Effects of the Brazilian phytopharmaceutical product Ierobina® on lipid metabolism and intestinal tonus

Journal of Ethnopharmacology 102 (2005) 137–142

Effects of the Brazilian phytopharmaceutical product Ierobina® on lipid metabolism and intestinal tonus L.M. Botion a , A.V.M. Ferreira a , S.F. Cˆortes b , V.S. Lemos a , F.C. Braga c,∗ a

Departamento de Fisiologia e Biofisica, Instituto de Ciˆencias Biol´ogicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil b Departamento de Farmacologia, Instituto de Ciˆ encias Biol´ogicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil c Laborat´ orio de Fitoqu´ımica e Biologia Farmacˆeutica, Faculdade de Farm´acia, Universidade Federal de Minas Gerais, Av. Antˆonio Carlos 6627, Belo Horizonte CEP 31.270-010, Brazil Received 7 June 2004; received in revised form 10 May 2005; accepted 16 May 2005 Available online 28 July 2005

Abstract Ierobina® is a Brazilian phytopharmaceutical product indicated for the treatment of dyspepsia. It contains the hydroethanolic extracts of Solanum paniculatum L. (Solanaceae), Remijia ferruginea D.C. (Rubiaceae), Jacaranda caroba D.C. (Bignoniaceae) and Erythraea centaurium (L.) Borkh. (Gentianaceae), species traditionally used to treat gastrointestinal disorders. The effect of Ierobina® on the digestive system was investigated in rats fed with normal or high-fat (HF) diets, at doses of 2.16, 4.32 and 8.64 mg/kg. The product did not affect the plasmatic levels of glucose, total cholesterol and HDL-cholesterol in the evaluated doses, whereas the triacylglycerol (TAG) concentration showed a dose-dependent increase in HF-fed animals. TAG-rich lipoprotein uptake, estimated by measuring total lipoprotein lipase activity in epididymal adipose tissue, was accompanied by TAG increase in HF-fed rats, after Ierobina® administration. The product also induced a concentration-dependent relaxant effect on spontaneous ileum contractions and on the rat ileum pre-contracted with carbachol. Together, these results support the indication of Ierobina® as an anti-dyspeptic agent. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Anti-dyspeptic agent; Triacylglycerol content; Total lipoprotein lipase activity; Carbachol pre-contracted ileum; Brazilian phytopharmaceutical product

1. Introduction Dyspepsia is a condition comprising a complex of symptoms in the upper gastrointestinal tract which includes, in addition to epigastric pain or discomfort, symptoms, such as heartburn, acid regurgitation, excessive burping or belching, a feeling of slow digestion, early satiety, nausea and bloating (Talley et al., 1992; Hunt et al., 2002). Several herbal products are recommended for the treatment of dyspepsia (Coon and Ernest, 2002). The use of bitter medicinal plants for treating this condition is well established and species, such as Artemisia absinthum, Quassia amara, Gentiana lutea, Menyanthes trifoliata, Humulus ∗

Corresponding author. Tel.: +55 31 3499 6951; fax: +55 31 3499 6935. E-mail address: [email protected] (F.C. Braga).

0378-8741/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jep.2005.05.046

lupulus, Carduus benedictus, Marsdenia condurango, Citrus aurantium and Erythraea centaurium, have had their efficacy attested (Schulz et al., 2001). Plants with choleretic effect, such as Cynara scolymus, Curcuma xanthorrhiza, Taraxacum officinale and Chelidonium majus, are also successfully employed for the treatment of dyspepsia (Schulz et al., 2001). Ierobina® is a Brazilian phytopharmaceutical product indicated for the treatment of dyspepsia. The formulation contains the hydroethanolic extracts of Solanum paniculatum L. (Solanaceae), Remijia ferruginea D.C. (Rubiaceae), Jacaranda caroba D.C. (Bignoniaceae) and Erythraea centaurium (L.) Borkh. (Gentianaceae). Except Erythraea centaurium, a European species, the other plants occur in Brazil and are popularly employed in the country to treat dyspepsia, among other medicinal uses (Pio Corrˆea, 1978).

