Analytical performance characteristics of thin and thick film amperometric microcells.

The analytical performance of amperometric microcells with different electrode geometries is compared for enzyme activity measurements. The microcells were fabricated with thin film photolithography or thick film screen-printing in four different designs. The cells made with the thin film process used flexible substrate with microelectrode array or a circular, disk-shaped working electrode. The screen-printed working electrodes had semicircle or disk shape on ceramic chips. Putrescine oxidase (PUO) activity measurement was used as a model. The determination of PUO activity is important in the clinical diagnosis of premature rupture of the amniotic membrane. An electropolymerized m-phenylenediamine size-exclusion layer was used to eliminate common interferences. The size exclusion layer revealed also to be advantageous in protecting the electrodes from fouling by putrescine (enzyme substrate). The electrode fouling of bare electrodes was insignificant for screen-printed electrodes, but very severe for electroplated platinum working electrodes. The microelectrode array electrodes demonstrated smaller RSD and higher normalized sensitivities for hydrogen peroxide and PUO activity. All the other electrodes were demonstrating comparable analytical performances.

Superior oblique tendon resection or inferior oblique muscle recession in vertical deviations.

This study reports the results on patients undergoing superior oblique (SO) tendon resections with or without inferior oblique (IO) muscle recession to correct vertical deviations. The design of this study was nonrandomized, baseline-controlled, and postsurgical versus presurgical and was performed in a solo practice affiliated with a university ophthalmology department. One hundred ninety-five patients underwent surgery. Patients were evaluated presurgically and postoperatively in the major fields of muscle action. Resections were based on measurements at 14 inches in the field of major function of the SO. The surgical approach was a radial, rather than circumferential, incision extending from the limbus to the tarsus parallel to the lateral border of the superior rectus, followed by resection of the SO tendon. Surgery resulted in improved fusion in 78% of the cases. Average deviation in the left superior oblique field in SO tendon resection only (n = 14) was reduced from 11.0 to 1.7 prism diopters, and fusion improved 85% after treatment. In 181 cases of SO tendon resection or IO recession, the left superior oblique field was reduced from 15.8 to 3.6 diopters. SO tendon resection was successfully utilized to treat underacting SO muscle and vertical deviations. A radial incision facilitated the surgical procedure, and its use is recommended to those performing the surgery.

Effect of probucol therapy on plasma fatty acid composition during postprandial lipemia in hypertriglyceridemia.

OBJECTIVE: To determine the effect of probucol (PR) on fatty acid composition of plasma lipids in patients with hypertriglyceridemia during the fasting and postprandial states. DESIGN: Open-label, single-center, 6-week treatment, baseline-controlled trial. SETTING: Outpatient clinical research center. PATIENTS: Six patients with established hypertriglyceridemia and no complicating medical conditions. INTERVENTION: Step 1 American Heart Association diet and no lipid-lowering medications for at least 4 weeks. Lead to a baseline standarized meal ingestion with postprandial blood samplings. After 6 weeks of treatment with 500-mg of PR twice daily and diet, the meal tests were repeated. MEASUREMENTS: The clinical status, 3-day food records, postprandial blood samplings (0, 2, 4, 6, and 8 hours) for lipid and fatty acids in whole plasma, triglyceride (TG), phospholipid (PL), and cholesteryl ester (CE) fractions. RESULTS: PR had the following effects: (1) In plasma, cholesterol, high-density lipoprotein cholesterol, apolipoprotein (Apo) A1, and ApoB were decreased postprandially. ApoC111 ratio (heparin-treated plasma versus precipitate) was decreased in the fasting state. (2) The saturated/unsaturated (S/U) fatty acid ratios in the PL, TG, and CE fractions were elevated postprandially and increased in CE in the fasting state. In the PL fraction it was due to an increase in the percentage of myristic, palmitic, stearic, and oleic acids and a decrease in linolenic, eicosatrienoic, and arachidonic acids. In the TG and CE fractions the changes were not due to any particular patterns of fatty acids. The ratio of arachidonic/eicosatrienoic acid was decreased postprandially in PL and CE fractions. The ratio of eicosatrienoic/linoleic acid was decreased in PL and increased in CE fractions. (3) The S/U ratio in the lipoprotein (Lp) B and LP(a) lipid components decreased in PL and CE. Lp(a) was more saturated with respect to fatty acids than LpB. CONCLUSION: PR treatment for 6 weeks increased postprandial S/U fatty acid ratios. This was due to a combination of an increase in saturated and monounsaturated levels and a decrease in polyunsaturated levels. The effect was most notable in the PL fraction. In those systems dependent on the pattern of fatty acids, the fatty acid compositional change could modify biological responses in clinically important ways during lipid-lowering therapy. The change toward saturation of fatty acids in the postprandial state may contribute to the antioxidant properties of probucol.

