scientific justification of the efficacy of elim’real

INOREAL: SCIENTIFIC JUSTIFICATION OF THE EFFICACY OF ELIM’REAL

NUTRAVERIS/INOREAL – Efficacy dossier on Elim’Real® – January 2015 1

SCIENTIFIC JUSTIFICATION OF THE EFFICACY OF ELIM’REAL®

Analysis of the scientific data related to the diuretic effects of Carum carvi, Filipendula ulmaria, Paullinia cupana, Solidago

vigaureae, Taraxacum officinale and Foeniculum vulgare

January 2015

HEAD OFFICE 18C Rue du Sabot 22440 PLOUFRAGAN FRANCE Phone: +33 (0)2 96 76 54 87 Fax: +33 (0)2 96 76 63 26 www.NUTRAVERIS.com

Applicant:



Table of contents

1. INTRODUCTION ......................................................................................... 3

2. CARUM CARVI ........................................................................................... 4 A. PRESENTATION OF THE PLANT .................................................................................................. 4 B. EFFICACY DATA ....................................................................................................................... 4

1. Traditional use ......................................................................................................................... 4 2. In vitro and animal data ........................................................................................................... 4 3. Human data ............................................................................................................................. 6

3. FILIPENDULA ULMARIA ............................................................................ 7 A. PRESENTATION OF THE PLANT .................................................................................................. 7 B. EFFICACY DATA ....................................................................................................................... 7

1. Traditional use ......................................................................................................................... 7 2. In vitro and animal data ........................................................................................................... 7 3. Human data ............................................................................................................................. 8

4. PAULLINIA CUPANA ................................................................................. 9 A. PRESENTATION OF THE PLANT .................................................................................................. 9 B. EFFICACY DATA ....................................................................................................................... 9

1. Traditional use ......................................................................................................................... 9 2. In vitro and animal data ........................................................................................................... 9 3. Human data ........................................................................................................................... 10

5. SOLIDAGO VIGAUREAE ......................................................................... 15 A. PRESENTATION OF THE PLANT ................................................................................................ 15 B. EFFICACY DATA ..................................................................................................................... 15

1. Traditional use ....................................................................................................................... 15 2. In vitro and animal data ......................................................................................................... 15 3. Human data ........................................................................................................................... 17

6. TARAXACUM OFFICINALE ..................................................................... 18 A. PRESENTATION OF THE PLANT ................................................................................................ 18 B. EFFICACY DATA ..................................................................................................................... 18


7. FOENICULUM VULGARE ........................................................................ 22 A. PRESENTATION OF THE PLANT ................................................................................................ 22 B. EFFICACY DATA ..................................................................................................................... 22


8. CONCLUSION ........................................................................................... 24

9. REFERENCES .......................................................................................... 25



1. Introduction

The purpose of this dossier is to present the efficacy of the botanicals included in

Elim’Real:

Carum carvi

Filipendula ulmaria

Paullinia cupana

Solidago virgaureae

Taraxacum officinale

Foeniculum vulgare

In this aim, all the data related to an oral intake of these plants will be analyzed. Moreover, all the studies assessing the in vitro or in vivo effects of these six botanicals will be also presented.



2. Carum carvi

a. Presentation of the plant

Common name: caraway

Latin name: Carum carvi

Family: Apiaceae

Part used: fruits

Main active compounds: polyphenols

b. Efficacy data

1. Traditional use The traditional use of caraway is recognized in the ESCOP, the Commission E and

the French pharmacopeia (ESCOP, 2003; Blumenthal, 1998; Pharmacopée Française 2005). Caraway is also present in the European pharmacopeia. Caraway is used for its carminative properties and for spasmodic gastro-intestinal complaints, flatulence and bloating.

Caraway is known in the traditional Moroccan medicine as a diuretic, notably the

aqueous fruit extract (Bellakhdar, 1997).

2. In vitro and animal data A study assessing the diuretic effects of caraway and Tanacetum vulgare in normal

rats has been published in 2007 (Lahlou et al., 2007). Since Elim’Real does not contain Tanacetum vulgare, only the results on caraway are presented. This controlled study evaluated the effects of an aqueous extract caraway on diuresis and sodium and potassium urinary excretion in normal adults Wistar rats weighting 150-200 g at the beginning of the study. In order to assess the diuretic effects of caraway, the authors have used a standard diuretic compound, furosemide, as control compound. The experiment has been divided in two parts. Firstly, animals were divided in 4 groups to assess the effect of a single oral administration. Secondly, animals were divided in 4 groups to assess the effects of repeated administration over 8 days. The 4 groups corresponded to: 1) control group supplemented with water, 2) caraway group (100 mg/kg bw), 3) Tanacetum vulgare group (100 mg/kg bw, and 4) furosemide group (10 mg/kg bw).



Regarding the single oral administration, urine was collected at 1, 2, 4, 6 and 24 h after administration. Levels of sodium and potassium have been assessed in urine and plasma. The caraway extract has induced an increased in diuresis in comparison to the control group 4h after administration (5.7 ± 0.3 mL vs. 3.0 ± 0.5 mL, p < 0.05). Urinary extraction was still higher after 6 and 24 h in the caraway group in comparison to the control group (after 24h: 12.8 ± 0.1 mL vs. 7.7 ± 0.7 mL, p < 0.01). The diuretic effect of furosemide has been faster and stronger than plants. However, cumulative urinary excretion over 24h was similar for caraway and furosemide (12.8 ± 0.1 vs. 18.5 ± 0.6 for caraway and furosemide respectively). Moreover, caraway has increased sodium (p < 0.001) and potassium (p < 0.05) urinary extractions. The effects of caraway were stronger than the one of furosemide. No effects of plasma sodium and potassium levels have been observed. Regarding the repeated administration, a significant increase in diuresis has been observed on the first day in the caraway group in comparison to the control group (9.3 ± 1.2 mL vs. 5.4 ± 0.7 mL, p < 0.05), and has significantly increased until the 6th day (20.2 ± 0.4 mL vs. 5.8 ± 1.0 mL, p < 0.001). Diuresis was stabilized after the 6th day. The diuretic effect of furosemide has been firstly stronger in comparison to caraway, but was similar after the 4th day. Regarding electrolyte excretion, caraway induced an increase in sodium excretion after the 4th day (p < 0.01), which was more significant between the 5th and the 8th day (p < 0.001). Potassium urinary excretion has not been affected in the various groups, as the plasma levels in potassium and sodium. Therefore, this study confirms the traditional use of caraway as diuretic botanical. Moreover, it appears that caraway is as efficient as furosemide for increasing diuresis and urinary sodium excretion. Moreover, the caraway extract has not induced any renal toxicity in rats at the tested dosage.