L.M. Botion et al. / Journal of Ethnopharmacology 102 (2005) 137–142

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The phytopharmaceutical Ierobina® is recommended to treat dyspepsia associated with the intake of high-fat meals; however, the product has never been evaluated pharmacologically to attest its efficacy as an anti-dyspeptic agent. Therefore, the main goal of the present work was to assay the action of Ierobina® on the digestive system, especially on the metabolism of lipids and intestinal tonus.

160 and 320 ␮L/kg body weight of Ierobina® solution). In the sequence, the animals were killed by decapitation, the blood was collected and plasma stored at −20 ◦ C to determine glucose, total cholesterol, HDL-cholesterol and triacylglycerol (TAG). Samples of epididymal adipose tissue were excised and stored at −80 ◦ C until use. 2.4. Total lipoprotein lipase activity (LPL)

2. Material and methods 2.1. Drugs Ierobina® was kindly furnished by Laborat´orio Belfar, Belo Horizonte, Brazil. Carbachol, albumin, lecitin and triolein were purchased from Sigma (USA) and [9,10-3 H]triolein was obtained from New England Nuclear (USA). 2.2. Ierobina® composition Detailed composition of Ierobina® is presented in Table 1. According to Laborat´orio Belfar, the product was manufactured with extracts prepared by percolation of the dried plant materials with ethanol–water solutions (Table 1). Ierobina® (10 mL) also contains nipagin (120 ␮g), nipazol (40 ␮g) and caramel colorant (160 ␮L), along with deionized water up to 10 mL. 2.3. Treatment of animals Animal experiments were performed according to the recommendations of the Brazilian Council for Animal Care and were approved by the Ethics Committee of the Universidade Federal de Minas Gerais. Male Wistar rats weighing between 250 and 280 g were housed in a temperature- and humiditycontrolled room with a 14-h light:10-h dark cycle. Animals were divided into two groups: normal diet, rats which were fed with standard rat chow (41% carbohydrate, 4% fat and 22% protein), and high fat (HF), rats fed with a high-fat diet (56% carbohydrate, 25% fat and 15% protein). Three days before the experiments, the rats were fasted by removing food from all animals at 14:00 p.m. and were re-fed on the following mornings from 9:00 to 11:00 a.m. On the third day, immediately before re-feeding, Ierobina® was administered by gavage and the respective diet was supplied for each group, for 2 h. The doses of 2.16, 4.32 and 8.64 mg/kg body weight were employed in the assays (respectively, equivalent to 80,

Samples of epididymal adipose tissue (50 mg) were homogenized with 500 ␮L of Tris buffer, pH 8.5, containing 0.05 mg/mL heparin, 10 mg/mL BSA and 2 mg/mL ¨ sodium deoxycholate (Iverius and Ostlund-Lindqvist, 1986). The substrate was prepared by sonication of 12 ␮Ci [9,103 H]-triolein in Tris buffer, using 3.6 mg lysolecithin and glycerol (5 mL) as emulsifiers, following incubation at 37 ◦ C, for 45 min (Nilsson-Ehle and Schotz, 1976). The reaction was stopped by the addition of 3.25 mL of methanol–chloroform–heptane 1.41:1.25:1 (v/v/v), followed by 1.05 mL of 0.1 M potassium carbonate–borate buffer, pH 10.5 (Belfrage and Vaughan, 1969; Nilsson-Ehle et al., 1972). The 3 H-labeled free fatty acids were quantified by liquid scintillation counting (n = 6) and LPL activity is expressed in mU (1 mU = 1 nmol of oleic acid released/min). 2.5. Isolated rat ileum The experimental procedure was performed as described by Roberts et al. (1999). Wistar rats 250–300 g were killed by cervical dislocation. A segment of the small intestine (≈15 cm) was removed from 2 cm above the ileocaecal junction and the intraluminal contents flushed out with Krebs-Henseleit solution (mM): NaCl 118.4, KC1 4.7, MgSO4 ·7H2 O 1.2, KH2 PO4 1.2, NaHCO3 25, glucose 11, CaCl2 2.5, containing ascorbic acid (0.1 mM) and EDTA (0.04 mM). Segments of approximately 2.0 cm length were mounted on tissue hooks and suspended in jacketed organ baths containing Krebs-Henseleit solution (pH 7.4) maintained at 37 ◦ C and bubbled continuously with 95% O2 /5% CO2 , under 5 mN force. Fort 10 (WPI Inc., USA) isotonic transducers connected to a CVMS system (WPI Inc.) with a PC were used to measure isotonic changes in the length of the tissues. Tissue strips were equilibrated for 60 min before the beginning of the experimental protocols. After this period, the effect of Ierobina® was examined on spontaneous contractions of ileum and in ileum strips pre-contracted with carbachol. The concentration of Ierobina® that produced 50%

