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Clinical trial of Cecropia obtusifolia and Marrubium vulgare leaf extracts on blood glucose and serum lipids in type 2 diabetics.

Abstract

Cecropia obtusifolia and Marrubium vulgare have been widely used in Mexican traditional medicine for the control of type 2 diabetes. In order to evaluate the clinical effect produced by the aqueous extract from these species on type 2 non-controlled diabetes mellitus, a total of 43 outpatients were included. Based on the European NIDDM (policy group) criteria, only patients with poor response to the conventional treatment were selected. All patients maintained their medical treatment and also received a prepared infusion of the dry leaves of the plant treatment for 21 days. In a double-blind manner, the patients were randomly grouped as follows: 22 patients were treated with C. obtusifolia and 21 with M. vulgare. The fasting blood glucose values were reduced by 15.25% on patients treated with C. obtusifolia, while cholesterol and triglycerides were decreased by 14.62% and 42.0%, respectively (ANOVA p<0.02). In the case of patients treated with M. vulgare, the plasma glucose level was reduced by 0.64% and cholesterol and triglycerides by 4.16% and 5.78%, respectively. When the results were compared between groups, significant differences in glucose and cholesterol diminution were found. The obtained results showed that the infusion prepared with the leaves of C. obtusifolia (containing 2.99[+ or -]0.14 mg of chlorogenic acid/g of dried plant) produced beneficial effects on carbohydrate and lipid metabolisms when it was administered as an adjunct on patients with type 2 diabetes with poor response to conventional medical treatment.

[c] 2004 Elsevier GmbH. All rights reserved.

Keywords: Diabetes mellitus type 2; Cecropia obtusifolia; Marrubium vulgare; Antilipemic agent; Hypoglycemic agent

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Introduction

Type 2 Diabetes Mellitus (DM) is one of the most common illnesses in the world. Worldwide, approximately 120 million people have diabetes and that could double in 10 years. In Mexico, DM affects 8.2% of the population between 20 and 69 years old, and has the first place of mortality between chronic degenerative diseases and represents 16.7% of deaths (Secretaria de Salud, 2000).

DM is the main factor responsible for renal failure, blindness, and non-traumatic amputations; the association between type 2 diabetes with poor metabolic control and the high incidence of mortality due to cardiovascular illness and nephropathy has been well demonstrated. Nevertheless, the adequate control of plasma glucose concentrations prevent micro-vascular complications. For these reasons the principal objective of medical treatment in patients with DM is the metabolic control (Donnelly et al., 2000).

The plant species Cecropia obtusifolia Bertol. commonly known as "guarumbo" and Marrubium vulgare L. popularly known as "marrubio" have been widely used in Mexican traditional medicine for the treatment of DM (Argueta et al., 1994). Previously, extracts prepared from leaves of C. obtusifolia have shown different pharmacological properties: hypoglycemic, antihypertensive, anti-inflammatory, analgesic, muscle relaxant and CNS depressant (Salas et al., 1987; Roman et al., 1991; Perez-Guerrero et al., 2001). The hypoglycemic effect was demonstrated in rabbits and streptozotocin-induced diabetic rats. Recently, the flavone isoorientin as well as chlorogenic acid were identified as the main constituents in water and butanolic extracts (Andrade-Cetto and Wiedenfeld, 2001). With relation to M. vulgare, it has been reported that leaf extracts possess vasorelaxant, antioxidative, antiinflammatory, hypotensive, antispasmodic, antinociceptive, and hypoglycemic effects (El Bardai et al., 2003; VanderJagt et al., 2002; Sahpaz et al., 2002; El Bardai et al., 2001; De Jesus et al., 2000). The hypoglycemic effect was demonstrated in rabbits and alloxan-induced diabetic rats (Roman et al., 1992; Novaes et al., 2001).

The main objective of the present work was to determine the effect produced by the oral administration of the aqueous extracts, prepared with the dried leaves from these plants, as adjunct treatment on type 2 diabetes.

Materials and methods

The current study is a randomized, double-blind and controlled clinical trial. The patients were informed about the benefits and possible risks of the study; they could withdraw at any time during the trial for any personal reason, or if he or she developed an adverse reaction to the treatments. Signed informed consent was subsequently obtained from each patient. The Institutional Ethical Committee approved the study.

Inclusion criteria

Outpatients from either sex with diagnosis of type 2 diabetes, with not more than 5 years evolution (30-60 years old) were selected. All patients must be under medical treatment, but showing fasting blood glucose [greater than or equal to] 140 mg/dl, independently of cholesterol and triglycerides level.

