leads to favorable plasma lipoprotein and platelet changes.

Treatment of hypertriglyceridemia with metformin. Effectiveness and analysis of results.

The triglyceride-lowering effect of metformin (N,N-dimethylbiguanide) was tested in a series of patients with stable hypertriglyceridemia (types IIB, III and IV) and with variable degrees of glucose intolerance. Metformin caused a 38% mean decrease of plasma triglycerides. A selective decrease of very low density lipoprotein cholesterol was observed without reciprocal increase of low density lipoproteins. Thirty patients completed the study. Eighteen, who showed a hypotriglyceridemic effect exceeding 30%, were considered as "Responders"; the other 12, where the effect was negligible, were considered as "Non-Responder". Analysis of the pre-and post-treatment glucose tolerance tests of Responders and Non-Responders showed that the former had, on the average, a normal glucose tolerance and insulin secretion, whereas the latter had an impaired glucose tolerance with increased insulin secretion. These parameters were only slightly modified by metformin. The conclusions of this study support the hypothesis that biguanides exert a triglyceride-lowering effect by decreasing lipoprotein secretion, independent of changes in glucose tolerance and/or insulin secretion.

Efficacy of cholestyramine does not vary when taken before or during meals.

Compliance to cholestyramine treatment, often unsatisfactory, may become further problematic because of the common indication that the resin should not be taken with meals. Since there is no convincing data on the validity of this therapeutic schedule, 10 type IIA hyperlipoproteinemic patients received cholestyramine either before or during the 3 major meals, according to a cross-over protocol. Plasma lipid levels were monitored after 4 and 6 weeks of each treatment schedule. The efficacy of the resin, in terms of total cholesterol (-16.5% together with food vs. -17.2% before food) and of low density lipoprotein cholesterol reduction (-22.8% with food vs. -23.1% before food) did not differ. The side effect profile was also not different between the two treatment protocols. These findings suggest that there are no significant interactions between food and the anion exchange resin and that the hypocholesterolemic effect does not depend upon a specific timing, supposedly close to the gallbladder contraction. They are particularly significant in view of the future availability of new resins in liquid form, suitable for intake during meals.

Ultrasonographic measurement of the common carotid artery wall thickness in hypercholesterolemic patients. A new model for the quantitation and follow-up of preclinical atherosclerosis in living human subjects.

Ultrasound high resolution B-mode imaging of human arteries allows in vivo an accurate and non-invasive determination of the thickness of the intimal-medial complex. A computer assisted procedure to measure this parameter at the level of common carotid arteries was developed. The average difference between duplicate thickness determinations was 4.6%. The thickness of the intimal medial complex of common carotid arteries was then measured in a group of hypercholesterolemic patients. This parameter was significantly greater in these patients as compared to controls (P less than 0.001). The prevalence of small plaques in the carotid arterial tree was also significantly increased in patients. Analysis of data showed that in controls, but not in patients, the thickness of the intimal medial complex increases with age (r = 0.46, P less than 0.05). Within the hypercholesterolemic group, intimal-medial complex values were greater in male patients and in smokers. It is concluded that the common carotid arteries of hypercholesterolemic patients show thickening of the intimal-medial complex. Cigarette smoking, male sex and age increase the extent of this modification. The determination of this parameter using a non-invasive technique may represent an important tool to monitor in vivo the progression and/or the regression of early atherosclerosis in man.

Influence of serum triglycerides on the HDL pattern in normal subjects and patients with coronary artery disease.