Table 1 Drug composition of Ierobina® (for 10 mL product) Plant name

Plant family

Part useda

Extracta

Extract in product (mL)a

Dry extract (%)a

Solanum paniculatum L. Remijia ferruginea D.C. Jacaranda caroba D.C. Erythraea centaurium (L.) Borkh.

Solanaceae Rubiaceae Bignoniaceae Gentianaceae

Aerial parts Stems Aerial parts Flowering tops

50% ethanol 15% ethanol 15% ethanol 20% ethanol

0.8 0.8 0.2 0.2

2.84 7.95 4.44 7.27

a

Data furnished by Laborat´orio Belfar.

L.M. Botion et al. / Journal of Ethnopharmacology 102 (2005) 137–142

of the maximal effect (IC50 ) was calculated graphically by linear regression. Isoprenaline was employed as positive control. 2.6. Analytical procedures Plasma glucose, total cholesterol, HDL-cholesterol and TAG were assayed by conventional enzymatic methods using kits produced by Labtest Diagnostica (Brazil). Assays were performed in replicates (n = 6) and results are expressed as means ± S.E.M. 2.7. Statistic Statistical significance was determined by an unpaired Student’s t-test and p < 0.05 was taken as the criterion of significance. 2.8. HPLC characterization of Ierobina® Analysis were carried out on a Merck-Hitachi apparatus (Germany) composed of pump L-6200A, automatic injector AS-2000A, UV–vis detector L-4250 and integrator D2500. An ODS column (250 mm × 4.0 mm, i.d., 5 ␮m) was employed (Merck, Germany) at a temperature of 40 ◦ C and flow rate of 1.0 mL/min. Analysis were performed at 210 nm. A linear gradient of H2 O (A) and CH3 CN (B) was employed: 0 min, 90% A, 10% B; 60 min, 10% A, 90% B, followed by 10 min isocratic elution. Solvents used were of HPLC grade (Merck, Germany) and were degassed by sonication before use. Ierobina® dry residue was dissolved in MeOH to a concentration of 10 mg/mL. After centrifugation at 10,000 rpm, the sample solution (10 ␮L) was injected.

3. Results 3.1. Effects on plasma lipids and glucose contents of rat liver Ierobina®

(4.32 mg/kg body weight) did not affect the levels of glucose, total cholesterol and HDL-cholesterol in

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Table 3 Relaxant effect induced by Ierobina® and isoprenaline in the rat ileum contracted with carbachol Quantity (%)

Effect (%)

Ierobina® 0.01 0.03 0.1 0.3 1.0 3.0

18.6 25.7 31.8 43.6 50.0 73.8

± ± ± ± ± ±

2.6 3.5 3.8 3.8 3.5 1.7

Isoprenaline 3.6 × 10−7 3.6 × 10−6 3.6 × 10−5 3.6 × 10−4 3.6 × 10−3

8.3 34.6 64.2 76.4 80.2

± ± ± ± ±

1.1 2.4 6.6 3.8 4.7

The results are expressed as mean ± S.E.M. of at least five experiments.

plasma of the animals fed with standard rat chow (p > 0.05) (Table 2). TAG plasmatic concentration increased 136% by high-fat feeding (p < 0.05), in comparison to the normal diet group (Table 2). The high-fat diet did not affect the plasmatic levels of total cholesterol, HDL-cholesterol and glucose (Table 2). Previous administration of Ierobina® (2.16, 4.32 or 8.64 mg/kg body weight) to high-fat diet rats also had no effect on total cholesterol, HDL-cholesterol and glucose plasmatic concentrations, whereas a dose-dependent increase in TAG levels was observed for animals from this group (Table 2). 3.2. Total lipoprotein lipase activity Administration of Ierobina® to high-fat diet rats resulted in the increase of TAG-rich lipoprotein uptake (Table 2), estimated by measuring total LPL activity in epididymal adipose tissue, as compared to the control group (p < 0.05). 3.3. Effect of Ierobina® on intestinal tonus Ierobina® (0.03–3.0%) induced a dose-dependent relaxant effect on the rat ileum pre-contracted with carbachol (IC50 = 0.96 ± 0.20%; Table 3). In addition,