More recently, another animal study has assessed the effects of aqueous extract of caraway seeds in experimentally induced diabetic nephropathy (Sadig et al., 2010). Rats were divided in 4 groups: 1) normal controls, 2) diabetic controls, 3) diabetic rats receiving 30 mg/kg of caraway extract, and 4) diabetic rats receiving 60 mg/kg of caraway extract. The supplementation was given orally for 60 days. The results have shown that diabetes induces an increase in urine volume. However, the caraway extract reduced urine volumes in comparison to diabetic controls rats. Urinary protein levels were also lowered in the supplemented rats in comparison to the diabetic control animals. Therefore, this study suggests a renoprotective effect of caraway in diabetic rats. However, no increase in diuresis has been observed, but the lack of normal control animal (i.e. non diabetic animal) supplemented with caraway does not permit to draw any conclusion on the diuretic effect of caraway in healthy rats.

The effects of caraway on diabetic nephropathy have been also assessed in an in

vitro study (Tupe et al., 2015). Results have shown that caraway may reverse some modifications in albumin glycation which is involved in the physiopathology of diabetic nephropathy. The authors concluded that caraway may be interesting for the management of diabetic nephropathy.



3. Human data

No clinical study has assessed the diuretic effects of caraway in humans. However, a study assessing the effects of caraway in humans has been recently published in two articles. In 2013, Kazemipoor et al. have published the results of a randomized, triple blind,

placebo-controlled trial assessing the effects of caraway on body weight in 70 overweight and obese women. Participants were asked to consume 30 ml/day of caraway aqueous extract or placebo for 90 days, without any changes in dietary habits and physical activity. In comparison to placebo, caraway has induced a significant reduction in body weight (p < 0.01), body mass index (p < 0.01), body fat (p < 0.01) and waist circumference (p < 0.01). Blood pressure, heart rate and plasma lipids have not been affected by the supplementation. The diuretic effect of caraway has not been assessed in this study.

More recently, the same research group has published a second article on this study

in order to evaluate the safety of caraway extract (Kazemipoor et al., 2014). No significant adverse events have been reported. The authors concluded that the caraway extract was safe at the tested dosage. Regarding renal function, no change in creatinine, uric acid and urea levels have been measured. Urine specific gravity was also similar in both groups at the end of the study.



3. Filipendula ulmaria


Common name: meadowswett or mead wort

Latin name: Filipendula ulmaria

Family: Rosaceae

Part used: flowering tips

Main active compounds:

Flavonoids, particularly spiraeoside Simple heteroside phenolic compounds, and notably salicylic

derivatives

b. Efficacy data

1. Traditional use The French Drug Agency (Agence du médicament, 1998) recognizes the diuretic

properties of Filipendula ulmaria and has authorized a health claim for medicinal herbal products, even if no clinical trial has demonstrated these effects in humans and animal studies are really scarce:

Traditionally used to facilitate the elimination function of the body Filipendula ulmaria is recognized by ESCOP for improving renal elimination, even

if published data does not substantiate this use. Filipendula ulmaria is present in the French pharmacopeia and in the European

pharmacopeia.

2. In vitro and animal data No in vitro or animal studies have investigated the diuretic effects of Filipendula ulmaria. One animal study has highlighted hepatoprotective and antioxidant effects of an

ethanolic extract of Filipendula ulmaria aerial parts (100 mg/kg bw) in rats treated by CCl4 (Shilova et al., 2006).



A study has demonstrated the inhibitory activity of Filipendula ulmaria on histidine

decarboxylase (Nitta et al., 2013). The authors of this experiments suggested that F. ulmaria may be used to treat histamine-mediated symptoms, such as allergies and stomach ulcerations.

3. Human data No clinical trial has assessed the effects of Filipendula ulmaria in humans.



4. Paullinia cupana


Common name: guarana

Latin name: Paullinia cupana

Family: Sapindaceae

Part used: seed

Main active compounds: Caffeine (2.5 – 7%) Theophylline or theobromine (< 1%) Non-hydrolysable tannins (12%, among which catechins 6% and

epicatechin 3.7%)

b. Efficacy data

1. Traditional use Guarana is present in the French pharmacopeia

Guarana is recognized as a stimulant, an anti-fatigue compound, and because of its

caffeine content, it may act on vasodilation, diuresis, energy metabolism, etc. (Witchl et al., 1999).

2. In vitro and animal data

Since no study has investigated directly the effects of guarana on diuresis, only experiments conducted with caffeine are presented. In order to clarify the mechanism of action of caffeine on diuresis, a study has

investigated the role of adenosine A1 receptors in the renal action of caffeine (Rieg et al., 2005). Experiments have been performed in normal mice (A1R+/+) or in adenosine A1 receptors knock-out mice (A1R-/-). Urinary excretion was determined in awake mice in metabolic cages over 3 h in response to caffeine (45 mg/kg), or vehicle (0.9 ml/30 g bw of 0.85% NaCl) given by oral gavage. Caffeine elicited a diuresis and natriuresis (in absolute terms and related to urinary creatinine excretion) in A1R+/+ but not in A1R-/- mice. Urine volume has been increased from 2.7 ±0.1 to 6.1 ± 0.8 µL/min in A1R+/+ mice. Sodium excretion has been increased



from 301 ± 18 to 832 ± 73 nmol/min in A1R+/+ mice. Moreover, urinary chlorure and calcium excretions have been also increased in A1R+/+ mice. All these parameters have not been affected in the A1R-/- mice. The data indicate that an intact A1 receptor is necessary for caffeine-induced inhibition of renal reabsorption causing diuresis and natriuresis.