Exclusion criteria

Patients affected by diabetic complications or with clinical and biochemical data of nephropathy were not accepted. Also excluded were pregnant women, patients with diagnosis of gestational diabetes, insulin-dependent or type I diabetics, people who needed to travel frequently, and hospitalized patients.

Plant material and drug preparation

During the summer of 1999 the fresh leaves from C. obtusifolia Bertol (Cecropiaceae) were collected from near Xalapa, Veracruz (Mexico) and M. vulgare L. (Labiatae) on Coajomulco, Morelos (Mexico); both were collected in a single occasion. The material was authenticated by Dr. Abigail Aguilar, IMSSM Herbarium Director, for which sample vouchers were stored for reference under the code numbers 13599 and 13601, respectively. For two weeks the leaves were dried under environmental temperatures and protected from direct light, and then milled. For blinding reasons, all plant materials (C. obtusifolia and M. vulgare) were packed individually into one gram filter-paper envelops, with identical presentation and identified as treatments A and B. The codes were open only at the end of the clinical evaluations. Ethylene oxide was used for sterilization. The chromatographic analysis of the utilized infusions (see below) showed the presence of chlorogenic acid only in the C. obtusifolia extract (2.99[+ or -]0.14 mg/g of dried plant).

Determination of chlorogenic acid content

Four infusions of each treatment were separately filtrated, and then dried with a rotary evaporator under reduced pressure. Once dry all products were defatted consecutively with 10 ml of hexane and 10 ml of chloroform. The final residues were dissolved in 20 ml of methanol and analyzed on a Merck Hitachi HPLC system, with an AS-2000A autosampler, an L-6200A intelligent pump system controller (DAD System Manager Software) and an L-4500 diode array detector. The samples were evaluated using a Chromolith RP-18e column 100 X 4 mm (Merck) at 25 [degrees]C with an isocratic mobile phase of [H.sub.3]P[O.sub.4] (pH = 2.5): C[H.sub.3]CN:MeOH (90:5:5), a flow rate of 1.4 ml/min and detection at 255 nm. The injection volume was 50 [micro]l. The retention time of chlorogenic acid (C3878-Sigma) was 5.5 min.

Calibration curve

A standard solution was prepared using authentic chlorogenic acid from Sigma. Calibration curve was constructed with dilutions of 20, 40, 80 and 160 [micro]g/ml in methanol. A volume of 50 [micro]l was injected and calibration curve was based on peak areas of the HPLC chromatograms. The calibration curve showed an [R.sup.2] of 0.996.

Adjunct treatment

All patients continued their medical treatment and dietary plan prescribed by their physician. In all cases the conventional drug prescribed was glibenclamide at dosage different.

Study design

A total of 43 patients from primary medical care of the IMSS General Hospital in Morelos, Mexico, were recruited during the last six months of 1999. Based on a random numbers table, the patients were distributed in one of the two treatment groups. They were informed and instructed about the normal procedure for drug preparation. Immediately before administering the drug, the patients were to prepare an infusion by introducing one of the envelops in a cup boiling water for 5 min. For 21 days this procedure was done three times a day, before every meal.

Before beginning and after finishing the treatment, the fasting determination of glucose, cholesterol, triglycerides, urea, creatinine and uric acid in blood were done. All biochemical determinations were done in an automatic equipment (Autolab) with standardized techniques by a certified external laboratory. In order to detect adverse reaction, the patients were evaluated every 7 days. An inquiry was done, which included questions about 50 collateral effects and 5 grades of severity (patients could indicate any other side effect). In order to detect any possible complication, at the end of the first and second week of treatment, the fasting blood glucose was determined (by the research group) in all patients by using an electronic portable equipment and blood glucose electrodes (Precision Plus electrodes, Medisense Laboratories). Every week the treatment adherence was evaluated by counting the used dosages. When the treatment produced a decrease in the basal concentration of glucose, cholesterol or triglycerides by at least 25%, it was considered effective.

Statistical analysis

In order to determine the statistical significance of results, an analysis of variance (ANOVA) was applied in two ways. For the analysis of side effects as well as efficacy differences between treatments, a [X.sup.2] test was done. Finally, the regression analysis was used for evaluating the effect of other variables--such as: gender, and body mass index (BMI)--upon the biochemical variables. Values of p[less than or equal to]0.05 were considered statistically significant.