The distribution and structure of high density lipoprotein (HDL) subfractions were examined by rate zonal ultracentrifugation in 200 consecutive subjects, 86 of whom showed a stable hypertriglyceridemia, 22 with coronary artery disease. Among the remaining 114 normotriglyceridemic subjects, 75 were healthy and 39 had coronary disease. The serum levels of the HDL2 subfraction were reduced by 22% in the 39 normotriglyceridemic coronary patients, and by 21% in the whole group of hypertriglyceridemic subjects. No difference in the HDL3 levels was found in any of the studied group. There was a clear negative correlation between HDL2 levels and triglyceridemia in the case of healthy people, not in coronary patients. By contrast, triglyceridemia was negatively correlated with the HDL3 flotation rate, both in healthy subjects and coronary patients at all triglyceride levels. Compositional data indicate that in hypertriglyceridemic subjects, HDL2 levels are reduced because of an enhanced transfer-exchanged process between the enlarged VLDL pool and HDL; in contrast, in coronary patients, a defective maturation of the HDL3 particle is the most likely underlying mechanism. Both in hypertriglyceridemic individuals, as well as in coronary patients, the HDL subfraction distribution is rather similar and drastically different from that of normotriglyceridemic healthy subjects. The mechanisms of the two conditions are probably different and, whereas a low concentration of HDL2 is definitely a major risk factor for normotriglyceridemic individuals, in the case of hypertriglyceridemics other factors may come into play in the final determination of the coronary risk.

Pharmacological studies on tiadenol in type IV patients. Evidence for a mechanism of action different from other lipid-lowering drugs.

Tiadenol [bis(hydroxyethylthio) 1-10 decane], a new absorbable hypolipidemic agent differing in chemical structure from clofibrate and related compounds, was tested in hypertriglyceridemic patients, both responsive and nonresponsive to dietary treatment. Tiadenol administration was remarkably effective in inhibiting fructose induced hypertriglyceridemia in diet responsive type IV patients; it was ineffective in patients with stable, diet refractory, hypertriglyceridemia. The significant reduction of plasma triglycerides (-42%) in sensitive patients, was not accompanied in this study, by the activation of plasma lipoprotein and hepatic lipases. In a second, longer term investigation of stable type IV patients, tiadenol administration resulted in significant triglyceride decreases in the very low density lipoproteins (VLDL) (-45%), as well as in the low and high density lipoproteins (LDL and HDL) (both -25%). The cholesterol content of LDL and HDL was not modified. In VLDL a significant reduction of apoprotein E was observed (from 15.2 +/- 4.9 to 11.9 +/- 5.9% of VLDL proteins). The reported observations are consistent with a difference in the mode of action of tiadenol from that of other lipid lowering agents, particularly of the clofibrate type.

Therapy with HMG CoA reductase inhibitors: characteristics of the long-term permanence of hypocholesterolemic activity.

Treatment with hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors has gained considerable success in the management of hypercholesterolemia. A large number of studies have shown the efficacy of these drugs in lowering plasma total and low density lipoprotein (LDL) cholesterol levels, but there have been less studies evaluating their effectiveness in standard clinical practice, particularly relating to the maintenance of hypocholesterolemic activity. In the present study, the long-term effectiveness of HMG CoA reductase inhibitors has been tested in 177 patients with familial hypercholesterolemia (FH) who had been on statin therapy (simvastatin or pravastatin) for at least 12 months and up to 5 years or longer. The mean 'dose normalized' LDL cholesterol reduction in the whole group was around 20%. However, in spite of a generally good efficacy of both statins in lowering total and LDL cholesterol, a wide variety of responses, either after short- or long-term treatment, was noted. Individual responses were calculated and patients classified into three different groups: (a) responders, (b) non-responders, and (c) response losers. Of the 177 patients, 4% did not respond to treatment and a further 10% showed an initial unsatisfactory response (LDL cholesterol reduction < or = 10%). Another 10% experienced a progressive loss of response over time. There appeared to be little difference between the two treatments in the long-term efficacy and no predictive index could be established. Treatment with HMG CoA reductase inhibitors is generally effective and well tolerated, but a non-negligible number of patients may show a primary non-response or a progressive loss of response.

Reduced triglyceridemia and increased high density lipoprotein cholesterol levels after treatment with acipimox, a new inhibitor of lipolysis.

