Chronic consumption of rebaudioside A, a steviol glycoside, in men and women with type 2 diabetes mellitus.

This trial evaluated the effects of 16 weeks of consumption of 1000mg rebaudioside A (n=60) a steviol glycoside with potential use as a sweetener, compared to placebo (n=62) in men and women (33-75 years of age) with type 2 diabetes mellitus. Mean+/-standard error changes in glycosylated hemoglobin levels did not differ significantly between the rebaudioside A (0.11+/-0.06%) and placebo (0.09+/-0.05%; p=0.355) groups. Changes from baseline for rebaudioside A and placebo, respectively, in fasting glucose (7.5+/-3.7mg/dL and 11.2+/-4.5mg/dL), insulin (1.0+/-0.64microU/mL and 3.3+/-1.5microU/mL), and C-peptide (0.13+/-0.09ng/mL and 0.42+/-0.14ng/mL) did not differ significantly (p>0.05 for all). Assessments of changes in blood pressure, body weight, and fasting lipids indicated no differences by treatment. Rebaudioside A was well-tolerated, and records of hypoglycemic episodes showed no excess vs. placebo. These results suggest that chronic use of 1000mg rebaudioside A does not alter glucose homeostasis or blood pressure in individuals with type 2 diabetes mellitus.

The hemodynamic effects of rebaudioside A in healthy adults with normal and low-normal blood pressure.

Rebaudioside A and stevioside are steviol glycosides extracted from the plant Stevia rebaudiana Bertoni and are used in several countries as food and beverage sweeteners. This randomized, double-blind trial evaluated the hemodynamic effects of 4weeks consumption of 1000mg/day rebaudioside A vs. placebo in 100 individuals with normal and low-normal systolic blood pressure (SBP) and diastolic blood pressure (DBP). Subjects were predominantly female (76%, rebaudioside A and 82%, placebo) with a mean age of approximately 41 (range 18-73) years. At baseline, mean resting, seated SBP/DBP was 110.0/70.3mmHg and 110.7/71.2mmHg for the rebaudioside A and placebo groups, respectively. Compared with placebo, rebaudioside A did not significantly alter resting, seated SBP, DBP, mean arterial pressure (MAP), heart rate (HR) or 24-h ambulatory blood pressures responses. These results indicate that consumption of as much as 1000mg/day of rebaudioside A produced no clinically important changes in blood pressure in healthy adults with normal and low-normal blood pressure.

Efficacy and safety of sibutramine for weight loss in obese patients with hypertension well controlled by beta-adrenergic blocking agents: a placebo-controlled, double-blind, randomised trial.

Sibutramine is a serotonin-noradrenaline reuptake inhibitor that is effective for long-term weight reduction and maintenance in obese patients when used as an adjunct to dietary and behavioural measures. Because the inhibition of noradrenaline reuptake may be expected to increase systolic and diastolic blood pressure (SBP and DBP) and pulse rate (PR), a 12-week multi-centre, placebo-controlled, double-blind study was designed to evaluate the efficacy and tolerability of sibutramine for weight loss in obese patients whose hypertension was well controlled (DBP < or = 95 mm Hg) by beta-adrenergic blocking agents (beta-blockers), with or without concomitant thiazide diuretics. Of the 61 patients randomised to sibutramine 20 mg once daily or placebo, 55 patients (90%) completed the study. After 12 weeks, sibutramine-treated patients lost significantly more weight than placebo-treated patients: mean weight reductions were 4.2 kg (4.5%) in the sibutramine group vs 0.3 kg (0.4%) in the placebo group (P<0.001). Greater weight reduction on sibutramine was accompanied by trends for greater mean reductions in serum triglycerides and very low density lipoprotein cholesterol. Sibutramine was well tolerated, and most adverse events were mild or moderate in severity. No sibutramine patient discontinued treatment because of an adverse event. Mean supine and standing DBP and SBP were not statistically significantly different between the sibutramine group and the placebo group at any post-baseline visit during the 12-week trial. At week 12, mean increases from baseline supine SBP and DBP, respectively, were 1.6 and 1.7 mm Hg for the sibutramine group vs increases of 0.4 and 1.3 mm Hg for the placebo group. At week 12, mean increases from baseline standing SBP and DBP, respectively, were 1.5 and 1.8 mm Hg for the sibutramine group vs an increase of 0.3 and a decrease of 0.8 mm Hg for the placebo group (P > 0.05 for treatment comparison). A statistically significant mean increase of 5.6 bpm (+/-8.25, s.d.) in supine PR from a baseline of 62 bpm was reported in sibutramine-treated patients at week 12, whereas placebo-treated patients had a mean supine PR decrease of 2.2 bpm (+/-6.43) (P < 0.001). In summary, sibutramine was well tolerated and effective in weight reduction. The addition of sibutramine did not result in an increase in BP in obese patients whose hypertension was well controlled by a beta-blocker. However, based on the potential for changes in BP and PR, obese patients being treated with sibutramine should be monitored periodically for changes in BP and PR and managed appropriately.

Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies.

BACKGROUND: Ezetimibe (SCH 58235) is a novel cholesterol absorption inhibitor that selectively and potently blocks intestinal absorption of dietary and biliary cholesterol. OBJECTIVE: Data from 2 multicenter, placebo-controlled, double-blind, randomized, parallel-group, 12-week studies of ezetimibe were pooled to evaluate the drug's effect on lipid parameters in patients with primary hypercholesterolemia. METHODS: After dietary stabilization (National Cholesterol Education Program Step I diet or a stricter diet), washout of lipid-altering drugs, and a 6-week placebo lead-in period, patients with baseline plasma low-density lipoprotein cholesterol (LDL-C) levels > or = 130 and < or = 250 mg/dL and plasma triglyceride (TG) levels < or = 300 mg/dL were randomized to receive either ezetimibe 0.25, 1, 5, or 10 mg, or placebo administered once daily before the morning meal in study A (dose-response study) or ezetimibe 5 or 10 mg or placebo administered once daily before the morning meal or at bedtime in study B (dose-regimen study). RESULTS: A total of 432 patients were included in this pooled analysis, 243 in study A and 189 in study B. The 5- and 10-mg doses of ezetimibe significantly reduced LDL-C levels by 15.7% and 18.5%, respectively (P < 0.01 vs placebo) and significantly increased high-density lipoprotein cholesterol (hDL-C) levels by 2.9% and 3.5%, respectively (P < 0.05 vs placebo). A reduction in plasma TG levels was observed (P = NS). With the 10-mg dose of ezetimibe, 67.8% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 22.0% achieved > or = 25% reduction. With the 5-mg dose, 54.0% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 15.3% achieved > or = 25% reduction. The decrease in plasma LDL-C levels was significantly greater with ezetimibe 10 mg compared with ezetimibe 5 mg (P < 0.05). Ezetimibe was well tolerated, with an adverse event profile similar to that of placebo. CONCLUSIONS: In these two 12-week studies, ezetimibe significantly decreased plasma LDL-C levels and increased plasma HDL-C levels, with a tolerability profile similar to that of placebo.

Evaluation of indapamide 1.25 mg once daily in elderly patients with mild to moderate hypertension.

The objective of this study was to evaluate the safety and efficacy of indapamide 1.25 mg once daily as monotherapy in elderly patients (65 years and older) with mild to moderate essential hypertension. Two hundred and seventy-nine (279) elderly patients were enrolled in a washout period, during which patients received single-blind placebo for 4 weeks. Patients demonstrating supine diastolic pressures between 95 mm Hg and 114 mm Hg at the end of the 4-week placebo washout period were entered into the 8-week double-blind treatment period. Two hundred and four (204) patients qualified for the study and were randomized to the double-blind treatment; 103 patients received indapamide 1.25 mg and 101 patients received placebo for 8 weeks. Overall, 177 patients (92 indapamide and 85 placebo) completed the study. The primary efficacy criterion was the mean change in supine diastolic blood pressure (DBP) from double-blind baseline to the end of 8 weeks of therapy. By week 8 of the double-blind treatment period, indapamide 1.25 mg produced a statistically significant (P = 0.0037) decrease in supine DBP of 8.2 mm Hg compared to a decrease of 5.3 mm Hg produced in the placebo group. Additionally, indapamide 1.25 mg was statistically (P = 0.0028) more effective than placebo in reducing supine systolic BP (SBP) (-10.1 vs -4.2 mm Hg). The incidence of drug-related adverse events during the double-blind treatment period was similar between the two treatment groups. A low dose of indapamide, 1.25 mg, given once daily for 8 weeks was effective as monotherapy with respect to BP reduction in an elderly population with mild to moderate hypertension. Indapamide 1.25 mg was safe and generally well tolerated in this elderly patient population.