Probucol modifica la composición en acidos grasos en pacientes con hypertrigliceridemicos con control de ingestas grasas / Probucol modify the fatty acid composition in patients hypertriglyceridemic whith control consumption fat

Se estudio el efecto de probucol sobre los parametros lipídicos tradicionales: colesterol total, colesterol HDL y trigliceridos, y no tradicionales apolipoproteinas AI, AII, B, CIII y E, así como la composición en ácidos grasos de trigliceridos fosfolípidos y ésteres de colesterol plasmático en seis pacientes hipertrigliceridemicos, cuya dieta fue estrictamente controlada. Se observo la disminución estadisticamente significativa del contenido de ácido aratidónico en los ésteres de colesterol y del ácido miristico en los fosfolípidos, así como el aumento significativo del contenido de ácido palmitoleico en los triglicéridos. No se observaron variaciones significativas en las concentraciones de lípidos tradicionales ni apolipoproteinas plasmáticas. Los resultados indican que probucol fue capaz de madificar el perfil de ácidos grasos de distintas fracciones lipídas plasmáticas que habitualmente se utilizan para medir el impacto del consumo graso.

Probucol modifica la composición en acidos grasos en pacientes con hypertrigliceridemicos con control de ingestas grasas / Probucol modify the fatty acid composition in patients hypertriglyceridemic whith control consumption fat

Se estudio el efecto de probucol sobre los parametros lipídicos tradicionales: colesterol total, colesterol HDL y trigliceridos, y no tradicionales apolipoproteinas AI, AII, B, CIII y E, así como la composición en ácidos grasos de trigliceridos fosfolípidos y ésteres de colesterol plasmático en seis pacientes hipertrigliceridemicos, cuya dieta fue estrictamente controlada. Se observo la disminución estadisticamente significativa del contenido de ácido aratidónico en los ésteres de colesterol y del ácido miristico en los fosfolípidos, así como el aumento significativo del contenido de ácido palmitoleico en los triglicéridos. No se observaron variaciones significativas en las concentraciones de lípidos tradicionales ni apolipoproteinas plasmáticas. Los resultados indican que probucol fue capaz de madificar el perfil de ácidos grasos de distintas fracciones lipídas plasmáticas que habitualmente se utilizan para medir el impacto del consumo graso. (AU)

Effect of 14 days' subcutaneous administration of the human amylin analogue, pramlintide (AC137), on an intravenous insulin challenge and response to a standard liquid meal in patients with IDDM.