The aim of another study was to evaluate whether caffeine mediates renal

natriuresis and diuresis in healthy and diseased liver through hepatorenal reflex (Ming et al., 2010). Intrahepatic (intraportal but not intravenous) caffeine (5 mg/kg) increased urine flow by approximately 82% in healthy rats. This effect was abolished by liver denervation. Intraportal infusion of adenosine decreased urine production, and this response was abolished by intraportal but not intravenous caffeine. Liver injury was induced by intraperitoneal injection of thioacetamide (500 mg/kg), and functional assessment was performed 24 h later. Liver injury was associated with lower (~30%) glomerular filtration rate, lower (~18%) renal arterial blood flow, and lower urine production. Intraportal but not intravenous caffeine improved basal urine production and renal ability to increase urine production in response to saline overload. This liver-dependent diuretic effect of caffeine is consistent with the hypothesis for the adenosine-mediated mechanism of hepatorenal syndrome.

An animal study has evaluated the effects of caffeine on the central micturition

reflex by measuring the degree of neuronal activation and by quantifying nerve growth factor (NGF) expression in rats (Cho et al., 2014). Following caffeine administration for 14 days, an urodynamic study was performed to assess the changes in bladder function. Subsequently, immunohistochemical staining to identify the expression of c-Fos and NGF in the central micturition areas was performed. Ingestion of caffeine increased bladder smooth muscle contraction pressure and time as determined by cystometry. Expression levels of c-Fos and NGF in all central micturition areas were significantly increased following the administration of caffeine. The effects on contraction pressure and time were the most potent and expression levels of c-Fos and NGF were greatest at the lowest dose of caffeine. These results suggest that caffeine facilitates bladder instability through enhancing neuronal activation in the central micturition areas.

3. Human data Several studies have demonstrated the weight loss effect of guarana, but these

studies have not investigated the diuretic effects of guarana. These studies are therefore not interesting for this dossier.

Conversely, some studies have assessed the diuretic effects of caffeine in humans. These studies are detailed hereafter.



In 1984, Massey et al. have assessed the effects of caffeine on urinary electrolyte

excretion in healthy females. 12 women drank decaffeinated coffee or tea to which 0, 150 or 300 mg of caffeine has been added. Urine samples were collected at 1, 2 and 3 hours after caffeine consumption. A non-significant increase in urine volume has been observed (463 ± 226 mL for 0 mg, 525 ± 279 mL for 150 mg, and 626 v 189 mL for 300 mg). However, total urine volume correlated significantly with dose of caffeine per body weight when 300 mg of caffeine was consumed. Moreover, increase in urine volume were observed after 1 and 2 h. Total urinary excretion of calcium, magnesium and sodium, but not potassium, increased significantly after caffeine intake. The increase output of calcium and sodium was mainly due to significantly increased urinary calcium and sodium concentrations.

In 1985, a similar study has been conducted in 15 healthy males (Massey et al.,

1985). Total urinary three hours excretion of calcium, magnesium, sodium and chloride increased significantly after caffeine intake. However, no significant difference in urine volume has been measured (414 ± 315 mL for 0 mg of caffeine, 381 ± 282 mL for 150 mg, and 486 ± 330 mL for 300 mg). Thus, this study did not highlight any significant diuretic effect of caffeine in healthy males.

A study has assessed the effects of dietary caffeine in renal handling of minerals in adult women (Bergman et al., 1990). 37 women (31-78 years) consumed a decaffeinated beverage to which 6 mg of caffeine/kg bw lean mass or no caffeine were added. An increase in urine volume over 2 hours has been measured (332 mL vs. 445 mL, mean difference 113 ± 20 mL, p < 0.0001). Moreover, urine creatinine, calcium, magnesium, sodium, chloride and potassium have been increased by the caffeine intake. Thus, this study clearly highlights the diuretic effect of caffeine in healthy women.

The effects of an oral 250 mg caffeine dose have been assessed in 8 healthy

subjects (Nussberger et al., 1990). All participants were on a methylxanthine-free diet for 1 week. One to 2h after caffeine ingestion, both systolic and diastolic blood pressure increased by 12 mm HG, whereas heart rate tended to increase. An increase in diuresis and in urinary sodium, potassium, and osmol excretion was observed within 1h. Interestingly, decaffeinated coffee did not induce any change in these parameters, clearly highlighting the involvement of caffeine. In addition, a significant increase in plasma epinephrine has been measured after caffeine ingestion, but not after decaffeinated coffee. Plasma immunoreactive atrial natriuretic peptide has not been affected by the caffeine. In conclusion, this study clearly shows that caffeine induce an increase in diuresis and in sodium and potassium urinary excretion in healthy subjects.

In order to compare the effects of caffeinated and non-caffeinated carbohydrate

electrolyte drinks on urine production at rest and during prolonged exercise, 6 subjects have been included in this study (Wemple et al., 1997). They received a carbohydrate electrolyte solution (35 mL/kg) with or without caffeine (25 mg/dL). Parameters were measured during 4h of rest or 1h of rest followed by 3h of cycling at 60% VO2max. At rest, mean urine volume between 60 and 240 min was greater



for the caffeine drink (1843 ± 166 mL) than for placebo (1411 ± 181 mL, p < 0.01), while the difference has not been observed during exercise (398 ± 32 mL for caffeine and 490 ± 57 mL for placebo). Plasma catecholamine concentrations was not different between placebo and caffeine, but were greater during exercise than rest (p < 0.01) and may have counteracted the diuretic effect of caffeine observed at rest. Thus, this trial demonstrates the diuretic effect of caffeine at rest in healthy subjects.

To investigate the impact of coffee consumption on fluid balance, 12 healthy volunteers were supplied with a standardized diet for 2 days after having abstained from consumption of methylxanthines for 5 days (Neuhauser-Berthold et al., 1997). During the first day, fluid requirement was met by mineral water. On the following day the same amount of fluid was supplied and the mineral water was in part replaced by 6 cups of coffee containing 642 mg of caffeine. This led to an increase in 24-hour urine excretion of 753 ± 532 mL (p < 0.001), a corresponding negative fluid balance and a concomitant decrease in body weight of 0.7 ± 0.4 kg (p < 0.001). Total body water as measured with bioelectrical impedance analysis decreased by 1.1 ± 1.2 kg or 2.7% (p < 0.01). Urinary excretion of sodium and potassium was elevated by 80 ± 62 mmol or 66% (p < 0.01) and 14 ± 12 mmol or 28% (p < 0.01), respectively. Caffeine exhibits consequently a significant diuretic effect.

