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Studies with Pharmacological Effects

Stevia also has shown promise in medical research for treating such conditions as obesity and high blood pressure. Stevia has negligible effect on blood glucose, therefore it is attractive as a natural sweetener to diabetics. See the following abstracts:

Ferri LA, Alves-Do-Prado W, Yamada SS, Gazola S, Batista MR, Bazotte RB. :

Investigation of the antihypertensive effect of oral crude stevioside in patients with mild essential hypertension.Phytother Res. 2006 Sep;20(9):732-6.
Programa de Pos Graduacao em Ciencias Farmaceuticas, UEM, Universidade Estadual de Maringa, Maringa, Av Colombo, PR, Brazil.


The antihypertensive effect of crude stevioside obtained from the leaves of Stevia rebaudiana (Bertoni) Bertoni (Compositae) on previously untreated mild hypertensive patients was examined. Patients with essential hypertension were submitted to a placebo phase for 4 weeks. The volunteers selected in this phase were randomly assigned to receive either capsules containing placebo during 24 weeks or crude stevioside 3.75 mg/kg/day (7 weeks), 7.5 mg/kg/day (11 weeks) and 15.0 mg/kg/day (6 weeks). All capsules were prescribed twice a daily (b.i.d.), i.e. before lunch and before dinner. After the placebo phase and after each dose of crude stevioside, body mass index, electrocardiogram and laboratory tests were performed. During the investigation blood pressure (BP) was measured biweekly and the remaining data were collected at the end of each stevioside dose step. All adverse events were prospectively recorded but no major adverse clinical effects were observed during the trial. Systolic and diastolic BP decreased (p < 0.05) during the treatment with crude stevioside, but a similar effect was observed in the placebo group. Therefore, crude stevioside up to 15.0 mg/kg/day did not show an antihypertensive effect. Moreover, the results suggest that oral crude stevioside is safe and supports the well-established tolerability during long term use as a sweetener in Brazil.

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Dyrskog SE, Jeppesen PB, Colombo M, Abudula R, Hermansen K.

Preventive effects of a soy-based diet supplemented with stevioside on the development of the metabolic syndrome and type 2 diabetes in Zucker diabetic fatty rats.
Metabolism. 2005 Sep;54(9):1181-8.
Department of Endocrinology and Metabolism C, Aarhus University Hospital, Aarhus Sygehus THG, 8000 Aarhus C., Denmark. stig.dyrskog@ki.au.dk

The world witnesses an explosive increase in diabetes, demanding intensified prevention and treatment not least for the low-income population. The plant, Stevia rebaudiana Bertoni, has been used for the treatment of diabetes in traditional medicine. We have previously demonstrated that stevioside, a diterpene glycoside isolated from the plant Stevia rebaudiana Bertoni, possesses insulinotropic, glucagonostatic, antihyperglycemic, and blood pressure-lowering effects in animal studies. We have also found that a dietary supplement, Abalon, of soy protein, isoflavones, and cotyledon fiber has beneficial effects on cardiovascular risk markers in type 2 diabetes.

The aim of this study was to investigate if the combination of stevioside and a dietary supplement of soy protein possesses beneficial qualities in the treatment of type 2 diabetes and the metabolic syndrome. We randomized male Zucker diabetic fatty rats into 4 groups and fed them the different test diets for 10 weeks: (A) standard carbohydrate-rich laboratory diet (chow), (B) chow+stevioside (0.03 g/kg body weight [BW] per day), (C) 50% soy (Abalon)+50% chow (adjusted for vitamins and minerals), and (D) 50% soy (Abalon)+50% chow+stevioside 0.03 g/kg BW per day. We measured plasma glucose, blood pressure, weight, and food intake once weekly. The animals were equipped with an intra-arterial catheter, and at week 10, the conscious rats underwent an intra-arterial glucose tolerance test (2.0 g/kg BW). Stevioside exerts beneficial effects in type 2 diabetic Zucker diabetic fatty rats, that is, lowers blood glucose (area under the glucose curve [AUC(30min)]: group A vs B, a 19% reduction; and group C vs D, a 12% reduction; P<.001). We did not detect any effect on insulin or glucagon responses. After 2 weeks of treatment, a decrease in the systolic blood pressure was observed in the stevioside-treated groups (P<.01). Abalon had beneficial effects on cardiovascular risk markers, that is, (1) lowers total cholesterol (P<.01), (2) reduces triglycerides (P=.01), and (3) reduces free fatty acids (P<.001). The combination of stevioside and soy supplementation appears to possess the potential as effective treatment of a number of the characteristic features of the metabolic syndrome, that is, hyperglycemia, hypertension, and dyslipidemia. A long-term human study of the concept in type 2 diabetic subjects is needed to verify these promising results in animal diabetes.

 

Hsieh MH, Chan P, Sue YM, Liu JC, Liang TH, Huang TY, Tomlinson B, Chow MS, Kao PF, Chen YJ.:

Efficacy and tolerability of oral stevioside in patients with mild essential hypertension: a two-year, randomized, placebo-controlled study.