Efficacious response with lower dose indapamide therapy in the treatment of elderly patients with mild to moderate hypertension.

A low dose (1.25 mg) of indapamide (Lozol, Rhône-Poulenc Rorer Pharmaceuticals, Collegeville, PA) was evaluated in 222 elderly patients (> or = 50 years) with mild to moderate essential hypertension in a multicenter, randomized, double-blind, parallel-group clinical trial. A 4-week single-blind placebo washout period was followed by an 8-week double-blind treatment period. Patients were randomized to receive indapamide 1.25 mg/day or to receive placebo. The primary efficacy variable was the mean change in sitting diastolic blood pressure from baseline to week 8. Eighty-one patients in the indapamide group (73%) and 87 patients in the placebo group (78%) completed the 8 weeks of double-blind therapy. Therapy with 1.25 mg of indapamide produced greater reductions compared with placebo in sitting diastolic blood pressure after 8 weeks of therapy, with statistical significance (P < or = 0.0015) seen after only 2 weeks of therapy and continuing throughout the 8 weeks. All secondary efficacy measures (sitting systolic blood pressure, standing systolic and diastolic blood pressures, and > or = 10 mm Hg decrease or final value of < or = 90 mm Hg in sitting diastolic blood pressure) also showed superior (P < or = 0.0014) improvement in the indapamide group compared with placebo after 8 weeks of double-blind treatment. During the 8-week double-blind treatment period, incidence rates for all adverse events and for drug-related adverse events were similar between the two treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of noninvasive bioelectric impedance to predict cardiac output in open heart recovery.

Cardiac outputs (CO) measured by bioelectric impedance (Z) and thermodilution (TD) were compared in ten stable, non-ventilated male coronary artery bypass patients (mean age 59 +/- 12 years) in an open heart recovery unit. The measurements were obtained blindly in three sequential body positions (supine, 45 degrees, final supine) using either a calculated value for resistivity (p) (based upon hematocrit with blood sampled at the time of the study) to estimate CO(Z), or assumed values of p = 135.5 omega cm and p = 150 omega cm. The results indicate high correlations between the two measurement methods (range: r = 0.97 to 0.99) in the initial supine position for all resistivity conditions followed by a progressive decline when body position was changed to 45 degrees and supine (range: r = 0.74 to 0.90). The highest overall correlations and closest absolute mean cardiac output values were obtained when p was calculated from actual hematocrit values obtained at the time of the study. Applying a two-way ANOVA to assess the simultaneous effects of method (TD vx. Z) and position change (supine, 45 degrees, supine), no significant main effects or interactions were found when cardiac output values were estimated using the calculated measurement of p. However, significant main effects of method were found when p was assumed to be either 135.5 omega cm (p > or = 0.005) or 150.0 omega cm (p > or = 0.0001), with impedance showing a tendency to overestimate cardiac output. In conclusion, our findings suggest that impedance is a valid method to estimate cardiac output in this subpopulation of patients in open heart recovery provided that p is calculated at the time the study is performed.

Comparison of labetalol and hydrochlorothiazide in elderly patients with hypertension using 24-hour ambulatory blood pressure monitoring.