In order to examine the effect of various combinations of beverages in hydration status of healthy male adults, a randomized, crossover study has been conducted in 18 healthy males (Grandjean et al., 2000). Subjects consumed water, carbonated, caffeinated caloric and non-caloric colas and coffee. The average caffeine intake ranged from 114 ± 26 mg/d to 253 ± 59 mg/d. No significant differences were observed among treatments regarding urine volume, urinary creatinine, urinary osmolality and urine specific gravity.

In 2005, a trial has examined whether 3 levels of controlled caffeine consumption affected fluid-electrolyte balance and renal function (Armstrong et al., 2005). Healthy males (21.6 ± 3.3 years) consumed 3 mg/kg of caffeine on days 1 to 6, and then (days 7 to 11) subjects consumed 0, 3 or 6 mg caffeine per kg per day. No changes in urine osmolality, urine specific gravity, urine color, and 24-h urine volume have been observed.

In order to assess the effects of caffeine on lower urinary tract symptoms, a

randomized, double-blind, placebo-controlled study has been conducted in healthy subjects without any urinary symptoms (Bird et al., 2005). Caffeine ingestion corresponded to 400 mg per day for a 70 kg person. During the first day on study medications, patients taking caffeine versus placebo voided a mean of 7.8 versus 6.4 times in a 24-hr period (p = 0.05). The mean total urine production was 2004 mL (caffeine) versus 1643 mL (placebo) (p = 0.06), while total fluid ingested was similar (2246 mL-caffeine, 2102 mL-placebo, p = 0.46). For the remaining 2 days there was no significant difference between the two arms. This study shows therefore that caffeine induce a short-time diuretic effect.

To examine the diuretic effect of energy drinks, Riesenhuber et al. (2006) have

conducted a randomized, placebo-controlled crossover study in 12 healthy male



volunteers (18-28 years). 4 drinks have been tested. One of the drinks was Red Bull Energy Drink® (containing 80 mg caffeine and 1 g taurine per 250 mL). The other three test drinks either lacked caffeine, or taurine or, as placebo, both. Urine was collected immediately before and for 6h after the drink. Urine output was recorder hourly, and osmolarity and Na+ were analyzed in the total 6h urine collection. Urine output and natriuresis increased with both caffeinated drinks. The mixed model analysis demonstrated that these effects were caused by caffeine (both alone and combined with taurine) for urine output (+243 mL/6h vs. placebo, 95% CI: 115-372, p < 0.001) and natriuresis (+27 mmol/6h, 95% CI: 13-41, p < 0.001). Caffeine has no effect on osmolarity. Finally, taurine had no effect on urine output, natriuresis and osmolarity. This study demonstrates that the diuretic and natriuretic effects of the tested energy drinks were largely mediated by caffeine. Taurine played no significant role in the fluid balance in moderately dehydrated healthy young consumers.

In 2007, another study has been conducted in order to determine whether a

caffeinated sport drink impairs fluid delivery and hydration during exercise in warm, humid conditions (28.5°C, 60% relative humidity) (Millard-Stafford et al., 2007). This study was randomized, double-blind and placebo-controlled. 16 healthy trained cyclists completed 3 trials: placebo, carbohydrate electrolytes, and caffeinated sport drink (195 mg of caffeine per liter). For each trials, subjects cycled for 120 min at 60-75 VO2max followed by 15 min of maximal-effort cycling. Trials were separated by at least 5 days. Subjects ingested half of a pre-exercise bolus of 6 mL/kg bw 10 min before exercise and the other half immediately before exercise. During cycling, subjects ingested 3 ml/kg bw (220 ml on average) of beverage at 15-min intervals. Total caffeine ingestion during the caffeinated drink trial was 1.2 mg/kg before exercise, 3.5 mg/kg after 60 min, and 5.3 mg/kg for the entire protocol. Urine output was similar after all drinks. Urine output was 280 ± 230 mL for placebo, 280 ± 180 mL for carbohydrate electrolyte, and 390 ± 270 mL for the caffeinated drink. Therefore, this study suggests that caffeine may not induce diuresis during exercise.

Since acute caffeine ingestion may increase urine volume, prompting concerns about

fluid balance during exercise and sport events, a recent meta-analysis has evaluated the caffeine-induced diuresis in adults during rest and exercise (Zhang et al., 2014). Only studies conducted in healthy adults have been included in the analysis. 16 studies have been retrieved by the authors. The mean caffeine ingestion was 300 mg. The overall effect size (ES) was 0.29 (95% CI: 0.11-0.48, p < 0.001), corresponding to an increase in urine volume of 109 ± 195 mL or 16.0 ± 19.2% for caffeine ingestion vs. non-caffeine conditions. Subgroup analysis confirmed exercise as a strong modulator. Moreover, females (ES = 0.75, 95% CI = 0.38-1.13, p < 0.001) were more susceptible to the diuretic effect than males (ES = 0.13, 95% CI= −0.05 to 0.31, p = 0.158).



The diuretic properties of caffeine are also cited in several reviews: In 1999, Stookey et al. published a review on the diuretic effects of alcohol and

caffeine. They notably estimated that the water losses due to caffeine were approximately 1.17 mL/mg caffeine.

Another review has focused in caffeine ingestion and fluid balance (Maughan et al.,

2003). The authors indicated that the available literature suggests that acute ingestion of caffeine in large doses (at least 250-300 mg, equivalent to the amount found in 2-3 cups of coffee or 5-8 cups of tea) results in a short-term stimulation of urine output in individuals who have been deprived of caffeine for a period of days or weeks. A profound tolerance to the diuretic and other effects of caffeine develops, however, and the actions are much diminished in individuals who regularly consume tea or coffee.