Due to the lack of previous clinical data for the plants under study, no power calculation was carried out; therefore it is considered a pilot study.

Results

As illustrated in Table 1, a total of 43 patients were included and 76.74% were women. Twenty-two subjects received the treatment prepared with C. obtusifolia and 21 were treated with M. vulgare. There were no significant differences between variables such as age, weight, height, BMI, doses of glibenclamide, SBP and DBP (ANOVA p>0.10).

As shown in Table 2, after 21 days of treatment, C. obtusifolia was able to reduce clinically and statistically the fasting blood glucose, serum cholesterol and triglycerides (p<0.02). When the differential effect produced by the 2 treatments was compared, only the reduction on fasting blood glucose showed significant differences; nevertheless, the cholesterol reduction was limitrophe (Table 3). That, could be attributed to the higher effect produced by C. obtusifolia in comparison with the extract from M. vulgare.

The comparison between the rates of therapeutic efficacy (reduction [greater than or equal to]25%) produced by the treatments, showed that C. obtusifolia reach the higher effectiveness by reducing fasting blood glucose and serum cholesterol (Table 4).

The number and percentages of patients per group that showed slight side effects were as follows: C. obtusifolia 3 (13.6%) and M. vulgare 5 (23.81%). No statistical differences were found by [X.sup.2] test. The side effects produced by C. obtusifolia were: excessive salivary flow, exhaustion and pyrosis; by M. vulgare were: nausea, oral dryness, sialorrhea, dizziness and anorexia. In the patients none of the treatments produced the adverse effects necessary for them to withdraw from the study.

The regression analysis did not show effect of gender and BMI on biochemical variables. All patients showed treatment adherence.

Discussion

The hypoglycemic effect produced by both species under evaluation has already been reported in anima! models. C. obtusifolia decreased the blood glucose in healthy rabbits by 18.9% in a tolerance glucose test (Roman et al., 1991), and M. vulgare reduce the blood glucose by 25.8% (Roman et al., 1992). Recently, chlorogenic acid was identified as the active hypoglycemic compound in C. obtusifolia (Andrade-Cetto, 2001). In our work, the HPLC analysis showed the presence of this compound only in the C. obtusifolia extract (2.99[+ or -]0.14 mg/g of plant).

The ANOVA test showed significant differences between the hypoglycemic effect produced by the adjunct treatments employed: C. obtusifolia (15.25%) and M. vulgare (0.64%). The hypoglycemic effect obtained with C. obtusifolia agree with that obtained by Roman et al. (1991) in an animal model, in which, this plant reduced the blood glucose 18.9%. The effect produced by the extract from M. vulgare was minimal and disagrees with that reported before on healthy rabbits (Roman et al., 1992).

In relation to the therapeutic efficacy for reducing the fasting blood glucose (at least 25% reduction), C. obtusifolia produced the higher rates (36.6%) while M. vulgare reached that effect only in two of 21 patients (9.52%, p<0.03 on [X.sup.2] test).

Other useful parameters for evaluating the metabolic control on diabetics are triglycerides and cholesterol (Rosen and Spiegelman, 2000). In the present study, the treatment with C. obtusifolia diminished the hypercholesterolemia from 241.27 to 206.0 mg/dl, reaching a therapeutic effect of 14.61% (ANOVA p<0.0001) and M. vulgare reduced the hypercholesterolemia by 4.18%. Considering the mean values, the group treated with C. obtusifolia reached a serum cholesterol value near 200 mg/dl, and that is considered the ideal value (Alberti and Gries, 1988). With regard to the hypocholesterolemic efficacy (at least 25% reduction of the basal values), C. obtusifolia reached the desired value in 18.1% of patients and M. vulgare did not show any improvement ([X.sup.2] p<0.04). In relation with triglycerides, C. obtusifolia decreased the basal hypertriglyceridemia from 340.5 to 197.48 mg/dl (42%) and the extract from M. vulgare reduced the basal values of triglycerides by 5.78%, but the differences were not significant. At the end of the study, the treatments maintained the mean of serum triglycerides below 200 mg/dl that in the base of the NIDDM Policy Group represents an acceptable control. For the hypotriglyceridemic efficacy (reduction [greater than or equal to]25%) the treatment formulated with C. obtusifolia reached the highest rates, (36.6%), while M. vulgare produced the desired effect on 28.5%, but without reaching statistical differences.

The treatments evaluated in this study did not produce important modifications of the parameters that measure the renal function. The serum levels of creatinine and urea did not show pathologic alterations at the end of the study.

