A combination of isolated phytochemicals and botanical extracts lowers diastolic blood pressure in a randomized controlled trial of hypertensive subjects.

BACKGROUND/OBJECTIVES: Isolated phytochemicals have been shown to reduce blood pressure; however, combinations of phytochemicals have rarely been tested in humans. We hypothesized that a combination of extracts from grape seed and skin (330 mg), green tea (100 mg), resveratrol (60 mg) and a blend of quercetin, ginkgo biloba and bilberry (60 mg) would reduce blood pressure (BP) in hypertensive subjects. SUBJECTS/METHODS: Eighteen individuals meeting BP requirements (⩾130 mm Hg systolic or ⩾85 mm Hg diastolic) and criteria for metabolic syndrome were enrolled in a double-blinded, placebo-controlled, crossover trial (ClinicalTrials.gov, NCT01106170). The 28-day placebo and supplement arms were separated by a 2-week washout period, and 14 -h daytime ambulatory BP was assessed at baseline and at the end point of each arm. RESULTS: BP was not altered after placebo. After supplement treatment, diastolic pressure was reduced by 4.4 mm Hg (P=0.024, 95% CI, 0.6-8.1), systolic pressure was unchanged and mean arterial pressure trended (P=0.052) toward reduction. Serum angiotensin-converting enzyme activity was similar between placebo and supplement arms, but urinary nitrate and nitrite concentrations were significantly increased (P=0.022) after supplementation. Human aortic endothelial cells treated with metabolites of the polyphenols used in the human supplement trial had a significant increase (P=0.005) in insulin-stimulated eNOS phosphorylation and greater (P<0.001) accumulation of nitrates/nitrites. CONCLUSIONS: Our clinical and in vitro data support the theory that this combination of polyphenols reduced diastolic pressure by potentiating eNOS activation and nitric oxide production. Such supplements may have clinical relevance as stand-alone or adjunct therapy to help reduce BP.

SMART: The microstent's ability to limit restenosis trial.

In this randomized, prospective, multicenter trial (n = 661) of patients with de novo or restenotic coronary lesions, 330 patients received the MicroStent(R) II (MSII), and 331 received the Palmaz-Schatz (PS) stent. The short-term procedural success rates were 94.4% and 95.7%, respectively (P = 0.47). The 30-day cumulative incidence of major adverse events [death, myocardial infarction, CVA, target lesion revascularization (TLR)] was 6.4% for the MSII and 4.5% for the PS stent (P = 0.31). The in-stent binary restenosis rate at 6 months was 25.2% for the MSII and 22.1% for the PS stent (P = 0.636). Using Kaplan-Meier estimates, the incidence of clinically driven TLR was 8.9% for the MSII and 9.2% for the PS stent at 180 days; at 270 days, it was 12.8% and 12.1%, respectively (P = 0.83). MSII and the PS stents were comparable with respect to short-term procedural success, complications, and late clinical and angiographic restenosis.

Comparison of direct and standardized testing of infected urine for antimicrobial susceptibilities by disk diffusion.

A total of 14,272 urine specimens were examined over one year to determine the validity of direct antimicrobial agent susceptibility testing against ampicillin, amoxicillin-clavulanic acid, cephalothin, gentamicin, norfloxacin, and trimethoprim. A comparison between direct and standardized disk diffusion tests was made for a total of 1,106 urine specimens containing > or = 10(5) organisms per ml in pure culture. There were 5,821 individual organism-antimicrobial agent challenges compared for the two testing methods, and there was complete agreement of susceptibility category in 5,492 comparisons (94.3%). Initially, discordant results were reduced from 5.7 to 2.1% when the intermediate category was considered susceptible. Intralaboratory variation was assessed by testing another 453 organisms by the standard National Committee for Clinical Laboratory Standards (NCCLS) method on two consecutive days; there was complete agreement in 96.1% of comparisons. When results of direct and standardized testing were simply classified as susceptible or resistant, there was 1.1% discordance. When simple same-day tests were used together with predictable patterns of susceptibility and resistance, 536 (48.5%) of 1,106 isolates could be identified satisfactorily to the genus or species level. For laboratory reporting purposes, the direct method is equivalent to the standard method when the urine being tested is infected with > or = 10(5) organisms of a single type per ml. The presence or absence of preexisting antimicrobial agents in urine did not appreciably influence the results. This procedure allows the earlier reporting of susceptibility results and facilitates less expensive identification of many organisms. Costs and benefits need to be determined in each institution.

Chondrocyte growth inhibition induced by homogentisic acid and its partial prevention with ascorbic acid.