5. Solidago vigaureae


Common name: European goldenrod or woundwort

Latin name: Solidago virgaureae

Family: Asteraceae

Part used: whole plant

Main active compounds: polyphenols

b. Efficacy data

1. Traditional use Solidago virgaureae is present in the French pharmacopeia and the European

pharmacopeia. Commission E, the French Drug Agency and ESCOP recognized that Solidago

virgaureae is traditionally used (Blumenthal, 1998; Agence du médicament, 1998; ESCOP, 2003):

To facilitate the digestive and urinary elimination function To facilitate renal water elimination

This diuretic effect is also recognized by several experts (Bruneton, 1999; Witchl et

al., 1999). In 2008, the European Medicines Agency published an assessment report of

Solidago virgaureae and recognized its traditional use as diuretic (EMA, 2008).

2. In vitro and animal data One study, published in 1991, has investigated the effects of various flavonoid

fractions of Solidago extract, among which Solidago virgaureae, in animals (Chodera et al., 1991). Rats were divided in 5 groups: a control group and four groups treated with various Solidago extract. Each group included 10 rats and all animals received 5 mL water per day. The supplemented groups received orally 25 mg of flavonoids mixture per kg bw per day, as a aqueous solution at 1% (i.e. 25 mL/kg bw/day). Control animals have received a similar volume with NaCl instead of Solidago



extracts. Urines have been collected for 24h. Results are presented in the table 1 below:

Table 1: Increase in urine volume over 24h

Group Urine volume on 24 h (in cm3) Increase in urinary

excretion (in %) Control 6.5 ± 0.3 5.0 - 7.5 - Solidago virgaurea L. 12.2 ± 1.0 7.5 - 17.0 + 88 Solidago gigantea Ait. 11.8 ± 1.4 7.0 - 19.0 + 82 Solidago Canadensis L. var. canadensis.

10.2 ± 0.7 7.5 - 19.0 + 57

Solidago Canadensis L. var. scabra..

10.4 ± 0.6 7.0 - 14.0 + 60

All Solidago extract has increased diuresis from 57 to 88% in comparison to the control group. The most important increase has been measured in the group supplemented with flavonoids from Solidago virgaureae (+88 %). A dosage of urinary electrolytes has been realized. The results are presented in the table 2 below.

Table 2: Electrolytes urinary excretion over 24h

Group Sodium (mmol/dm3) Potassium (mmol/dm3) Calcium (mmol/dm3) Control 31.83 +/- 1.91

26.13 – 41.10 87.82 +/- 6.12 67.03 – 113.15

1.35 +/- 0.22 1.03 – 2.62

Solidago virgaurea L. 17.82 +/- 1.33 13.23 – 25.07

68.04 +/- 4.31 48.34 – 70.12

4.08 +/- 0.29 2.51 – 4.93

Solidago gigantea Ait.

12.64 +/- 1.74 5.67 – 18.25

55.42 +/- 7.82 33.46 – 76.35

1.64 +/- 0.15 1.42 – 2.23

Solidago Canadensis L. var. canadensis.

15.86 +/- 1.24 12.24 – 22.11

56.45 +/- 6.27 41.03 – 89.07

2.11 +/- 0.08 1.73 – 2.54

Solidago Canadensis L. var. scabra..

16.25 +/- 1.27 13.03 – 22.10

50.25 +/- 4.15 34.23 – 69.07

1.65 +/- 0.14 1.03 – 1.90

The authors reported a significant reduction in sodium and potassium urinary excretions with all Solidago flavonoids extracts. Conversely, three extracts, among which Solidago virgaureae, have increased calcium urinary excretions. The study demonstrates therefore that flavonoids from Solidago virgaureae possess a diuretic activity.

Comparison of diuretic activity of different fraction of Solidago virgaureae extracts on

Sprague-Dawley rats showed significant diuretic and saluretic activity of some fractions of the extract (Kaspers et al., 1998). The hydroxycinnamic acid fraction (100 mg/kg per os) significantly increased sodium and potassium extraction in urine. This activity did not differ from furosemide efficacy (10 mg/kg). There was no influence on calcium extraction in both groups. The flavonoids fraction (100 mg/kg) did not elevate urine volume or ion excretion. Conversely, a significant increase in urine volume and saluretic activity for



sodium and potassium ions was demonstrated for the saponin fraction (25 mg/kg – 100 mg/kg). The effects were comparable to furosemide.

More recently, a study has investigated the in vitro effects of S. virgaureae on rat and human bladder contraction (Borchert et al., 2004). The aqueous extract of S. virgaureae leaves inhibited carbachol-induced contraction of rat and human bladder. This inhibition was dose-dependent (final concentration 0.01 – 0.1%) and was mediated by a direct but non-competitive effect on muscarinic receptors. The authors suggest that these effects may contribute to the beneficial effects of S. virgaureae in patients with bladder dysfunction.

3. Human data

No clinical trial assessing the effects of Solidago virgaureae in humans has been retrieved. The EMA assessment report of S. virgaureae presents 5 non-controlled, non-randomized open trials (EMA, 2008). All these studies have been written in German and two studies are confidential. However, results described in the EMA opinion indicate that S. virgaureae increase urine volume in healthy subjects by 27%. Significant results were also reported for subject with inflammation of urinary tract.

Therefore, even if these studies were non-controlled and non-randomized, they

confirm the traditional use of S. virgaureae as diuretic botanical.



6. Taraxacum officinale


Common name: dandelion

Latin name: Taraxacum officinale

Family: Asteraceae

Part used: Leaf

Main active compounds: Lactones sesquiterpenes, and notably taraxinic acid Tritepenoids, among which cycloartenol Potassium

b. Efficacy data

1. Traditional use Dandelion leaves are traditionally used for (Blumenthal, 1998; Bruneton 1999;

Agence du médicament, 1998; ESCOP, 2003; Wichtl et al., 1999): The management of dyspepsia symptoms Facilitating digestion and intestinal transit Stimulating hepatic and biliary functions Increasing diuresis

Taraxacum officinale is present in the French pharmacopeia and the European

pharmacopeia. Commission E recognizes the use of dandelion leaves for the management of minor

digestive disturbances (Kemper Kathi et al., 1999). It also recognized the use of dandelion leaves and roots for the improvement of biliary and urinary function.