Individuals with insulin-dependent diabetes mellitus (IDDM or type 1 diabetes) are deficient in both insulin and amylin, peptides secreted by the beta cell. We have investigated the effects of amylin replacement therapy employing the human amylin analogue, pramlintide (25, 28, 29-pro-human amylin, previously referred to as AC137), upon the responses to a standardized insulin infusion (40 mU. kg-1. h-1) for 100 min and a liquid Sustacal meal (360 kcal) in 84 healthy IDDM patients. Following baseline evaluations, patients were randomly assigned to receive subcutaneous injections of placebo, 30, 100 or 300 micrograms pramlintide 30 min before meals for 14 days. There was no meaningful difference between adverse events reported by the 30-micrograms pramlintide and the placebo groups, but ten subjects withdrew due to nausea, eight of these in the 300-micrograms dose group. Peak plasma pramlintide concentrations for the 30-micrograms group were 21 +/- 3 and 29 +/- 5 pmol/l on Days 1 and 14, respectively. These values are similar to postprandial plasma amylin concentrations in normal volunteers. The plasma glucose, free insulin, glucagon, epinephrine and norepinephrine concentrations during the insulin infusion test before and after therapy were identical in each of the group. Prior to pramlintide therapy, Sustacal ingestion produced a 4.0-4.8 mmol/l rise in plasma glucose concentrations in each of the groups. Pramlintide therapy reduced postprandial hyperglycaemia as reflected by the 3-h incremental AUCglucose (AUCglucose above or below fasting glucose concentration) Day 1 vs Day 14: 30 micrograms, 322 +/- 92 vs -38 +/- 161 mmol/l.min, p = 0.010; 100 micrograms, 317 +/- 92 vs -39 +/- 76 mmol/l.min, p = 0.001; and 300 micrograms, 268 +/- 96 vs -245 +/- 189 mmol/l.min, p = 0.077. Thus, pramlintide therapy with these regimens did not appear to impair either in vivo insulin action or the counter-regulatory response to hypoglycaemia but did show a clear effect of blunting postprandial hyperglycaemia following a standardized meal.

Triglyceride enriched lipoprotein particles correlate with the severity of coronary artery disease.

A group of 100 male normotensive, non-obese, non-diabetic subjects who had undergone coronary angiography were studied to determine relationship between the severity of coronary artery disease (CAD) and plasma lipids, apolipoproteins and lipoprotein particles defined by their apolipoprotein composition. CAD was found in 84 and no measurable lesions were found in 26 subjects. The severity of CAD was determined on the basis of size and number of lesions and expressed in terms of a global CAD score. Low density lipoprotein (LDL)-cholesterol showed a tendency to be higher in CAD patients than in CAD-free subjects (216 vs. 205 mg/dl, P = 0.07). HDL-cholesterol showed a tendency towards lower values in CAD patients compared to CAD-free subjects 35 vs. 41 mg/dl, P = 0.07). In univariate analysis the severity of CAD correlated with (i) complex, apolipoprotein (apo) B containing particles (Lp-B-complex, r = 0.31, P = 0.005), (ii) HDL-cholesterol (r = -0.30, P = 0.005), (iii) apoC-III in heparin precipitate (r = 0.30, P = 0.005) and (iv) plasma triglycerides (r = 0.25, P = 0.02), all of which are related to triglyceride-rich lipoproteins. A comparison between the two subspecies of complex lipoprotein particles revealed that those containing apolipoproteins B, C-III and E (Lp-B:C:E complex) were more closely associated with CAD score (r = 0.27, P = 0.01) than those containing apolipoproteins A-II, B, C, D and E (Lp-A-II:B-complex). LDL-cholesterol also correlated with the global CAD score (r = 0.23, P = 0.03). In multiple regression analysis only HDL-cholesterol (P = 0.003), apoC-III-ratio (P = 0.007), Lp-B-complex (P = 0.02) and Lp-B:C:E-complex (P = 0.04) showed significant correlation with CAD score. The results of this study demonstrate that some of the triglyceride rich lipoprotein particles represent a risk factor for CAD and support the clinical usefulness of specific assays capable of distinguishing lipoprotein particles on the basis of apolipoprotein composition.

Effects of lovastatin on ApoA- and ApoB-containing lipoproteins. Families in a subpopulation of patients participating in the Monitored Atherosclerosis Regression Study (MARS).