Clin Ther. 2003 Nov;25(11):2797-808.
Department of Medicine, Taipei Medical University--Wan Fang Hospital, Taipei City, Taiwan.

 

BACKGROUND: Stevioside, a natural glycoside isolated from the plant Stevia rebaudiana Bertoni, has been used as a commercial sweetening agent in Japan and Brazil for >20 years. Previous animal and human studies have indicated that stevioside has an antihypertensive effect.

 

OBJECTIVES: This study was undertaken to investigate the long-term (2-year) efficacy and tolerability of stevioside in patients with mild essential hypertension. Secondary objectives were to determine the effects of stevioside on left ventricular mass index (LVMI) and quality of life (QOL). METHODS: This was a multicenter, randomized, double-blind, placebo-controlled trial in Chinese men and women aged between 20 and 75 years with mild essential hypertension (systolic blood pressure [SBP] 140-159 mm Hg and diastolic blood pressure [DBP] 90-99 mm Hg). Patients took capsules containing 500 mg stevioside powder or placebo 3 times daily for 2 years. Blood pressure was measured at monthly clinic visits; patients were also encouraged to monitor blood pressure at home using an automated device. LVMI was determined by 2-dimensional echocardiography at baseline and after 1 and 2 years of treatment. QOL was assessed using the Medical Outcomes Study 36-Item Short-Form Health Survey. Electrocardiographic, laboratory, and QOL parameters were assessed at the beginning of treatment, and at 6 months, 1 year, and 2 years.

 

RESULTS: One hundred seventy-four patients (87 men, 87 women) were enrolled in the study, and 168 completed it: 82 (42 men, 40 women; mean [SD] age, 52 [7] years) in the stevioside group and 86 (44 women, 42 men; mean age, 53 [7] years) in the placebo group. After 2 years, the stevioside group had significant decreases in mean (SD) SBP and DBP compared with baseline (SBP, from 150 [7.3] to 140 [6.8] mm Hg; DBP, from 95 [4.2] to 89 [3.2] mm Hg; P < 0.05) and compared with placebo (P < 0.05). Based on patients' records of self-monitored blood pressure, these effects were noted beginning approximately 1 week after the start of treatment and persisted throughout the study. There were no significant changes in body mass index or blood biochemistry, and the results of laboratory tests were similar in the 2 groups throughout the study. No significant difference in the incidence of adverse effects was noted between groups, and QOL scores were significantly improved overall with stevioside compared with placebo (P < 0.001). Neither group had a significant change in mean LVMI. However, after 2 years, 6 of 52 patients (11.5%) in the stevioside group had left ventricular hypertrophy (LVH), compared with 17 of 50 patients (34.0%) in the placebo group (P < 0.001). Of those who did not have LVH at baseline, 3 of 46 patients (6.5%) in the stevioside group had developed LVH after 2 years, compared with 9 of 37 patients (24.3%) in the placebo group (P < 0.001).

 

CONCLUSIONS: In this 2-year study in Chinese patients with mild hypertension, oral stevioside significantly decreased SBP and DBP compared with placebo. QOL was improved, and no significant adverse effects were noted.

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Jeppesen PB, Gregersen S, Rolfsen SE, Jepsen M, Colombo M, Agger A, Xiao J, Kruhoffer M, Orntoft T, Hermansen K. :

Antihyperglycemic and blood pressure-reducing effects of stevioside in the diabetic Goto-Kakizaki rat.

Metabolism. 2003 Mar;52(3):372-8.
Department of Endocrinology and Metabolism, Molecular Diagnostic Laboratory, Aarhus Amtssygehus, Aarhus University Hospital, Aarhus, Denmark.

 

Stevioside, a glycoside present in the leaves of the plant, Stevia rebaudiana Bertoni (SrB), has acute insulinotropic effects in vitro. Its potential antihyperglycemic and blood pressure-lowering effects were examined in a long-term study in the type 2 diabetic Goto-Kakizaki (GK) rat. Rats were fed 0.025 g x kg(-1) x d(-1) of stevioside (purity > 99.6%) for 6 weeks. An intra-arterial catheter was inserted into the rats after 5 weeks, and conscious rats were subjected to arterial glucose tolerance test (2.0 g x kg(-1)) during week 6. Stevioside had an antihyperglycemic effect (incremental area under the glucose response curve [IAUC]): 985 +/- 20 (stevioside) versus 1,575 +/- 21 (control) mmol/L x 180 minutes, (P <.05), it enhanced the first-phase insulin response (IAUC: 343 +/- 33 [stevioside] v 136 +/- 24 [control] microU/mL insulin x 30 minutes, P <.05) and concomitantly suppressed the glucagon levels (total AUC: 2,026 +/- 234 [stevioside] v 3,535 +/- 282 [control] pg/mL x 180 minutes, P <.05). In addition, stevioside caused a pronounced suppression of both the systolic (135 +/- 2 v 153 +/- 5 mm Hg; P <.001) and the diastolic blood pressure (74 +/- 1 v 83 +/- 1 mm Hg; P <.001). Bolus injections of stevioside (0.025 g x kg(-1)) did not induce hypoglycemia. Stevioside augmented the insulin content in the beta-cell line, INS-1. Stevioside may increase the insulin secretion, in part, by induction of genes involved in glycolysis. It may also improve the nutrient-sensing mechanisms, increase cytosolic long-chain fatty acyl-coenzyme A (CoA), and downregulate phosphodiesterase 1 (PDE1) estimated by the microarray gene chip technology. In conclusion, stevioside enjoys a dual positive effect by acting as an antihyperglycemic and a blood pressure-lowering substance; effects that may have therapeutic potential in the treatment of type 2 diabetes and the metabolic syndrome.