2. In vitro and animal data A study, published in 1974, has compared the diuretic effect of dandelion leaves

and roots in mice (Racz-Kotilla et al., 1974). Animals have been divided into four groups: 1) control group, 2) dandelion leaves (various concentrations), 3) dandelion



roots (various concentrations), and 4) furosemide (positive control, 80 mg/kg bw). The authors have evaluated both the diuretic and weight loss effects of the supplements. Diuretic effect: The authors have investigated the effects of a single administration of dandelion extracts. The table 3 below summarizes the findings of this experiment. Table 3: Diuretic and sodium and potassium urinary excretions after a single dose

Concentration (%)

Diuretic index Urinary excretions

Roots Plants Sodium Potassium

Roots Leaves Roots Leaves 0.5 1.08 1.28 1.12 1.47 1.04 1.12 1.0 1.12 1.45 1.25 2.08 1.09 1.24 2.0 1.42 1.49 2.58 3.21 1.98 1.80 4.0 1.09 1.90 1.64 6.29 1.66 4.04

Furosemide 1.87 1.90 3.60

The results have therefore shown that the diuretic effect was stronger with the dandelion plant extract than with the root extract. The authors have then measured the effects of a 30-day long supplementation with the same dandelion extract. The results of this experiment are presented in the table 4 below.

Table 4: Diuretic and sodium and potassium urinary excretions after 30 days of supplementation

Concentration (%)

Diuretic index Urinary excretions

Roots Plants Sodium Potassium

Roots Leaves Roots Leaves 0.5 1.42 1.48 2.26 2.67 1.57 2.12 1.0 1.45 1.67 1.81 2.65 1.90 2.33 2.0 1.53 1.79 1.54 2.70 2.88 3.14 4.0 1.71 2.07 1.36 4.04 3.30 3.42 6.0 1.25 1.49 1.28 1.65 2.65 4.01

Once again, the results confirm the higher diuretic activity of the dandelion plant extract in comparison to the root extract. Moreover, contrary to the single dose experiment, this second experiment showed that the extract concentration did not affect the diuretic activity. However, the highest activity diuretic activity and the highest effect on sodium and potassium urinary excretion have been measured for the extract titrated at 4%. This extract was almost equivalent to furosemide. It should be noted that the higher potassium excretion observed with dandelion may be due to the high potassium content of the extract (4.25%, approximately 3 times higher than in other diuretic botanicals). Weight management: This experiment has been performed in mice (28 – 30 g) and rats (180-200 g). During 2 weeks, animals have received a normal diet and body weight was measured every three days. Then, body weight was remained stable for 2 weeks by reducing food intake. At the end of this preparation period, animals have been divided in 16 groups



(n = 20). The modifications of body weight have been measured after 30 days and are presented in the table 5 below. Table 5: Modification in body weight after 30 days of supplementation, expressed in comparison to baseline body weight

Daily intake (mL/kg bw)

Body weight modification in comparison to baseline (% of initial body weight)

Herb Root Plant Water

Mice

2 - 3.8 - 14.0 -19.2 + 2.0 4 - 9.4 - 16.0 -21.7 + 2.0 8 - 12.7 - 23.9 -31.3 + 2.0

12 - 10.2 - 22.4 -30.7 + 4.6 Rats 8 - 10.2 - 21.5 -28.2 + 2.5

These results show that, in mice and in rats, dandelion extracts have induced a significant decrease in body weight. The highest effect has been observed with a daily intake of 8 mL/kg bw. It should be noted that weight loss was more significant during the first two weeks of the study than during the second period. Finally, in order to assess the relationship between the diuretic effect and weight loss, the authors have analyzed the weight loss of 20 animals and the diuretic effect in 16 animals. The result of this analysis is presented hereafter. Table 6: Relationship between weight loss and diuretic activity of dandelion extracts

Daily intake (mg/kg bw)

Herb Roots Plant Diuretic index

Weight loss

Diuretic index

Weight loss

Diuretic index

Weight loss

2 0.95 -3.6 1.45 -10.3 1.67 -13.8 4 1.14 -5.4 1.53 -14.7 1.79 -20.3 8 1.28 -10.2 1.71 -21.5 2.07 -28.2

12 1.18 -6.9 1.25 -18.2 1.49 -25.9 The authors observed that the highest weight loss corresponded to the highest diuretic index. The overall analysis suggests the existence of a relationship between the diuretic index and the weight loss. In conclusion, this study demonstrates the diuretic effects of dandelion extracts, mainly the plant extract. Moreover, this diuretic property may promote a reduction in body weight.

3. Human data One human clinical trial has investigating the diuretic effect of Taraxacum

officinale (Clare et al., 2009). This pilot study has been conducted in healthy female subjects, aged between 18 and 65 years (mean age 37.9 years). Subjects monitored their fluid intake for 4 consecutive days and urine output for 3 consecutive



days starting on the second day. On the third day (day 0), subjects consumed 8 mL of a dandelion leaves ethanolic extract at 8:00 am, 1:00 pm and 6:00 pm. The mean daily frequency of urination was 8.0 ± 0.76 on the day -1 (i.e. control day) and 9.0 ± 0.93 on the day 0. This frequency decreased to a normal value on the day +1 (8.1 ± 1.1). The increase in urination frequency with dandelion was statistically significant (p < 0.05). Interestingly, the increase in frequency was mainly observed between 8 am and 1 pm, i.e. after the first dose. The increase after the second dose (1 to 6 pm) was significant, but less important. Finally, no change in urine volume over 24 h has been measured. In conclusion, this pilot study confirms the beneficial effects of Taraxacum officinale on diuresis, notably after the first intake in the morning.