The safety and efficacy of labetalol and hydrochlorothiazide (HCTZ) were compared in a group of 34 patients aged 65 years or older with mild to moderate essential hypertension. After a 4-week placebo run-in period, during which all previous antihypertensive medication was discontinued, patients were randomized to receive either labetalol (100 mg bid) or HCTZ (25 mg bid). The patients' blood pressure and heart rate were evaluated biweekly and drug dosage was titrated (up to 400 mg and 50 mg bid of labetalol and HCTZ, respectively) to achieve a standing diastolic blood pressure less than 90 mm Hg. Patients underwent 24-hour ambulatory blood pressure monitoring at the end of the placebo run-in period and again after the 6-week titration period. Both labetalol and HCTZ significantly (P less than .01) reduced standing systolic (-19.4 vs -27.7 mm Hg) and diastolic (-14.0 vs -15.2 mm Hg) blood pressures following 12 weeks of treatment. Both antihypertensives effectively controlled the 24-hour ambulatory blood pressure, however, the labetalol group experienced a significantly lower rate of rise in diastolic blood pressure (P = .02) and mean arterial pressure (P = .02) during the acceleration period (400-1200) compared to the HCTZ group. HCTZ caused significant decreases in serum potassium (P less than .01) and alkaline phosphatase (P less than .05) and increases in uric acid (P less than .01) and urea nitrogen (P = .07). These results indicate that labetalol may offer some unique advantages over thiazide diuretics that may be particularly important in the treatment of elderly patients with hypertension.

Blood pressure changes following extracorporeal shock wave lithotripsy and other forms of treatment for nephrolithiasis.

Hypertension has been reported as a possible sequela of extracorporeal shock wave lithotripsy (ESWL). To evaluate this issue as well as the risk of hypertension following other current non-ESWL treatment options for urolithiasis (percutaneous nephrostolithotomy [PCNL], combined PCNL and ESWL, ureteroscopy, and spontaneous stone passage), detailed blood pressure measurements were made in 961 patients at least 1 year after treatment. All follow-up blood pressures were measured with random-zero blood pressure devices. This study includes 731 patients who received ESWL only (with an unmodified lithotriptor), 171 patients treated with ureteroscopy or spontaneous stone passage (control subjects), 25 patients who received PCNL only, and 34 patients treated with both ESWL and PCNL. In patients who received ESWL only, the annualized incidence of hypertension (2.4%) did not differ significantly from that in control patients (4.0%). Among patients who received ESWL, no correlation was found between the incidence of hypertension and unilateral vs bilateral treatments, the number of shock waves administered, the kilovoltage applied, or the power (number of shock waves times kilovoltage). However, there was a significant rise in diastolic blood pressure after treatment with ESWL (0.78 mm Hg), but not in the control group (-0.88 mm Hg). The long-term significance of this change in diastolic blood pressure following ESWL is unknown and requires further study.

The role of lithotripsy and its side effects.

The relative roles of extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy currently are being debated. Both treatment modalities are applicable to most upper urinary tract calculi. However, there are some important distinctions between the 2 techniques. Over-all, extra-corporeal shock wave lithotripsy is associated with significantly lower morbidity than percutaneous nephrostolithotomy but stone-free rates are lower for extracorporeal shock wave lithotripsy than for percutaneous nephrostolithotomy. This difference is slight for kidneys containing minimal stone burden but increases in direct proportion to increasing stone burden. The morbidity of extracorporeal shock wave lithotripsy also increases with increasing stone burden. When applied to the treatment of staghorn calculi the morbidity of both techniques is comparable but the stone-free rates are significantly better with percutaneous nephrostolithotomy. Treatment with extracorporeal shock wave lithotripsy produces changes in the kidney similar to that of renal trauma, consisting primarily of intraparenchymal and perirenal hemorrhage and edema. While the acute effects of extracorporeal shock wave lithotripsy are well tolerated by most patients, the long-term sequela of this form of therapy is not well established. Potential long-term adverse effects reported include loss of renal function, hypertension and an increased rate of new stone occurrence. The effect of shock waves on renal parenchyma in experimental animals is dose-dependent (number of shock waves). Magnetic resonance imaging of patients treated with extracorporeal shock wave lithotripsy demonstrates morphological abnormalities in or around the kidney in 63 to 85 per cent of the cases (average number of shock waves 1,200). Despite these observations the safe limits of extracorporeal shock wave lithotripsy in humans have yet to be established. Further study regarding this issue and the potential long-term adverse effects of extracorporeal shock wave lithotripsy is needed urgently.