In some patients, the treatments produced only mild and temporary side effects, for which it was not necessary to interrupt the treatment.

The glycemic control produced by C. obtusifolia in this study could be compared with the effect produced by Zygophyllum gaetulum; the administration of 1 g/kg per day of a decoction of the leaves from this plant reduced the fasting blood glucose by 50% by the third week. However, it should be noted that the utilized doses of this plant were considerably higher (Jaouhari et al., 1999).

The hypoglycemic effect produced by C. obtusifolia as an adjunct treatment of glibenclamide on patients with non-optimal response to medical treatment was similar, but with lower magnitude, to that obtained on diabetics with secondary failure to sulfonylurea-metformin subjected to insulin therapy. In these patients, the fasting blood glucose and cholesterol was decreased (Lopez-Alvarenga et al., 1999). The effect on fast glucose produced by the latest example was higher than that obtained with the C. obtusifolia extract; nevertheless, it must be noted that the utilized doses of this plant was the lowest used in Mexican traditional medicine (3 g/day).

In yet another clinical study, on diabetics with suboptimal metabolic control, who were treated with the maximum doses of sulfonylureas, the addition of metformin to the treatment during 12 weeks, reduced the fasting blood glucose by 25.75%, the serum cholesterol by 9.43%, and triglycerides by 11.07% (Mughal et al., 2000). In comparison with this study, the hypoglycemic effect produced by C. obtusifolia was lower than that produced by metformin (10 percentage points). However, the reduction produced by C. obtusifolia on serum cholesterol and triglycerides was increased by 5 and 31 percentage points, respectively.

It has been demonstrated that thiazoladinediones and glitazone decrease fasting blood glucose, cholesterol and triglycerides, and this may result in their potential ability to reduce macrovascular complications (Freie, 1999). The results obtained with C. obtusifolia resemble the effect produced by roglitazone (1-2 mg) or pioglitazone (30 mg/day). They were administered as an adjunct treatment of sulfonylureas on diabetics, in which, they were able to reduce the blood glucose concentration by 21% and 19.14%, respectively (Wolffenbuttel et al., 2000; Yamasaki et al., 1997).

All these results show that the antihyperglicemic effect produced by C. obtusifolia, at the prescribed dose, is lower than that produced by insulin, metformin and glitazones. Nevertheless, one must consider that it was evaluated as a crude extract, with a similar preparation used in traditional medicine. An enriched extract, with active compounds (i.e. chlorogenic acid) in higher concentrations, should increase the potency of this plant species.

In spite of the small sample size included in the study, we can conclude that the aqueous extract from C. obtusifolia as an adjunct treatment, possesses an interesting pharmacological effect on type 2 diabetics with poor metabolic control. It was able to significantly reduce (p[less than or equal to]0.04) the fasting blood glucose, in comparison with M. vulgare-treated group, while the total serum cholesterol and triglycerides were diminished, with only mild and limited side effects.
Table 1. General characteristics of patients at the beginning of the
study

Parameter C. obtusifolia (n = 22)
 Mean SE 95% IC

Age (years old) 50.68 1.57 47.39 53.96
Weight (kg) 66.81 1.76 63.12 70.49
Height (m) 1.53 0 1.53 1.53
BMI (kg/[m.sup.2]) 28.23 0.78 26.58 29.87
Glibenclamide (mg/day) 13.40 0.89 11.53 15.26
SBP (mm Hg) 124.54 2.05 120.27 128.80
DBP (mm Hg) 77.72 1.76 74.05 81.38

Parameter M. vulgare (n = 21) ANOVA p
 Mean SE 95% IC

Age (years old) 50.76 1.74 47.11 54.40 0.97
Weight (kg) 65.12 2.37 60.15 70.08 0.57
Height (m) 1.55 0.01 1.52 1.57 0.55
BMI (kg/[m.sup.2]) 27.01 0.76 25.41 28.60 0.28
Glibenclamide (mg/day) 13.80 0.96 11.79 15.80 0.77
SBP (mm Hg) 126.42 2.58 121.03 131.80 0.56
DBP (mm Hg) 81.66 1.63 78.25 85.06 0.10

Table 2. Effects produced by C. obtusifolia and M. vulgare upon
different metabolic parameters in patients with type 2 diabetes