7. Foeniculum vulgare


Common name: fennel

Latin name: Foeniculum vulgare

Family: Apiaceae

Part used: fruit

b. Efficacy data

1. Traditional use Fennel is traditionally used for (Blumenthal, 1998; Cahiers de l’agence, 1998;

ESCOP, 2003; Witchl et al., 1999): The management of digestive disorders such as mild, spasmodic

gastrointestinal ailments, bloating, flatulence. As adjunctive treatment for pain management in functional digestive

disorders. Fennel is present in the French pharmacopeia and the European pharmacopeia

2. In vitro and animal data A study conducted in rats has evaluated the effects of aqueous extracts of

Marrubium vulgare L. and Foeniculum vulgare L. on blood pressure and urine volume (El Bardai et al., 2001). Only the results on fennel are developed hereafter. Healthy normotensive or hypertensive rats have received orally 190 mg of a lyophilized aqueous extract of fennel per kg bw for 5 days. The supplementation was equivalent to 1000mg of fennel per kg bw. A significant reduction in blood pressure has been measured in hypertensive rats. This hypotensive effect has led to an increase in urine volume (+ 80%) from the third day (p < 0.05) and to higher potassium and sodium urinary excretions (p < 0.05).



3. Human data A review on the traditional uses of medicinal plants has classified fennel in the

hypotensive plants (Wright et al., 2007). This reduction in blood pressure may be associated to an increase in urinary excretion and a higher urinary sodium level.

More recently, another review has focused on the medicinal properties of Foeniculum

vulgare Mill. in traditional Iranian medicine and modern phytotherapy (Rahimi et al., 2013). The authors indicated that fennel possesses diuretic activities, which may be useful for bladder and kidney diseases. Moreover, they estimated that the hypotensive effects of fennel can be mediated through diuretic and natriuretic activities.



8. Conclusion

This dossier presents the scientific data related to the diuretic effects of the botanicals

included in Elim’Real. The diuretic effects of Filipendula ulmaria are mainly known thought the traditional use of this plant. Conversely, the effects of Carcum carvi and Foeniculum vulgare on diuresis are been clearly demonstrated in animal studies.

Taraxacum officinale is recognized for its traditional use as diuretic. Until recently,

these effects were still unclear, but recent animal studies and one human clinical trial have confirmed the increase in diuresis observed after the consumption of dandelion.

Regarding Solidago virgaureae, animal studies have also demonstrated its diuretic

effects. These effects have been confirmed in some human studies. However, these trails are not available and are only presented in a scientific opinion of the European Medicines Agency.

Finally, guarana (Paullinia cupana) has been widely studied for its beneficial effect on

body weight. No study has investigated directly the diuretic effect of guarana, but a large number of human clinical trials have clearly demonstrated the diuretic effect of caffeine, the main active compound of guarana. These diuretic effects of caffeine may be higher in women than in men, and seem to be counteracted by physical exercise.

In conclusion, all the botanicals included in the Elim’Real formula are traditionally

recognized as diuretic plants. Available scientific data clearly substantiate these diuretic effects, and demonstrate consequently the diuretic effect of Elim’Real.



9. References

Bruneton J. “Pharmacognosie, Phytochimie, Plantes Médicinales”. 3ème édition Lavoisier. 1999. Editions TEC&DOC.

Cahiers de l’Agence n°3. Agence du médicament. 1998

ESCOP Monographs, second edition, 2003. ESCOP (European Scientific Cooperative on Phytotherapy).

Pharmacopée Européenne 8.0

Pharmacopée Française Xème édition. 2005

Witchl M., Anton R. “Plantes thérapeutiques, Tradition, Pratique Officinale, Science et Thérapeutique”. 3ème édition. 1999. Editions TEC&DOC. Carum carvi

Bellakhdar J. La Pharmacopée Marocaine Traditionnelle, Médecine Arabe Ancienne et Savoirs Populaires. 1997. Edition Ibis Press. p.150.

Blumenthal M. “The Complete German Commission E Monographs”. American Botanical Council. 1998.

Kazemipoor M, Radzi CW, Hajifaraji M, Haerian BS, Mosaddegh MH, Cordell GA. Antiobesity effect of caraway extract on overweight and obese women: a randomized, triple-blind, placebo-controlled clinical trial. Evid Based Complement Alternat Med. 2013;2013:928582.

Kazemipoor M, Radzi CW, Hajifaraji M, Cordell GA. Preliminary safety evaluation and biochemical efficacy of a Carum carvi extract: results from a randomized, triple-blind, and placebo-controlled clinical trial. Phytother Res. 2014 Oct;28(10):1456-60.

Lahlou S, Tahraoui A, Israili Z, Lyoussi B. Diuretic activity of the aqueous extracts of Carum carvi and Tanacetum vulgare in normal rats. J Ethnopharmacol. 2007 Apr 4;110(3):458-63. Epub 2006 Oct 19.

Sadiq S, Nagi AH, Shahzad M, Zia A. The reno-protective effect of aqueous extract of Carum carvi (black zeera) seeds in streptozotocin induced diabetic nephropathy in rodents. Saudi J Kidney Dis Transpl. 2010 Nov;21(6):1058-65.

Tupe RS, Sankhe NM, Shaikh SA, Kemse NG, Khaire AA, Phatak DV, Parikh JU. Nutraceutical properties of dietary plants extracts: Prevention of diabetic nephropathy through inhibition of glycation and toxicity to erythrocytes and HEK293 cells. Pharm Biol. 2015 Jan;53(1):40-50. Filipendula ulmaria

Nitta Y, Kikuzaki H, Azuma T, Ye Y, Sakaue M, Higuchi Y, Komori H, Ueno H. Inhibitory activity of Filipendula ulmaria constituents in recombinant human histidine decarboxylase. Food Chem. 2013 Jun1;138(2-3):1551-6.



Shilova IV, Zhavoronok TV, Suslov NI, Krasnov EA, Novozheeva TP, Veremeev AV, Nagaev MG, Petina GV, “Hepatoprotective and antioxidant activity of meadowsweet extract during experimental toxic hepatitis”, Bull Exp Biol Med. 2006 Aug;142(2): 216-18.

Paullinia cupana

Armstrong LE, Pumerantz AC, Roti MW, Judelson DA, Watson G, Dias JC, Sokmen B, Casa DJ, Maresh CM, Lieberman H, Kellogg M. Fluid, electrolyte, and renal indices of hydration during 11 days of controlled caffeine consumption. Int J Sport Nutr Exerc Metab. 2005 Jun;15(3):252-65.