Acipimox (5-methylpyrazine carboxylic acid 4-oxide) is a new inhibitor of lipolysis with long-lasting activity, whose plasma lipid lowering potential was demonstrated in early clinical trials. The hypolipidemic effect of acipimox was investigated in two double-blind cross-over trials versus placebo. The first trial, carried out in 12 type IV patients, showed a significant triglyceride lowering effect (-35%) following 4 weeks of drug administration at a 250 tid dose. The same regimen, maintained for 9 weeks in 18 type IIA patients, failed to induce a significant reduction of total cholesterolemia. However, in 10 subjects, in whom lipoprotein cholesterol fractionation was carried out, a significant reduction of low density and highly significant increase in high density lipoprotein cholesterol levels (respectively -11% and +20%) were observed.

Clofibrate and tiadenol treatment in hyperlipoproteinemias. A comparative trial of drugs affecting lipoprotein catabolism and biosynthesis.

Changes in plasma lipoprotein levels and platelet reactivity were evaluated during sequential treatments with clofibrate and tiadenol, two hypolipidemic agents with apparently different mechanisms, in 27 hyperlipoproteinemic patients. The objective of the study was to determine the pattern of plasma lipoprotein variations, induced by a drug mainly affecting lipoprotein catabolism (clofibrate) and by a drug affecting biosynthesis (tiadenol), and to single out-patients specifically responding to either treatment. Both drugs proved significantly active in type IIA and IV hyperlipoproteinemias, not in type IIB. Clofibrate significantly lowered very low density lipoprotein (VLDL) associated cholesterol in all three hyperlipoproteinemia phenotypes, and it also lowered VLDL triglycerides in type IV, while increasing high density lipoprotein (HDL) cholesterol in type IIA patients. Low density lipoprotein (LDL) cholesterol levels were minimally reduced by clofibrate in type IIA (-4%), and increased in types IIB (+ 14.2%) and IV (+ 6.1%) patients. Conversely, tiadenol lowered VLDL cholesterol and triglycerides to a lesser extent, but it did significantly reduce LDL cholesterolemia in type IIA (-17.6%), while increasing HDL cholesterol in type IIB. Statistical evaluation of the results did not permit identification of parameters associated with the response to either drug, although individuals specifically responding to one or the other agent, or to both, were detected in all three phenotypes. The sensitivity to the major platelet aggregating factors, ADP, adrenaline and collagen, was not significantly altered after drug treatments. Evaluation of the hypolipidemic response to agents with different mechanisms may be of help in selecting the best treatment for individual patients.

Changes in high-density lipoprotein subfraction distribution and increased cholesteryl ester transfer after probucol.

The effects of probucol (500 mg twice daily) on high-density lipoprotein (HDL) subfractions and cholesteryl ester transfer from HDL to lower density lipoproteins were tested in a series of patients with Type II hypercholesterolemia. In this placebo-controlled crossover trial, patients received probucol or placebo for 8 weeks, then switched to the other agent for another 8 weeks. Probucol significantly lowered total, low-density lipoprotein and HDL cholesterol levels. HDL subfractions, separated by rate zonal ultracentrifugation, showed a dramatic reduction in HDL2, whereas changes in HDL3 were not significant. Both subfractions eluted at a characteristically lower volume, indicating a reduced flotation rate. These findings were confirmed by gradient gel electrophoretic separation, which showed a typical reduction or disappearance of HDL2b particles and the prevalence of particles in the HDL3a-HDL3b electrophoretic range in almost all patients. After treatment, cholesteryl ester transfer from HDL to lower density lipoproteins was significantly increased in all patients. These data suggest that probucol may accelerate HDL particle conversion, leading to improvement in reverse cholesterol transport from the periphery to the liver, through HDL and very low density lipoprotein.

Relation between the HDL apoproteins and AI isoproteins in subjects with the AIMilano abnormality.