Comparison of the effects of pindolol and atenolol on hemodynamic function in systemic hypertension.

A randomized double-blind study was performed on a group of mild hypertensive patients (WHO class I) to compare the hemodynamic effects of pindolol and atenolol. Blood pressure (BP) was monitored with a mercury gauge sphygmomanometer, while cardiac function and peripheral arterial flows were measured by the noninvasive technique of bioelectric impedance. After a 2-week washout period, patients with a diastolic BP greater than 95 mm Hg but less than 114 mm Hg were randomized into the pindolol (29 patients) or atenolol (28) treatment groups. Patients were treated with 1 of the 2 drugs in an incremental fashion for 12 weeks. Cardiovascular function was measured after the washout period and at the end of the 12-week treatment period. Baseline hemodynamics were similar in both groups. The 2 drugs were equally effective in lowering both systolic and diastolic BP. Hemodynamically, pindolol lowered BP by decreasing total peripheral resistance (-406 +/- 145 dynes.s.cm-5) while atenolol decreased cardiac index (-0.2 +/- 0.1 liters/min/m2) associated with a decrease in heart rate (-12 +/- 2 beats/min). Regarding peripheral vascular beds, pindolol lowered arm vascular resistance (-198 +/- 72 mm Hg/liter/min) and leg vascular resistance (-73 +/- 25 mm Hg/liter/min), especially when subjects who did not respond to pindolol were excluded from the analysis. Both arm (5.5 +/- 5.4% increase above baseline) and leg (1.2 +/- 4.4% increase above baseline) arterial flow indexes were maintained with pindolol. Conversely, atenolol decreased the arm arterial flow index (-9,8 +/- 5.6% decrease below baseline), but not significantly and with no change in resistance (+54 +/- 62 mm Hg/liter/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of naloxone on hemorrhagic shock in the beagle.

Naloxone reverses the hypotension in various types of hemorrhagic shock models. What has yet to be firmly established is the mechanism by which naloxone reverses the hypotension. In a canine hemorrhagic shock model, impedance cardiography and invasive methods were used to measure various cardiovascular parameters. All dogs (beagles, 10-15 kg) were bled to and maintained at a mean arterial blood pressure (MAP) of 60 mmHg for 90 min and were then given either naloxone (2 mg/kg; n = 6) or an equivalent volume of saline (n = 6) intravenously (IV). After another 90 min observation period, the shed blood was reinfused. No significant differences in the preshock and shock cardiodynamics were noted between the naloxone and the control animals. During the treatment period, MAP was significantly increased in the naloxone group. There was no increase in cardiac output (CO), stroke volume (SV), end diastolic volume (EDV), dP/dt max, dP/dt/P, or HI (the impedance contractility index) over control animals. The most significant parameter improvement was total peripheral resistance (TPR). The data suggest that naloxone in this hemorrhagic shock model improves hemodynamics primarily by increasing vascular resistance.

Effects of a platelet-activating factor antagonist, CV-3988, on different shock models in the rat.