Bergman EA, Massey LK, Wise KJ, Sherrard DJ. Effects of dietary caffeine in renal handling of minerals in adult women. Life Sciences 1990;47:557-64.

Bird ET, Parker BD, Kim HS, Coffield KS. Caffeine ingestion and lower urinary tract symptoms in healthy volunteers. Neurourol Urodyn. 2005;24(7):611-5.

Cho YS, Ko IG, Kim SE, Hwan L, Shin MS, Kim CJ, Kim SH, Jin JJ, Chung JY, Kim KH. Caffeine enhances micturition through neuronal activation in micturition centers. Mol Med Rep. 2014 Dec;10(6):2931-6.

Grandjean AC, Reimers KJ, Bannick KE, Haven MC. The effect of caffeinated, non-caffeinated, caloric and non-caloric beverages on hydration. J Am Coll Nutr. 2000 Oct;19(5):591-600.

Maughan RJ, Griffin J. Caffeine ingestion and fluid balance: a review. J Hum Nutr Diet. 2003 Dec;16(6):411-20.

Massey LK, Wise KJ. The effect of dietary caffeine on urinary excretion of calcium, magnesium, sodium and potassium in healthy young females. Nutr. Res. 1984;4:43-50.

Massey LK, Berg TA. The effect of dietary caffeine on urinary excretion of calcium, magnesium, phosphorus, sodium, potassium, chloride and zinc in health females. Nutr. Res. 1985;5:1281-4.

Millard-Stafford ML, Cureton KJ, Wingo JE, Trilk J, Warren GL, Buyckx M. Hydration during exercise in warm, humid conditions: effect of a caffeinated sports drink. Int J Sport Nutr Exerc Metab. 2007 Apr;17(2):163-77.

Ming Z, Lautt WW. Caffeine-induced natriuresis and diuresis via blockade of hepatic adenosine-mediated sensory nerves and a hepatorenal reflex. Can J Physiol Pharmacol. 2010 Nov;88(11):1115-21.

Neuhäuser-Berthold, Beine S, Verwied SC, Lührmann PM. Coffee consumption and total body water homeostasis as measured by fluid balance and bioelectricalimpedance analysis. Ann Nutr Metab. 1997;41(1):29-36.

Nussberger J, Mooser V, Maridor G, Juillerat L, Waeber B, Brunner HR. Caffeine-induced diuresis and atrial natriuretic peptides. J Cardiovasc Pharmacol. 1990 May;15(5):685-91.

Rieg T, Steigele H, Schnermann J, Richter K, Osswald H, Vallon V. Requirement of intact adenosine A1 receptors for the diuretic and natriuretic action of the methylxanthines theophylline and caffeine. J Pharmacol Exp Ther. 2005 Apr;313(1):403-9.



Riesenhuber A, Boehm M, Posch M, Aufricht C. Diuretic potential of energy drinks. Amino Acids. 2006 Jul;31(1):81-3.

Stookey JD. The diuretic effects of alcohol and caffeine and total water intake misclassification. Eur J Epidemiol. 1999 Feb;15(2):181-8.

Wemple RD, Lamb DR, McKeever KH. Caffeine vs caffeine-free sports drinks: effects on urine production at rest and during prolonged exercise. Int J Sports Med. 1997 Jan;18(1):40-6.

Zhang Y, Coca A, Casa DJ, Antonio J, Green JM, Bishop PA. Caffeine and diuresis during rest and exercise: A meta-analysis. J Sci Med Sport. 2014 Aug 9. pii: S1440-2440(14)00143-1.

Solidago virgaureae

Borchert VE, Czyborra P, Fetscher C, Goepel M, Michel MC. Extracts from Rhois aromatic and Solidaginis virgaurea inhibit rat and human bladder contraction. Naunyn Schmiedebergs Arch Pharmacol. 2004 Mar;369(3):281-6.

Chodera A., Dabrowska K., Sloderbach A., Skrzypczak L., Budzianowski J. “Effect of flavonoid fractions of Solidago virgaurea L. on dieresis and levels of electrolytes”. Acta. Pol. Pharm. 1991. 48(5-6) : 35-37.

EMA, European Medicines Agency. Assessment report on Solidago Virgaurea L., herba. 2008. Doc. Ref. EMEA/HMPC/285759/2007.

Kaspers U, Poetsch Fn Nahrstedt A, Chatterjee SS. Diuretic effects of extracts and fractions obtained from different Solidago species. Naunyn Schmiedebergs Arch Pharmacol. 1998;358:Suppl. 2:S. R495.

Taraxacum officinale

Clare BA, Conroy RS, Spelman K. The diuretic effect in human subjects of an extract of Taraxacum officinale folium over a single day. J Altern Complement Med. 2009 Aug;15(8):929-34.

Kemper Kathi J., MD, MPH, “Dandelion (Taraxacum officinalis)”, The Longwood Herbal Task Force and The Center for Holistic Pediatric Education and Research, 1999

Schutz K., Carle R., Schieber A. “Taraxacum--a review on its phytochemical and pharmacological profile”. J. Ethnopharmacol. 2006 Oct. 11. 107(3):313-323. Epub. 2006 Jul 22.

Foeniculum vulgare

El Bardai S, Lyoussi B, Wibo M, Morel N. “Pharmacological evidence of hypotensive activity of Marrubium vulgare and Foeniculum vulgare in spontaneously hypertensive rat”. Clin Exp Hypertens. 2001 May;23(4): 329-43.



Rahimi R., Ardekani MR. Medicinal properties of Foeniculum vulgare Mill. in traditional Iranian medicine and modern phytotherapy. Chin J Integr Med. 2013 Jan;19(1):73-9.

Wright CI, Van-Buren L, Kroner CI, Koning MM. “Herbal medicines as diuretics: a review of the scientific evidence”. J Ethnopharmacol. 2007 Oct 8;114(1):1-31.

This physiological dossier has been realized by NUTRAVERIS, with rigor and objectivity, to ensure that all the information presented in this document are reliable. However, legislation and regulatory status of health claims related to food and food supplements involve legal

uncertainty and may be subject to various interpretation. NUTRAVERIS declines to be responsible for any loss or damage resulting from the use of this dossier.

scientific justification of the efficacy of elim’real

Documents