The apoprotein AIMilano (AIM) is the first described molecular abnormality of human apolipoproteins. In order to achieve a better understanding of the biochemical role of high density lipoproteins (HDL) and of their subcomponents, nine members of the AIM family were studied. Five showed the characteristic biochemical features of the AIM abnormality. All were hypertriglyceridemic; their plasma and very low density lipoprotein (VLDL) triglycerides had a significant negative correlation with the HDL cholesterol (HDL-C) levels (r = -0.961, p less than 0.01 and r = -0.939, p less than 0.05, respectively). Compositional studies of HDL in these subjects revealed a marked triglyceride (TG) enrichment, with reduced cholesterol content. HDL-C and/or phospholipid (PL) levels correlated significantly with the AIM apoprotein in HDL (r = 0.995, p less than 0.001 for HDL-C and r = 0.994, p less than 0.001 for HDL-PL) but not with the other HDL apoproteins, suggesting that only apo AIM in monomeric form, can bind lipids. Isoelectric focusing studies on the isolated AIM isoproteins from the five affected subjects revealed an isoprotein distribution markedly different from normal AI. A possible structural role for isoprotein AI1 is suggested by the strong correlation between HDL content of this isoprotein and HDL-C and HDL-PL levels (r = 0.965 and r = -0.990 respectively, both p less than 0.001). AI4 and AIM was nearly doubled, as compared to normal AI. The reported results may be of help for a better understanding of the role of the major HDL apoprotein and of its isoproteins in lipid binding and lipoprotein metabolism.

Meta-analysis of the relationship between asymptomatic bacteriuria and preterm delivery/low birth weight.

The relationship between asymptomatic bacteriuria and prematurity/low birth weight (LBW) is still a controversial issue, despite many studies. Meta-analysis, a research tool designed to analyze and combine the results of previous studies, may resolve this discrepancy among contradictory results of clinical trials. The purpose of this study was to examine the relationship between asymptomatic bacteriuria and preterm delivery/LBW using meta-analysis. Reports from the literature were classified according to study design into cohort or randomized-treatment control trials. Meta-analysis of cohort studies showed that untreated asymptomatic bacteriuria during pregnancy significantly increased rates of LBW and preterm delivery. Nonbacteriuric patients had only about two-thirds the risk (typical relative risk = 0.65; 95% confidence interval 0.57, 0.74) of LBW and half the risk (typical relative risk = 0.50; 95% confidence interval 0.36, 0.70) of preterm delivery of those with untreated asymptomatic bacteriuria. These reduced risks correspond to a 3.4 (confidence interval 1.8, 5.0) percentage-point difference in LBW and a 3.8 (1.1, 6.4) percentage-point difference in preterm delivery. The analysis of randomized clinical trials showed that antibiotic treatment significantly reduced the risk of LBW (typical relative risk = 0.56; 95% confidence interval 0.43, 0.73), with a substantial reduction of 6.4 (confidence interval 3.3, 9.5) percentage points in the rate of LBW. We conclude that clinical and epidemiologic evidence indicates a strong association between untreated asymptomatic bacteriuria and LBW/preterm delivery and that antibiotic treatment is effective in reducing the occurrence of LBW.

Ureteropelvic junction obstruction in utero and ex utero.

Seventy cases of ureteropelvic junction obstruction, bilateral or unilateral, were followed prospectively throughout gestation and postnatally for an average of 2.3 years. Cases of ureteropelvic junction obstruction with a renal pelvis dilated less than 1 cm uniformly did well; those with a pyelectasis more than 2 cm, both bilateral and unilateral, had a favorable outcome in approximately three-quarters. Surprisingly, pelvis dilatation between 1-2 cm had a better outcome if bilateral than if unilateral.

Is genital colonization with Mycoplasma hominis or Ureaplasma urealyticum associated with prematurity/low birth weight?