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Liu JC, Kao PK, Chan P, Hsu YH, Hou CC, Lien GS, Hsieh MH, Chen YJ, Cheng JT.:

Mechanism of the antihypertensive effect of stevioside in anesthetized dogs

.Pharmacology. 2003 Jan;67(1):14-20.
Department of Medicine, Taipei Medical University--Wan Fang Hospital, Taipei, Taiwan.

 

Stevioside is a sweet-tasting glycoside isolated from the leaves of Stevia rebaudiana. It has been used as a noncaloric sugar substitute in Japan and Brazil for decades. Previous studies have shown that it lowered blood pressure in spontaneously hypertensive rats by intravenous injection. This study was designed to evaluate the hypotensive effect of stevioside in dogs and to define the underlying mechanism. After nasogastric administration of stevioside powder (200 mg/kg), the blood pressure of healthy mongrel dogs began to significantly decrease at 60 min and returned to baseline level at 180 min. The reduction of blood pressure was more rapid (at 5-10 min) and effective after intravenous injection. However, no significant change of blood pressure was noted after injection through left vertebral artery, implicating that the hypotensive effect is not related to the central nervous system. Stevioside also showed significant hypotensive effects in renal hypertensive dogs, in a dose-dependent manner. In cultured rat aortic smooth muscle cells (A7r5 cell line), stevioside can dose-dependently inhibit the stimulatory effects of vasopressin and phenylephrine on intracellular Ca(2+) in a calcium-containing medium. However, no intracellular Ca(2+) inhibitory effect was observed in calcium-free medium, implicating that stevioside may inhibit the Ca(2+) influx from extracellular fluid. Our present data show that stevioside did not influence the calcium ionophore (A23187) induced Ca(2+) influx, indicating that the antagonistic effect was through Ca(2+) channels. This study confirmed that stevioside is an effective antihypertensive natural product, and its hypotensive mechanism may be probably due to inhibition of the Ca(2+) influx.

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Hsu YH, Liu JC, Kao PF, Lee CN, Chen YJ, Hsieh MH, Chan P. :

Antihypertensive effect of stevioside in different strains of hypertensive rats.

Zhonghua Yi Xue Za Zhi (Taipei). 2002 Jan;65(1):1-6.
Department of Medicine, Taipei Medical University-Wan Fang Hospital, Taiwan, ROC.

 

BACKGROUND: Stevioside is a natural sweet-tasting glycoside isolated from the herb Stevia rebaudiana, composed of stevia, a diterpenic carboxylic alcohol with three glucose molecules, mainly used commercially as sugar substitute. Previous study has shown that it can lower blood pressure in anesthetized spontaneously hypertensive rats (SHR). This study was undertaken to evaluate the antihypertensive effect of stevioside in different strains of hypertensive rats and to observe whether there is difference in blood pressure lowering effect.

 

METHODS: Noninvasive tail-cuff method was employed to measure blood pressure. Stevioside at the concentrations of 50, 100 and 200 mg/kg were administered intraperitoneally (ip) to normotensive Wistar-Kyoto rats (NTR), SHR, deoxycorticosterone acetate-salt (DOCA-NaCl) sensitive hypertensive rats (DHR) and renal hypertensive rats (RHR).

 

RESULTS: Significant hypotensive effect of stevioside administered ip was noted in different strains of rats at the dose of 50 mg/kg. When stevioside was increased to the concentrations of 100 and 200 mg/kg, ip, it also caused slow and persistent lowering of blood pressure in SHR and NTR. Data also showed that stevioside given at the concentrations of 100, 200 and 400 mg/kg ip resulted in lowering of blood pressure in SHR dose-dependently. Blood pressure returned to previous levels after the drug was discontinued for 2-3 days. Drinking of 0.1% stevioside solution in mature SHR could have antihypertensive effect and also prevented hypertension in immature SHR.

CONCLUSIONS: This study reconfirmed stevioside has hypotensive effect and the effect is more prominent in hypertensive rats.

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