Table 2 Effects of Ierobina® on the plasmatic levels of glucose, triacylglycerol, total cholesterol, HDL-cholesterol and LPL activity in ratsa Treatment

Glucose (mg/dL)

Triacylglycerol (mg/dL)

Lipoprotein lipase activity (nmol/mL)

Total cholesterol (mg/dL)

HDL-cholesterol (mg/dL)

Normal diet Normal diet plus Ierobina® , 4.32 mg/kg High-fat diet

142 ± 6 131 ± 11 148 ± 10

75 ± 8 69 ± 9 177 ± 16*

– – 1.61 ± 0.16

210 ± 37 194 ± 4 196 ± 26

39 ± 2 40 ± 4 32 ± 5

High-fat diet plus Ierobina® 2.16 mg/kg 4.32 ␮L/kg 8.64 ␮L/kg

134 ± 6 141 ± 8 135 ± 5

199 ± 10* 230 ± 16*,# 250 ± 12*,#

1.99 ± 0.15 2.25 ± 0.04# 2.10 ± 0.05#

213 ± 12 226 ± 39 209 ± 25

35 ± 2 40 ± 2 38 ± 7

a * #

Values are expressed as means ± S.E.M. (n = 3–6). p < 0.05 vs. normal diet. p < 0.05 vs. high-fat diet.

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Fig. 1. HPLC fingerprint obtained for Ierobina® . Chromatographic conditions: see Section 2.

isoprenaline also induced a concentration-dependent relaxation in the rat ileum pre-contracted with carbachol (IC50 = 6 × 10−6 ± 1 × 10−7 %; Table 3). Therefore, Ierobina was 105 -fold less potent than isoprenaline, a ␤-adrenoceptor agonist, in relation to its relaxant effect in the rat ileum. 3.4. HPLC fingerprint HPLC analysis of Ierobina® indicated a complex profile, with the predominance of peaks from high polar compounds (Fig. 1), in accordance with the polarity of hydroethanolic extracts present in the product.

4. Discussion In the present study, we have investigated pharmacological evidence to support the use of Ierobina® in the treatment of dyspepsia. Our results indicated that administration of this phytopharmaceutical product to rats, at dosages equivalent to those recommended for humans, improved lipid absorption and had spasmolytic effects on isolated ileum. Ierobina® contains extracts of Solanum paniculatum, Remijia ferruginea, Jacaranda caroba and Erythraea centaurium. Except Erythraea centaurium, the phytopharmaceutical product is composed of Brazilian plants found in the cerrado, a savanna like vegetation. The three species are popularly employed to treat different diseases; however, reports on their biological activities are scarce. The bark of Jacaranda caroba are traditionally employed as bitter, astringent, diuretic and anti-syphilitic, whereas its leaves are used as tonic and anti-syphilitic (Pio Corrˆea, 1978). In