Mycoplasma species have been implicated in the pathogenesis of prematurity, intrauterine growth retardation, low birth weight (LBW), and preterm premature rupture of membranes. The purpose of this study was to review the available literature to determine whether there is an association between genital colonization with Mycoplasma hominis or Ureaplasma urealyticum and prematurity/LBW. Twelve studies were reviewed: nine cohort studies, two case-control studies, and one randomized clinical trial of treatment. The overall isolation rate of M hominis from the genital tract was 27.2%, whereas that of U urealyticum was 70.4% (cohort studies). Results from the randomized clinical trial showed that treatment did not alter the rate of prematurity in women carrying mycoplasma species in the genital tract. None of the cohort studies supported an association between genital colonization with U urealyticum and prematurity/LBW. Similarly, no association between M hominis and prematurity/LBW could be demonstrated in seven of the eight and in six of the eight cohort studies, respectively. On the other hand, two case-control studies showed an association between U urealyticum colonization and prematurity without an association with M hominis. We conclude that the weight of the evidence does not support an association between genital colonization with mycoplasma species and prematurity/LBW.

New microporous cholestyramine analog for treatment of hypercholesterolemia.

A new, microporous, uniformly reticulated preparation of cholestyramine is described. The preparation, cholpor, has a higher exchange capacity for chloride than does cholestyramine and swells very little in water. It is 15--20% more potent than chloestyramine in the in vitro binding of sodium cholate; moreover, the binding velocity is considerably higher than that of cholestyramine. Colestipol hydrochloride, also used as a reference anion-exchange resin, is about half as potent as the other two resins; its binding velocity is similar to that of cholpor. Cholpor may be prepared in a suspension form of good palatability. Preliminary clinical findings in short-term trials showed a cholesterol-lowering effect similar to that of cholestyramine with lower doses and fewer side effects.

Detection and management of anatomic congenital anomalies. A new obstetric challenge.

Whereas once the obstetrician was primarily concerned with diseases affecting the mother, the scope of antenatal fetal care has expanded to include a broader range of fetal diseases such as growth disorders and congenital anomalies. The feasibility of identifying congenital anomalies before birth has created an entirely new field of obstetrics. The specialist is now expected to be informed about the differential diagnosis, pattern of inheritance, mechanism of disease, prognosis, optimal obstetric management of the pregnancy, and counseling for future pregnancies.

Metabolic approach to the diagnosis and treatment of atherosclerotic peripheral vascular disease.

Metabolic and clinical peculiarities of patients with peripheral vascular disease (PVD) were evaluated in two studies. In the first study lipid and lipoprotein composition of 20 patients with PVD were examined. Twelve of these patients were normolipidemic, the other 8 hypertriglyceridemic. Ten normolipidemic and ten hyperlipidemic age-matched subjects served as controls. High density lipoprotein cholesterol (HDL-C) levels were markedly reduced in the hypertriglyceridemic, both with (35.1 +/- 5.0 mg/dl) and without (36.2 +/- 11.7 mg/dl) PVD as compared to the normolipidemic patients (47.0 +/- 6.3 mg/dl) and controls (48.1 +/- 10 mg/dl). All the PVD patients showed an increased apolipoprotein B content in the very low density lipoproteins (VLDL) as compared to controls (p less than 0.001). A significant correlation between VLDL-cholesterol and apo B levels was detected in both groups; however, two distinct populations could be clearly separated (slopes of the regression lines: PVD patients = 0.350; controls = 0.215, p less than 0.0001). These data suggest a possible discriminatory power of VLDL-apo B levels in PVD patients independent of other metabolic parameters. In the second study, the clinical activity of metformin (N, N-dimethylbiguanide) a widely used antidiabetic agent, on arterial blood flow was evaluated in 15 patients with PVD. Flow was determined by quantitative strain-gauge plethysmography during a cross-over trial, comparing 6 months of drug and placebo administration. Metformin (850 mg tid) significantly increased arterial flow after a standardized ischemia in both sequences. In spite of the minimal changes of plasma lipid levels during metformin, a highly significant increase of HDL-C levels (+8.3% during the whole treatment) was demonstrated. Plasma levels of isoprotein AI-1 were also raised during the metformin period. Although the mechanism/s of the beneficial effects of metformin on flow cannot, at present be defined, the reported results underline the significant therapeutic potential of this metabolic drug treatment in PVD.