To establish whether lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, exhibits a specific effect on apolipoprotein (apo) A- and apoB-containing lipoproteins, 63 subjects, a subset of the 270 Monitored Atherosclerosis Regression Study (MARS) patients with hypercholesterolemia (190 to 295 mg/dL) and documented coronary artery disease, were randomized into either lovastatin 40 mg twice daily or matching placebo tablets twice daily. Both groups consumed a diet containing 27% calories as fat (polyunsaturated fat/saturated fat ratio, 2.85) and a daily cholesterol intake of less than 250 mg. The plasma lipid and apolipoprotein profiles were determined at the time of randomization and after 2 years of treatment, and the levels of apoA- and apoB-containing lipoprotein families were measured after 2 years of treatment. After this treatment period, the drug group was characterized in comparison with the placebo group by significantly reduced levels of total cholesterol (33%), triglycerides (30%), very-low-density lipoprotein cholesterol (36%), low-density lipoprotein cholesterol (43%), apoB (36%), apoC-III (18%), and apoE (17%) and slightly but insignificantly increased levels of high-density lipoprotein cholesterol (6%) and apoA-I (1%). The 2-year levels of lipoprotein containing apoA-I but no apoA-II (LpA-I) and lipoprotein containing both apoA-I and apoA-II (LpA-I/A-II) particles separated by immunoaffinity chromatography on an anti-apoA-II immunosorber did not differ between the two treatment groups. However, the apoB-containing lipoprotein (Lp) families defined by apolipoprotein composition and separated by immunoaffinity chromatography on anti-apoA-II and anti-apoC-III immunosorbers were affected in a selective manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral torsemide in patients with chronic congestive heart failure: effects on body weight, edema, and electrolyte excretion. Torsemide Investigators Group.

STUDY OBJECTIVE: To assess the effects of torsemide on the primary end point of change in body weight from baseline, and the following secondary end points: urinary sodium, potassium, and chloride excretion, and urine volume after the first dose of drug. DESIGN: Randomized, parallel, double-blind, multicenter study in patients treated with torsemide 5 mg (n = 19), 10 mg (n = 18), or 20 mg (n = 14), or placebo (n = 15) for 7 days. PATIENTS: Sixty-six patients with New York Heart Association class II or III congestive heart failure and edema. RESULTS: At the end of the study, patients treated with torsemide 10 and 20 mg demonstrated a significant reduction in body weight compared with those receiving placebo (-1.62 and -1.30 kg, respectively), and those treated with torsemide 5 mg did not (-0.60 kg). The severity of edema decreased with increasing torsemide dose. Torsemide caused no greater frequency of adverse effects with increasing dose. CONCLUSION: Orally administered torsemide 5, 10, and 20 mg once/day for 7 days were well tolerated. Doses of 10 and 20 mg were effective in producing weight loss.

Triglyceride-rich lipoprotein interactions with Lp(a).

We found a significantly reduced incidence of increased lipoprotein(a) (Lp(a)) levels in subjects with triglycerides (TG) greater than 150 mg/dl compared with those with TG levels lower than 150 mg/dl. This was the case in patients with angiographically documented coronary artery disease (CAD) and in subjects with no CAD. We explored the potential role of lipoprotein lipase (LPL) in mediating this relationship. Lp(a) and LDL2 exhibited a minimal effect on the rate constant for degradation of VLDL-TG by LPL (13% inhibition). Binding analyses indicated no differences between VLDL and LDL with respect to Lp(a) binding, and lipolysis only reduced binding by 30% at 75% degradation of VLDL-TG. Our study indicates that the inverse relationship between elevated plasma TG and Lp(a) levels is not caused by activation of LPL by Lp(a) either due to failure of Lp(a) to bind to VLDL or its lipolytic remnants. It is hypothesized that this relationship could stem from the enhanced clearance of TG-rich lipoproteins in individuals with higher levels of Lp(a) by receptor-mediated events.

Once-daily, extended-release gemfibrozil in patients with dyslipidemia. The Lopid SR Work Group I.

This randomized, parallel-group, multicenter clinical trial compared a newly developed, once-daily, extended-release formulation of gemfibrozil (Lopid SR) and gemfibrozil twice daily (Lopid) in terms of lipid-regulating effects and toxicity. Patients were men and women with elevations of low-density lipoprotein cholesterol and low levels of high-density lipoprotein cholesterol. The trial consisted of a 1-week screening period, an 8-week diet baseline period (Step One Diet), and a 24-week double-blind treatment period (extended-release gemfibrozil 1,200 mg once daily vs gemfibrozil 600 mg twice daily). At the end of the trial, the 2 treatment groups showed comparable improvements in all primary lipid factors: mean percent changes in triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were -32, +10 and -10% for extended release (n = 325) and -36, +11 and -10% for twice daily (n = 330). The 90% confidence interval for the relative difference between the treatment means fell within the equivalence bounds of +/- 35% for all 3 factors, demonstrating equivalence of efficacy. Adverse events were reported at low rates and were similarly distributed in frequency and intensity between treatment groups; they were preponderantly mild or moderate, and gastrointestinal effects were the most frequent. The once-daily formulation of gemfibrozil may afford better control of dyslipidemia through improved compliance by patients who have this asymptomatic disease.