Research in recent years has implicated many vasoactive mediators in causing or maintaining the shock process. One of the newer mediators to be considered is platelet-activating factor (PAF). The present group of experiments examined the effects of a PAF antagonist, CV-3988, on PAF, endotoxin, and hemorrhagic hypotension in rats. Sprague Dawley male rats (250-350 g) were lightly anesthetized with halothane and instrumented to measure mean arterial pressure (MAP). Hypotension induced by PAF (3.0 micrograms/kg) (iv) was attenuated only by CV-3988 (10 mg/kg). The other compounds tested which were unsuccessful were MK-771, TRH, benoxaprofen, fenoprofen, FPL-55712, naloxone, diphenhydramine, verapamil, and methylprednisolone. In another set of rats, hypotension was induced by endotoxin (E. coli 0127:B8) (40 mg/kg) (iv). Animals were pretreated with saline or CV-3988 (10 mg/kg) (iv) 5 min prior to endotoxin administration. CV-3988 was able to attenuate the drop in MAP. Representative MAP (mmHg) measured 60 min after endotoxin administration was 72 +/- 7 for the saline group (n = 6) and 99 +/- 5 (P less than or equal to .05) for the CV-3988 group. No animal in either group survived 24 hours. In another series of animals which were pithed and vagotomized, hypotension, induced by endotoxin (6 mg/kg) (iv) could be attenuated by CV-3988. Representative MAP (mmHg) difference from baseline measured 30 min after endotoxin administration was -17 +/- 3 for the saline group (n = 7) and 0 +/- 2 (P less than or equal to .05) for the CV-3988 group. Hypotension induced by another endotoxin (Salmonella abortus equi) could also be attenuated by CV-3988. In the final set of experiments, hypotension was induced by an acute hemorrhage (30 cc/kg). In these animals, CV-3988, however, had no effect in attenuating the drop in MAP. These data demonstrate that CV-3988 can attenuate the hypotension of PAF and endotoxemia but not of hemorrhage. Also, the data suggest that PAF works directly in the rat to cause hypotension and not through other mediators. The hemodynamic effects of CV-3988 in the endotoxin model are partially mediated through peripheral mechanisms. Further work is needed to better characterize the effects of CV-3988 and other PAF antagonists in different shock models.

Benoxaprofen attenuation of lethal canine endotoxic shock.

Our prior work demonstrated in a canine endotoxic shock model (LD100) that the cyclooxygenase inhibitor ibuprofen given 60 minutes after endotoxin administration could improve hemodynamics but not survival over control animals. The present study was designed to examine the effect of benoxaprofen, a dual lipoxygenase and cyclooxygenase inhibitor, in the same canine endotoxic model (LD100) and compare it to ibuprofen treatment. After thiopental anesthesia (25 mg/kg IV), animals were instrumented to measure various cardiovascular parameters. Endotoxic shock was induced by injecting Escherichia coli (0111:B4) endotoxin (1 mg/kg IV). Benoxaprofen (10 mg/kg IV; N = 13), ibuprofen (12.5 mg/kg; N = 6), or saline (N = 12) was injected 60 minutes after endotoxin administration. During the treatment period, both benoxaprofen and ibuprofen increased mean arterial pressure, heart rate, and vascular resistance to the same degree over the control animals. Benoxaprofen did increase dP/dtmax while ibuprofen did not. Twenty-four-hour survival was 0% for the control animals (N = 12), 0% for the ibuprofen group (N = 6), and 61.5% for the benoxaprofen group (N = 13). In an additional set of experiments, benoxaprofen (N = 8) was given 120 minutes after endotoxin administration and demonstrated similar improvements in hemodynamics and survival. These data demonstrate that benoxaprofen could improve survival in an otherwise lethal endotoxic model and suggest that the products of the lipoxygenase pathway may contribute to the lethality of an LD100 endotoxic shock model.

The effects of vasoactive mediator antagonists on endotoxic shock in dogs. I.

Many vasoactive mediators have been implicated in causing or maintaining the hypotension of endotoxic shock. What has yet to be firmly established is the relative importance of each of these mediators in a given shock model. In a canine endotoxic shock model (LD100), we studied the effects of opiate and prostaglandin inhibition 60 min after endotoxin administration. After thiopental anesthesia, the animals were instrumented to measure various cardiovascular parameters. Endotoxic shock was induced by injecting E. coli endotoxin (0111:B4) (1 mg/kg i.v.). Drug intervention occurred 60 min after endotoxin administration. Naloxone (2 mg/kg i.v.) improved mean arterial pressure (MAP) transiently. A more significant increase of MAP (85% of preshock levels) was attained after ibuprofen (12.5 mg/kg i.v.) administration secondary to an increase in total peripheral resistance (TPR). All groups had 0% 24-hour survival. These data suggest that the endogenous opioids, presumably inhibited by naloxone, seem to contribute little to this lethal canine endotoxic shock model. By contrast, the prostanoids which are inhibited by ibuprofen appear to be more hemodynamically significant in this model.