Group Before treatment After treatment
 Mean SE 95% IC Mean SE 95% IC

C. obtusifolia
F B Glucose 250.94 11.88 226.22 275.65 212.65 13.60 226.22
Cholesterol 241.27 17.77 204.31 278.22 206.00 11.03 183.04
Triglycerides 340.50 122.03 86.71 594.28 197.48 25.17 145.11
Urea 25.85 1.43 22.87 28.82 24.84 1.58 21.53
Creatinine 0.70 0.02 0.63 0.76 0.71 0.02 0.66
Uric acid 3.48 0.32 2.80 4.15 3.65 0.28 3.06

M. vulgare
F B Glucose 252.16 13.85 223.25 281.06 250.53 13.15 223.09
Cholesterol 204.80 10.92 182.01 227.58 196.23 7.81 179.93
Triglycerides 151.13 10.68 128.84 173.41 142.39 13.95 113.28
Urea 28.90 1.39 25.98 31.81 29.97 1.64 26.54
Creatinine 0.79 0.03 0.72 0.85 0.73 0.03 0.65
Uric acid 3.06 0.23 2.57 3.54 3.10 0.23 2.61

Group After treatment Difference ANOVA p
 95% IC Mean SE 95% IC

C. obtusifolia
F B Glucose 275.65 38.28 13.20 10.80 65.75 <0.02
Cholesterol 228.95 35.27 12.10 10.08 60.45 <0.0001
Triglycerides 249.84 143.01 112.25 -90.43 376.45 <0.02
Urea 28.14 1.01 1.15 -1.39 3.41 <0.0002
Creatinine 0.75 -0.01 0.02 -0.06 0.04 <0.003
Uric acid 4.23 -0.17 0.16 -0.52 0.18 <0.0001

M. vulgare
F B Glucose 277.96 1.62 10.93 -21.11 24.35 <0.001
Cholesterol 212.52 8.57 7.16 -6.37 23.51 <0.001
Triglycerides 171.49 8.73 9.45 -10.98 28.44 <0.001
Urea 33.39 -1.06 1.56 -4.32 2.20 <0.02
Creatinine 0.80 0.05 0.03 -0.01 0.11 <0.004
Uric acid 3.58 -0.03 0.13 -0.31 0.25 <0.001

Data are mg/dl.

Table 3. Comparison of differences on metabolic parameters before and
after finishing the treatment

Parameter C. obtusifolia M. vulgare
 Mean SE 95% IC Mean SE 95% IC

FB glucose 38.28 13.20 10.80 65.75 1.62 11.19 -21.72
Cholesterol 35.27 12.10 10.08 60.45 8.57 7.16 -6.37
Triglycerides 143.01 112.25 -90.43 376.45 8.73 9.45 -10.98
Urea 1.01 1.15 -1.39 3.41 -1.06 1.56 -4.32
Creatinine -0.01 0.02 -0.06 0.04 0.05 0.03 -0.13
Uric acid -0.17 0.16 -0.52 0.18 -0.03 0.13 -0.31

Parameter M. vulgare ANOVA p
 95% IC

FB glucose 24.96 0.04
Cholesterol 23.51 0.06
Triglycerides 28.44 0.25
Urea 2.20 0.28
Creatinine 0.11 0.08
Uric acid 0.25 0.54

Values are mg/dl.

Table 4. Comparison between rates of therapeutic efficacy (reduction
[greater than or equal to]25%) on type 2 diabetics treated as adjunct
with C. obtusifolia and M. vulgare

 Therapeutic efficacy rate [X.sup.2]
 C. obtusifolia M. vulgare p

Glucose 0.363 0.095 0.03
Cholesterol 0.181 0.000 0.04
Triglycerides 0.363 0.285 0.58


Received 21 April 2003; accepted 12 January 2004

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A. Herrera-Arellano (a,*), L. Aguilar-Santamaria (a), B. Garcia-Hernandez (b), P. Nicasio-Torres (a), J. Tortoriello (a)

(a) Centro de Investigacion Biomedica del Sur, Instituto Mexicano del Seguro Social. Xochitepec, Morelos, Mexico

(b) Hospital General Regional No. 1, "Lic. Ignacio Garcia Tellez", Instituto Mexicano del Seguro Social. Cuernavaca, Morelos, Mexico

*Corresponding author. Tel.: +52-777-361-21-94; fax: +52-777-361-21-55.

E-mail address: armandoha_mx@yahoo.com.mx (A. Herrera-Arellano).
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Author:Herrera-Arellano, A.; Aguilar-Santamaria, L.; Garcia-Hernandez, B.; Nicasio-Torres, P.; Tortoriello,
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Date:Nov 1, 2004
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