Cartilage damage termed ochronotic arthritis is the major pathology occurring in adult patients with alcaptonuria. We have investigated the effects of homogentisic acid (HGA), the metabolite accumulating in patients with alcaptonuria, on the in vitro proliferation of rabbit and human articular chondrocytes and human fibroblasts. Growth of these chondrocytes in monolayer decreased proportionally to increasing concentrations of HGA (0.001 mM to 1.0 mM). Substantial growth inhibition and morphologic abnormalities of chondrocytes were produced by a concentration of HGA (0.05 mM) similar to that found in serum of patients with alcaptonuria. Human fibroblasts required higher concentrations of HGA for a comparable degree of growth inhibition. The addition of ascorbic acid (0.57 mM) reduced this growth inhibition and prevented the morphologic changes.

Usefulness of recanalization to luminal diameter of 0.6 millimeter or more with intracoronary streptokinase during acute myocardial infarction in predicting "normal" perfusion status, continued arterial patency and survival at one year.

To determine whether arteriographic dimensions of the acutely recanalized coronary lumen provide information about regional perfusion or clinical outcome, quantitative arteriography was used to measure minimum luminal diameter achieved with intracoronary streptokinase administration in 44 patients with acute myocardial infarction (AMI). Degree of coronary reperfusion was independently assessed visually using the criteria applied in the multicenter Thrombolysis in Myocardial Infarction study. Minimum diameter and qualitative reperfusion grade were both assessed from 172 coronary injections during thrombolysis. Partial perfusion (grade 1 or 2) was seen in 95 of 135 injections (70%) in which the minimum diameter was less than 0.6 mm and complete perfusion (grade 3) was seen in 35 of 37 injections (95%) in which it was 0.6 mm or more (p less than 0.001). Repeat cardiac catheterization was performed at 5.5 +/- 4.9 weeks after AMI (n = 20). When vessels were opened acutely to a minimum diameter of less than 0.6 mm, 5 of 12 vessels (42%) were reoccluded at the time of restudy and 8 of 29 patients (28%) died within 12 months. By contrast, 0 of 8 vessels (0%) were reoccluded when the artery was opened to a diameter of at least 0.6 mm (difference not significant), and only 1 of 15 patients (7%) died (p less than 0.05). Of the patients with grade 1 o r 2 perfusion at the end of the thrombolytic infusion, 7 of 19 (37%) died within 12 months and 2 of 4 vessels (50%) reoccluded; of the patients with grade 3 perfusion, 2 of 25 (8%) died (p less than 0.05) and 2 of 16 vessels (13%) reoccluded (difference not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperemic myocardial perfusion imaging for noninvasive detection of coronary disease in man: comparison of treadmill exercise and intravenous dipyridamole infusion.

To further understand hyperemic myocardial perfusion imaging, the effects of exercise and intravenous dipyridamole on coronary flow, coronary stenosis luminal area, stenosis flow resistance, and regional myocardial perfusion were evaluated in patients with arteriographically documented coronary artery disease. Coronary hemodynamics were assessed in 24 patients undergoing routine diagnostic catheterization. Coronary flow was measured by coronary sinus thermodilution. Computer assisted stenosis measurements were made. During isometric handgrip coronary sinus flow increased to 1.7 X baseline value, and epicardial coronary arteries constricted to increase predicted stenosis flow resistance by 40%. A 4-minute intravenous dipyridamole infusion (0.56 mg/kg) increased coronary sinus flow to 2.4 X baseline with, on average, no change in the stenotic coronary lumen diameter. During simultaneous isometric handgrip and dipyridamole infusion coronary sinus flow increased to 3.3 X baseline value and stenosis flow resistance increased an average of 36%. Regional myocardial perfusion was assessed in 33 patients by thallium201 myocardial perfusion imaging following maximal treadmill exercise and again following intravenous dipyridamole infusion. Regional thallium201 imaging effects were correlated with measurements of angiographic coronary disease. Sensitivity and specificity for detecting a greater than or equal to 50% stenosis were 85% and 64% (p less than .005), respectively, for dipyridamole and 84% and 68% (p less than .005) for exercise thallium201. In summary, coronary blood flow increases with isometric exercise and is near maximal following intravenous dipyridamole. Quantitative arteriographic techniques demonstrate isometric exercise-induced constriction of coronary stenoses and increased stenosis flow resistance. Stenosis flow resistance increases following intravenous dipyridamole only for severe (greater than or equal to 65%) lesions. Treadmill exercise and intravenous dipyridamole are comparably effective hyperemic stimuli for creating regional perfusion differences for the noninvasive detection of coronary disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Incomplete lysis of thrombus in the moderate underlying atherosclerotic lesion during intracoronary infusion of streptokinase for acute myocardial infarction: quantitative angiographic observations.