Effect of cilazapril on exercise tolerance in congestive heart failure.

Cilazapril (C), an angiotensin-converting enzyme inhibitor with effective antihypertensive efficacy, was examined for its ability to alter exercise tolerance testing (ETT) and respiratory oxygen uptake in 33 patients with congestive heart failure (CHF). C was administered in capsules daily to patients with New York Heart Association Class II or Class III CHF for 12 weeks, in parallel double-blind treatment groups of 0 mg (n = 8), 0.5 mg (n = 8), 1.0 mg (n = 9), and 2.5 mg (n = 8). The blood pressure (BP) was reduced by 2.5 mg C: systolic BP (SBP) from 126 to 114 mm Hg; diastolic BP from 76 to 69 mm Hg. The maximum heart rate (MHR) during ETT was increased by 2.5 mg C from 137 to 143 bpm, as was the double product (MHR x maximum SBP x 0.01) from 237 to 251. There was an insignificant change in duration of exercise (548-610 s), anaerobic threshold (AT), and maximum oxygen uptake (14.1-15.7 ml/kg/min). The results suggest a positive effect of 2.5 mg C on energy utilization in CHF patients.

Lipid peroxide levels in type II hyperlipoproteinemic subjects.

The purpose of this study was to evaluate, under the most rigorous precautionary measures against in vitro oxidation, whether the baseline lipid peroxide levels in hypercholesterolemic subjects were higher than those in normolipidemic subjects. Two methods were employed: thiobarbituric acid (TBA), and hemoglobin-methylene blue (HbMB). Blood was collected into EDTA tube and centrifuged at 4 degrees C for 30 min to collect plasma, then protected from in vitro oxidation with preservatives and N2. Serum was from blood samples allowed to clot at 20 degrees C for 1 h, then protected from oxidation. Determination of lipid peroxide was carried out within 2 h of blood collection. Results from 35 hypercholesterolemic and 34 control subjects showed that lipid peroxide levels obtained from both methods were significantly higher in serum than in plasma for both groups, suggesting a greater rate of lipid peroxidation occurred in serum during clot formation. However, no significant difference in lipid peroxide levels was found between patients and controls in either serum or plasma by either assay method. No correlation existed between lipid peroxide values and plasma cholesterol or LDL-cholesterol levels. These results suggest that the mechanism for a higher tendency towards atherosclerosis in hypercholesterolemic subjects is not related to baseline levels of plasma lipid peroxide.

Effect of gemfibrozil on fatty acids in lipid fractions of plasma from patients with hypertriglyceridemia.

The fatty acid composition of plasma triglycerides, phospholipids, and cholesterol esters have been studied during gemfibrozil (G)-induced lipid-lowering treatment in six patients with hypertriglyceridemia. Gemfibrozil caused significant plasma triglyceride reductions from 776 +/- 573 to 226 +/- 82 mg/dL (P < .001). Gemfibrozil therapy also caused significant changes in the plasma lipid fatty acid composition, mainly by increasing palmitoleic acid (16:1) in triglycerides (2.1-5.6%) and cholesterol esters (2.2-3.7%), concomitant with the significant decrease in the content of the linoleic acid (18:2) in phospholipids (20.1-16.0%) and triglycerides (18.0-15.2%). The ratio of unsaturated fatty acids (20:3 + 20:4/18:2) was increased in the phospholipid fraction. These findings support a G effect on the desaturation of fatty acids in patients with hypertriglyceridemia. Because fatty acid composition was significantly altered by G, those biologic systems dependent on the pattern of fatty acids may be modified in clinical important ways.

Clinical effect of indolidan in congestive heart failure.