some regions, the leaves are used as a bath for infection treatment and the infusion of the leaves have internal use as anti-syphilitic and depurative. The macerate of its leaves prepared with cacha¸ca, a sugar cane spirit, are externally employed for cicatrization and to treat ulcers (Di Stasi and Hiruma-Lima, 2002). The barks of Remijia ferruginea (syn. Cinchona ferruginea St. Hil.) are popularly employed as a substitute for true quina (Cinchona), as tonic and bitter, but not as a febrifuge (Pio Corrˆea, 1978). Its roots are mashed with milk and taken early in the morning as a vermifuge (Schmeda-Hirschmann and Rojas de Arias, 1990). The infusion of Solanum paniculatum leaves is employed against bronchitis and cough; the macerate of its roots is used to treat arthritis and that of the fruits for anemia. Its roots and fruits are also popularly recommended as bitter, to treat jaundice, hepatitis and intestinal fevers (Pio Corrˆea, 1978). The decoction from the leaves is employed to treat intestinal parasites, being also indicated for stomach disorders (Di Stasi and Hiruma-Lima, 2002). Erythraea centaurium, an exotic species in Brazil, is employed in several European countries as eupeptic, bitter, tonic, choleretic and anti-diabetic, among other uses (Alonso, 1998). In Brazil, it is popularly used as bitter, to treat dyspepsia, parasites and fevers (Pio Corrˆea, 1978). As far as we know, the effect of these plants on dyspepsia has never been investigated, except for Erythraea centaurium (Tyler, 1994; Alonso, 1998; Schulz et al., 2001). Our results showed that Ierobina® did not have any effect on carbohydrate metabolism, since the plasma concentration of glucose did not change after drug administration. Regarding lipids, Ierobina® increased plasma TAG levels only in animals fed with a high-fat diet without any effects on cholesterol levels. The mechanisms to explain the increase of plasma TAG concentration, observed after Ierobina® administration, can be hypothesized to be due to an increase of lipid absorption or a reduction in the clearance of TAG-rich particles in the postprandial state, mainly TAG carrying chylomicrons. There are a number of studies showing that the administration of a high-fat diet to rats increases TAG plasmatic level (Carmena and Grundy, 1991; Han et al., 2003; Larsen et al., 2003; Jeong et al., 2004). Also, it has been demonstrated that defective clearance by LPL increases TAG concentration in plasma (Grundy, 1984; Patsch et al., 1992; Frayn, 2002). Since TAG-rich lipoprotein uptake was elevated, evaluated by measuring adipose tissue LPL activity, the increase in plasma TAG after the intake of a fat rich meal suggests an effect of Ierobina® on intestinal lipid hydrolysis and absorption. The increase in lipoprotein lipase activity, after the intake of a high-fat meal, has been previously reported (Deshaies et al., 1988), which is in accordance with the results obtained in the present study. Although many questions concerning the underlying mechanisms remain to be answered, it is clear that the administration of Ierobina® previously to the ingestion of a high-fat meal increases the intestinal absorption of triacylglycerols.

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In addition to the metabolic effects of Ierobina® , the phytopharmaceutical produced a relaxant effect on spontaneous and carbachol-induced ileal contractions. Together, these results support the indication of the phytopharmaceutical product Ierobina® as an anti-dyspeptic agent. The chemistry of the species Jacaranda caroba has never been investigated. On the other hand, several triterpenes were isolated from other Jacarada spp., including ursolic, 2␣-hydroxyursolic, 2␣,3␣-dihydroxyurs-12-en-28oic, betulinic, jacarandic and jacoumaric acids, along with ␤-sitosterol (Ogura et al., 1977a,b; Varanda et al., 1992; Lourenc¸o et al., 2002). Species of Remijia are recognized sources of quinidine, among other alkaloids. However, the chemistry of Remijia ferruginea remains unknown. Phytochemical studies on the species Solanum paniculatum revealed the presence of steroidal saponins (Ripperger et al., 1967; Ripperger and Schreiber, 1968) and alkaloids (Blankemeyer et al., 1998). Several steroids and triterpenes have been isolated from Erythraea centaurium, including ␤-sitosterol, stigmasterol, campesterol, brassicasterol, ␦-7stigmastenol, ␤-amyrin, erythrodiol, oleanolic and maslinic acid (Belavita et al., 1974; Aquino et al., 1985). As far as we know, none of the compounds isolated from these species has ever been evaluated as an anti-dyspeptic agent. On the other hand, the secoiridoid glycosides gentiopicrin, cetapicrin and swertiamarin, among others, have been isolated as the bitter constituents from Erythraea centaurium (Alonso, 1998; Schulz et al., 2001). Hence, further studies are required to identify the compounds responsible for the anti-dyspeptic action of Ierobina® . In conclusion, the present study furnishes evidences to support the use of the phytopharmaceutical product Ierobina® in the treatment of dyspepsia.

Acknowledgements This work was supported with a grant by CNPq (Brazil) (Projetos Fitoter´apicos No. 52.1199/01.8) and with funds from Laborat´orio Belfar (Belo Horizonte, Brazil). CNPq is also acknowledged for providing a research fellowship (F.C.B.).

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