Thrombolytic recanalization of the obstructed coronary lumen was studied in 32 patients receiving intracoronary streptokinase for 60 to 90 min during acute myocardial infarction. The process was viewed at high arteriographic magnification and was quantified with computer-assisted measurements from repeated single-plane views. The variability of the method for this application was 0.15 to 0.18 mm on minimum diameter estimates. Structural details were seen that are not commonly appreciated at conventional magnification. The recanalized lumen appears to form along an interface between the thrombus and the vessel wall, progressively enlarging its minimum arteriographic diameter to 0.65 +/- 0.24 mm (+/- 1 SD) at the end of the short-term infusion of streptokinase reflecting a final percent stenosis of 77 +/- 10%. In nine infarct lesions found patent 5 +/- 3 weeks later, the recanalized lumen further improved an average of 0.34 mm in minimum diameter (p less than .005) and 13% stenosis (p less than .01). A thin film of contrast medium surrounding the obstructing thrombus faintly defined the boundaries of the original atherosclerotic lumen in all but two cases. The "original stenosis" measured 1.25 +/- 0.32 mm in minimum diameter and 56 +/- 14% stenosis when first visualized; it was unchanged throughout the course of infusion of streptokinase. In five patients catheterized 10 +/- 12 weeks before their infarction, the original stenosis averaged 1.15 +/- 0.22 mm in the preinfarct angiogram, as compared with 1.17 +/- 0.23 mm in its faintly defined form during thrombolytic therapy (p = NS). In 10 cases, this original lesion was less than a 50% stenosis, and in 21 cases less than 60%.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary artery dilation and hemodynamic responses after isosorbide dinitrate therapy in patients with coronary artery disease.

The response to sublingual isosorbide dinitrate (ISDN) was studied in 10 men with suspected coronary artery disease undergoing coronary arteriography. A Swan-Ganz catheter was placed in the pulmonary artery to record hemodynamic response. Diseased coronary segments were identified during routine Judkins selective coronary angiograms. Sublingual isosorbide dinitrate (ISDN) (5 or 10 mg) was then given with the catheters in place. Multiple sequential single-view coronary angiograms and pulmonary and systemic hemodynamic responses were recorded over 30 minutes after drug administration. At 30 minutes, there was a 53% reduction (p less than 0.01) in pulmonary capillary wedge pressure and a 15% decrease (p less than 0.05) in systemic and pulmonary vascular resistance, with a net 13% decrease (p less than 0.01) in cardiac output and 20% decrease (p less than 0.01) in mean arterial pressure. Quantitative arteriography demonstrated substantial dilation of luminal cross-sectional area in both normal and diseased coronary arterial segments. Normal epicardial segments were grouped according to luminal area (1 to 4, 4 to 8 and more than 8 mm2) and demonstrated maximal area dilation at 10 minutes of 55% (p less than 0.01), 29% (p less than 0.01) and 16% (p less than 0.05), respectively. Diseased epicardial segments (stenosis 50% or greater) dilated 51% (p less than 0.01) at 10 minutes. Calculated stenosis resistance decreased 40% (p less than 0.01). Diseased segments in small and middle-sized arteries (1 to 8 mm2) are 4 times more reactive than those in larger arteries (more than 8 mm2), with peak dilation of 77 vs 21% (p less than 0.01) at 30 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino acid derived latent isocyanates: irreversible inactivation of porcine pancreatic elastase and human leukocyte elastase.

Several amino acid derived azolides (I) have been synthesized and investigated for their inhibitory activity toward human leukocyte elastase and porcine pancreatic elastase. The inhibitory activity was found to be dependent on the nature of the precursor amino acid ester. Thus, compounds derived from L-valine methyl ester 3, L-norvaline methyl ester 5, DL-norleucine methyl ester 9, and L-methionine methyl ester 10 were found to inhibit irreversibly both enzymes. Compound 10 was found to be a specific and selective inhibitor of human leukocyte elastase. In contrast to these, inhibitors derived from glycine methyl ester 1, D-valine methyl ester 4, and D-norvaline methyl ester 6 were found to be inactive. The results of the present study show that latent isocyanates derived from appropriate amino acids can serve as selective inhibitors of serine proteases and are of potential pharmacological value.

Vesicle interactions with antibody and peptide hormone: role of vesicle composition.

Artificial lipid vesicles (artificial membranes) were shown to bind human 125I-antithyroglobulin (anti-Tg) and human 125I-thyrotropin. Vesicles made with gangliosides bound more antibody and hormone than vesicles lacking them. These gangliosides contained a variety of carbohydrates including glucose, galactose, N-acetyl-galactosamine, and sialic acid. The in vivo stability of antibody-vesicle complexes was a function of vesicle composition: vesicles were most stable when formed from phosphatidylcholine, cholesterol, and gangliosides. Anti-Tg-vesicle complexes bind to thyroglobulin, indicating that at least some of the antibody associated with the vesicle still retains ability to bind to its specific antigen. The addition of a specific antibody or hormone to artificial lipid vesicles may serve as a mechanism to confer specificity to the vesicle in vivo.