Indolidan (IN) experimentally inhibits type IV phosphodiesterase. It was administered to twelve patients (age 64 +/- 15 years) with New York Heart Association (NYHA) class 2-3 congestive heart failure in which digoxin and diuretic therapy were continued. IN was administered i.v. at 1,180 +/- 340 micrograms (15 micrograms/kg) over two hours. After 24 hours, IN was given p.o. at 231 +/- 44 micrograms. The time course effect of IN i.v. revealed an increase in cardiac index and a decrease in pulmonary capillary wedge pressure and blood pressure. Daily oral administration of IN or placebo was carried out for up to 3 months. There were no significant hemodynamic changes of chronically administered IN. The maximum oxygen uptake increased in placebo relative to IN therapy. IN tended to be arrhythmogenic as evidenced by a general increased frequency of ventricular premature contractions of both single and paired type. Therefore, IN had some hemodynamic efficacy on acute i.v. and p.o. administration but not during chronic therapy, and there was negative safety features of arrhythmias.

Environmental health and the South African community.

The success of an environmental impact assessment programme will depend on the perceptions of a community. There are differences in the opinion of the population groups of South Africa concerning the perceived environmental threats to health.

Hemodynamic effects of calcitonin in the normal rat.

Calcitonin (CT) was administered acutely (IV 4-8 U/kg) and chronically (SC 2 U/kg/day x 150 day) to normal male rats. Measurements included heart rate (HR), mean blood pressure (MBP), cardiac index (CI), peripheral vascular resistance (PVR), and stroke volume index (SVI). The MBP was higher in CT rats examined under pentobarbital anesthesia. Upon awakening from anesthesia, rats chronically on CT exhibited impaired recovery of CI and SVI. Hemodynamic effects were not seen in rats acutely treated with CT. Heart weight was unchanged in chronic treatment with CT. Therefore, CT had minimal hemodynamic effects in the normal male rat.

Lipid and apolipoprotein levels during therapy with pinacidil combined with hydrochlorothiazide.

This study determined the effect of pinacidil on the concentration of plasma lipids and apolipoproteins in male patients previously equilibrated with 25 mg hydrochlorothiazide twice daily. Pinacidil therapy given to 52 hypertensives at 25 to 100 mg daily for 8 weeks resulted in a reduction of systolic and diastolic blood pressure concurrently to reductions in plasma cholesterol and triglycerides with no change in low density lipoprotein-cholesterol (LDL-C) and high density lipoprotein-cholesterol (HDL-C). There was an associated decrease in apolipoproteins (Apo)B, C-III and E and elevation in ApoA-I. A parallel placebo group of 44 patients experienced reduction in diastolic blood pressure and an elevation in ApoA-I. These changes indicate that pinacidil will be a useful antihypertensive agent having properties on lipoprotein metabolism which would favor decreased risks of atherosclerosis.

The effect of food on pharmacokinetics and pharmacodynamics of fenoldopam in class III heart failure.

Eighteen patients with New York Heart Association class III congestive heart failure were given single 100 mg oral doses of fenoldopam with food or fasting in a random-order single-blind crossover trial. Before and after each fenoldopam dose, thermodilution cardiac output, right atrial pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure (PCWP) were measured with a balloon-tipped pulmonary artery catheter, and heart rates and blood pressures were recorded with an automated sphygmomanometer. Compared with fasting, bioavailability of fenoldopam was decreased significantly when administered with food: mean peak plasma fenoldopam level decreased from 26.5 (+/- 4.1 SEM) ng/ml to 10.9 (+/- 1.7 SEM) ng/ml (p = 0.0004) and mean area under the concentration-time curve was decreased from 44.7 (+/- 5.8 SEM) ng.hr/ml to 26.8 (+/- 4.1 SEM) ng.hr/ml (p = 0.0001). Fenoldopam administration to fasting patients resulted in decreases in mean arterial pressure, systemic vascular resistance, and PCWP and significant increases in cardiac index without change in heart rate. The maximum changes in mean cardiac index, systemic vascular resistance, and PCWP were greatest 1 hour after oral administration and did not persist beyond 3 hours after administration. In fasting patients, changes in cardiac index were correlated with plasma fenoldopam levels, whereas changes in PCWP and mean arterial pressure did not correlate significantly with the observed fenoldopam level.